L'acide chloroxicarbonique,qui peut tout aussi bien\177tre consid\177r\177comme un chlorure d'oxidede carbone,offre une compositionsi simpleet si remarquableque,s'ilr\177alisaittoutes les r\177actionsque I'on a droitd'en esp\177rer,on parviendrait\177 reproduire,\177 sonaide,lescombinaisonslespluscurieusesde la chimieorganique...(Read to the french\177 Acad\177miedesSciences\177 on december16and 31,1833).

Die Chlorkohlens\177ure(Phosgen),welcheeben so gutals das ChlorLirdes Kohlenoxydsbetrachtetwerden kann,besitzt eine so einfache und merkwLirdigeZusammen-setzung, dab wenn es allen Reaktionen entspr\177che,dieman die Recht davon erwarten k6nnte, man damn gelan-gen wL\177rde,die merkwLidigstenZusammensetzungenderorganischenChemiewiederhervorzubringen....(Translationpublishedin \177 Annalender Chemie \177).

Chloroxycarbonicacid (phosgene)which can also beconsideredas a carbon oxidechloride,offers a composi-tion which is simpleand yet remarkable.If it producesallthe reactionswe expectof it, we will be able to reproducesomeof the most fascinatingcombinationsin organicche-mistry.

lean BaplisleDumas Jean BaptisteDumas (b.1800Al\177s, France - d.1884

Canne,France),Frenchchemistand politician.Tutor at theEcolePolytechnique(Paris1821),one of the founders ofthe EcolePolytechnique(Paris1821), oneof the foundersof the Ecole Centrale des Arts et Planufactures (Paris1829),Professorof Chemistryat the facult\177desSciencesde Paris, at the facult\177de Pl\177decine,Lecturer at theColl\177gede france, Memberof the Acad\177miedes Sciences(1832),electedat the Acad\177mieFran(::aise(1875).)))

L'acidechloroxicarbonique, qui peut tout aussi bien

\177tre consid\177r\177 comme un chlorure d'oxidede carbone,offre une composition si simple et si remarquable que, s'il

r\177alisait toutes les r\177actions que I'on a droit d'en esp\177rer,

on parviendrait \177 reproduire, \177 son aide,lescombinaisonslesplus curieuses de la chimie organique... (Read to the french\177 Acad\177mie desSciences\177 on december16and 31,1833).

Die Chlorkohlens\177ure (Phosgen),welche eben so gutals das ChlorLir des Kohlenoxyds betrachtet werden kann,besitzt eine so einfache und merkwLirdige Zusammen-

setzung, dab wenn es allen Reaktionen entspr\177che, dieman die Recht davon erwarten k6nnte, man damn gelan-gen wL\177rde, die merkwLidigsten Zusammensetzungen derorganischen Chemiewieder hervorzubringen....(Translation

published in \177 Annalen der Chemie\177).

Chloroxycarbonic acid (phosgene)which can also beconsideredas a carbon oxide chloride, offers a composi-tion which is simple and yet remarkable. If it producesall

the reactionswe expectof it, we will be able to reproducesomeof the most fascinating combinations in organic che-mistry.

leanBaplisleDumas Jean Baptiste Dumas (b.1800Al\177s, France - d.1884

Canne, France), French chemist and politician. Tutor at the

EcolePolytechnique (Paris 1821),one of the founders ofthe EcolePolytechnique (Paris 1821), oneof the founders

of the EcoleCentrale des Arts et Planufactures (Paris1829),Professorof Chemistry at the facult\177 desSciencesde Paris, at the facult\177 de Pl\177decine, Lecturer at the

Coll\177ge de france, Member of the Acad\177mie desSciences(1832),electedat the Acad\177mie Fran(::aise(1875).)))

Prefa(e

At the early beginnings, organic chemistry was taken by

the scientific community as the chemistry of living matter.After the discovery of the synthesis of urea by W\177hler in

1828,organic chemistry was defined as the chemistry ofcarbon-containing compounds.

Almost the entire amount of the carbon available on

the earth surfaceexists in the form of carbonicacid (freeor as calcium salts) and in fossil fuels obviously originatedfrom living matter. It is well known that carbon dioxide is

the necessaryingredient in the life cycle of animal and

plants. Therefore,organic chemistry must be consideredasstrongly relatedto the chemistry of carbon dioxide and its

derivatives.Carbonic acid dichloride called\177{ \177\177, discove-

red by John Davy in 1812,appearsstill nowadays the only

efficient simple activated form of carbon dioxide, and

despite intensive researchdone to replace it with lessnoxious starting material, phosgeneremains a substitute

for carbon dioxide, l\177oreover, becauseof the presenceofacid chloridefunctions, phosgeneexhibits a large rangeof other chemical reactionswhich make it a very useful

multipurpose tool in organic chemistry.The first chemical studies on phosgenechemistry have

beenassociatedwith the development of organic chemis-try during its classicalera (1820- 1940).In the periodafter world war two, phosgenechemistry has experienceda tremendousgrowth and wide interest.Vast numbers)))

Preface

of scientific papers and patents have been published by

several thousands of organic chemists working in academicand industrial researchlaboratories.

By now, although phosgenechemistry is establishedasa fully-grown chemistry with well documented text books,monographs and reviews, it seemsthat truly importantfacetsof new and unusual aspectsare somewhat neglec-ted. In this book, I have tried to provide an essentially com-

plete survey of the work done for a quarter century atSNPE group in the chemistry of phosgeneand related

compounds, with specialemphasison unusual, unexpectedand new reactionsor applications.

Phosgeneis widely used in organic chemistry as a

building block providing the C = O such as in carbamates,carbonates,isocyanates,ureas,heterocyclesetc., or as a

reagent for chlorination, dehydration, alkylation, de-alkyla-tion, protection and activation etc.

Consequently, I have chosento divide this book in two

volumes :Volume 1 includes introduction, some considerations

on physical propertiesand chemical reactivity, and four

chapters devoted to phosgeneand derivatives as building

blocks.Volume 2 presentsapplicalEions of phosgeneand deri-

vatives as reagents and the general conclusion.Of course,selectionof topics to be included in these

two volumes is undoubtedly influenced by the author's

personal interest. So I would like to make here my apolo-gies to any of my colleagueswho may found their own

work discussedinadequately.Also\177 becausenothing comesfrom nothing\177 in other

terms becauseeverything has predecessors,it is importantto note that if .John Davy discoveredphosgene,Jean-Baptiste Dumas \177 invented \177 its chemistry and may be the-reforeconsideredas the true pioneerin the chemistry ofphosgene.To take stock of this question, I have included in

the first volume one sectiondedicatedto the history ofphosgenechemistry.

Preface

Furthermore, I wish to expressmy gratitude to all my

colleaguesfrom SNPE group and from the US and French

Universities who have participated along these last 25years in the development of news aspectsof phosgenechemistry.

Finally, I would particularly like to acknowledge Pro-fessorRoy Olofson(ThePennsylvania StateUniversity) for

his unfailing enthusiastic support during our more than ten

years collaboration on the development of new synthetic

reagentsand preparative methods in phosgeneand relatedcompounds chemistry. I am deeply grateful to him for his

patience,wisdom and kidness and for being a model as ascientist and a teacher.

Jean-PierreG.SENET

Buthiers, Seine-ebMarne,France

August 1997)))

Contentsfirst volume

(ll\177pter

(hapter \177

(hapter \"\177

Introduction .........................................................................7

Section1-1History of phosgenechemistry ............7

Section1-2Toxicity of phosgene............................10Section1-3Breakdown of consumption of

phosgenein the industry .....................11Section1-4 Classification of phosgenereactions ...11

Characteristicsof phosgene............................................15Section2-1 Physical properties..............................15Section2-2 Chemical reactivity of phosgene..........16

Phosgeneand derivatives as building blocks.............27

Section3-1 Reaction at a carbon center................27

Section3-2 Reactionsat an oxygen orsulfur center ........................................31

3-2-1Highlights of someparticular chloroformates

starting from alcohols or phenols ......................343-2-2Reaction of phosgene at oxygen center of

unconventional substrates ..................................483-2-2-1Reaction of phosgene with glycerol ......................483-2-2-2Reaction of phosgene with epoxides ....................3-2-2-3Reaction of phosgene with aldehydes and

ketones.novel c\177-chlorinated chloroformates

and related reagents ..............................................533224Vinylicchloroformates, carbonates and

carbamates ............................................................81

Section3-3-1

3-3-2

3-3-3

3-3 : Reactionsat a nitrogen center.........105Highlights of some reactions of phosgenewith amines, imines, oxazolines .......................105Reaction of 1-chloroalkyl chloroformates with

amines, synthesis and useful applicationsof 1-chloroethyl carbamates ............................1151-Chloroalkyl carbonates as acylating agentsfor the synthesis of carbamates .......................129)))

Contentsfirstvolume

(\177ontents

3-3-4

3-3-5

Section3-4-13+2

3-4-33-4-4

Reaction of phosgene and its derivativeswith carbamates, ureas and amides .................132Reaction of phosgene with sulfonamides,preparation of sulfonyl isocyanates .................141

3-4 : Ring formation reactions..................143Cyclisation between two oxygen atoms ...........143Cyclisation between an oxygen anda nitrogen atoms ..............................................151Cyclisation between two nitrogen atoms .........167Cyclisation between a nitrogen and a sulfur

atoms ................................................................173

secondvolume

Chapter4

Chapter

Phosgeneand derivatives as reagentsSection4-I Chlorination

(Acid chlorides, Imidoyl and Chloroiminium chlorides,Alkyl Chlorides, Chlorinated Phosphorous com-pounds chlorination of heterocycles, etc.)

Section4-2 Dehydration

(Nitriles and Isonitriles)

Section4-3 Alkylation of phenols and amines

Section4-4 Protection and activation offunctional groups

(Amino acids protection and activation, protectionof hydroxyl groups, activation of carboxylic acids, etc.)

Section4-5 N and O- dealkylation

Conclusion

Is any conceivable nontoxic option to overcomephosgene in its industrial applications ?

D

i lllslory of

phosgene\177hemislry

Introduction

The story of phosgenediscovery(Ref. 1)

In the early beginning of the 19th century, chlorine gaswas still uniformly consideredas a combination of muriatic

acid (hydrochloric acid) and oxygen called , oxymuriaticacid \177.

However, in 1810,Dr. John Davy, Sir Humphry Davy's

younger brother, expressedthe opinion that oxymuriaticacid was, as a matter of fact, an elementary substance.This opinion was not at all acceptedand severalscientists,in order to refute the arguments of Dr. Davy, tried there-fore to remove oxygen content of oxymuriatic acid by

treatment with charcoal at a white heat or with carbonmonoxide [Scheme1].

M + 0 \177 MOMuriat\177c acid Oxygen Oxymuriat\177c acid

De-oxygenationM 0 + CO =. M + CO2

Carbon monoxide Murlatlc acid

Scheme 1 :Expected de- oxygenation of oxymuriatic acid (chlorine).

This was the opening of the so called \177 chlorine contro-versy \177 betweenDr. John Davy and Dr. Murray, fervent

supporter of the official theory. This debate took the form

67)))

Introduction Introduction

of letters contributed to << Nicholson's Journal >), both

authors arguing from their own experiments.In an experiment of fundamental importance, after

having exposeda mixture of onevolume of carbonicoxideand onevolume of oxymuriatic acid to bright sunshine, Dr.Davy noticed that the colorof the chlorine has entirely

disappeared,and that the remaining gas occupiedthe

spaceof one volume. After addition of ammonia, he found

no tracesof carbonicoxideand observedan effervescenceof the ammoniacal salt formed with nitric acid.He alsonoticed that the new gas resulting from the evident action

of oxymuriatic acid and carbonicoxide did not fume when

thrown into atmosphereand that it had a most intolerable

suffocating odor and that water absorbedit very slowly.Theseresults were however again contestedby Dr.

Murray who, to support his opinion that oxymuriatic acidand carbon monoxide do not react, quoted unsuccessfultrials from French chemists Gay-Lussacand Thenard :

<< ...mais \177 quelque dosequ'on air m\177l\177 le gaz acidemuriatique oxl\177n\177 sec,et/egaz oxide de carbonepr\177pa-

r\177 avecle fer et le carbonatede barite, quelque forte qu'ait\177t\177 la lumisre \177 laquelle on les a exposes,enfin quelquelong qu'ait \177t\177 le contact, il n'y a point eu d'action \177.

At last, in an important and well-argued letter readto the Royal Society on February 6,1812,Dr. Davyrefuted all the arguments of Dr. Murray and, on the basisof careful and indisputable experiments, proved the realityof the new gas [Scheme2].

LightCI2 + CO ) COCI2

Chlorine (1vol.) Carbon monoxide ( 1 vol.) Phosgene ( 1 vol)\"

Oxymurlat\177c acid \"

Scheme2:1-he discovery of phosgene.

To designateit, he suggesteda simple name, that ofPhosgene (or phosphene),from ancient Greek roots, light )\177 and \177 to produce\177.

The infancy of the phosgenechemistry

In spite of his neat discovery, Dr. Davy has not fore-seenthe prolific potentiality of phosgeneas an outstanding

building block and reagent in chemistry. However, while

treating phosgenewith ammonia, he was very closeto ano-ther discovery of extreme importance, that of the elucida-tion of the nature of urea.

Dr. Davy noticed that phosgenedissolvesin alcohol,but without mentioning any reaction.

In 1833,French chemist Jean-BaptisteDumas while

adding absolute ethyl alcohol in a flask containing phosgene,discoveredits first synthetic derivative (Ref.2).He noticeda strong and instant heating, and after work-up and analy-

sis, he identified the resulting compound as a new chlo-roxicarbonic ether (ethyl chloroformate).

Dumas immediately had an inkling of the importanceof phosgenechemistry with this prediction

<( L'acidechloroxicarbonique, qui peut tout aussi bien

\177tre consid\177r\177 commeun chlorure d'oxidedecarbone,offre

une composition si simple et si remarquable que,r)alisait routes les r\177actions que I'on adroit d'en esp)rer,on parviendrait \177 reproduire, \177 son aide,lescombinaisonslesplus curieusesde la chimie organique \177.

Translation \177 Phosgeneexhibits such a simple and

remarkable composition that, should

it realizeall the reactionsone is entit-

led to hopefor, one could reproduce,\177

thanks to it, the strangest combinations

in organic chemistry \177.

All investigations since then have

clearly fulfilled the expectationofDumas who may be thereforeconsi-deredas the pioneerin the chemistryof phosgene.

Jean-Baptiste DUMAS (1800-IB84)Pioneer in the Chemistry of Phosgene

89)))

Tntroduction Tntroduction

Phosgene is a highly toxic gas which was usedas achemical weapon during World War I.

At high concentration, it causesseverepulmonary irri-

tation and can induce delayed pulmonary edema.It is thereasonwhy all personswho have been exposedto phos-gene,even in very low concentration, must seea physicianimmediately. Some relationships between phosgeneconcentrations in air and physiological effectson humansare summarized in table 1-1.The table 1-2gives compari-son betweensome toxic gases.

Perception of odor ..............................................> 0.4 ppmRecognition of odor ............................................> 1.5ppmIrritation in eyes,nose,throat, and bronchi .........> 3 ppmBeginning of lung damage ...................................> 30 ppm-min

Clinical pulmonary edema ...................................> 1.50 ppm-min

L(CT)0.................................................................~ 300 ppm-min

L(CT)50...............................................................- .500 ppm-min

L(CT)100.............................................................~ 1300 ppm-min

lbble I 1 Con\177enttatiot\177 effect relattonshtps of phosqene exposure tn hamcms(\177et \177).

Gas Odoridentification L(CT)0-30min exp.ppm ppm

Phosgene 1.5 10Chlorine 1 873Carbon monoxide No 4 000Ammonia 5 30 000

Table 1-2: Comparison between some toxic gases,

Due to these high toxicity properties, the presenceoflarge quantities of phosgeneon a site must be strictly trea-ted as major hazard. The regulatory requirements in trans-

portation and safety know-how in the handling and storageof phosgene, have restricted its uses to specialized companies.Custom synthesis is a common practice in this field, becausethe transportation of raw materials to phosgeneproducers is

preferredto the transportation of phosgeneitself.

13Breakdownolphosgene\177nSlllnplion

ihe industry

14

phosgenereal:liolls

Although information in this field is generally kept

confidential, worldwide phosgeneproduction is estimatedto range from 6 to 8 millions tons/year.

The breakdown of phosgeneconsumption is the follo-

wing :- Di and polyisocyanates (TDI, THDI)for polyurethanes .........................................85%- Aromatic polycarbonates..............................10%- Hanufacture of fine chemicals .....................

The consumption of phosgenefor fine chemicals,about 300,000T/year is roughly divided into :- 50% for perestersand percarbonatesused as poly-

merization initiators,- 25 % for agrochemicals,- 25 % for pharmaceuticals and dyestuffs.

Since the pioneering study by Dumas, phosgenechemistry, especiallydevoted to fine chemicals, has grown

tremendously and still remains in an active field of investi-

gation with 2500papersand patents published eachyear.Almost all the chemical reactionsof phosgenecan be divi-

ded into two classes,depending on wether the structural

unit remains in the final product or not.

First class: Reaction of phosgeneas a building block tointroduce the structural unit \177 carbonyl \177. Someexamplesare given in table 1-3.

1011)))

Tntroduction Tntroduction

Substrate

Aromatic : Ar-H

Alcohol or phenol: R-OH

Primary amine : RNH2

Secondary or tertiary amine :R 1 R2R3N

(R3- = H or alkyl)

cz-Amino acids H2N-CHR-COOH

Aldehydes : RCHO

Product

Ar-C-CI Acid chlorideII

OAr-C-Ar Aromatic ketone

II

O

R-O-C-CI ChloroformateII

O

R-O-C- O-R CarbonateII

O

R- N =C=O Isocyanate

RI\\ CarbamoylN-C-CI chlonde

R2\"

II

O

RI\\ /R1

N-C-N UreaR 2\" II \\R 2

O

O

R\177N.. \177

N-Carboxy Anhydride

HO (NCA)

CII

c\177

-Chloro alkylR- CH-O-C-CI ChloroformateII

O

Sulfonamide : FLSO2NH 2 RSO2- N---- C=O Sulfonyl

Isocyanate

Table I-3:Examples ofphosgene reactions to introduce the group >C=O.

Secondclass: Phosgeneand derivatives as reagents

Su bstrate Product

Carboxylic acid : R-COOH n-C-Cl AcidchlorldeII

O

(+ R1OCOCI) R-C-O'Rlll

Esler

O

Alcohol : R-OH

N,N-Disubstituted : R1R2NCHO

formamide

Primary amide : R-CONH2

Alkyl formate : R-OCOH

Phenol : At-OH

Amino acid : H2N-CHR-COOH

Tertiary amine: R1R2R3N

(R3 =

alkyl)

R- CI Alkyl chloride

R\177\\+ Cl\"

N---CHCI Vilsrneier sail

R2/

R-C\177N Nitrile

R- O-CHCl2 t ,1-D\177chloromethyl elher

At- O-Me Aryl methyl ether

RO- C-NH-CH-COOH N- ProtectedII I amino acidO R

RI\\N-Dealkylated amine

NH

R2z

Aryl methyl ether : Ar-O-HeAr-O-\177 \177-\177

Aryl benzoate

(+ PhCOCI o+ catalyst)

At-OH Phenol

Table I-4,\" Examples of phosgene and derivatives asreagents,

1213)))

Characteristicsofphosgene

Physicalproperlies

At ambient temperature and pressure,phosgeneis acolorlessgas which exhibits an irritating and suffocatingodonAt low concentrations, it has a characteristic odor like

moldy hay. However, the odor threshold of phosgeneis

higher than its toxic limit and one must remember that the

senseof smell fails to detectsmall concentrations in air.

Somephysical propertiesof phosgenearepresentedin

table 2-1.

CAS number 75-44 - 5Molecular weight 98.92Structure Planar molecule

Inter atomic distances : C-O= 0.128nm

C-Cl= 0.168nm

Melting point -130\302\260C

Boiling point +8.2\302\260C

Vapor pressure 1.6atm.(20\302\260C) ; 3.99atm.

(50\302\260C)

Vapor density 3.42Liquid density 1.43

(O\302\260C); 1.275

(50\302\260C)

Conversion factor I ppm = 4.043m\177/m3

Odor Reminiscent of moldy hay

Table2-1:Principal physical properties of phosgene,

15)))

Characteristicsof phosgene

Chemi(alrea(\177i\177i\177y of

phosgene

A large part of phosgenereactivity may be accountedfor on the basisof two main mechanisms :

a) Nucleophilic attack on carbonyl function :

Scheme3.

+Ci\"

b) Electrophilic reactions,especiallyFriedel & Craftsrelated reactions:

COCl2 + MCl

Lewis acid

O+ \\\\

Scheme4.

Becausesome important aspectsof the mechanism ofthe nucleophilic reactionswith phosgeneseemedsome-what neglectedor unknown in the previous art, SNPEteams have focused their efforts in terms of basic and

applied researchon the catalysis of such reactions.Themain goal of this active and long investigation was toimprove industrial phosgenation processesand to extendthe range of substrates ableto reactwith phosgene.

As a consequence,this investigation succeededin deve-lopment of many improved processesand the discovery ofseveral previously unknown reactionswhich are discussedin this book.

The principal obstacleto progressin this field has beenthe difficulty of establishing the catalytic mechanism of phos-

Characteristicsof phosgene

genereactions.Two catalytic paths areobviously possible-substrate activation by means of an increasing of its

nucleophilicity ;-phosgeneactivation by improvement of the << leavingcharacter,, of chloride anion.

Concerning phosgenereactions with active hydrogen sub-strates [Scheme.5]:

CatalystNu--H + COCI2 \177 Nu--C--CI

II

oScheme5.

+ HCl

mechanistic studies performed with the help of Nantes

University in France (Ref. 4) resulted in the revelation ofsubstrate activation based on nucleophilicity of chlorideanion in the caseof Q+ CI- type catalyst (quaternaryammonium chloride for example).The mechanism of nucleo-

philic assistanceof thesecatalysts can be understood as an

increaseof the nucleophilicity of the substrate by protonabstraction followed by the condensationof the promotedanion on the electrophile(phosgene)[Scheme6] :

Nu--H

Cl,\177Nu0Scheme5.

+ Gcr1/2 - 1/2-

Nu .....H......CI

o+ Q\321\207 CI- + HCI

This mechanism has beenconfirmed by reacting a seriesofonium chloridesalts with phenol using 3sCI NI\"IR determi-nation as physical probe as shown in table 2-2.

1617)))

Characteristicsof phosgene Characterislicsof phosgene

Range of

phosgenation

efficiency (a)

HIGH

MEDIUM

LOW

Q + CI - Line width 1/2(Hz) (c)

TMCA (b) 240Tetra hexyl ammonium 220.5chloride

Benzyl tributyl ammonium 145.5chloride

Tetrabutyl ammonium 141chloride

Benzyl trimethyl ammonium 58chloride

(a) Phosgenation of phenol into phenyl chloroformate or carboxylic acids into

acid chloridesGI

(b) Tetramethyl chloroformamidinium chloride : Me MeN\177

Me\" I MeGI

(c) Line width of the chloride anion resonance ;n the system onium chloride

salt/phenol (solvent : CH3CN)

Table2-2.'General correlation between catalyst efficiency and nucleophilidty ofchloride anion. Study by35CI NMR.

We pointed out that the C-nucleophilicity of chloride

anion is alsoacting. In the courseof our researchrelatedto the reaction of phosgenewith carbonyl compounds, we

roalkyl chloroformates when treated with phosgenein the

presenceof a Q+ Cl- catalyst (Ref. 5). The assumedmechanism involves the nucleophilic attack of the chloride

anion on the aldehyde followed by the acylation ofthe intermediate chloroalkoxideanion by phosgene[Scheme7] :

Q+

Thesuccessof this new synthetic route to o\321\236-chodnated

chloroformates which are very useful intermediates

(seechapter 3,section3-2) is strongly dependenton the

nucleophilic power of the chloride anion as shown in table2-3:

Catalyst

(5 mol. %)Nucleophilicity lIChloro ethyl chloroformate

(Hz) Yield %

Benzyl tributyl

ammonium

chloride

145.5 95

Benzyl trimethyl

ammonium 58 0chloride (No reaction)

Table 2-3:Correlation between nucleophilicity determined by 35CI NMR and

results obtained in phosgenation of acetaldehyde.

The roleof the nucleophilicity of the chloride anion is

KCI/18crown 6 as catalysts for the phosgenation of

aldehydes.Tracesof HCl (moisture) inhibit the reaction because

HCl2- anion exhibits much less nucleophilicity than Cl-.

Including hydrochloric acidscavengersuch as little toluenediisocyanate in the mixture generally solvesthe problem.

18 19)))

arac;eris;icsof phosgene Charac;eris;icsof phosgene

The nucleophilicity of the chloride anion is of courseafunction of the nature of the counterion (\177+. To increasethe nucleophilicity, one can either or both increasethebulkiness and the dispersal of the positive charge of the

counterion. We discoveredthat hexaalkyl guanidiniumchlorides are very efficient and powerful phosgenation

catalysts [Scheme8]:R R

\1771

4- X = CI or HCI2X-

R/N\177RR=n Bu : HBGCI\"

R = Me ' \"

HMGCI\"

Scheme8 .\" Hexaalkyl guanidinium chlorides.

We introduced these guanidinium salts in a 198_5patent (Ref. 6) on the conversion of carboxylic acidstoacid chlorides with phosgene.In this process,only 0.02mol. % of HBGCl was required, two ordersof magnitudeless than the quantities of other catalysts typically used.Many new other applications including phosgenereactionswith phenols, thiols, aldehydes, epoxidesor O-demethyla-tion methods have beendevelopedlater and arediscussedin this book.

Moreover, these new catalysts may be consideredthemselves as phosgenederivatives becausethey are madefrom phosgene and secondary amines by the schemedepictedbelow [Schemec)]:

RRq R\\ /NH + COCI2\177 N--C--N/ /

II\\

R R O R

COCI2

CI- R R\\ -/ CI-R\\

+ /CI 2 R2NH\177- NIl

+R,,,

R,\\R +

NH HCl/N\177'N__ R N/C\177N/ / '

R /I I

RR

R R

COCI2 N + CI-.HCI --\177- R

IIFi P%\"

90oc \\ /C\177 / + N-C-CIN N /R R O

Scheme9 .\" Preparation of hexa alkyl guanidinium chlorides

This industrial processleads to hexabutylguanidinium

chloride hydrochloride (HBGCI.HCl)which, as above men-

tioned, failed as a catalyst in the reaction requiring high

C-nucleophilicity of chloride anion. Pure HBGCl may beobtained by shaking a solution of HBGCI.HClwith excess10% NaOH.The dried (HgSO4)organic layer is concen-trated and then treated at 100\302\260C under vacuum (0.2torr)for 24 h. The off-white powder obtained is stored under

nitrogen.The decompositionof methyl chloroformate is a very

convenient method to establish a nucleophilicity powerscaleof the chloride anion in onium chlorides, allowing thus to

easily comparea priori the catalytic efficiency of different

candidates.It is known that the decarboxylation of methyl

chloroformate is catalyzed by (\177+ Cl- type compoundsthus producing only methyl chloride and carbon dioxide

accordingto a pure SN 2 reaction (Ref.7) [Scheme10]:

Q+Cl\" + CH3--O--C-- \177 CH3Cl + CO2+ Cl\"II

OScheme 10:Decomposition of methyl chloroformate

20 21)))

Characlerisli(sof phosgene Chara(terisli(sof phosgene

We used this specificreaction on IR analysis as kinet

chemical probe (Ref. 8). Among the various oniuf

chlorides commonly encountered,hexabutyl guanidiniuf

chloride (HI3GCl) exhibits the highest activity as shown i

table 2-4 .-

Catalyst Relative rate constant

HBGCI 100HHGCI 47

Tetrahexyl ammonium chloride 42Benzyl tributyl ammonium chloride 27

Trioctyl methyl ammonium chloride 14

Table 24:Relative rate constant values of SN 2 decomposition of methyl chlo\177

formate at 70\302\260E in the presenceof onium chloride catalysts (1%).For HBGEI, the k value is 12.52min. \1771

(Re\320\210 8).

As expectedconsidering table 2-4, hexabutyl guanidnium chloride displays higher catalytic activity than it

hexamethyl analogue. However, HMGCl offers soreadvantages becauseof its solubility in water which makeeasier elimination by aqueouswashings and because\177

precipitates in severalphosgenation media after removal cphosgeneexcess.

To sum up, hexabutyl guanidinium chloride exhibit

someparticularities due to its extraordinary bulkiness an,

the hydrophobicity of the the n-butyl substituent:However, the dispersalof the positive charge is somewhacounterbalancedby the out of plane distortion of the bulk

substituents as suggestedby molecular modeling calcul\177

tions on HBGCl using the CSCChem 3D program (Ref.9'Due to this kind of geometry and for reasonsof symmetr\177

it is assumed that the chloride anion will be locatedalonthe central axis and will interact weakly with the positivcenter[Scheme11]:

Scheme 11:Molecular model of hexabutyl guanidinium chloride

Although hexamethyl guanidinium chloride (HMGCI) is

lessactive than its hexabutyl congener,it is very useful in

several industrial applications, becauseof its good water

solubility, and alsobecauseits hydrochloride is often inso-luble in organic mediums. Thesetwo propertiesallow easyremoval of the catalyst after reaction.

For example, phosgenation of octane thiol proceedsrapidly in presenceof HMGCI, even at 30\302\260C to give octyl

thiochloroformate [Scheme12]:HMGOI

n Oct-S-H+ OOOI2 \177 n Oct-$--O--OI\321\207 HMGOI.HOI

30\302\260O IIoScheme 12:Synthesis of n octyl thiochloroformate in presence of HMGCI.

After completion of the reaction and removal of phos-gene excess,HMGCI.HCIwhich precipitates completely is

filtrated thus giving very pure product (Ref.10).Another approach is to have a catalytic system strictly

insoluble in all media and thereforeeasily removable by fil-

tration and indefinitely reusable.Such heterogeneouscata-

lyst offersmany advantages, particularly in the caseof pro-ducts difficult to purify by distillation becauseof ther-

mal instability or too high boiling point.

22 23)))

Characteristicsof phosgene

We have recently reported the preparation of silica-supported guanidinium salts, especiallypentabutyl propyl-guanidinium chloride grafted on silica beads,and their usesas phosgenation heterogeneouscatalysts (Ref. 11).For

example, starting from macroporous silica glass beadshaving the following characteristics:-diameter :1 mm- specificsurface: 78m2/g-porousvolume : 0.9cm3/g-OHcontent :4.8FI mol./m2

we obtained at pilot scalea catalytic system bearing 0.085meq./gof active sites.

The synthesisroute we developedis depictedonscheme13:

CI-Bu Bu

\\ + /(MeO)3-Si-(CH2)3-NHBu+ N=C--=N

I\\Bu/ CI Bu

OH

(A) + Silica / Silicabeads \177 beads

\\ Final treatmentOH with Me3SiCI

(MeO)3Si(CH2)3 Bui I

/1\"4. /1\"4\177--\177

Bu \177 Bui\177+

CA) Ncr

Bu/

\\Bu

\177 OSiMe3

Si(CH2)3 Bu

r,l. \177N

Bu/\"\177,,'+

\\Bu

Bu/N\\BuCI-

Scheme 13 .\" Synthesis route to silica-supported guanidinium chloride catalyst.

Sincethis supportedcatalyst is stable, insoluble and

composedof mechanically strong particles of 1 mmdiameter, it can be easily recovered by filtration and bereused.The high stability and activity of silica supportedguanidinium salts, along with the ability to reusethe solid

catalyst weredemonstrated on repetitive batch phosgena-tions of carboxylic acids.

Characteristicsof phosgenet

/The utility of silica supported guanidinium salts was

alsowell establishedin reactionssensitive to reversal while

heating. Thus, we discoveredthat treatment of aldehydeswith oxalyl chloride in the presenceof a {{ naked \177 catalyst

(e.g.,HBGCI)produces1-chloroalkyl oxalyl chloridesin

60-97%yields (Ref. 12)[Scheme14]:

O O

R...jk.H+

CI\177L.\177CI

\"CI-\" CI

.\177\177-.......R O

O HBGCI OR = CH3 : bp 56-58\302\260C/20mm

97% yield

Scheme 14 .\" Reaction ofexcessoxalyl chloride with aldehydes.

However, with aromatic aldehydes or with chloral,

heating in the presenceof the catalyst during distillation

resulted in reversion to the aldehyde and attempts toentirely remove the fatty HBGCI catalyst, for example by

pentane trituration failed due to the partial solubility ofthis salt in the non-polar medium.

This problem was overcomeby utilizing the supportedcatalyst above described.In a typical example, distilled

1,2,2,2-tetrachloroethyloxalyl chloride was thus obtainedfrom chloral in 95% yield after 4 h reaction.

2425)))

Phos[leneand derivativesas buildin blocks

,i{eactions,I (\177rl)on

(\177lll\177r

In the courseof severalstudies, we demonstrated that

the Friedel-Craftsreactionof phosgenewith aromaticsdependscritically on the purity of catalyst, the presenceofwater and on the ratio catalyst/substrate.

Generally, condensationof phosgenewith aromatics in

presenceof Lewis acids affords benzophenonesas the

main products, unless a specialmean is employed to remove

the intermediate complex[Scheme15]:

AICI 3R + COCI2 \177 R \342\200\242AICI3

O

\177R R \342\200\242AICI 3

Scheme 15:Friede\177Craftsreacdon ofphosgene with aromatics.

Note that the adduct ketone/AlCl 3 is much morestablethan the adduct acid chlofide/AlCl 3.

For example, condensation of diphenyl ether with

phosgeneunder Friedel-Crafts conditions gives 4,4'-diphe-noxy benzophenoneas the major product (Ref. 13).We

developedan improved processwhich leadsto a very pureproduct with low content of xanthone [Scheme16]:

27)))

Phosgeneand derivalivesasbuildingblocks Phosgeneand derivalivesas buildingblocks

\177\177CICH2CH2CI

2 O + COCl2 \177.

AlCl 3

Yield > 80%Purity >99.9%

O

Traces( < O.1%)

Scheme 15: Preparation of high purity 4,4;diphenoxy benzophenone,

High purity 4,4'-diphenoxy benzophenoneis a key star-ring material for the production of high molecular weightpolymers. Thus, its polycondensation with terephtaloylchloride in presenceof FriedeI-Crafts catalyst gives poly-ether-etherketones(PEEK) with the structure depictedonscheme17:

\1770\177\1770'\177\" Ol/nScheme 17, Structural unit of thermoplastic poly ether ether ketones

Poly ether etherketonesareusedas high performanceengineering thermoplastics which offer an unique range ofpropertiesamong them :- continuous working temperature of 250\302\260C ;-

high chemical resistance;-hydrolysisresistanceon serviceof thousands of

hours at temperature in excessof 250\302\260C in steam under

pressure;-easily processible.

Another example is the Friedel-Crafts phosgenereactionwith o.xylenegiving 3,3',4,4'-tetramethylbenzophenonein

high yield and free of isomers(Ref. 14).This substituted

benzophenoneis easily oxidized into benzophenonetetra-carboxylic acid dianhydride (BTDA) widely used for themanufacture of polyimides [Scheme18]:

MeMe, Me

[\177Me

AICI 3 \177\177_2 + COCI2 \177 Me Meo Xylene \177O\177

Yield :85%M.P.: 143\302\260C

O O

Oxidation

j\177\177\177== BTDA

Scheme 18.'Synthesis of benzophenone tetracarboxylic dianhydride

Friedel-Crafts reaction of phosgenewith heterocyclicaromatic compounds is also difficult to stop at the acidchloride stage.However, under selectedconditions, hetero-aromatics such as thiophene can be directly acylated to

give thiophenecarbonyl chloride [Scheme19](Ref. 1.5):

COCI2 + AICI 3 +

\177S\177

CH2CI2\177,-

S\177CI

Addition of thiopheneat -20c'Cin the mixture OPhosgene + AICI 3 Yield : 96%

No 3-isomer

Scheme 19:Preparation of 2-thiophenecarbonyl chloride

2-Thiophenecarbonyl chloride is used as intermediate

in the synthesis of many pharmaceuticals. For example, its

condensation with protectedL-4-hydroxyproline followed

by deprotectiongives a product claimed as antiinflamma-

tory and antidystrophic agent (Ref.16).

Nucleophilic addition of vinyl ethersto phosgeneis an

efficient synthetic route to valuable 3-alkoxy and 3-phe-noxy acryloyl chlorides.We studied an improved processbased on literature data (Ref. 17)under specialcatalytic

conditions [Scherne20]:

2829)))

Phosgeneand derivativesasbuildingblo\321\236ks Phosgeneandderivativesasbuildingblo\321\236ks

+ ----\" c,RO Cl Cl R.T. - HCl Cl

/LRO\"

\"Cl j ( E- configuration)

Scheme20:Phosgenation of vinyl ethers to give 3alkoxyacryloyl chlorides

E-3-alkoxyacryloyl chloridesare high potential interme-

diates in organic synthesis, especiallyfor the preparation ofvarious heterocycles,such as coumarins [Scheme21]:

OH

+ Et-O-CH\177CH-C-CI\177II oO

M.p. :223-4{'CYield :60%

Scheme21.P/epu/ulion of Ayapin uMng 3ethoxyauyloyl chloHd\177 (R\177L 18)

or quinolines [Scheme22]:

NH 2

II 87%0 0

H2SO4

F\177POCl3

F\177,-\17790% O 87.5% ClH

Scheme22:Synthesis of quinoline derivatives, valuable intermediates for the preparation of herbicides

(Re\320\210 19)

Another valuable application of 3-alkoxyacryloyl chlo-rides is the preparation of N-alkoxyacryloyl carbamatesaccordingto an original processdevelopedat SNPE Group

[Scheme23]:

Reactionsan oxyp\177en

or sulfurcenter

RO RO\177

\"\177:=+ Et-O-C-NHSiMe3 -\177-\177.

\"\177o II

oCI

O - Me3SiCI HN

o\177OEt

Scheme23. Preparation of Ethyl N-alkoxyacryloyl carbamate

N-alkoxyacryloyl carbamatesoffer an interesting optionto avoid the use of toxic and expensivealkoxyacryloyl iso-cyanates in the synthesis of uracil derivatives with antiviral

activity [Scheme24] :

OHO.NH2

MeON\177=0o

HO OMeO HO

',-.2-1)Cyclisation NH

- MeOH\177,

HO\177N\177O2) 12 / HNO3

HO

Scheme24.'Preparation of uracil derivatives as antivirals (ReL 20)

Phosgenereacts easily with aliphatic mona or poly

hydroxy compounds at room temperature or below toafford corresponding aliphatic chloroformates in goodyields. In contrast, phenols are quite inert toward phosge-ne, even at temperatures as high as 150\302\260C. Reaction of

phosgenewith phenols requires an acid scavengersuch astertiary amine or a mineral base (room temperature or

below) or a catalyst (seesection2-2)such as HBGCI.HCl

(temperature higher than90\302\260C) [Scheme25].

3031)))

Phosgeneand derivalivesas buildingblocks Phosgeneand derivalivesas buildingblocks

R1-OH \177 R-O-C-O-R1IIHCI

R-OH + COC\177 \177R-O-C-Cl\177- O- HCI II \177Scavenger

O \177.or catalystAr-OH \177\"

no reaction

Ar-OH + COC!2 Ar-O-C-CIIIo

scavenger,T<20\302\260C

or catalyst, T> 90\302\260C

R-O-C-O-ArII

o

R-OH \177\"R-O-C-O-Ar

\177Scavengercatalyst^.1nu'\177

'\177r

Ar -OH Ar-O-C-O-AtII

oScheme25:Reactions of phosgene with alcohols and phenols

Aliphatic and aromatic chloroformates can reacfurther, easily with aliphatic hydroxy compounds to yiel

carbonate diestersand only in presenceof baseso

catalysts with phenols.The chemistry of chloroformates has been alread

reviewed in depth (Ref. 21) and this section3-2 is limite

to unusual or unexpectedproducts or reactions,mostl

developedin SNPE Group.Table3-1gives someexampleof non conventional chloroformates.

...chloroformate

Chloromethyl

Structure

CI-CH20-C-CIII

O

R.N.

22128-62-7

B.P.

\302\260C/mm

106/760

Applications

Pharmaceuticals

AgrochemicalsPhoto resists

Trichloromethyl

1-Chloroethyl

1,2,2,2-Tetrachloro

ethyl

CI3C-O-C-CIII

o

CI

OH3-C HIO\177I'CI

0CI

Cl3C-CHIO-C-CIII

0

503-38-8 125/748

Phosgene{{diphosgene(als\302\260calledSUbstitute,,)

50893-53-3\"

117/760 Antibiotics (pro drugs)

(+) 95597- N-dealkylation of

56-1 t. amines

Pharmaceuticals

98015-53-3 80/14 Peptide chemistry,

pharmaceuticals

Vinyl CH2=CH-O-C-CIII

O5130-24-5 89 90/ Polymers

760 Contact lenses

Pharmaceuticals

N-dealkylation

IsopropenylH3

CH2=C-O-C-CIIt

O

2.2-Dichloro vinylCI2C=CH_O_C_CI

IIO

2,2,2-Fluorodinitro I ?\302\2602

ethyl F__C_CH2_O_C.CI

\177 II

NO 2 O

t-Butyl (CH3)3C-O-C-CIII

O

57933-83-2

113421-96-8

31841-79-9

24608-52-4

94.5/ Pharmaceuticals

747 Peptide chemistry

82-85/ Polymers (optical

120 fibers)

Agrochemicals

58/2

3-4/0.9-1.7

Dec.

Explosives

Propellants

Peptide chemistry

(this chloroformate

\177s very unstable)

2-Oxo-1 3-dioxolan CH 20-C-Cl23385-72-04-yl methyl /\177/ OI

0

Table 3-1:Someunusual aliphatic chloroformates.

Dec. UV curable acrylic

resins

Hydro gels

Blowing agents for

plastic foams

Foods additives

32 33)))

Phosgeneand derivativesas buildingblocks Phosgeneandderivativesasbuildingblocks

Highlighlsof some

parli(ular(hloroformalesand (arbonales

slarlingfromal(oholsor

phenols

In the courseof previousstudiesdevoted to new

substituted chloroformates,we were interested in the

synthesis of nitro and aminoalkyl chloroformates.Thus, for application in explosivesand propellants, a

safeprocessfor the preparation of 2,2,2-fluorodinitroethyl

chloroformate was developedstarting from fiuorodinitro-

ethanol (Ref. 22).Seetable 3-1.The caseof aminoalkyl chloroformates is more compli-

cated becauseof the instability of chloroformates in pre-senceof amines. It is well known (Ref. 21)that aliphatic

chloroformatesdecomposeby two paths depicted in

scheme26:

I IH--C--C--O-C-CIII

I I o

(a) I I

\177 H--C--C--CII I

+ CO2

(b)\177 \177

Scheme26: Decomposition paths of aliphatic chloroformates

+ HCl + CO2

Temperature of decomposition varies widely depending :-on the structure of the aliphatic radical ;-on the presenceand nature of other compounds, espe-cially amines or quaternary ammonium salts (SNi or SN2

mechanisms).Therefore,the preparation of aminoalkyl chloroformates

requires carefully selectedconditions (Ref. 23):-Low temperatures (below+10\302\260C) ;-Addition of amino alcoholsinto phosgenesolutions ;

-Solventsselectedin order to have a completeprecipi-tation of the hydrochlorides ;- Filtration carried out away from any traceof moisture.

Amino chloroformates are generally isolatedas their

hydrochlorides and stored under dry nitrogen at low

temperature (< +5\302\260C). They are interesting potent inter-

mediates for pharmaceuticals.Thus, 2-(N,N-dieth\177/lamino)

ethyl chloroformateis used in the preparationof new

cardiovascular agents for the acylation of quinolylthiadia-

zinone (Ref. 24) [Scheme27] :

S\177/Me \177 OMe

oOI\177__N,

Et

Et

Scheme 27:New cardiovascular agent.

The manufacture of aromatic chloroformates bearing

electronswithdrawing groups is posing a problem. For

example,the phosgenation of p-nitrophenol in presenceofa catalyst to afford p-nitrophenyl chloroformate is equili-

brated.The balanceis easily tipped towards starting mate-rials by elimination of phosgeneexcess.As a consequence,attempts of purification by distillation give rise to the for-mation of 4,4'-dinitrodiphenyl carbonateand, more hazar-

dous,phosgeneaccordingto the mechanism depictedonscheme28:

Catalyst

o

O2N O, \177

Q+ c,-

O2 N --\177--O Q+

O2N\177-OQ+ + COCI2

p-nitrophenylchloroformate

\177)2N\177-'\177OICO + O+CI-

2Scheme28: Theproblem of p-nitrophenyl chloroformate synthesis.

Again, this difficulty was overcomeby completeelimi-

nation of the catalyst from the mixture beforedistillation

thus giving a pure and stablechloroformate.

34 35)))

Phosgeneand derivativesas buildingblocks Phosgeneand derivativesas buildingblocks

p-Nitrophenyl chloroformate is widely usedin industrial

chemistry, especiallyas a protecting agent or as a phosgenesubstitute in the synthesis of urethanes. For example, anew amine photogenerator was preparedfrom p-nitrophe-

nyl chloroformate (Ref. 2,5)accordingto the scheme29.

NO2p.Nitrophenyl

\177_chloroformate

MeO CH2-OH \177

MeO

NO 2

2,6-dimethyl

\177OpiperidineMeO

=\177 Me

- p. NitrophenolMeO O==\177

\177N.\177. ]

NO 2

MeO\177-\177kOMeO

O==\177o\177N02

5\177herne 29.' Preparation of a new amine photogenerator.

In another example, p-nitrophenyl chloroformate was

required to introduce a sophisticated carbamate function

in a multi-steps synthesis of retroviral proteaseinhibiting

compounds (Ref. 26).The structure of the intermediate

carbonateis given in scheme30.

p.Nitroph enyl

/f--S\177chlor\302\260formate /F-S

_\1770\177\177 N\177 NO2

N'Y'OH yield :78% O

OScheme 30 .\" Preparation of a key intermediate for the synthesis of retroviral

protease inhibitors.

Thefinal result of the reaction of phosgenewith certain

hydroxy compounds may dependdrastically on the catalystused.For example, the phosgenation of 3,5-dichloro-2-hydroxy pyridine in toluene, in presenceof DMF, gives

2,3,5-trichloropyridine in goodyields.This compound is avaluable intermediate for producing herbicides(.Ref. 27).Surprisingly, we found that the phosgenation in presence

of hexabutylguanidinium chloride hydrochloride (HBGCl.

HCl) beads quantitatively to 3,5-dichloro-2-pyridinylchloroformate (Ref. 28).On further heating, in presenceof HBGCI.HCl,this new chloroformate decomposesslowly

to afford starting material and phosgenealmost quantita-

tively (reversereaction, seescheme31).

COCI21

CAT. : II

HBGCI.HCl IIT:80\302\260C

T:110\302\260C \177

H +Cl-

Aq.NH3

STRUCTURALPROOF i-PrOH

Et3N

CI CI 87%

\177 OVERALL

\"N\177

\"CIYIELD

Scheme31.'Unusual reaction of phosgene with 3,5-dichloro-2-pyridone.

36 37)))

Phosgeneand derivalivesasbuildinblocks Phosgeneandderivalivesasbuildinblocks

Phosgenein excessreactswith thiols in presenceof a

catalyst to afford thiochloroformates. However, in indus-

trial processes,it is often difficult to avoid formation of

sideproducts, especiallydisulfides and thiocarbonates.As already discussedin section 2-2, use of HMGCI.HCI

catalyst, soluble during the reaction, insoluble affcer completion

and removed by simple filtration, gives high quality products.For example, n-octyl thiochloroformate, useful intermediate

for the manufacture of herbicides[Seescheme32]is obtai-

ned in quantitative yield, without any tracesof sideproducts.Moreover, the filtered catalyst is indefinitely reusable.

CI--,,,\177N, N

\177,SyII1\177

Foliar active herbicideintroduced by Chemie-Linz AG

n-Oct-- Trade mark\"

Lentagran

OScheme32.PYRIDATE from n Octyl thiochloroformate.

Chlorination of methyl chloroformate and dimethyl car-bonateaffords useful phosgenesubstitutes :chloromethyl

chloroformate [I], trichloromethyl chloroformate [11]alsocalled\177 Diphosgene\177 and bis(trichloromethyl) carbonate

[111]known as \177 Triphosgene \177 [seescheme33]:Cl 2 , hv

CH3-O-C-CI\177CICH2-O-C-CIII -

HC\177 II0 0[I] bp. 106oC

Cl2,hv

- HCI

C[2,hv

CI2CH-O-C-CI \177- CI3C-O-C'CI[ II ] \"Diphosgene\"II -

HC\177 II bp. : 128\302\260CO OVapor pressure/

10mm / 20\302\260C

6 Cl 2CH3-O_C.O_CH3

-Cl3C_O.C.O--CCl3

II20\302\260C, 28h\" IIo r-6 HCI O

[111 J \"Triphosgene\"

rnp. : 80\302\260C

bp. : 206\302\260(\177 (dec.)Scheme 33:Chlorination products from methyl chloroformate and dimethyl carbonate.

The propertiesof chloromethyl chloroformate which

has beenmade alsoby phosgenation of monomeric formal-

dehyde (Ref. 29),are discussedfurther in section3-2-2.Someinteresting relationships between {{ Diphosgene

phosgene(Ref. 30)and the dismutation of phosgeneinto

carbon tetrachloride and carbon dioxide (Ref. 31) aredepictedin scheme34 :

Charcoal Lewis acid+ Pressure (FeCI3)

2 COCl2\177 Cl3C-O-C-Cl,,\177-- CCl4+ CO2

IIQ+ Cl \" 0 Lewis acid

type catalyst + pressure

Scheme34.'Reverse dismutation of phosgene.

The reversibility of the decomposition ofinto carbon tetrachloride and carbon dioxide is still acontroversial topic.However, the production of phosgeneby reaction of carbon tetrachloride and carbon dioxide

over catalysts such as Lewis acidswas recently claimed in

Russian patents (Ref.32).The reaction is assumed to pro-ceedthrough the formation of trichloromethyl chlorofor-mate or bis(trichloromethyl) carbonate.

At the presenttime, one crucial question still remains :what is the industrial value of \177 Diphosgene\177 and \177 Triphos-

gene \177 as liquid and solid substitutes for phosgene? Are

the two reagentsreally saferthan phosgene?Both reagentshave proved to be useful substitutes for

phosgenein all its main applications.Indeed,they are sold

commercially as the efficient equivalents of 2 and 3 phos-gene moleculesrespectively in processesyielding chloro-formates, carbonates,carbamates,ureas and isocyanates,aswell as in chlorinations, carboxylations and dehydrations

\342\200\242(For a recentreview of {{ Triphosgene \177 use in organic syn-

thesis, seeRef. 33).Accurate amounts can be easily weighed, limiting pro-

blems due to excessreagent.It is possiblealsoto increasereagent concentrations comparedwith phosgeneitself.

However, there is little prospectthat either reagent will

be utilized in significant industrial processes.

38 39)))

Phosgeneand derivativesasbuildingblocks Phosgeneandderivativesasbuildingblocks

Both reagents decomposeto phosgeneon heating,

slowly when pure, very rapidly and quantitatively in pre-senceof a nucleophile such as a \177 naked ,, chloride anion

[Scheme35]:

\177, 2 COCI2 + Cl

c\177 Fc*-c\177/

cI 0\177,\177

0 cI

0 I

CI3C--O--\177:---CI

CO+C;I 2

03 COCl2

+

Cl-

Scheme35.'Decomposition of ,, Diphosgene ,, and ,\177 Triphosgene

As noted by 5. Damle (Ref.34), the toxicity of both

diphosgeneand triphosgene is exactly the same of phos-genesinceboth decomposeon heating and upon reactionwith any nucleophile.Even a trace ofmoisture leadsto for-mation ofphosgene.

Thus, in any transportation or handling accident,both

compounds are phosgene.The manufacture of symmetrical or mixed carbonates

by reaction of chloroformates with alcoholsor phenols iswell documented.In the courseof different studies devo-ted to the manufacture of aromatic carbonates,we have

designeda one-stepprocedurethat affords diphenyl car-bonatein excellentyield and purity using simple equipmentand no solvent [Scheme36]:

OH Neat

2 + COCI2 \177 O--\177-OCatalyst

mp : 41\302\260C(1-5% tool.) O

bp : 182\302\260Cmp 79.5\302\260C

bp : 315\302\260C

Scheme36.Improved diphenyl carbonate synthesis.

4o

+2H

Table3-2 gives a cornparison betweensomecatalysts

Time for 100%Catalyst Temperature conversion

HBGCI.HCl 160- 175 \302\260C 7.75H

HMGCI.HCI 165- 170\302\260C 5.25HIHIDAZOLE 160- 170\302\260C 2.50HHBGCI.HCI = Hexa n-butyl guanidinium chloride hydrochloride.HP1GCI.HCI =

Hexarnethyl guanidinium chloride hydrochloride.

lbble 3-2 .' Comparison of the efficiency of some catalysts in the synthesis ofdlphenyl carbonate in bulk (3% Mol. Catalyst/phenol)

Among the numerous applications of diphenyl carbo-nate, the preparation and chemistry of dichlorodiphenoxymethane appears somewhat neglected.This phosgenederivative can be preparedin goodyield by treatment ofdiphenyl carbonatewith phosphorus pentachlorideat high

temperature (Ref. 35)accordingto scheme37 :PCl5180- 200'\177c

- POCI3

CI

cIbp : 183-187\"C / 12mm

mp :42-44\302\260C

80%yield\177 heine 37.Preparation of dichlorodiphenoxy methane.

Besidesbeing a key starting material for the prepara-tion of polyorthocarbonates,dichlorodiphenoxy methaneis a versatile synthon for the construction of heterocyclicsystems of medicinal interest (Ref. 36).Its condensationwith cyanamide affords diphenyl cyanocarbonimidate in

high yield (Ref. 35)as shown in scheme38:CI

N-CN

\177\177

__\177AcOet

\177__...[\177.

_\177O- -O + NH2CN \177 O O

80\302\260C

Cl

91%yieldmp: 156-8\302\260C

\177cheme 38 .\" Preparation ofdiphenyl cyanocarbonimidate from dichloro diphe-noxy methane.

41)))

Phosgeneand derivativesasbuildingblocks Phosgeneandderivativesasbuildingblocks

Theavailability of diphenyl cyanocarbonimidate provides

a simple, low cost, high yield accessto N-cyanoguanidines

which are active as histamine H2 antagonists.

For example, researchersfrom Smith Kline &,'French

Laboratorieshas described(Ref.36)a new facilesynthesis

of the anti-ulcer drug, Cimetidine (\177{ Tagamet \177) depictedon

scheme39:

N'CNMe f--S \177 /\177 Room temp.

HNx,\177,

NH 2'\177 \177 Yield > 90%

Me f--SUe\177S\177__\177

'k/_\177,' \177 OPh Me'NH2-- NHMe

H N-CN Yield >90% H N-CN

Scheme39:Preparation of Cimetidine from diphenyl cyanocarbonim\177da\177

Scheme40 shows someother examplesof applications

in heterocydic chemistry (Ref. 3.5).

H2 i-PrOH

[I /J /REFLUX\"'-\177 / lh/ NH 2

'

i-PrOH, RT, 1h

i-PrOHRT, 2h

MP.278\302\260C

74%'

MP. : 175\"C

N/CN\177 \177

'NH2NH2

H\177-\177/NH2HN O ,

N

15min 86%MP. : 160-1\302\260C

MP. :190-2\177C

Scheme40:Examples of diphenyl cyanocarbonimidate (I) applicatio, ns.

42

N

The decarboxylation of aromatic carbonatessubstitu-

ted by electronwithdrawing groups is an efficient method

to get substituted diphenyl ethers.We found that pentaal-kyl guanidines are superior catalysts for the synthesis of

4,4'-dinitrodiphenyl ether from 4,4'-dinitrodiphenyl carbo-nate (Ref.37).The generally acceptedmechanism involves

nucleophilic attack by the substituted guanidine at the car-

bonyl of the carbonateto form an acylated guanidinium

phenoxide salt. In a secondstep, the p.nitro phenoxideanion attacks the aromatic ring of the a\177lated guanidi-

nium cation (SNAr reaction) to leadto the expectedetherafter lossof CO2 [Scheme41].

N

\177- Ar OAr + CO2 + RN N

R

AF=

Scheme41:Mechanism of the decarboxylation of 4,4'-dinitrodiphenyl carbonate

catalyzed by pentaalkyl guanidines

Nucleophilicity of the guanidine must be, carefully

controlled,to avoid arylation of the catalyst' itself. This

could be easily accomplishedthrough a properchoiceofthe substituents. Note also that delocalization of chargeover the three nitrogens in the assumed intermediate gua-nidinium cation enhancesthe nucleophilicity of its counter

anion, e.g.the p.nitro phenoxide anion.

With 2-methyl-l,l,3,3-tetrabutyl guanidine as catalyst,

the decarboxylation proceedsat temperature lower than

those described with conventional base catalysts. Theresult is even better comparedwith using 4-N,N-dimethy-

lamina pyridine (DfIAP) as shown in scheme42.43)))

Phosgeneand derivativesas buildin\177 blocks

4,4'-Dinitrodiphenyl ether can be easily hydrogenatedto 4,4'-diaminodiphenyl ether especiallysuitable for the

manufacture of polymers such as polyimides.The required pentaalkyl guanidines were easily prepared

through phosgenation of the appropriate urea to give the

corresponding chloroformamidinium salt which reactswith

an excessof amine to yield the expectedguanidine (Ref. 37).

160\"C\177 O2N\177--O--\177--NO2+ 002

4,5HCatayst : DMAP : 77% yield(5 Mol. %)

Bu2N\177NMe : 88% yieldBu2N

H2

Pressure

Scheme42.Improved synthesis of 4,4'-dinitro diphenyl ether and 4-4'-diamino

diphenyl ether

One of the most convenient esterification methods

developedearlier was based on the decarboxylation ofunstable mixed carboxylic-carbonicanhydrides preparedby

reaction of chloroformates with carboxylic acids(Ref. 38)accordingto scheme43.

CH2CI2R]O-C-Cl+ R2-C-Cl \177 R]O-C-O-C-R2

II II Etsa II II

O OO\177C

O O

Examples :Et-O-C-O-C-CH3 Et-O--C-O-C-\177-\177NO 2

0 o o 0bp : 64-7\302\260C / 20mm mp : 56-7\302\260C

Scheme43:Preparation of mixed carboxylic-carbonic anhydrides.

Phosgeneandderivativesas buildin\177 blocks

The courseof the decompositionof the mixed anhy-

drides [Scheme44]which leadsto the formation of expec-ted esters(path A) or to a mixture of symmetrical carbo-nates and anhydrides (path B) strongly dependson thestructures of the chloroformate and the carboxylic acid but

alsoon the choiceof the catalyst.. Becauseselectivepro-duction of estersif of great interest, we have studied the

thermal instability of the mixed anhydrides and developeda new efficient and selectiveesterification reaction with

chloroformates using a silica supportedguanidinium

catalyst (Ref. 39).This method will be discussedin vol. 2section4-4.

R\177O-C-R\177

O

R10-C-O-C-R2

O O 2

\177 1/2 R\177O-C-OR

O O OScheme44:Decomposition paths o\177 mixed carboxfliocarbonic

lhe use of the mixed carboxglic-carboaicanhgdridesalsoa \177owerful method of carboxglic acidsactivatioa forthe formation of amide bounds in

\177e\177tide chemistrg (seevol. 2, section4-4).

8eactionof chloroformates with sodium alkgl carbo-nates, easilg available through reactioaof carbon dioxide

with sodium alkoxides, affords dicarbonatesalso called\177grocarbonates as shown ia scheme45.

R-O-C-CI+ R]-O-C-O-Na\177R-O-C-O-C-O-R1

II II- NaCl II II

O O O OScheme45: Preparation of dicarbonates from chloroformates.

4445)))

nea_nd derivativesasbuildinblocks

Pyrocarbonatesfind useful applications in severalfields, such as :- Preservatives for wines, soft drinks, fruit juices,especially

in the caseof diethyl pyrocarbonate :R -- R 1 = Ethyl.-Blowing agents for plastics, polyurethane foams asFreon \177' substitutes. For example, t.butyl methyl

pyrocarbonate (R =methyl, R t = t. butyl)was claimed

as a foaming agent addedduring processingof polymersto achieve a cellular structure by liberation of carbondioxide (Ref.40).- Protection of amino groups.Di-t.butyl dicarbonate called

(Boc)20(which is not made from the very unstable

t.butyl chloroformate) is well known as the most popular

reagent for the preparation of t.Bocprotectedamines,

especiallyt.Boc-amino acidsin peptide chemistry.

We reported the synthesis (data on table 3-3)and

some applications of dibenzyl dicarbonate (Ref. 41) and

diallyl dicarbonate (Ref.42).

Dicarbonate Yield mp or bp

Dibenzyl dicarbonate 79 % mp. 28 \302\260C

Diallyl dicarbonate 82 % bp.65 \302\260C/0.05

(60 % distilled) Torr

Table3-3:Synthesis of new useful dicarbonates.

Dibenzyl dicarbonate offers some advantages in the

preparation of N-benzyloxycarbonyl amino-acids, compa-red to the widely used benzyl chloroformate. For example,

preparation of dipeptide-freeN-benzyloxycarbonyl glycine

is easily achieved under standard pH-stat conditions if the

pH is carefully regulated.

Diallyl dicarbonate was used for the allyloxycarbonyl

protection of amino compounds including amino acids,amino sugars and nucleosides.Except for the reaction with

amino acids,the reagent doesnot require an additional

base, and the only by-products, allyl alcohol and carbon

dioxide are both volatile. For example, N-allyloxycarbonyl

glucosaminewas obtained analytically pure by simple

evaporationof the reaction mixture.

Phosgeneand derivativesas buildinblocks

Thesetwo reagents, Z20and (AIIoc)20, conveniently sup-plement the known chloroformates for the protection ofamines.

Cyanoformate estersmay be prepared through reaction

of alkyl chloroformates with cyanides salts by proceduresusing phase-transfer catalysis with 18-crown-6(Ref.43)or qua-

ternary ammonium salts (Ref.44)according to scheme46.R-O-C-CI+ NaCN \177' R-O-C-CN+ NaCI

II or KCN PhasetransferII or KCIO catalysis O

Sideproduct : RO-C-ORII

OScheme46:Preparation of cyanofom\177ate esters from chloroformates.

Although convenient for the preparation of small quan-tities of cyanoformate esterssuch as ethyl cyanoformate,we found the method to be unsatisfactory for the produc-tion on a larger scalebecauseof the formation of carbo-nate estersreducing the yield.

In the courseof our studies devoted to the scaling upof ethyl cyanoformate preparation, we noticed that the

sidereaction is strongly related to the nucleophilicity of the

cyanide anion which dependson the structure of the coun-ter cation of the catalyst. Ouitegoodresults can beachieved

by a proper choiceof the catalyst as depicted in scheme47.

CH2CI2/ H20EtO-C-CI+ NaCN

HM='CIG

EtO--C-CN + NaCIII Catalyst: IIO T:< 20\302\260C

Obp. : 35\302\260C / 30mm

Sidereactio\177n : Yield 83-6%distilled

Q+CI+ NaCN Q+CN-+ NaCI

EtO--C-CN + Q+CN- \177.__ NC-C-CN + EtO-Q\321\207

O O

EtOQ+ + EtO-C-CN\177 EtO-C-OEt+ Q+CN-II II

O O

Diethyl carbonate formed : with HMGCI : < 1%with HBGCI : 10%

Scheme47.Improved preparation of ethyl cyanoformate.

46 47)))

Phosgeneand derivativesas buildingblocks Phosgeneand derivativesas buildin\177 blocks

Ethyl cyanoformate is an effectivedipolarophile under-

going 1,3-dipolaraddition to azides,for examplewith ethyl

azidoacetate to afford tetrazoleaceticacid derivatives(Ref.45).Tetrazoleaceticacid is a key starting material for

the preparation of pharmaceuticals such as the antibiotic<< Cefazolin >> [Scheme48].

The chemistry of cyanoformate esters has been the

subject of a recentreview (Ref. 46).

110\302\260c COOEtEtO-C-CN+ EtO-CCH2N3\177N\177

II II 98%I<1.- a

,N-CH2COOEtO O

1 N HCI N\177IN -CH2COOH\177

N..-65% N

N\177

\177.--

,N-CH2-C-NH Na\177 \"\177[\177..,,,

Sh I\1771\177oa3

\"Cefazolin\"

O/j-\177

\177CH2S\177\" S

COOHScheme 48 .' Preparation and use of tetrazoleacetic acid starting from ethylcyanoformate.

3-\177-\177

Reactionof

phosgenealoxygen \177enter

of unconventional

substrates

Reactionof phosgene

with \177lycerol

The reaction of large excessphosgenewith glyceroldoesnot afford the correspondingtrischloroformate but amonochloroformate bearing a five membered cyclic carbo-nate function (2-oxo-l,3-dioxolan-4-ylmethyl chloroformate

(I) as shown on scheme49.The correspondingalcohol(11)

can be easily obtained through transesterification between

glycerol and diethyl carbonateunder basicconditions.

OH

OH OH

OCOCI

ExcessCOCi2 \177\" CICOO OCOCI

/\177/--

OCOCI

(i)

OyO Quantitative

OHO

yield

/\177--(11)

Et2CO3-2 EtOHBasiccatalyst

\177- 0 0y bp. 160\302\260C / 0.8mm

OScheme 49:Preparation of chloroformate-carbonate through phosgenation of

glycerol,

The chloroformate (I) and the corresponding alcohol (11)are very interesting intermediates for numerous applications :-

Blowing agents adaptedto the production of cellulated

or expandedpolymers (Ref. 47),for example by reaction

of (11)with maleic anhydride [Scheme.50].

O-C

o,;,, '--<\302\260\302\260\302\260\"

OyU+ \177

OyO mp. 112-4\302\260C

O O O Dec.' 150<'C(pure)112'\177C (with1%aazco3)

Scheme50:Preparation of a foaming agent for expanded polymers.

- Leavening systems for preparing baked goodsto

supply carbon dioxide required (Ref.48).- Extractants for metals.For example,compounds obtained through reaction of

chloroformate (I) with trimethylol propaneand with poly-

ethylene glycol are highly effective chelating agents sui-

table in hydro-metallurgy to recovervaluable metals ions

from aqueoussolutions (Ref.49) [Scheme51].48 49)))

Phosgeneandderivativesas buildingblocks Phosgeneand derivativesas buildin\177 blocks

/\177--ococI

EtC(CH2OH)3 + Pyridine

oyO(I)Acetone

O88% Yieldmp, : 120\302\260C

\302\260

o oEt

\177_.\177 o--LL- O\320\205

o\"j\" o o-\177 o

0%

HO(CH2CH20)n-H + 2CH2Cl2 o.,.[r-

83% yield ox[i/OO Mn =900 OSoluble in toluene

Scheme51:Cyclic carbonates suitable for the extraction of metals from aqueoussolutions.

-- Paint powders for automotive, for example the reaction pro-duct of methacryloyl chloride and the alcohol (11)(Ref. _50).

-Ultraviolet-curableacrylic resins.The reaction of chloroformate (I) with acrylic acid fol-

lowed by the decarboxylation of the unstable mixed car-boxylic-carbonic anhydride formed, gives the 2-oxo-l,3-dioxolan-4-yl methyl acrylate in good yield (Ref. _51 ). Thereaction of (I) with 2-hydroxyethyl acrylate in the presenceof a baseaffords a new acrylic monomer, SNPEcodenum-

ber CL1042,in excellentyield (Ref. 51) [Scheme52].

00001// _Et3\"o

\302\260

\302\260 72 Ojo Yield

O,\177]/O\177Pyridine

0,.\1770 0II CL10420 93% Yield

mp, 42\302\2600

Scheme 52:Preparotion of UV-curable monomers from glycerol chloroformote-carbonate.

The study of light-induced polymerization of the new

compounds, especiallyCL 1042,demonstrated the out-

standing reactivity of acrylic monomers containing five

membered cyclic carbonatefunction (Ref. _52). Photopo-lymerization even occurswithout any addedphotoinitiator.

Thesenew monomers combine high reactivity and

intensive cure to give hard but still flexiblematerials.CL1042was used in _50% amount as reactive diluent in

formulation with polyurethane oligomers bearing pendant

acrylate groups (Ref. _53).CL1042was alsoemployed to

synthesize copolymerswith pendant cyclic carbonategroups.Their chemical modification by ring openingreaction provided a convenient method for preparing func-

tional polymers (Ref. 54),as shown on scheme_53 :

--CH2-ca--

o

--CH2CH--o

60\302\260C

Scheme53:Chemical modification of copolfmers containing pendant cfclic car-bonate functions.

Reaction ofphosgenewith

epoxides

The reaction of phosgenewith an epoxidecatalyzed by

pyridine to afford \177-chloro chloroformates is well known

(Ref. 5.5).Unfortunately, this reaction often leadsto non

regio-specificring opening of the epoxidesand producesbis-\177-chlorocarbonates as sideproducts in yield up to20-30% [Scheme54].

50 51)))

Phosgeneand derivativesasbuildinblocks

PyridineR CI R

o..r_+o

Cl Cl

O (A) (B) + [:\177-chloro

carbonate.,

Scheme 54 .\" General react/on of epoxides with phosgene.

When the reactionsof monoalkyl epoxideswith phos-genewere conducted,within 2-6 h, using HBGCIor silica-

supported guanidinium chloride as catalyst, neat or in

toluene solution, the results are strikingly different. Thering opening reaction gave single products with C-CIbond

formation at the carbon that lacks the substituent. I'lore-over, the reaction did not produceany of the symmetricalcarbonate.The \177}-chloro chloroformate (A) (seescheme_54)are thus isolated in nearly quantitative yields (Ref. _56).

For example, the phosgenation of n-butylglycidylether in toluene, in presenceof 0._5 tool.%HBGCI,at 30\302\260C

within 2 h, gave the corresponding 1-chloromethyl-2-n.butoxy ethyl chloroformate in 96% yield. This chloro-formate is the key starting material for the preparation ofan intermediate carbamateused in the (( Febarbamate \177

manufacture as shown in scheme5_5.

n.BuO Toluene

n.BuO\177_--/+ 00012 \177' OCOCI

Cat. : HBGCIO 2 H -50\302\260C

CI--'96%Yield

NH 3 / H20 n.BuO--\177\177 )__O.C_NH 2

90%Yield

Cl\177/ II rap, 35.3\302\260C ( hexane )0OCONH 2

I

'\"\"'\"\"-- Oin. Bu

o\" eL...4 NHE

\" Febarbamate \"

( Tranquilizer )

Scheme55:Preparation of intermediate carbamate for a pharmaceutical manu-

facture.

Phosgeneandderivativesas buildinblockst/

In another example, 1-chloromethyl-2-chloroethylchloroformate was easily preparedby catalyzed addition of

phosgeneto epichlorhydrin using the sameprocedure.This

chloroformate is an useful intermediate for a simplepreparative route to new fluoroisopropenyl carbamates

(Ref. 57) depictedin scheme_56 :

k_7,.,/'--CI CI

\"--k.)_+ COCI2 \177 O-C-el95% YieldO Cat. : HBGCI Ci.--/ II distilled

O bp. : 93\302\260C / 20mm

R1

C'---xkr__

R\\ Base

C,\177_._ IIN\177/R2

O-C-Cl4 NH \177 O-Cc\177 II R 2\"

ClO O

R 1

Bu4N, 3eq.

F\177_ \177I.N/R2\177_

O- 72% yield with :THF R1 = i Pr ; R

2 =cyclohexylO65\"C,8h

\177ctyenye 56: New isopropenyl carbamates from phosgene and epichlorhydrine,

Reaclion ofphosgenewith

aldehydesandketones:novel

\177\321\236 chlorinatedchloroformates

and relatedreagents

Photochlorination of alkyl chloroformates, generally

limited to the caseof methyl chloroformate and ethyl

chloroformate, was the only method for the preparation of

1-chloroalkyl chloroformates before the work done at

SNPE [Scheme57].

CICI2,UV

RCH2-O-C-CI \177 RCH- O-C-CIII

- HO II

O CI OCI2,UV

Et2CO \177

\177- CH3CH-O--C-OEt-HO II

O

+ large amounts of

other (poly)chlorinated

compounds

Scheme57 .\" Photochlorination of alkyl chloroformates and diethyl carbonate.

This method useful for chloromethyl chloroformate

synthesis gives poor yields and bad quality in the caseof

52 53)))

Phosgeneand derivalivesasbuildingblocks Phosgeneandderivalivesas buildingblocks

1-chloroethyl chloroformate, and completely fails with

higher chloroformates, becauseof the lack of selectivity ofthe radical chlorination.

Eighteen years ago, in the course of unsuccessful

attempts to preparevinyl chloroformate by phosgenationof aldehydes in presenceof tertiary amines, especiallypyri-

dine, we discovereda new route to e\177-chloroalkyl chloro-formate (Ref.58)as presentedin scheme58:

7\177H2C\177

CH-O--\177

-CI

OCHoClo/

CH3CHO+ OOOI2 + Pyridine \177( Catalytic \177 CIamount) \"\177 I

CH3-CH-O-C-CI63% II

OScheme 58:Theorigin of the discovery of the new u-chlorinated chloroformatesroute.

The value of this new route immediately was recogni-zed because1-chloroethyl ethyl carbonatewhich could beobtained from 1-chloroethyl chloroformate and ethanol

already was on the market as an alkylating agent to preparethe orally active antibiotic {{ Bacampicillin \177.

Not long after, together with OIofsonand coworkersat

Penn State University, we found that aldehydesare readi-ly converted to 1-chloroalkyl chloroformates when treatedwith phosgenein the presenceof a \177{ naked Cl\" \177 catalyst

(Ref.5).The reaction has beenfound to proceedcleanly in

good to excellentyields and to be quite general with

almost all aldehydes, but not with most ketones (Ref.59).Ona laboratory scale,oneof the favored catalyst is the

benzyl tri-n-butyl ammonium chloride (BTBAC).The most

important reagent, (z-chloroethyl chloroformate(\177

ACE-Cl\177),

typically is isolatedin 96% yield by stirring acetaldehydewith phosgene(1.1eq.)neat for an hour in the presenceof 3 mol. % BTBAC.Even chloromethyl chloroformate canbe prepared using this process,but it is essential tointroduce the monomeric gaseousformaldehyde into the

reactoralready containing the catalyst and phosgene,sothat formaldehyde reacts immediately, thus avoiding its

repolymerisation (Ref. 60).However, in this last case,wefound the procedure difficult to scale up, becauseoftechnical problems of formaldehyde polymerization. Note

that the reaction doesnot work with the polymeric forms

of formaldehyde, either trioxane or paraformaldehyde..Someresults aregathered in table 3-4(Ref.5, 58,60).

R

H

Me

Me

Et

CI3Ci-Pr

CH2 = CH

Cyclohexyl

Phenyl

Catalyst Yield Boiling point

(mol. %/aldehyde) % \302\260C/mm

BTBAC(1.8) 42 (a) 106/760BTBAC(3.0) 96 77/180

18-Crown-6(5.7) 78 117/760KCI (35.2)

BTBAC(9.0) 89 62-3/52BTBAC(10.7) 65 75-9/19BTBAC(12.5) 87 58-9/28Pyridine (10) 54 38/10Pyridine (10) 87 90-3/10

BTAC(10.3) 87 81-3/1

Pyridine (10) 68 70/0.4

(a)With respect to the phosgene used

CatalystR-CHO + COCI2

CI

R-CH-O-C-CIII

O

Table3-4:Preparation of some l-chloroalkyl chloroformates.

The yields and recoveriespresentedin this table arethosefor isolatedmaterials (purity > 99%).

Phosgenecan be replacedwith either diphosgeneor

triphosgene in the same conditions to give the correspon-ding 1-alkyl chloroformates in very goodyields (Ref.61).

54 55)))

Phosgene

and derivalivesasbuildingblocks

For safety reasons,becausea possiblereversibility ofthe reaction between phosgeneand aldehydes wassuspected,we thoroughly studied the thermal stability of1-chloroalkyl chloroformates.This stability greatly dependson the structure of the R radical.Simple alkyl compoundsare much more stable than the aralkyl compounds which

begin to decomposeat 60\302\260 C or below.It is important tonote that the only products of thermal decompositionarethe derived 1,1-dichloridesand carbon dioxide [Scheme59].In contrast, the chloroformate from chloral reverts

easily to the aldehyde and phosgenewhen heated.This

decompositionis catalyzed by \177 naked Cl-\177 and particular

precaution must be taken in the handling of tetrahaloethylchloroformates, and more generally in the caseof 1-chlo-roalkyl chloroformates containing strong electron with-

drawing groups (with regard to the mechanism of the

decomposition,seefarther on in this section).

CII Heating

CH3CH-O-C-CI -\177 CH3CHCI2 + CO2II T>> 100\302\260C

O

\177\177Heating

\177CH-O-C-CI \177- CHCI2 \321\207 CO2\177I II T

>\17760\302\260C

CI 0CI

I Heating

CI3C-CH-O-C-CI \177 CI3C-CHO+ COOl2II or Q\321\207 crO

Schema 59 .\" Thermal stability of l-chloroalkyl chloroformates.

1-Chloroalkyl chloroformates like conventional chloro-formates reacteasily with alcohols,either in the presenceof baseor simply by heating to give the expected1-chloralkyl carbonates.1-Chloroalkylchloroformatesreactalsowith phenols, but only in presenceof a base toafford 1-chloroalkyl aryl carbonates.

1-Chloroethyl ethyl carbonateitself was first preparedby M\177iller by heating ethanol with 1-chloroethyl chlorofor-

56

Phosgeneand derivalivesas buildingblocksII

mate previously prepared through chlorination of ethyl

chloroformate in direct sunlight (Ref.62).The addition of 1-chloroalkyl chloroformates to alco-

hols or phenols is a quite general method and gives goodto excellentyields.5omeexamplesaregiven in table 3-5.

R R1 Method

H Et Pyridine

Yield bp. \302\260C/mm Ref.

(%) mp. \302\260C

76 bp.53/14 63

Me Et Pyridine

He Et Heating (70\302\260C)

He i-Pr Pyridine

He t-Bu Pyridine

He Cyclohexyl Heating

He Benzyl Pyridine

Heo\177CH2 - Pyridine

Me Phenyl Pyridine

\1770Me

Me PyridineMe

Cl3C t-Bu Pyridineo

Cl3C\177,_

Triethylamine

o

97 bp.67/22 6480 bp. 160/760 562 bp.57-9/10 6590 bp.88/20 6477 bp. 77/1 5NPE

94 bp. 100/0.564

88 bp.95/0.2 64

94 bp. 117/0.564

98 rap. 98-100 64

87 mp. 68-70 66

83 rap. 108\302\260C 67

CI Base (pyridine) CII or heating I

R-CH-O-(\177-CI+ R1-OH - HCI

\177-

R-CH-O-(\177-O-R1

O O

Table 3-5:Preparation of l-chloroMkyl carbonates.

The useof a trialkyl amine, for example triethyl amine,as a scavengeris not recommendedbecause1-chloroalkylchloroformates reactvery easily with tertiary alkyl amines

to afford N,N-disubsituted carbamates(Ref.68)as discus-sedin section3-3.

Although pyridine appearsas oneof the bestscavengersin the processusing a base,any excessmust be avoided

57)))

/

Phosgenes buildinblocks

,\177ecause of the formation of a quaternary ammonium saltas depictedon scheme60:

O. OEt

\302\251o

Scheme 60 .\" Ouaternary ammonium salt from pyridine and 1-choroethyl ethylcarbonate.

In the courseof our work devoted to the developmentof an industrial processto manufacture ton lots of 1-chlo-roethyI ethyl carbonate,we studied the main sidereactionwhich is the transesterification of the desiredproduct withethanol [Scheme61].

CH3-CH-O-\177-O-EI+ El-OH \177.\177. EI2CO3 + CH3CHO+ HCI

OAldo sation,

2 CH3CHO dehydration\177- CH3ICH\177CH.CHO

\177_- H20 _ H20CH3-(CH\177CH-)n-CHO \177. max absorption increaseswith n

Scheme 61:Main side reactions in the preparation of l-chloroethyl ethyl carbonate.

Experimentally, the rate of formation of diethyl carbo-nate was found to be proportional to the concentration ofboth 1-chloroethyl ethyl carbonateand ethanol, so thatthe reaction rate may be expressedin term of followingequation with an assumedfirst orderwith respectto bothreactants :

d [EtOH]/dt= k [EtOH][MeCHCIOCOOEt]At

75\302\260C, the k value was determined at 7.2x 10-`5tool.-1.i.min-1.The heat of activation was calculatedat 25 kcal.mol.-1.

In the past 2_5 years,there have beennumerous publi-cations and patents claiming applications of 1-haloalkylcarbonatesto mask acid or hydroxy functions of certaintypes of active compoundssuch as parmaceuticalsorpesticidesaccordingto the scheme62.

58

Phosgeneand derivalivesas buildinblocks

xI Base

\177)--OH + R-CHO-C-OR1

II Ro I

X = CI Br, I (\177\177O-CH-O'C-OR\177\342\200\242

IIA.I.= Active ingredient OScheme 62 .'Modification of-OH functions (from carboxylic acids or phenols)using (z-chloroalkyl carbonates.

This kind of application was initially developedto produceBacampicillin, a prodrug from Ampicillin [Scheme63].

\177OH2 H S Me

N

\177N \177-\177'Me Oo

OMe\177--

O Et

Scheme 63 .Semi-synthetic antibiotic , Bocampicillin , from Ampicilhn andl-iodoethyl ethyl carbonate.

Current penicillins or cephalosporins clinically used for

injection are not suitable for oral administration becauseoftheir low absorption from the gastro-intestinal tract. The pro-drug approach by chemical modification into bio-labile deriva-tives with improved physicochemical properties (i.e.lipophilici-

ty) that enablesbetter transport through biological barriers, isa powerful mean for improving drug delivery. The successofsuch approach requires a latentiating group stable in both gas-tric acidic and basicintestinal conditions, and easily removable

by enzymatic hydrolysis. The modification of carboxylic acidfunction or phenolic function by the alkyloxycarbonyloxyalkylestergroup is especially suitable as shown in scheme64.

Drug--C-OH+II0

Drug delivery

R ChemicalR

I modificationIX-CH-O-C-OR1

\177 Drug--C-O-CH-O-C-OR1

II- HX II IIO O O

Drug--C-OH+ R-CHO + F\177-OH + CO2Esterase II

OScheme 54.'Theprodrug concept apphed to drug with a carboxyh'c function.

59)))

Phosgeneand derivalivesas buildin\177 blocks

Tomeet all requirements needed,it is possibleto selectthe radicalsR and R1,for example :

R = H or methylR1 = Et, isopropyl, cyclohe\320\247yl, even sugar derivatives

(seefarther on in this section).

BesidesAmpicillin, 1-chloroalkyl alkyl carbonatesand

particularly 1-chloroethyl ethyl carbonate(CEEC),1-chlo-roethyl isopropyl carbonate (CEIC), 1-chloroethyl cyclo-hexyl carbonate(CECC)and chloromethyl ethyl carbonate(CEMC), have been proposedto modify numerous com-pounds. Among the many types of prodrugs patentedwhich require this method, there are examplesof :- Antibiotics such as CefpodoximeProxetil from Sankyo

Co.,Ltd.(Ref.69),Cefotiam Hexetil from Takeda Chem.Indust., Ltd (Ref. TO,71)- Antiflammatories and analgesicssuch as Ampiroxicamfrom Pfizer and Toyama Chem. Co.(Ref. 65,72)or aderivative of Diflunisal (Ref. 73)-Antihypertensives, for example TCV 116from TakedaChem. Indust., Ltd (Ref. 74)- Herbicides(Ref. 75).

Some structures of these pro-active ingredients aregiven in scheme65.

Phosgeneand derivalivesas buildin\177 blocks

N,OMeI

H HN=\177

S/\"\177NNr--\177S\"h \177N\177s\\Nxx/N\177x Meo

0Me

\177J\" 0 \177j\177 0\"\1771\"

Me Me\177\" 0\177 0\177j\177j

CEFPODOXIME PROXETIL (CS-807} CEFOTIAM HEXETIL (SCE-2174)

/\177 .S,N

MeH

Me,\177O0 N,\177

J F

O\177M\177)_..0\177._

(\177Et0\1771\177

O-Et 00

DIFLUNISAL Der\177vatwe

AMPIRQXlCAM

Scheme65,\" Examples ofProdrugs from 1-chloroalkyl alkyl carbonates.

Chemical modification of agrochemicals, to improvetheir pesticidal propertiesand to reduce toxicity toward

nontarget organisms, has been the object of intensiveresearchin both academiaand industry, especiallyin thefield of insecticides(Ref. 76).For example, \177 Carbosulfan \177

is a very active systemic herbicide derived from \177 Carbo-furan \177 and much lesstoxic for mammalians than its parentcompound.

In order to improve transport through biologicalbarriers of the plants, we thought that the chemical modi-fication of known pesticideswith 1-chloroalkyl alkyl carbo-nates containing sugar or glycerol moiety should be ofsomeinterest. For this purpose\177 we synthesized at labora-tory scaleseveral new o\177-chlorinated carbonates(Ref. 77).The products preparedand results obtained are depictedon scheme66.

6061)))

Phosgeneand derivativesas buildingblocks

CH2CI2 , Pyridine

Diacetone-D-Glucose

O-C-CIII

0 93%

OOyO

bp :Dec. O

\177--\177

0,)\177_

Cl T \1770\177

CH2012,Pyri dine pO

O\177\177oO\177\"

99.7% \177Scheme 55:Some new 1-chloroolkyl alkyl carbonates, useful starting moteriolsfor the preporotion of prodrugs end propesticides.

The 1-Chloroalkyl carbonate(11),obtained through thereaction of 1-chloroalkyl chloroformate with glycerol car-bonate was used for the preparation of a proherbicidederived from .Acifluorfen \177 (Ref. 77) [Seescheme67].

CI

__\177\1771)DMF / Nail

F3C O NO2 \177,.

COOH 2)(11),\177:Nal

CI

F3C--\177O-\177NO20920/0/\177--0,>q f\"\" 0

o\302\260

Scheme 57 .\" Proherbic/de from Acifluorfen.

62

Phosgeneand derivativesas\177

buildingblocks

1

Sincein terms of leaving group ability in SN 2 reactionsI > Br > Cl, oeiodoalkyl alkyl carbonatesare the reagents ofchoicefor the chemical modification of either carboxylicacid or phenolic functions. However, these o(-iodocarbo-nates exhibit severeinstability (Ref. 78) and are generallypreparedin-situ or just beforeuse(Ref. 79,80,81).

Thus, researchefforts in different industrial laborato-ries have been directedtoward the preparation of 1-bro-moalkyl alkyl carbonatesassumed to be more stable thanthe 1-iododerivatives, and more reactive than the parentchloro compounds.For example, 1-bromoethyl ethyl car-bonatewas made by the halide exchangeof 1-chloroethylethyl carbonatewith LiBr or NaBr, or by a radical type bro-mination of diethyl carbonate(Ref. 82).However, in thecaseof halide exchange,the conversion is low and a mix-ture results. Even with a large excessof bromide salt, thisproblem remains. Radical bromination was found to giveunsatisfactory results for the samereasonsthan the chlo-rination, and failed in the caseof unsymmetrical dialkyl car-bonatesbecauseof its non-regioselectivity.

We reporteda new method consisting of using a vola-tile bromine containing reagent (E-Br), especiallyHBr, anda catalyst to accomplish the exchange(Ref. 83,84).Theequilibrium is driven to the desiredproduct by removal ofthe more volatile E-Cl formed as shown in table 3-6.Thistable gathers someresults thus obtained.

1-Bromoethyl phenyl carbonate(bp.72-7 \302\260C/0.4 ram)was preparedin 91%yield from THS-Brand 1-chloroethylphenyl carbonateusing this technic.

It should be noted that 1-bromoalkyl carbonatescanbe alsoeasily obtained through HBr addition to the doublebond of vinyl alkyl or vinyl aryl carbonates(Ref. 8.5)Thisprocesswill be describedin section3-2-2-4devoted tovinylic chloroformates and derivatives.

63)))

Phosgeneand derivativesas buildin\177 blocks

R1 Catalyst Temp. Time Yield bp.Eq. \302\260C Hours % \302\260C/mm

Me Et none 80 1

Pie Et HgBr2 65 24 80 0210/18'

0.038Me iipr TBAB(a) 85 6 82 B0-3/18

0.014n-Bu He BTBAC(b) 85 7 69 60-2/2

0.019HBr was added continuously by bubbling the anhydrous gas into the medium

(a)TBAB : tetra n-butyl ammonium bromide

(b)BTBAC : benzyl tri-n-butyl ammonium chloride

CI BrI I

RCH-O-(\177-O-R1 + HBr \177\177

RCH-O-(\177-O-R1 + HCI

O O

Table 36:Preparation of some l-bromoalkyl alkyl carbonates.

In orderto complement the usual 1-chloroalkyl carbo-nates synthesis, we decidedto find a new route to a broa-der classof these compounds.More particularly, we tried

to openaccessto carbonatesin which the alcohol(R1-OH)doesn'texist and to the previously unknown 1-fluoro-alkylcarbonates.

Our efforts succeededin the discovery of a different

method of preparation based on the reaction of an alde-hyde with a halogenoformate in presenceof a catalyst

(Ref.86,87), as depictedin scheme68.

Catalyst X

6o- 10ooc I

R-CHO + R1-O-C-X \177\" R-CH-O-C-OR1

II 32-90% II0 0x = F, Cl, Br, I

Scheme68:New route to l-haloalkyl carbonates.

Phosgeneand derivativesas buildin\177 blocks

Besidesthe synthesis of 1-chloroalkyl carbonates,this

method is general enough to be used for the preparationof 1-fluoroalkyl, 1-bromoalkyl or 1-iodoalkylcarbonatesasshown in table 3-7. However, the method gives poorresults or even failed when the haloformate is too unstable

in presence of the catalyst (see section 3-2-1).For

example, attempts to prepare1-chloroethyl ethyl carbonate(CEEC)itself in 1,2dichloroethaneat 60\302\260C with 0.05equ.pyridine, gave almost total decompositionof ethyl chloro-formate.

R R1

CH3 Ph

CH3 CHCI-CH3

CH3 CH=CCI2

CH3 Ph

CH3 Ph

X Catalyst Temp. Time Yield bp \302\260C/Torr

\302\260C Hours % mp [\302\260C]

CI Pyridine 80 5 71 67-8/0.15CI Pyridine 60 4 49 67-72/9CI Pyridine 80 1.5 83 44-5/0.1Br Pyridine 83 1 82 74-9/0.03

I Pyridine 70 1.5 80 93-7/0.45[.59-61]

CI Pyridine 80 5 76 60-1/11CI Pyridine 80 4 88 90-5/0.05

F DHAP 82 24 32 82-6/0.03F KF/ 65 2 76 82-5/2.5

18-C-6F KF/

18-C-6CI Pyridine

CCI3 CH2CI

CCI3 CHCI-CCI3

CCI3 Ph

H (CH2)7CH3

ICCI3 Et

Ph C(CH3)=CH2

65 20 72 77-8/5

83 20 67 92-6/0.2

Table 3-7:Preparation of 1-haloalkyl carbonates.

None of the catalysts tested : quaternary ammonium

salts, N,N-dimethylamino pyridine (DHAP), 1-methyl imi-

dazole, tertiary amines, Michler's ketone, quinoline etc.performed as well as pyridine. For the preparation of1-fluoroalkyl carbonate, the best catalytic system found

was the KF/18-crown-6complex.To avoid sidereactions,only aldehydes without hydrogen at 02should be used in

this case.

64 65)))

Phosgeneandderivativesas buildin\177 blocks Phosgeneand derivativesas buildin\177 blocks

Fluoroformates (Ref. 88) and phenyl iodoformate

(Ref. 89)usedherewere preparedaccordingto literature

procedure (see also farther on in this section).The

preparation of isopropenyl chloroformate,as well as2,2-dichlorovinyl chloroformate will be presented in

section3-2-2-4.At the beginning of our work devotedto new potential

applications of 1-chloroalkyl chloroformates and 1-chlo-roalkyl carbonates,available literature data as well as our

preliminary experiments indicated strong variations in the

products distribution resulting from nucleophilic attacks.Scheme69gives someexamplesdemonstrating that the

types of obtained products strongly dependon the nature

of reactant.

EtO-\177-O-CH-CH3

o

EtO-C-FII Ethyl fluoroformateo

I

I

EtO--C-O-CH-CH3II

O 1-Iodoethyl ethyl carbonate

,R1

CIR1R\177

RO-C-NI

II 'R20RO-C-O-CH-CH3 _ Base O

II

O-C-R1

RO -C-O-CH-CH3IIo

Cl oCH3-CH-O-C-CI \177 CH3-CHCI2

CI OI II a+

C\177-

CI3C-CH-O-C-Cl \177, CI3C-CHO+ COCl2

Scheme 69:Examples of variations ofnucleophilic attacks pathways to 1-chlo-

roalkyl chloroformates and carbonates.

In fact, 1-chloroalkyl chloroformates and derivatives

posea very interesting mechanistic problem, since they

present two reactive electrophilic centerswhich may be

66

attacked by nucleophiles following three different path-ways as shown in schemeTO:

A1I A\177 O

Nu-C-Z + R-CliO+ C[

R--CH-O--C--Z \177

II

R-CH-O-C-ZI

NuO

II

R-CH-O-C-NuI

Cl

+ Cl-

+z

Scheme 70:Possible types of nucleophilic attacks to 1-chloroalkyl-oxycarbonylderivatives.

Researchin our laboratoriesover the last fifteen yearshas beendirectedto understanding the mechanisms which

are operative in nucleophilic attacks of 1-chloroalkyloxy-

carbonyl compounds, in orderto be able to further predictnew potential reactionsas well as to improve existingmethods.

The reactionsfactorsassumed to affect the productsdistribution and the kinetics of the reactions are thefollowing :-

Strength of nucleophilicity of the nucleophile.-Strength of electrophilicity of centerA and B.-Nucleofugacities of 1-chloroalkoxide anions and Z anions.-Solvent and temperature effects.-Stericeffects.Our approachwas outlined in the framework of the

Hard-Soft Acid-Basetheory (HSAB, Ref. 90).In a short

definition, the HSAB theory states that hard nucleophilesprefer to react with hard electrophilesand soft nucleo-philes prefer to reactwith soft electrophiles.

There are two electrophiliccentersin the 1-chloroalky-Ioxycarbonyl derivatives (designatedA and B in scheme70).Center B is a carbon sp3

hybridized and is softerthan

the carbonyl group, centerA.

Thefactors that influence the degreeof hardness work

67)))

Phosgeneand derivalivesas buildin\177 blocks Phosgeneandderivalivesas buildin\177 blocks

for both centersA and B in the same way. That is electronwithdrawing groups (in R or Z) increasethe hardness ofboth centers:-\177 In term of the R group

The following orderof hardness is proposedfor centersA and B :

R = CCI3> Aryl > Alkyl > H

Note that is also the same order for nudeofugacity

(leaving group capability) in a A1,2type reaction\177 In term of the Z group

Electron withdrawing groups in the R radical will makecentersA and B both harder. Theorderchosenin our work

was based on the Infra-Red carbonyl stretch. Assumingthat electronwithdrawing Z groups will give a higher C=Ostretch, we establishedthe order of decreasinghardnesspresentedin table3-8.

O R \177

IIOAr -NI \177 OR 1 SAr N'

-P(OR1)2 'R 2

C=Ostretch 1840 1780 1780 1775 1765 1745 1740 1729

Cl OI II

R-CH-O-C-Z R =Alkyl

Table3-8.Decreasing hardness order of centers A and Basa function ofZ group.

The nucleophiles we studied can be placedin one ofthree categories:-\177 Hard \177 nucleophiles :F-, R-COOH,ROH,R1R2NH, -OCN.-

\177 Borderline \177 nucleophiles :ArO-, ArNH2, Imidazole, Br-, CI-.-\177 Soft \177 nucleophiles :I-, -SCN,RS-, ArS-, (R10)R2p(=x)s-,(RO)3P,CN-.

The reaction.s of 1-chloroalkyl chloroformates with

amines, as well as further reactionsof the resulting pro-ducts arenot dicussedhere in this sectionand are reservedfor section3-3.

One of the first representative reaction with hard

nucleophileswe developedwas the reaction of 1-chloroal-kyl carbonateswith fluorides anion. This reaction proceedsthrough A1 attack mechanism, which is in accordto the

HSAB theory, thus converting 1-chloroalkyl carbonatestofluoroformates in goodyields (Ref.91).

In the preferredliterature, most fluoroformates areprepared from their analogous chloroformates through

halogen exchangeusing excessKF activated by a little 18-Crown-6.However, this method proved to be impracticalfor tertiary alkyl fluoroformates and/or benzyl fluorofor-

mates, either because the corresponding chloroformates

are not stableor becauseof the lack of selectivity of the

fluoride attack. Acylation of the respectivealcoholswith

COF2 or COFClrequires complexequipment not accessibleto standard laboratoriesand/or multipurpose plants.

When the easily available 1-chloroethyl carbonates(RCHCI-OCO2R1; R = CH3)areheated,neat or in solution

(benzonitrileor diglyme) with KF in the presenceof18-Crown-6,they fragment to aldehydes and fluoro-formates in goodto excellentyields (Ref.92)as shown in

table 3-9.

R1 Catalyst Solvent Temp/press Time Yield bp

(18-06) \302\260C/mm h % \302\260C/ram

mole/% [rap. \302\260C]

t- Butyl 6 None 70/37 30 84 40-2/175t. Amyl 5 None 70/14 34 83 35-6/361-Adamantyl 4 None 120/1.236 76 [30-2]Benzyl 5 None 55/1.2 4 60 44-6/1Cholesteryl 9 Ph-CN 40/3 31 82 [114-7]Phenyl 5 None 75/20 1.5 70 60-3/20

.ClO

CH3-CH-'O=\177-OR\177+/...

KF \177R1-O-\177-F

+ CH3\"CHO+ KCI

0

Table 3-9.'Fluoroformates prepared from 1-chloroethyl carbonates.

68 69)))

Phosgeneand derivativesas buildin\177 blocks Phosgeneandderivativesas buildin\177 blocks

It should be noted that this new methodology exempli-fies an unusual conversion of an ester to an acid halide.

Becausethe radical R = CCl3 inductively increasesthe

hardness of the electropholiccenterA and makes 1,2,2,2-tetrachloroethoxideanion a better leaving group than

1-chloroethoxide,1,2,2,2-tetrachloroethyltert-butylcarbonate is a more reactive acylating agent than the

analogous carbonatefrom acetaldehyde(R = CH3)and

doesn'trequire a catalyst. Thus, heating 1,2,2,2-tetrachlo-

roethyl tert-butyl carbonateat 50\302\260C for 8 h with KF in the

polar solvent DMF under vacuum of 20 mm, with a simul-

taneous treatment of the distillate with ethylene glycol,

pure t.butyl fluoroformate (BOC-F)was isolated in

75-79%yield [.Scheme71].O CI 50\302\2600

II I20mm press.

t.Bu-O-O-O-OH-OCI3 + KF \177 t.Bu-O--O-F+ CI30-OHO-1.5eq. DMF II

Oca80%yield

Scheme 71 :Economics for commercial synthesis of 800-F:NO CATALYS\177

These results are of particular interest sincet. butyl

fluoroformate (BOC-F) has been highly recommendedby$chnabel (Ref. 93) and Carpino (94)as a substitute for

the expensive di-tert.butyl dicarbonatecalled(BOC)20.Indeed,BOC- F is an extremely cleanand efficient reagentfor the amino protection of amino-acids into BOC-AA.

However, the reagent is not stableenough to be ship-

pedsafely becauseit decomposesmore or lessrapidly into

isobutene, carbon dioxide and HF, thus developing auto-genous pressurein containers.This has led SNPE and its

subsidiary I.SOCHEHto manufacture and reactBOC-Fon

site, thus offering low costprotectedamino compounds.Furthermore, we succeededin the preparation of

FI\"IOC-F (c)-fluorenylmethyl fluoroformate) as a crystallinesolid (mp. 41

\302\260C).This reagent exhibits the samestability as

FI\"IOC-ONSu and can be easily shipped.Comparedwith

FHOC-ONSu,FHOC-Fgives similar to superior results in

the protection of amines in peptidessynthesis.

Fluoroformates offer alsosomedecisiveadvantages ascarboalkoxylating reagentsfor polar reactants.While chlo-roformates reactexplosively with DM50(Pummerer reac-tion) and exothermically with DMF (Vilsmeier-Haack reac-tion), Olofsonand coworkers (Ref. 9:5)have found that

fluoroformates are stable in this solvents below 100\302\260C.

.Severalimportant classesof hydroxyl and amino-contai-

ning compounds only soluble in polar solvents such asDP150and DP1F can be easily and efficiently carboalkoxy-lated with fluoroformates. For example,percarboethoxyla-tion of glucosewas readily achieved in good yield with

ethyl fluoroformate in DP150as shown in scheme72.

OH .OCO2Et

H OH \177

ETOCO2

OHIn DMSO EtOCO2---\177-\177\177 \177O.

CO2Et

KF,1 Oh, 60\"C UL'U21:[

I\177-D-GLUCOSE 89% yield

mp :100Scheme 72:Efficient synthesis of penta-O-(ethoxycarbonyl)-D-glucose.

Under selectedconditions, fluoroformates included

BOC-Freacteasily with products containing phenolic func-

tions to afford aromatic carbonatesin high yields. This

result proved to be suitable for the production of valuable

monomers used in resist materials for microelectronic.Recentprogresshas been made in microelectronic

devicefabrication, particularly in microlithography used tomanufacture the high-resolution circuit elementsof inte-

grated circuit (Ref. 96).Deep-UVphotolithography basedon chemically amplified resist is likely to be the first tech-nology that met the severeperformance criteria required.Thebestknown chemically amplified resist is basedon poly

(4-t-butoxycarbonyloxy styrene) or copolymers(Ref. c)7).As shown in scheme 73, irradiation of the resist

results in the decompositionof an addedphotoactive acid

generator(Crivello's salt) thus liberating a Br6nsted'sacid,which upon heating leadsto cleavageof the t-BOCprotec-ting group. The irradiated regionsaresoluble in basicwater

70 71)))

Phosgeneand derivativesas buildin\177 blocks Phosgeneand derivativesas buildin\177 blocks

and insoluble in organic solvents. Image development canbe achievedeither with aqueousbaseaffording a positive-tone image or with an organic solvent to give negative-tone

image.

Ph3S+ SbF6-

Photoactiveacid generator

O

av\177 Ph2S + H+SbF6

-

H+

Scheme 73 .'Photocatalyzed removal of the BOCprotecting group ofpoly (80C-oxystyrene).

The required monomer, 4-t-butoxycarbonyloxystyrene,is widely describedin the literature. Because4-hydroxy sty-rene is difficult to isolatedue to its rapid polymerization,

BOC-oxystyrene is generally preparedby treatment of 4-acetoxystyrene with strong basethus giving the correspon-ding phenoxide, immediately followed by addition of(BOC)20in THF solution (Ref. 98).

At SNPE Group, we developedprocessessuitable for

the manufacture of either BOC-oxystyrenefrom 4-ace-toxystyrene and BOC-For directly poly (BOC-oxystyrene)through reaction of BOC-Fwith poly (4-vinyl phenol),I'dARUKA Lyncur I'd from I'dARUZEN Petro-chemical Co.Ltd. As shown in scheme74, these processesare quite

simple and afford goodyields (Ref. c29).Researchersfrom Nippon Telegraph and Telephone

Corp.disclosedpositive-working resists developablewith

alkali aqueoussolutions, consisting of a novolak resin, an

acid-generating agent and 2,2-[p-(t-butoxycarbonyloxy)phenyl] propane(Ref. 100).In our laboratories, the latter

was readily prepared in good yield through reaction ofbisphenol A with BOC-F,using usual procedure.

O- -CH3 \177, O-t-BuOKO

K+

BOC-F BOC-oxystyreneRN :87188-51-080%overall yielddistilled

\"\177n

NaOH

Diglyme

+ BOC-Fin excess 25\177'C

OH

Mn = 1100-1500

bp. 90-3/ 0.06mm

'\177n

95%yield after

\177,

workup

0Scheme 74 :Preparation of 4-t-butoxycarbonyloxy styrene and its polymer usingBOE F.

Similar to the case of fluoride attack, the reaction ofthe soft nucleophile iodideanion with 1-chloroalkyl carbo-nates is in good accordancewith the HSAB theory. Thereaction proceedsselectively through B mechanism to give

1-iodoalkyl carbonates[Scheme75].Thepoorstability of such compounds has beenalready

mentioned in this section.Caubereand coworkers (Ref.78) reportedthat when 1-iodoethylalkyl carbonateswereheatedin toluene at 75-105

\302\260C, they decomposerapidelyto form the corresponding alkyl iodides.

II Acetone I II

R-CH-O-C-O-R\177 + Na+l-

\177 R-CH-O-C-O-R1 + NaCI\177 Toluene A

CI O

R-CH-O-C-CI+R1-OH+ Nal \177R 1 - OH = n-C12H25-OH \177

= 1-Adamantyl -\177= Ph-CH2CH2-OH \177

Scheme 75:New preparation of alkyl iodides.

R 1-1

81%\177

Isolated76 %

Iyields

81%

7273)))

Phosgeneand derivativesas buildingblocks

Becauseduring the reaction the authors observedthetransient back formation of the correspondingfreealcoholR1-OH,they demonstrated that the reaction can be pepformed one-potfrom 1-chloroethyl chloroformate, alcoholand Nal, thus discovering a new preparation of alkyliodidesas shown in scheme7.5.

Another example of soft nucleophile attack accordingto the HSAB theory was given by the reaction of thiocya-nate salts with 1-chloroethylcarbonates affording thecorresponding1-thiocyanoand/or1-isothiocyanoethylcarbonatesin goodyields (Ref.101).

Becauseof the interest of compounds containing bothcarbonateand isothiocyano groups in phytosanitary che-mistry, the mechanism of the reaction was thoroughly stu-died in order to understand the origin of the N-boundedcompounds (Ref.102).Someexamplesof the reaction aregiven in table 3-10.

R H SolventTime (I)+(II) (I)/ (II)/

h. % (I) +(11) (I)+ (11)

,'

Et K I\"leOH 23 58 1 0, Et NH4 I\"leO H 76 78 1 0

\177'

Et K HCONH2 4 76 0.83 0.17, Et NH4 HCONH2 4.75 86 0.85 0.15

,'

t-Bu NH4 HCONH2 17 89 0.79 0.21, n-CSH17 K PleOH 73 70 0.93 0.07\177 Ph NH4 HCONH2 72 51 1L 0I

ICI SCN N=C=S

I I SolventI CH3-CHO-F-OR+

4MSCN \177CH3_CHO_\177.OR+ CH3-C

HO-\177.OR' O R.T., (I) 0 (II) 0Table 3-10:Reaction of 1- chloroethyl carbonates with MSCN \177 protic solvent at 20\302\260C

From this study, the authors concludedthat most iso-thiocyanates (11)must be due to a N-condensation of thethiocyanate anion rather than an isomerization. Because-N=C=Sis harder nudeophile than \"SCN, attack of the iso-thiocyanate anion to the carbonyl will explain the observeddecomposition.

74

Phosgeneand derivativesasbuildingblocks

However, the authors discoveredthat in acetone,in thepresenceof Bu4PBr but in the absenceof alkali thiocya-nate, thiocyanates (I) were readily isomerized under mildconditions to the correspondingisothiocyanates(11)asshown in table 3-11.

R Time Yield, isolated (II)hours

Et 72 81t-Bu 13 81n-C8H17 26 56Ph-CH2 48 82

SCN N=C=SI Acetone

CH3-CHO-li\177-OR

\177-- CH3-CHO-li\177-ORBu4PBr

(I) 0 56 C (11) 0Table 3-11.\" Isomen\177ation of 1-thiocyanoethyl carbonates to 1-[\177othiocyanoethylcarbonates.

The authors proposedthe mechanism given in scheme76 (Ref. 101).

SCN

I tr N:C=S

I Bu4PBr

SH3-CH-O-C-OR

--\177,-ICH3-CH-O--\177-OF

\177CH3-CH-O-C-ORII

IIOL+ Bu\177PSCN

O

Scheme 76 .\" Proposed mechanism of 1-thiocyanoethyl carbonate \177omerization.

It could be suggestedthat the bromine atom wouldgive a more marked cationic like transition state.Thereforeaccording to the HSAB theory, the substrate would beattacked by the harder sideof thiocyanate anion.

As predicted,the soft nucleophile cyanide anion reactswith 1-chloroalkyl carbonates to afford 1-cyanoalkylcarbonates in good yields as shown with the exampledepictedin scheme77.

O KCN, 18-C-6 O\"

_\177Et20 ,I

_\177CICH2-O-C-O Me \177 N\177-C-CH2-O-C-O Me25\177'C, 4 days 90 %

Scheme 77:Example of 1-cyanoalkyl carbonate preparation.

75)))

_

tPhos\177ene

andderivativesas buildin\177 blocks|Scheme78 gives two examples[reactiona and c] of

the preparation of insecticidal phosphoricacidestersfromdialkyldithiophosphate anions and 1-chloroethyl ethyl car-bonate claimed in a patent (Ref. 103).

SII

(EtO)2-P-S-NH4*

CH3CN,70\302\260C, 7h\177-

\177 74%a

s.P(OEt)2 (a_)

CIS

(EtO)2-p.S- NH4+ O-C-OEt

/\177\" O-C-OEt-

\177 II78%

II \\ Nal, THF, reflux, 3 h O ( b )O

c\177.

PrS\177 \177.O % /SPrEtO/P'-.S_ H2Me2N+

s.P\\\177-

\177OEt 85%

H20 , DMF, 70\302\260C, 7 h / -O-C-OEtII

OScheme 78:Reaction of dialkyldithiophosphate anions with l<hloroethyl carbonate.

Reaction b in scheme78 was performed in our labora-tories.In reaction c, the thiophosphate anion is an ambidentnudeophile and can attack with either the oxygen or the sulfur.As found, attack with sulfur is in accordwith the HSAB theory.Someother examplesof attack of 1-chloroethyl ethylcarbonatewith soft nucleophile phosphorous compoundsaregathered in scheme79(Ref. 104).

OII O\177p(OEt)2

(EtO)2--P- Na+

/\177O-C-OEt 77%THF,0\302\260C,1 h

O

\"\177 O-C-OEtBu3P +PBu3

II

\177\"

\"\177O-C-OEt67%

00

( \177to)ap

0 0\17750\302\260C, \1778 h

\177-

(\177tO)\177-P-C-O\177t5g%

Scheme 79:fxamples of reactions of 1-chloroeth.gl eth\177l carbonate with phosphorouscompounds.

76

Phosgeneand derivalivesas buildin\177 blocks1

/The last reaction with triethyl phosphite appearsto be

a violation of the HSAB theory.As already developedin the start of this section,the

reaction of carboxylate anions with 1-chloroethyl carbo-nates is widely used for the preparation of commercialprodrugs. The hard nucleophile RlCOO- attacks selectivelythe soft centerB, that is apparently contrary to the HSAB

theory. However, the required use of added Nal mayfavour a cation-like transition state, the cationic interme-diate having thereforetwo hard electrophilic centersand Battack would not be in violation of the rule [Scheme80].

Cl O [ I- O

\177

II t IIO-C-OR+ I- \177L

/\"O-C-ORDMF

B

O

R\177COO-

\177-C-R

1

\177//\"'O-C-ORII

OScheme 80:Assumed mechanism of the reaction ofcarboxylate anion with1-chloroethyl carbonates.

N-protectedamino acidshave beenconverted to activeestersfor subsequentpeptidecoupling by treatment withthe tetrachloroethyl carbonateof N-hydroxysuccinimide,2,4,5-trichloropenol,pentafluoro phenol, etc.(Ref. 67).

The reaction proceedsby initial attack of the carboxy-late on the carbonyl and releaseof either chloral and chlo-ride anion (A1 mechanism) or N-oxysuccinimide (or phe-noxide) anion (A2 mechanism) as depictedon scheme81.

RCOO-2Cl3C-CH-O-;-C--O-Act

A1 \177 \177'Cll \177IO1\177 \177A2J ActO- % \177

R-C-O-C-O-ActCI3C-CHO+ R-C--O--C--O--CH-CCI3\" \"o o

R-C-O-Act + Cl- + Cl3C-CHOII

OScheme 81 .\" Assumed mechanism of active esters synthesis using 1,2,2,2-tetrachloroethyl carbonates.

77)))

Phosgeneand derivativesas buildin\177 blocks Phosgeneandderivativesas buildin\177 blocks

l\"]ixed aryl and oximido tetrachloroethyl carbonatesarecrystalline and stablecompounds easily obtained by reac-tion of tetrachloroethyl chloroformate with substituted

phenols or N-hydroxy imides as shown in table3-12.

Act-Yield mp (\302\260C)

Crystn solv.% bp (\302\260C/mm)

83 108 Pet.ether

O2N \177'-\177 66 121-122 Pet.etherNO 2

Cl

Cl--\177 92 150-5/0.02Cl

F\177-- 91 80/0.05F F

\177 98 120 Ethyl acetate(31

OI (31

NNN\177

O 85 145-147 Dichloromethane

CI O CI Oi

I II Pyridine I II

L

CI3C-CH-O-C-CI+ Act-OH --\177-CI3C-CH-O-C-O-Actortriethylamine

Table 3-12:Preparation ofsome aryl and oximido tetrachloroethyl carbonates.

The new method provides an easy preparation of N-

protectedamino acid active ester derivatives using cheapreagents, in a reaction where the by product is water

soluble and easily eliminated from the reaction mixture.

The processis illustrated by the isolation of the N-succin-

imidyl esterof BOC-Alanine in 94 % yield from activation

of BOC-Ala with 1,2,2-2-tetrachloro-ethylN-succinimidyl

carbonate.The method will be developedin volume 2,section4-4.

Again, accordingto the HSAB theory, secondaryand

primary amines reactwith 1-chloroalkyl carbonatesas hard

nucleophiles through A1 attack mechanism to afford car-bamatesin high yields.This reaction has beenshown to bevery general under different reaction conditions utilizing

differents types of amines including amino acids(Ref. 64,66,105,106,107).Scheme82below displays the gene-ral picture of the reaction.

CII R2 K2CO3/THF/H20 R 2

R-CH-O-C-OR1+HN\"

20\302\260C

\177 R10-C-N'

II 'R3 50 -95% II 'R3O O

R = H, CH3 , CCI3R1 = alkyl, aryl

+ R-CHO

Scheme 82 : 1-Chloroalkyl carbonates as reagents for the synthesis of carba-ma tes.

In terms of the rate of the reaction and the yield, the

following trends are observed:CI O CI O O

I II I II II

Cl3C-CH-O-C-OR1\177 CH3-CH-O-C-OR1 > CICH2-O-C-ORt

The releaseof an aldehyde can be a severelimitation in

the use of this reaction since the aldehyde formed canreact with the starting amine to lead to a considerabledecreaseof the yield of the expectedcarbamate.However,this difficulty can be simply overcomedepending on the

choiceof the respectivestructure of the carbonateand the

amine, and on the reaction conditions (Ref.64).Therefore,1-chloroalkyl carbonateshave beenproposed

as new acylating agents and thus arevaluable precursorstocarbamates,thiocarbamates and unsymmetrical ureas asoutlined in section3-3, this volume.

1,2,2,2-Tetrachloroethyl-t.butyl carbonate(BOC-OTCE)was especiallydeveloppedas a crystalline, nontoxic reagentfor the N-BOCprotection of amino acids(Ref. 66)[seesection3-3].

78 79)))

Phosgeneand derivalivesas buildinblocks Phosgeneandderivalivesasbuildinblocks

In related chemistry, the Arbusov reaction products of

1-chloroethyl chloroformate and trialkyl phosphites wereeasily converted into amino alkyl phosphonatesas depic-ted in scheme83(Ref. 108).

cI cI

CH3-CH-O-C-CI+ (i.PrO)3P-\177CH3-CH-O-C-P(Oi.Pr)2II 100% II II

O O O2

@NHO O

CH2CI2 ,0\302\260C, 1 h\177

(i'PrO)2P-C-Nx.\177/\17793%

Scheme83.'Acylation ofphosphonate compound.

Some interesting miscellaneous reactionshave beenalsoexplored.For example, 1,2,2,2-tetrachloroethylchlo-roformate reactswith carboxylic acidsat 110\302\260C without

solvent to afford acid chloridesor cyclic anhydrides in high

yields (Ref. 109).Sincethe reaction doesn'trequire any catalyst, such

result cannot be explained by the decomposition of the

chloroformate to phosgene and chloral. The assumedmechanism is given in scheme84.

HOOC\177-\177COOH

Proposed mechanism:

R-COOH-\177

CI

I NeatR-COOH + CI3C-CH-O-C-CI\177R-COCI + CI3C-CHO+ CO2 + HCI

II 110\302\260C 2 hO ' 80-90% distilled

R = Ph, cyclohexyl, 017H35,CH3-CH=CH,etc.

\177, \177 90%O O

\177 R-COCI

Scheme 84 .\" Preparation of acid chlorides or anhydrides through reaction of1,2,2,2-tetrachloroethyl chloroformate with carboxylic acids.

8O

In another case,we have observedand studied the

rearrangement of 1-chloroallyl chloroformate to E,Z-3-

chloro-l-propenylchloroformate (Ref.110)[Scheme8.5].CI O Neat CIH2C\177

ZnCI 2 , 0.012eq. O90\302\260C, 2 h

bp : 82-41\302\260C / 32mmE/Z=3.1/181%yield

Scheme85:Rearrangement of 1-chloroallyl chloroformate.

While studying the mechanism, we demonstrated the

reversibility of the rearrangement in presenceof TiCI4.

3-Z-Z 4 Vinylic

\177:hloroformales,

rarbonatesand(arbama\177es

The synthesis and chemistry of 1-alkenyloxycarbonyl

species[Scheme86]have been areas of major researchinterest in academiclaboratoriesas well in the industry,

especiallyat the early beginnings for polymers applications.

\\ /?\177

C\177O_C

1-Alkenyloxycarbonyl group

II

O

CH2=CH-O-C-CI Vinyl chloroformate

II

OCH3

I

OH2=C-O-C-CI Isopropenyl chloroformateII

O

CI2CzCH_O-C_CI2,2-Dichlorovinyl chloroformate

II

O

CH2\177_CH-O-C.O-R Vinyl carbonate

II

OO

O4 E - Butadienyl carbonate

Scheme86:fxamples of vinylic oxycarbonyl species.81)))

Phosgeneandderivativesasbuildingblocks Phosgeneandderivativesasbuildingblocks

Huch of the early work describedin the literature wascenteredaround vinyl chloroformate classically made by

the gasphasepyrolysis of ethylene glycol bis-chloroforma-te at 460-480\302\260C (Ref.111,112,113).However, this route

proved to be industrially and economically impracticablebecauseof low yields (11-44%)and formation of largeamount of chlorinated sideproducts and tars. Scheme87presents the decompositionpathways of ethylene glycol

bis-chloroformate.

-CO2

o

o

-CO2

__\177,c\177

cI

-co2HCI

cI

-CO2

Scheme 87 .\" Pyrolysis of the bis-chloroformate ofethylene glycol at 450-480\302\260C

Besidesthe severedifficulties encounteredin the sca-ling up, this processwas stymied by tile impossibility of

generalization to other 1-alkenyl chloroformates.For

example in the sameconditions, pyrolysis of the bischloro-formate of propylene glycol affords selectively the 1-pro-penyl chloroformate instead of the desired isopropenylchloroformate as shown in scheme88(Ref. 111).

CI_C_O.CH_CH2_O_C.CI

0 0bp :104-6\302\260C

arm. pressureCI

Scheme88.\" Pyrolysis ofthe bis-chloroformate of propylene glycol.

In an obscure short paper published in 1934(Ref.114),Hatuszak reportedthe first preparation of the pre-viously unknown isopropenyl chloroformate. While wor-

king as a physical chemist at the US Bureau of Hines, heisolatedthis compound by microfractionation from a reac-tion mixture of 70 ml of acetoneand 7 ml of liquid phos-geneafter half an hour at room temperature.

Several chemists teams in the world, as well as resear-chersin our laboratoriesattempted to reproducethis exci-ting simple and cheap process.Unfortunately, whateverthe conditions and catalysts used,all the carried out trials

failed and the only products isolated were mesityl oxideand various chlorinated compounds.The conclusion ofmost investigators was that Platuszak did not isolate iso-propenyl chloroformate but a mixture of chlorinated pro-ducts. However, as shown in table 3-13,the propertiesgiven by Matuszak closelycorrespondto thoseof the iso-propenyl chloroformate made by the mercury process(seefarther on in this section).

Isopropenyl Boiling point Density Refractive indexchloroformate \302\260C/mm 20 \302\260C/20 \302\260C 20\302\260C

Phosgenation ofacetone 93/746 1.103

Phosgenation of

chloro-mercuri 94.5/747 1.121 1.4138acetone

Table 3-13:Comparison of properties of the product obtained by Matuszak andproperties of the isopropenyl chlororoformate made by the mercury process.

82 83)))

Phosgeneandderivativesasbuildingblocks

In spite of numerous failures to preparevinyl chlorofor-mate and isopropenyl chloroformate by direct phosgenationof either acetaldehydeor acetone,we acceptedthe chal-lenge to find economicalroutes to vinylic chloroformatesand their derivatives, vinylic carbonatesand carbamates.

We have shown in 197.5investigations that easily enoli-zable aldehydescould reactwith chloroformates to afford

vinyl carbonatesin goodyields as illustrated in scheme89.O O

(EtO)2P-CH2-CHO + RO-C-Cl\177 (EtO)2PCH=CH.O.C_ORII

IIO OR=Me bp :128-9/1.5mm; 63%R=Et bp:138/1.5mm; 70%

Scheme 89:Reaction ofalkyl chloroformates with diethyl (2-oxoethy/phosphonate).

Olofsonand coworkers(Ref. 115)found that reactionof ketoneswith LiTHP producedenolateswhich were spe-cifically O-acylatedwith chloroformates when hexamethylphosphorotriamide (HP1PT) was added in the reactionmixture thus giving alkenyl carbonatesin 49-90% yield.

Therefore,our first ideawas to O-acylatesimple enolateswith phosgene.In a first courseof attempts, we investiga-ted the reaction of phosgenewith alkaline metals enolates.For example we preparedlithium enolateof acetaldehydethrough cleavageof tetrahydrofuran by n- butyllithium

(Ref.116)and reactedwith phosgeneunder various condi-tions. Unfortunately, no trace of vinyl chloroformate wasfound in all experiments performed [Scheme90].

O\177+ n-BuLi

COCI2

--.-\177-H2C\177CH_ O- Li+

+ n-C4Hlo + CH2=CH2

H2C=CH-O-C-CIII

oScheme 90.'Reaction of phosgenewith the lithium enolate of acetaldehyde.

84

Phosgeneand derivativesasbuildingblocks!The phosgenation of enol silanes was studied in a

secondstageof our investigations. Severalsilyl enol ethersfrom acetaldehyde,acetone,cyclohexanonewere prepa-red accordingto general proceduresgiven in the literature.

However, again, all the attempts failed, the only productsisolated resulted from C-acylation of the enols.For example,phosgenation of the enol silane of acetonein presenceofcatalytic amount of mercury (11)chloride afforded 2,4,6-heptanetrione asthe major product as depictedin scheme91.

y + Me3SiCI + Et3N

O -Et3N . HCI OSiMe3

\177 O-C-CI

\177 +00012

=\177/0 0 0

OSiMe 3

Scheme91:Phosgenation of the enol silane from acetone.

The phosgenation of the tributyltin enolateof acetoneledto the same results although sometrials performed at low

temperature (below-

20\302\260C)showed the possibility to obtain

small amounts of isopropenyl chloroformate. It is noteworthy

that, in a recent work devoted to a new synthesis of retinal

(Vitamin A aldehyde), Bienaym& from Rh6ne-Poulenc (Ref.117),obtained isopropen-l-yl chloroformate in low yield

through phosgenation of the reaction product of tributyltin

methoxide with 1-acetoxyisopreneasdepictedin scheme92.

\177 0\302\260 C \177OAc + Bu3SnOMe \177OSnBu3

CH2Cl2

COCl2 \177\177

OiC-CI + Bu3SnClCH2CI2/ Toluene

II

o28% yieldunstable product

Scheme92.'Prepara rio n of isopren- 1-yl chloroforma te.

+ AcOMe

85)))

Phosgeneand derivativesasbuildingblocks Phosgeneand derivativesasbuildingblocks

,\177t this point of our investigations, we thought that the

good way to synthesize enol chloroformates may be thereaction of phosgenewith c\177-C-metallated aldehydes and

ketones.With this new courseof action, we wereable for

the first time to obtain the desiredcompounds by treating

chloromercury acetaldehydeor chloromercury acetonewith

phosgenein polar solvent.,\177t about the same time, Olofsonand coworkers turned a

similar conceptinto a practicable laboratory route to enol chlo-roformates (Ref. 118).When we becameacquainted with this

work, contact\177 were initiated which were later to provide thebasis for a long collaboration in new areasof chloroformate

chemistry between SNPE and Penn State University.In the first step of the SNPE process,chloromercury

acetaldehydeand chloromercury acetoneare easily prepa-red by reaction in water of vinyl acetate and isopropenylacetate respectively with a 1:1mixture of mercury (ll)oxide and mercury (11)chloride(Ref. 119).

In the secondstep, the dried chloromercurials com-pounds are treatedwith phosgeneat 80\302\260C in nitrobenze-ne as the key solvent (Ref.120).Vinyl chloroformate and

isopropenyl chloroformate are isolated by simple distilla-

tion in 75-85% yield rseescheme93].I J 1/2 HgCI 2 H20

H2C\177CO-CCH3+/ 1/2 HgO

\177CIHgCH2--C-R + CH3COOHII II

O 0R=H, mp:134\302\260C,97%yieldR = Me, mp : 105\302\260C, 90% yield

RNitro benzene

I

CIHgCH2-C-R + COCI2 \177, H2C\177C-O-C-CIII 80 \302\260c II

0 75-85% 0R = H ; bp :89-90\302\260C/760 mmR = CH3 ; bp :94.5\302\260C/747 mm

Scheme93:Preparation ofvinyl and isopropenyl chloroformates by the mercuryprocess.

The system was designedto recyclethe HgCI2 in nitro

benzenewithout removal from the reactor.However, the

processwas severely handicapped by the bad reputationof mercury compounds whatever the strictly controlled

safety precautions and efficient cleaning up methods used.Tocircumvent the difficulty, we attempted to start from

other c\177-C-metallated keto compounds.Thus, we preparedacetonyltetracarbonylferrate by the reaction of disodium

tetracarbonylferrate (Caution : pyrophoric !)with chloroa-cetone in THF according to literature data (Ref. 121).Phosgenation in situ afforded isopropenyl chloroformatebut in very variable and non-reproducible yields not excee-ding 50% as depictedin scheme94 (Ref.122).

THFNa2Fe(CO) 4 +

ClCH2-\177I-CH3 20o\177CH3-\177I-CH2Fe(CO)4-Na+

O -NaCI OCH3

cOQ2 I

\177' H2C\177C-O-C-CI + NaCI + \"

Fe3(CO)12\"<50% II

OScheme 94:Isopropenyl chloroformate through phosgenation of acetonyltetra-carbonylferrate.

The studies in this area were not further pursued.However, it seemsthat several high-potential possibilitiesstill remain untapped. Togive lust one example, the phos-genation of the reaction product of zirconium tetrachloride

with acetone:CI3ZrCH2COCH3 describedby Josephand

Blumenthal (Ref. 123),should yield, under selectedcondi-tions, isopropenyl chloroformate.

In the courseof other studies related to dehaloge-nation methods through electrosynthesis with sacrificial

anode,we thought that the dehalogenation of 1,2-diha-Ioalkyl chloroformates should provide with an interestingroute to vinylic chloroformates.lnorderto checkthe feasi-bility of such process,we carried out a set of exploratory

experiments under aprotic conditions using 1,2-dibromoe-thyl chloroformate and 1,2-dibromoisopropylchloroforma-

te as starting materials (Ref. 124),these materials having

been made by bromination of vinyl and isopropenyl chlo-roformates. The electroreductionwas performed in an

undivided cellequippedwith a stainlesssteelcathodeand

a consumable zinc anode using acetonitrile as the solvent

and Bu4N+BF4-as the electolytic salt.The promising resulLs

obtained are given in schemec)5.

86 87)))

Phosgeneand derivativesasbuildingblocks Phosgeneand derivativesasbuildinblocks

eR O

CH3CN , Bu4N+BF4R O

Br B/\177\"rO/jL'CI Zn anode

\177-

/'\177\" o/JL'cIC\302\260nstantcurrent(l'lA/dm2) R=H; 54% yieldTemperature :30'-C R= Me ; 76% yield2.1Faraday !mole

Scheme 95:Preparation of vinylic chloroformates by electroreduction of 1,2-dibromoalkyl chlo rofo rma tes.

Thesepretty good results prompted us to find a practi-cal route to 1,2-dihaloalkyl chloroformates.

1,2-Dichloroethylchloroformate is a known productmade by classicalchlorination of vinyl chloroformate with

02.We have developeda new, easily practicableroute bytreatment of 4-chloroethylenecarbonate with PCI5 at110\302\260C which gives a mixture of the desiredchloroformateand the dichloro isomer in a 95 : 5 ratio as depictedin

scheme96.Careful fractional distillation afforded the 1,2-dichloroethyl chloroformate in 65% pure yield (Ref.125).

\177 CI2 , hv PCI 5 CI

%o__.%o__. oCCI4 110\"C CI CI

O--\177O O CI CI58% dist. Distill. / 95:5107\302\260C/10 mm 91-2\302\260C / 90mm

CI

Scheme 9\177 .Novel preparation of 1,2-dichloroethy! chloroformate.

The starting material, the 4-chloroethylenecarbonatewas preparedby standard photo-chlorination of the cheapethylene carbonateas describedin the literature.

Unfortunately, the dechlorination of 1,2-dichloroethylchloroformate by the electroreductionmethod affordedonly very bad yields of vinyl chloroformate, whatever theconditions selected.Moreover, all the attempts to preparethe 1,2-dibromoethyl chloroformate failed.

At this point of our investigations, and on accountof the

cI

high commercial interest of vinylic chloroformates derivatives

(seefarther on in this section), we decidedto focus our

efforts on the synthesis of alkenyl carbamates and carbo-nates by methods which do not require vinylic chlorofor-

mates.

1-Chloroalkyl carbonates and carbamatesare easilymade from reaction of 1-chloroalkyl chloroformates with

alcoholsand amines through standard processes(seesec-tion 3-2-2-3,this volume) or original methods developedby SNPE researchteams (section3-3).If a simple methodfor the ]\177-elimination could be devised, the ready availabili-

ty of 1-chloroalkyl carbamatesand carbonateswould seemto make these compounds attractive precursorsto vinylic

carbamatesand carbonates.Olofsonand coworkersdiscovereda relatively simple

processof thermal elimination of hydrochloric acid from 1-chloroethyl carbamatesto producevinyl carbamatesin

high yields (Ref. 126).In a typical example, N-(vinyloxy-

carbonyl) piperidine was obtained in 89% yield just by

refluxing N-(1-chloroethyloxycarbonyl) piperidine for 3 h in

o.dichlorobenzenecontaining 1.2eq.recyclable2,4,6-col-lidine as an acid scavenger[seescheme97].

H3C_C\177

H.O.\177I. N\177_/\177

o.Dichlorobenzene\177, H2C=CH-O-\177- N\177__\177Collidine, 1.2eq_O Reflux, 3 h O

89% distilled

bp. 123-8\"C / 47 mm

Scheme97:Preparation of VOC-piperidine from ACE-piperidine.

Without collidine, the reaction has been proved towork but is much slower.When the methyl of the 1-chlo-roethyloxycarbonyl group is substituted by alkyls, the eli-mination is easier,probably due to inductive stabilization

of the carbocationintermediate.Theeffectsof various conditions such as addedmineral

or organic salts (to catalyse the EI elimination), temperatureand solvents were carefully studied by Wooden (Ref.127).

Some representative examplesof the method aregathered in table 3-14.

88 89)))

Phosgeneandderivativesas buildingblocks Phosgeneand derivativesas buildingblocks

RI R2 -NR3R4 Base Solvent Yield

(%)

H H --N\177 Collidine o.DCB 82

H Pie -N\177 Collidine Tetrachloro 84ethylene

H H--'\177'\177 Collidine Bromo 78

benzeneN/

R' H \177 Collidine Bromo 86Zo-V benzene

Pie l\"leMe + c[

_N(CH2)aNMe 3None 1,2-Dichloro 97 Light red

ethane gumCI

R\177\\I R3

1

R3CH-CH-O-C-N'

R

\\C\177 CH_O_C_ N

'R2

II 'R4R 2

II 'R4O O

bp.(\302\260C/mm)

134-6/49

86-90/0.5

81-5/0.2

125-7/0.6

Table 3-14:Preparation of 1-alkenyl carbamates from 1-chloroalkyl carbamates.

As illustrated in table 3-14,many extra functionnalitiesare

t\177lera\177edl Somemoieties even catalyze the elimination by

increasing salt concentration (seelast example in the table).The value of hexabutylguanidinium chloride (HBGCI or

HBGCI.HCI)as an acylation catalyst has been already out-lined in section2-2of this volume. In a later study devotedto the evaluation of potential facilitation of E1 eliminationin sensitive systems by including HBGCI,Kreutzberger (Ref.128)proposed a modification of the Wooden methodbasedof the use of a \177 salt promoter \177.

In refluxing tetrachloroethylene (121\302\260C),with collidine

as the acid scavenger,the guanidinium salts are superior totetrabutyl ammonium bromide (TBAB). Moreover, thecomparisonsof experiments without collidine in o.dichlo-robenzeneunder vacuum demonstrated a decisiveadvan-tage of HBGCI.HCIover TBAB as shown in scheme98.

The efficiency of HBGCIwhich allows to avoid the useof collidine combined with its thermal stability at tempera-,foresexceeding200\302\260C made this salt a prime candidate as\177 salt promoter \177 in this process.

9o

cI

H3C-CH-OoC-N OII \177o

o.DCB \177\177, H2C\177---CH-O-C-N 0

150\321\236C, vacuum il \177Catalyst :0.055eq. O

Catalyst :-TBAB,9 h. 100%completionnon isolated, 80 % by NMR

20% decomposition.-CHBG.HCI,7 h, 100%completion100%yield NMR, 85 % isolated.

Scheme98:Comparison of two E 1 promoters in the synthesis of N-(vinyloxy-car-

bonyl) morpholine.

In contrast to the carbamate chemistry, thermal elimina-

tion of hydrochloric acid from 1-chloroalkyl carbonatesrequires much higher temperature and is accompaniedby

major yield destructive sidereactions.Thekey to an economi-cal route to vinylic carbonateswas discoveredby Olofsonand

coworkers (Ref. 129).This discovery was the consequenceofa beautiful observation made by Dang, Olofson'sstudent, on

the formation of neopentyl fluoroformate and, unexpectablyof vinyl neopentyl carbonatewhile heating 1-chloroethyl

neopentyl carbonatewith KF in benzonitrile (Ref. 130).Treatment of enolizablealdehydes with fluoroformates

and KF in DP1SO(55-100\302\260C

for 15-24h) afforded 1-alkenyl

carbonatesin 72-92% yield. According to Olofson'sstu-

dies,the activated fluoride anion acting as a basedeproto-nares the aldehyde to yield an enolatewhich reactsrapid-

ly with the fluoroformate to give the desiredvinylic carbo-nate as shown in scheme99 (Ref.131).ExcessKF neutra-

lisesthe HF which is liberated in the reaction as KHF 2.o

nl\\ IIDMSO RI\\

CH-CH + F + KF \342\200\242 C=C-O + KHF 2R2/ R2/

RI\\DMSO

R\177\\

C\177-C-O- + RO-C-F \177 C=C-O-C-OR+ F/

II n 2/ II

R2 O OScheme 99:Mechanism of the reaction of fluoroformates with aldehydes in

presence of KF in DMSO.

Note that the reaction alsocan be carried out in ace-tonitrile if 18-crown-6is used as a catalyst. In this latter

9|)))

Phosgeneand derivativesas buildingblocks Phosgeneandderivativesas buildingblocks

case,chloroformates may be substituted for fluorofor-mates if two equivalents of KF are included in the medium.

Some results obtained using the fluoroformatesmethod are presentedin table 3-15.

n R

1 Et

1 C6HS-CH2-1 i-Pr

2 - CH2CH2CH2-2 CH2CH2-O-CH2CH21 Et

1 CF3-CH2-

RI R2 Temp., \302\260C Yield bp.Time, h % \302\260C/mm Hg

H H 55/20 73 43-5/45H H 70/15 87 112-5/4H H 80/5 86 44-6/33H H 80/24 92 130-2/O.5H H 90/8 80 123-30/O.7

Ple Pie 90/24 74 45-7/16H H 80/20 81 43-4/2..5

R1XC=CH_O_C_O/R

R2'\177 /n

Table 3 15.Preparation of 1-alkenyl carbonates flora aldehydes, fluoroformale\177

and KF in DMSO.

The good yield obtained in the last experiment of table3-15is notable, becausethe 2,2,2-trifluoroethyl vinyl carbo-nate has beenproposedas useful monomer in optical fibers

applications (Ref.132).1-Alkenyl chloroformates, especially vinyl and isopropenyl

chloroformates, aswell as vinylic carbonatesand carbamateshave found number of valuable applications in various fields.

In orderto illustrate the considerablepotential of thesevinylic compounds in organic syntheses, selectedtypes ofapplications arepresentedin the following pages.

The use of vinyl chloroformate and its derivatives asmonomers in the manufacture of thermoplastic or crosslin-

ked polymers is the oldestapplication developed.Polymerization and copolymerization of vinyl chlorofor-

mate (Ref. 133,134,135),vinyl carbonatesand carba-mates (135,136)using standard radical initiators (e.g.per-oxydicarbonates) to yield high molecular weight polymersand random copolymers is well documented.More recently,

in a work carried out to assessthe kinetics of radical poly-merization ofsomevinyl alkyl carbonates,Ebdon and cowor-kers showed that contrary to the conclusions of the previousstudies, the compounds can be polymerized readily to give

polymers of high molecular weight with conventional radicalinitiators such as benzoyl peroxide(Ref.137).

The chemical modification of poly (vinyl chloroformate)and its copolymers has been also studied. Treatment ofsuch polymers with amines, alcoholsand phenols affordsthe corresponding poly (vinyl urethanes) and poly (vinyl

carbonates) (Ref. 138,139).Poly (mixed anhydrides)have beenalsopreparedby chemical modification of poly

(vinyl chloroformate) by carboxylic acids under variousconditions (Ref. 140,141,142).

The materials obtained from polymerization of vinyl car-bonates and carbamatesarehard (but not brittle) clearther-

moplastics with high decomposition temperatures, excellentchemical resistanceand varying glasstransition temperatures.

It is noteworthy that the heretoforenot accessibleat

acceptablecost diethyleneglycol bis-vinyl carbonatecalled\177 CVD \177 [seescheme100]is made in 80% yield using the

fluoroformate processas depictedin table 3-15.o o

,CH2CH2-O'C-O-CH\177CH 2 ,CH2CH2-O-C-O-CH2-CH=CH2o,

CH2CH2-O-C'O'CH\177CH2II

CH2CH2-O-\1771

-O\" CH2\"CH\177

CH2

o oCVD CR -39

Scheme 100:Comparedstructures of two monomers for the fabrication of opti-calplastic lenses.

CVD is known to polymerize an order of magnitudemore easily (Ref. 143)than the analogous bis-allyl carbo-nate marketed under the designation CR-39which is the

leading material for casting prescription eyewearsincedecades.The crosslinked homopolymer of CVD exhibits

similar propertiesbut with the advantages of much betterscratch resistanceand higher hardness and modulus.

Hethacryloxyethyl vinyl carbonateprepared from hydro-

9293)))

hosgeneand derivativesasbuildingblocks

xyethyl methacrylate and vinyl chloroformate [Scheme101] was claimed as an UV curablecrosslinking agent use-ful in the formulation of hydrogels for contact lensesmanu-

facture (Ref. 144).

o\177Ok__/O

+ \177 0=\177

0H

0--\177--'\177\"

O\\ 0--/<'

CI 0 \1770%

Scheme 101:Synthesis of methacryloyloxyethyl vinyl carbonate used in the pre-paration ofbiomedical articles,

Aromatic bis-vinylcarbonates, for example the reactionproduct of vinyl chloroformate with bisphenoI-A [Scheme102],are recommendedfor the preparation of highly sen-sitive, high-contrast positive working resists (Ref. 145).o

o4 \177 Me

oScheme 102:Aromatic his-vinyl carbonate for the manufacture of high perfor-mance photoresists,

New N-vinyloxycarbonyl leucine alkyl estershave beensynthesized from vinyl chloroformate and polymerized toyield polymers and copolymers optically and physiologicallyactive with liquid crystals properties(Ref. 146).

Vinyl carbonatesand carbamatescontaining chromophore

groups have beenprepared and claimed as useful polymeri-sablephotoinitiators for photoreticulable polymers (Ref.147).

Polymers and copolymersof vinylic carbonatesand car-bamates may find interesting applications as aroma and fla-

yours releasing agents.For example, isopropenyl menthyl car-bonate has beenpatented (Ref.148)as an useful monomerfor the manufacture of a smoking composition comprising an

admixture of tobaccoand a menthol-release agent. Recently,Harwood et al (Ref.149)have published a new preparationof enol carbonatesincluding especially isopropenyl menthylcarbonate by selectiveO-acylation of ketones sodium

Phosgeneand derivativesasbuildingblocks

/enolatesgeneratedin the presenceof N,N,N',N'-tetramethy-lethylene diamine (TP1EDA) as depicted in scheme103.

In our continuing trials to extent the scopeof the vinyliccarbonatessynthesis through the fluoroformate process,vinyl menthyl carbonate was obtained in excellent yield

(80%)from menthyl fluoroformate. The polymer of vinyl men-

thyl carbonate was alsoproposedasmenthol-release agent. It is

noteworthy that this polymer can beeasily prepared by reactionof menthyl fluoroformate with poly(vinyl alcohol) in DP1SO.

r\177 O1)Nail ( 1.1eq.)

\177

TMEDA ( 1 eq.)THF, reflux OY +

L'v\177 o.-JC-ci2) Addition of enol\177t e O..J[\177 O.\177O -- i\177 solution to chloro- \177formate ; THF, 0\302\260C 79 % yield(-)-Menthyl chloroformate

Scheme 103:Effident synthesis ofisopropenyl menthyl carbonate for the manu-facture of polymeric menthol-release agents.

Vinylic chloroformates, as well as their derivatives arenot limited to rolesas monomers.

Initial Olofson'spublications (Ref. 150,151)outlinedthe use of vinyl chloroformate (VOC-Cl) as a reagent for

amine protection, especiallyin peptidesynthesis, via the

electrophile-labilecarbamate.Amino acidsare convertedto their N-vinyloxycarbonyl derivatives by standard acyla-tion with VOC-CI, for example by Schnabel'spH-stat pro-cedure.The most significant advantage of the VOC-groupis associatedwith its removal which is facilited by the high

reactivity of the C=Cbound toward electrophiles.Acid-

induced hydrolysis with HCI or HBr in Ac-OHor with HCI

gas through an inert solvent containing the peptidefollo-

wed by warming the hydrohalide adduct in ethanol affords

the deblockedpeptidesalt in excellentyield. The value ofthe methodology was underscoredin an efficient processfor the construction of the heptapeptide sequence,H-Ser-Phe-Leu-Pro-VaI-Asn-Leu-OH (all L) (Ref. 151).

Isopropenyl chloroformate (IPCF) has no value in

amine protection but appears to be the most versatilechloroformate for acid activation. Thus, IPCF was proved

9495)))

Phosgeneand derivativesas buildingblocks Phosgeneand derivativesas buildingblocks

to be an excellentreagent for the amino acid activation in

peptideamide bound formation via the mixed anhydrideintermediate as depictedin scheme104(Ref. 152).\"r .o o .]

H2

N\"T\"'COOMe w O R2

R2Boc..\177 \177N.\177J,,.COOMe

I\177\" + CO2 + yR 1 H O

Scheme 104:Amino acid activation for peptide amide bound formation by iso-propenyl chloroformate.

Reaction of N-protected amino acidsactivated by iso-propenyl chloroformate with primary, secondaryand ter-tiary alcoholsin presenceof 4-dimethylamino pyridine ascatalyst affords the corresponding estersin goodyield asshown in scheme105(Ref. 153).

R

p N.\177COOH===\177/

Et3N-- + O-C-CI

H II

ODMAP [ RRI\"oH

\177 / /L. .DMAP+ R10-

-oo2 /P-N- \";1\"

'. H OAcetoneL

\177 p_N -J'\177O-R1

H O

Scheme 105:IPCF activation for one-potesterification of N-protected amino adds.

Someexamplesare given in table 3-10.

(z-Amino esters Yields (%) mp (\302\260C) [(z]D,Cl, i\"leOH

Z-Ala-OCH2-pNO2C6H4 78 99-100 -16.3Boc-Phe-OBzl 92 64-5 -6.3Boc-VaI-OCH2-o,p Cl2C6H3 85 110-1 - 10.5Fm ooTrp-O-[2.3-O-(isopropyli- 65 61-2 -12dene glyceryl]

Boc-VaI-O(+) Bornyl 60 54-7 - 75Z-Phe-O-t.Bu 88 B1-2 -9.9Z-Pro-O-t.Bu 90 - -51Z-Trp-O-t.Bu 60 70-1 -5.2

Table 3- 16:cz-Amino esters by IPCF activation of N-protected (z-amino acids.

It is noteworthy that Takeda and coworkers(Ref. 154)recently proposedallyl isopropenyl dicarbonatemade from

isopropenyl chloroformate and sodium allyl carbonateas aconvenient reagent for the preparation of allyl estersofcarboxylic acids.Allyl isopropenyl dicarbonatereactswith

carboxylic acidsin the presenceof DP1AP under mild neu-

tral conditions to give allyl esters in high yields. Allyl esterswhich could be deprotected by palladium catalysts areespeciallyuseful in the caseof unstable compounds under

acid or basic conditions, for example O-glycopeptides,penicillin derivatives, etc.

The condensationof a chiral N-protected amino acidwith Pleldrum's acid in the presenceof isopropenyl chloro-formate and DI\"IAP is the key for a stereospecificsynthesisof N-protected Statine (Ref. 155).The novel route toStatine is depictedin scheme106.

Boc__N\177COOHO\177:

\177\"BocNH

O.\177

AcOEt OH

H(I)

IPCF\177

_\177BOC--

DMAP O\177O -Acetone O

H2 \177 88% from (I)

Adam's\177\177, NHBoc\177UH Acetone \177

catalyst\177 Boo--N: J \177 \177COOH\177 1)aaoH I

\177HN-Boc-StatineO 2)HQ

\177cheme \17705 :\177tereospecific synthesis of \177t\177tine #ore IPEE

96 97)))

Phosgeneand derivativesasbuildingblocks Phosgeneand derivativesasbuildingblocks

_/N

-Et

1 ) HCI

2) EtOH

Plore recently, a similar synthetic strategy was utilized

to prepare the Dolastatin 15via acylation of Pleldrum's

ester(150).In this work, isopropenyl chloroformate wasfound to give the best results of several mixed carbonicanhydrides derived from the required starting carboxylicacid when used in the presenceof 5 molar equivalents ofDI\177IAP. Dolastatin proved to exhibit promising remarkableanticancer properties.

Olofsonand coworkers alsointroduced vinyl chlorofor-

mate as a reagent for the N-dealkylation of tertiary amines

(Ref.157,158,159).Comparedwith commonly utilized rea-gents in N-dealkylation procedures,the use of VOC.-CIleadsto significantly improved yields under milder conditions com-bined with greater discrimination between alkyl groups in

unsymmetrical amines. The procedureis illustrated by the

selective N-deethylation of N-ethyl piperidine to afford piperi-dine.HCI in 90%yield (Ref.159)as depictedin scheme107.

The N-dealkylation selectivities follow the order : ben-zyl; allyl; t.butyl >> s.alkyl _> n.alkyl >> piperidine scission.

The methodolo\177 was subsequently applied to the pre-paration of the potent analgesic Nalbuphine and the potentnarcotic antagonists Naloxone and Naltrexone (Ref. 100).

1,2-DCE A O

VOC-CI\177

'Et CI--\177

N--\177

0\302\260C L90%

O\177,

100%\177\"

\177NH.HCI

Scheme 107:N-Deethyla tion of N-ethyl pipefidine with vinyl chloroformate.

However, vinyl chloroformate largely has beenreplacedfor N-dealkylation by 1-chloroethyl chloroformate which

shows similar dealkylation selectivities and equally easyrepla-cement of N-alkyl by the carbamate group (seesection3-3).

Vinyl chloroformate might find interesting applicationsin Pummerer related rearrangements. Thus, VOC-CIreactswith sulfoxides to yield o\177-chlorosulfides as shown in sche-me 108(Ref.161).In this type of reaction,VOC-CIis more

reactive than the commonly usedreagents.

o

Me.,s,.O\177.\177O..\177Ci Me,.s,O.O ] Me,.S

1 ._o.CO2\177-

./..L..__CI

Scheme 108:Pummerer rearrangement with vinyl chloroformate.

With penicillin J]-sulfoxide, VOC-CIinducesa novel

rearrangement involving cleavageof the C-5-Cbound asdepictedin scheme109,

H O ZNH_ S. /56%

\177CO2Me O O

Scheme 109:Novel rearrangement from penicilfin l\177-sulfoxide and vinyl chloro-

formate.

Alkenyl carbonatesreadily add HBr to give 1-bromoal-kyl carbonateswhich are better alkylating agents for the

modification of carboxylic acidfunctions than 1-chloroalkylcarbonates as already mentioned in section 3-2-2-3(Ref. 85). For example, 1-bromoethyl tisopropyl carbonate (BEIC) was preparedat pilot scalein 92 % distilled

yield by bubbling HBr through vinyl isopropyl carbonate,neat, at 20-25\302\260C as depictedin scheme110.

HBr, 1.1eq.Neat Br O /20-25oc

- /-04-04--7 h 92% (98% pure)

bp:78\302\260C/100 mm

d 2\302\260 : 1.34Scheme 110:Preparation of 1-bromoethyl isopropyl carbonate (BEIE).

Besidesthe synthesis of vinylic carbonatesand carba-mates, Olofsonand coworkers reporteda simple synthesis of

1-(1,3-butadienyl)carbonates and carbamates(Ref. 162).Crotonaldehyde and its congenersare easily and often

stereospecificallyconverted to trans-butadienyl carbonatesand carbamatesby treatment with potassium tert.butoxide

98 99)))

Phosgeneandderivativesasbuildingblo(ks Phosgeneand derivativesas buildingblo(ks

followed with addition of a chloroformate or carbamoylchloride as depictedin scheme111.Someexamplesaregiven in table 3-17.

THFY 0

KOt.Bu 0

HsC/_\177H+ Z-C-el ,

Y,N/__\177O--/k/zII -78oc

H 0 \177 H

Y = H, Me, CI

Z = OR or NF\177R2

Scheme 111:Alkyl dienyl carbonates and carbamates from reaction ofcrotonal-

dehydes with KOt.Bu and acyl chlorides.

Y Z Yield (%) bp (\302\260C/mrn)

H O-Et 83 42/3H O-Allyl 58 55/0.8H O-CH2CCI3 68 99/0.7He O-Et 78 48-51/0.6CI O-Et 32 58-61/I.5H N(Et)2 75 74-84/I

Table3-17:Preparation of trans- 1-(1,3-butadienyl) carbamates and carbonates.

The alkyldienyl carbamates were utilized both at

Pennstate University and at 5NPE in parallel studies todevelopa stereospecificsynthesis of (_+)

- Hernandulcin

and congeners(Ref. 163).The intensely sweetsesquiterpene,Hernandulcin, was

isolated from a plant known to the Aztecs as TzonpelicXihuilt or c\177 sweet herb , (Lippia dulcis). Hernandulcin

which could be consideredthe prototype of a new classofdietary sucrosesubstitutes is said over 1000times swee-ter than sucrose.However to a human panel at SNPE,while tasting synthetic Hernandulcin made by the new

methodology, someaftertaste and a slight bitterness was

perceivedby 50% of the persons.In our method, the N,N-diethyl butadienyl carbamates

(I) reactsboth regio and stereospecificallyto methyl vinylketone to give the cyclohexene(11)in 89% yield, which in

turn adds the Grignard's reagent (111),again re\177io and ste-

reospecificallyto form (IV) which, after LAH reduction and

oxidation affords (+) - Hernandulcin (V) as depicted in

scheme112,o o

Et-N\177L- O o II H O

I\177,\177

k Me TiC'4

(Et)2N-C\177\177MgBr

(I) H + Me(111)

Me

-\177

Me\" v(ll)

oII H OH O OH

M\177v)V .\1772) Pyridinium Me\"

v.\177chlorochromate (V)

Scheme 112:Novel preparation of the sweet sesquiterpene Hernandulcin,

In the courseof several investigations devotedto the

synthesis of new halogen substituted carbamates and

phosphonato estersfor agricultural screening, we wereinterested in the compoundscontaining the 2,2-dichlorovi-nyloxycarbonyl unit.

Various insecticidesusedextensively in the world conti-nue to take advantage of the toxicity to insects of particu-lar patterns of halogens in the molecule.Tobe more accep-table than many other agricultural agents in today's ecolo-gically sensitive society, they must contain functionalities

guaranteeing ready degradation by environmental agents.A report published thirty years ago(Ref. 164)outlined

the potential insecticidal activity of 2,2-dichlorovinyl car-bamates and carbonates.However, progressin this areahas been stifled because 2,2-dihalovinyl chloroformateswere unknown. For the preparation of the phosphonatoester (A) assumedto exhibit interesting insecticidal pro-perties as compared to the well known insecticideDichlorvos, we neededthe heretoforeunknown 2,2-dichlo-rovinyl chloroformate [seescheme113].

100101)))

Phosgeneand derivativesas buildin\177 blocks Phosgeneand derivativesas buildin\177 blocks

o oCI2C=CH-O-P(OMe)2 CI2C\177CH-O-C-P(OMe)2

IIDichlorvos (A) Ofrom Arbuzov reaction of

dichlorovinyl chloroformate

Scheme 113:Comparedstructures ofthe insecticide Dichlorvos and a parent com-pound containing the 2,2-dichlorovinyloxycarbonyl unit.

The facile preparation of 1,2,2,2-tetrachloroethylchlo-roformate by treatment of chloral with phosgenein the

presenceof a reusable,naked CI-,catalyst has beenalrea-dy describedin section3-2-2-3.We thought that if this

chloroformate could be induced to undergo a Boord elimi-

nation of chlorine, the desired2,2-dichlorovinyl chlorofor-

mate would be easily available as shown in scheme114.CI O O

I IIDechlorination

II

CI3C-CH-O-C-CI \177, CI2C__--CH-O-C-CIScheme 114.'Expectedroute to 2,2-dichlorovinyl chloroformate.

However, several precedents in the literature would

seemto negate a favourable outcomefor such a scheme.For example, the treatment of 2,2,2-trichloroethyl acetatewith zinc leads to 1,1-dichloroethylenein a dramaticallyexothermic process.Sincechloroformate anion is a betterleaving group than acetate,it should competewith chloride

for that role.Chloroformate ion alsoshould be lost in an

anticipated subsequentzinc-mediated elimination to yieldthe explosivechloroacetylene.Horeover,the well-known

decomposition of chloroformate in presenceof zinc saltsprovides another problem.

Despitethesestrong omensof failure, the reaction wassuccessfully performed (Ref.165,166).When zinc dust

was added in small portions to a solution of 1,2,2,2-tetra-chloroethyl chloroformate in THF at room temperature,dichlorovinyl chloroformate was isolatedin 75% distilled

yield. Initiation of the reaction after addition of the first

portion of zinc is variable in time and no more zinc should

be added until the first portion has been consumed to

Yield

bp.Scheme

avoid any uncontrollable exotherm. No induction periodwas found in the same reaction from 1-chloro-2,2,2-tri-bromoethyl chloroformate but the yield of 2,2-dibromovi-nyl chloroformate was only 33% [Scheme115].

O oCI2C---CH-O-C-CI Br2C\177CH-O.C-CI

75 % 33%

82-5\302\260C / 120mm

115.2,2-dihalovinyl chloroformates.

68-3\302\260C/12 mm

Both chloroformates are stable for at least severalmonths at room temperature if all tracesof the byproductszinc salts are carefully removed by distillation.

Even more surprising, we discoveredthat 2,2-dichlorovi-

nyl chloroformate is isolated in 50% distilled yield when

chloral is treated with phosgeneand zinc dust in methyl ace-tate (Ref.167).Efforts were made to generalize this processby extending the reaction to other oechloroand o\177-bromo

aldehydes and ketones as shown in table 3-18(Ref. 167).When Z is hydrogen, alkyl or aryl, the chloroformate is obtai-

ned only when A and B are halogen or alkyl but not hydrogen.

A B Z Yield (%) bp. (\302\260C/mm)

CI CI Ph 66 86-8/0.4Me Me Ph 54 57-74/0.5He I\"1e CN 67 80-3/10He He P(O)(OHe)2 83 -CI He H 56 68-71/52

-(CH2)5- H 59 48-50/0.7He -(CH2)4- 68 80-2/8

O O,A II Zn

B Z\"CA/k-\177-('O-/k/'x-C--C-Z+ COCI2 \177-

I

Table 3 18.'Preparation of substituted vinylic chloroformates from u-halo carbo-

nyl cpds.

102 103)))

Phosgeneand derivativesas buildingblocks Phosgeneandderivativesasbuildingblocks

It is noteworthy that the reaction applied to 2,2-dichlo-ro-l,3-cyclohexanedione leadsto the previously unknown

dichlorocyclohexenonethrough a clean decompositionof the intermediate enol chloroformate asdepictedin sche-me 116.

0 CI FO CI

\177)00012Zn

IYW-__0 - 002

I

Scheme 115.\" Preparation of 2,3-dicbloro-2-cyclobexen-1-one.

CI

Thevalue of being ableto include cyano and phospho-nato groups among allowed Z substituents is of particularinterest. Severalmodel experiments were carried out to

guarantee the efficiency of these enol chloroformates asacylating agents. Thus, many carbonates, carbamates,phosphonato estershave been obtained in goodto excel-lent yields from reaction of the new chloroformates with

alcoholsor phenols, amines, trialkyl phosphites (Ref.168).Significantly, 1,2-dichlorovinyl carbonatesand carba-

mates may have an interesting future asspecialty monomers,for example ascorematerials in all-plastic optical fibers.

It is known that the optical absorption which is the

major drawback of the classicalplastic materials such asPMMA, is dominated by the higher harmonics of the car-bon-hydrogen stretching vibrations. The value of polymersfrom 2,2-dichlorovinyl chloroformates derivatives has todowith their lower optical absorption as comparedto stan-dard plastics in the visible and near-infrared regions of the

spectrum (0.6to 1.5l\177m).

Somenew 1,2-dichlorovinyl car-bonatespreparedby standard proceduresin 90-95% yield

for that purpose aregathered in table 3-19(Ref.169).

Entry IHonomer bp. (\302\260C/ram) ND20 Density20

I CI2C=CH-OC(O)OC6F5 115/151.4663 1.6582 CI2C=CH-OC(O)OCD3 56/15 1.4590 1.4203 C12C=CH-OC(O)OCH2CC13 142/760 1.5005 1.604

Table 3-19.\" New vinylic carbonates asmonomers for optical fibers applications,

Their polymerization and copolymerization with vinylacetate or vinyl methyl carbonate was also studied.Whatever the radical initiator used (AIBN, benzoyl peroxi-de,dicyclohexyl percarbonate)the monomers are too hin-

deredto self-polymerize.

Monomer (I) and (2)polymerize with vinyl acetate togive alternating 1:1copolymerswith an unusual head totail structure and Tg 95\302\260C and 75-90\302\260C respectively.

3-3Reactionsat a nitrogen

center

iI

I\177ighlights ofome reactionso|phosgene

with amines,imines,

oxazolines

Phosgenereactswith tertiary amines at low tempera-tures to afford unstable crystalline I :Ior 1:2phosgene-amine adducts.In the case of tertiary alkylamines, thesecomp.lexesdecomposewith elimination of alkyl chloridesto give carbamoyl chloridesand then isocyanatesas depic-ted in scheme117.

104 105)))

Phosg\177_ne inex\177ces\177s

R3 N + COCI2-60to + 20\"C

R',N-C-Cl 00

RIoi ,R

N-O-N- RCIR' R

Amine in excess- 60to+20'C

2 R3N + COCI2

,R+Cl-

I

T>20\302\260C

R-N-C-CI

CI-+ + Cl

R3N-\177-NR3O

Scheme 117:Reaction of phosgene with tertiary alkyl amines.

+ COCI2

The originally proposed1:2structure (11)for the phos-gene-pyridine adduct was deducedby analogy to the com-monly observed1:1pyridinium salt (I)as shown in scheme118.However, as a conclusionof a study of low tempera-ture 130NMR and solid-state130CP/MAS spectra,King

Jr. and coworkers (Ref. 170)assigned a dihydropyridine-

pyridinium (2-DHPP)structure (111)to the 1:2salt.

ol ol-

o,-

/=\177_//o \177/=\177o (,)

92.4% yield z/\177 N . Om\177. 84-7\177'C 6ec.\177

+ cr

Scheme 118:Structure of the 1:2phosgene-pyridine adduct.

Note that the adduct (111)which can be storedat leastone year at room temperature and which reverts easily toits components in solution was proposedas a convenient

(safe ?) storage system for phosgeneunder the term, phosgene-in -a-can )) (Ref. 170).

The reaction of phosgenewith secondaryamines ortheir hydrochlorides is a well known useful route to carba-moyl chloridesas shown in scheme119(Ref. 171).

1 ) 0\302\260C

F\177NH+ OOOI 2

2) Reflux \177Toluene \177 /N--%

R OR2NH'HCI + COCI2

Reflux \177Scheme 119:Preparation of carbamoyl chlorides from secondary amines.

Caution !several carbamoyl chlorides are mutagenic

and carcinogenicsuspectedagents.Low molecular weight

products exhibit high toxicity levels.For example, dime-

thylcarbamoyl chloride is a powerful lachrymator and a

confirmed carcinogen and mutagen. Extreme care should

be taken to avoid inhalation or skin contact.In orderto developvarious new applications of carbamoyl

chlorides, we were interested in the synthesis of compounds

containing functional groups such as ether oxidesof tertiary

amines. Thus, we studied and scaledup an improved processfor the production of N-chlorocarbonyl morpholine basedon

a modification of literature data (Ref.172)[Scheme120].N-chlorocarbonyl morpholine has found somevaluable

applications to convert amino acidsto N-morpholinocar-

bonyl amino acids,for example N-morpholinocarbonyl-(L)-

phenylalanine [Scheme120]for the preparation of renin-

inhibiting peptides.

/---N Toluene

c\177N\177

I

O,k___./NHIHC

I + COCl2 _--- (I)

Reflux

> 95% distilled yieldbp. : 153\302\260C / 73 mm

NaOHTH

/ H2O/---%N \177O-\177N

(I) + H-Phe-OH \177'- \17780% yield H coOHmp. : 134\302\260C

Scheme 120:Preparation of N-chlorocarbonyl morpholine and condensation with

L-phenylalanine.

107]06)))

Phosgeneand derivativesasbuildingblocks Phosgeneandderivativesas buildingblocks

Such modified peptideswere proposedfor the treat-ment of hypertension, originally in a patent from Squibb(Ref.173)and then in numerous patents from other companies.

In another example, N-chlorocarbonylmorpholine is used(besidesseveral other phosgenederivatives) in a multi-stepsynthesis of FK-906,an antihypertensive renin inhibitorfrom Fujisawa in phase II in Japan, as depictedin scheme121(Ref. 174).

O/---\177N\177

CI+

H3C,N\177,OH3

Et3N

\177 O H\177--N,

\177-

t.BOC

H3C, H3Q

\177N._\177

N

\177.__ N,CH3

CF3COOH

O/\177'kN __\177N-'\177.N,C

H3

\177 O 't.aoc\177 \177

\"\177)H

oIIH O

-\":/\177 O'/'hf\177 H3C O \177

2) BASE \177H2 \177 ,N\177 \177R ,PPd/C q N% \177 \177

\177 \177 O H3C\177 \177OH

\177 o\177\177) (coco\177

H3C O \177CH3

.30\177

H3C O

\177CH3

Scheme 121:N-Chlorocerbonyl morpholine in the preperetion of the hypertensiverenin inhibitor FK-905.

Some work in our laboratories was also devoted toimprove the preparation processof carbamoyl chloridescontaining tertiary alkylamine functions,such as N-chloro-

carbonyl, N'-methyl piperazine hydrochloride. This carba-moyl chloride is for example used in the synthesis of the

sedative and hypnotic pharmaceutical Zopiclone as shownin scheme122(Ref.1T5).

\177 Aproticsolvent \177 Oii

Me N NH + COCl2 \177- MeN N-C-CI.HCI\\\177 ./ 0\302\260C, 2-3h \177

97% yield

N--

\177N\177J\177 O

H2N\177el

\177

:/\177__\177\177

\177N \177/\177N\177

O OO

\177 II

MeN N-C-CI.HCIX ./

O

Red_

uction\177,-

[\177

N

\177.\177Z\177N # ClN

\177L-\177/

\177. //OH

O

O\177C-N N-Me// \177

OScheme 122:5ynthesis of carbamoyl \177hloride derived #ore N-methyl piperezine endits use in the prepe\177tion of Zopidone.

While studying the reactivity of carbamoyl chlorides, wefound that they reacteasily with aldehydes in the presenceof a Lewis acid as the catalyst to afford 1-chloroalkyl carba-mates in goodyield as shown in scheme123(Ref.176).Thechemical properties of 1-chloroalkyl carbamates which canbe obtained by other routes arediscussedin section3-3-2.

108109)))

Phosgeneand derivativesasbuildingblocks Phosgeneand derivativesasbuildingblocks

CIRI\\ ZnCl2 R\177 I

N-C-Cl + R-CHO \177- N-C-O-CH-RR2

II60\302\260C

R2IIO 1 -5h O

R1\\

\177N-- = N-- 90% yield

R2

Scheme 123:Reaction of carbamoyl chlorides with aldehydes.

N-MethyI-N-methoxycarbamoyl chloride made by phos-genation of methoxy methyl amine hydrochloride is a veryuseful intermediate for the synthesis of N-methoxy ureasherbicides.However, we found the method to be unsatis-

factory for the production on a large scale,becauseofrather low yields and alsoof technical difficulties. Toover-come these problems, we developeda new procedurebasedon the reaction of phosgenewith methoxy methylamine sulfate as depictedin scheme124.Sulfuric acidfor-med is easily removed by decantation (Ref. 177).

MeO\\ '\177

Toluene MeO\\

t2

HCI

NHJ \342\200\242H2SO4 + 2OOOI2 \177- 2 N-C-CI +/ [I H2SO4Me/ 2 95\302\260C, 5 h Me/ O

80%dist. yieldbp. 60-7\302\260C / 36mBar

Scheme 124 .\" Preparation of methyl methoxy carbamoyl chloride from the sulfu-ric acid salt of methoxy methyl amine.

Among the more than 30methods available for the

preparation of isocyanates,phosgenation of primaryamines or their hydrochlorides still remains the most popu-lar. The method is employed on a large scalefor the indus-trial production of mono and polyisocyantes.

Four phosgenation proceduresare used.The proce-dures without any acid scavengerare the methods com-monly employed for the production of almost all commer-cial isocyanates.

A- Without acid scavenger

Two stepsprocessRNH 2 + COCI2 \177RNH-C-CI + RNH 2.HCIT< 20\302\260C

II

OOOOI2

RNH--C-CI + RNH2.HCI \1772 RNCO+4HCI

II T> 100\302\260C0

A2 One step process

ChlorobenzeneRNH 2.HCI + COCI2 \177, RNCO +3 HCI

T= 100-140\"C

B - With acidscavenqer

B1 Anhydrous medium

Example :

TolueneN,N-Dimethyl aniline

\177__NH2( 1 eq.)

+ COCI2+ 5\302\260C

B2 Biphasic processExample :

\177o.Dichlorobenzene

NH 2 + COCl2 \177,

NaOH / H20

+ 5\302\260C

-NCO

87%

bp : 60\302\260C / 8 mm

---NCO73 % yieldbp. 84-5\302\260C

110 111)))

i

Phos\177eneand derivativesas buildin\177 blocks

In the course of several studies devoted to the syn-

thesesof unusual isocyanates,we developedan improved

processfor the preparation of the already known ethyl-

2,6-diisocyanatohexanoateby phogenation of L-Lysine

ethyl esteras depictedin scheme125(Ref. 178).

COCI2

HCI.H2N\177NH2\"HCI.---- OCN\177NCO

COOEt CHCI3/NaOH COOEt

50% dist. yieldbp. 101\302\260C / 0.01mm

Scheme 125.' Phosgenation of L-Lysine ethyl ester to the corresponding isocyanate.

This diisocyanate is especiallyuseful in the preparation

of biocompatible polyurethanes or polyureas.In another example, surprisingly, we found that the

phosgenation of a substituted isoxazolamine hydrochloride

doesn'tafford the expectedfree isocyanatebut a peculiar

dimer according to the mechanism depictedon scheme

126(Ref. 179).

NH 2.HCI TOLUENE NH-C-CI

\177 \177o\177N

IIIsOxazOlamlne

35\"60\302\260C

O m+ COCl2 \"-

RR - HCl

0 R

Scheme 126'A peculiar isocyanate dimer from phosgenation of substituted isoxa-

zolamines.

112

Phosgeneandderivativesasbuildi\177n\177

blocks/

This dimer reacts as two moleculesof free 5- alkyli-

soxazolyl-3-isocyanatewith secondaryamines or with alco-

hols to give the correspondingureas or carbamatesuseful

as agrochemicals or fine chemicals intermediates. For

example, 3-amino-5-tert-butyl isoxazoleis a key interme-

diate for 3-(5-tert-butylisoxazolyl)-1,1-dimethylurea (com-

mon name :Isouro______O_n)

which is useful as a herbicide for

sugar caneand other crops(Ref. 180)[Scheme127].Me

H N-Me

Scheme 127.\" Isouron.

The reaction of phosgenewith CH-acidimines followed

by dehydrochloridation in the presenceof triethylamine

affords N-substituted vinyl carbamoyl chlorides in good

yields. For example, N-methyl-N-vinyl carbamoyl chloride was

preparedin 67%distilled yield through phosgenation of ethy-

lidene methyl amine as depicted in scheme128(Ref. 181).If there is no hydrogen atom available on the p-carbon,

for example in the caseof the Schiff's base of tert-butyl

amine and formaldehyde, N-(1-chloralkyl) carbamoyl chlo-

ride are obtained in excellentyields [Scheme128].

\302\260'k\177- 1Toluene

COCl2 ClEt3N \177X

Cl

CH3N:CH .CH3\177IMe--N |\177,N--\177

0.10o0L )---Me\177

Reflux Me O3 h CI 67% yield

bp. 63\302\260C / 23mm

\177_

Toluene\177._N,

CH2Cl

N\177CH2 + COCl2 \"\" |\177-Cl20\302\260C

1.5h O 90% yieldbp. 117\302\260C/25 mm

mp. 17\302\260C

Scheme 128.\" Reaction ofphosgene with Schif t\177s bases.

113)))

Phosgeneand derivativesas buildin\177 blocks

It is noteworhy that N-(1-chloroalkyl) carbamoylchlo-rides are valuable starting materials for the synthesis ofpesticides.We have carried out some trials basedon lite-rature data (Ref. 182)in order to synthesize N-phenyI-N-

chloromethyl carbamoyl chloride by phosgenation of1,3,5-triphenylhexahydro-s-triazine as shown in scheme12c).However, all the efforts to appreciably improve thedescribedyield (24%) failed, the bestyield obtained beingaround 50%.

Ph-N\177N.Ph \177\1770H2Cl

L\177N/I

+ 30OCI2 \1773X.\177__\177 tCI

I\177h <50% OScheme 129.' Attempt to prepare N-pheny-N-chloromethyl carbamoyl chlonde ingood yield.

Phosgenereacts also readily with substituted oxazo-lines, for example 2-phenyloxazoline, to afford dependingon the conditions either N-(2-chloroethyI-N-chlorocarbo-nyl amides or isocyanato ethyl estersas depictedon sche-me 130(Ref. 183,184).

Toluene

O.\177,NO

(a) / COC[2\177

0/\177-CH2CH2-Cl/ 1oo\302\260c 47 %cI

bp. 132-4\302\260C / 0.7mm

(b)\177COCI2

\177_ \177cNaOH / H20 \1770\302\260C \177O-CH2CH2-NCO

97 %bp. 109-16/0.1mm

Scheme 130.\" The two pathways for the phosgenation ofphenyl oxazoline.

Process(b) in scheme130was appliedto the industrial

preparation of isocyanatoethyl methacrylate (I.E.M.)asdepictedin scheme131(Ref. 185).

Phosgeneandderivativesas buildin\177 blocks

Et \177-- H-CH3 \177\177 O 100\302\260C

- H2096.5%CH2OH 175\302\260C

98%

OOOI2NaOH / H20 \177

\177- \177 /CH2CH2-NCO10to 18\302\260C 0\1770\177 88%

I.E.I\177I. bp. 211\302\260C

Scheme 131.'Industrial process for the preparation of I.E.M.

I.E.M.is an interesting monomer which combines towell-known functionalities in on molecule.Unfortunately,I.E.M.exhibits a very high level of toxicity. It is recommen-ded that the averageeight-hour working environment notexceed0.025ppm.

-3-2Rea(liensl-chloroelhylioroformales

ith amines:synlhesis

and usefulpplicalionsofl-(hloroallqlcarbamales

1-Chloroalkyl chloroformates reacteasily with primaryand secondaryamines under the same standard conditionsusedwith classicalchloroformates(Ref.21).

The processis illustrated in the conversion of piperidi-ne to N(1-chloroethyloxycarbonyl) piperidine. Piperidine(2.3eq.)in ether was addedto a cooledsolution of 1-chlo-roethyl chloroformate in ether.The piperidine hydrochlori-de was filtered off and the expectedcarbamate was isola-ted from the filtrate in 77% yield (Ref. 127).

Someexamplesof representativecarbamatesobtainedby this method aregathered in table 3-20.

114115)))

Phosgeneand derivativesas buildingblocks Phosgeneand derivativesas buildin\177 blocks

R R 1 R2

H H Ple

H OH 3-CLC0H4

Me (CH2)5Et CH2CH2-O-CH2CH2

i-Pr Me Cyclohexyl

Pie--N,,\177

N

GI Base

Yield bp.(%) (\302\260C/mm)

68 83/3 18676 rap. 55-7 18777 70-2/0.4 12784 95-7/0.9 12792 111-13/0.6127

73 80/0.5 188

CI O R 1

I II /--\177R-CH-O-C-N\\R2

R-CH-O-C-CI+HN,R 2

_ HCI

Ref.

Table 3-20:Preparation of 1-chloroalkyl carbamates by reaction of 1-chloroalkylchloroformates with primary and secondary amines.

We discoveredthat 1-chloroethyl chloroformate is

undoubtedly the best reagent for the selectiveN-dealkyla-tion of tertiary amines (Ref. 189).

Thus, in the initial test system (N-deethylation of N-

ethylpiperidine), the use of oechloroethyl chloroformate

(acronym :ACE-C0 surpassedthe yield obtained with vinylchloroformate : (I) ->(IV), 99% vs 90% as shown in sche-me 132(Ref.189).

Besidesits interest for the synthesis of 1-chloroethylcarbamatesfrom tertiary amines and the N-dealkylationof tertiary amines, this result is also quite unexpected.With most chloroformates other than vinyl chloroformate

(VOC-Cl), for example : EtOCOCl,Cl3CH2OCOCl, Ph-

CH2OCOCl,the cationic intermediate analogous to (11)fragments to alkyl chloride,carbon dioxide and (I).

\177N

ACE-Cl //\177x ,C-O-CH'CH31-et ---.-/\\ ..,+ c,- /

(I)DCE

L--et (11)

O CI

\177II I Me-OH

N-C-OCHCH3\177\177, /NH.HCI

+ CH3CH(OMe)2(111)

Warm99\302\260/\177 (IV) + CO2

Scheme 132:N-Deethylation ofN-ethyl piperidine via N-(1-chloroethyl-car

Thus, only traceyields of alkylcarbamates are obtained

and the tertiary amine primarily catalyzesthe decarboxyla-tion of the chloroformate. Phenyl chloroformate itself pre-viously recommendedfor N-dealkylation (Ref. 190)affor-

ded PhOC(=O)-piperidinein only 34% yield.The high-yield dealkylation with ACE-Cl is therefore

very surprising. Presumably, the -CHCl-CH3 unit is too hin-

deredto undergo competitive SN 2 attack by Cl-and the 1-chloroethyl cation generatedby an alternative SN 1 (El)cleavagemust be too unstable. Becausethe substituent is

electron withdrawing, ACE-Cl is more reactive toward ter-

tiary amines than simple alkyl chloroformates.Olofsonand Hartz have thoroughly studied the scope

of the new N-dealkylation processwith ACE-Cl (Ref. 68-191)and shown that the selectivities follow the sameorderas thoseof VOC-Cl : benzyl; allyl; t.butyl >> s.alkyl >n. alkyl >> piperidine ring scission.In its reactivity, ACE-Cl

parallels VOC-Cl with the advantage that the conditions

required for ACE removal are much milder thus expandingthe functionalities allowed in the amine to be dealkylated.

Even N-dealkylation of aromatic amines occurscleanly

with ACE-Cl as it is illustrated in a strigent test by the

conversion of N,N-diethyl aniline to 1-chloroethyl N-methyl-

N-phenyl carbamatein 87 % yield (R.ef.68).Caub\177re and

Bacheletused this methodology while operating without asolvent for the demethylations aswell as for the deethylationsof dialkylamino benzofurans in good yields (Ref.192).

116117)))

Phosgeneandderivativesasbuildingblocks Phosgeneand derivativesas buildingblocks

Olofsonand Plartz have developednumerous applicationsof ACE-CI to the N-dealkylation of significant tertiaryamines, especially in the field of analgesicsand narcoticantagonists alkaloids, for example in a brilliant synthesis ofNalbuphine from Oxycodonein 69% overall yield (Ref.191).Thescopeand limitations of ACEoCIas a new reagentfor the selective,high-yield N-dealkylation of tertiaryamines will be examined in section4-.5of vol. 2.

Chloromethyl chloroformate reacts also selectivelywith tertiary alkyl amines to afford O-chloromethylN,N-dialkyl carbamatesin yields ranging from 83to 99%(Ref.193).

For example, N-methylpiperidine was refluxed with1..5eq.of chloromethyl chloroformate in 1,2-dichlorome-thane (DCE)for 30min.. After vacuum evaporation of thevolatiles, the distilled O-chloromethyl carbamate was isola-ted in 97 % yield.

Totest the scopeof the reaction, the over-the-coun-ter antitussive Dextromethorphan was N-demethylated tothe morphinan in 87 % yield as depictedin scheme133.

\177 CICH2.0_C.CI

[\177N-MeReflDuCx\177 ,5h

\177'

'\177 \177 '1

Scheme 133:N-Demethylation of Dextromethorphan by chloromethyl chlorofor-mate.

Someexamplesof 1-chloroalkyl carbamatesobtainedthrough N-dealkylation of tertiary amines are gathered intable 3-21(Ref. 127,193).

118

F

R Tertiary amine Carbamate yield (%)

OH

OX___/N-Me

O,x__/N-C-OCH2CI 96

O OH Me-N N-Me CICH20C-N N-C-OCH2CI

99

OH Me, Me, II

N-Et ,N- C-OCH2CIMe' Et (a)0

Me, II

N- C-OCH2CIMe

\177

(b)

0 0

HN\177

C'OMeN

\177C'OMeMe o.C.oCH2CI

oEt,

II I

Me Et3N N-C-OCH-CH3Et

(a): (b)

8:1

96

83

96

0 CI

r\"le

OX__/N-Me

O,x__/N-C-OCH-CH3 84

Table 3-21.\" Preparation of 1-chloroalkyl carbamates by reaction of R-CHCI-

OC(=O)CIwith tertiary amines.

The value of 1-chloroethylcarbamatesas starting mate-rials for the synthesis of vinyl carbamateshas beenalreadypointed out in section3-2-2-4of this volume.

As already discussedin section3-2-2-3,1-chloroalkylcarbamatespresenttwo electrophilic centerswhich may beattacked by nucleophilesfollowing differents pathways asshown in scheme134.

Similar to he caseof reaction with 1-chloroalkyl carbo-nates studied in section3-2-2-3,carboxylatesanions reactwith 1-chloroalkyl carbamatesto give alkylation derivatives

119)))

Phosgeneand derivalivesas buildin\177 blocks Phosgeneandderivalivesasbuildingblocks

through a B attack mechanism. This reaction was widely

used in numerous patents on prodrugs.

R1

Nu C-N + R-CHO + crA1 II

O \\R2

A\177I A1 O O

R1

R CH 0 C--N \177 R-CH-O C-N, + CI\177-

Nu A1,2\177

NuO

B

\"\177 A2\177II R 1

B A \177,R-CH-O C-Nu + HN

IR2

cI

Scheme 134:Possibletypes of nucleophilic attacks to 1-chloroalkyl carbamates.

For example this conceptwas applied to the synthesisof novel (acyloxyalkoxy) carbonyl bioreversible moietiesfor

primary as well as secondaryamines functions in drugs asillustrated with the caseof a prodrug from the antibacterial

Norfloxacin in scheme135(Ref. 194).

o oO\"\177\"

N\"\177'\"1

Et CH3COO O1.

\"

N 4..] Et

F\177'\177\"COOH O\177Me

g\177\"-\177\"\177/\177'O OFrom reachon of Nodloxac\177n mp. 215-7\302\260C

with 1-chloroethyl chloroformate

Scheme 135:Preparation of a prodrug derived from Norfloxacin.

COOH

Sincethe -NR 1R2group makes centerA and B both

much lessharder than doesthe ORgroup, we expectsomedifferencesbetween the reactivities of 1-chloroalkyl carba-mates and 1-chloroalkyl carbonates.For example the reac-tion of the hard-soft borderline nucleophiles phenoxidetype anions with 1-chloroalkyI-N,N-dilakyl carbamatespro-ceedsselectively through B mechanism to give exclusively

alkylation instead of acylation as shown in scheme136.

THF

25\302\260C

No catalyst :60%,18h\\

O\177

F\177

0.1eq.Nal :80O/o,18hO-O\177

N 1 eq.Nal :97 % 3h\177o

\\\177 '

Me

Scheme 136,\" Reaction of N (1-chloroethyloxycarbonyl) piperidine with sodium 4-phenoxyphenoxide.

Someresults obtained in our laboratoriesfor pesticidesscreeningpurposesare gathered in table 3-22.

R -NR 1R2 Ar-O Time Yield

(h) (%)

He -NHe2 Ph-O-Ph-O 4 90He -NHe2 p.CF3-Ph-O-Ph-O 4 76He Plorpholino Ph-O-Ph-O 4 90He Morpholino pmCF3-Ph-O-Ph-O 3 83CH2=CH- -NEt2 Ph-OPh-O 1 82

Cl 0 ArO 0I II /R1 THF

I II ,R1R-CH-O-C--N + Ar-ONa \177 R-CH-O-C--NR

2 Nal, 1 eq. R2

25 \302\260C

Table3-22,\" Reaction of 1-chloroalkyl carbamates with sodium phenoxides.

In opposition to the preceding case,the reaction ofphenoxides anions with 1-chloroalkyI-N-monoalkyl carba-mates leadsto acylation instead of alkylation as shown in

scheme137.

CI OII Ph-O.-Ph-ONa

CH3-CH-O C-NHCH3 \177., O \177 O-C-NHCH 3THF, Nal h

25\"C, 12h 65% O

Scheme 137:Reaction of sodium phenoxy phenoxide with 1-chloroethyI-N-methylcarbamate.

120 121)))

Phosgeneand derivativesasbuildinblocks Phosgeneandderivativesasbuildinblocks

However, it is not certain whether the isocyanateor the

carbarnate is the acylating agent in such reaction.In fact,as depictedin scheme138,it is possiblethat this reactioncould proceedthrough a mechanism involving the transient

formation of methyl isocyanaterather than through the

normal addition (A1) directly to the carbonyl group follo-wed by lossof acetaldehyde.

cI o

Ar-O C-NHCH3II

oScheme 138:Possiblemechanism of the reaction of 1-chloroethyI-N-methyl car-bamate with phenols.

The study of the reaction of 1-chloroethyI-N-methyl car-bamate with phenols was undertaken in the hope that it

might replacethe noxious methyl isocyanate(M.l.C)in the

preparation of insecticidal N-methyl carbamates.Surprisingly, we found that the reaction of an alcohol

with 1-chloroethyI-N,N-dialkylcarbamates can proceedthrough B mechanism to give alkylation rather than acyla-tion (Ref.195).This result appearsto be a violation of the

HSAB theory. In a typical example, N-(1-chloroethyloxy-

carbonyl) piperidine was added to a stirred mixture ofsodium hydrocarbonate and methanol at 25\302\260C. The reac-tion was instantaneous. Solidswere removed by filtration,excessalcoholwas then distilled off and the resulting pro-duct was isolated by flash chromatography in 96% yield

[Scheme139].CI O-Me

I

ExcessMe-OHI

NaHCO 3O 96%25 \302\260C

Scheme 139.\" Synthesis of N-(1-methoxyethyloxycarbonyl) piperidine.

More than twenty 1-alkoxyethyI-N,N-dialkyl carbamateshas beenpreparedby this methodology which should havesomeinterest in the design of new prodrugs.

The samekind of reactionsoccurswith thiols and thio-

phenols as shown in scheme140.

CI THF( 2 +

O\177N\177.

\177

50\302\260C , 2h

CI O THF

./ \177 Et + PhSNa

, 25\"C, 2 hEt

S

70% /

oO\177

79%

N Et

Et

5cheme 140\342\200\242Reaction of thiols with 1-chloroethyI-N,N-dialkyl carbamates.

According to the HSAB theory, secondaryand primaryamines react as hard nucleophiles through A1 attack

mechanism with 1-chloroalkyl carbamatesto affords ureas.However, the reaction is slower and lesseasy than the

reaction of amines with 1-chloroalkyl carbonates and

strong nucleophilic amines are generally required to reachgoodyields.

Thus, the reaction has somevalue for the synthesis ofknown ureasderived from methoxymethyl amine such asthe herbicideLinuron [seescheme141](Ref. 196).

\177OMe

HN..

CI---\177.l-\177-O-CH2CIMe

\177 CI\177/\177

\177-N\177H\177 N'MeOMeO 93% O

Scheme 141 .\" Preparation of the herbicide Linuron from chloromethyI-N(4-chloro-

phenyl) carbamate.

122 123)))

I

Phosgeneand derivalivesas buildin\177 blocks

The reaction of secondaryamines with 1-(1-chloroe-thyloxycarbonyl) imidazole demonstrates the powerful

nucleofugacity (leaving group efficiency) of the chloroe-thoxide anion as shown in scheme142(Ref. 197).

Ol

-\177 N C-O-CH-CH3CI Et\" II

N\177 [ /Et O\177I....\177N-C-O-CH-CH

3 + 2HN\\

II Et \177THF

O \\Et

mp. 50\302\260C 78 %\" -J

II EtObp. : 106/ 0.2mm

mp.:41\302\260C ( Lit. 38-43\302\260C)

Scheme 142:Reaction of 1 (1-chloroethyloxycarbonyl) imidazole with diethylamine.

In the courseof our studies dedicatedto the reactivityof 1-chloroalkyl carbamatestoward primary and seconda-ry amines, we discoveredthat the easyto prepare1,2,2,2-tetrachloroethyl carbamatesare valuable versatile interme-diatesfor the synthesis of N-nitrosoureas (Ref. 198).

N-(2-Chloroethyl)-N-nitroso ureas are an active classofantitumor agents, which are usually obtained by nitrosa-

tion of the previously preparedurea. Becauseof difficul-

ties in achieving regioselectivenitrosation, several authors

have su\177ested alternatives processes.Unfortunately, the

starting materials proposedare either unstable such as car-bamoyl azides(Ref. lC)9)or extremely toxic such as the 2-chloroethyl isocyanate (Ref. 200).

Although we have noticed that 1,2,2,2-tetrachloroethylcarbamates(I) do react with amines to give ureas in

modest yield, we thought that when the carbamates(I) arenitrosated to (11),the reactivity of the carbonyl should begreatly enhancedand good yiels of N-nitrosoureas (111)would beobtained.As depictedin scheme143,the results

are quite good,the only drawback being that someminor

impurities may arisefrom the reaction of the amino com-pounds with the releasechloral (Ref. 201).

The carbamates(I) are easily preparedfrom the requi-

Phosgeneand derivalivesas buildin\177 blocks

red amine and 1,2,2,2-tetrachloroethylchloroformate just

by refluxing in THF or dioxane without any acid scaven-ger.Thereaction mixture is easily freed from hydrochloricacid by heating and evaporation of the solvent generally

gives (I) as pure crystals.Table3-23 gives someexamplesof carbamatesobtained by this method.

Cl 0 Dioxane CI OCI3C\177O\177CI

+ R'NH 2 .-\177Reflux, 2 h OI30

\177'\177 O\177\"N\"

R1

72-99% H (I)CI O O

N204 / NaOAc\177 \177. R1

R2NH2

\177 CI3C, 0rN\" \177,\177

R2..N.I\177.N.R1H

CCI4'0\302\260C

(11)NO K2CO3/ H20 H 1'40

(111)THF, 20\302\260C 72-95%from (I)

Scheme 143:Novel preparation of N-nitrosoureas.

Entry R1 Yield mp. (\302\260C)or

(%) bp (\302\260C/mbar)

1 Cl-CH2CH2- 96 81-22 F-CH2CH2- 72 11.5-20/73 (L)-HO2C-CH2CH(COOH)- 9c\177 131-3

Table3-23:1,2,2,2-tetrachloroethylcarbamates (I)prepared.

The 1,2,2,2-tetrachloroethylcarbamates(I) are then

nitrosated with nitrogen tetroxide by a known procedure.The intermediates nitrosocarbamates(11)are obtained asoils and used as are in the next stepto afford the expectedN-nitrosoureas (111).For example, the antitumor drugLomustine was preparedin 87 % yield from the carbamate

[(I),entry 1of table 3-23].5ome results obtained by this

method aregathered in table 3-24.

124125)))

Phosgeneandderivalivesasbuildingblocks Phosgeneandderivalivesasbuildingblocks

Entry R 1 R2 Yield from (I) mp.(\177o) (\302\260C)

1 Cl-CH2CH2- c-C6H11- 87 87-82 F-CH2CH2- c-C6H11- 72 44-53 CI-CH2CH2- C6H5- 75 78-804 Cl-CH2CH2- HOCH2CH2- 9.5 oil

5 ClCH2CH2- Et-OOC-CH2-' 88 oil

Table3-24.\" N-Nitrosoureas (111) prepared (seescheme 143),

Some other interesting miscellaneous chemistry of

chloroalkyl carbamateshas been alsoexplored.Thus, asalready mentioned, acrolein add its congenersH2C=CR-Clioare easily converted to the chloroformates H2C=CRCH(Cl)OC(=O)Clwhich rearrange in the presenceofZnCl 2 to the allylic isomer ClCH2-CR=CHOC(=O)Cl.We

preparedsomecarbamatesderived from these chlorofor-mates for testing as agrochemicals.

One example using 2-chloroacrolein as starting material is

given in scheme144(Ref. 202).Industrially, 2-chloroacrolein is

easily made in up to 97%yield by adding chlorine to aqueousacrolein followed by steam distillation of the resulting mixture.

CI

oCl

\177--\177OCClH

63% distilled

bp, 94-7/ 22mmZ:E 15:1

+ COCI2 \177BTBAC

Me

Me N 0Me

0..OCCI

ZnCI 2 , 0.01eq.CI

100\302\260C, 5 h91%distilled

bp 71-82/ 20mm

Me

(31

mp. 103\302\260C

Me

N 0m\177.

5\177 \177C

Scheme 144.\" Example of 3\177hloroalkenyl carbamate synthesis for testing.

In continuation of our studies on the synthesis and

reactivity of 1-chloroalkyl carbamates,and becauseour

group was involved in the chemistry of 1,1-dimethyl hydra-zine (UDMH), we have examined the reactionsof 1-chlo-roalkyl chloroformates with unsymmetrical dialkyl hydra-zines.During this work, we discoveredunexpectedly a newefficient generatorof the heretoforedifficult to prepareN,N-dimethylamino isocyanate(Ref.203).Thus, five men-bered ring carbalkoxy aminimides were prepared fromUDMH and 1-chloroalkyl chloroformates in three steps[Scheme145].Upon heating, these aminimides give high

yields of Me2N-N=C=O.This unusual isocyanatedimerizesor can be trapped in the presenceof a nucleophile.

In a preferredexample,when UDMH in anhydrous THFwas added to a solution of 1-chloroethyl chloroformate in

THF at 10-20\302\260C, the intermediate carbazate(a) was for-med. After filtration to remove the UDMH hydrochloride,we accomplisheda cyclisation to (b)justby refluxing theTHF solution for 1 h..The resulting hygroscopic salt (b)precipited immediately in 71%overall yield. In solid form,

(b) is stableundefinitely at room temperature. The cyclicaminimide (c) was then easily preparedfrom (b) by treat-ment with a resin supportedbase in high yield. The threestepsof the synthesis are depictedin scheme145.

Me, CI THF Me, Me,N NH 2 +

\177/\177

0 ----\177.-N NH +/N

NH2.HCIMe

/Me

\177/

CI 10-20\302\260C Me/ \177-0 Me0 (a) 0

U DM HACE-Cl

.\177Me CI

Me, 0 Amberlite 0N NH IRA-4OO(OH

0/.\177.

Me\177/\1770

THEO'\177NH CI- N-

Me\177e,\177, \177Reflux,

/\177N'Me \177Me

\177lh Me Me + Me Me +

(b) (c)71%from (a) 91%from (b)

mp : 145-50\302\260C dec. mp. 170-2\302\260C

Scheme 145:New cyclic aminimide from UDMH and ACE-CI,

126127)))

Phosgeneandderivativesasbuildingblocks

Carbalkoxy aminimides have receivedlittle attention in

the literature and to our knowledge, cyclic carbalkoxy ami-nimides have never beforebeensynthesized.

Dialkylamino isocyanatesare known transient interme-diates and, in the absenceof other reagents,have beenshown to dimerize. When the cyclic aminimide (c)was hea-ted at 130\302\260C under vacuum (0.3ram) for 3 h, (d) wasobtained in 89% yield. At higher temperature (d) was for-med but rearranged to (e)as depictedin scheme146.

The chemistry of aminimides has beenreviewed elsew-here(Ref.204,205)and the chemistry of dimethyl amino

isocyanate,preparedin the form of dimer (d) through a

phosphoramide synthesis, studied (206).

o

Me Me + 130\302\260C/003mm

(\321\236)

or refluxingin acetonitrile

Me\177

N N=C=OMe'

+ CH3CHO

Me Me+ , Me\177

Me N N- N N.... \"o\177-.\177o 190o\"c,o\177.\177o

89%or 100%N

5 min'

(e)MeZ Me Me

\177N Me(d) 92% ; bp, 100\302\260C / 0,06mm

Scheme 146:Thermal decompositionof the cyclic carbalkoxy amin/de (c) to giveN,N-dimethyl amino isocyanate.

Our method representsa simple, rapid and high yield

preparation of N,N-dimethylamino isocyanate.This interes-

ting intermediate has been the subject of several publica-tions and is useful for the synthesis of a wide variety of

heterocycles,carbazates,and other moleculescontaining a

hydrazine group.We have preparedseveral carbazatesand semicarba-

zidesjust by heating the cyclic carbalkoxyaminimide (c)and

the nucleophile (:Null) for 1 h in refluxing 1,2-dichloroe-thane. Someexamplesare given in table 3-25.

333/ Chloroalkylcarbonatesas

acylatin\177

agentsfor thesynthesisofcarbamates

andliocarbamates

Phosgeneand

Entry

1

2

derivativesas

:Nu-

Et-O- 87

Ph-CH2-N(He)- 89

O S-MeII I

95Me2N-C-C= N-O-

buildingblocks

Nu-COINH-NMe 2Yield (%)

.,\177\"--.\177 s Me4\177]\177... N/\177--

N-- 74

5 EtO2C-CH2-NH- 76

Table3-25:Preparation of UDMH derivatives through reaction of cyclic carbal-

koxy aminimide (c) with a nucleophile :Nu-H.

The reaction of secondaryand primary amines with 1-chloroalkyl carbonatesto afford carbamatesin high yieldhas been already tackled in term of mechanism in section3-2-2-3(Ref. 64,66,105,106,107).

At the beginning, while studying the synthetic potentialof 1-chloroethyl ethyl carbonate,we found that it readilyreactswith amines at the carbonyl function to give the cor-responding ethyl carbamatesin good to excellentyields.We thought therefore that 1,2,2,2-tetrachloroethyltert-butyl carbonate(I) (codenumber CN 916)should be avaluable reagent for the Boc-protectionof amino acids[Scheme147](Ref.66,207).

(I)was easily preparedin goodyield from 1,2,2,2-tetra-chloroethyl chloroformate and tert-butanol by a simpleprocedure.In a typical example,pyridine (1eq.)was slow-ly addedto a cooled

(0\302\260C)solution of t.butyl alcohol and

1,2,2,2-tetrachloroethylchloroformate (1 eq. of each).After stirring for 4 h at 20\302\260C, washing with water and eva-poration of the solvent and recrystallization from hexane,(I) was obtained in 87% yield (mp. 70\302\260C).

128 129)))

Phosgeneand derivalivesasbuildingblocks

We discoveredthat (I) satisfactorily reactswith various

amino acidsin standard conditions.The reaction mixture is

freed from excessreagent and byproducts by extraction

with ether and the Boc-amino acidsare readily obtained byconventional extraction and crystallisation pr-ocedu,e\177

accordingto scheme147.

O CI R Dioxane / H20 / Et3N/ II I I 20ocO-C-OCH-CCI3 + H2N CH-COOH .-\177

0) o R

78 -91%Yield

--tO-C-NH-CH-COOH + CI3C-CHO

Scheme 147:tert-Butoxycarbonylation of amino acids by 1,2,2,2-tetrachloroethyl-tert-butyl carbonate (1).

Reagent (I) proved to be especiallyuseful in the caseofunprotected hydroxy amino acids as examplified by the

synthesis of Boc-L-Serineand Boc-L-Tyrosine [.Seetable 3-26].The 1-chloroethyl congenerof (I), the 1-chloroethyl-

tert-butyl carbonate(11)which is a medium boiling liquid

(bp. 88\302\260C/20 mm), was found to give unsatisfactory

results, becauseit is much lessreactive than (I), and alsobecauseof the formation of acetaldehydeand its conse-quent reaction with the starting amino compound.

Some examples of preparation of N-Boc-amino acidswith (I) are shown in table 3-26.

Amino acid Yield of P1elting point [cz]20DN-Boc-AA (%) (\302\260C)

Gly 86 85-8L-AIa 90 80-I -24,c 2.1AcOH

L-Phe 79 85-87 +28,c 1.5EtOH

L-Pro 91 132-3 -60,c 2.0AcOH

L-Tyr 82 206 (DCHA salt) +32,c 1.8MeOH

L-Asp 60 117-9 -5,c 1.0HeOHL-Ser 78 139-40 +8, c 2.8HeOH

Table 3-26.\" Preparation of N-Boc-amino acids using 1,2,2,2-tetrochloroethyl-tert-

butyl carbonate (I).

Phosgeneandderivalivesasbuildingblockst

The crystalline 1,2,2,2-tetrachloroethyl fluorenylmethyl carbonateobtained in 98% yield (mp. 98-100\302\260C)

from 1,2,2,2-tetraethylchloroformate and fluorene metha-nol proved to be suitable for the preparation of Fmoc-amlnu acidsiI\177 good to excellentyields (Ref, \302\2514).

The reaction was alsoperformed with various types ofamines using different kinds of 1-chloroalkyl carbonates(Ref. 64) and was proved to be quite general exceptwith

weakly nucleophilic amines.Someexamplesof carbamatesobtained by the reaction of 1-chloroethyl carbonateswith

primary and secondaryamines aregiven in table 3-27.

Entry R 1R 2

R 3 Yield mp (\302\260C)

(%) bp. (\302\260C/ram)

1 Et -(CH2)5- 88 bp 95/182 Ph-CH 2- H Ph-CH2- 84 bp 175/0.13 Ph-CH 2- H HO-CH2CH2- 74

bp 170/0.5rap. 62-3

4\177O\177

H He 79 mp. 148/5 Ph-CH 2 -(CH2)2-O-(CH2)2- 84 bp. 140/1

mp. 49.5

CI O 0

CH3-CH-O-C-O-R1 + HN,

/ --\177,.R\177-O-C--N,

R 3R3

Table3-27.\" Carbamates prepared from 1-chloroethyl carbonates.

Imidazole alsoreactswith 1,2,2,2-tetrachloroethyl-tert-butyl carbonate(I) or with 1-chloroethyl-tert-butyl carbo-nate (II) to give its tert-butyloxycarbonyl derivative in _50and 86% yield respectively as shown in scheme148.

O CIi HN/\177N O\177 N,,\177N

t

O-C-O-CH-R 0'K2CO3/H20 rap. 47\302\260C

(I) R = CCl3 5\"10\302\260C

With: (I) 50%(11) R :CH3 (11) 86%

Scheme 148:Preparation of 8oc-imidazole.

130131)))

Phosgeneand derivativesasbuildinblocks

The application of the abovemethod to the synthesesof insecticidescarbamates Carbofuran (entry 4, table 3-2T)and Aldicarbe was briefly studied.Thus, Carbofuran wasreadily obtained in 79%yield from 1-chloroethyl benzofu-ranyl carbonatewhich was itself obtained in 89% yieldfrom the correspondinghydroxy benzofuran.

The method was alsosuccessfully applied to the reac-tion of 1-chloroethyl-S-ethyl thiocarbonate to give thiocar-bamates,for example the herbicideMolinate as depictedinscheme149.

CI O CI O

CH3-CH-O C-CI + Et-SH -\177 CH3-CH-O C-S-Et80% bp : 78\302\260C / 20mm

/ \177

HN\\ r/--

\\ tl

\177

\177 /'\177

C-S-Etbp. 141\"C/13mm

70%

Scheme 149.New preparation of the herbicide Molinate.

\177 \177 4 Reactionof phosgene

and its derivarives with

(arbamates,ureasand

amides

As part of our program concerning the study of safealternatives to the handle of the extremely hazardousmethyl isocyanate (MIC), we were interested in the deve-lopment of new routes to 3,5-dioxo-l,2,3-oxadiazolidinederivatives which are valuable as pharmaceuticals andagrochemicals.

In a typical example, we developeda new syntheticstrategy that doesnot use MIC for the preparation of theherbicide Methazole.Methazole was classically madethrough the reaction of MIC with 3,4-dichlorophenylhydroxylamine followed by treatment with methyl chloro-formate and cyclisation as shown in scheme1.50.

Phosgeneand derivativesas buildinblocks

/\177 H2 \177 CH3NCOCl\177/

\177

NO2 \177C'\1777

'/\177NHOH \342\200\242

\177,-

,,--\"\177 Pt/CCI poisoned CI

O O

C,\177N-C-NHMe

COCI2},- CI\177/\177/ N\177'\177NMe

\" or MeOCOCI \177CI

OH CI OM\177th\177zol\177

Scheme 150.\" Classicalsynthesis of the herbicide Methazole.

In our laboratories,the reaction of phosgenewith

methyl N-methyl carbamateby an improvement of the pro-cedure describedin the literature (Ref. 208)affordedmethyl N-chlorocarbonyI-N-methyl carbamate(I) in high

yield. The one-potcondensationof the intermediate (I) ledto Methazole in excellentyield as depictedin scheme151.

For safety reasons,we thoroughly studied the thermal

stability of the intermediate (I).We found that it decom-posesto methyl isocyanateon heating, very slowly when

pure, more rapidly and quantitatively in presenceof anucleophile, according to the mechanism depictedin scheme152.

o oII

Selectedsolvent\177--

CIMeNH-C OMe + COCl2 \177\" Me N

Pyridine )/OMe60\302\260C,

2 h (I) 093%bp. 85\302\260C / 13mm

(I) + CI\177NH-OH2)Heating\"

\177CI

\177 OH Me.J

Ci/ (\") IC'\177?-C'I\177\"C-OMe\177

O

Scheme 151:Preparation of Methozole \177ithout methyl isocyonote.

132133)))

Phosgeneandderivativesas buildin\177 blocks

O\177CICI

HeatMe N /\177 --\177,-Me-N=C=O+ MeCI + CO2

Scheme 152:Thermal instability of methyI-N{hlorocarbonyI-N-methyl carbemate (I).

Horeover,(I) exhibits a high level of toxidty. In ordertoover\321\236ome these problems, we investigated other routesand dis\321\236overed a novel and saferroute to Hethazole,star-ting from the interesting intermediate (111)as shown in

scheme153.COCI

I MeOHMeN C-OMe

(\177) 0NaH --

MeNH C-OMe....---II MeOCOCIO

(111) +

CI\177NHOHCI

Scheme

0

.C-OMeMe -N

(111)_ T 'C-OMe

// Low mp. stable solidObp, 86 \302\260C/8 mm

LD5o(Rat) :2850mg / kg

Cat.H+--\177 Methazole 92 %

15h , 60\302\260C

153:Novel and safe preparation of Methazole.

Also, carbamatescan be modified by other acylating

agents than phosgeneand chloroformates.In the courseof our attempts dedicatedto the search

of new pesticides,we were interested in the design ofproinsecticides,especiallyprocarbamateswhich are lesstoxic to mammalians than the parent carbamates.N-Acyl-

N-methyl or N-sulfenyI-N-methyl carbamatesderived fromCarbofuran or Aldicarbe are quite effective insecticidesand are often equal to superior to their parent compoundagainst insects.

In collaboration with SIPCAM (Italia) we studied the

synthesis and activity as insecticidesof two new types ofCarbofuran derivatives (V) et (VI) depictedin scheme154(Ref.209,210).

Phosseneandderivativesasbuildin8blocks

,\177 SCI2

O...\177/N-

SiMe3 -\177O

\" Me3SiCI

OII sQ2MeO-CC-NHMe \177 MeO-CC--N-S-CI

\177 (IV)

\177-O\177le\177 (v)O\177 \177N-s_cI --\177\"\177O Me

\177F\" CH2CI2 O-C-N, /-- -',O Pyridine II Me\"S N, OoO OII Me

0

Me O (VI)

O-C-N--SN C-C-OMett Me Me II

O OO-C-NH CH3

II

OScheme 154:Syntheses ofnew sulfenyl Carbofurans.

The reaction of phosgenewith substituted ureas is well

known. Phosgenereacts with tetrasubstituted ureas as achlorinating agent to afford chloroformamidinium chloridesin high yields. This topic will be discussedin volume 2.

In the caseof N,N'-dialkyl ureas,phosgeneis attackedby both oxygen and nitrogen atoms to give a mixture ofchloroformamidinium chlorides (A) (O-acylation of the

ureas) and allophanoyl chlorides (B) (N-acylation) asshown in scheme155(Ref.211).

CA) + CI-

.\177

\177- RNH--=C--=NHR 4- CO2O O-Acylation I

RNH-C-NHR + COCI2

N-Acylation Q'XC-CI

\177 R-N'(B)

\177,C-NHR

OScheme 155:Phosgenation pathways of N,N'-dialkyl ureas.

+ HCI

The distribution of O-acylationand N-acylation can beslightly controlled by the reaction conditions, but structuralfeatures of the N,N'-dialkyl ureas seemto be the dominantfactors.

134135)))

Phosgeneand derivalivesasbuildinblocks Phosgeneand derivalivesasbuildinblocks

Acylation reaction which affords chloroformamidinium

chloride is of great interest for the commercial synthesis ofcarbodiimides, especially dicyclohexylcarbodiimide (seevolu-

me 2).In the case of low molecular weight subtituents, the

separation of products (A) and (B) is very easybecauseofthe insolubility of the salt (A) in organic solvents.Scheme156presentstwo examplesof phosgenation of N,N'-disub-

stituted ureas.

IICOCI= O\\xc_ CI + CI-

\177 Me--N + MeNH--=C--=NHMeMeNH-C-NHMeDCE -NHMe CI1 h, 20\"C O insoluble in ether

71% mp. 36\302\260C

\177 DCE \177HN NH + COCI2 \177 HN N CI 86%y l h Y \177[\177 mp. 155-7\302\260C

O 80\"C (C) O O

Scheme 156.\" Examples of phosgenation of N,N'-disubstituted ureas.

N-Chlorocarbonyl-2-imidazolidone (C) is for instance

used in the preparation of pharmaceuticals such as the

antibiotic Azlocillin [Scheme157].\177 Phenylglycine

HNyN

\177I...CI

(C) O O O O COOH

Coupling agent

\177,,

N\177H2N S H\177/NA

COOH COOH

Scheme 157:Preparation of the antibiotic Azlocillin,

In orderto produce methyl isocyanate in good safety's

conditions, Bayer A.-G.has developedan industrial processbasedon the reaction of diphenyl carbonate with N,N'-climethyl

urea at high temperature according to scheme158(Ref. 212).

oII

200-250\302\260C

+ MeNH--C-NHMe\1772MeN=C=O+ 2 Ph-OH

5\177henle 158 Pmparc/tson of MIC through let?orlOn Of dlpl'lenyl ca/bonate w\177th

It is noteworthy that in this process,one mole of phe-nol is releasedfor one mole of HIC produced.

We studied at a laboratory scale a similar route ofsynthesis starting from phenyl chloroformate instead ofdiphenyl carbonate(Ref. 213).The new processpresentsthe advantage that only half a mole of phenol is formed

per mole of MIC.

Thus, phenyl chloroformate was reactedwith dimethylurea in toluene at reflux to give methyl N-phenoxycarbonyl-N-methyl urea (D)in 95 % yield. No addedbasewas requi-red. The intermediate (D) decomposedon heating at180\302\260C in presenceof a selectedbasic catalyst to affordHIC in quantitative yield [Scheme159].

ococl oNO\177_ __\177II

Toluene 0+ MeNH-C-NHMe \177 Me- (D)

Reflux ),--NH Me0 95%

0 \177 Ph mp. 98\"C

N\177IC

Catalyst:B

\177_

2 Me-N=C=O + PhOHMe-

180\302\260C

0Scheme 159.\" Novel preparation of MIC from phenyl chloroformate.

It is well known that oxalyl chloride reactswith non-

substituted amides to afford acyl isocyanatesin high yields

(Ref. 214).In contrast, phosgeneacts as a dehydratingagent to give nitriles as shown in scheme160.This inter-

esting reaction, its mechanism and applications will bediscussedin volume 2.

136 137)))

Phosgeneand derivalivesas buildinblocks Phosgeneandderivalivesasbuildinblocks

0II ocl-c-c-cl

IIo II \177 R--C-N=C=O + CO+ HCI

R_C_NH 2\177

CI--C-CI \177R--C\177_\177N + CO2 + 2 HCI

II

OScheme \1770 .\" \177eoctions of oxalyl chloride and phosgene with primor\177 omides.

Acyl isocyanates,especiallytrichloro acetyl isocyanate(TAI), 2,6-difluorobenzoyl isocyanate (DFBI)andmetha-

cryloyl isocyanate (HAl) are very valuable intermediatesfor pharmaceuticals, agrochemicals,plastics,adhesivesand

coatings.The structures, physical data and types of appli-cations of these three major acyl isocyanatesare given in

table 3-28.

Name Structure Data Applications

TAICI3C_C_NCO

bp : 80\302\260C/27 mm Pharmaceuticals :prep. of

II LDso> 20OOmg antibiotics such as sodiumO Cefuroxime

HAlCH3

I bp. 122\302\260C

H2C=C-C-NCO(Atm. press.)II

OF

\177-\177-NCObp. mm80\302\260C/0.3

Table 3-28:Valuable industrial acyl isocyanates.

Vinyl functionalized resins

for adhesives, coatings,

fibers, electronic, medical

materials etc.

Synthesis of difluoro

-benzoylureas as insecticides

(numerous patents)

The demonstrated utility of these high-reactive isocya-nates prompted us to searchfor a phosgenation processmore economicalthan the oxalyl chloride route. Our

attempts succeededin the development at a laboratoryscaleof a method basedon the reaction of phosgenewith

N,N-disilyl amides as depictedin scheme161(Ref. 21_5).

F F

Et3N

\177-'\177C N'SiMe3

\177-'\177C.NH 2 + Me3SiCI \177 -\177---\177

II Reflux\"\177-\177 IOI

SiMe3F O F

65% dist.

F bp. 68\302\260C/0.15 mm

Neat\177, -N=C=O + Me3SiCI ( 100%recovery)

COCI27 -

8\302\260C FO

DFBI 54% dist. ; bp. 100\302\260C / 0.25mm

Scheme 161:Novel preparation ofDFBI by phosgenation of N,N-bis(trimethylsi-lyl)-2,6-difluoro benzamide.

It is noteworthy that, in the courseof our studies onthe preparation of acylisocyanates,we put some improve-ments to the known procedureby condensation of aroylchlorideswith sodium cyanates.We found that specialcatalysts and solvants must be used for receiving satisfac-tory yields as depictedin scheme162(Ref.216,217).

F F

-CI + NaOCN \177, -N=C=OSRCI4 0.05eq.

F0

180\302\260C, 2 h F

70% dist.bp. 83-8\302\260C / 10mm

Scheme 162:Preparation of DfBI from 2,6-difluoro benzoyl chloride.

The scopeand limitations of this processwill be pre-sented in volume 2 in the chapter dedicatedto the che-mistry of acid chlorides.

During our continuous collaboration with Ishihara

Sangyo Kaisha Ltd, we prepared2-chloronicotinoyl iso-cyanate and patented the synthesis of interesting newinsecticideseffective against larvae, especially from lepi-doptera (Ref. 218).The synthesis is depictedin scheme163.

138139)))

Phosgeneand derivativesasbuildingblocks

CI CI

\177/='\177--C-NCO + H2N O CF3 \177,

('\177'00 Ci N'\321\236'\177

68\302\260/\302\260 YieldcScheme 163:Preparation of a new N-pyridylcarbonyI-N\177p\177enyl urea asinsecticide

In the reactionswith N-substituded amides, phosgenegenerally a\177ts as a \177hlorinating agent yo give Vilsmeiersalts (seevolume 2).As in the \177ase of primary amides, theuse of N-silyl amides is often required to observeN-a\177yla-

tion in reasonableyields.The preparation of 4-ethyl-2,3-dioxo-l-piperazine\177ar-

bonyl \320\210hloride provides with a good illustration of a com-merdal pro\177ess through a silylation (Ref.219).We studied

thoroughly the pro\177ess depi\320\210ted in s\177heme 164,and

brought some improvements. This \177arbamoyl \320\210hloride isusedfor the preparation of antibiotics su\320\210h as Piperadllinor Cefoperazone.

Dioxane\177 Et3N

Et--N NH + Me3SiCI

COCI2

Et--N SiMe3

o o

+ Me3SiCI

to berecycled

Piperacillin Et_N\177N\177O\177

COOHScheme 164:Phosgenation ofdioxopiperazine and structure of the derived anti-bio tic Piperacillin.

Phosgeneandderivativesasbuildingblocks]

/3-3-5 p.Toluene sulfonyl isocyanate (PTSI)is an interesting

R,a\321\236tion of highly-reactive isocyanatewhich has found severalvaluable

hlos\177ene

with applications such as :fmamides: -

dehydrating agent for mastic and filler resins, especiallypreparation for building trade ;elsulfonyl - chemical intermediate for the synthesis of hypoglycemiciso\177yanates pharmaceuticals, for exampleTolbutamide or Gliclazide :

0-key starting material for the preparation of resinsfor nail

lacquers,to replaceconventional arylsulfonamido formal-dehyde resins which releasecarcinogenicformol (Ref.220).

The synthesis of p. toluene sulfonyl isocyanateby phos-genation of p.toluenesulfonamide in presenceof an alkyl

isocyanate as the catalyst, generally n-butyl isocyanate,iswell describedin severalpatents and publications [Scheme165].

Chlorobenzene

Me---\177SO2NH2 + COcI2 \177,

Me--\177SO2NCOBUNCO PT$1

rap. -2\302\260C

bp. 270\302\260C

Scheme 165:Preparation of p.toluene sulfonyl isocyanate (PTSI).

In orderto economically improve the industrial processand to avoid side reaction such as the formation of tosylchloride, we thoroughly studied the mechanism of the

phosgenation. We demonstrated that contrary to the

impressions given in the literature, the sulfonyl urea (11)isnot the only true intermediate in the reaction [Scheme100].Ourtrials showedthat the phosgenation proceedsina first stagethrough the readily and quantitative formationof the insoluble symmetrical sulfonyl urea (I) which reactswith butyl isocyanateto afford sulfonyl urea (11)and PTSI.The intermediate (11) reacts then, more slowly, with

phosgeneto give PTSIand regeneratesbutyl isocyanate.The assumedmechanism is depictedin scheme106(Ref.221).

140141)))

I

Phosgeneandderivativesas buildin\177 blocks Phosgeneandderivativesasbuildingblocks

1)

The formation of tosyl chloridewas shown to proceedthrough phosgenation of PTSIitself, thus affording chloro-carbonyl isocyanatewhich polymerizes.

Me---\177SO2NH2 + COCI2 \177

Me---\177SO2NH-\177I

-N HSO2-\177Me

o O)

2) (I) + Bu-NCO \177

(II) O PTSI

3) (11) + OOOi2 \177PTSI + Bu-NCO + 2 HCI

Sidereaction :

Me---\177--SO2NCO+ COCI2 \177

Me---\177--SO2-CI+ CI-C-NCO

IIoScheme 166.\" Mechanism fo the catalysed synthesis of PT51.

3 4 Rin\177

formationreactions

This chapter usesan organization basedon the natureof the two heteroatoms involved in the closing of the ringby the carbonyl group : O<->O; O<->N; N<->N ; N<->S.

34/Cyclisation

betweentwooxygen atoms

Although ethylene carbonatecan be easily made byphosgenation of ethylene glycol, the only industrial processis the carbonatation of ethylene oxide [Scheme167].

HO-CH2CH2-OH + COcI2- 2HCl \177 /\177

oyo\177--70

+ 002 /Catalyst O

Pressure

Scheme 167.Preparation of ethylene carbonate.

However, the phosgenation processhas much morevalue in lesssimple products.We previously have treatedin section3-2-2-I the reaction of excessphosgenewith

glycerol which affords a monochloroformate containing afive membered cyclic carbonatefunction.

The phosgenation of catecholis of high interest, becau-se the resulting o-phenylene carbonateis the key startingmaterial for the preparation of the insecticidePropoxur asshown in scheme168.OH Toluene / H20

\177==+ COCI2 \177- O

OH NaOH0-

5\302\260C 85%O mp. 120\302\260C O

MeNH 2

\177,\177O-C-NHMe\177 \177,\177,,\177O-C-NH

Me

\177 \"OH

\177

\1771\"\1770---//

Scheme 168.Preparation ofthe insecticide Propoxur.

142143)))

Phosgeneand derivativesas buildin\177 blocks Phosgeneandderivativesas buildin\177 blocks

Phosgenation of 2,3-butanediol presentsa high poten-tial value in the pharmaceutical field. The cyclic carbonatethus obtained can be photochemically chlorinated to give a

vinylene carbonate(I) asdepictedin scheme169(Ref.222).

W + COCI2HO OH

hv\177

0\17700

DCE

20\302\260C

160\302\260C

- HCI

W 6%

O,,,\177O

bp. 120\302\260C / 12mm

O

\177 63%\177

%0 bp. 130\302\260C/

6 mm(\177) o

Scheme 169:Preparation ofvinylene carbonate derived from 2,3-butane diol.

The substituted vinylene carbonate(I) can be usedforthe preparation through chlorination and dehydrochlorina-tion of the intermediate (11) which is the key reagent forthe production of Lenampicillin [.Scheme170].

CICH2x\177CH3

%0(\177l) o

\177 0\177.-- NH Lenampicillin

{ /\177' k\177 S,k\177 \\ (Antibiotic)

Scheme 170:Substituted vinylene carbonate for the modification ofantibiotics.

(11) is also used in the synthesis of Cefcanel,a new

cephalosporinfrom Kyoto Yakuhin and Astra (Ref.223).It is noteworthy that the vinylene carbonate(I) in sche-

me 169can be obtained by phosgenation of acetoinasdepictedin scheme171(Ref.224).

OX\177O H

+ COCl2DCE

N,N,-Dimethylaniline

\"\177/ 72%\177

O...,/O mp. 79-80\302\260CIIO

Scheme 171.\" Phosgenation ofacetoin.

King Jr reporteda facilesynthesis of chlorinated dioxo-lanonesby a simple, one-pot,direct addition of phosgeneto 1,2-diones(Ref.225).Thus, the reaction of 2,3-butanedionewith phosgenein the presenceof pyridine affords

trans-4,5-dichloro-4,5-dimethyl-l,3-dioxolane-2-onein82% yield as shown in scheme172.

CH2CI2 \177+ COcI2 i-Pyridine in OyOcatalytic am. O

CI Me

.\17782%HCI

Meb' /CI mp. 88\302\260C

\177

O..\177O

OScheme 172:Phosgenation of2,3-butane dione.

In an obscurepaper, Pews reportedthe formation ofbromomethyl ethylene carbonatethrough an unusual ther-mal rearrangement of 2,3-dibromopropyl ethyl carbonate(Ref. 226).We studied the scopeand limitations of thisreaction and defined the bestconditions of the processasshown in scheme173.

144145)))

Phosgeneand derivativesas buildingblocks

Br

- EtBr

a) 200\302\260C, without \177catalyst

or Br

\177 Ob) 150\302\260C in the

\177. O-----\177

presenceof aEt/

selectedcatalyst v\177O

B:Br

---\177 a) 88%

O,.\177O

b) 95%

OScheme 173.'Unusual accessroute to substituted ethylene carbonate.

Chlorinated derivatives of ethylene carbonateitself are

very interesting and valuable compounds.When ethylene carbonate is monochlorinated, the

chloroethylene carbonate thus obtained is the starting

material for the synthesis of vinylene carbonatewhich is

used in radical polymerization to yield high-molecular

weight polymers and copolymersor in Diels-Alder cycload-ditions [Scheme174] (Ref. 227).

CI Ether

\177 CI2 , hv \177 Et3N \177 Vinylene

%O----\177-

%O\177

%Ocarbonate

- HCIReflux, 5 h mp. 22\302\260C

O O O bp. 162\302\260C

Scheme 174:Preparation of vinylene carbonate.

When ethylene carbonateis partly chlorinated, the two

dichlorinated products (111)and (IV) formed cannot be

separatedby distillation and an 85:15mixture of (111): (IV)

only is available commercially.We discoveredthat (IV) cleanly decomposesto chlora-

cetyl chloride in presenceof \177 naked chloride anion \177. This

method which destroys preferentially (IV) allows to recover

(111)in 92 % yield by subsequent fractional distillation

[.Scheme175].

Phosgeneandderivativesasbuildingblocks

\177_\177,.c

cI\177 2 CI2 , hv

CI I

/__\177CI

%0 %0+ %o- 2 HCl(111) O Oo (\177v)

Decomposition of (IV)

O

O.\177O

Q\321\207 Cl

0

\177 CICH2-C-CI + CO2

Scheme 175:Preparation of pure dichloro ethylene carbonate (111).

(111)was claimedas the key for the synthesis of novelexplosivesas shown in scheme176(Ref.228).

Cl

,\177/Cl02N\" N/\177 N

-NO2.NHNO 2

oyO+ H2C, \177 \177

(111) ONHNO2

oyOO

Scheme 176.Novel explosive from dichlora ethylene carbonate.

Photochemical perchlorination of ethylene carbonateaffords tetrachloroethylene carbonate (V) in high yield

(Ref. 229).When (V) is treated with a traceof a nucleo-phile, it cleavesquantitatively to oxalyl chloride and phos-gene[Scheme177](Ref. 230).

This decompositionis today's standard processfor themanufacture of oxalyl chloride.

146 147)))

Phosgeneandderivativesas buildingblocks Phosgeneand derivativesasbuildinblocks

CI CI mp.- 17\302\260C4 CI2 , hv CI_ i i _Ci/\177k m \177 bp. : 78-80\302\260C/35 mmo - 4

--u'Y\302\260

d25:1.710 0CI CI Catalyst

Cl-\177_\177CI\" cr\"

\177-+ COCl2

O'-,]i/\302\260

CI OO Oxalyl chloride

Scheme 177:Preparation of tetrachloroethylene carbonate and its decompositionto oxalyl chloride and phosgene.

While studying the catalyzed decompositionof tetra-

chloroethylene carbonate(V) by onium salts, we observedthe formation of a little trichloroacetyl chloride.Since(V)

present three reactive electrophiliccenters: the carbonyl

group and the two carbon both linked with two chlorine

atoms, it can be attacked following two different pathways

as diagrammed in scheme178.

Cl O

O.3.OI

O o O\177)

\"\177-\C,-")C,\177,\\ If attack to the

\", C012

= CO2

OScheme 178:Possibletypes of nucleophific attacks to tetrachloroethylene carbo-

nate by CI.

We thought that if a catalyst for directing cleanly the

reaction either to the formation of oxalyl chlorideor to tri-

chloroacetyl chloride could be devised,the ready availability

of (V) would seemto make this compound a very attactive

intermediate. This work is currently under investigation.

Also, we discoveredthat tetrachloroethylene carbonatecan be used as a highly effective chlorinating agent for acid

chlorides preparation asdepictedin scheme179(Ref.231).

CI CI

+CI.\177]\177oCI

Neat

2 R-COOH \177.2 RCOCI

O\177100-150\302\260C 4-CO4-002 2 HCI+

O No catalyst95-100%

Scheme 179:Preparation ofacid chlorides using tetrachloreethylene carbonate.

The main issue under discussion is how this reactioncan work without any catalyst. In contrast to oxalyl chloride,phosgenerequires a catalyst to convert carboxylic acid toacid chloride.Thus, the above reaction would give acidchloride in no more than 50% yield.

Furthermore, we studied the describeddechlorinationof tetrachloroethylene carbonate(V) to dichlorovinylenecarbonate(Vl) with zinc (Ref.229).(Vl) is an interestingintermediate which as a cyclophile permits simultaneousintroduction of masked o,-hydroxy keto and o,-diketo func-tions respectively into the cycloadducts(Ref. 232).Oneexample is given in scheme180.

CI CI Ether

Cl,\177=.\177CI

85%dist.Cl'd/\177

CIZn(Cu)(DMF)

\177- mp. 19.5\302\260C

OyO Reflux, 10hO O

O (Vl) YObp. 147\302\260C

CIAcetone \177 H20

[\177OOH\177H2 + (Vl) = O \177OHCH2 hv

\177O\177%O 80%Room temp.

Scheme 180.\" Synthesis and example ofuse ofdichlorovinylene carbonate.

Phosgenation of hydroxamic acidsaffords nitrile carbo-nateswhich has beensuugested as isocyanatesprecursors(Ref.233).

Onedemonstrative exampleappliedto the synthesis ofisopropenyl isocyanateis given in scheme181(Ref. 234).Note that the use of a catalyst such as ferric salts permitsto lower the required decompositiontemperature.

148 ]49)))

Phosgeneandderivativesasbuildingblocks

H20

==k+ NH2OH.\1772SO\177

\177\177NaOH

NHOH

coOMe O

H20 / CH2C\1772 =\177 85% yield dist.

COC\1772 '\177N\177 bp. 38-40\302\260C/ 0.1mm\177 O,..,/O rap. 34\302\260C

NaOH

pH :4-6 O

\177\177 N=C=O

O

COC\1772

_\177oCH

OOH \177Mandelic acid

H2N,\177S,\177 Mek

COOH

scheme 181:Preparationof isopropenyl isocyanate.

phosgenationof o\177-hydroxy

acidsaffords cyclicmixed

carboxy\177ic-carbonicanhydrides

which can be used as acti-

vated form of acid function in reaction with amines to

afford amides as i\177ustrated by the example givenin sche-

me 182(Ref.235).O

I

NaHCO3

Cefamandole(Antibiotic)

GOOH

scheme 182.\" Preparationof Cefamandole.

Phosgeneand derivativesasbuildingblocks

Cydisationbetween

oxygen andnitrogen atoms

Phosgenereactseasily with amines containing a hydroxylfunction in 2 or-3position to afford oxazolidones(cyclicfive membered carbamates)or oxazinones(cyclic six mem-beredcarbamates)respectively.

The preparation of 3-H-benzoxazol-2-onefrom o-ami-nophenol and urea is well known but the reaction is accom-panied by the formation of tars and other sidereactions.In contrast, phosgenereactscleanly with o-aminophenol.We have deviseda simple processwithout any acid sca-venger which affords pure benzoxazolonein excellentyieldas depictedin scheme183(Ref. 236).

H

\177'\177NH2

Chlorobenzene

[\177\177=

+ COCI2 \177- O\177 -OH 100\302\260C , 4 h

-2 HCI 96%yieldrap. 139\302\260C

Scheme 183:Improved phosgenation process to benzoxazolone.

Benzoxazoloneis a valuable compound for severalapplications, for example as a key starting material for themanufacture of Phosalone,an insecticideused mainly oncotton [Scheme184].

H H

0 --\177 0CI

SsII

,CH2CIII

,CH2_S.P_(OEt)2

\177\177=(eto)2P-SNa

O \177 OCI CI

Scheme 184.Synthesis ofPhosalone.

Someother interesting substituted benzoxazolonesarealso used as pharmaceuticals, for example the musclerelaxant Chlorzoxazone[Scheme185](Ref. 237).)))

Phosgeneandderivativesasbuildingblocks Phosgeneandderivativesasbuildingblocks

This brief presentation outlines the utility of the NCA's.

But this is only part of the picture. Added to this are ure-

thane N-carbo\320\247y anhydrides calledUNCA's we developedunder licenseof BioresearchInc.(Ref.249).UNCA's which

are both protectedand activated form of amino acidsare

highly effective coupling agents for the synthesis of pep-tides as illustrated in scheme198.

0 R 0 R 0Z-O- -N + H2N,,,,,v,.,,\177

\177Z-O-C-NHCH-C-NH-,\177,',v\177w

\177O .CO2O N-protected peptide

Scheme 198:Principle of use of UNCA's ascoupling agents in peptides synthesis.

UNCA's are crystalline solidswhich are stable in the

absenceof water and nucleophiles.They react readily and

cleanly with amino functions without racemization. Carbon

dioxide is the only by-product which allows facile purifica-

tion and isolation.

Oneexampleof synthesis of UNCA's is given in scheme199.

Fmoc-CI+50-70%

Scheme 199:Example of preparation of UNCA's.

m

Fmoc--N\177oo

O

Omp. 106-7\302\260C

c\177 : + 28.7\302\260

Let us now considerto what extent the previous reaction

of phosgenewith o\321\236-amino acid can be applied to p-amino

acidsto yield six membered cyclic O-acylcarbamates.

2H-3,1-Benzoxazine-2,4(1H)-dioneknown as isatoic

anhydride (VI) is the most popular six memberedcyclic

O-acyicarbamate.The synthesis of isatoic anhydride by

ring closure of anthranilic acid with phosgene is well

described(Ref. 250).However, we have developedan

improved phosgenation processwhich leadsto higher yieldand purity as demonstrated in scheme200(Ref. 251).

1)H20/ HCI

2)COCI2 .T< 50\302\260C

j 95%pure

O

]\177.COOH

\177N.,,\177NH2 O

Chlorobenzene, COCI2(Vl)

20\302\260C, then 105\302\260C

mp. 252\302\260C

96.5%yield99.9%pure

Scheme200..Comparison between described (a) and SNPE (b) routes to isatoicanhydride.

Isatoic anhydride (Vl) is an extremely versatile com-pound becauseof the easeof its reactionswith nucleo-philes or electrophilesas outlined in a rewiew (Ref. 252).

For example it is claimed as a starting material in thesynthesis of the analgesicGlafenine as shown in scheme201(Ref. 253).

O

(Vl)H 2

CI O

CI '-L,,,.\177%N H

OH

Deprotection\177-

CI'\177Scheme201.Preparation ofGlafenine.

158159)))

Phosgeneandderivativesas buildingblocks Phosgeneand derivativesas buildingblocks

H

+ COCi2 : O\177 OI4

mp. 191\302\260C

Scheme 185:Preparation of Chlorzoxazone(muscle relaxant).

Oxazolopyridines, such as the novel analgesic(111)now

being in clinical trials, constitute a medicinal classof hete-

rocyclic compounds.Phosgenation of 2-amino-3-hydroxy

pyridine in the presenceof pyridine as scavengerand sol-

vent leadsto the oxazolopyridine (I) in excellentyield as

shown in scheme186(Ref. 238).

\177OH

Pyridine

\177==+ COCl2 \177--O

NH2 (I) H 95.5%mp. 210\302\260C

1\177)\177> oN/---\177N\177\177 Novel analgesic

Scheme 185:Preparation and u\177e of an oxazolopyridine.

\177e re\177ioisomeric system (11)derived from the readily

available 3-amino-2-pyridoneis less easy to prepare.Guillaumet and coworkersreportedthe synthesis of (11)via

a one-stepprocessusin\177 diphos\177ene (Ref.239).The reac-

tion was carriedout in CH2CI2/THFmixture in presenceof

triethyl amine at-78\302\260C, and the product isolated and puri-

fied by flash chromatography [Scheme187].H

(\177)

\177.\177H2

c.3cococ,L\177

=;-- 0 78%THF / CH2CI2 ,

H-

78\302\260C, 6 h rap. 252\302\260C

Scheme 187:Preparation ofoxazolo[5,4-b]pyridin-2 (1H)-one.

In aliphatic serie,we have developedthe synthesis of

N-(2-hydroxyethyl) oxazolidone(IV) at an industrial scale,

according to the processdepictedin scheme188(Ref.240).Neat

\177 ,CH2CH2-OH Catalyst /--kO O + HN\177 O NY \177C\"2CH2-O\" 115\"45\302\260C Y --\177'--- OH

O 3-4mbar O- HOCH2CH20H (IV) 100%

Scheme 188.\" Preparation ofN-(2-hydroxyethyl) oxazolidone.

The substituted oxazolidone(IV) is especiallyuseful asbuilding block for acrylic monomers synthesesor for phar-maceuticals.

Thus, the esterification of (IV) by acrylic acid affords anew acrylic monomer, SNPE codenumber CL959,in goodyield as shown in scheme189.

/---k Toluene0 N + H2C=CH-COOH \177Y \177---OH H2SO4

O 75\302\260C/300 mmOv)

\177 \\\\0 CL959O....../N--\177 _./\177 bp. 155\302\260C/2 mm

II \"--u \",, Low viscosity0Scheme 189.\" Preparation of new UV-curable monomer from N-(2-hydroxy-ethyl)oxazolidone.

Acticryl CL959has widespreadapplications,mainlyas reactive diluent in fast drying coatings (Ref. 241).It isuseful in various industrial sectorsfor :- classicalcoatings for wood,paper, plastics,metals ;- adhesives,pressuresensitive adhesives;-

optical fibers ;- electronics,photo-resists.N-(2-Hydroxyethyl) oxazolidone(IV) should be also a

valuable intermediate for the synthesis of N-arylpipera-zineswhich are widely used in the preparation of pharma-ceuticalssuch as the neuroleptic Fluanisone.

Squibb reportedan interesting example at the 207 thACS National l'leeting depictedin scheme190(Ref.242).

152 153)))

Phosgeneandderivativesas buildingblocks Phosgeneand derivativesas buildingblocks

\177 Ts-CI \177

O\"'\177\"

N \177OH Base\177

OY N\177-O'TsO O

0v)

ArNH 2

O'-,\177\"

N

--\177__ N H_Ar

OScheme

HBr 30%/ AcOH /\177k\177 HN N-Ar

Heat40-91%

190:Novel preparation of N-arylpiperazines.

Oxazolidonescan be alsopreparedfrom the reactionof primary amines with 2-haloalkyl chloroformates. This

method has found widespreadapplications in various sec-tors of the chemical industry. The industrial preparation

processof the systemic fungicide Oxadixyl is a good first

illustration [Scheme191](Ref. 243).

Me

--NH-NH2

MeOII

Me-O-CH2-C-CI

CICH2CH2\"O-C-CI Me

0

Me H OCI

Me HYNaOH

,N\177,O

\177/\177----kO-

M\177

\302\260xadixyL

5theme 191:Industrial scalepreparation ofthe fungicide Oxadixyl.

The reaction of phosgenewith amines containing an

-OH function in 3-position readily affords oxazinones asalready mentioned.

The preparation of the antidepressant Caroxazonedepictedin scheme192illustrates the value of the method

(Ref. 244).

I\177H\177NHCH2COOE t

NH3\177.-

I\177OH

'CH2NHCH2-\177I-NH2

OCOCI2

\177,\177

O=, \"\177

O CaroxazoneNaHCO3

NV\177NH 2H20/ CH2CI2

Scheme 192:Preparation of the antidepressant Caroxazone.

The intermediary synthesis of oxazinonesderivatives isthe key for the N-hydroxypropylation of substituted ani-lines used as componentsin hair dyes (Ref. 245, 246).One example is given in scheme193.

NH 2O

CI-(CH2)3-O-C-CI NaOH

HO K2CO3Me

CIO

Me =. Me NH-(CH2)3-OH

HO HO

Scheme 193.'Hydroxypropylation of substituted anilines for the preparation ofhair dyes.

Phosgenereactswith cz and \177amino acidsto yield fiveand sixmemberedO-acylcarbamatesrespectively.

Thus, phosgenehas proven to be very effective in the

preparation of N-carboxy anhydrides (NCA) from cz-aminoacids.Thesecompounds:2,5-dioxo-1,3-oxazolidines(V),also calledLeuch'sanhydrides have widespreadapplica-tions especiallybut not only in peptidessynthesis [Scheme194].

154155)))

Phosgeneand derivativesas buildingblocks Phosgeneand derivativesas buildingblocks

coc,i

COOH OOHR--\177

(large excess)\177,

R

NH2

LNH-\177-CI

O

o

__\177N\177,

2 HCI C-CIR =

R---\177

(V) H O - CO2 NH2'HCI

NCA

%COCI2 C-CI C-CI--.

R----\177--.

R----\177

NH-C-Cl - HCI N=C=OII

OScheme 194.\" 5eneral picture ofN-carboxy anhydrides preparation and further

reactions.

Although sensitive to traces of moisture and more

generally to nucleophilic attacks, NCA are now producedand sold in large quantities. The scopeand limitations oftheir chemistry, as well as their.applications are not discus-sedin details here in this section and arereservedfor sec-tion 4-4 in vol. 2 dedicatedto the protection and activation

of functional groups.However, some representative examplesof applica-

tions are given in the presentsection.The NCA coupling method is conceptually simple and

elegant.This method is now used in efficient large scaleproduction of peptides,for example for the preparation of

semi-synthetic dipeptides Enalapril and Lisinopril (Ref.247).The synthesis of Ala-Pro which is the key buildingblock to synthesize Enalapril is diagrammed in scheme195.

156

Ocoo- CoCI2 , excess/\177-r\177

Me\\--/ \177 Me--\177N<

95%NH3\321\207

3.5h, 30\302\260C

unisolatedL-Alanine H O

1)\177-\177N\177COOKH

\177, Me\177N\177cooH

Ala-Pro\177

2) H\321\207

H2N O 90%Scheme 195.\" Preparation of Ala-Pro through Ala-NCA.

Enalapril (structure in scheme196)is an angiotensin-converting enzyme (ACE) inhibitor for the control of hyper-tension.

COOEt Me C,OOH

% /,)--CH2CH2--C--N--C--C--N\177H H 0

Scheme 196:Enalapril.

In another example, Sarcocine-NCApreparedbyphosgenation of sarcosine,followed by cyclisation in thepresenceof triethyl amine is used for the preparation oflipopeptide-basedbranched polymers forming thermotro-pic and lyotropic liquid crystals as shown in scheme197(Ref. 248).

THF

MeNHCH2_COOH \177- Me_N,/\177O Sar-NCA

1)COCI2 yO2) Et3N O

H2N(CH2)12-NH2OII

H2C-----CH-C-CI

Boc-F\177 Boc--HN-(CH2)12-NH2

\342\200\242

- H2C\177---CH-C--HN-(CH2)12.NH.Bo cTHF, Et3N II

O1)Sar-NCA

H2C\177CH-C-HN-(CH2)\1772-NH-(Sar)6-Sar_H2) Deprotection II

OScheme 197.\" Preparation of Sarcosine.NCA and use in the preparation ofoligo-mers for lipopeptides.

157)))

Phosgeneandderivalivesas buildingblocks Phosgeneand derivalivesasbuildingblocks

Phosgenereactswith hydrazides to afford 1,3,4-oxa-diazolinones.One well known example is the synthesis ofthe selectiveherbicide Oxadiazonfrom Rh6ne-Poulenc

[Scheme202](Ref. 254).

cl--I--\1771

-clc\177

o +CI NH-NH 2 \177' CINH-NH-\177:

iPr-O iPr-OO

COCI2

iPr-O OScheme202:Preparation of the herbicide Oxadiazon.

Oxadiazon =

We have studied the preparation of 5-ethyl-1,3,4-oxa-diazolinone (VII) by phosgenation of propionyl hydrazideas depictedin scheme203(Ref. 255).

EtToluene

Et-C-NHNH2 + COCI2 \177' O NHII

60\302\260C, 5 hO II

(VII)100% O

(VII) + EtNH 2

Et-C-NH-NH 2II

O

Toluene\177 Et-C-NH-NH-C-NHEt

50-70\302\260C, 4 h II II

97 % O O

+ Et-NCO

Scheme203.'Preparation and use of 5-ethyl 1,3,4-oxadiazolinone.

Compound (VII) can be further transformed to triazo-Iones,useful building blocks for pharmaceuticals such asEtoperidone or Nefazodone(seecyclisation betweentwonitrogen atoms, next section).In the caseof Etoperidone,this transfomation avoids the use of toxic ethyl isocyanateto get the required intermediate as shown in scheme203.

3,5-Dioxo-l,2,4-Oxadiazolidineshave been found as amoiety of the natural excitatory amino acid Quisqualic acidand their synthesis by numerous methods has beenextensi-vely studied by Zinner and co-workers (Ref. 256).Reactionof methyI-N-chlorocarbonyI-N-methyl carbamate, (VIII),(preparation given in section 3-3-4, this volume) with

hydroxylamine affords 3,5-dioxo-4-methyl-l,2,4-oxadia-zolidine (Acronym :P1ODD)in good yield as shown inscheme204 (Ref. 2.57).

O\177_

OcI 1 ) NaOH / H20 ,/\177 NH

Me--N\">,--O_Me//+ HCINH2OH

2)) HCl\177\"

Me-Ny(\177

O(VIII)

O 90%mp. 101\"c

(CHCl3)Scheme204.'Improved preparation of MODD.

While exploring new alternatives to the handle of loweralkyl isocyanates,we thought that the nitrosated MODDcould be a good candidate for a new synthesis of methylisocyanate through a t\177vo-components safe processaccor-ding to the mechanism depictedin scheme205(Ref.258).O O

HN_/\177

N

I\177,,

N-Me \177

ON/\177+ CO2+ N20O

Scheme 205.'Expected generation of methyl \177ocyanate by a two-componentssafe process.

160161)))

Phosgeneand derivativesasbuildingblocks

Sometrials appliedto a model reaction by trapping the

methyl isocyanate as butyl N-methyl carbamatewerevery

promising as demonstrated in scheme206.

Oz\177NH

n-Bu-OH

Me-Ny\177

+ n-Bu-OH \177, Bu-O-C-NHMe + t-BuOHt-Bu-ONO II

O 50\302\260C, 2 h O85%

Scheme205:Use ofMODD/t-butyl nitrite asmethyl isocyanate precursor.

Furthermore, while studying the potential applications

of HODD as a building block for the synthesis of 2-acyl-3,5-dioxo-l,2,4-oxadiazolidines,we discoveredthat it is a

very good leaving group. This led us to the design of the

previously unknown symmetrical 2,2'-carbonyl-bis(3,5-dioxo-4-methyl-l,2,4-dioxazolidine), (acronym :COHODD),as a new coupling reagent for the preparation of carba-mates from hydroxy compounds and primary or seconda-

ry amines (Ref. 259).COHHODwas readily obtained in goodyield by simple

phosgenation of HODDin refluxing toluene in presenceof

hexamethylguanidinium chloride hydrochloride (HHGCI.HCl)as the catalyst [Scheme207].

Toluene

O,k\177

O O\177-NH

HMGCI.HCI,0.5mol %N\177J\177 N..\177

2Me-Ny

\177)

+ COCI2 \177-

MeNy\177)

(\177NMeReflux, 3 h

O \"MODD\" 82% O Omp. 204\302\260C \"COMODD\"

Scheme207:Preparation of EOMODD.

Comparedwith 1,1'-carbonyldiimidazole,COHODDisa crystalline, stable and non-hygroscoDic compound. HODDreleasedafter use of COHODDas coupling reagent iswater soluble and thereforecan be easily recycled.Hore-over, in contrast to imidazole, HODDis acidic (pKa mea-sured at 20\302\260C :3.6).This characteristic can be very useful

in the caseof substrates sensitive to basicconditions.

Phosgeneand derivativesasbuildingblocks

MODDreadily reacts with hydroxy compounds toafford 2-alkoxycarbonyI-MODD. These intermediates donot needto be isolatedand are reactedwith an excessofamine to give the corresponding carbamate in good yieldas depictedin scheme208(Ref. 260).For example, theinsecticideAldicarbe was obtained in 85% yield withoutuseof the noxious methyl isocyanate.

O

COMODD + R'-OH\177.

R,O.Io\177_N,o\177..\177-\177e

- 1 MODD

R2-NH2\177- R\177O-C-NHR2 85-90%- 1 MODD

II

O\177: Synthesis of AIdicarbe without MeNCO

Me2-C-CH=N_O_C.NHMe 85%overall yieldI II mp. 99-100ocSMe O

Scheme208..COMODD as an useful tool for carbamates synthesis.

It is possibleto prepareBOC-or Z-amino acidsfromthe isolated 2-BOC-or 2-Z-HODDbut the method wasfound of little synthetic interest mainly becauseof the sen-sitivity of 2-alkoxycarbonyI-P1ODDtoward hydrolysis.However, Z-amino acidswere obtained in medium yieldsand werefound to be freeof dipeptidesimpurities.

We discoveredalso that COMODDreacts with car-boxylic acidsto give the unstable mixed anhydrides (IX)which are rapidly decarboxylatedto the 2-acyI-P1ODD(X).As abovementioned, (X) are not isolated but are reactedin situ with an amine to afford the corresponding amidesas shown in scheme209(Ref. 260).

This reaction has been successfully applied to the cou-pling of amino acids.Yields are generally good and thedipeptidesare easily freed of by-products by simplewashes.The HODDreleasedor its sodium salt are readilysoluble in water and thus are easily separatedfrom thefully protecteddipeptide.

162163)))

Phosgeneand derivativesasbuildingblocks Phosgeneand derivativesasbuildingblocks

COMODD + R1-COOH \177

- 1 MODD

O

.\177 R \"\177_

N,o\177.\177\302\260\177)e

R2-NH2-\177-. R\177-C-NHR

2- CO2 - 1 MODD II

O(X)

Scheme209:COMODD as an useful tool for amides synthesis.

In a typical procedure,one equivalent of COHODDis added to a solution of the protectedamino acid and

N-methylmorpholine (2 eq.)in acetonitrile or dichlorome-

thane and stirred at room temperature for I h. The amino

acidesteror its hydrochloride isthen addedand the reaction

mixture is stirred for an additionnal hour. After conventional

washesof the organic phase, the dipeptide is crystallizedfrom a suitable solvent. As shown in table 3-29,several

dipeptideswerepreparedand no deviations werefound in

their optical rotations.

Dipeptide Yield (%) mp. (\302\260C) [c\177]D

\302\260

BOC-Phe-GIy-OEt 80 80-8 -4(c I EtOH)

Z-VaI-GIy-OEt 06 105-166- 27 (c I EtOH)

Z-Leu-Phe-OHe 74 80-81 - 20 (c 2 HeOH)Z-Ala-Phe-OP1e 88 90-98 -10(c I EtOH)

Z-Phe-Ala-OP1e 83 127-129-22(c1.25EtOH)

Bz-Leu-Gly-OEt 78 137-139 -4 (c3.1EtOH)

BOC-Tyr(OBzl)-GIy-OEt 79 117-119+ 2 (c0.5EtOH)

Table3-29:Preparation ofdipeptides using COMODD asa coupfing agent.

In a secondpublication, we reportedthe use ofCOHODDfor the one-potesterification of carboxylic acids,especiallyamino acids,under mild conditions (Ref.261).

The reaction was efficient with both primary and

secondaryalcohols.Providing that an excessof the alcoholis added,tertiary alcoholsareesterified in medium but still

satisfactory yields. The reaction is catalyzed with DHAP,but no basewas necessaryif the alcoholalready containeda pyridine function. We assumethat the reaction proceedsthrough the mixed anhydride (IX) as depictedin scheme210.

COMODD + R\177-COOH\177_

- 1 MODD

R\177_C.O_C_N \"\177N-Me 1Ii II 'o---& /o o

(\177x)

o]

--'\177\"R'L NMe2, Me \177RLC-OR2-CO\177

-\177 MOOD II

O O

Scheme210:COMODD asa reagent for the direct estefification ofcarboxylic acids.

In a typical procedure,COHODD(I eq.)and the

appropriate alcohol(1.1eq.)are addedwithin 5 rain. to asolution of the acid (I eq.),triethylamine (1,1eq.) andDI\"IAP (0.1eq.)in dichloromethane and the reaction mix-

ture is stirred at room temperature for 2 h. Conventional

acidicand basicwashesafford the correspondingester in

goodyield. For example esterification of Z-AIa-OH with p-nitrobenzylic alcoholusing this method gave the expectedester in 89% yield (rap.95-96\302\260C).

No sign of racemizationwas detectedin the synthesesof amino estersexamined.

AcyI-I\"IODD (X) provided by activation of N-protected-0\177-amino acidsand O-protected-0\177-hydroxy acids withCOHODDhave beenproved to besuitable for the synthesisof ]3-ketoesteras depictedin scheme211(Ref.262).

164 165)))

Phosgeneandderivalivesasbuildingblocks

R \177-COOH

.io\302\260

>COMODD R \177

\177O\177

OR2

CHR3

Et3N, 0cC yNMe. 75\177C

80-98% O(X)

75-95%

O R 3

II I

R\177-C-CHCOOR2

Scheme211.\" UseofCOMODD in the synthesis of \177-keto esters.

This activation was successfully usedin the preparationof unusual \177amino-[3-hydroxy esterssuch as the protectedderivative of (354R55)-Isostatine from D-allo-isoleucineasshown in scheme212(Ref.202).

Me...y/Et1)

COMODD98%

Z-N/\"\177COOH 2) Li OH \177CH2 H O

EtO 82%

Me...y/EtNaBH4 Anti

\177\" Z-N/'\"r''\177COOEt ( de< 96%)H

\177H

Scheme212.\" Preparation of(354R55) Isostatine with COMODD.

Me...y/Et

Phosgeneandderivalivesasbuildingblocks

{\177yclisalion

be\177veen lwonitrogen a\177oms

Phosgenation of ethylene diamine type compounds is awell establishedmethod for the preparation of 2-imidazo-lidones (cyclicfive membered ureas).The utility of thismethod is illustrated by the synthesis of a valuable inter-mediate (I) for D-biotine manufacture. We have developedan improved interracial processwhich affords (I) in goodyield and high purity as shown in scheme213.

\177_\177 \177

1)KOH / H20 / Hydrophobic solventH H\177 COCl2N N \177,

H.\177\\H 2) H20: HCI

HOOC\"e\177COOH

O

N N mp. 172.5\302\260C. o.(0 H H

-OH H

(GH2)4GOOH

D-Biotine(Vitamin H)

Scheme213.\" Preparation ofthe key intermediate for the synthesis of Biotine.

Phosgenereactswith cyanohydrazines to yield 3-hydroxy-5-chloro-l,2,4-triazoles.Theutility of the processis demons-trated by the preparation of the key intermediate for the

production of the soil-appliednematocide Isazofos(Ref.263).Thus, phosgenation of 1-cyano-l-isopropylhydrazi-ne in THF gives a transient N-chlorocarbonyl compound (11)which is cyclized to (111).This salt, insoluble in THF is recove-red by filtration and the desiredproduct (IV) is isolated in

goodyield by simple acidification asdepictedin scheme214.

166167)))

Phosgeneandderivativesasbuildingblocks Phosgeneandderivativesas buildingblocks

THF

,,\177N_NH2

CI-CN.\177/

COCl2

/H \177\"

,N-NH2CN

.\177NAnhydrous

--NH NH3 \177,Cl\"

\177,\177*\177O

\" N-N

CI.\177Z\177 Nk/\177\"

O-NH+

[II)N Cl

\177 (Ill)

HCl / H20 \177(IV)N-N

\177

Cl\177,\177 Nk/\177- OH 92%yield

Scheme214:Describedprocess for the preparation ofa intermediate used for theman ufacture of Isazofos.

While exploring the synthesis and chemistry of urazoles,we studied an alternative processstarting from carbazatewhich avoids the handling of the extremely noxious cyanogenchloride.The new synthesis of (IV) is diagrammed in

scheme21.5(Ref. 264).

MeO-C-NH-NH 2II

O

-N-NHICIOMeH II

O

H20 / KOH

Acet\302\260ne

\177=:=\1771

Pt/H2\177 NINH- -OMe ---\177

O

MeOH / H2SO4 W 85%\177 N-NHIC-OMe

IIrnp. 161\302\260C

KOCN ,20\302\260C O\177 ONH 2

\177/\177oiDichlorobenzene

.\177\177

N-N POCI3 N-N100% O\177=/\"-

N/\177--\"O Catalyst Cl\177'\177 N

k/\177\" OH

78% H 160\302\260C

(IV) 26%mp. 186\302\260C mp. 105.5\302\260C

Scheme215:Synthesis and use of l-isopropyl urazole.

Note also that reaction of methyI-N-chlorocarbonyI-N-methyl carbamate(preparation through phogenation givenin section 3-3-zLthis volume) is very suitable for thepreparationof numerous urazoles..Someexamplesarepresentedin table3-30(Ref.265).

R Yield (%) mp. (\302\260C)

H 56 238-9Pie 81.4 122-3Ph 89.5 222-3

O'\177cI1) I-bO / NaOH

R.N_NHRNH--NH2 +

Me-N\177__

\177

\321\236=:Z, \"\177OOMe 2) HCl /H20 ON

O AcOEt extract. Me

Table3130:Use of rnethyI-N-chlorocarbonyI-N-rnethyl carbamate for the prepara-tion ofurazoles.

The biological activities of condensedpyrimidine sys-tems as diuretics, antitumor agents or as antagonists ofconstituents of nucleic acid and of folic-folinic acid familyof vitamins prompted differents authors to study thesynthesis of cyclicsix membered acylureas such aspyrido[2,3-d]pyrimidinones (Ref.266).

Reaction of phosgenewith 1-amino nicotinic acidaffordedthe 3-azaisatoicanhydride (V). Treatment of (V)in DMF with propargylamine yielded the 1-aminonicotina-mide (VI). Phosgenation of (VI) in pyridine under reflux

gave the expectedproduct (VII) as depicted in scheme216.

168169)))

Phosgeneand derivativesas buildingblocks

[\177COOH

COCi2\177,

NH 2

O

NHC H2 --C--CH2

2 (v0mp. 137-8\302\260C

O

\177N.\177

HC--CCH2NH2

O DMF , 50 C(V) H 57\302\260'\302\260

O

Pyridine, Oreflux, 6 h H63% (VII)

mp. 240-2\302\260C

Scheme216:Example of preparation of cyclic six membered acytureas through a\177 double phosgenation ,process.

5-Ethyl-l,3,4-oxadiazolinone(VIII), preparedby phos-genation of propionyl hydrazide as already describedin

section3-4-2,is a key building block for the synthesis forthe synthesis of 1,2,4-triazol-3-onestype antidepressants(Ref 255).

Thus, we obtained the triazolone (IX) in 7_3 % overall

yield according to scheme217without the need of the

highly toxic ethyl isocyanate.(IX) is suitable for the manu-

facture of Etoperidone [Stucture given in scheme218](Ref.267). Et Et-NH 2

Toluene\"\177-\177

N. TolueneEt-CNH-NH2 + COCI2 \177' O NH

II 60\302\260c, 5 h y 50-70\302\260C, 4 hO(vm) o

OH20 / NaOH

Et\177NANH-Et-C-NH-NH-C-NH-EtII II loo\302\260c, 1 h \177--\177 73%O 0 Et! mp. 125-7.5\302\260C

97% from propiohydrazide (IX}

Scheme 217:Preparation ofthe key intermediate for the manufacture ofEtoperidone.

0Et-- NAN

,(CH2)\177--

N/--XN-\177Et

CI

Scheme218:Etopefidone (anti\177lepressant).

Phosgeneand derivativesas buildingblocks

In another study, we deviseda new route to the triazo-lone intermediate (X) useful for the synthesis of Nefazo-doneas depictedin scheme219(Ref.255,268).

Nefazodone.HCIwas launched in 1994in the US andin Canadaby BristoI-Meyers Squibb as Serzone\177 for thetreatment of depression(Ref.269).

OH

NeatII\177 + Et \177 OCH2CH2NH-C-Et

O\177 175\302\260C

I 0 h (A)

H20 /ethylene glycol\177 (A) + NaOH \177- OCH2CH2NH2

145\302\260C, 4 h(B)

Steps1 + 2 :86%overall dist. yield

Et bp. 99-102\302\260C/7 mm

\"\177N, TolueneSt_e#33 (B) + NH

80-85\302\260C

O 4h O OII II

(VIII)

Et.C.NH_NH_C_NHC H2CH20_@1 ) KO H / H20 O

2 h reflux

O\177-\177 (C) . OCHCH2__N. _\177H

2) HCI / H20\177.\177N (X)Et

Recryst. from MEK

Steps3+ 4 : 80%yieldmp. 138\302\260C

CI

Et\"\177-1\177

Nefazodone(Anti-depressant)

Scheme219:New synthesis ofan useful intermediate (X) for Nefazodone.

170171)))

Phosgeneand derivativesas buildingblocks

N-Hethyl carbamatesare valuable products, especiallyas pesticides,for example the insecticideCarbofuran, aswell as numerous pharmaceuticals. Industrially, the reac-tion of methyl isocyanate with hydroxy compounds is by

far one of the most widely utilized proceduresfor theproduction of numerous N-methyl carbamates.

The Bhopal incident (India, 1984)has dramatically out-

lined the high toxicity level of methyl isocyanate and

moreover its very exothermic self-polymerization which

requires extreme care during its production and storage(Ref. 270).

In this volume, we have already examined somealter-natives to the synthesis in situ and/orto the useof methyl

isocyanate.We thought that 1,3-dimethyl diazetidine

dione (XlI) (methyl isocyanatedimer) should be a suitable

methyl isocyanateprecursorwhich can releasemethyl iso-cyanate in safeconditions. This dimer was preparedfrom

N-chlorocarbonyI-N-methyl N'-methyl urea (XI) obtained by

phosgenation of N,N'-dimethyl urea as previously describedin scheme1.56,section3-3-4.Cyclization of (X]) in a suitable

solvent and in presenceof a basesuch as DABCO afforded

the expecteddimer (X]I) as depictedin scheme220.

O'k\177

Solvent

\177CI DABCO (XlI)

Me-N H \177, Me-N N-Me Cas:36909-44-1

o\177--N.

1h, 30\302\260C

\177/

Me 83% O(Xl) mp. 98\302\260C

Recryst. hexane

Scheme220:Preparation of methyl isocyanate dimer.

The NHR and IR analytical data of (XlI) are the follo-

wing :1H NHR (CDCI3)8 2.87ppmIR 1780cm1.

This dimer was thermically (170\302\260C)or catalytically

decomposedto 100%methyl isocyante asshown in scheme221.

Phosgeneandderivativesasbuildingblocks

Without catalyst

/[J\177

N-Me

Me-N,\177/O (Xll)BusP

0.5h , 90\302\260C

Scheme 221:Use of (XII) asmethyl isocyanate generator.

2 Me-NCO

3 4-4C.vclisalionbelweena

nilro\177en atomand a sulfur

atom

L-2-Oxothiazolidine-4-carboxylate(OTC):./COOH

S\177NHO

is a non-toxic precursorof cysteine proposedas a pro-drug capableof penetrating into living cells.Therefore,itsorally or parenterally administering to humans provides amethod of restoring the glutathione level of numerous tis-sueswhere 5-oxoprolinaseis present, especiallyin the liver

(Ref. 271).In HIV-seropositive patients, it was proved toincreasethe levelsof gluthatione, the lack of which is sus-pectedto be a factor of their immunodeficiency (Ref.272).

OTCis available by several methods, among themthe reactionsof phosgene(Ref. 273)or more recently tri-

phosgene(Ref. 274),with L-Cysteine or L-Cysteine methylesterappearthe more convenient.

We developedat a laboratory scalea biphasic phos-genation processfrom L-Cysteine hydrochloride at control-led pH as depictedin scheme222(Ref.275).

172173)))

Phosgeneand derivativesasbuildingblocks Phosgeneandderivativesas buildingblocks

/_\177COOHHS

NH2.HC I

Toluene

1)COCI2, KOH/H20T: 10\302\260C

2) HCI

3)Solvent extraction

70%

Scheme222.'Preparation ofOTCby phosgenation.

/__\177,COOH

S.\177NH OTC0Cas: 19771-63-2mp. 168\302\260C

[c\177]\177

0 :-61\302\260

It is noteworthy that OTCcan have other types of phar-maceutical applications than the delivery of cystein into

the human body. For example, nitrated derivatives of OTCwere recently patented as valuable coronary vasodilators

which replacenitroglycerin without having its disadvan-

tages (Ref.276).An example of synthesis of these new

interesting pharmaceuticals is given in scheme223.

/_.\177/COOHS NH

+

\177 OTC0HNO3.H2N-CH2CH2ONO2

Et3N

(EtO)2P(O)CN

in THF

O

S\177,[\177,

N Hmp. 130-1\302\260C

( AcOEt )O

Scheme223.\" Preparation ofa nitrated derivative of OTCasa vasodilator.

This is the end of volume 1 mainly dedicatedto the useof phosgeneand its direct derivatives as building blocksproviding the carbonyl group in organic molecules.

Obviously, several major topicsrelated to this type ofapplications are inadequately discussedor even purely and

simply forgotten. Pleaseforgive me for theseinadequacieswhich are not at all intentional.

Also, the reader wiil understand that some sensitivesubjectshave been deliberately omitted for confidentialityreasons.

It is obvious that substantial work remains to be doneand it is the author's secrethopethat this first volume willserveas a catalyst to open the way to new researchon the

chemistry of phosgene.

174175)))

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