Synthesis of Tetrahydrofuran and Pyrrolidine Derivatives ...

Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Science and Technology 946

Synthesis of Tetrahydrofuran andPyrrolidine Derivatives Utilising

Radical Reactions

Organochalcogenides in Reductive, Carbonylativeand Group-Transfer Cyclisation

BY

CECILIA ERICSSON

ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2004

List of Papers

This thesis is based on the following papers:

I Diastereocontrol by Trialkylaluminums in the Synthesis of Tetrahydrofurans via Radical Cyclization. Ericsson, C.; Engman, L. Org. Lett. 2001, 3, 3459. (Supplementary material included.)

II Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/ Reductive Cyclization. Berlin, S.; Ericsson, C.; Engman, L. Org.

Lett. 2002, 4, 3. (Supplementary material included.)

III Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin-3-ones. Berlin, S.; Ericsson, C.; Engman, L. J. Org. Chem. 2003, 68,8386. (Supplementary material included.)

IV Microwave-Assisted Group-Transfer Cyclisation of Organotellurium Compounds. Ericsson, C.; Engman, L. Submitted.

Contents

Summary in Swedish ......................................................................................1

1. Introduction.................................................................................................51.1. Stability of radicals..............................................................................61.2. Nucleophilic and electrophilic radicals ...............................................71.3. Radical chain mechanisms ..................................................................8

1.3.1. Radical precursors .......................................................................91.3.2. Initiators.......................................................................................91.3.3. Metal hydrides ...........................................................................10

1.4. Radical cyclisations...........................................................................101.4.1. Cyclisation of the 5-hexenyl radical ..........................................121.4.2. Stereoselectivity.........................................................................12

2. Diastereocontrol by trialkylaluminums in radical cyclisation ..................142.1. Lewis acids in radical reactions.........................................................142.2. Diastereocontrol in the cyclisation of 3-oxa-5-hexenyl radicals .......15

3. Synthesis of tetrahydrofuran-3-ones and pyrrolidin-3-ones via radical carbonylation/cyclisation ..............................................................................21

3.1. Formation of acyl radicals.................................................................213.2. Synthesis of tetrahydrofuran-3-ones .................................................223.3. Synthesis of tetrahydrofuran-3-ones on solid phase..........................273.4. Synthesis of pyrrolidin-3-ones ..........................................................29

4. Microwave-assisted aryltelluro- and phenylseleno-transfer cyclisations..344.1. Group- and atom-transfer reactions...................................................344.2. Microwave-assisted chemistry ..........................................................354.3. Group-transfer cyclisations ...............................................................35

Acknowledgements.......................................................................................41

References.....................................................................................................42

Abbreviations

acac acetylacetonate AIBN 2,2´-azobis(isobutyronitrile) Ar aryl atm atmosphere Bn benzyl Bu butyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMF N,N-dimethylformamide eq equivalent Et ethyl EWG electron withdrawing group FMO frontier molecular orbital gNOESY gradient-enhanced nuclear Overhauser effect spectroscopy Hex hexyl HOMO highest occupied molecular orbital In initiator LA Lewis acid LUMO lowest unoccupied molecular orbital Me methyl M-H metal hydride NMM N-methyl morpholine NMP N-methyl-2-pyridone NMR nuclear magnetic resonance NOE nuclear Overhauser effect P pressure Ph phenyl SH2 bimolecular homolytic substitution SOMO singly occupied molecular orbital THF tetrahydrofuran TMS trimethylsilane Tol tolyl Ts toluenesulfonyl TS transition state TTMSS tris(trimethylsilyl)silane

1

Summary in Swedish

Syntes av tetrahydrofuran- och pyrrolidinderivat

med hjälp av radikalreaktioner

Organiska kalkogenföreningar i reduktiv och karbonylativ cyklisering samt

grupptransfercyklisering

Radikaler är vanligt förekommande i vår omgivning. Inom biologi och medicin har ordet ”radikal” dock ofta en negativ klang. Radikaler bildas t.ex. när kroppen omsätter mat till energi. Eftersom de är mycket reaktiva kan de skada kroppsegna molekyler såsom DNA, kolhydrater och proteiner. Man tror att radikaler har stor betydelse för åldringsprocessen och för uppkomsten av bl.a. Alzheimer’s sjukdom, cancer samt hjärt- och kärlsjukdomar. Antioxidanter, som t.ex. vitamin C och E, kan reagera med radikalerna och därmed skydda oss mot deras skadliga inverkan. Kroppen producerar även medvetet radikaler för att angripa och döda bakterier och virus. I naturen håller ozonlagret på att brytas ned pga av utsläpp av freoner. När freonerna utsätts för solens UV-ljus bildas radikaler som i sin tur bryter ner ozonet.

Polymertillverkning utgör den viktigaste tillämpningen av radikalkemi inom industrin. Större delen (75% eller 108 ton) av världens alla plaster är tillverkade genom radikalreaktioner. Förbränning av bensin och andra bränslen involverar också radikaler. Inom organisk kemi kan radikaler användas för att tillverka nya kemiska föreningar, något som exemplifieras i den här avhandlingen.

År 1900 beskrev Moses Gomberg vid University of Michigan den första kolcenterade radikalen, trifenylmetylradikalen. Vid den här tiden uppfattades radikaler mest som kuriosa och den allmänna åsikten var att radikaler är alltför reaktiva för att kunna få någon användning för syntes av organiska molekyler. Sedan dess har radikalernas rykte förbättrats avsevärt. Vad gäller kemo-, regio- och stereoselektivitet har de visat sig tämligen förutsägbara. Många nya reaktionstyper har utvecklats och ett stort antal föreningar har tillverkats genom radikalreaktioner.

2

Det här arbetet är inriktat på radikalcykliseringar. Radikaler kan addera till dubbelbindningar och om dessa är belägna i samma molekyl kan cykliska föreningar erhållas. Vi har använt selen- och tellurorganiska föreningar som utgångmaterial för radikalreaktioner. Eftersom Se-C- och Te-C-bindningar är relativt svaga är det möjligt att klyva dessa homolytiskt och på så sätt skapa radikaler.

Avhandlingen sammanfattar tre delprojekt: (i) Kontroll av diastereoselektivitet vid syntes av tetrahydrofuraner via radikalcyklisering. (ii) Syntes av tetrahydrofuran-3-oner och pyrrolidin-3-oner via radikalkarbonylering/reduktiv cyklisering. (iii) Grupptransfercykliseringar av organiska selenider och tellurider med hjälp av mikrovågsuppvärming.

(i) Vid syntes av disubstituerade tetrahydrofuraner via radikalcyklisering erhålls två olika diastereomerer: cis och trans (Schema I). Produktfördelningen styrs av vilken konformation som har lägst energi i övergångstillståndet. Vi valde att tillsätta olika Lewis-syror för att försöka förändra fördelningen. Vid cyklisering av förening I utan tillsats av Lewis-syra bildades trans-isomeren (trans-II) i överskott. När trietylaluminium (Et3Al) tillsattes inverterades cis/trans-förhållandet och cis-isomeren (cis-II)erhölls i störst mängd.

OR OR

AIBN/n-Bu3SnH

h , 17oC

PhSe

OR

trans-II cis-III

AIBN/n-Bu3SnH,

Et3Al

h , 17oC

cis/trans ~1/5 cis/trans ~5-7/1

OR

Et3Al

R

O

Schema I. Syntes av 2,4-disubstituerade tetrahydrofuraner via reduktiv cyklisering. Diastereoselektiviteten kan kontrolleras med hjälp av trietylaluminium. I de båda fallen är huvudisomeren och det förmodade övergångstillståndet utritade.

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(ii) I detta delprojekt har vi utnyttjat radikalers förmåga att addera till kolmonoxid. Detta är ett smidigt sätt att införa karbonylgrupper i organiska molekyler. Utgångsmaterialen (IV) för radikalreaktionerna tillverkades i två steg utgående från epoxider (III, X = O) och aziridiner (III, X = NH) (Schema II). I radikalreaktionen bildas en kolcenterad radikal (V) genom homolytisk substitution av en tris(trimetylsilyl)silylradikal på selen. Den bildade radikalen adderar en molekyl kolmonoxid. Denna reaktion är reversibel. För att driva jämvikten mot karbonylering utförs reaktionen under 80 atmosfärers tryck av kolmonoxid. Den nya radikalen (VI) adderar till dubbelbindningen och en cyklisk förening (VII) bildas. Efter reduktion erhålls tetrahydrofuran-3-oner (VIII, X = O) och pyrrolidin-3-oner (VIII, X = NH).

TTMSS/AIBN/CO (80 atm)

III(X = O, NH)

X

PhSe

R

EWG

R

X

CO

5-exo-cyklisering

X

O

REWG

XR

EWG

O

XR

EWG

X

O

R EWG2 steg

IV(EWG = CO2R, SO2Ar)

V VI VII

VIII

(Me3Si)3SiH

(Me3Si)3Si

(Me3Si)3SiSePh

(Me3Si)3Si

Schema II. Syntes av tetrahydrofuran-3-oner och pyrrolidin-3-oner via radikalkarbonylering/reduktiv cyklisering.

(iii) På senare år har intresset att använda mikrovågor som energikälla för uppvärmning av reaktionsblandningar ökat. På detta sätt kan energiöverföringen ske på ett mer kontrollerat sätt än med traditionella metoder. Reaktionerna kan även utföras vid mycket högre temperaturer, vilket leder till förkortade reaktionstider. För 20 år sedan gjordes reaktioner i vanliga hushållsmikrovågsugnar. I dessa är mikrovågorna utspridda i hela ugnen och detta är inte optimalt för uppvärmning av små mängder lösningsmedel. Nu finns apparatur speciellt anpassad för kemiska tillämpningar där mikrovågorna koncentreras till reaktionskärlet. Dessutom kan parametrar som temperatur och tryck kontrolleras med stor noggranhet

4

vilket höjer säkerhetsnivån betydligt för användaren. Vi har uttnyttjat mikrovågstekniken för att utföra grupptransfercykliseringar av organiska kalkogenföreningar (Schema III). Med hjälp av mikrovågsuppvärmning har vi syntetiserat tetrahydrofuranderivat X genom grupptransfercyklisering av förening IX. Vi lyckats förkorta reaktionstiderna från ett par timmar till några få minuter. Dessutom har det varit möjligt att använda miljövänliga lösningsmedel som t.ex. vatten.

Mikrovågor

R2

R1

O

TeAr

R2

R1 TeAr

O

Etylenglykoleller vatten

IX X

Schema III. Mikrovågsassisterad grupptransfercyklisering av organotelluriumföreningar.

5

1. Introduction

In 1900, Moses Gomberg discovered the first organic radical, the persistent triphenylmethyl radical (Scheme 1).1 Almost 30 years later, Paneth showed that simple alkyl radicals also exist, although they are much less stable.2

Scheme 1. Two resonance forms of the triphenylmethyl radical. For steric reasons, the phenyl groups are slightly twisted.

In 1937, Hey and Walters published a review where they explained various known reactions by radical mechanisms.3 During the 1930´s and 1940´s four of the most important elementary reactions of free radicals were defined:

– recombination/homolytic cleavage A• + B• A–B

– homolytic substitution (SH2) A• + B–C A–B + C•

– addition/elimination A• + B=C A–B–C•

– electron transfer A• + e A ; A• A+ + e

Most radical processes that we use today can be explained by these pathways, or simple variations thereof. During the first half of the 20th

century, radicals were considered unreliable, unpredictable and prone to give complex mixtures of products. To be useful in synthesis, the factors that influence the selectivity of radical reactions also had to be understood. It took almost eight decades after Gomberg’s isolation of the trityl radical before research had advanced to a level where it was possible to reliably predict the reactivity of organic radicals. Since then, radicals have proven to be both chemo-, regio- and stereoselective in their reactions, and not particularly difficult to generate.4

6

Radical reactions are essentially insensitive to solvents used and functional groups elsewhere in the molecule. This is in contrast to more traditional ionic chemistry where you can have problems with aggregation of carbanions and ion-pairing in carbocations. Also, in conventional synthetic sequences, functional groups often have to be protected. Since radicals are not basic, protection of acidic functional groups is a problem that does not bother radical chemists. Neither does aggregation or ion-pairing. Therefore, radical chemistry has been extensively used in the synthesis of natural products.5

1.1. Stability of radicals

The lifetime of a radical can be affected both by thermodynamic and kinetic factors. Kinetic stabilisation is often caused by steric hindrance of a reaction (the activation energy is raised). This is the major reason for the stability of the propeller shaped triphenylmethyl radical. Thermodynamic stabilisation is due to interactions that lower the energy of the radical. The most important factors are summarized below.

Since there are only seven valence electrons on the carbon bearing the unpaired electron, electron donating groups serve to stabilise radicals. Tertiary radicals are more stable than secondary and primary ones. The stabilisation is shown as orbital overlap with the C-H sigma bond (Scheme 2). There are also examples of substituents that stabilise via electron donation. Heteroatoms with free electron pairs (e.g., oxygen, nitrogen and sulphur) act in this way.

HHH

HH

HH

H

HH

H H

H

H

7e- 8e- 7e-8e-

ORR

ROR

R

R

Scheme 2. Hyperconjugation in ethyl and t-butyl radicals (left) and stabilization viaelectron donation (right).

Electron withdrawing aryl groups, esters and nitriles can stabilise radicals via conjugation. When electron density is delocalised over several atoms, the overall energy of the system is lowered (Scheme 3).

O

ORR

R

O

ORR

R

Scheme 3. Stabilisation of radicals via conjugation.

7

If a radical is stabilised by one donor and one acceptor, the resulting effect is larger than the sum of the two. This is called the captodative effect. The radical formed when the antioxidant vitamin C donates a hydrogen atom is stabilised in this way (Scheme 4).

O

O OH

OH

O

HO

O

O OH

OH

O

HOelectron donation

O

O OH

OH

O

HO

conjugation

O

HO OH

OH

O

HO

Vitamin C

O

O OH

OH

O

HO

O

O OH

OH

O

HO

conjugation

O

O OH

OH

O

HO-H

Scheme 4. Captodative effect in the ascorbyl radical.

1.2. Nucleophilic and electrophilic radicals

Although radicals are neutral species, they can be either nucleophilic or electrophilic in their behaviour, depending on the carrier of the unpaired electron.6 This is exemplified in the copolymerisation of styrene and methyl acrylate (Scheme 5).4j When a radical adds to styrene, the more stable benzylic radical is formed. This species is nucleophilic and reacts rapidly with the electron deficient double bond in methyl acrylate. The new radical,

to an ester, is electrophilic and reacts more rapidly with styrene than with methyl acrylate. In this way a copolymer is formed with high regioregularity.

Ph

CO2Me

Ph

Ph

CO2Me CO2Me

Ph

electrophilicradical

Ph

CO2MePh

nucleophilic radical

Scheme 5. Copolymerisation of styrene and methyl acrylate is controlled by the reactivity of radicals.

8

The difference in reactivity can be explained by frontier molecular orbital (FMO) interactions. Nuclophilic radicals have a high-energy singly occupied molecular orbital (SOMO). This makes the interaction with the alkene lowest unoccupied molecular orbital (LUMO) important. Alkenes carrying electron withdrawing substituents have LUMOs of suitable energy to react rapidly with nucleophilic radicals. Radicals carrying electron withdrawing groups (electrophilic radicals) have a low-energy SOMO. Here, the interaction with the alkene highest occupied molecular orbital (HOMO) is the more important.

1.3. Radical chain mechanisms

Almost all synthetically useful radical reactions occur by chain mechanisms. In the most commonly used procedure, a metal hydride is present. It has two duties: to reduce certain radical species and keep the chain reactions going. The process can be divided into three steps: initiation, propagation and termination (Scheme 6).

Initiation: In In•

In• + M-H In-H + M•

Propagation: M• + R1-X M-X + R1•

R1• R2

•

R2• + M-H R2-H + M•

Termination: In•, M•, R1•, R2

• recombination non-radicals

Scheme 6. Schematic presentation of a metal hydride mediated chain reaction.

In order to get a chain-reaction going under mild conditions an initiator (In) – a molecule that easily forms radicals – is used in catalytic amounts. During initiation this labile material is decomposed to form radicals (In•). These are reduced by the metal hydride (M-H). In the first propagation step, the metal centered radical reacts with the radical precursor (R1-X) via homolytic substitution. The radical R1

• thus formed undergoes some sort of transformation (R1

• R2•), which is often an inter- or intramolecular

addition. The resulting radical is then reduced by the metal hydride to form R2-H, the principal product of the radical reaction. The mediator radical is then ready to start the next cycle of the propagation sequence.

9

Termination reactions remove radicals from the reaction mixture and are therefore highly unwanted processes. Recombination of two carbon-centered radicals is close to diffusion controlled. Therefore, it is necessary that the concentration of radicals is kept low (~10-7 M).

1.3.1. Radical precursors

Radical precursors suitable for this type of chain reactions are organohalides and organochalcogenides. Other examples of precursors include xanthates7

and Barton esters8 (Figure 1). Generally, the reactivity is higher for an atom further down in the periodic table. For example, the reactivity towards stannyl radicals generally decreases in the following order: I > Br > SePh OC(S)SMe > Cl > SPh.9 Since M-X bonds are usually stronger than C-X bonds, the propagation step M• + R1-X M-X + R1

• is often exothermic.

R ON

OS

Barton estersxanthates

RS O

R

S

Figure 1. General structure of xanthates and Barton esters.

1.3.2. Initiators

A frequently used radical initiator is 2,2´-azobis(isobutyronitrile) (AIBN). Upon thermolysis10 or photolysis,4f the bonds between the tertiary carbons and the azo-group are homolytically cleaved to give two carbon-centered radicals and a molecule of nitrogen (Scheme 7). At low temperatures, triethylborane together with catalytic amounts of oxygen is often used for initiation.11 Ethyl radicals are thought to be formed as outlined in Scheme 7.

NN

CN

CN

NN

CNCN

h

N22CN

Et2BOO. Et.Et3B O2

SH2

Scheme 7. Initiation of radical reactions by AIBN using heat or light (upper) or Et3Bwith oxygen (lower).

10

1.3.3. Metal hydrides

In the metal hydride mediated chain reactions shown in Scheme 6, radical precursor R1-X is transformed into a reduced product R2-H. In order to favour an inter- or intramolecular reaction (R1

• R2•), the hydrogen

atom donor must not be too efficient. Otherwise, reduced starting material R1-H would be formed.

The most commonly used hydrogen atom donor is tri-n-butyltin hydride (n-Bu3SnH).12 In order to avoid reduction of untransformed R1

• by n-Bu3SnH, its concentration should be kept as low as possible. This can be achieved by slow addition or by using it in catalytic amounts together with a stoichiometric amount of a reductant capable of reducing n-Bu3SnX to n-Bu3SnH (e.g., NaBH4).

13

The use of n-Bu3SnH has several drawbacks. It is toxic and it gives rise to tin compounds which can be difficult to separate from the desired product. Therefore, much research has been invested into finding alternative hydrogen atom donors.14

A commonly used replacement is tris(trimethylsilyl)silane (TTMSS).15 It is a slower hydrogen atom donor and therefore sometimes more useful. Another advantage is its lower toxicity. Tri-n-butyl germanium hydride can also act as hydrogen atom donor.16 Due to its high cost, it has not been widely adopted.

1.4. Radical cyclisations

One type of chain reaction that will be more extensively discussed in this thesis is radical cyclisation. A radical cyclisation product results when a radical is added to an unsaturation elsewhere in the molecule. This process is often more successful than intermolecular addition.

In the radical cyclisation there are two possibilities for ring-closure: endo-and exo-cyclisation (Table 1). The regioselectivity in the cyclisation of unsubstituted alkyl radicals is controlled by the difference in rates for exo-and endo-cyclisation (Table 1).

Cyclisation of the 5-hexenyl radical gives the highest selectivity (exo/endo 58). Also, among these reactions, it is the one that occurs with the highest rate.

Since ring-opening occurs faster than ring-closure, smaller ring systems are difficult to make (Table 1, entries 1 and 2).

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Table 1. Rate constants at 25 oC for exo- and endo-cyclisation of primary-alkyl radicals.4e

kendo

k-endo

kexo

k-exo

Entry Radical kexo (s-1) kendo (s

-1) kexo/kendo k-exo

1 1.8 · 104 not obs. - 2.0 · 108

2 1 not obs. - 4.7 · 103

3 2.3 · 105 4.1 · 103 58 -

4 5.2 · 103 8.3 · 102 6 -

5 <70 1.2 · 102 <0.6 -

Cyclisation to give larger rings often results in formation of mixtures of endo

and exo-products. However, there are ways to circumvent these selectivity problems. Porter and co-workers synthesised 14-membered rings via radical cyclisation (Scheme 8).17 The high selectivity for endo-cyclisation in this case is due to the radical stabilising effect of the ketone.

O

I

n-Bu3SnH,

NaCNBH3,

AIBN O

(84%)

Scheme 8. Macrocyclisation using a ketone to control exo/endo-selectivity.

12

1.4.1. Cyclisation of the 5-hexenyl radical

Cyclisation of the 5-hexenyl radical takes place via a chair-like transition state (Scheme 9). The reaction is kinetically and not thermodynamically controlled. The orbital overlap between the C1 SOMO and the alkene LUMO is better for C5 than C6. This means that 5-exo-cyclisation occurs much faster.18

123

45

6 5-exo-cyclisation

6-endo-cyclisation

Kinetic product

Thermodynamic product

Scheme 9. Kinetic vs thermodynamic control in the cyclisation of the 5-hexenyl radical.

1.4.2. Stereoselectivity

In the cyclisation of monosubstituted 5-hexenyl radicals two diastereomers can be formed: the cis and the trans isomer. As mentioned above, the cyclisation takes place via a chair-like transition state and the TS of lowest energy is the one where substituents adopt pseudo-equatorial positions. Beckwith and Houk provided both computational and experimental data on the stereoselectivity in the cyclisation of 5-hexenyl-radicals.18 The influence of a methyl substituent in various positions can be seen in Scheme 10. Obviously, the selectivity in this simple cyclisation is not very impressive (1.9/1 – 4.8/1 in favor of the predominating diastereomer).

13

cis/trans = 2.6/1

1-substituted 5-hexenyl radical

cis/trans = 1/1.9


cis/trans = 2.9/1


cis/trans = 1/4.8


Scheme 10. Diastereoselectivity at 25 oC for cyclisation of the 5-hexenyl radical carrying a methyl substituent in positions 1-4.18d

14

2. Diastereocontrol by trialkylaluminums in radical cyclisation

2.1. Lewis acids in radical reactions

Lewis acids have often been used to control selectivity in radical reactions.19

To control enantioselectivity,20 chiral Lewis acids are often employed.21

There are also examples where a Lewis acid is only used to preorganize the structure and the enantioselectivity is induced by chiral stannanes.22 Lewis acid complexation has been used both to enhance the level of selectivity and to reverse it. In radical allylation,23a-c,e reduction23c and alkylation23d of -halo-ester derivatives and radical addition to acrylate derivatives23c the Lewis acid affects both the stereoselectivity and the yield (Scheme 11).

PhCO2Me

OMe

I

1 eq MgBr2.OEt2: 87%, anti/syn: 42/1

39%, anti/syn: 1/5

PhCO2Me

OMe

PhCO2Me

OMeTMS

Et3B/O2

Scheme 11. Diasterocontrol in radical allylation by Lewis acid-addition.23b

Yang and co-workers have performed group-transfer cyclisations of -bromo- -ketoesters and -phenylseleno- -ketoesters with good diastereoselectivity24 and enantioselectivity,25 using Lewis acids as catalysts and inducers of stereoselectivity. Enholm and co-workers demonstrated that 5-hexenyl26 and 6-heptenyl27 radical cyclisations can be highly diastereoselective, using a carbohydrate scaffold and a Lewis acid. Regioselectivity (exo/endo) in radical cyclisation has also been controlled by addition of Lewis acids.28 Maruoka and co-workers managed to control the cis/trans-selectivity in cyclisation of 4-substituted 5-hexenyl radicals and the olefin geometry in intramolecular additions to alkynes by addition of aluminum tris(2,6-diphenylphenoxide).29

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2.2. Diastereocontrol in the cyclisation of 3-oxa-5-hexenyl radicals

In the synthesis of 2,4-disubstituted tetrahydrofurans by cyclisation of 2-substituted 3-oxa-5-hexenyl radicals, the cis/trans-ratio is in the range of 1/3-1/5.30 Previous work in our group has shown that the diastereoselectivity in the synthesis of 2,4-disubstituted pyrrolidines by cyclisation of 2-substituted 3-aza-5-hexenyl radicals depends on the steric bulk of the N-substituent.31 With unprotected nitrogen, the trans-isomer is formed in excess. When nitrogen is protected with a bulky group, the selectivity is reversed. It was therefore interesting to see if it would be possible to achieve similar diastereocontrol in the synthesis of tetrahydrofurans by Lewis acid complexation to oxygen.

Radical precursors were synthesised in two steps from epoxides according to a procedure developed in our group some time ago (Scheme 12).30 By treatment with benzeneselenolate in ethanol at room temperature, regioselective opening from the sterically least hindered side occurred readily. The resulting -hydroxyalkyl phenyl selenides were then allylated using allyl bromide/NaH in refluxing THF.

R

PhSe

O

PhSe

R OHR

O(PhSe)2NaBH4

EtOH

NaHAllyl bromide

THF,

Scheme 12. Synthesis of -allyloxyalkyl phenyl selenides.

Cyclisation was performed in benzene with photoinitiation at 17 C, using AIBN as initiator and n-Bu3SnH as hydrogen atom donor. Initially, in order to evaluate various Lewis acids, the benzyl substituted radical precursor 1a

(Table 2) was used as a model substrate. Three equivalents of the Lewis acid were employed and the product was analysed after 15 h.

16

Table 2. Lewis acids evaluated in the cyclisation of compound 1a.

1a 2a

OBn

PhSe

Bn O

n-Bu3SnH, AIBN,

Lewis acid

Benzene, 17 oC, h

Entry Lewis acid Yielda (%) Cis/trans ratio

1 - 77 1/4.5

2 Ni(acac)2 0b

3 (C6F5)3B 0b

4 BF3·OEt3 34 (56c) 1/3.5

5 Ti(O-i-Pr)4 25 (69c) 1/4

6 TiCl4 0d

7 GaCl3 0e

8 MeAlCl2 0e

9 Et2AlCl 26e 4.5/1

10 Zn(OTf)2f 75 1/4

11 Me2AlOPhg 64 1/4.1

12 Me3Al 74 5.8/1

13 Et3Al 79 5.1/1

14 i-Bu3Al 69 6.8/1 a Isolated yield. b Only starting material was recovered. c Based on consumed starting material. d 2-Chloro-3-phenyl-propyl phenyl selenide was formed. eAllylbenzene was formed. f Only partly dissolved. g The reaction was performed in toluene. 1 Eq of phenol was added to Me3Al at –78 oC before selenide, AIBN and n-Bu3SnH were added.

Unfortunately, some of the Lewis acids prevented initiation of the radical reaction [Ni(acac)2, (C6F5)3B], or made the reaction proceed with very low conversion [BF3 OEt2, Ti(O-i-Pr)4; Table 2]. Lewis acids capable of releasing a nucleophilic chloride converted the starting material either into the corresponding -chloro selenide (TiCl4) or to allylbenzene (MeAlCl2,Et2AlCl, GaCl3).

Some Lewis acids did not seem to affect the reaction at all [Zn(OTf)2,Me2AlOPh].

To our delight, it was possible to invert the diastereoselectivity with trialkylaluminums. In the presence of three equivalents of i-Bu3Al, 2-benzyl-4-methyl tetrahydrofuran (2a) was formed as a 6.8/1-mixture of cis- and trans-isomers in 69 % isolated yield.

17

To further explore the influence of the amount of trialkylaluminum present and the effect of the groups attached to aluminum, the cyclisation was performed in the presence of 1.5, 3, 6 and 12 equivalents of Me3Al,Et3Al and i-Bu3Al (Table 3).

The assumption was that bulkier groups on aluminum would increase the diastereoselectivity. However, it was found that selectivity was not significantly higher with i-Bu3Al compared to Me3Al. Probably, i-Bu3Aldoes not bind to the substrate as well as Me3Al. By increasing the amount of Lewis acid, the diastereoselectivity was generally improved.

When trimethyl- and tri-iso-butylaluminum was used, there were problems with incomplete conversion of starting material. Thus, cyclisation in the presence of 12 equivalents of Me3Al produced only a 55 % of cyclised material. If the reaction time was increased to 30 h and a second portion of AIBN and Bu3SnH was added after 15 h, the yield was raised to 85 %. Since Et3Al did not cause any problems with conversion, three equivalents of Et3Alwere used in further studies of the reaction.

Table 3. Cyclisation of compound 1a in the presence of 1.5, 3, 6 and 12 equivalents of trialkyl aluminum.

Entry Lewis acid Equivalents Yielda (%) Cis/trans-ratio

1 Me3Al 1.5 84 2.1/1

2 Me3Al 3 74 5.8/1

3 Me3Al 6 60 7.6/1

4 Me3Al 12 55 (85b) 7.8/1

5 Et3Al 1.5 87 4.7/1

6 Et3Al 3 79 5.1/1

7 Et3Al 6 81 6.3/1

8 Et3Al 12 80 7.1/1

9 i-Bu3Al 1.5 71 3.5/1

10 i-Bu3Al 3 69 6.8/1

11 i-Bu3Al 6 45 6.9/1

12 i-Bu3Al 12 55 6.9/1 a Isolated yield. b Reaction time = 30 h, another portion of AIBN and n-Bu3SnH was added after 15 h.

Replacement of the benzyl for a butyl in the 2-position of the radical precursor slightly increased diastereoselectivity (Table 4, entry 1).

In the synthesis of bicyclic compounds, the exo-isomer was favoured in the absence of additive. Addition of three equivalents of Et3Al to the cyclisation of selenide 1c changed the diastereoselectivity from 1:3.2

18

(endo:exo) to 11.4:1 (Table 4, entry 2). A similar effect was seen in the cyclisation of compound 1d, derived from cyclooctene oxide: endo:exo-diastereoselectivity was reversed from 1:7.6 to 6.8:1. In addition to cis-fused products, small amounts of trans-fused products were also formed (Table 4, entry 3). The amount of such products decreased when the Lewis acid was added.

Table 4. Radical cyclisation in the presence and absence of Et3Al.

Entry Starting material Product Without Lewis acid 3 eq of Et3Al

Yielda

(%)Cis/trans-

ratio Yielda

(%)Cis/trans-

ratio

PhSe

OBu OBu60 (97b) 1/4.5 7.4/172 (92b)1

O

SePh

O

1/3.2c66 (80b) 76 (87b) 11.4/1c2

SePh

O O

6.8/1c71e61d 1/7.6c3

O

Ph SePh

O

Ph

77 1/1.71/3.8724

1b 2b

1c 2c

1d 2d

1e 2e

a Isolated yield. b NMR-yield. c Endo/exo-ratio. d In additon, 21 % of trans-fused products were also obtained. e In addition 12 % of trans-fused products were also obtained.

As expected, triethylaluminum did not influence diasteroselectivity in the synthesis of 3,4-disubstituted tetrahydrofurans as much as it did for 2,4-disubstitued ones (Table 4, entry 4). Since the phenyl-group is relatively far away from the oxygen, no steric interaction with the Lewis acid is possible. According to the Beckwith-Houk transition state model, the major product in the unperturbed cyclisation of compound 1e would be the cis-isomer (Scheme 10, Chapter 1). However, when substituents larger than methyl are present in 1-substitued hexenyl radicals, steric interactions becomes so severe that cyclisation occurs preferentially via the alternative TS (with an axial 1-substituent).

19

Due to decomposition during reaction/workup, Lewis acid sensitive compounds such as 1f and 1g (Figure 2), failed to produce radical cyclisation products.

1f

OPh

PhSe

1g

OBuO

PhSe

Figure 2. Lewis acid-sensitive substrates.

The change in selectivity by Lewis acid-complexation can be rationalised by using the Beckwith-Houk transition state model. In the absence of a Lewis acid, TS A is favoured, resulting in the formation of trans-isomer (Scheme 13). After Lewis acid-complexation to oxygen, the substituent, due to steric interactions, is forced to adopt an axial position. Such a conformation (TS D), will give rise to a cis-disubstituted product. In order to test this hypothesis, cyclisation of compound 1a in THF containing 3 equivalents of Et3Al was carried out. The trans-isomer was obtained as the major isomer (cis/trans = 1/5.1) in 85% yield. Since THF competes favourably for Et3Al,no Lewis acid-effect could be observed.

DC

BA

Cis-isomer as major product

Trans-isomer as major product

Lewis acid-assisted cyclisation

Cyclisation without additive

OR

LAO

R

LA

R

O

R

O

Scheme 13. Transition states considered in the presence and absence of Lewis acid.

20

For construction of bicyclic tetrahydrofurans (Table 4, entries 2 and 3), the effect of triethylaluminums was even larger than for simple systems. One can assume that the unperturbed cyclisation occurs via a chair-like transition state (where the cyclohexane ring also adopts a chair conformation; Scheme 14). To minimize steric interactions between the Lewis acid and the closest methylene of the cyclohexane moiety, cyclisation via a boat-like transition state may be the most favourable pathway in the presence of triethylaluminum.

Lewis acid-assisted cyclisation

Cyclisationwithout additive

OOLA

OO

exo-2c endo-2c

O

chair-likechair

O

LA

chair boat-like

Scheme 14. Proposed transition states for formation of bicyclic compounds 2c.

In conclusion, we have shown that it is possible to control diastereoselectivity in the synthesis of 2,4-disubstituted and 2,3,4-trisubstituted tetrahydrofurans via radical cyclisation. Whereas the unperturbed reaction is exo- or trans-selective, cyclisation in the presence of trialkylaluminums often occurs with more than inverted selectivity.

21

3. Synthesis of tetrahydrofuran-3-ones and pyrrolidin-3-ones via radical carbonylation/cyclisation

3.1. Formation of acyl radicals

Acyl radicals are commonly formed by homolysis of an acyl-heteroatom bond, where the heteroatom can be hydrogen, metal (e.g., Co, Ni or Mo), halogen or chalcogen (Scheme 15).32

R

O

Cl

R

O

H

R

O

SR

R

O

SePh

R

O

P(O)Ph2

R

O

R

O

M

M = Co, Mo, Ni

Scheme 15. Different approaches to acyl radicals.

In the early 1990’s, acyl radical formation via carbonylation of alkyl radicals in an atmosphere of CO started to become synthetically useful.33,34 The pioneering work was carried out by Ryu and Sonoda. Their first publication in the field was concerned with the synthesis of aldehydes from alkyl bromides and aryl iodides via radical carbonylation/reduction under 65-80 atm of CO in the presence n-Bu3SnH/AIBN.35 Radical carbonylation allows acyl radical formation from readily available starting materials. Also, it is a good complement to transition metal catalysed carbonylation.

22

During the last decade aldehydes,35 ketones,36 esters,37 lactones,38

thiolactones,39 amides,40 acyl selenides41 and carboxylic acids42 have been synthesised via radical carbonylation.

Experiments and kinetic data43-46 show that carbonylation works well for primary, secondary and tertiary radicals. For stabilised radicals (e.g., allylic and benzylic), decarbonylation is fast and very high pressures have to be employed to drive the equilibrium towards carbonylation.

3.2. Synthesis of tetrahydrofuran-3-ones

In 1999, Evans and co-workers published a total synthesis of kumausallene, a nonisoprenoid sesquiterpene found in the red algae Laurencia Nipponica.47

One intermediate in the synthesis, a 2,5-disubstituted tetrahydrofuran-3-one, was prepared by radical cyclisation of a selenol ester (Scheme 16).

Kumausallene

O

O.

Br

H

H

H

Br

H

OBnO CO2Me

O

BnOO

CO2Me

O

SePhBnO

OH6 steps

TTMSS,Et3B, O2

Scheme 16. Synthesis of kumausallene by Evans and co-workers.

In their synthetic route, six steps were needed to arrive to the desired organoselenium radical precursor. We thought it would be interesting to try to develop a more straightforward synthetic route to tetrahydrofuranones based on regioselective ring-opening of epoxides with benzeneselenolate and -tellurolate.30 Assuming the hydroxyl group could be vinylated, precursors for radical carbonylation/cyclisation could be obtained in only two steps (Scheme 17).

23

R'

R

O

R'

XPh

OH

R

O

O

EWGR'

R

R'

XPh

OEWG

R +CO

X = Se, Te

reductivecyclisation

Scheme 17. Strategy for the synthesis of tetrahydrofuranones.

Radical precursors were synthesised by vinylation of -hydroxyalkyl aryl chalcogenides using ethyl propiolate and N-methyl morpholine (NMM)48 or E-1,2-bis(phenylsulfonyl)ethylene and NaH49 (Table 5). These reactions worked well for primary and secondary alcohols, but failed for tertiary ones (compound 3l could not be obtained).50 The vinylic ethers (3a-k) were formed exclusively as E-isomers.

Table 5. Preparation of O-vinylated -hydroxyalkyl phenyl chalcogenides 3a-l.

Ethyl propiolate/NMM orE-1,2-bis(phenylsulfonyl)ethylene/NaH

CH2Cl2 or THF

3 a-n

R1

R2

XPh

OH

R1

R2

XPh

OEWG

OBn

XPh

CO2Et

3a, X = Se, 95%3b, X = Te, 64%

O

SePh

CO2EtPhO

3f, 85%

OBu

SePh

CO2Et

3i, 76%

OBn

SePh

SO2Ph

3k, 79%

OBnO

XPh

CO2Et

3c, X = Se, 83%3d, X = Te, 80%

O

SePh

CO2Et

3j, 64%

O

SePh

CO2Et

Ph

3g, 89%

O

SePh

CO2Et

3l, 0%

SePh

OCO2Et

3h, 86%

OPh

SePh

CO2Et

3e, 83%

24

The radical chemistry was performed under an atmosphere of pressurized CO. The propagation steps for the radical carbonylation/cyclisation of selenide 3a are shown in Scheme 18. After homolytic substitution at chalcogen and carbonylation, 5-exo-cyclisation occurs. The electron withdrawing ester serves to increase the rate of cyclisation. Since the resulting radical 4 is stabilised by the electron withdrawing group, no further carbonylation takes place.

The major side reaction in the process is reduction of the radical prior to carbonylation. Benzyl substituted radical precursor 3a was used to optimize the reaction conditions (Table 6).

3a

4

OCO2Et

O

Bn

R3M

Bn O

CO2Et

Bn O

CO2Et

O

CO

Bn O

CO2EtPhSe

R3MSePhR3MH

OCO2Et

O

Bn

Scheme 18. Chain mechanism for radical carbonylation/cyclisation.

Table 6. Optimisation of reaction conditions for radical carbonylation/cyclisation.

3aBenzene

65a

Bn O

CO2EtPhSe

Bn O

CO2Et

OCO2Et

Bn

O

R3MH/AIBN

CO

Entry R3MH PCO (atm) Isolated yield of compound 5a (%)

Isolated yield of compound 6 (%)

1 n-Bu3SnH 60 20 66

2 TTMSS 60 81 6

3 TTMSS 80 86 0

4 n-Bu3GeH 80 86 6

25

Initially, n-Bu3SnH was used as the hydrogen atom donor and the reaction was performed under 60 atm of CO. The results were not very encouraging: only 20% of cyclised product 5a was formed along with 66% of reduced starting material 6 (Table 6, entry 1).

The slower hydrogen atom donor TTMSS gave much better results (81% of the desired product; Table 6, entry 2). However, at 60 atm of CO, a small amount (6%) of reduced starting material was still formed. By increasing the pressure of CO to 80 atm, premature reduction was completely suppressed (Table 6, entry 3).

n-Bu3GeH was also used as hydrogen atom donor but the results were not as good as those with TTMSS. Therefore, subsequent cyclisations were performed under 80 atm of CO using TTMSS as hydrogen atom donor.

Table 7. Preparation of tetrahydrofuran-3-ones 5a-k.

TTMSS/AIBNCO (80 atm)

BenzeneR2

XPh

OEWG

R1

3a-k

O

O

R2

R1

EWG

5a-k

a Prepared from compound 3a. b Prepared from compound 3b. c Prepared from compound 3c.d Prepared from compound 3d. e Inseparable mixture of diastereomers. Stereochemistry not determined.

O

O

CO2EtPhO

5f, 82%, cis/trans 4/1

O

O

CO2EtBnO

5c,c 42%, cis/trans 7/1

5c,d 40%, cis/trans 7/1

O

O

CO2Et

Ph

5g, 0%

O

O

CO2EtBn

5a,a 86%, cis/trans 9/1

5a,b 81%, cis/trans 9/1

O

O

CO2EtPh

5e, 64%, cis/trans 8/1

O

O

CO2Et

5h, 78%e

O

O

CO2EtBu

5i, 77%, cis/trans 7/1

O

O

CO2Et

5j, 65%e

O

O

SO2PhBn

5k, 59%, cis/trans 9/1

26

Radical carbonylation/cyclisation was high-yielding for most O-vinylated -hydroxyalkyl phenyl chalcogenides (Table 7). Carbonylation of compound 3g failed and reduced starting material was isolated as the only product in 56% yield. Since benzylic radicals are very stable, carbonylation is expected to be inefficient in this case.

Cyclisation of radical precursors derived from 1,2-disubstituted epoxides afforded insepararable mixtures of four different isomers (Table 7, compounds 5h and 5j). Since the barrier for inversion of secondary carbon-centered radicals is low, carbonylation could give rise to two diastereomeric acyl radicals. Either of these would then give rise to two diastereomers of the cyclised product.

Organotellurium radical precursors worked equally as well as their selenium counterparts (Table 7, compounds 5a and 5c). However, radical carbonylation/cyclisation of compounds 3c and 3d gave unexpectedly low yields of tetrahydrofuran-3-one 5c (40 and 42%, respectively). As a by-product in these reactions, 1,4-dioxan 7 (Scheme 19) was isolated as a single diastereomer (with all three substituents in equatorial positions) in 32 and 30% yields, respectively. Formation of the dioxane probably occurs via a 1,5-hydrogen atom shift (driven by the formation of a more stable radical), followed by 6-exo-cyclisation (Scheme 19, right). When selenide 3c was subjected to radical cyclisation in the absence of CO under an N2

atmosphere, compound 7 was isolated in 82% yield along with 3% of reduced starting material.

5c 7

3c (X = Se)3d (X = Te)

Ph OO

PhX CO2Et

OH

OCO2Et

Ph

O

O

Ph

CO2Et

OO

CO2EtPh

OOPh

O

CO2Et

O

OCO2Et

OPh

Ph OO

CO2Et

1,5-H-shiftCO



Scheme 19. Unexpected side-reaction in the radical carbonylation/cyclisation of compounds 3c and 3d.

27

2,5-Disubstituted tetrahydrofuran-3-ones prepared were enriched (cis/trans = 9/1-4/1) in the cis-isomer. This is in accord with the Beckwith-Houk transition state model – cyclisation takes place via a chair-like TS with the substituent in an equatorial position (Scheme 19, left). The stereochemistry was determined by gNOESY experiments. The cis-isomers always gave rise to a 1,3-NOE across the ring (Figure 3).

In order to isomerise the mixture of diastereomers into the thermodynamically more stable trans-2,5-disubstituted tetrahydrofuran-3-one, the mixture of diastereomers of 3a was heated at reflux in benzene with 0.1 eq of DBU. Unfortunately, under the best conditions, only a 1:2-mixture of cis and trans isomers could be obtained.

O

O

H HEWG

R

NOE

Figure 3. Characteristic 1,3-NOE for the cis-isomer of 2,5-disubstituted tetrahydrofuran-3-ones.

3.3. Synthesis of tetrahydrofuran-3-ones on solid phase

In solid phase synthesis it is desirable to have a linker that is stable under a variety of conditions, but still cleavable to allow release of the product. If kept away from strong bases, oxidants and radicals, polymer supported selenium is relatively stable. The selenium linker was developed almost at the same time by Ruhland51a and Nicolaou51b in 1998. Since then, it has found extensive use in combinatorial chemistry52 as well as in total synthesis of natural products.53 There are several reports about radical reactions on solid phase.54 However, to the best of our knowledge, radical carbonylation has so far not been tried on solid phase.

Brominated resin (9) was synthesised by treatment of crosslinked (1%) polystyrene (8) with bromine using thallium(III) acetate as catalyst (Scheme 20).55 Subsequent lithiation with n-butyllithium, insertion of selenium into the carbon-lithium bond and air oxidation afforded diselenide resin (10).51a

air

8 9 10

Se SeSeLiBrCCl4

Tl(OAc)3/Br2

THF

1) n-BuLi2) Se

Scheme 20. Synthesis of diselenide resin 10.

28

The loading of selenium was determined by elemental analysis for nitrogen after reduction and carbamoylation (Scheme 21).

Se N

O

SeSe

1) NaBH4

2) N,N-Dimethylcarbamoyl chloride

EtOH

Scheme 21. Carbamoylation for determination of the loading of selenium.

For preparation of a polymer supported radical precursor, reduced diselenide resin was allowed to react with benzyloxirane (Scheme 22). After washing and filtration, the resin was treated with excess TTMSS/AIBN in benzene at 80 oC. Based on the loading of selenium, 1-phenyl-2-propanol (12) was isolated in almost quantitative yield. Subsequent O-vinylation of resin-bound alcohol 11 occurred by treatment with ethyl propiolate in NMM at 60 oC.The outcome of this reaction was controlled in a similar way as described above (91% yield of vinyl ether 6).

Se

OBn

CO2Et

TTMSS/AIBNCO 80 atm

SeSe

Se

OHBn

1) NaBH4, EtOH

2) Benzyloxirane

Ethyl propiolate

NMM Benzene

TTMSS/AIBNBenzene

TTMSS/AIBNBenzene

11

12 (97%)

OHBn

6 (91%)

OBn

CO2Et

10

13

O

O

Bn CO2Et

5a

[TTMSS]=0.1M (55% +12% of 6)

[TTMSS]=0.3M (37% +42% of 6)

Scheme 22. Synthesis of a tetrahydrofuran-3-one on solid phase.

29

Treatment of resin bound vinylic ether 13 with TTMSS/AIBN under 80 atm CO under dilute conditions (0.01 M TTMSS) resulted in a very low product yield. When a higher concentration (0.1 M) was employed, the desired product 5a was isolated in 55% yield along with 12% of vinyl ether 6 (yields are based on the loading of selenium in the resin and calculated over three steps). A further increase in the silane concentration caused a decrease in product yield (37%) and an increase in by-product formation (42%).

3.4. Synthesis of pyrrolidin-3-ones

Since nitrogen analogues of epoxides – aziridines – are readily available, it was interesting to try to extend the chemistry developed to the synthesis of pyrrolidinones. The initial strategy involved ring-opening of aziridines with benzeneselenolate, followed by a Michael addition to an electron deficient alkyne (Scheme 23, upper). When performed under acidic conditions, ring-opening is a high-yielding reaction.31a However, the next step, vinylation with methyl propiolate/NMM, occured very slowly at room temperature.56

Heating of the reaction mixture at 80 oC in DMF gave rise to a complex mixture of products. The corresponding N-tosylated derivative was found to be even less reactive.

NH

R CO2Me

O

CO/[H]R

PhSe

NH

CO2Me

R

N

CO2Me

R

PhSe

NH2

R

NH

Scheme 23. Two routes to 2,5-disubstituted pyrrolidin-3-ones.

30

Another strategy considered involved vinylation of the aziridine prior to ring-opening (Scheme 23, lower). 57 To our delight, this reaction worked well. Michael adducts were formed in quantitative yields under neat conditions from methyl propiolate and dimethyl acetylenedicarboxylate. Conjugate addition to ethynyl p-tolyl sulfone did also work well, but THF was required as a solvent. Except for sulfone 14h, the E-isomer of the addition product was predominating (Table 8).

Table 8. Preparation of N-vinylated aziridines 14a-h.

Methyl propiolate,dimethyl acetylenedicarboxylate orethynyl p-tolyl sulfone

R2

R2

N

EWG

R2

R1

NH

12a-h

Bn

N

CO2Me

14a, quant., E/Z 6/1

t-Bu

N

CO2Me

14d, quant., E/Z 9/1

t-Bu

N

CO2Me

CO2Me

14g, quant., E/Z 10/1

NPhO

CO2Me

14b, quant., E/Z 6/1

N

CO2Me

14e, quant., E/Z 5/1

Bn

NSO2Tol

14h, quant., E/Z 1/>25

Hex

N

CO2Me

14c, quant., E/Z 7/3

N

CO2Me

14f, quant., E/Z 5/1

31

Since the aziridines carry an electron withdrawing N-substituent, they can be ring-opened with benzeneselenolate generated in situ by sodium borohydride reduction of diphenyl diselenide (Table 9). Ring-opening was regioselective and was complete within 2-3 h at room temperature for most of the substrates. The two exceptions were compound 14g derived from dimethyl acetylene dicarboxylate (requiring stirring overnight) and compound 14f derived from 8-azabicyclo[5.1.0]octane (requiring reflux in methanol for 3h).

Table 9. Preparation of radical precursors 15a-h via aziridine ring-opening.

R2

R2

N

EWG R1

NH

SePh

R2EWG

EtOH

(PhSe)2, NaBH4

14a-h 15a-h

Hex

SePh

NH

CO2Me

15c, 96%,a (85),b E/Z 1/4

NH

CO2Me

SePh

15f, 92%,a E/Z 2/5

SePh

NH

CO2Me

15e, 95%,a E/Z 2/3

Bn

SePh

NH

SO2Tol

15h, 92%,a E/Z 9/1

a Isolated yield after NaBH4/BrCH2CO2H-treatment. b Isolated yield after chromatography on neutral

alumina. c Stereochemistry not determined, E/Z was either 2/3 or 3/2.

SePh

NH

CO2MePhO

15b, 96%,a (73),b E/Z 2/1

t-Bu

SePh

NH

CO2Me

15d, 95%,a (83),b E/Z 1/>25

t-Bu NH

CO2Me

CO2MeSePh

15g, 92%a,c

Bn

SePh

NH

CO2Me

15a, 98%,a (84),b E/Z 4/5

Ring-opened aziridines 15a and 15c-g were all enriched in the Z-isomer. In one case (compound 14a) the E- and Z-isomers of the aziridine were separated. When ring-opened separately they gave the same mixture (E/Z =4/5) of isomers of 15a. This seems to indicate that the ring-opening is thermodynamically controlled.

32

Attempted purification of products 15 on silica caused decomposition. Pure vinylogous carbamates were instead obtained by chromatography on neutral alumina. As judged by the 1H NMR spectrum of crude product, the major impurity was diphenyl diselenide. An expedient way to remove it without column chromatography involves reduction with sodium borohydride in ethanol, followed by addition of excess of bromoacetic acid.58 The phenylselenoacetic acid thus formed can then be removed by extraction with an aqueous solution of NaHCO3.

Radical carbonylation/reductive cyclisation was performed as described above for tetrahydrofuranone synthesis (80 atm of CO using TTMSS as hydrogen atom donor). This reaction worked well for all selenides except for radical precursor 15h with a vinyl sulfone acceptor (Table 10).

Table 10. Preparation of pyrrolidin-3-ones 16a-h via radical carbonylation/cyclisation.

TTMSS/AIBNCO (80 atm)

NH

OR1

R2EWG

R1

NH

SePh

R2EWG

Benzene

15a-h 16a-h

a Inseparable mixture of diastereomers. Stereochemistry not determined.

16f, 68%a

NH

O

CO2Me

16c, 65%, cis/trans 3/1

NH

O

CO2MeHex

16b, 85%, cis/trans 3/1

NH

O

CO2MePhO

16e, 65%

NH

O

CO2Me

16h, 0%

NH

O

SO2TolBn

16g, 68%, cis/trans 1/>25

NH

O

CO2Met-Bu

CO2Me

16d, 71%, cis/trans 12/1

NH

O

CO2Met-Bu

16a, 79%, cis/trans 4/1

NH

O

CO2MeBn

33

Products were purified on silica. Although they contained an unprotected secondary amine they were surprisingly mobile. This could be due to intramolecular hydrogen bonding to the ester. Some of the pyrrolidinones were rather unstable. Compounds with bulky substituents to nitrogen could be isolated and stored for a shorter period in the freezer. Pyrrolidines 16a-c decomposed rapidly and were N-tosylated prior to characterization to improve stability.

The stereochemistry of the products was again determined by gNOESY experiments. A 1,3-NOE was detected for cis-disubstituted compounds. For compound 16g, an NOE was seen between the t-butyl group and the cis-configured methyl ester. Generally, diastereoselectivity was slightly lower than obtained in the synthesis of analogous tetrahydrofuran-3-ones.

In conclusion, by using carbon monoxide as a one-carbon synthon, novel radical methodologies for the synthesis of tetrahydrofuran-3-ones and pyrrolidin-3-ones from epoxides and aziridines, respectively, were developed.

34

4. Microwave-assisted aryltelluro- and phenylseleno-transfer cyclisations

4.1. Group- and atom-transfer reactions

In the most common version of a group/atom-transfer reaction, a carbon-halogen/chalcogen bond R-X is added intra- or intermolecularly across a double bond (Scheme 24).

R'R X RR'

X

Scheme 24. Group-transfer addition to an alkene.

As compared to reductive radical reactions (Chapter 1, Scheme 6), group-transfer reactions have several advantages. The functional group within the radical precursor is not removed from the product and can be used for further transformations. Also, premature reduction of the initially formed radical R•

- a competing reaction in reductive cyclisation/addition – is not encountered. The chain mechanism for the group-transfer process is shown in Scheme 25.

R. R'

R X

RR'

X

RR'

Scheme 25. Chain mechanism for group- and atom-transfer reactions.

The number of useful radical precursors is limited, though. Among halides, iodides are the most frequently used. Bromides and chlorides are often too unreactive. Among chalcogenides, phenyltellurides show a similar reactivity as iodides. The reactivity of phenylselenides parallels that of bromides.59

Xanthates have also proven to be well suited for group-transfer reactions.7

35

Aryltellurides have successfully been used for carbotelluration of alkynes,60 alkenes,61 isonitriles62 and quinones63 and for the decarbonylation of aryltelluroformates.64 These reactions are often initiated by photolysis or thermolysis.

4.2. Microwave-assisted chemistry

During the last 20 years, the equipment for microwave-heating of organic reactions has become increasingly more available.65 Microwaves are electromagnetic radiation with frequencies in between those of infrared and radio waves. This energy is too low to cause vibrational excitation of molecules. However, polar molecules try to adjust their dipolar moment along the field of the microwaves. The heating of the sample is caused by this rotation. Since the heat is evolved in the bulk of the solvent, the sample is uniformly heated. Problems with hot spots on the glass wall can be avoided and results are often more reproducible than with conventional heating. Since microwave-assisted reactions in most cases are performed in closed vials and heating is very rapid, it is possible to perform reactions at temperatures far above the boiling points of the solvents used.

Since the middle of the 1980’s, a large number of microwave-assisted reactions have been published.65 They have proven especially useful in combinatorial chemistry.66 However, there are surprisingly few examples of microwave-assisted radical reactions.67 Curran and Hallberg showed a few years ago that hydrodebromination, reductive 5-exo-cyclisation and intermolecular addition could be substantially accelerated by microwave heating.67b

4.3. Group-transfer cyclisations

Previously, a procedure for group-transfer cyclisation of -allyloxyalkyl aryl tellurides was developed in our group (Scheme 26).30 The reaction was performed in refluxing benzene using 0.4 eq hexabutyldistannane as initiator. We were curious to see if a more environmentally benign protocol for this process could be developed using microwave heating.

OR

TeAr

OR

TeAr(Bu3Sn)2, h

Benzene

Scheme 26. Hexabutyldistannane-promoted phenyltelluro-transfer cyclisation.

36

Radical precursors for the group-transfer chemistry were synthesised as described previously (Chapter 2). Thus, epoxides were regioselectively ring-opened with arenetellurolate in high yields and allylated using allyl bromide and NaH (Table 11).

Table 11. Arenetellurolate ring-opening of epoxides and O-allylation.

R1

R2

O(ArTe)2, NaBH4

EtOH

Allyl bromide, NaH

THF

R1 TeAr

OHR2

17a-g

R1 TeAr

OR2

18a-f

During the initial studies, radical precursor 17b was irradiated for 2-10 min in various solvents at various temperatures. Of the conditions tried (iso-propanol at 200 oC, NMP at 250 oC, diethylene glycol dimethyl ether at 250 oC, ethylene glycol at 250 oC, water at 180 oC), the latter two gave the most promising results.

The electronic properties of an aryltelluro group can be affected by substitution in the aryl moiety. In order to see if this was of any importance in the group-transfer reaction, tellurides 18a-c, carrying both electron withdrawing and electron donating substituents, were heated to 250 oC in ethylene glycol. Group-transfer cyclisation of telluride 18b (with an unsubstituted phenyl-group) was complete in 3 min and tetrahydrofuran derivative 19b was isolated in 69% yield (Table 12, entry 2). Cyclisation of tellurides 18a and 18c (carrying electron donating and electron withdrawing substituents, respectively) afforded similar yields of group-transfer products (Table 12, entries 1 and 4). However, the electron donating properties of the 4-methoxyphenyl group makes tellurium more susceptible to oxidation and isolation of the product was more difficult.

Entry R1 R2 Ar 2-Hydroxyalkyl aryl telluride,

isolated yield (%)

2-Allyloxyalkyl aryl telluride,

isolated yield (%)1 -(CH2)4- p-MeO-C6H4 17a, 89 18a, 80

2 -(CH2)4- Ph 17b, 98 18b, 84

3 -(CH2)4- p-CF3-C6H4 17c, 82a 18c, 80a

4 H Bn Ph 17d, 92 18d, 81

5 H Bn p-CF3-C6H4 17e, 95 18e, 80

6 H PhOCH2 Ph 17f, 91 18f, 72

7 H CH2=CH(CH2)2 Ph 17g, 80a -aFrom reference 30

37

When the cyclisation of compounds 18b and 18c was performed in water at 180 oC, the difference in reactivity was striking (Table 12, entries 6 and 8). Whereas the reaction of compound 18c failed to go to completion even after prolonged heating (10 min), group-transfer cyclisation of telluride 18b

was complete within 5 min.

Table 12. Influence of aryl substituents on microwave-assisted group-transfer cyclisation of secondary-alkyl aryl tellurides 18a-c.

Microwaves

TeAr

O

18a-c

O

TeAr

19a-c

Entry 2-Allyloxyalkyl aryl telluride

Conditionsa Additive (0.5 eq)

Reactiontime (min)

Product, isolated yield

(%), endo/exo-ratio

1 18a, Ar=p-MeO-C6H4 A - 3 19a, 65, 1/1.1

2 18b, Ar= Ph A - 3 19b, 69, 1/1.1

3 18b, Ar= Ph A (ArTe)2 3 19b, 73, 1/1.1

4 18c, Ar= p-CF3-C6H4 A - 3 19c, 67, 1/1.1

5 18c, Ar= p-CF3-C6H4 A - 5 19c, 61, 1/1.1

6 18b, Ar= Ph B - 5 19b, 72, 1/1.3

7 18b, Ar= Ph B (ArTe)2 5 19b, 74, 1/1.3

8 18c, Ar= p-CF3-C6H4 B - 10 19c, <10, 1/1.3 aA: Ethylene glycol, 250 oC; B: Water, 180 oC.

Some experiments with additives were also carried out. The corresponding diaryl ditelluride was added to some of the reactions (Table 12, entries 3 and 7) without any significant difference in yields and reaction times. Hexabutyldistannane prolonged reaction times and lowered yields.

We were also interested to see if primary-alkyl phenyl tellurides could be induced to undergo group-transfer reactions under these conditions. Telluride 18d was heated to 180 oC in water (Table 13, entry 1). Cyclisation was very slow and only trace amounts of product was formed after 10 min. When the reaction was performed in ethylene glycol at 250 oC, it was complete in 6 min and product 19d was isolated in 74% yield (entry 2). p-Trifluoromethyl aryl telluride 18e was slightly less reactive. After 10 min, a 60% yield of compound 19e was isolated (entry 3).

38

Table 13. Microwave-assisted group-transfer cyclisations of primary-alkyl aryl tellurides.

Microwaves

TeAr

OR

18d-f 19d-f

O

TeAr

R

Entry 2-Allyloxy-alkyl aryl telluride

Ar Conditionsa Reaction time (min)

Product, isolated yield (%),

cis/trans-ratio1 18d, R=Bn Ph B 10 19d, <10, 1/2.4

2 18d, R=Bn Ph A 6 19d, 74, 1/1.8

3 18e, R=Bn p-CF3-C6H4 A 10 19e, 60, 1/1.8

4 18f, R=PhOCH2 Ph A 6 19f, 63, 1/1.5aA: Ethylene glycol, 250 oC; B: Water, 180 oC.

All tetrahydrofuran derivatives prepared were obtained as cis/trans- or endo/exo-mixtures of diastereomers (Tables 12 and 13). Due to the high reaction temperatures employed in the microwave-assisted group-transfer reactions, selectivity is not as good as that obtained in refluxing benzene using hexabutyldistannane as initiator.30

To demonstrate that the protocol developed is not limited to tetrahydrofuran synthesis only, cyclopentane derivative 20 was prepared as shown in Scheme 27.

Microwaves

Ethylene glycol

250oC, 10 min

TeAr

HO

17g

TeAr

HO

20 (58%, cis/trans: 1/1.1)

Scheme 27. Synthesis of a cyclopentanol derivative via group-transfer cyclisation.

It would be interesting to compare the reactivity of primary- and secondary-alkyl aryl tellurides with that of tertiary ones. Unfortunately, all attempts to synthesise such compounds failed. For example, ring-opening of isobutylene oxide with benzenetellurol under acidic conditions would be expected to produce a tertiary-alkyl phenyl telluride. Unfortunately the reaction gave only a low yield of 2-hydroxy-2-methyl-propyl phenyl telluride. Ring-opening of tetramethyloxirane with benzenetellurolate proceeded extremely slowly. All attempts to allylate the tertiary alcohol formed resulted in decomposition.

39

We also found it interesting to try to extend the protocol to group-transfer reactions of organoselenium compounds. Phenyl selenides are known to be less reactive than the corresponding organotellurium derivatives. Examples in the literature are limited to compounds that could give rise to a stabilised organic radical after homolytic cleavage of the C-Se-bond.68 Compound 21,the selenium analogue of compound 18b, failed to react even after 20 min at 250 oC in ethylene glycol. Substitution in the PhSe-moiety with a dimethylamino-group para to selenium did not cause any improvement.

SePh

O

21

Group-transfer cyclisation of benzylic selenide 1e was more successful (Scheme 28). After 5 min at 250 oC in ethylene glycol, selenide 22 (cis/trans

= 1/2.1) was isolated in 75% yield along with 13% of cyclised but reduced compound 2e. Addition of 0.5 eq of diphenyl diselenide to the reaction improved the yield of group-transfer product to 91% and lowered by-product formation to 4%. To the best of our knowledge, this is the first example of group-transfer of a benzylic phenylselenide. However, attempts to extend the group-transfer cyclisation to -phenylseleno esters and nitriles resulted only in decomposition products.

Ph SePh

O

1e

O

Ph SePh

22

Microwaves

Ethylene glycol

250oC, 5 min

O

Ph

2e

(75%, cis/trans: 1/2.1)

With 0.5 eq (PhSe)2 (91%, cis/trans: 1/2.1)

(13%, cis/trans: 1/2.1)

(4%, cis/trans: 1/2.1)

Scheme 28. Phenylseleno group-transfer cyclisation.

By-product formation in the cyclisation of the benzylic selenide is probably a result of slow phenylseleno-transfer from the starting material. Thus, the radical formed after cyclisation can be reduced by hydrogen atom abstraction from the solvent. Added diphenyl diselenide serves as a PhSe-donor and improves the yield of group-transfer product 22.

40

In conclusion, we have shown that group-transfer reactions of organotellurides and organoselenides can be substantially facilitated and improved by microwave-heating. Not only are reaction times shortened from a few hours to 3-10 minutes, but also, with some type of substrates, can environmentally benign solvents be used.

41

Acknowledgements

Alla ni som på något vis bidragit till att det här arbetet varit möjligt, TACK!Det är några jag vill tacka lite extra:

Först och främst, min handledare Prof Lars Engman för hjälp, stöd och bra handledning under dessa år.

Grupp LE, speciellt Dr Stefan Berlin, David Shanks, Dr Takahiro Kanda,Dr Michael McNaughton, Dr Jonas Malmström, Matthis Persson, Amelie

Fagerlund och Dr Magnus Besev.

Prof Philippe Renaud, for giving me the opportunity to stay in your group for three months and learning me more about organoboranes.

David Shanks, Dr Takahiro Kanda, Dr Stefan Berlin, Matthis Persson,Tomas Gustafsson, Dr Karl-Johan Winberg, Fil Lic Jenny Ekegren, for helping me to improve this thesis and making the errata-list shorter.

Personal Chemistry (Dr Vijay Gupta, tack för all hjälp) och avdelningen för

farmaceutisk organisk kemi för tillgång till er mikrovågsutrustning.

Teknisk och administrativ personal, det skulle inte fungera utan er!

Docent Adolf Gogoll och Stefan Modin för hjälp med instrument och datorer.

Lab 4016/4017 – det bästa labbet på Kemikum! Kalle, Susanna, Anna,Ludvig, tack för många roliga timmar framför dragskåpen, trots ett och annat elakt ord man fått stå ut med ;-)

Trevliga människor som är och som har varit på avdelningen för organisk kemi, fram för allt: Magnus E, Judit, Cecilia, Niclas, Jenny, Sophie,

Helena M, Charlotte, Göran (tack för exemplarisk guidning i Zermatt).

Vänner från Norrland (och utflyttade norrlänningar), för att ni finns, om än inte på gångavstånd.

Tvåbenta vänner från hästvärlden och, såklart, Stjärna!

Sist, men inte minst, vill jag tacka min familj: mamma, pappa och Maria föratt ni alltid finns och alltid ställer upp.

42

References

1. Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757. 2. Paneth, F.; Hofeditz, W. Chem. Ber. 1929, 62, 1335. 3. Hey, D. H.; Walters, W. A. Chem. Rev. 1937, 21, 169. 4. (a) Giese, B. Radicals in Organic Synthesis: Formation of C-C bonds;

Pergamon Press: Oxford, 1986, (b) Regitz, M.; Giese, B., Eds. Houben-Weyl, Methoden der Organishen Chemie; Band E19a, C-Radikale, Teil 1+2, Georg Thieme Verlag: Stuttgart, 1989. (c) Curran, D.P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford, 1991; Vol 4, p 715 and 779. (d) Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic Press: New York, 1992. (e) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry;Wiley: New York, 1995. (f) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis, Volume 1: Basic Principles, Wiley-VCH: Weinheim, 2001. (g) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis, Volume 2: Applications, Wiley-VCH: Weinheim, 2001, (h) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions – Concepts, Guidelines and Synthetic Applications; VCH: New York, 1996, (i) Giese, B.; Kopping, B.; Göbel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996,48, 301, (j) Parsson, A. F. An Introduction to Free Radical Chemistry;Blackwell Science: Oxford, 2000.

5. (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237, (b) Koert, U. Angew. Chem. Int. Ed. Engl. 1996, 35, 405.

6. Lowry, T. H.; Richardsson, K. S. Mechanism and Theory in Organic Chemistry,Harper and Row: New York, 1987.

7. (a) Zard, S. Z. Angew. Chem. Int. Ed. Engl. 1997, 36, 672, (b) Quiclet-Sire, B.; Zard, S. Z. Phosph. Sulf. Silicon 1999, 153-154, 137.

8. Barton, D. H. R.; Crich, D.; Potier, P. Tetrahedron Lett. 1985, 26, 5943. 9. (a) Ingold, K. U.; Lusztyk, J.; Scaiano, J. C. J. Am. Chem. Soc. 1984, 106, 343,

(b) Beckwith, A. L. J.; Pigou, P. E. Aust. J. Chem. 1986, 39, 77. 10. Lewis, F. M.; Matheson, M. S. J. Am. Chem. Soc. 1949, 71, 747. 11. Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 2547. For a

review of the use of organoboranes as sources of radicals, see Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415.

12. Neumann, W. P. Synthesis 1987, 665. 13. Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554. 14. Baguley, P. A.; Walton, J. C. Angew. Chem. Int. Ed. 1998, 37, 3072. 15. (a) Lesage, M.; Chatgilialoglu, C.; Griller, D. Tetrahedron Lett. 1989, 30, 2733,

(b) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188. 16. Chatgilialoglu, C.; Ballestri, M.; Escudié, J.; Pailhous, I. Organometallics 1999,

18, 2395. 17. Porter, N. A.; Chang, V. H.-T.; Magnin, D. R.; Wright, B. T. J. Am. Chem. Soc.

1988, 110, 3554.

43

18. (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482, (b) Beckwith, A. L. J.; Lawrence, T.; Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 484, (c) Beckwith, A. L. J. Tetrahedron1981, 37, 3073, (d) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,3925. (e) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.

19. For a review of the use of Lewis acids in radical chemistry, see Renaud, P.; Gerster, M. Angew. Chem. Int. Ed. 1998, 37, 2562.

20. For reviews of enantioselective radical reactions, see (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163, (b) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263.

21. (a) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997, 38, 5955, (b) Sibi, M. P.; Manyem, S.; Subramaniam, R. Tetrahedron, 2003, 59, 10575.

22. (a) Dakternieks, D.; Schiesser, C. H. Aust. J. Chem. 2001, 54, 89, (b) Dakternieks, D.; Perchyonok, V. T.; Schiesser, C. H. Tetrahedron: Asymmetry, 2003, 14, 3057.

23. (a) Gerster, M.; Audergon, L.; Moufid, N.; Renaud, P. Tetrahedron Lett. 1996,37, 6335, (b) Guindon, Y.; Guérin, B.; Chabot, C.; Ogilvie, W. J. Am. Chem. Soc. 1996, 118, 12528, (c) Guindon, Y.; Rancourt, J. J. Org. Chem. 1998, 63,6554, (d) Mero, C. L.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 5155, (e) Enholm, E. J.; Lavieri, S.; Cordóva, T.; Ghiviriga, I. Tetrahedron Lett. 2003,44, 531.

24. (a) Yang, D.; Gao, Q.; Lee, O.-Y. Org. Lett. 2002, 4, 1239, (b) Yang, D.; Zheng, B.-F.; Gu, S.; Chan, P. W. H.; Zhu, N.-Y. Tetrahedron: Asymmetry 2003, 14,2927, (c) Yang, D.; Yan, Y.-L.; Law, K.-L.; Zhu, N.-Y. Tetrahedron 2003, 59,10465.

25. (a) Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J. Am. Chem. Soc.2001, 123, 8612, (b) Yang, D.; Gu, S.; Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem. Int. Ed. 2002, 41, 3014.

26. Enholm, E. J.; Cottone, J. S.; Allais, F. Org. Lett. 2001, 3, 145. 27. Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959. 28. Kim. K.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 67. 29. Ooi, T.; Hokke, Y.; Tayama, E.; Maruoka, K. Tetrahedron 2001, 57, 135. 30. Engman, L.; Gupta, V. J. Org. Chem. 1997, 62, 157. 31. (a) Besev, M.; Engman, L. Org. Lett. 2000, 2, 1589, (b) Shanks, D.; Berlin, S.;

Besev, M.; Ottosson, H.; Engman, L.; J. Org. Chem. In press. 32. For a review on acyl radicals, see Chatgilialoglu, C.; Crich, D.; Komatsu, M.;

Ryu, I. Chem. Rev. 1999, 99, 1991. 33. For reviews of radical carbonylations, see (a) Ryu, I.; Sonoda, S. Angew. Chem.

Int. Ed. Engl. 1996, 35, 1050, (b) Ryu, I. Chem. Soc. Rev. 2001, 30, 16. For a review on C1-synthons (including CO) in radical reactions, see (c) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177.

34. The first report on radical carbonylation was published in 1939 by Faltings; (a) Faltings, K. Ber. Dtsch. Chem. Ges. 1939, 72B, 1207. Free radical carbonylations were also performed in the 1950´s by researchers at DuPont. Since extremely high pressures (>1000 atm) had to be employed and/or the reactions suffered from low yields, these reactions were not synthetically useful; (b) Brubaker, M. M.; Coffman, D. D.; Hoehn, H. H. J. Am. Chem. Soc. 1952,74, 1509, (c) Coffman, D. D.; Pinkey, P. S.; Wall, F. T.; Wood, W. H.; Young, H. S. J. Am. Chem. Soc. 1952, 74, 3391, (d) Foster, R. E.; Larchar, A. W.; Lipscomb, R. D.; McKusick, B. C. J. Am. Chem. Soc. 1956, 78, 5606, (e) Sauer, J. C. J. Am. Chem. Soc. 1957, 79, 5314, (f) Cramer, R. J. Am. Chem. Soc. 1957,

44

79, 6215, (g) Coffamn, D. D.; Cramer, R.; Mochel, W. E. J. Am. Chem. Soc.1958, 80, 2882.

35. Ryu, I.; Kusano, K.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc.1990, 112, 1295.

36. (a) Ryu, I.; Kusano, K.; Yamazaki, H.; Sonoda, N. J. Org. Chem. 1991, 56,5003, (b) Ryu, I.; Yamazaki, H.; Kusano, K.; Ogawa, A.; Sonoda, N. J. Am. Chem. Soc. 1991, 113, 8558, (c) Ryu, I.; Yamazaki, H.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1993, 115, 1187, (d) Brinza, I. M.; Fallis, A. G. J. Org. Chem. 1996, 61, 3580, (e) Nagahara, K.; Ryu, I.; Yamazaki, H.; Kambe, N.; Komatsu, M.; Sonoda, N.; Baba, A. Tetrahedron 1997, 53, 14615, (f) Ikariya, T.; Kayaki, Y.; Kishimoto, Y.; Noguchi, Y. Prog. Nucl. Energy2000, 37, 429, (g) Kishimoto, Y.; Ikariya, T. J. Org. Chem. 2000, 65, 7656,

37. Nagahara, K.; Ryu, I.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1997, 119,5465.

38. (a) Tsunoi, S.; Ryu, I.; Okuda, T.; Tanaka, M.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1998, 120, 8692, (b) Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. Org. Lett. 2000, 2, 389

39. Ryu, I.; Okuda, T.; Nagahara, K.; Kambe, N.; Komatsu, M.; Sonoda, N. J. Org. Chem. 1997, 62, 7550.

40. (a) Ryu, I.; Nagahara, K.; Kambe, N.; Sonoda, N.; Kreimerman, S.; Komatsu, M. Chem. Commun. 1998, 1953, (b) Ryu, I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838, (c) Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara, H.; Schiesser, C. H.; Kuriyama, H.; Miyazato, H.; Minakato, S.; Komatsu, M.; Ryu, I. Org. Biomol. Chem. 2003, 1, 4262.

41. Ryu, I.; Muraoka, H.; Kambe, N.; Komatsu, M.; Sonoda, N. J. Org. Chem.1996, 61, 6396.

42. Sugiura, M.; Hagio, H.; Kobayashi, S. Chem. Lett. 2003, 32, 898. 43. For kinetic data on addition of primary alkyl radicals to CO, see (a) Bakac, A.;

Espenson, J. H. J. Chem. Soc., Chem. Commun. 1991, 1497, (b) Bakac, A.; Espenson, J. H.; Young, Jr. V. G. Inorg, Chem. 1992, 31, 4959, (c) Nagahara, K.; Ryu, I.; Kambe, N.; Komatsu, M.; Sonoda, N. J. Org. Chem. 1995, 60, 7384.

44. Boese, W. T.; Goldman, A. S. Tetrahedron Lett. 1992, 33, 2119. 45. For kinetic data on reduction of acyl radicals, see (a) Chatgilialoglu, C.;

Lucarini, M. Tetrahedron Lett. 1995, 36, 1299, (b) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Pedrielli, P.; Pedulli, G. F. Organometallics, 1995, 14, 2672,

46. Brown, C. E.; Neville, A. G.; Rayner, D. M.; Ingold, K. U.; Lusztyk, J. Aust. J. Chem. 1995, 48, 363.

47. Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem. Int. Ed. 1999, 38, 3175.

48. Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C. K. Tetrahedron Lett. 1995, 36, 417.

49. Evans, P. A.; Manangan, T. J. Org. Chem. 2000, 65, 4523. 50. More recently we have been able to vinylate tertiary alcohols using microwave-

assisted chemistry. 51. (a) Ruhland, T.; Anderssen, K.; Pedersen H. J. Org. Chem. 1998, 63, 9204,

(b) Nicolaou, K. C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem. Commun.1998, 1947.

52. (a) Nicolaou, K. C.; Mitchell, H. J.; Fylaktakidou, K. C.; Suzuki, H.; Rodríguez, R. M. Angew. Chem. Int. Ed. 2000, 39, 1089, (b) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem. Int. Ed. 2000, 39, 734, (c) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122,2966, (d) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;

45

Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939, (e) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao, G.-Q.; Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954, (f) Nicolaou, K. C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 9968,

53. Nicolaou, K. C.; Winssinger, N.; Hughes, R.; Smethurst, C.; Cho, S. Y. Angew. Chem. Int. Ed. 2000, 39, 1084.

54. (a) For a review on radical reactions on solid support, see: Ganesan, A. in reference 4g, p 81. For examples of radical reactions on solid support, see: (b) Sibi, M. P.; Chandramouli, S. V. Tetrahedron Lett. 1997 38, 8929, (c) Miyabe, H.; Tanaka, H.; Naito, T. Tetrahedron Lett. 1999, 40, 8387, (d) Caddick, S.; Hamza, D.; Wadman, S. N. Tetrahedron Lett. 1999, 40, 7285, (e) Berteina, S.; De Mesmaeker, A.; Wendeborn, S. Synlett 1999, 1121, (f) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Lett. 1999, 40, 4535, (g) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 64, 2174, (h) Watanabe, Y.; Ishikawa, S.; Takao, G.; Toru, T. Tetrahedron Lett. 1999, 40,3411 (i) Miyabe, H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443, (j) Jia, G.; Iida, H.; Lown, J. W. Synlett 2000, 603, (k) Wendeborn, S.; De Mesmaeker, A.; Brill, W. K.-D.; Berteina, S. Acc. Chem. Res. 2000, 33, 215, (l) Jeon, G.-H.; Yoon, J.-Y.; Kim, S.; Kim, S. S. Synlett 2000, 128, (m) Enholm, E. J.; Gallagher, M. E.; Jiang, S.; Batson, W. A. Org. Lett. 2000, 2, 3355, (n) Timár, Z.; Gallagher, T. Tetrahedron Lett. 2000, 41, 3173, (o) Plourde, Jr. R.; Johnson, Jr. L. L.; Longo, R. K. Synlett 2001, 439, (p) De Luca, L.; Giacomelli, G.; Porcu, G.; Taddei, M. Org. Lett 2001, 3, 855, (q) Miyabe, H.; Fujii, K.; Tanaka, H.; Naito, T. Chem. Commun. 2001, 831, (r) Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 3519, (s) Enholm, E. J.; Gallagher, M. E. Org. Lett.2001, 3, 3397, (t) Caddick, S.; Hamza, D.; Wadman, S. N.; Wilden, J. D. Org. Lett. 2002, 4, 1775, (u) Dublanchet, A.-C; Lusinchi, M.; Zard, S. Z. Tetrahedron2002, 58, 5715, (v) Kumar, H. M. S.; Chakravarthy, P. P.; Rao, M. S.; Reddy, P. S. R.; Yadav, J. S. Tetrahedron Lett. 2002, 43, 7817, (w) Miyabe, H.; Nishimura, A.; Fujishima, Y.; Naito, T. Tetrahedron 2003, 59, 1901, (x) Harrowven, D. C.; May, P. J.; Bradley, M. Tetrahedron Lett. 2003, 44, 503, (y) Miyabe, H.; Konishi, C.; Naito, T. Chem. Pharm. Bull. 2003, 51, 540.

55. Farrall, M. J.; Fréchet, J. M. J. J. Org. Chem. 1976, 41, 3877. 56. Grigg, R.; Savic, V. Chem, Commun. 2000, 873. 57. Gelas-Mialhe, Y.; Touraud, E.; Vessiere, R. Can. J. Chem. 1982, 60, 2830. 58. Clive, D. L. J.; Daigneault, S. J. Org. Chem. 1991, 56, 3801. 59. Curran, D. P.; Martin-Esker, A. A.; Ko, S.-B.; Newcomb, M. J. Org. Chem.

1993, 58, 4691. 60. (a) Han, L.-B.; Ishihara, K.-I.; Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda, N. J.

Am. Chem. Soc. 1992, 114, 7591, (b) Yamago, S.; Miyazoe, H.; Yoshida, J. Tetrahedron Lett. 1999, 40, 2343, (c) Fujiwara, S.; Shimizu, Y.; Shin-ike, T.; Kambe, N. Org. Lett. 2001, 3, 2085, (d) Yamago, S.; Miyoshi, M.; Miyazoe, H.; Yoshida, J. Angew. Chem. Int. Ed. 2002, 41, 1407.

61. (a) Crich, D.; Chen, C.; Hwang, J.-T.; Yuan, H.; Papadatos, A.; Walter, R. I. J.Am. Chem. Soc. 1994, 116, 8937, (b) Yamago, S.; Iida, K.; Yoshida, J.-I. J. Am. Chem. Soc. 2002, 124, 2874, (c) Yamago, S.; Iida, K.; Yoshida J. J. Am. Chem. Soc. 2002, 124, 13666, (d) Goto, A.; Kwak, Y.; Fukada, T.; Yamago, S.; Iida, K.; Nakajiama, M.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 8720, (e) Yamago, S.; Iida, K.; Nakajiama, M.; Yoshida, J. Macromolecules, 2003, 36, 3793.

62. (a) Miyazoe, H.; Yamago, S.; Yoshida, J. Angew. Chem. Int. Ed. 2000, 39,3669, (b) Yamago, S.; Miyazoe, H.; Sawazaki, T.; Goto, R.; Yoshida, J.

46

Tetrahedron Lett. 2000, 41, 7517, (c) Yamago, S.; Miyazoe, H.; Goto, R.; Hashidume, M.; Sawazaki, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 3697, (d) Yamago, S.; Miyazoe, H.; Nakayama, T.; Miyoshi, M.; Yoshida, J. Angew. Chem. Int. Ed. 2003, 42, 117.

63. Yamago, S.; Hashidume. M.; Yoshida, J. Tetrahedron 2002, 58, 6805. 64. Lucas, M. A.; Schiesser, C. H. J. Org. Chem. 1996, 61, 5754. 65. (a) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665, (b) Berlan, J.

Radiat. Phys. Chem. 1995, 45, 581, (c) Caddick, S. Tetrahedron 1995, 51,10403, (d) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron2001, 57, 9225, (e) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,35, 717.

66. (a) Larhed, M.; Hallberg, A. DDT 2001, 6, 406, (b) Wathey, B.; Tierney, J.; Lidström, P.; Westman, J. DDT 2002, 7, 373, (c) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95.

67. (a) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.; Bari, S. S.; Newaz, S. N.; Banik, B. K.; Chaudhary, A. G.; Barakat. K. J. J. Org. Chem.1991, 56, 6968, (b) Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1999, 64, 4539, (c) Lamberto, M.; Corbett, D. F.; Kilburn, J. D. Tetrahedron Lett. 2003, 44, 1347, (d) Wetter, C.; Studer, A. Chem. Commun. 2004, 174.

68. (a) Byers, J. H.; Lane, G. C. Tetrahedron Lett. 1990, 31, 5697, (b) Byers, J. H.; Harper, B. C. Tetrahedron Lett. 1992, 33, 6953, (c) Byers, J. H.; Lane, G. C. J.Org. Chem. 1993, 58, 3355, (d) Curran, D. P.; Geib, S. J.; Kuo, L. H. Tetrahedron Lett. 1994, 35, 6235, (e) Curran, D. P.; Eichenberger, E.; Collis, M.; Roepel, M. G.; Thoma, G. J. Am. Chem. Soc. 1994, 116, 4279, (f) Byers, J. H.; Whitehead, C. C.; Duff, M. E. Tetrahedron Lett. 1996, 37, 2743, (g) Back, T. G.; Gladstone, P. L.; Parvez, M. J. Org. Chem. 1996, 61, 3806, (h) Renaud, P.; Abazi, S. Synthesis 1996, 253, (i) Abazi, S.; Rapado, L. P.; Shenk, K.; Renaud, P. Eur. J. Org. Chem. 1999, 477. See also references 24a and 42.

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