CBAPTER-III Development of new synthetic methodologies

S E C T IO N -A

3.1. LSyiithesis o f novel unsym iiic tr ica l b is - l , 2 , 3 -f r iazo les

3.1.0. G en era l in troduction :

Synthetic chemistry has had a very great past and its overall impact on science is

remarkable. F’articularly the past few decades have seen a fiiscinating development o f

synthetic organic chemistry. Chemists are constantly working to d iscover new and

improved reactions. One o f the primary motivating goals o f this research is the

development o f cleaner, more efficient transformations to shorten synthesis and save

the money on chemicals. Several highly selective procedures have been developed

which allow the preparation o f complex molecules with excellent regio-, chemo-,

diastereo- and enantio- selectivities.’ The usual procedure for the synthesis o f organic

compounds is the stepwise formation of the individual bonds in the target molecule.

However, it would be much more efficient if one could form several bonds in one

sequence without isolating the intermediates, changing reaction conditions, or adding

reagents." It is obvious that this type o f reaction would allow the minimization o f

waste and the amount o f solvents, reagents, adsorbents and energy compared to the

stepwise reactions. The strategy o f using reactions in tandem is also aimed at

shortening syntliesis. Tandem reactions are commonly known by the vague phrase

“ multistep one-pot reactions.” However, more rigorous definitions have been

suggested. H o ’s definition is probably the most descriptive, “ Tandem reactions are

combinations o f two or more reactions whose occurrence is in a specific order, and if

they involve sequential addition of reagents the secondary reagents m ust be integrated

into the products.” Tandem reactions have several advantages over a series o f

individual reactions. First, they allow construction o f com plex structures in as few

steps as possible. In theory, they also eliminate the need for a purification step (or

steps). Since the intermediates are not isolated, it becomes easier to work with

sensitive or unstable intermediates. Finally, employing reactions in tandem will save

cost and amoLints o f reagents, solvents, and reduce the amount o f waste that is

generated. Chemists have grouped tandem reactions into three categories. The first is

“cascade or domino” reactions in which both or all reactions take place

simultaneously without the need for additional reagents or a change in reaction

conditions. Everything that is necessary for both reactions is incorporated into the

134

C hapier - II I

starting materials. The second class, “consccutive” reactions, is where the

intermediate formed hi the first reaction has the necessary functionality, but additional

energy must be added in order to overcome an activation barrier. The last class is

“sequential,” where the fiinctionality for the second reaction has been created but

additional reagents must be added in order for the second reaction to occur. We are

here interested in domino reactions which would allow an ecologically and

economically favorable production.

T he name ‘domino reactions’ was chosen irom the game where one puts up several

domino pieces in one row and in agreement with the time resolved succession o f

reactions, if one knocks over the first domino, all the others follow without changing

the conditions. The useliilness o f a domino reaction is correlated firstly to the number

o f bonds which are formed in one sequence (bond forming efficiency or bond forming

economy), secondly, the increase in structural complexity (structure economy), and

thirdly, to its suitability for a general application. According to Tietze “/I dom ino

r e a d ion is a process involving hvo or more bond-form ing transform ations (usually C-

C bonds) which take p lace under the same reaction conditions w ithout adding

additional reagents and catalysts, and in which the subsequen t reactions result as a

consequence o f the functionality fo rm ed in the prev io u s step. ” They allow the

efficient synthesis o f complex molecules from simple substrates. A general way to

improve synthetic efficiency and also to give access to a multitude o f diversified

molecules is the development of domino reactions which allow the formation o f

complex compounds starting from simple substrates in a single transformation

consisting of several steps.

A cascade reaction or tandem reaction or domino reaction is a consecutive series o f

intramolecular organic reactions which often proceed via highly reactive

intermediates. The substrate contains many functional groups that take part in

chemical transformations one at the time. Often a fxinctional group is generated in situ

from the previous chemical transformation. The definition includes the prerequisite

“ intramolecular” in order to distinguish this reaction type from a multi-component

reaction. In this sense, it differs from the definition o f a biochemical cascade. The

main advantages o f a cascade reaction in organic synthesis are that the reaction is

often fast due to its intramolecular nature; the reaction is also clean, displays high

135

C hapter - H I

136

C hapter - 111

atom economy and does not involve workup and isolation o f many inteimediates. The

quality and importance o f a domino reaction can be correlated to the num ber o f bonds

generated in such a process and the increase o f complexity. They can be performed as

single, two and multi-component transformations. Thus, most o f the known multi-

component processes but not all can be defined as a subgroup o f dom ino reactions.

Among the numerous types o f known organic reactions available to use in tandem,

cycloadditions are particularly attractive. While there are many types o f

cycloadditions known, our focus is on the I, 3-dipolar cycioaddition reactions (also

known as [3+2] cycloadditions). As well established, 1, 3-dipolar cycioaddition

reactions are important tools for the synthesis o f a variety o f 5-membcred heterocyclic

compounds that are difficult to access through other routes. In the past two decades,

much work has been carried out to examine and optimize these reactions with various

dipoles.''

1, 3-I)ipolar-cycloadditioii reaction:

The 1, 3-dipolar cycioaddition is a reaction between a 1, 3~dipole and an

alkene/alkyne known as a dipolarophile. Like the Diels-Alder reaction, it is also a

concerted process. The 1, 3-dipolar cycioaddition is also referred to as a [3+2]

cycioaddition. The [3+2] nomenclature refers to the num ber of atoms in the two

reacting molccules, i.e., a three-atom unit and a two-atom unit (scheme 1). By

analogy, the Diels-Alder reaction could also be called a [4+2] cycioaddition. The 1, 3-

dipolar cycioaddition is also amenable to Lewis acid catalysis.

/ / / ^--— ----—Sfc Y\ ^

Y 4- \Z-

1,3-dipole dipolarophile

Sclierae 1: I, 3-dipolar cycioaddition

1, 3-dipoles are important class o f compounds with resonating structure as shown

below:

R R

x - Y = z ----------- -- - / V ,

X,Y,Z = C, N , 0 , S , P .....

Scheme 2; Resonating structures o f I, 3-dipoIes

137

C haplcr - I I I

Dipoles vary in stability greatly. Some can be isolated and stored, others are relatively

stable, but are usually freshly prepared. Others are so unstable that are generated and

reacted in silu.

R eactiv ity Profile o f l,3-I)ipo!es: The reaction between dipoles and dipolarophiles

fits into the following general profile:

(a) It is ciicrently accepted that cycloadditions are concerted processes - i.e., they have

no distinct intermediates, but the bond formation m ay be asynchronous, (b) The

reaction rates are not influenced much by solvent polarity indicating little change in

polarity between reactants and transition state, (c) Rates o f reaction between dipoles

and dipolarophifes vary considerably. This can be explained by Frontier Mofecuiar

Orbital Theory (Figure 1), which exclusively considers the interaction between

molecular orbital o f the dipole and dipolarophile ignoring all other variables.

® 0A a X — Y ....... I

i I

/ i, / ''i ^«rbiht

y

\0E3IIALS ) - i S'- 1

D'.-l \ / / HOMODr?01AR0F3IlE \J-

(J U biiiiijiij 1 wl'sial

Ll'WO

crbitsi

HoyoiK'tt-iioafcs

ijrbi'bl

"..

LVilO f i t tioudiiif:

I 1 Oirbib!

.KitUOlKtliR

O ffltM lSB.\WPOLE

Figure 1; Molecular orbital diagrams of dipole and dipolarophile.

The most important interactions are those between the Low est U noccupied M olecular

O rbilal (LUMO) o f one reactant and the H ighest O ccup ied M olecular Orbited

(HO M O) o f the other reactant. Possible combinations are with FIOMOdjpoie-

LUMOfjjpoiaropiiije ( h Figure 2) and LUMOjjipoie-HOMOjjipoiaiophiie i ^ y p ^ Figure

138

C hapter - I I I

2). The one dominant depends on the difference in energies between the relevant pairs

o f orbital. The closer the two overlapping orbital are in terms o f energy, the more

important the interaction is and a faster reaction takes place. I f the energy gap

between the two combinations is similai', both are important and the interaction is

i-eferred to as Type II.

HOMO

Lf.MO

dipole

i - 1

dip&!3ropl)iic-

.. \j IVMO

JO■r,rj

"■fcX HOMO / \ i’r *

I - I's, , J

TYPE I isjtsr.'icijsu

..y

T:yP£ III inU-ractioii

Figure 2: hiteractions between dipole and dipolarophile.

M cchsmism of 1 ,3-dipolar cycloiiddition:

Thei'e are certain characteristic features o f the 1, 3-dipolar cycloadditions irrespective

o f the reactants. The reactants are oriented in a two-plane complex and interact via

their n-orbitals in a tt'^s-tc^s process (Scheme 3). Much attention has been given to the

problem about the timing o f two-bond formation process (i.e. c-d/ a-e bond

formation).

C \

0 ^\ yr \A

-XU-

1)7)

\ JScheme 3: Typical I, 3-dipolar Interaction

Is it pertinent to Icnow, vvliether synclironized or successive bond fo rm ing p rocesses

are involved. Calculations on transition state (TS) geom etry give am biguous results

regarding the bond forming processes as they depend on the method chosen. A b -in itio

calculations favor a symmetrical or close to sym m etrica! transition state vvitli

synchronized bond formation, whereas parameterized M IN D O calculations result in a

highly unsymmctrical and late transition state o f zw itter ionic or biradical character.

Apparently calculations are not refined enough to allow reliable quantitative

predictions. Hence sonie times these are also included am ong the no-m echanism

reactions.

Rcgioselcctivity o f dipolar cycloaddition reactions:In many cases the reactions are highly regioselective if not regiospeciHc. An

unsymmctrical dipolarophile may give two possible regioisom ers depending on which

w ay the dipole adds to it. Below are mentioned some o f the param eters which decide

the regiochemistry o f dipolar cycloaddition reactions:

» Monosubstituted olefins and acetylenes show high regioselectivity and give 5-

substituted derivatives for both electron donating and electron withdraw ing

groups. Very strong electron withdrawing groups (e.g. - S O 2 R) gives

predominantly 4-substituted derivatives.

« 1, 1-Disubstituted olefins show high regioselectivity and give 5, 5-

disubstituted products. Strong electron w ithdraw ing groups give 4, 4-

disubstituted products.

® 1, 2~Disubstituted olefins and acetylenes give mixture o f regioisomers.

® Both electron withdi'awing and electron donating groups and strain in the

dipolarophiles increases the reactivity o f the dipolarophiles.

e The addition is a concerted c/.y-addition (suprafacial).

0 The regioselectivity o f the acetylenes are less pronounced than that o f olefins.

3.1.1. P rev ious inctliods for th e synthesis of triaxoles a n d bis-tr iazo lcs;

Since the basic intermediates for the synthesis o f the desired bis-triazoles are the

butyny! triazoles, it is pertinent to know about these molecules in detail first and then

relate this to the dimeric ones com m only called bis-triazoles. K eeping the biological

importance o f triazole moieties into consideration, numerous synthetic m ethods for

the preparation o f 1, 2, 3-triazole derivatives have been developed. Recently,

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C hap ter - I I I

140

C h a p ter - I I I

improved methods have been reported for the synthesis o f different substituted 1, 2, 3-

triazoles. These different m ethods can be discussed as follows:

A. C o p p e r (I) ca ta ly zed ‘c lick c lie ii i isfry’ a p p r o a c h : T h e Cu (I)-catalyzed, s tepwise

cycloaddition o f azides to terminal alkynes exhibits broad scope and provides I, 4-

disubstituted 1, 2, 3-triazoles in excellent yields and high reg ioselectiv ity (Schem e

4) . '

1 mor/o C u S 0 4

RNj + ------------------R'Sodium ascorbato

H jO / t -B u O H (1:1)

r.t., 12-24 hR'

Scheme 4: Copper (I) catalyzed azide-alkyne cycloaddition

B. P a l lad iu m csitalyzcd cycloadd ition : 2 -A lly l- l , 2, 3-triazoles w ere prepared by the

palladium-catalyzed three com ponent coupling (TCC) reaction o f alkynes, allyl

methyl carbonate and trimethylsllyl azide. A n -a llylpalladium azide complex, which

undergoes the I, 3-dipolar cycloaddition with alkynes, is proposed as a key

intermediate in the TCC reaction (Scheme 5).^’

2.5 moI% Pdj(dba)3. C H C Ij

.OCOjIVIe + TfWSN, ,,0.2eq. P(OPh)3 A c O E t , hea t, 4 -24 Ii

R

Scheme 5: Palladium catalyzed azide-alkyne cycloaddition.

C. T B A F -ca ta ly zed [3-1-2] cyc loadd ition : TB A F-cata lyzed [3+2] cycloaddition o f 2-

ary l- l-n ilroethanes with TMSN3 under solvent-free conditions (Schem e 6 ) /

,N 0 2 0-1 etc TB A F . 3 H2O2eq, TIVISN3

CN 300 C, 0.15-3 hSolvent free

Scheme 6: TBAF catalyzed azide-alkyne cycloaddition.

D. T h e rm a l cyc loadd ition o f eiiol e thers : 1, 2, 3-triazoles were prepared in good to

moderate yields by cycloaddition o f alkyl azides onto e n d ethers under solvent free

14]

Chapier - / / /

conditions. The reaction can access ring-fused triazoles that are unavailable by azide-

allcyne cycloadditions and is easily scalable. T he 1, 2, 3-triazole products bear

functionality that may be readily derivatized (Scheme 1 )^

-R ' neat

200 » C , 6 h

N

MeO

Sat. N H ,C I

Sclieiiie 7: Solvent free thermal azide-enol ether cycloaddition

E. 'Pailadlum m ed ia ted cycloiuldition o f A lkeny l b ro m id es: A palladium-catalyzed

synthesis o f lH-1, 2, 3-triazoles from sodium azide and alkenyl brom ides with yields

ranging from 4 5 -9 3 % is reported (Scheme 8).®

.Br + NaNj

1 moi % Pd2dba3 4 tnol % xantphos

Dio)(ans, 900 C, 14 h

N NH

A r

■J

Scheme 8: Palladium catalyzed azide-alkenyl bromide cycloaddition.

A m ongst all, Huisgen’s 1, 3-dipolar cycloaddition between an alkyne and an azide is

traditional and extensively used method.'*’ However, because o f the high activation

energy (24-26 kcal/mol), these cycloadditions are often very slow even at elevated

tem perature (80-120 °C for 12-24 h) and produce mixtures o f reg io isom ers ."

AP h — N j + R -

1,4-clisubstituted triazole 1,5-disubstituted triazole

S chem e 9: Huisgen’s cycloaddition between an azide and an acetylene.

The im provem ent o f the regioselectivity o f the reactions is an attractive target.'^ A

num ber o f synthetic strategies have been developed for the regioselective synthesis o f

1, 4-disubstituted-], 2, 3-triazoles. For example, copper (I)-catalyzed azide alkyne 1,

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C h a p ter - 111

3"dipolar cycloaciditiori (CuA A C) which results in the form ation o f 1, 4- substituted 1,

2, 3-triazoies, is am ong the recent advances in the chem istry o f organic azides

(Scheme 4). T he very success o f the C uA A C highlights the need for selective access

to the com plem entary regioisomers, the I, 5-disubstitiited triazoles.''* Contrary to the

innumerable existing methods for the generation o f 1, 4 -d isubstitu ted triazoles, only

few m ethods for the generation o f 1, 5 -disubstituted triazo les are known. These

methods m ainly employ the reactions o f sodium, lithium, or m agnesium acetylides

with organic az ides ' ' '(Schem e 10). Also incase o f ruthenium ca ta lyzed cycloadditions

between azides and acety lenes , 'M , 5-disubstituted 1, 2, 3-triazoles are the major

pi’oducts formed (Scheme 11),

P h - -B r1) W lg,THF, 50 »C, 15 min

2) 1 eq. PhNj^ r.t. SOmin

Ph MgBr Ph

Schcme 10: Magnessium acetyiideand azide cycloaddition.

[Ru]

Ru(OAc)2(PPh:02

Cp*RuCl(PPh3)2

Cp*RuCl(PPh3)2

Cp*RuCi(NBD)

= / ~^N—N

C r ^ '

85%

100%

100%

100%

15%

Scheme 11: Ru-catalyzed cycloaddition o f benzyl azide and phenylacetyiene.

In continuation o f our interest in the nucleophillic addition o f resonance stabilized

organometailics to I, 3-dipoles, w e attempted this reaction for the generation o f

regiospecific triazole systems via addition o f resonance-stabilized allenylmagnesiiim

bromide to azides which resulted in a serendipitous formation o f 5 -bu tyny la led- l, 2,

3- triazoles in a dom ino fashion. Since aromatic heterocycles are vakiab le synthetic

templates for the preparation o f new com pounds with specific biological o r material

properties, the pursuit o f these properties requires efficient synthetic routes that allow

rapid assem bly and variation o f multiple pendant substituents on the heteroaromatic

core, or the construction o f diverse aromatic heterocycles w ith defined substitution

patterns. In recent years, attention has been increasingly paid to the synthesis o f bis-

heterocyclic compounds, which exhibit various biological activities'^’"'' including

antibacterial, fungicidal, tuberculostatic and plant growth regula tive properties. Bis-

heterocyclic com pounds have found numerous applications as electrical materials,

biologically active molecules,^' chelating agents and metal ligands^'^ ow ing lo which,

they have attracted great deal o f attention in recent years. Furthermore, it was

indicated in several reports^'^ that bis^heterocyclic com pounds displayed much belter

antibacterial cictivity than mono-heterocyclic compounds. O f particular interest would

be the /;/.v-heterocycles that encompass triazoles as their com ponents , which gained

importance due to their diverse applications and pharm acological activities. Bis-

triazolc based size-specific mRNA hairpin loop binding agents have been developed

to target m RN A s coding for proteins.^'^ Recent studies have d isclosed a series o f 1, 2,

3- triazole based /j/.y-heterocyc!es as potent HIV-1 protease inhibitors for the

inhibition o f viral replication.^^ EfTorts are being m ade to com bine the variety o f

multiple heterocyclic cores in a single m olecular fram ework as symmetrical or

unsymmetrical I)/'s, tris or multiple heterocycles to exploit th e pharmacological and

altered physical properties o f the resulting multivalent ligands.^^’ There are several

reports available in literature for the synthesis o f various com binations o f bis-

heterocycles. But, no such report was found for the synthesis o f bis-heterocycles

encom passing I, 2, 3-triazoIe moieties with two carbon spacers in between.

Involvem ent o f the ‘domino-click’ approach for the generation o f bis-triazoles has not

been reported anywhere though a few recent reports about the formation o f bis-

triazoles resulting from the oxidative dimerization (Schem e 12) under basic ‘c lick’

conditions have appeared.^^

143

___________ ______________________C hap ter - / / /

144

C hap ter - I I I

B r

Br

0,N

C u/C uS04MeCN/baseBn-Njair, 25 »C

18 h

Sclicnic 12: Oxidative dimerizalion of triazoles.

Keeping the biological importance o f the individual triazole m oieties into

consideration, herein we have developed a novel s trategy to com bine such

heterocycles through a 1, 3-dipo!ar cycloaddltion o f 5 -bu tyny l-l , 2, 3-triazole

(prepared by the domino addition o f allenylmagnesiuni brom ide to aromatic azides)

to aromatic azides using the high yielding and regioselective ‘click chem istry ’

approach.

3.1,2. P re s e n t a p p ro a c h :

As seen above, there is a wide range o f pharm acological activities and

application potential associated with triazole and bis-triazole systems. T he synthesis

o f these biologically important heterocyclic systems through easier and economical

methods has been the subject matter o f intensive research during the past three

decades. Thus herein is described the design for the synthesis o f a library o f

unsymmetrical bis-1, 2, 3-triazoles based on a s tepwise synthetic route involving

dom ino addition o f allenyl magnesium bromide to aryl azides resulting in a

serendipitous formation o f 5- butynylated triazoles in good yields (>70%) instead o f

C u 5 0 , ,5 H j0

N __ Sod . A sco rb a to' ‘ 2 M g B r.T H F , r . t \ \ y l te r t -B u to n o l:H ,0 ,

1 0 4 5 m ln R

S ch em e 13: ‘Domino*click’ synthesis o f bis-triazoles.

4-butynylated triazoles, 5-butynylated triazoles upon Cu(I) catalyzed 1, 3-dipolar

cycloaddltion with aryl azides generated bis-1, 2, 3-triazoles in quantitative yields.

The products together with the approach for their synthesis being novel, the

intermediate 5-butynylated triazoles and the final product, the bistriazole, were

145

characterized by IR, 'H / 'V J-N M R and mass spectral analysis. T he in term ediate 3

undergoes a high yielding regioselective Cu(l) catalyzed 1, 3-dipolar cycloaddition

with aryl azides (click reaction) to afford quantitative yields o f the product i.e., b is-!,

2, 3-triazoles 5, which were isolated in pure form after precipitation. Thus our m ethod

offers a novel synthesis o f structurally diverse bis-heterocyclic m olecular fram ew orks

generated through a ‘click chem istry ’ protocol.

-,N ~N=N.

2

+ _

M g B r

'NN N

J

MgBr

n/igBr

N=NAr-

B r

S ch le n k com pleK

Sclieiiic 14: Plausitile mechanism for the formation of 5-butynyl triazoles.

3.1.3. E x p e r im e n ta l P a r t :

G e n e ra l : Melting points were recorded on Buchi M elting point apparatus D-545; IR

spectra (KBr) were recorded on Bruker Vector 22 instrument. N M R spectra were

recorded on Bruker DPX200 or 500 instrument in C D C I3 with TM S as internal

standard for protons and solvent signals as internal standard for carbon spectra (Peaks

picked at 125 MHz). Chemical shift values were mentioned in S (ppm ) and coupling

constants are given in Hz. M ass spectra were recorded on ESI-esquire 3000 Bruker

Daltonics instrument. The progress o f all reactions was m onitored by T L C o n 2 x 5

cm pre-coated silica gel 60 F254 plates o f thickness 0.25 m m (Merck). The

chrom atogram s were visualized under UV 254-366 nm and iodine.

Gciiersil P ro c e d u re . To a suspension o f Mg turnings (1.6 g, 66.6 m m ol) in specially

dried T H F with HgC)^ (5 m g, 1% w/w o f propargyI brom ide) was added propargyl

brom ide (3.05 m L o f an 80% wt. soln. in toluene, 4 inmol) in small portions while

stirring the mixture at ambient conditions. (Note: A small grain o f H gC h is generally

required to promote formation o f the reagent). The m ixture was stirred at room

146

C hap ter - I f f

temperature for 2 h to give a cloudy light green solution. The allenylniagnesium

bromide generated as above was cooled to 0-5° and added d rop w ise to a solution o f

3-methylphenyl azide 1/ (I g, 7,4 m m oi) maintaining the tem perature between 0-5°.

The m ixture was allowed to attain room temperature. T he organic layer w as separated

and the aqueous layer extracted with A cOEt (2x20 mL). The com bined oi'gaiiic layers

were dried over anhydrous NaaSO^t and evaporated under reduced pressure to afford

crude product, which was subjected to chrom atography (silica gel, 60-120 mesh,

elution; hexane/AcO Et gradient) to afford pure 5 -(B ut-3~yn-l-y l)- l-(3 -m ethy lpheny l)-

lH -l ,2 ,3 - tr iazo le 3/ (1.09 g, 5.18 mmol, 70% yield) as a co lorless liquid. 3-M ethyl

butynyl triazole (0.5 g, 2.3 mmol) was stirred in 5 m L o f /er/-butanol and H 2 O (1:1

mixture). CUSO4 (0.54 g, 2.5 mmol) and sodium ascorbate (1.25 g, 5.0 m m ol) was

charged into the reaction mixture. After 15 min, 3-m ethylphenyl azide (0.04 g, 3.0

mrnol) was added to the above mixture, which was then stirred for 8 h. The mixture

was diluted with AcOEt, the organic layer was separated, and the aqueous layer

extracted with A cO Et (2x20 mL). The combined organic layers were dried over

anhydrous Na2S 04 evaporated under reduced pressure to afford crude product 5/,

which was subjected to precipitation in hexane-A cO Et, affording pure bis-triazole 5/

(0.71 g, 2.0 mmoi, 90% yield) as an amorphous brown solid (only entries 2 and 12).

147

C hap ter I I I

T ab lc -I : B is- tr iazo les synfliesized th ro u g h ‘D o m in o -C l ic k ’ a p p r o a c h .

Entry T ria z o le Azide Y ie ld (%)

JbUfi

" VvM >3~

. x y

W = N = N

OMe

^COOH

9 2

91

8 9

91

88

9 0

, r \ \N.H

NOj

_N = N = N

N = N = N

4- —W=N = N

9 0

91

9 3

92

148

C hap ter - 111

in

NO,

N = N = N

, n = n = n

N = N = M

N O,

8 9

90"

9 0

8 9

a. A ll co m pou iu ls are syrupy liqu ic ls/sem i-so lids unless otherw ise m entioned b. A in o r jilio t iJ i w h ite so lid , ni.p. 195-197 'C.

c, A in o rphou s brow n .so lid , m.p, 174-177 C,

Spcctral da ta :

l - ( 4 “iT ic t! io x y p lie n y l) -5 - (2 -( l-m - to ly H H - l,2 ,3 - tr ia z o l”4 -y l)e tliy l)-1

tr ia z o le (5 a ):

'H N M R ( C D C b , 200 MHz):

13C N M R ( C D C l 3 , 125 MHz):

IR (KBr, cm '') : ESr-MS:C, H, N analysis for C2 0 H 2 0 N 6 O:5.38; K 23.51.

6 2.44 (s, 3H); 3.12 (m, 4H ); 3.87 (s, 3H); 7.02 (d, 2H, J = 8 .8 9 Hz); 7.35 (m, 6H); 7.50 (s, IH), 7.60 (s, IH).5 21.40, 23.44, 24.53, 55.63, 114.74, 117.53,119.41, 121.14, 126.71, 128.00, 129.53, 138.1 1,140.03, 148.22, 161.12.3 4 5 3 ,2 9 1 3 ,2 8 6 5 , 1593, 1212, 1080 and 685.383 (M '^+N a).

C, 66.65; H, 5.59; N, 23.32; Found: C, 66,83; H,

149

C hapter - 111

4 -(4 -(2 -(3 -{ 4 -m c th o x y i) l ie i iy I ) -3 H -l ,2 ,3 - - tr ia z o l-4 -y l)e t l iy l)~ lH - l ,2 ,3 - tr ia z o I - l-

y l ) b e n Z ”O ic ac id (S b):

Am orphous white solid, m.p.: 'H N M R (C D C l 3 , 200 MHz):

13C M M R (C D C l3 , 125 MHz):

lR (K B r, cm '') : ESl-MS:C, H, N analysis for C2„H ,sN603:

195-197 “C.5 3,10 (t, 2 H , ,/ =5.97); 3 .12 (t, 2H, J --=5.97)-, 3.84 (s, 3H); 7.08 (d, 2H, ,7= 8 .90 Hz); 7.37 (d, 2H, J =8.90 Hz); 7.72 (s / lH ), 7.93 (d, 2H, .7=8.63 Hz), 8.21 (d, 2H, / = 8 .9 0 Hz); 8.33 (s, IH).8 22.50, 23.59, 54,45, ! 14.15, 115,43, 119.17,119,21, 120.13, 126.36, 127.43, 130.78, 131.06, 147.23,200.12.3 4 1 3 ,2 9 2 2 ,2 8 6 0 , 1593, 1234, 1017 and 690.391 (M 'V H ) .

C, 61.53; H, 4.65; N, 21 .53; f-ound: C, 61.71; H, 4.82; N, 21.79.

l-(4 .m c tlio x y p lie n y l)~ 5 -(2 -( l-{ 3 -» iitro p !ie iiy I)- lH ~ l,2 ,3 ~ tr ia2 ',o l-4 -y I)c ii!y I)- lH -

1 ,2 ,3 - tr ia z o le (5c):

N O ,

'H N M R ( C D C l 3 , 200 MHz);

X N M R (C D C lj, 125 M H z):

IR (KBr, c n r ') : ESl-MS:C, H, N analysis for C 19H 17N 7 O 3 :

5 3.10 (t, 2H, J = 5 .7S); 3,23 (t, 2 H , , / = 5 .78); 3,85 (s, 3H); 7,05 (d, 2H, J - 8 . 9 4 Hz); 7.38 (d, 2H, J - 8 .9 4 Hz); 7 .7 3 -7 M (m , 2H); 8.22-8.32 (m, 2H); 8.42 (s, IH); 8.68 (m, IH).8 22.20, 23.69, 55.45, 113.15, 116.43, 118.17,119.41, 120.13, 127.36, 127.43, 130.78, 132.06, 142.33, 148.25.3393 ,2897 , 2867, 1582, 1244, 1018 and 689.392 (M ' '+ H),

C, 5 8 .3 1; H, 4.38; N, 25.05; Found: C, 58.54; H,

150

C h ap ter - 111

4.5; N, 25.21.

i -{ 4 -n ie tI io x y p lie e y l) -5 - (2 - ( l“/ ; - to ly H H - l ,2 ,3 - t r i a z o l - 4 - y l ) e t i iy I ) - lH “l ,2 ,3 - t r ia z o ic

(Sd):

‘H N M R (C D C b, 200 MHz):

13C N M R (CDCI3 , 125 MHz):

IR (K B r, cm ''): ESl-MS:C, H, N analysis for C2oH2oNf,0:

5 2.45 (.y, 311); 3.15 (m, 4M); 3.87 (s, 3H); 7.02 (cl, 2H, J = 8 . 8 9 Hz); 7.18 (d, 2H, . /= 8 .8 9 Hz), 7.37 (d, 2H, J =8.90 Hz); 7 .4 7 (d, 2H, J =8.90 Hz);7.50 (s , lH ), 7.80 (s, IH).5 18.50, 22.23, 23.59, 54.45, 114.15, 115.43,119.17, 119.51, 120.13, 126.36, 127,33, 130,78,135,06, 147.23,3423, 2932, 2876, 1593, 1234, 10179 and 694.383 (M" + Na).

C, 66,65; H, 5,59; N, 23,32; Found: C, 66.42; H, 5,68; N, 23.54,

I - (3 - c I i Io ro p h c n y l) -S - (2 - ( l - / ; -n i t ro p l ic n y H H - l ,2 ,3 " tr ia z o I -4 -y i)e t l i iy l) - lH - l ,2 ,3 -

tr ia x o le (5e);

( p y n o .

Cl

'H N M R (CDCI3 , 200 MHz):

13‘C N M R (C D C l 3 , 125 MHz):

IR (K B r, cnV'): ESI-MS:C, H, N analysis for C ,gH,4 C lN 7 0 :

S 3.17-3.40 (m, 4H); 7 .34-7.57 (m, 2H); 7.77 (m, 2H), 7.86 (s, IH); 8.17 (d, 2H, J - 7 . S 5 Hz); 8,30 (d, 2H,,/=7.<S5), 8.55 (s, IH).S 19,25, 21.23, 23.56, 1 14,15, 115,43, 119,17,119,51, 120.13, 126.36, 128.33, 130,87, 136.06,146.23.3 4 1 1, 2945, 2898, 1597, 1265, 1067 and 702.418 (M ' + Na),

C, 54,62; H, 3.57; N, 24.77; Found: C, 54.85; H,3.38; N, 24.86.

151

C hap ter - III

l - ( 3 - n i4'ro p lic n y l) -5 ' ( 2 - ( l - m - t o l y l - l H - l 52,3 - t r ia z o l - 4 - y l ) e t f iy l ) - lH - l ,2 ,3 - t r ia z o lc

(5 t);

'H N M R (CD Cb, 200 MHz):

13C N M R (CDCij, 125 MHz):

IR (KBr, cm '') : ESI-MS:C, H, N analysis for C 1QH17N 7 O 2 :

5 2.44 (,v, 3H); 3.17-3.25 (m, 4H); 7,39 (cl, 2H, . / = 7.40 Hz); 7.50 (s, 2H), 7 .70-7 .82 (m, 4H); 8.36 (m, 2H).5 19.54, 21.23, 23.59, 114.15, 116.41, 119.17,119.51, 120.13, 128.32, 127.35, 130.88, 136.06,146,23, 153.22.3 4 1 7 ,2 9 5 4 ,2 8 5 6 , 1587, 1235, 1079 and 698.398 ( M ‘ + Na),

C, 60.79; H, 4.56; N, 26.12; Found: C, 60.95; H, 4.72; N, 26.34.

l - (3 -n itro p h c n y I ) -S - (2 -( I - (3 - iH tro p I ie i iy l) - IH - I ,2 ,3 - f r ia z o l-4 -y f )c f f iy I ) - lH - l ,2 ,3 -

tr ia z o le (5g):

NN=n NO,

'N O ,

'H N M R ( C D C l 3 , 200 MHz):

13C N M R (CDCI3 , 125 MHz):

IR (KBr, cm-'): ESI-MS:C, H, N analysis for CisH|4NsO.|:

5 3.21 (t, 2H, J= -5.44); 3 .30 (t, 2H, J ^5 .4 4 ); 7.79 (m, 4H, .7=7.40 Hz); 7.87 (s, IH), 8.15 (d, 2H, J =7.82 Hz); 8.38 (m, 2H), 8.54 (s ,lH ).5 19.47, 21.34, 22.89, 114.15, 116.67, 119.77, 118.52, 120.13, 127.32, 128.35, 130.32, 136.18, 146.56, 154.31.3 4 1 9 ,2 9 6 5 ,2 8 5 7 , 1580, 1265, 1099 and 714.407 (M ' + H).

C, 53.20; H, 3.47; N, 27.57; Found: C, 53.11; H, 3.62; N, 27.34.

152

C hapter ~ III

5-(2-(l-(3"iiitrophenyl)--lH-l,2,3-triazoI-4-yI)etIiy!)~l-o~toIyHH-l,2,3-friazole

(5h ):

M _/T ^

f ,N~N N O ,

'H N M R ( C D C I 3 , 2 0 0 M H z ) :

'-^C N M R ( C D C I 3 , 125 MHz):

IR (KBr, cm-'): E S l-M S :C, H , N a n a ly s i s fo r C 19H 17N 7 O 2 :

5 2 .3 6 (s, 3 H ) ; 3 ,0 9 (m , 4 H ) ; 7 .2 2 ( 111, 2 H ) ; 7 .43 (m , 4 H ) , 7 .6 8 (s, H i ) ; 7 .7 1 - 7 .8 4 (m , 2 H ) , 8 ,1 7 (d, I H , ,7 = 7 . (5(5).

S 18.54, 2 1 .2 3 , 2 3 ,5 9 , J 1 4 . J 5 , 117 .41 , 119 .17 ,1 19 ,51 , 120 .13 , 1 2 8 .3 2 , 1 2 7 .3 5 , 1 3 0 .8 8 , 136 .06 ,1 4 6 .2 3 , and 155 .2 3 .3 4 1 8 , 2 9 5 4 , 2 8 5 6 , 1 5 87 , 1 2 3 5 , 1079 a n d 698 ,3 9 8 ( M ^ + N a ) .

C , 6 0 .7 9 ; H , 4 ,5 6 ; N , 2 6 ,1 2 ; F o u n d : C, 6 0 .9 5 ; H, 4 .7 2 ; N , 2 6 ,3 4 .

l - o - . to ly l-5 - (2 - ( l - m - to Iy H H - l ,2 ,3 4 i ia z o I - 4 - y l ) e t l ! y I ) - M - l ,2 ,3 - t r ia z o le (51):

'H N M R ( C D C I 3 , 2 0 0 M H z ) :

13C N M R ( C D C I 3 , 125 M H z ) :

I R ( K B r , c m ' ' ) : E S l - M S :C , H, N a n a ly s i s fo r C2 0 H2 0N 6 :

5 2 ,0 7 (s, 3 H ) ; 2 .1 5 (s, 3 H ) ; 3 .1 2 (m , 2 H ) ; 7 .54 ( m , 2 H ) ; 7 .63 (s, I H ) ; 7 .7 4 (m , 3 H ) , 8 .0 8 -8 ,2 3 (m , 3 H ) ; 8 ,5 7 ( s , l H ) .

5 19.68, 19 .19 , 2 1 ,5 8 , 2 3 .3 8 , 1 1 6 .1 0 , 121 .14 ,122 .22 , 124 .7 , 129 ,8 2 , 1 3 0 ,3 0 , 131 .31 , 132.0 , 135 ,80 , 136 .80 , 13 7 .8 3 , 1 4 0 .0 1 , 148 .2 0 . .

3 4 1 7 , 2 9 4 4 , 2 8 5 6 , 1 587 , 1 2 3 5 , 10 7 9 a n d 695 .3 6 7 (M^' + N a ) .

C , 6 9 .7 5 ; H , 5 .8 5 ; N , 2 4 .4 0 ; F o u n d : C, 6 9 ,9 0 ; H , 5 ,5 2 ; N , 2 4 .6 1 .

153

5 -(2 -(!~ (2 -iiiitro p lie iiy I)-l

(5J):

C hapter - I I I

I - 1,2 ,3 4 r ia z o I -4 -y l)e ti iy i) - l- /? ~ to ly H H -1 ,2 ,3 - tr ia z o le

'H N M R (C D C l3 , 200 MHz):

13C N M R (C D C b, 125 MHz):

IR (KBr, cm"'): ESI-MS:C, H, N analysis for C 1 9H 17M 7O 2 :

5 2.45 (s, 3H); 3.21-3.23 (m , 4H); 7.38-7.45 (cl, 2H, .7=8.00 Hz); 7.70 ( d, 2H , J - 8 . 0 0 H z ), 7.81 (m , IH); 7.90 (w , 3H), 8.14 (in, 211).6 19.85, 23.00, 23,54, 125.19, 125.27, 127.31, 129.71, 129.97, 130.89, 133.80, 134.97, 140.39, 144.60.3427, 2966, 2865, 1576, 1235, 1079 and 687.376 (M '^+H ).

C, 60.79; H, 4.56; N, 26.12; Found: C, 60.61; H, 4.72; N, 26.29.

S -(2 " ( l- (3 -n if ro p I ie n y i) - lH - l ,2 ,3 - tr ia z o l-4 -y l)e tf iy l) - l- / ;~ to ly I - lH “l,2 ,3 - f r ia z o !e

(5 k ):

'H N M R (C D C 13, 200 MHz):

'^C N M R (CDCI3 , 125 MHz);

IR (K B r , cm ‘‘); ESI-MS:C, H, N analysis for Ci9Hr/N702:

6 2.45 (s, 3H); 3.08-3.22 (m, 4H); 7.33 (s, 4H);7.50 (s, IH), 7.52-7.72 (m, 4H), 7.89 (d, IH, ./ - 7 .8 9 H z ).5 15.82, 21.24, 23.33, 118.90, 122.73, 125.56,130.23, 132.51, 133.69, 133.80, 135.61, 136.81, 139.97, 142.41, 144.43, 151.16.3417 ,2986 , 2865, 1576, 1233, 1089 and 677.398 (M^ + Na).

C, 60.79; H, 4.56; N, 26.12; Found; C, 60.92; H,4.30; N, 26.26.

154

Chapter - III

l~m-to!yi-5-(2-(l-ffi-tolyHH-l,2,34riazoM ~yl)e«iyl)-lH-l,2,3~triazol(5l):

A m orphous white solid, m.p: 'H N M R (CDCI3 , 200 MHz);

13C N M R (CDCb, 125 MHz):

IR (KBr, cm' ):

ESl-MS:C, H, N analysis for C2 0 H2 0 N6 :

174-177 “C.S 2.33 (.y, 3H); 2.43 {s, 3H); 3.05 {t, 2H, . /= 6 .2 Hz); 3.20 (/, 2H, .7=6 ,2 Hz); 7.25-7.59 {m, 8 H); 7,73 (.y, IH); 8.18 (.v, 1H).5 19.8, 19.9, 22.8, 23.8, 117.0, 120.4, 122.2,125.7, 129.1, 129.8, 130.3, 132.0, 135.8, 136.8,137.8, 140.0, 146.2.3429, 3138, 2922, 2860,1593, 1494, 1165, 1089, 1047, 786, 690.367 (M'^ + Na).

C, 69.75; H, 5.85; N, 24,40 Found: C, 69,80; H, 5.82; N, 24,51.

5 ~ ( 2 - ( l - ( 3 - n i lT o p l i e n y l ) - lH - l ,2 ,3 - t r ia z o l“4 - - y l ) e t l iy l ) - l " p l ie n y l - lH - l ,2 ,3 - t r l a z o l e

(5 m ):

N-

N=n NOj

‘H N M R (CDCI3, 200 MHz);

13C N M R (CDCI3 , 125 MHz);

IR (K B r, c n r ' ) : ESI-MS:C, H, N analysis for CigHisNyOs:

5 3,16 (t, 2H, J ^6 .9 0 ), 3.26 (t, 2 H , ./ =6.90)-, 6.11 (d, IH, J =^7.51); 7.05 (d, IH , .7=7.57), 7.47 (m, 2H), 7.51 ( m, 2H), 7,79 (m , 2H), 8.16 (d, IH , J ^7 .5 5 ), 8,33 (d, IH, .7=7.55), 8.56 (s ,lH).5 23.23, 24.32, 121.81, 125.35, 125.56, 127.43,128.70, 129,64, 131.53, 131.78, 132.58, 133.83,136.17, 136.53, 144.76, 146.21,3398, 2995, 2865, 1577, 1236, 1096 and 678.384 (M ^+ Na),

C, 59.83; H, 4.18; N, 27.13; Found: C, 60.09; H,4.30; N, 27.26,

155

5 - (2 ~ { l- - (2 -n itro p lie iiy l)~ lH - li2 ,3 - tr ia z ( ) I -4 - -y l)e tl iy ! ) - l-p lie n y l- lH - l,2 ,3 - tr ia z o le

(5i,)i

C hapter - H I

'H N M R (CDCI3 , 200 MHz):

13C N M R ( C D C l 3 , 125 MHz):

IR (KBr, c m '‘): ESl-MS:C, H, N analysis for C,.sH,5N702:

5 3.13 (t, 2H, 7.0/?), 3,23 (2H, ./= 7.00); 7,29(d, 2 H , ./ =7./?2); 7.48 (s, 5H), 7.60 ( m, IH), 7.63 (s, IH), 7.57 (s, IH), 8.08 (s , l H).5 23.33, 24.41, 122,81, 125,34, 125.56, 127.85,129,70, 129.76, 130,17, 130.78, 132.58, 133.83,136,17, 136.84, 144.42, 146,01.3397, 2985, 2865, 1577, 1236, 1096 and 678.384 (M"' + Na),

C, 59.83; H, 4,18; N, 27.13; Found: C, 59.68; H, 4.30; N, 27.34.

3.1.4. C onclus ion : In conclusion, w e have developed an unprecedented, convenient

strategy for the synthesis o f novel, biologically important iinsymmetrical bis-1, 2, 3-

Iriazoles employing a dom ino reaction followed by the copper catalyzed ‘click’

protocol. T he main advantage associated with this protocol is the regioselectivity

offered for the generation o f both 1, 5 and 1, 4-disbstitu ted-l, 2, 3-triazoles.

156

C hap ter - I I I

S E C T IO N -B

3.2. L iq u id p h ase syn thes is of' g ly d d ic es te rs

3.2.0. I n t ro d u c t io n :

Ever since Merriiield introduced the methods for solid-phase peptide synthesis,

insoluble polym er supports have been utilized for num erous synthetic methodologies

to facilitate product purillcation.^^'^' A lthough highly successful, solid phase

synthesis still exhibits several shortcom ings due to the nature o f heterogeneous

reaction conditions. N onlinear kinetic behavior, unequal distribution and/or access to

the chem ical reaction, solvation problems and odier pure synthetic problems

associated with solid phase synthesis have led several research centers to pursue

alternative m ethodologies to restore hom ogenous reaction conditions. By replacing

insoluble cross linked resins with soluble polym er supports, the familiar reaction

conditions o f classical organic chemistry are reinstated, and ye t product purification is

still facilitated through application o f rnacromolecular properties. This methodology,

termed liquid phase synthesis, in essence avoids the difficulties o f solid phase

synthesis while preserving its positive aspects. Thus the central feature o f this

m ethodology being the combined advantages o f both classic organic solution phase

synthesis as well as solid-phase synthesis, through the application o f linear

hom ogeneous polymers.^^

The term liquid phase synthesis was fu'St used to contrast the differences between

solid phase peptide synthesis and a method o f synthesis on soluble

polyethyleneglycol,^"’ Although soluble polym er supported synthesis might be a

less am biguous label than liquid phase synthesis, the latter term is more prevalent in

the literature. In keeping it with previous reviews,^'*'^^ the phrases “classical” or

“ solution-phase” synthesis will be used to describe hom ogenous reaction schemes that

do not imply polym er support while liquid phase synthesis will be reserved for

methodologies incorporating a soluble rnacromolecular carrier to facilitate product

isolation, ft should be noted that although the starting material and subsequent product

is kept soluble by the attached polymer, some reactions in liquid phase synthesis may

in fact, be heterogeneous due to the presence o f insoluble catalyst or reagents (e.g.

catalytic hydrogenation).

P ro p e r t i e s o f so luble p o ly m er su p p o r ts :

Polymers em ployed as soluble supports for liquid phase synthesis must;

(1) be com m ercially available or rapidly and conveniently prepared.

(2) dem onstrate good mechanical and chemical stabilities.

(3) provide appropriate functional groups for easy a ttachm ent o f organic moieties.

(4) exhib it high solubilizing pow er in order to d issolve m olecular entities with

low solubility and permit the developm ent o f a general synthetic methodology

independent o f the physicochemical properties o f target com pounds.

Additionally, it should be realized that polymer supports bought or prepared in the

laboratory exhibit not one discrete m olecular weight bu t instead consist o f

m acrom olecules with variable sizes. As polym er properties vary with chain length,

the m olecular weight range o f the support should be narrow (i.e. polydispersity

approaching unity). Soluble supports in general should have m olecular weights high

enough to be solid or crystalline at room temperature and y e t not excessively high

such that solubilities in a variety o f solvents is limited.

The polym eric carrier must withstand the reaction conditions used in solution-phase

synthesis and consequently most soluble supports used in liquid-phase synthesis

possess hydrocarbon oi‘ alkyl ether backbone structures. By variation o f terminal and

pendant functional groups o f these two backbones structures, polym er properties are

determined and may provide sites for a ttachment o f organic moieties. If the conditions

o f polymerization and choice o f m onom er allow for suitable po lym er

functionalization, then anchoring o f the initial synthetic structure m ay be made

directly to the support for liquid-phase synthesis; however, often a linking group must

be em ployed to ensure anchor stability throughout synthesis, improve accessibility to

reagents and facilitate cleavage for product recovei'y.

C hosen polym ers for liquid-phase synthesis must also provide a reasonable

com prom ise between loading capacity and solubiiizing power. T he loading capacity

o f a po lym er support is a measure o f the num ber o f anchoring sites per gram o f

polymer and is expressed in units o f millimoles per gram (mmol/g). High loading

capacities are advantageous to reduce the total expenditure for polymer supports and

to a l low m anageable amounts o f material in m edium or large-scale applications.

Solubilizing power can be defined as the ability o f the m acrom olecular carrier to

maintain a hom ogeneous solution o f the polymer-bound organic moiety; this property

157

C h ap ter ~ I I I

158

C hapter - H I

is especially important in cases where the unbound moiety is insoluble in the reciction

m edium . High solubilizing power is desirable to ensure hom ogeneous reactions and

high yields throughout the synthetic scheme. Generally, so lubiliz ing pow er decreases

as loading capacity increases because as the po lym er is further loaded, the solubility

properties o f the polymer-organic moieties conjugate are increasingly determ ined by

the propei’ties o f the attached compounds. Thus, it is im portant to achieve a

com pound-to-support ratio that limits solubility changes and yet provides economic

and manageable synthesis. Furthermore, in choosing a po lym er with high loading

capacity, one must consider the influence o f neighboring anchoring sites. The

m ultiple attachments o f compounds to a polymer support m a y result in nonequivalent

reactivity o f bound moieties distributed unequally along the polymer backbone. In

some situations, excess reagents or longer reaction times m ay allow near-quantitative

reaction o f anchored com pounds on heavily laden polymers; however, other reactions

may require linkage exclusively to polymer termini to provide adequate accessibility

to polymei-bound reagents o r enzymes.

M e th o d s o f s e p a ra t in g po lym ers from reac t ion m ix tu res :

Several methods have capitalized on m acromoleeular properties in order to achieve

product separation in liquid-phase synthesis. M ost frequently, the hom ogeneous

polymer solution is simply diluted with a solvent that induces precipitation o f the

macromoleeular support. Analogous to solid-phase synthesis, the resulting

heterogeneous mixture is filtered to isolate the polym er-product conjugate while

excess reagents and impurities are rinsed away. Some po lym ers may be amenable to

recrystallization to minimize inclusion complexes that may form during precipitation

and proper choice o f solvents and temperature m ust be made for satisliictory recovery

and purification.

Although precipitation/crystallization is the fastest and m ost com m on mode o f

product separation, other methods have been used to isolate m acrom olecular supports

from low' molecular weight impurities. Dialysis using a sem i-perm eable membrane

has achieved polymer purification.'^^ This procedure becomes less time consum ing in

ultra-filtration (also called dia-filtration or membrane filtration) when pressure

gradients speed the separation o f polymer from the reaction supernatant using a

membrane; additionally, centrifugation methods allow convenient isolation o f

13V

C hap ler - I I I

biom olecules and could be applied to more general p o lym er separations. Crel

permeation chromatography and adsorption chrom atography have also been suggested

as m eans to remove excess reagents and byproducts aw ay from polym eric products,

It is im portan t to realize that these m acrom olecule-based m ethods isolate polymer-

bound products from soluble impurities, but do not generally purify the product from

other polym er-bound byproducts. Such byproducts arise from incomplete reactions or

side reactions; and in classical solution chemistry, similar byproducts are removed

during product purification at each step o f a multistep synthesis. A lthough avoiding

the multiple, laborious purification steps o f classical chemistry , support-based

m ethodologies in large part do no t provide for the purification o f intermediates.

Instead, reactions must be optimized and driven to completion to avoid a complicated

final mixture o f products. Some liquid-phase methods, however, have been developed

to achieve high purity o f products without quantitative reaction yields.

A na ly tica l m e th o d s in l iq u id -p h ase synthesis:

Not hindered by the heterogeneity intrinsic to solid-phase systems, liquid-phase

synthesis permits product characterization on soluble po lym er supports by routine

analytical methods. LJV-visible, [R, and N M R spectroscopy and even TLC may be

used to monitor reactions without requiring preliminary cleavage from the polymer

support.^^’ ®’'’ ”"'®’^' Moreover, aliquots taken for characterization may be returned to

the reaction flask upon recovery from these nondestructive analytical methods.

Chemical methods such as titration and derivatization can be routinely peiformed and

allow subsequent characterization in the presence o f the bound soluble support. Even

peptide coupling reactions on soluble polymers have been m onitored without cleavage

from polyethylene glycol by using ninhydrin or fluorescarnine reactions or

potentiometric t i I r a t i o n h o w e v e r , potentiometric titrations give unreliable results for

peptides longer than hexapeptides.^^

P o ly e th y len e G lycol (PE G ):

Polyethylene glycol (PEG), polyethylene oxide (PEO), po lyoxyethylene (POE), and

polyoxirane all represent the same linear polymer formed from the polym eriza tion oi

ethylene oxide. By convention, PEG usually indicates the polyether of molecular

w eight less than 20,000; PEO signifies polymers o f higher m olecular weights, and

POE and polyoxirane have been applied to polymers o f a wide range of molecular

l()U

C hapter - H I

weight/*" T he term PEG is as a symbol for polyethylene g lycols o f 2000 to 20,000

m olecular weight utilized as supports. These limits have been set by the physical

properties o f the polymer;

PEGs o f molecular weight 2000 to 20,000 are crystalline solids with stoichiometric

loading capacities depending upon the hydroxy! groups present; lower moleculai-

w eight PEGs exist as liquids at room temperature, and higher molecular weight PEGs

have low loading capacities. It should again be em phasized that polym ers exist as a

distribution o f molecular weights; however, the polydispersity o f com m ercial PEGs is

quite narrow.'’"

D epending on polymerization conditionSj PEG tei'mini m ay consist o f h y d ro x y l

groups or may be selectively functionalized. Com mercially ava ilab le PEG is produced

through anionic polymerization o f ethylene oxide to yield a polyethei- stixicture

possessing either hydi'oxyl groups at both ends, or a m ethoxy group at one end and a

hydroxyl group a t the other. In this section, the term-PEG will be used to represent

polyethylene glycol with hydroxyl functionalities at one end and m ethoxy group at the

other.

3.2.1. P re se n t w o rk :

Cross-linked polymer supports are now ubiquitous throughout the fields o f

combinatorial chemistry, organic synthesis, catalysis and r e a g e n t s . H o w e v e r ,

em erging problems associated with the heterogeneous nature o f the ensuing chemistry

together with the difficulties associated with ‘on-bead’ spectroscopic characterization

prom pted the development o f soluble polymers as alternative matrices for the

production of combinatorial libraries.^'^ The lower reactivity o f polystyrene- bound

substrates, attributed to a pseudo-dilution effect, can be circum vented in the case of

soluble polymers, as reactions o f soluble polymer-bound substrates and unbound

reactant show the same kinetics, with the additional advantage o f being able to

separate the unbound byproducts and excess reagents by preferential precipitation of

PEG in solvents. Moreover, polyethylene glycols are relatively cheaper and are

am enable to two-phase reactions as compared to cross-linked polystyrenes.

Epoxides are am ong the most widely used intermediates in organic synthesis^^’acting

as precursors to com plex molecules due to strains incorporated in their skeletons^^

because o f which they can undergo facile chemical transform ations such as ring

161

C hapter - I I I

opening by substitution, reaiTaiigemeiit as well as insertion, Synthetic utility o f

epoxides lies in the fact that they can be ring opened with a range o f nucleophiles with

high or often complete stereoselectivity and regioselectivity/*'^ Recently Epoxy

carboxylates have also been used as precursors to enantiopure epoxy lactones and

am ino hydroxyl acids using different asymmetric approaches."’’ B esides their

importance as reactive intermediates, many biologically active com pounds also

contain these three membered rings. Epoxides have also been proved to posses

m u ta g e n ic / ‘ cancer inhibiting and herbicidal properties.^’” Darzens condensation

being one o f the important approaches for the generation o f synthetically valuable

glyc id ic esters in high yields is adopted in m any industrial processes. For instance

diltiazem hydrochloride^’’ originally developed and marketed by T anabe Seiyaku is

one o f the most potent calcium antagonists and has been w idely used in the world for

over 20 years for the treatment o f cardiovascular diseases. S incc methyl (2R, 3S)-3-(4-

methoxyphenyl) glycidate was recognized as a key intermediate for diltiazem,

extensive research has been performed to get the com pound in its optically active

form. One o f the most direct approaches to this epoxide being the Darzens

condensation o f aromatic aldehydes with a-halo acetic esters and the alternate method

involves asymmetric epoxidation o f methyl 4-methoxycinnamate,' ' ’ To date, an

industrial synthesis o f (-)~glycidate has, therefore, been conducted by means o f a

poor-yielding (43% yield) kinetic resolution o f (±)"glycidates (obtained through

■ Darzens condensation route) using a lipase-catalyzed enantioselective hydrolysis.

Polym er suppoi'ted organic synthesis has emerged as an im portant paradigm for the

high throughput screening in modern drug discovery. Innum erable such protocols-

both solid phase and liquid phase, have been developed from time to tim e to cater the

needs o f growing demands o f combinatorial chejnistry. Despite the immense

significance o f Darzens condensation in industrial chemistry, to our knowledge there

has been no report so far that reveals an attempt to translate this chemistry either on

solid phase or liquid phase using any polymeric support.

\bZ

C hap ter - f l l

0 - o „HO

© =

DCC, DWlAP.CHjCI

6

Meo-PEGjooQ

;a»OHC,

0 y,B r

0

8

S c h e m e 1 5 ; L i q u i d p lu is e s y n t h e s i s o f g l y c i d i c e s t e r s t h r o u g i i D a r z e n s e p o x i d a t i o n .

T a b i c II; D a r z e n s c o n d e n s a t i o n o f P E G - e s t e r s o f a - h a i o a c i d s w i t h a r o m a t i c a ld e h y d e s .

a. Ail compounds are charecterizeci by 'H N M R in CDCl^. Reaction conditions; 12 hrs reaction at r.t.

ontry a-Halo PEG-esters Aldehy'dea Glycidic acid PEG ester (8) Yield (%)

a0

O H C h ^ ^ N O j

85

b

0

O H C - ^ ^ C I

0

83

c0

P E G O '^ ^ V ^ ^ ' '

0,NO H C - i ^

011 0 N O ,

peg o - ^ \ Z A . ,X 80

cl

0

P E G O '^ ^ X ^ ^ ''

\

78

0O

P E G O ''^ ^ V -'^ '’ O H C H ^ ^ ^ y — DM©

01 0

pego ' ^ \ / A . ^80

f

O

O H C - < ^ ^ ^ F

01 0

U - ,83

3.2.2. R esu lts a n d d iscussion :

Keeping in view the importance o f glycidic esters and D arzens epoxidation as a

standard protocol for the generation o f these com pounds on com m ercia l scale, we, in

continuation o f our interest in the developm ent o f novel liquid phase methodologies,^’

herein present a facile synthesis o f glycidic esters em ploy ing Darzens epoxidation

approach at ambient temperature under liquid phase conditions. PEG bound a -h a lo

esters were prepared by the condensation o f various a -h a lo acetic acids and M eO-

PEG (Aldrich, tiverage M,i ca. 2000) using carbodiim ide coupling. Quantitative

condensation could be ascertained by complete absence o f hydroxyl groups as seen on

IR (with 0.5 rnmol/g loading as determined by IR, N M R analysis).The glycidic estei's

were synthesized using PEG-esters o f haloacetic acid and arom atic aldehydes in the

presence o f NaNI V N a H under nitrogen atmosphere using T H F a s solvent. Although

in principle a variety o f aldehydes, ketones and a~haloesters can be used for such a

stiidy/'^ keeping in view the higher chemical yields associated with aromatic

aldehydes in solution phase chemistry, we limited our s tudy to aromatic aldehydes

and different a-haloacetic esters. Aromatic aldehydes and PEG-ester were stirred

under nitrogenous atmosphere in the presence o f strong base such as N aH /N aN H 2 .

The reaction was then allowed to run for twelve hours under ambient conditions.

Precipitation o f polyethylene glycol using excessive quantities o f EtaO and successive

washings afforded the products 8 in pure form. Since most o f the epoxide signals in

'H fall into the PEG region, the success o f the reaction w as proved by nucleophillic

opening o f the epoxides by allylation using allyl zinc brom ide as the nucleophile

resulting in the formation o f com pound 9. Furthermore, nucleophilic opening o f

glycidic ester with o-aminothiophenol resulted in the formation o f com pound 10.

Even though the signals due to C2 and C3 protons m erge with PE G peaks, the

aromatic signals o f o-aminothiophenyl moiety are clearly revealed in the 'H N M R o f

PEG bound compound. This is an important key intermediate, cyclization o f which

results in the formation o f benzothiazepinone-an important precursor for the synthesis

o f deltiazem. The reaction consists o f an initial K noevenegal type reaction followed

by an internal SN^ reaction,^’ involving a cyclic transition s t a t e , k i n e t i c s o f which

has been proved to be o f pseudo-first order.

163

C hapter - III

164

C haplet - i n

P EG O

oV A

1)

2) DRY TH F

SHOMe

10

C l

N -HCI / \

H3C CH3

11Diltiazein Hydrochloiicle

Scheme 16: Nucleophilic opening o f PEG-bound epoxides.

3.2.3. E x p e r im e n ta l section;

General. N M R spectra were recorded on Bruker DPX 200 o r 500 M H z instrument in

CD C I3 with TM S as internal standard for protons (Peak suppression for PEG was

pcribrm ed from 5= 3.3 to 4.1 ppm). Chemical shift values are m entioned in 5 (ppm)

and coupling constants are given in Hz. IR spectra (KBr) were recorded on Bruker

V ector 22 instrument.

P o ly m e r s u p p o r te d , a-I ia lo es ters (7):

G e n e ra l p ro c e d u re : Bromoacetic acid (0.5 g, 3.5 mmol), DCC (0.206g, Im m ol) and

a catalytic amount o f DM AP (O.OOSg) were added to PEG -m onom ethyl e ther (l.Og,

approximately quantitative loading i.e. 0.5 m mol/g as determined by IR, N M R

analysis) in dry CH2Cl2(15 mL).The mixture was stirred at room temperature, for 1 2 -

14 h. The precipitated urea was removed by filtration and the filtrate w as concentrated

to one third o f its original volume and diluted with Et2 0 (3x200 mL). The precipitate

was collected, washed with Et2 0 and dried, affording the polym er supported a-ha lo

esters as colorless solid,

P E G b o u n d a~P epoxy esters i.e. F E G -g lye id ic es ters (8 ):

M eO -PEG -brom oacetate (0.5 g, 0.25 mmol) was dissolved in dry D C M (10 mL)

under inert atmosphere and stirred at ambient conditions, 4-chloro benzaldehyde (0,35

165

g, 2.5 m m ol) was added to the mixture. Then N a N H 2 as base (0.03 g, 0.85 m m ol) was

charged into the reaction m ixture and /eft for stirring at am bien t conditions up to 1 2 h.

W orkup was performed in a way similar to the first step and the product characterized

through ' n N M R and IR. The sam e protocol w as applied for the synthesis o f other

epoxides also.

P E G -3-(4 -n itrop lie i iy l) o x ira i ie -2 -ca rb o x y la tc (C o m p o u n d 8 a):

0

PEGO

C hapter - H I

'f l N M R (CDCI3 , 200 MHz):

IR (KBr, cm-'):

3.4-4.6 (m, PEG and C 2/C3 H signals), 5 7.15 (d, 2H,J==8.92J, 8.25 (d, 2H , J ^8 .9 2 ).3445, 2884, 1967, 1748, 1613, 1467, 1344, 1114, 963,

PEG-3-(4-cliloroplJcnyI) o x i ran e -2 -ca rb o x y ia te (C o m p o u n d 8 b):

0

PEGO

'H N M R (CDCI3 , 200 MHz): 5 3.4-4.6 (m, PEG and C2/C3 H signals), 7.43 (d,211, J= 8.21), 8,02 (d, 2 H , ,/ -S ,2 7 ) .

IR (KBr, c n f ') : 3292, 2923, 2853, 1741, 1603, 1467, 1359, 1114,963,

P E G -3-(4-n ie tl ioxyp!icnyl) ox ira i ie -2 -ca rboxy la te (C o m p o u n d 8 c):O

PEGO-"j

\

OMe

'H N M R (CDCI3 , 200 MHz):

IR (KBr, cn f ') :

5 3.S-4.6 (m, PEG, C2/C3 and -O M e proton signals), 3.78 (s, 3H), 6.99 (d, 2H, J = 8 3 2 ), 7.85 ( d , 2 H , ,/ =5.32).3287, 2921, 2853, 1748, 1611, 1592, 1374, 1020, 877, 849, 790, 694.

P E G - 3 ~(4 -(d ln ic t t iy lan il 5J0 )phcny l) o x iran c -2 -c a rb o x y la te (C o m p o u n d 8 d):

166

C hapter - I I I

P E G O '

'H N M R (CDCI3 , 200 MHz):

SR (KBr, cnV'):

5 7.72 (d, 2H, 6.68 (d, 2H, , / =S‘.^0), 3.4-4.6 (m, PEG and C2/C3 H signals), 3.12 (s, 6H). 3445, 2923, 2853, 1749, 1611, 1467, 1359, 1113, 1020, 842.

P E G -3 - (2 “iiiitroplienyl) o x in in e -2 -c a rb o x y la te (C o m p o u n d 8e):

P E G O

H N M R (CDCI3 , 200 MHz):

IR (KBr, cm "'):

5 3.4-4.6 (m, PEG and C2/C3 H signals), 7.54- 7.7.74 (m, 2H), 7,89 (d, IH, J =8.08), 8.21 (d,1H,./-S.0<S).3292, 2883, 1748, 1467, 1359, 1280, 963, 842.

PEG -3-(4 -flourop lie iiy !) o x ira i ic '2 -ca rb o x y la te (C o m p o u n d 81):

P E G O s Z A

‘ H N M R (CDCI3 , 200 MHz):

IR (KBr, cm ''):

5 3.4-4.6 (m, PEG and C2/C3 H signals), 7.06- 7.16 (m, 2H;, 8.02 (dd, 2H, J=-8.31}.3443, 2887, 1750, 1629, 1508, 1359, 1280, 963, 842,

E p o x id e c leavage using ^^-amijiothioplienol as nuc leoph ile : PEG bound glycidic

ester 8 (1.0 g, 0.5 m m ol) was heated with o-aminothiophenol (0.165 g, 1.5 mmol) and

catalytic quantity o f DIPEA (0.1 mmol) in dry toluene (80 “C) for 12 h under nitrogen

followed by evaporation and usual precipitation affording the aniline-ester 10 which

w as characterized by 'H NM R.

167

C hapter - I I I

PE€F-3-(2-ami!iiophciiylthio)"3-(4-cliloroplicnyI)-2~Iiydroxy pB 'opanoate

(C o m p o u n d 10b):

'M N M R (CDCI3 , 200 MHz): 5 3.44-4.66 (m, PEG and C2/C3 H signals), 4.88(s, IH), 6.57 (t, IH , J =7.84), 6,71 (d, 1H, , / =7.84), 7.14 (m, 2H), 7.43 (d, 2H, J ^-8.39), 8.03 (d ,2 H ,J = 8 .3 9 ) .

IR (KBr, cm ''); 3465, 3176, 2952, 2850, 1903, 1752, 1612,1 5 4 9 ,1 4 9 4 ,1 2 3 4 ,8 4 9 ,6 3 8 .

E pox ide cleavage using allyl zinc b ro m id e as nucleoph ile : Ally! Z inc reagent was

■ generated by stirring ally! bromide (0.25 g, 2.1 mmol) with freshly activated Zn (0.2 g,

3.2 mmol) in dry T H F under nitrogen. Formation o f a c lear solution on dissolution o f

Zn indicated the generation o f the reagent. Polymer bound epoxide 8 (1.0 g, O.Smmol

loading) dissolved in dry TH F (10 mL) was added to the allyl zinc reagent in one

portion and the mixture was stirred at ambient tem perature for 1 0 h, at the end o f

which the reaction w'as quenched by the addition o f saturated N H 4 CI solution (1

niL). Workup involved the evaporation o f TH F under reduced pressure, followed by

dissolution o f residue wdth C H 2CI2 (20 mL). Lfndissolved inorganic salts were

separated by llltrtition and the filtrate was concentrated. Finally the product was

obtained by the precipitation o f the concentrated filtrate with excess o f E t 2 0 ( 2 0 0

mL), and then by filtration,

P E G -3 -(4 “(d im ethy ia ii iino)p lieey l)-2"hydroxy liex -5-enoatc (C orapoiu it l 9d):

/PEGO

HO

'H N M R (CDCI3 , 200 MHz): 5 3,10 (s, 6 H), 3.41-4.46 (m, PEG and C2/C3 Hsignals), 5.00-5.10 (m, 2H), 5.20' (m, 2H), 5.9

168

Chapter - / / /

(m, IH), 6.68 (cl, 2H, . / ^8 .7 6 ), 7 .72 (cl, 2H, J =5’. 76).

lR (K B r , c n r ' ) : 3540, 3254, 2935, 2853, 2009, 1748, 1611,1565, 1567, 1453, 1354, 1222, 1154, 1034, 877, 847, 730, 664.

3.2.4. C onclus ion :

In conclusion, a facile and unprecedented liquid phase synthesis o f industrially and

biologically important glycidic esters using polyethylene glycol as support has been

presented here. The liquid pheise Darzens epoxidation w as found to be general with

regard to various aromatic aldehydes and PEG bound halo-esters.

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