Reactions of Polyvinyl and N-Methyl Pyrrolidone Bromine Complexes with Dithioacetals and Ketene Dithioacetals

3.1 Introduction

E ven though the concept of immobilizing reagents on a support

material as in catalytic hydrogenation and in numerous other

heterogeneous reactions that occur at the interface of a solid was known a

century ago. the subjcct has got widespread acceptance after Merrifield's solid-

phase peptide synthesis.' A wide range of polymeric reagents was developed

for use in organic s>i:lthesis and those based on cross-linked polymers have

become more popular due to the ease of h a n d ~ i n g . ~ The reaction can often be

driven to completion by using excess of reagent without the fear of separating

the unspcnr rcagents or the polymeric byproducts from the product mixture. A

polymeric reagent is a system that combines the unique properties of

conventional reactive moieties hound to it and those of high molecular weight

polymer. I hc reactivit:r. of a functional group bound to a polymer backbone

varies ibrm a solutior~ phase synthesis and depends on the nature of the

polymer hackbone. the conformation of the polymer chain, the

microenvironnient of the reactive functional groups, the relative occurrence of

the functional groups in [:he chain. the stereochemistry around the functional

group, thc overall topology of thc macromolecular matrix and the solvent and

swelling characteristics.

3.2 Polymer- supported halogen complexes

I'he halogen containing reagents based on polymers such as polystyrenes,

polyacrylamides. ~~oly(viny lpyrrolidene)~, poly(viny1pyidine)s and

ply(viny1pyridin-styrent2)s wcrc developed for oxidation, addition as well as

halogenation reactions. Kessct and co-workers have reported oxidation of

primary and secontlary alcohols to aldehydes and ketones using

polyvinylthioazolium hydrotribromide 1 in aqueous sodium h y d r ~ x i d e . ~ The

resin was easily synthesized by radical copolymel-isation of 4-methyl-5-

vinylthiazole. styrene ant1 divinylbenzene followed by treatment with HBr and

bromine.

Pillai et al, reported polystyrene-supported t-butyl hypochlorite and

hypobroniite to effect oxidation of alcohols to carbonyl compounds and for

halogenation.' The same group has shown the utilities of chloramine-T and

bromamine-1' supportxi on polystyrene in the oxidation of alcohols and

halogenation of ketones.' I'olystyrene-supported benzyltriethylammonium

dichloroiodate and tlibromoiodate were reported as polymeric anionic

oxidants." A polymeric reagent electrochemically produced from cross-linked

poly(4-vinylpyridine)-:;upported hydrobromide was found to oxidize secondary

alcohols tcr corresponding ketones.' Pillai et 01. developed bromo derivatives of

pc~ly(vinylpyrrolidonc)s as reagents for the oxidation of alcohol^.^ A series of

polymeric oxidants 2 3 and 4 based on a co-polymer of acrylamide and

divinylbenzene for oxidizing primar). and secondary alcohols to aldehydes and

ketones, respectively were developed by Sreekumar et al. They could succeed

in binding the activt: functions IC:12~. IC1, and IBr2- on these acrylamide-based

supports. '

I'cllyact?/lamide-hrorninc complexes were developed by Pillai et al. for

oxidation. bromination and addition reactions and observed that highly polar

solvents enhanced reaction rate in the case of NNMBA cross-linked

reagents."' " l'hc sane reagenLs were also used in the bromination of carbonyl

compounds." %upan reported the use of poly(4-vinylpyridinium-styrene)-

supported dichloroioc;latc for the addition reactions of alkenes.'"

Polymer-bound tlromides have been prepared for use in the bromination

of ~ariety of aromatic rnolecules." The polymer used was based upon cross-

linked co-polystyrene-4-vinyl(N-hexylpyridinium bromide), which was treated

with chlor~ne or bromine to give the two reagents 5 and 6. Both reagents

displayed regioselcctive,~ara-bromination for a range of substituted benzenes.

Bromine complexes with various polymers bearing basic units

(pyridine. piperidinc amdl pyrazine) were investigated by the same group and

the role of polymer matrices on reactivity was tested by three types of organic

reactions: elcctrophil~c addition, aromatic substitution and free radical

substitution. Pyridine complex was most reactive in all the three types of

reactions." Sinisterra di:scribcd the use of poly (N-bromoacry1amide)s as

heterogeneous reagents for alpha halogenation of ketones.'"abicky has

developed complexes of bromine and bromine chloride with poly(4-

vinylpyridine)~ 7 to us1 in the addition reactions with alkenes and alkynes. 16

7

l 'hc complexes of bromine with poly(vinylpyridine-styrene)",

poly(vinqlpqridine N-oxide-styrene) and poly(vinylpyridiniun7bromide-styrene) l 8

were used in addition reactions of double bond-containing compounds. These

reagents showed stereospecificity in the addition.

A licile brornomethoxylation ot'alkenes using a new polymer supported

brorninechloride resin 8 under microwave condition has been reported I j J recently. Reactions using this resin were regioselective, following

Markovnikov's addition rules, and also chemoselective in which only isolated

double bonds were bromomethoxylated, keeping the conjugated double bonds

inert to the rcaction comditions.

Amherlyst-A26 resin in its tribromide form effects para-bromination of

phenols with high yields and selectivity; the resin is easily recovered by

filtration and can be reconverted into the tribromide form by addition of

bromine.'" Poly(4-methyl-5-vinylthiazolium) hydrotribromide (P4M5VTHT),

incorporating 45% ol' bromine. was found to be a stable, and effective

brominating reagent fbr. various unsaturated ketones and ole fine^.^' The

anlinomethylpolystiren'e-supported (diacy1oxy)iodobenzene ragent 9 has been

used lbr the oxidaton of hydroquinones and phenols to the corresponding

quinones.~" I-hus. Multaiyama aldol reactions were performed at -78 OC in

dichloromcthanc afford the products in very good yields.

'2 polymer~c dcr~vative of the coupling reagent 1 -(3-dimethylaminopropyl)-

3-ethylcabodiim~de (EsDC) 10 has been prepared and utilized in amidation by

Llesa~ and later utilixd by Adamczyk et al. for the generation of thiol esters 13.

(Schernc I ) ' I

10 0 + R'SH

H OH CHCI, - lRJ-SR

11 12 13

Scheme 1

3.3 General methods for the synthesis of thiolesters

For the preparation ot' some synthetic intermediates such as B- oxothiolesters. to be used in the total synthesis of alkaloids such as rigidin and

related molecules, we needed to develop an efficient method for the partial

hydrolysis of tx-oxoketene dithioacetals. P-Oxothiolesters are valuable

synthons in organic synthesis. I(-Oxothiolesters have got a distinct advantage

over simple thiolesters due to the presence of multiple reactive sites. Due to the

relative weakness of the overlapping of the C (2p) and S (3s) orbitals to carbon-

sulfur double bond. (1C-S'-R.) oS thiol ester when compared with (C=O+R) in

carboxylic esters, the tx-hydrogen acidity is enhanced and processes like

enolate li)rmation and Claisen condensation are favored. They are mild acyl

transfer ligenls that undergo transesterification reactions with various

hetcronucleophiles. They can be transformed into ketones and has been utilized

in the total synthesis of natural products like f u ~ i ~ o r u b i n . ' ~ Recently application

of this l'unctional grclup has been extended into the synthesis of proteins by

chemical legation of lbenzyl thio~esters'~ and as a latent carboxylic acid in the

n~acrolactonization applicable to the dilactonic pyrroliridine alkaloids.26

Inspite of tl1.e wide utility of (3-oxothiolcarboxylates in organic

synthesis. there are only limited methods available in the literature for their

synthesis. An economically and environmentally viable method for the

synthesis 01' this molecule is still desirable. Our research group has recently

developetl a new syn~:hesis of (3-oxothiolesters ti-om a-oxoketene dithioaceta~s.~'

The conventional ways to prepare thiolester 15 in fidr to good yields include

the reaclion ot' acid chlorides 14 with thallous 2.-methylpropane-2-thiolate , !X (Scheme -).

14 IS

Scheme 2

I h~olestcr\ 17 were prepared in good yields by reacting thioacetylenes

16 with p-toluenesulfonic or trifluoroacetic acid in dichloromethane in the

presence ot silica (Scheme 3).'"

p-TsOH --.-

0 R ' K - - - . - ~ ~ '

silica R'JI-~~z 16 17

Scheme 3

Recently palladium catalyzed thiocarbonylation of prochiral 1,3-

con.jugated dienes 18 with thiols and carbon monoxide has been developed as

an efficient method fix the synthesis of optically active (3,y-unsaturated

thiolester\ 19 (Scheme 4)."' llsing a similar apprclach the same group has

successfully thiocarbo~~ylated enynes, allenes with thiols to afford thiolesters .31

R3 $. Pd (OAc),iPPh, R1 ~2 R4

-. - R~S*R~ 400 psi of CO 0 R~ R5 CH2C12, 11O0C

F:', R2, R3, R4, R5, R6and R' = H, alkyl. aryl or cycloalkyl.

18 19 Scheme 4

Aldehydes 20 were converted into thiolesters 21 by a Tishchenko-type

reaction using diisobutylaluniinium chalcogenoate (Scheme 5).32 The method is

effective liv the synthesis 01' thiolesters from aromatic as well as aliphatic

aldehydes except pivalaldehyde. In another approach u-oxotrithioorthoesters

generated from methyl carboxylate in presence of NBS in THF or HgO in

aqueous IiBF4 in T I IF afforded tx-oxothio~carboxylates.~~

Scheme 5

p-Ketothio1ester:j have got a distinct advantage over simple thiolesters as

synthons owing to the presence of multiple reactive sites. Inspite of the wide

utility of k3-ketothiolesters in organic synthesis, there are only limited methods

available in the literature tbr their synthesis. Synthesis of 0-ketothiolester

~isually starts with another thiolester. Ethyl acetothiolacetate 23 has been

prepared in low yield by the self-condensation of ethyl thiolacetate 22 in

presence of sodium (!Scheme 6).j4 Later this method was improved by Wall and

co-workers using isol~ropyl magnesium bromide as the base.35

22 2.3 Scheme 6

Similar reactlor1 wah studied by Wilson and liess3' under different

conditions and has shown that best results could be obtained when isopropyl

magnesium chloridc or magnesium chloroethyl mercaptide was used as the

base. This method has limited practical utility as a rnethod for the preparation

01' b-diothiolesters. since thiolesters do not undergo clean crossed claisen

condensations. k3-Kt:tothiolestcrs 26 are formed by the addition of enolates

derived Srom ketones 24 to acylating agents such as S,S-dimethyl

dithiocarhonate 25.''

24 25 26

Scheme 7

Ilikctene 27 can be converted into p-ketobromothiolester 28 by

bromination followed by treatment with butanethiol in 73% yield (Scheme 8). 38

Scheme 8

7'hc same product was prepared in 76% yield by acylation of Meldrum's

acid 29 with bromoacetyl bromide 30 followed by reaction of t -butanethio~.~~

The bromothiolester 28 was used in the preparation of t-butyl-4-diethyl

phosphono-3-oxohutaicthiote 31 (Scheme 9),40 a valuable reagent for Wittig-

Homer rreac~ion.

28 3 1

Scheme 9

Ilic pliosphor~o-3-oxobutancthioatr 32 was used by Ley and Woodward

for the s:i.nthesis of y.6-unsatured b-ketothiolesters 33 by Wittig-Homer

reaction (Scheme lo)." 'Ihe compound finds application in the total synthesis

of'nat~lral product^.^'

20 32 33

Scheme 10

3.4 Results and Disc~lssion

Sol~d-supported reagents have been utilized for a large number of

diverse and interesting chemical manipulations. One of the main difficulties

encountered by a synthetic chemist while developing a supported reagent is the

time needcd to synth82size the expensive polymer backbones. If we utilize

con~mercially available polymer supports for developing new reagents, then it

will be economic as well as time saving. Thus we have brominated the

commercially available polyvinylpyrrolidene (PVP) and the resulting polymer

supported bromine reagent (PVP-Br2) was utilized for the efficient conversion

of a-osoketene dithioacet.als to p-oxothiolesters.

3.4.1 Partial hydrolysis of a-oxoketenedithioacetals to thiolesters using bromine complexed on polyvinyl pyrrolidone

Bromine is CCIJ was added to commercially available polyvinyl pyrrolidone

t&en in ('('I, and kcpt at rtmm temperature for 4 h. 711e resulting polymer supported

bromine reagent was tiltered and excess bromine was evaporated by aeration and

kept in a11 airtight bottle. When amylketenedithioacetals 34 prepared from

substituted acetophenones werc allowed to react with four equivalents of the

reagent based on bromine capacity of the resin in chloroform at 60 'C for 3-4 h

with occasional shaking. the corresponding thiolesters 35 were obtained in

ex cell en^ >icld. 11nu:s tr-i~soketene dithioacetal 34a. prepared from

acetophellone was heated with the resin in chloroform and after the completion

of the reaction, as indicated by the TIX. the reaction mixture was cooled and

filtered. I'hc resin was washed with chloroform and the filtrate together with the

chlorofornl washings were evaporated under vacuum to get D-ketothiolester 35a

as a pale ye l lo~ . liquid. 'This on further purification by filtering through a short

column packed with silica gel using hexane to afford the thiolester in 80%

yield. I 'hc structure of the conlpound has been confinned by comparing its IR, I I3 NMR. "c' NMR and MS data with that already reported in ~iterature.~'

We have compared the efficiency of the commercially available non-

cross linked polyvinyl pyrrolicione (PVP) with co polymers of pyrrolidone for

the above iranshrmation. Different polymers of N-vinyl pyrrolidone having 2%

cross-linking agents likc hexanedioldiacrylate (HDODA), tetraethyleneglycol

diacrylate ( T E D ) N.N'-methylene-bis-acrylamide (NNMBA) and

divinylben~cne (DVH) were selected for the study. These polymers were

prepared by suspension polymerization. The microporous polymer beads

(200-300 inesh) were treated with bromine in CCI4 after swelling in the same

solvent t i~r 2h. The polymer bromine complex formed was filtered and excess

bromine uas removed by aeration. The bromine capacity, given in Table 1, of

these reagents was estimated following the Schoeniger method43 in which

50 nlg of the complex was added to ice-cooled dimethylformamide and 1 g of

potassium iodide was added to the suspension. The liberated iodine was titrated

with 0.5 N sodium thiosuiphate solution. The bromine capacity of each polymer

depends o n their swelling properties which in turn depends on nature of cross

linking agenl used. 1 Elus more hydrophobic DVB cross-linked resin showed

least efticiencj and HL:IO[)A cross linked resin showed maximum efficiency in

adsorbing bromine.

Whrn thc kete~ne dithioacetal derived from acetophenone 34a was

treated with polyvinyll?yi~olidone-bromine complexes having various cross-

linking agents. thc corresponding thiolester 35a was formed in excellent yields.

The efficrc~~cy of different polymer bromine complexes for converting ketene

dithiocetal 34a to 35a are also summarized in Table 1. The result shows a linear

relationship bet\veen bromine capacity of the polymer and their efficiency for

converting l a to 2a.

Table 1 : Efkct i ~ f different cross linking agents on brominated vinyl pyrrolidone polymers for converting 34a to 35a

- -~ ~ ~ ~~~~ -.

I C'rais inking agent Bromine Capacity No. used (mmoligm)

Yield %

1 DVH 3.3 64

5 Non C ross linked 4.5 80

Comparing the efficiencies of non-crosslinked polyvinylpyrrolidone

bromine complex with cross-linked ones, there is little difference in their

efficiencies f i~ r the partial hydrolysis of ketene dithioactals. Therefore we have

used bromine complex of the commercially available less expensive polyvinyl

pyrrolidonc(PVP-Br2) For the conversion of other substituted ketene dithioacetals

to the corresponding thiolesters. The reaction was found to be general for other

substituted benzoylketene dithioacetals 34b-e giving the corresponding P- oxothiolestcrs (35b-e) i n excellent yields (Scheme 11). The compounds were

characterized by comparing their spectral data with literature reports.27

Scheme 1 1

- -

Product 35 -- - - - - R ' Yield (%)

a H 90

'I he dcylketencs dithioacetals prepared from aliphatic acyclic ketones

36a-f (Scheme 12) also underwent partial hydrolysis leading to the formation of

thiolesters ct'fectitely. 'Thus, the acylketene dithioacetal 36a prepared from

ethyl methyl ketone on treatment with PVP-Br2 coniplex in chloroform and

heated at (10 "C' lilr -3 h followed by filtering through a short silica column

affords the thiolestcr 3'7a in 95'% yield as pale yellow liquid.

Scheme 12 0

R ; '. RZ Resin 4 fold -- M e s s CHCl3,m

.36 37

- ~ -- ~~-~~ ~

I'roduct 37 R ' RZ -- - -. -~~ ~

Yield (%)

a CEI? CH3 95

b ('H3CHZ CHI 92

c ('I:[3CH?CH2 CH3CH2 88 d CH; H 98

c ChHi CH3 93

C'H; - ----

CH3C0 --

90

I'hc ihiolester .57a was characterized by spectral data. Proton NMR

spectrum of 37a (300 MHz, C'DCI,, Fig 1 ) shows a three proton doublet at

6 3.39 with a coupling constant 7 Hz corresponding to methyl group. A three-

proton singlet at & 2.2:) ppm is due to methyl sulfanyl group and another three

proton singlet at 6 2.35 lppm corresponds to the acetyl protons. A one proton

quartet at 3.76 ppm with ;t coupling constant 7 Hz is due to methynic proton.

13 Thr struclure was further confirmed by C NMR spectrum. The ',c spectrum o f 37a (75.4 MHz. C'I>CI, Fig. 2) shows peaks at 6 11.65 and at 6

13.29 corresponds to rnethylthio group and methyl group adjacent to methynic

carbon respectively. Shc peak at 6 28.12 ppm is due to methyl carbon adjacent

to carbon) 1 group and tlhat at 6 61.69 ppm is due to the methynic carbon. The

thiolester carbony1 carbon appears at 6 196.80 ppm and the acetyl carbonyl

appears a! 6 202.35. I'he mass spectrum (EIMS, Fig 3) shows molecular ion

peak at miz 146. Othcl. prominent peaks are at 129, 97, 83, 57 and 55.

--.~ ~~ ~ - -~-~L

~ ~

X I - - - 1 ~ l , . , , r... . r ~ ~ , , , , ~ . , 7~...~ --.-, . .,., . ,-'. -..---

Figure I '[-I NMR (300 MHz. CDCI,) Spectrum of Compound 37a

Figure 2 "C NMK (75.47 MHz, CDC13) Spectrum of Compound 37a

Figure 3 ElMS of Compound 37a

Thiolcsters 37b-f was generated by the partial hydrolysis of the

corresponding ketenc dithioacetals 36 on reaction with the PVP-Br2 resin under

similar conditions as pale yellow liquids in 88-92% yields. All new compounds

were characterized with the help of spectral data and the details are given in the

exper-imcntai section. Attempts LO synthesize thiol ester from cinnamoyl ketene

dithioacetal also aftbrded an unstable yellow solid.

3.4.2 Deprotection of dithioacetals and dithioketals

As an extension of thc previous work on partial hydrolysis of ketene

dithioacetals. we havc treated the protected formyl ketene dithioacetal derived

from a-torniyl acetophenone hetenedithioacetal with four fold excess of PVP

bromine cc)nlplex in chlorofonn. We expected that. the formyl group will

remain protected ant1 \.he ketendithioacetal moiety would undergo partial

hydrolysis. Surprisingly by treatment of protected a-formyl ketene dithioactal

gave the parent aldehyde on treatment with PVP-Br,. This motivated us to

examine whether bromine co~nplexed polymer reag,ent is effective for the

deprotcction ofdithioacel:als and dithioketals.

Carbony1 group protection from nucleophilic attack is an important

process during many rnulti step synthetic transformations." Cyclic thioacetals

and ketals have been widely used as carbonyl protecting group because of their

stability under acidic and basic conditions and the ease of their introduction

and removal. Numerous methods have been developed for the cleavage of

thioacetals and kctals to the parent carbonyl derivatives. These include

hydrolysis in the prcijence of different transition-metal ions4', oxidation of

sulfur to a higher oxidation state4". hydrolysis4' and use of alkylating agents.48

Thioacetals have bcen deprotected by the combined use of molecular oxygen

and cataljlic amount:; of B ~ ( N ~ ~ ) , . ~ H ~ O . ~ ~ Non-metallic reagents such as

trin~ethylouoniurn tetl-afluoroborate'". trifluorosulphonates' and oxides of

nitrogen" have also bizen used for deprotection. Different naturally occurring

clay supported reagents have recently gained considerable attention as a

reagent 1iir the cleavagc of thioacetals and ketals because of its selectivity to

the functional group and economical, practical and recent environmental

demands. Natural kaolinitic clay has been utilized by Bandgar et al. for the

selective cleavage of thioacetals. under solventless conditions. Due to its

specific activity in thl: regenel-ation of aldehydes, the methodology is useful for

the chen~oselcctivc rennoval ol' a thioacetal in the presence of a thioketal

(Scheme 13). Phenolic. methylenedioxy, and methoxy groups tolerate the

reaction conditions."

s--, H-l ,c) .,

Kaol~n few droos FHO

Scheme 13

C'laq upported nitrates have been successfully utilized to cleave cyclic

and acycl~c thioacetal tierived from aldehydes and ketones. Clayfen was

employed b!, Varma ei* ul. to deprotect thioacetal derivatives 40 under solvent-

free condit~ons and with the help of microwaves. Only draw back is substrates

having lice phenolic moieties undergo some ring nitration (Scheme 14). '~

, *. ,.., . 0 .-,,PI? Clayfen

._i. ,i - .. ..'<' $ neat. MW 900W. 20 sec

90% 0

40 41

Scheme 14

C l e a n was also reported by Meshram to be good catalystlreagent for

this deprotcction reaction, carried out in dichloromethaneSS or under solventless

conditions using mia.owave irradiation." ~ l t h o u ~ h both methods tolerate

common groups such as esters and ethers. they fails in the selective cleavage of

thioacetals in the presence ofacetonides.

An midant like metal nitrates supported on silica gel has been widely

used by sc\cral groups for the thioacetals deprotection. Thus S ~ O ~ / C U ( N O ~ ) ~ ~ ~

o r SiO- l ' c ( ~ 0 ; ) ~ ' ~ reagent combination regenerate:; the corresponding ketones

43 and aldehydes kam 1.3-dithiolanes 42 and 1,3-dithianes (SchemelS).

42 43

Scheme 15

Silnilarly, the redgent combinations like oxone on aluminas9 or dimethyl

sulfoxide and silica gel chloride"" also affords aldehydes from thioacetals. The

development of newer methodologies for dethioacetalization process is still an

active arc3 of research as evident by the increasing number of publications

found in recent literat~lre. .14

As an extension of the previous work on partial hydrolysis of ketene

dithioacetals. we have treated the protected formyl ketene dithioacetal 45

derived tiom 44 with PVP bromine complex in chloroform. Surprisingly the

expected thivlester 468 was not formed. From spectral and analytical data the

structure ol' tho product was confirmed to be a-formyl ketene dithioacetal 45

(Scheme 16).

O SMe 0 SMe 0 0 I ' " ,>I.

PVPl Br,

[ , -r SMe

S . ~- ' S -1 CHCI, yleld 98% 60 'C [ 4 (J'ys- u

45 46

Scheme 16

' f h ~ s observatioil motivated us to further investigate the utility of the

reagent as dethioacctalizing agent. We have prepared different cyclic

thioacetals and ketals Srorn the respective aldehydes and ketones by reacting it

with 1.2-cthanc dithiol in presence of catalytic amount of TiCI,. Initially

benzaIdeh?.de dithioacelal deprotection was studied as a model experiment. The

ciithir~rtce~al was treated with lour-fold excess of PVP-Br, reagent in chloroform

at 60 "<' l i ~ r 3 hours. I'LC' showed complete disappearance of the starting

dithioacctal. GCMS analysis of the crude reaction mixture showed formation of

benzaldehqde in 88"0 yield. We have further generalized the process by

selecting dithioace[al:s derived from different substiluted benzaldehydes. The

results are summarized i n Scheme 17.

Scheme 17

Product 48

o Bt CH? 64 - - -- - -- -

*Yield of the product formed after 3h (GC).

turthcr studies on depn~tection process were conducted using

dithioketals. I)ithiokt.lals derived from acetophenone and p-bromoacetophenone

were studieti. I'he reagent was found to be less efiicien for the deprotection of

dithioketals.

3.4.3 Bromine in h-methyl2-pyrrolidone: a new selective brominating reagent

Alier the studies on bromine complexes on polyvinylpyrrolidone for the

partial hjdrolysis of' a-oxoketenedithioacetals to thiolesters. we examined the

behavior ol' bromine complexed to N-methyl pyrrolidone itself. Bromine is a

highly versatile reagi:ni. which can undergo wide variety of reactions like

addition, substitution etc. and the selectivity depends on the reaction conditions

and the bronrinating reagent used. Selective bromination at a particular reaction

sight in presence of other reactive centers without any protection or

deprotection is a challenging goal in many synthetic programs. The bromides

thus generated are potential precursor for carbon-carbon bond forming reactions

via cross coupling rr:actions such as Heck, Suzuki, Stille rtc. leading to

complex target molecules.

7'reiitment of' ;ani.line 49 with n-butyllithiurn and then trimethyltin

chloride gacc the tin arnide (PhNtI-SnMe3) in situ. Without isolation of the tin

arrlide. reaction with bromine and workup with aqueous fluoride ion gave

p-bromoaniline 50 in '76 % yield, with no dibromoarriline or o-bromoaniline

(Scheme 18). This constitutes a good general method for the regioselective

bromination of aromatic amines."

1 n-BuL,. THF. -78 OC

/=\ 2 R3SnCI. THF, -78 OC - ---- B r - ( = & w 2

3 Br,. 7 5 "C-n 4 aqueousKF 76%

49 50

Scheme 18

rx-Hromoalkanc>n<:s were synthesized by the reaction of alkanones with

hexan~ethylcnetetranline-bromine complex and basic alumina in solvent free

conditions under microwave i r r a d i a t i ~ n . ~ ~ Reactions of mono-substituted

aromatics or moderate activity with bromine in the presence of stoichiometric

amounts ol' ~eol i te NaY proceed in high yield and with high selectivity to the

corresixuiding par~l-bromo products. The zeolites car1 easily be regenerated by

heating and can be r~:u:ied. Furia and coworkers have reported that vanadium

bromoperoside catalyses the oxidation of bromide ion by hydrogen peroxide to

a bromine cquivalenl intermediate which is useful in bromination reactions

(Scheme 1 O)."

5 1 52

Scheme 19

Nucleophlic 1.2-addition of bromine by perbromide reagents was

reported recently. Pyridiniunl perbromide (PPB) and trimethyl(pheny1)

anlmoniuniperbromide ('I'MPAP) were used for mild and selective bromination

of u,(3-unsaturated ketones 53. I'MPAP has been used for addition of bromine

selectivelq a1 a$-unsaturated carbonyl group even in the presence of other

carbon-carhon double honds affbrding 54 in good yields (Scheme 2 0 ) . ~ ~

:53 54 Scheme 20

Seki!a and CCI-workers developed 2-bromo-2-cyano-N,N-dimethyl

acetamide(HC'I)A) as a brominaiing reagent. It brominates a-carbon of ketone

55 with high selectivity of mono bromination affording 56 (Scheme 21).65

55 56 Scheme 21

ht3S is uscd fi)r allylic bromiuation in solvents such as CC4 or CH2C12

etc, and considered as a selective brominating agent. In presence of water NBS

selectively oxidizes secondary alcohol. NBS has used in aqueous 1,2-

dimethoxyethane lilr generation of HOBr. Pure NBS effects side chain

c~xidation ol'aron~atic hydrocarbons. Some cases it is used fore decarboxylation

of tr-amino acids and dicarhoxylic acids. 2-Selective 0-brotnination of N-

fonnyl u.lMehydro amino acid esters 57 was investigated by Nunami and

coworkers (Scheme 7:!).""

OHC:~. RxH NBS N COzMe -----' OHC, I "XR N COZMe ti A

Scheme 22

Jur!jappa rt ul. have reported the bromination of a-aroyl ketene-S,S-

acetals 59 wing N-bromosuccinimide (1.2 equiv.) as the brominating reagent.

The bromination occurred at the a-position of the ketenedithoacetal group

afford 60 in high yields (Scheme 23)."

59 60 Scheme 23

l o g i n an insight into the reaction of polyvinylpyrrolidone bromine

complex. \be have carried out the reaction of a-oxoketene dithioacetals with N-

methyl pyrrolidone bromine complex. The ketene dithioacetal ( 1 mmol) was

dissolccd in excess NMP (10 ml,) containing bromine (1.1 mmol) and stirred at

room tcmperirlure i'or 3 hours. Subsequent aqueous work up, extraction with

diethyl ether- and filtration through a short silica gel column using hexane

aftbrdcd a pale yellon oil in 95 % yield (Scheme 24). This compound was

identiliccl as 2-bromo-3.3-bis(methylsulfanyl)-l-pher~yl-2-propen-l-one 34a by

comparing the spectral data with literature values." Ketene dithioacetal derived

from suhstituted acetophenones also afforded the corresponding bromo

derivatices 61b-e in excellent yields.

Scheme 24

sue C SMe ... ..

R 'f .. ."-.ASMe Br2, NMP -----

1 d . 3 hr

~ ~- ~

I'roduct 6 1 ~ ~ ~-

R Yield (9'0)

a H 97

Wc have cxtentled the reaction to substituted 1,3-dithiolane 2-

ylidenes 51 derived from substituted acetophenones. The reactions were

examined with N-methyl pyrrolidone bromine complex. The reaction

proceeded as expected lo afford I -bromo- I-(1,3-dithiolan-2-y1iden)- l-aryl-

I-ethanone 63 in excellent yields (Scheme 25)

Scheme 25

~~~. ~-~~

Product 52 - ~~-

R Yield (%) -- 3 H '3 2

b C I 04

Z rnechan~bt~i fir the selectibe bromination ol'ketene dithioacetals in the

presence of broniln~: in N-tnethyl pyrrolidone may be depicted as follows

(Scheme 26).

RS. , sR

Scheme 26

'I'hus we have developed a simple procedure and a new reagent for

brorninat~ot> and may substitute the expensive NBS for a-bromination of

ketene dithioacetals as well as other bromination reactions. Our group is

currently irlvestigatirlg the usefulness of this new reagent as a selective

brominating agent.

3.5 Experimental

Melting points are uncorrected and were obtained on a Buchi-530 melting

point apparatus. 1R spectra were recorded on Shimadzu IR-470 spectrometer and

the frequencies are reported in em-'. Proton NMR spectra were recorded on a

Bruker LXX-300 (300 MHz). Bruker WM 300 (300 MHz) or on a Bruker

AMX 400 (400 Mllzj t;pcctrometer in C:DCl,. Chemical shifts are expressed in

parts per million downtield from internal tetramethyl silane. Coupling constants

J are given in Hz. klectron impact mass spectra were obtained on a Finnigen-

Mat 312 ir~strumetlt and GCMS spectra were recorded in Shimadzu 5050

Ail reagents were commercially available and were purified before use.

l'hc pre~iously reported ketene dithioacetals were prepared by the known

procedure and anhydrous sodium sulphate was used as drying agent.68 All

purified compounds gave a single spot upon TLC analyses on silicagel 7GF

using an ethyl acctatelhexane mixture as eluent. Iodine vapors or KMn04

solution in water uas used as developing agent for TLC.

3.5.1 General procedure for the preparation of P-oxothiolcarboxylates 35 and 37

.lo the acylketcne dithioacetal (5 mmol) dissolved in chloroform

(50 mL). the bromine complexed resin (PVP-Br2, 3.8g, 20 mmol) was added

f o l l o ~ e d by few drops o f water. 'The mixture was kept at 60 "C for 2-4 h with

occasional shaking. When the reaction was complete (TLC), the mixture was

filtered and the reagent was washed with chloroform (3 x 10 mL). The combined

organic layer was then washed with cold saturated sodium bicarbonate solution

(2 x 30 ml.) followed by water (2 x 50 mL). The filtrate together with the

chloroform washings \&/ere evaporated under vacuum to afford p-ketothiolesters

35 or 37 which were fi~rther purified by passing through a short column packed

with silicagel using hex.ane.

o o S-.Methvl-3-0x0-3-phenylpropanethiode (35a) cJJvu SCH, Pale yellow liquid; Yield: 1.9 g (97%). Spectral data has been previously reported."

C I O H I O ~ Z S

3% S - M e t h y l - 3 - 0 x 0 - 3 - 1 j - c h 2 o r o p h r n y l ) p r w (35b) p8 P

SCH3 Pale yellow liquid; Yield: 2. lg (!>5%), Spectral data has (.,, :5;' becn previously reported.27

C loH9C102S

35 h

>~-Methr~i-3-o~uo-3-(J-bromoph~~nyl)propunethoute (3%)

Pale qellou liquid; Yield: 2.4g (92%), Spectral data has

been prek lously reported."

S-Metl1j~l-3-o.uo-3-(4-methylpht~nyl)propanethioute (35d)

Pale yellow liquid; Yield: 1.5 g (88%), Spectral data has

been previously reported.27

S-Me/hvl-.~-oxo-3-(4-methoxyphen~~r)propanethioate (35e)

I'de yellow liquid; Yield: 1.8 g (91%), Spectral data has

been previously reported.27

S-Methvl-2-metl7yl-3-oxobutunethiote (37a) Pale yellow

liquid; Yield: 1.4 g (95%). 'HNMR (300 MHz, CDC1,)

6 = 1.38 (d, 3H. J = 7 HZ, CH3CH), 2.23 (s, 3H, SCH3),

2.15 (s. 3t1, CHI), 3.76 (q, IH, .I = 7 Hz, CH3CH); l3c NMR (75.47 MHz, CDC13) 6 = 11.70, 21.84, 28.12, 61.69,

196.80. 702.35 ppm.; EIMS mk (%) 146 (w, 15), 129

(2'7). 1 15 ( I 8). 97 (69) 83 (82),57 (88), 55 (100).

S-,bleth~~i-2-methyl-3-oxopentaunethiote (37b)

Pale yellow liquid, Yield: 1.5 g (96%). 'H NMR (300

MlIz, C'l)C'13) 6 .= 1.37 (t, 3H, J = 7 HZ. CH,CH2), 2.33

( d . j = 7 11z. 3H. CH?), 2.34 (s, 3H, SCH3), 2.57 (q, 2H, J

- 7 tIz. ('F/,CH3), 3.76 (q, 1 H, -1 = 7Hz, CH). I3C NMR

(75.47 Mfiz. (I'LICI,) 6 = 8.05, 12.32, 14.08, 35.12,

6 1.47, 198.42. 205.76 ppm. EIMS m/z (9'0) 160 (M', 22)

I3 1 (15). 1 13 (68). 104 (100). 75 (92), 57 (88).

H3C ; i

SCH,

.T-Mell7yi-2-eth,vl-3-oxohexanethioate (37c) Pale yellow

liquid: Yield: 1.7 g (96%). IR (neat) v,,,,icm-' = 1697,

1667. 1595, 1448, 1169, 955; 'H NMR (300 MHz,

CDCl;) 6 = 0.88 ( t , 3H, J = 7 Hz: CH,), 0.99 (t, 3H, J =

7 Hz, ('H,). 1.66 (m, 2H. CH,), 2.25 (m, 2H, CH2), 2.34

(t. 2H. Cff?). 2.37 (s, 3H, SCH,), 2.47 (t, lH, J = 7 Hz,

C'H). '-'c' NMR (75.47 MHz. CDCI,) 6 = 9.72 (SCH,),

13.46 ((7 I,). 13.96 (CH,), 20.14, 22.63, 40.16, 43.76,

199.1 I (c;lrbonyl) and 225.7 1 (carbonyl) ppm. EIMS

m/z (%t) I88 (M', 17), 187 (32), 158 (28), 129 (29), 115

(>!2), 99 (48), 85 (1 00).

S.-Met/??[-3-oxobufanethioate (37d)

Pale yello\v liquid; Yield: 1.2 g (95%), Spectral data has

bcen previously reported. 27

S-Mefh.vl-2-methyl-3-oxo-3-phenylpropanethioafe(37e)

Pale yellow liquid; Yield: 1.8 g (93%). IR (neat)

v,,,,,/crn~l - 1725, 1626, 1456, 851; 'H NMR (300 MHz,

C'I)Cl,) 6 .- 1.55 (d, 3H, J = 7Hz, CH3CH), 2.29 ( s , 3H,

SC:H3). 3.68 (q, IH, J = 7 Hz, CH,CH), 7.38-7.62 (m,

3M. aromatic), 7.99 (d, 2H. J = 7 Hz, aromatic); ')c NMR (75.47 MHz, CDCI,) 6 = 11.86, 13.72, 56.35,

128.01. 128.79. 131.24, 133.59, 194.87, 196.90 ppm.

EIMS m;z (%) 208 (M+, 8), 191 (12). 161 (25), 149 (7),

105 (100,.

.'~-Methyl--2-ucel).I-3-oxobutanetl~iote (37f)

Pale yellow liquid; Yield: 1.5 g (90%). 'H NMR (300

Mtlz. c1)('1,) 6 = 2.13 (s, 6H. CH,), 2.72 ( s , 3H,

!;C.H,). ELMS m/z (%) 175 (M' +I, 22). 143 (34), 101

199), 85 (25).

S L H , , ' I 2-Benzo.vl-3,3-6is(methylsulphanyl)acry/aldehyde 60

I 1 SLH)

ti yellow colored oil. Yield: 2.4 g (98%). Spectral data has c.,2fl,2t,2s2

ibeen previously rep~rted.~ '

60

3.5.2 General procedure for the dethioacetalization

l o the dithio;~cetal or dithioketal (10 mmol) dissolved in chloroform

(SO ml,). the bromine complexed resin (PVP-Br,), 40 mmol (7.5 g) was added

fc~llowed hq feu drops of water. The mixture was kept at 60 "C for 3 h with

occasional shaking. I'he reaction mixture was filtered and the reagent was

washed with chloroti)im (3 x 10 ml,). The combined organic layer was then

washed with cold saturated sodium bicarbonate solution (2 x 30 mL) followed

by water ( 3 x 50 mL). The filtrate together with the chloroform washings were

evaporated under vacuurrl to aftord the respective aldehydes or ketones which

were furthcr purified by passing through a short colunln packed with silicagel

using hexa~ic. l'he slsuctures of known compounds were confirmed by

comparing the analytical results with the reported values.

CI40

II i Benzrrldehyu'r 48a yield 8.5 g (85%), bp 66 "CI12'l o n (reported bp, 62 "Cil ~ ~ o r r ) . ' ~

CHO I ?

p-Chlorobenzaldehyde 48b yield 1.3 g (92%), mp J '

CI 46-48 "(' (reported mp 47 "c)." L7H5CI0

CHO I p-Mrtliorybenzaldehyde 48c yield 1.2 g (90%),

I H ~ C O bp 133-135 "CIl2Torr (reported hp, 134-135

CnH802 OC/l2 1

/I-.bfefhylhenzaldehy& 48d yield 1 g (87%), bp 113-1 15 "Cll2Torr (reported bp, 106"c'/I o? '~rr) . '~

Acerophenorze 48e yield 6.9 g (58%). bp 65- 67"C/5Torr (reported bp, 67"~:15~orr) . '~

p-Bromoacetophenone 48f yield 1.3 g (64%), mp 50-5 1 "C (reported mp 5 1-52 'c)."

3.5.3 Bromination ol'3., 3-bis (methylsu1fanyl)-1-aryl-2-propen-1-one

To an ice colti N-methylpyrrolidone (7 mL. 70.8 mmol), bromine

(10 mmol) was added and stirred well for 5 min. The appropriate

ketenedithioacetal (10 mrnol) was added to it and stirring continued for further

0.5 h, allowing the temperature to come to room temperature during this period.

The reaction mixture was then poured into ice-colt1 water, extracted with

diethyl ether. 'The organic phase was washed with saturated sodium bicarbonate

solution ant1 dried over arthydrous Na2S(14 Evaporation of the solvent afforded

the: crude product which was iurther purified by colunin chromatography over

silica gel using hexane ieth~yl: acetate (9: I ) as the eluent.

u SCH, propm-I-onr 61a was obtained from by the

I SCH3

BI reaction of 3. 3-bis (methylsulfanyl)-1-phenyl-2- L I , ~ I < B ~ O S ~ propen- I -one ( I0 mmol) with bromine as brown oil;

61a yield 2.9 g (97%). Spectral data has been previously

reported."'

Z-h1~o1no-3,3-hi,sfrwetii~~l ,\111f(~n.v/) -1-(4-chliro

phen1d)-2-pvopc~n-l-onr 61b \%as obtained by the

reaction of 3. 3-his (nielhyl sulfany1)-1-(4-chloro

phenyl-2-propen- l -one ( 10 mmol) with bromine as

pale yellow oil. Yield 3.2 (05V0). Spectral data has

been previou!;ly reported."

2-brorno-3, 3-his irneti11.1 suIfnnyl)-1-(4-bromo-

phenj>l)-2-propen-1-one 6 l c was obtained by the

reaction of 3. i -h i s (methylsulfany1)-1-(4-bromo

phenyl)-2-propen- I -one ( 10 nimol) as pale brown

oil. Yield 3.'7 g (98%). Spectral data has been

previously reported."'

2-bromo-3, 3-bis ln1ethj.l sltlftmnj1)- 1-{&methyl

phenyli-2-pro~?ej?-I-one 61d was obtained by the

reaction of 3, li-bsis (methll sulfany1)-I-(4-methyl

pheny I-2-propen-. 1 -one ( I 0 mmol) with bromine as

pale yellow oil. Yield 2.9 g (02%). Spectral data

has been previou:;ly reported."-

2-hromo-3, 3 bis(rnrth~:l szc(fiinv1)-I-(4-rnethoxy

phen.vli-2-propen- /-one 61 e was obtained by the

reaction of 3. 3-bis (methyl sulf'anyl)-I -(4-methoxy

phenyl)-2-propen- 1 -one ( I 0 rnrnol) with bromine as

brown oil. Yield ?; g (90%). Spectral data has been

previously reported."'

1 -hromo- 1-(1,3-d~thiolaw-2~~1iir'eni- 1-phenyl-1-

ethanone 63a .iva; obtained h> the reaction of (1.3-

dithiolan-2-yliden)- I-phenyl- l -ethanonc: (1 0 mmol)

with bromine a.; pale bronn oil. Yield 2.7 g (92%)

EIMS: (nilz, %) = :i02(m". 14). 300 (m+ 14) 272 (6).

224 (16). 196 (18). 105 (100).

2-h1~o1no-2-(1.3-dithiolan-2-yliden)-1-(4-chloro

pheny1)-I-ethanone 63b was obtained by the

reaction of (1,3-dithiolan-2-yliden)-I-(4-chloro

pheny1)-1-ethanone (10 mmol) with bromine as pale

yellow oil. Yield 3.1 g (94%). EIMS (m/z, %) =

336 (n1+2. 32). 334 (m+, 20). 3 10 (6). 308 (16), 306

(IS). 256 (lo), 226 (6), 228(6), 222 (20), 224(27),

197 (8). 139 (89), 113 (32), 1 1 1 (100).

I-hromo-I-(l,3-dithiolan-2-yliden)-I-(4-methyl

phenv1)- I-ethanone 63c was obtained by the reaction of

(1,3-dithiolm-2-yliden)- 1 -(4-methyl pheny1)- l-

ethmone (1 0 mmol) with bromine as pale brown oil.

Yield 2.8 g (90%). EIMS: (m'z, %) 3 16 (m+2, 16),

314 (m+, 16), 288 (12), 236 (23), 208 (21), 210 (7),

1l9i91).91(100).

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