reactions of polyvinyl and n-methyl pyrrolidone...
TRANSCRIPT
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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