PARTIAL HYDROLYSIS OF ~ h r j ~ t e r 3

3.1 Introduction Ketenedithioacetal functionality can be considered as synthetic equivalent of a

carboxylic acid ester or a thiolester. a-Oxoketenedithioacetals have attracted

considerable interest as versatile multifunctional synthons in the past couple of

decades.' Some of their transformations involve initial addition of a nucleophile to the

carbonyl group resulting in the formation of an intermediate having a ketenedithioacetal

group, which can be subsequently converted to esters or thiolesters under appropriate

conditions. This is exemplified by the reductive or alkylative carbonyl group

transposition of a-oxoketenedithioacetals leading to the formation of a,P-unsaturated

esters and thiolesters* Simple ketenedithioacetals are transformed into the respective

thiolesters under acid catalyzed hydro lys i s .~hough ketenedithioacetals undergo partial

hydrolysis to thiolesters under acid catalyzed conditions in the presence of mercury

salts, a convenient procedure for the direct conversion of a-oxoketenedithioacetals to

P-oxothiolesters is still lacking. However, complete solvolysis of a-

oxoketenedithioacetals to the respective P-ketoesters have been reportedJ The

alkenoyl ketenedithioacetals also could be converted to the respective y,&unsaturated

p-ketoesters by boron trifluoride etherate catalyzed methanolysis in the presence of

mercuric salts.'

3.2 f3-Oxothiolcarboxylates: Synthesis and Reactions

Thiolesters are known to be important intermediates in organic synthesis. They

are also used by nature in enzymatic acylation process. Reactions involving enolates

derived from thiolesters find applications in biomimetical synthesis of several complex

natural products.6 P-Oxothiolesters have got a distinct advantage over simple thiolesters

as synthones owing to the presence of multiple reactive sites. Inspite of the wide utility

of P-oxothiolcarboxylates in organic synthesis, there are only limited methods available

in the literature for their synthesis.

3.2.1 j3-Oxothiolcarboxylates: Synthesis

In 1929 Baker and ~ e i d ' prepared ethylacetothiolacetate 2 by the self-

condensation of ethylthiolacetate 1 in presence of sodium. However, this method gave

only a low yield of the thiolester. Later this condensation was improved by Wall and co-

workers8 using isopropylmagnesium bromide as the base to afford the p-oxothiolester 2

in a better yield (Schemel).

1 2

Scheme 1

Wilson and ~ e s s ~ have studied the Claisen condensation of aliphatic thiolesters

under different conditions and have shown that best results could be obtained when

rnagnesiun bases such as isopropyl magnesium chloride or magnesium chloroethyl

mercaptide was used as the base (Scheme 2)

3 4

Scheme 2

However, this method has limited practical utility as a method for the

preparation of P-oxothiolesters, since thiolesters do not undergo clean cross Claisen

condensations. Liu and co-workers1\hae studied the thiolester version of Dieckmann

condensation for preparing cyclic (I-ketoesters. They have used sodium hydride as the

base in DME, in the presence of ethanediol as a catalyst (Scheme 3).

'KH2$sR

NaH. ethanedml(cataLL

RS DME

Scheme 3

The addition of sodium 1-butyl mercaptide to diketene 8 has been shown to be a

usefhl method for preparing 1-butyl thiolester 9 by Ley et a1 (Scheme 4).12

7 8 9

Scheme 4

P-Ketothiolesters are also formed by the condensation of malonic or methyl

malonic half thiolester I 1 with imidazolidines 10 derived from carboxylic acids (Scheme

5)12

11

Scheme 5

(3-Ketothiolesters are also formed by the addition of enolates derived from

ketones to acylating agents such as S,S-dimethyl dithiocarbonate 14 (Scheme 6) ' '

Scheme 6

Ley and woodward15 have reported the synthesis of y,&-unsaturated B- ketothiolesters 18 by the Wittig-Horner reaction of t-butyl-4-diethylphosphono-3-

oxobutanethioate 17 with carbonyl compounds. An illustrative example is shown in

Scheme 7. The 3-0x0-diethyl phosphonobutanethioate 17 was prepared from the 4-

brom-3-0x0-obutanethiote16 obtained by the bromination (3-oxothiolesters derived from

diketenel' or meldrums acid1"

NaH (2 eq.) THF -

/ SBU'

Scheme 7

3.2.2 P-Oxothiolcarboxylates: Reactions

I)-Ketotiiioicste~s resemble fi-ketocsters in reactivity. One advantage of P- ketothiolesters, which promises wide synthetic application.'x is the relative ease of

removal of the thiolester group. The reductive removal of alkylthio group from P- ketothiolesters leading to the formation of respective aldehydes could be achieved by

treatment with Raney Nickel under neutral conditions.'' Like P-ketoesters alkylation or

acylation reactions of P-ketothiolesters are also possible involving the anions or the

dianions20 Alkylation at the a-position was achieved by deprotonation with sodium

hydride in DME followed by treatment with alkyl halide (Scheme 8). For the alkylation

at they- position, a combination of sodium hydride and butyl lithium is used (Scheme 9).

Scheme 8

21 22

Scheme 9

P-Ketothiolesters could be transesterified with the help of thiophilic catalysts.

Thus, in the presence of silver(l)trifluoroacetate, P-ketothiolesters undergo rapid

transesterification with amines2' or a l c o h ~ l s . ~ " ~ ~ ~ . ~ ~ ' rransesterification with amines leads

to P-ketoamides (Scheme 10). This method provides an excellent alternative access to

P-ketoamides in view of the difficulties associated with their preparation from P- kctoesters."

24

Scheme 10

Transesterification with 2-hydroxy esters followed by Dieckmann cyclisation

provides a direct route to acyl tetronicacid derivatives, 27 that are present in a number

of biologically active natural products (Scheme 11). 22

Scheme 11

Selective alkylation through dianions coupled with the advantage of

transesterification could be effectively used for the synthesis of a number of P-keto

macro~ides.'~ For example, the dianion generated from I-butyl acetothiolacetate when

allowed to react with 1-butyl dimethylsilyl protected iodoalkanols, the corresponding y-

alkylated products were obtained. Subsequent transesterification in the presence of

copper(1)trifluoroacetate afforded the macrolide 29 (Scheme 12).

28 29

i NaH,DME; ii. nBuLi; iii. I(CH2),0TBDMS; i a HF, 1. CuOCOCF3, CH2CI*

Scheme 12

A number of naturally occurring pigments have also been synthesized by

employing the multiple reactivity of P-oxothiolcarboxylates. For instance, the naturally

occurring fuligorubin A, 33, have been synthesized starting from t-butyl-4-

diethylphosphono-3-oxobutane thioate 30 (Scheme 13).27

NaH(2.l eq.). m oOc LBu S

Scheme 13

A few examples discussed here highlight the potential of 13-oxothiolesters as

useful synthetic intermediates in organic synthesis. A more general method for the

synthesis of P-oxothiolesters would expedite hrther studies on their applications in

organic synthesis.

3.3 Results and Discussion We have first treated functionalized ketenedithioacetals with protic acids in non-

nucleophilic solvents expecting the formation of corresponding thiolesters. Though the

formation of partially hydrolyzed products could be observed on TLC, good yields of

thiolesters could not be obtained under these conditions. Later we have examined

various Lewis acids in non-nucleophilic solvents. Boron trifluoride etherate in dioxane

gave clean conversion of a-oxoketenedithioacetals to 13-oxothiolesters in good yields

3.3.1 Boron Trifluoride Assisted Partial Hydrolysis of a-Oxoketenedithioacetals

Aroyl ketenedithioacetals prepared from substituted acetophenones were

allowed to react in the presence of boron trifluoride etherate in refluxing

dimethoxyethane (DME). The ketenedithioacetal prepared from [I-chloroacetophenone

34a was treated with one equivalent of boron tritluoride etherate in DME at refluxing

temperature for three hours. The reaction mixture was poured over saturated sodiim

bicarbonate solution and extracted with dichloromethane. The residue obtained after the

removal of solvent from the organic layer was chromatographed to give S-methyl p-

chlorobenzoyl thiolacetate 35a as a crystalline solid of mp 86-87 'C in 67% yield.

(Scheme 14).

34a 35a

Scheme 14

Among other solvents examined for this transformation, dioxane gave better yields

of the product. When this reaction was carried out in refluxing dioxane for 1 5 h , .90%

of the thiolester 35a was obtained after a similar work up and purification by silicagel

chromatography (Scheme 15). The S-methyl /I-chlorobenzoyl thiolacetate 35a was

characterised by spectral data. Proton NMR spectmm of 35a shows that this compound

exists mostly in enol form (90 MHz, CDCI3. Figure 1). The enol moiety, hydrogen

bonded to the carbonyl group, shows its signal at 6 13.18 ppm. The vinylic proton

comes at 6 6.08 ppm. The two doublets centred at 6 7.36 and 7.71 with coupling

constants 9Hz are due to the aromatic protons.

Figure 1 'H NMR (90 MHz, CL)C13)Spectrum of Compound 35a

The "C NMR spectrum of 35a (22.4 MHz, CDCI:, Figure 2) also shows that the

compound exists mostly in the enol form. The peak at 6 194.84 ppm is due to the

carbonyl carbon and the one at 6 166.89 ppm is due to the hydrogen bonded enol

carbon. Signal due to the tnethylthio group appears at 6 1088ppm. A small peak at

61 1 8 7 ppni could be due to the methylthio group of the keto form. The peak at 53.37

ppm is due to the methylene carbon of the keto form. The vinylic carbon showed its

signal at 6 96.84 ppm. Other signals due to the aromatic carbons in the l3c NMR were

at 6 127.39, 128.58, 129.92, 131.00, and 137.44ppm.

Figure 2 "C NMR(22.4 MHz, CDCIJ Spectrum of Compound 3%

The mass spectrum of 35a (EIMS. Fig. 3) shows tnolecular ion peak at m/z 228.

The base peak was at mlz 139, which is due to [CIC6H4COI4. Other important peaks are

18 1 [due to CIC6&COCH2CO+] and I I1 [due to CIC6H4'].

The 1R (KBr) spectrum 35a (Figure 4) shows carbonyl stretching at 1680 and 1625

cm". Other important absorptions in the IR spectrum were at v 1560, 1535, 1480(C=C),

1440, 1390, and 1210 cm-'.

Figure 3 EIMS of Compound 35a

Figure 4 IR (KBr) Spectrunl of Compound 35u

Other substituted benzoyl ketenedithioacetals 34h-e also gave the respective P- oxothiolesters 35h-e in moderate to good yields (Scheme 15). All products were

characterised with the help of spectral data. (See experimental)

Scheme 15

34,35

a

b

c

d

e

The ketenedithioacetal prepared from acyl heterocycles also gave P- ketothiolesters under these conditions. Thus, the ketenedithioaceatal36, derived from 2-

acetyl thiophene, gave the corresponding P-ketothiolester 37 in 48% yield, on treatment

with boron trifluoride etherate in refluxing dioxane for 4 h, as a pale yellow liquid

(Scheme 16).

R Yield (%) Keto:Enol

CI 90 5:95

H 52 47:53

Br 5 9 50:50

CH; 5 8 65:35

OCH3 48 75:25

Scheme 16

The thiolester 37 exists as a mixture of keto and enol tautomers in the ratio

93:07 in CDCI, as shown by the proton NMR spectrum (Figure 5). In the proton NMR

(400 MHz, CDCI,) spectrum, the methylene group comes in resonance at S 4.15 ppm.

The weak signal at 6 5.92 ppm is due to the vinylic proton of the enol form. The signal

at 6 2.22 ppm is due to the methylthio group of the enol form and the signal at 6 2.29 is

due to the methylthjo group of the keto form. The aromatic protons of the thiophene

ring (keto form) appeared as three multiplets between 6 7.03 and 7.08 ppm. 6 7.58 and

7.62 ppm and 6 7.67 and 778ppm.

Figure 5 ' H NMR(4OO MHz, CDC13) Spectrum of Compound 37

The methylene carbon of the keto form comes at 6 54.14 ppm in the "C NMR

spectrum (100.4 MHz, CDCI?. Figure 6). The peaks corresponding to the carbonyl

carbons come at 184.04 and 191.66 ppm. "C NMR also shows the presence of the enol

form as inferred from the peak at 9588ppm, due to the vinylic carbon. The signal at 6 =

11.97 is due to the methylthio group. The peaks due to aromatic carbons of the keto

form appears at 6 128.24, 133.73, 135.15, and 142.95 ppm. The weak peaks present at

6 163.33, 136.41, 130.11, 128.57, 128 0 ppm were due to the enol form.

Figure 6 13C NMR (1 00.4 MHz, CDC13) Spectrum of Compound 3 7

The major absorption bands in the IR (neat) spectrum are at 1650, 1615(C=0),

1540, 1420(C=C), and 1255 cm".

The a-oxoketenedithioacetals derived from cyclic ketones also underwent facile

partial hydrolysis. The ketene dithioacetal 38 derived from a-tetralone gave the

corresponding thiolester 39 in 97% yield (Scheme 17). This was isolated as a pale

yellow solid with melting point 56-58 'C and the structure was confirmed with help of

spectral data.

Scheme 17

The proton NMR spectrum of 39 (90 MHz, Figure 7) shows that the thiolester

39 exists mostly as the en01 tautomer. It exhibits a sharp singlet in the NMR spectrum at

6 13.4 pprn due to the hydroxy group of the enol form. The methylthio group comes as

a singlet at 6 2.3 pprn The methylene protons show a multiplet between 6 2.41 and 6

2.75 ppm. The aromatic protons show two multiplets, one between 6 7.08 and 7.35 pprn

(3H) and the other between 6 7.72 and 7.90 pprn (IH).

Figure 7 'H NMR (90 MHz, CDC13) Spectrum of Compound 39

The 13c NMR spectrum of 39 (22.4 MHz. CDC13, Figure 8) shows the carbonyl

carbon at 6 196.10 ppm. The carbon at the enolised carbonyl group appears at 6 162.59

ppm. The vinylic carbon shows a signal at 6 105.52 pprn The keto form is also present

in small amounts as inferred from the peak at 6 6 1.2 1 pprn due to the methyne carbon of

the keto form. Other peaks due to the enol form were present at 6 21.29, 27.62(CH~),

124.91. 126.52, 127.15, and 130.76(arom) ppm.

The mass spectrum of 39 (Figure 9) shows the molecular ion peak at m/z 220.

The peak at m/z 173 is the base peak, which is due to [ C I I H ~ O ~ ] ' . Other prominent

peaks are at mlz 145 (due to [C~OH~O] ' ) , 115 and 105.

IR spectrum of 39 (Figure 10) shows the OH stretching at 3450cm.'. The

carbonyl stretching bands are present at 1680 and 1610 cm-'. Other prominent

absorbtions were at 1550, 1455(C=C), 1250, and 1 110 cm-'.

Figure 8 ''c NMR (22.4 MHz, CDCIJ) Spectrum of Compound 39

Figure 9 EIMS of C.bmpound 39

Figure 10 ZR (KBr) of Compound 39

Ketenedithioacetals prepared from aliphatic cyclic ketones also gave

corresponding thiolesters in good yields. When the ketenedithioacetal prepared from

cyclohexanone 40 was allowed to react with borontrifluoride in dioxane at room

temperature the S-methyl cyclohexanone-2-thiolcarboxylate 41 was isolated as a pale

yellow liquid in 64% yield (Scheme 18). The NMR spectrum shows that the compound

exists in the enol form

Scheme 18

The acyl ketenedithioacetals prepared from aliphatic acyclic ketones also

underwent partial hydrolysis leading to the formation of thiolesters effectively even at ,

room temperature. However, the reaction was not clean at reflux temperature and the

product mixture showed several spots on TLC. Thus, the acyl ketenedithioacetal 42

prepared from acetone gave S-methyl-3-oxobutanethioate 43 in 35% yield on treatment

with boron trifluoride etherate in dioxane at room temperature for 5.5 h (Scheme 19)

BF,.Et20.Dmme

SMe

42 43

Scheme 19

The enolate anions generated from acyl ketenedithioacetals on treatment with

strong bases undergo addition to aromatic aldehydes and this provides a convenient

method for the synthesis of cinnamoyl ketenedithioacetals. Synthetic applications of

these cinnamoyl ketenedithioacetals including cyclisation to cyclopentanoids and

cycloaromatisation reactions have been studied in detail by Junjappa and c o - w ~ r k e r s . ~ ~

Their utilization in the synthesis of polyenesters by carbonyl group transposition

reactions has also been well explored.29

We have also studied the reaction of cinnamoyl ketenedithioacetal 44a, prepared

by the Claisen-Schmidt condensation of the ketenedithioacetal derived from acetone and

benzaldehyde, with boron trifluoride etherate in refluxing dioxane. The

ketenedithioacetal 44a was treated with one equivalent of boron trifluoride etherate in

dioxane. The reaction mixture was refluxed for 2 h and was poured into cold water after

cooling. Neutralized with saturated sodium bicarbonate solution and extracted with

dichloromethane. The residue obtained after the evaporation of the solvent from the

organic layer was column chromatographed over silicagel to afford the y,6-unsaturated

P-oxothiolester 45a in 87% yield. Further purification by recrystalization from methanol

gave an yellow crystalline product with melting point 56-58 "C

The proton NMR spectrum of 45a shows that it exists as a mixture of keto and

enol tautomers in the ratio 25:75. The enolic OH exhibits a singlet at 6 12.52 ppm in the

proton NMR spectrum (90 MHz, CDCI?, Figure l I). The singlet at 6 2.35 ppm is due to

the methylthio group. The methylene protons of the keto form show the signal at 6 3.91

ppm as a singlet. The vinylic proton (C-4) of the enol form appears as a doublet centred

at 6 6.40 pprn (16 Hz). The vinylic proton (C-4) of the keto form also gave a doublet at

6 6.78 pprn (16 Hz). The singlet at 5.6 pprn is due to the vinylic proton (C-2) of the enol

form. The aromatic protons along with the vinylic protons of C-5 appear as a multiplet

between 6 7.18-7.63 ppm.

I I 1

Figure 11 ' H NMR(90 MHz, CIICIj) Spectrum of Compound 45a

The 13c NMR spectrum of 45a (22.4 MHz, cDc1.1, Figure 12) shows signals

due to three carbonyl groups at 6 190.70, 191.92 and 194.37 pprn The peak at 6

194.37 pprn is due to the carbonyl carbon of the enol form. Other two peaks, one at 6

190.70 pprn and the other at 6 191.92 pprn were due to the carbonyl groups of the keto

form The C-3 of the enol form appears at 6 165.96 ppm. While the a-carbon appears at

6 101.10 ppm. Thile the peak due to the methylene group of the keto form appears at 6

55.33 ppm. The signal at 6 10.64 pprn is due to the methylthio group corresponding to

the enol form while that at 6 11 75ppm is due to that of the keto form. Other peaks in

the "C NMR spectrum are at 6 120.97, 124.73, 127.36, 128.25, 128.49, 128.61,

129.24, 130.58, 133.71, 134.85, 138.13 and 144.57 ppm corresponding to aromatic and

the vinylic carbons of keto and enol forms.

~ m n ~ ~ ~ n ~ i r j r n n ~ ~ ~ ~ n ~ ~ ~ ~ ~ ! ~ n n n p n ~ ~ ~ n ~ ~ m m j m n ~ r q m n n ~ ~ m n ~ q m ~ ~ n ~ ~ ~ 0 :.10 :30 ::C ::C 102 30 Rc7

Figure 12 "C NMR(22.4 MHz, CDCII) Spectrunr of Compound 45a

The molecular ion peak in the mass spectrum of 45a (Figure 13) is present at

d z 220 and the base peak at mlz 13 1 is due to [PhCH=CHCO]'. Other important

peaks in the mass spectrum are at d z 173 due to [PhCH=CHCOCH2CO]', and at d z

103 due to [PhCH=CH]'. IR spectrum of 45a (Figure 14) shows carbonyl stretching at

1635 cm.' Other major absorptions are at 3400 (OH), 1580, 1440, 1415(C=C), 1260,

1 170, and 1080 cm-I.

Cinnamoyl ketenedithioacetals 44b-e, prepared by the Claisen-Schimdt

condensation reaction of substituted benzaldehydes with acyl ketenedithioacetals, were

also allowed to react with boron trifluoride etherate under the above conditions and the

respective y,6-unsaturated thiolesters 45b-e were isolated in good yields (Scheme 20).

All products were characterised with help of spectral data (See the experimental

section).

Scheme 20

44,45

a

b

c

d

e

Figure 13 EIMS of Compounrl45a

R' R' Yield (%) Keto:Enol

H H 87 25:75

CI H 92 5:95

OCHz H 70 50:50

NO2 H 65 5:95

H CH? 67 5:95

Figure 14 IR (KHr) Spectrum of Conipound 45a

Thiophene-2-carboxaldehyde was also subjected to Claisen-Schmidt

condensation with the ketenedithioacetal derived from acetone and the alkenoyl

ketenedithioacetal 46 thus obtained under the above conditions afforded the

corresponding y.6-unsaturated P-ketothiolester 47 as an yellow crystalline solid with

melting point 62-63 O C , in 90% yield (Scheme 21). Spectral data of the compound are

given in the experimental section. Spectral data show that the compound exists mainly

in the en01 form.

SMe

:?::>@ SMe

Scheme 21

The reaction was also carried out using the polyenoyl ketenedithioacetal 48. The

ketene dithioacetal 48 was prepared by the Claisen-Schmidt condensation of the 5-

phenyl-2.4-pentadienaldehyde with acyl ketenedithioacetal Partial hydrolysis of the

polyenoyl ketenedithioacetal gave the D-ketothiolester 49 in 88% yield as orange yellow

crystals with melting point 108-1 10 "C (Scheme 22).

Scheme 22

The thiolester 49 exists in the en01 form as seen from the NMR spectrum (300

MHz, CDCI,, Figure 15). The singlet due to the enol OH appears at 6 12.33 ppm in the

proton NMR spectrum and the signal due to the vinylic proton (C-2) appears as a

singlet at 6 5.43 ppm. The methylthio group shows the singlet at 6 2.29 ppm and the

vinylic proton at the a-carbon of the enol form appears as a doublet at 6 5.74 ppm with

a coupling constant of 15Hz The remaining vinylic protons together with the aromatic

protons come as two multiplets between 6 6.30-6.84 ppm and between 6 7.10-7.36 ppm

The "C NMR spectrum of 49 (75.47 MHz. CDC12, Figure 16) shows trace

amounts of keto form as obvious from ;I low intensity peak at 6 54.82 ppm which is

due to the methylene carbon. The a-carbon of the enol form comes at 6 10015ppm.

The peak at 6 10.02 ppm is due to the methylthio group. The carbonyl group comes at

193.54, and the enolised carbonyl group shows the signal at 6 165.37 ppm. Other peaks

in the "C NMR spectrum due to the enol form are at 6 125.72, 127.34, 127.71, 127.08,

134.97, 138.23, and 142.36 ppm which are due to the vinylic and aromatic. carbons.

- Figure 15 'H ~ ~ ~ ( 3 0 0 MHz, CCnCIj) Spectrum of Compound 49

1 - 1 Figure 16 "C NMR (75.4 MHz, CI)CIJ)) Spectrum of Compound 49

Two small peaks at 6 190 01 and 6 19 I 57 ppm were due to the carbonyl groups of the

keto form

The IR spectrum of 49 (Figure 17) shows the carbonyl stretching at 1625 cm-'.

Other prominent absorptions are at 3500(OH, enol), 1600, 1565, 1550(C=C), 1400,

1080, and I000 cm".

, ".(, 0 I

p

, : ,

i 1 I i

i i ! !

' i ! '

1.. .~ . . - . . . . . . .~ ~ . . ~ . . . .

: 8 , 5 1 , 1 ' . L ,

Figure 17 IR (KBr) Spectrunl of Compound 49

The acid catalysed partial hydrolysis of ketenedithioacetals involves partially

reversible protonation of the carbon-carbon double bond followed by hydration of the

intermediate dithiocarbocation 51 (Scheme 23)"

53

Scheme 23

Partial hydrolysis of a-oxoketenedithioacetals in the presence of boron

trifluoride would probably involve an intermediate charge transfer complex 54

Hydration of this complex during the workup followed by loss of methylthio group

would result in the formation P-oxodithioester (Scheme 24)

55

Scheme 24

The results described above show that Lewis acids such as boron trifluoride

etherate in a moderately polar non nucleophilic solvent like dioxane is an efficient

combination for the partial hydrolysis of a-oxoketenedithioacetals to P-ketothiolesters.

Ketenedithioacetals prepared from aromatic, aliphatic, and cyclic ketones could be thus

effectively transformed to the respective thiolesters. Cinnarnoyl ketenedithioacetals also

react smoothly under these conditions giving excellent yields of y,6-unsaturated P- ketothiolesters. Extension of this methodology to polyenoyl ketenedithioacetals lead to

the formation of S-methyl polyenoyl thiolacetates.

3. 3. 2 Poiy (N-vinylpyrro1idone)-Bromine Complex: A Polymer Supported

Reagent for Effective Partial Hydrolysis of Functionalized

Ketenedithioacetals

Polymer supported reagents suitable for single step reactions have been

developed for use in organic synthesis3' A large number of such functionalized

polymers are now in use as catalysts or as reagents in conventional organic

transformations. The advantages of polymer supported reagents to traditional organic

reagents are that they may be used in excess to ensure complete transformation. In

addition, the product contamination by reagents could also be avoided and the spent

resin may be recycled. Finally, the product purification is also simplified in reactions

involving polymeric reagents as the reagents may be removed by simple filtration.

Polymeric peracids.32 and polymer supported chromium(V1)reagents~ have been

used to canyout oxidation of organic molecules. For instance, a number of Cr (111) and

Ce (1V) catalysts 57 anchored on to the commercially available Nafion 5 1 1 are used for

the oxidation of alcohols to the respective ketones.'"

X= Cr ( I l l ) or Ce (IV)

Sherrington has developed a polyilnide supported molybdenum ( 1 ~ ) " 59 which

has been. found useful as a catalyst for the epoxidation of alkenes. For example.

epoxidation of cyclohexene with 1-BuOOH in the presence of this catalyst affords

cylohexeneoxide 60 (Scheme 25).

Scheme 25

Another example involves the application of a polystyrene bound tin halide 60 in

the sodium borohydride assisted reductive removal of halogen from alkyl halides. It has

been shown that this reaction proceeds with high efficiency in the case of a number of

alkyl halides.36

61

A polystyrene supported organotinhydride species 62 have been developed by

~ e w r n a n n ~ ~ . ' ~ and co-workers to carrp out dehalogenations, dehydroxylations and

deaminations in free radical chemistry.

Bu

CH2-CH2-Sn-H I

Bu

62

Polymer bound catalysts are used to carry out cross aldol reactions between

acetals or aldehydes with silyl enolethers. For example, a polymer bound trityl

perchlorate39 63 is used widely as a catalyst in Mukiyama aldol reactions to afford the

adducts in very good yields.

~ o z u m i ~ ~ and co-workers have used a polymer bound palladium complex as a

catalyst for the allylic substitution of allyl acetates. In addition, polymer supported N-

haloamides and imides have been used for the oxidation of a ~ c o h o ~ s . ~ ~ ~ ~ ~ ~ ~ ' Another

application involves halogenation of organic molecules either by nucleophilic

displacement or by electrophilic addition. For example, bromination of ketones and

alkenes in excellent yields by poly (vinylpyridinium hydrobromideperbromide) resins has

been reported.u

Polymer supported reagents are being extensively used in organic

reactions. 45.46.47.48 A large variety of polymer bound reagents have been developed for

oxidation such as polyvinyl pyridine N-oxide supported dichromateJ9 and polyvinyl

pyridine bound silver d i c h r ~ m a t e . ~ ~ Resin bound reducing agents have been developed

for use in a number of reduction r e a c t i ~ n s . ~ ' . ~ ~ Reports on the reduction of organic

compounds with polymer supported reagents include reductive cleavage of disulfides to

thio~s, '~ use of alumina supported materials for reduction of alkenes and ketone^,'^ and

various reductions brought about by polymer supported metal hydrides."

64

The polymer supported tetra-alkyl ammonium borohydride 64 has been used as a

reagent for the reduction of acyl azides, a q l sulfonyl azidess6 and conjugated olefinic

bond^.^'.^' Polymer bound reagents have also been prepared to carry out a number of

other synthetic reactions. For example, functionalized polymeric reagents are known to

take part in Wittig reaction with aldehydes and ketoness" A few examples of polymer

bound phosphonium salts (65, 66, and 67) from which Wittig reagents can be generated

are shown below.

Recently Grela et a/. have reported the application of immobilized sodium on

polyethylene or polypropylene in acyloin condensations.'" In addition, chloroacetone

have been converted to 0-oxoalkyl (acetonyl) esters by the reaction with polymer

bound carboxylates such as 68 6'

Examples for the application of polymer bound reagents in halogenation

reactions involve the use of poly-4-vinylpyridiniumpoly(hydrogenfluoride) for

hydrofluorination and bromofluorination of alkenes and alkynes.62 Polymer bound

brominating agents are also reported, for instance, brominated or chlorinated resins (69

and 70 respectively) prepared from crosslinked co-polystyrene-4-vinyl benzene(N-hexyl

pyridinium bromide) was found to be useful for the regeoselective bromination of

substituted ben~enes.~ '

69 70

Koshy and Pillai have recently demonstrated that a complex of bromine and

crosslinked poly-N-vinyl pyrrolidone is an efficient and selective reagent for the

bromination and oxidation of a variety of substrate^.^' They have used this resin for the

double bond addition of bromine to unsaturated compounds. The reactivity of these 65

resins were comparable to 2-pyrrolidone hydrotribromide (PHT) or poly(4-

vinylpyridinium bromide perbromide)."J

A co-polymer of 4-vinyl pyridine and N-vinyl pyrrolidone crosslinked with 1,6-

hexanedioldiacrylate (HDODA) forms a complex with bromine. This complex has been

shown to be an excellent reagent for oxidization and halogenation reactions depending

on the reaction conditions."" We have studied the reactivity of this resin with a-0x0

ketenedithioacetals expecting the bromination of the a carbon atom. Similar bromination

of a-oxoketenedithioacetals has been reported with N-bromosuccinimide6' When the

ketenedithioacetal derived from acetone was treated with the brominated resin, we could

isolate only the thiolester instead of the expected brominated product. Thus, the a-

oxoketenedithioacetal 34a. prepared from p-chloroacetophenone in chloroform was

treated with four equivalents of the resin at 60 "C for 2-4 h with occasional shaking.

When the reaction was completed. as indicated by the TLC, the reaction mixture was

cooled and filtered. The resin was washed several times with chloroform and the filtrate

together with the chloroform washings was evaporated under vacuum. The crude P- ketothiolester was purified by passing through a short column packed with silcagel using

hexanelethyl acetate as the eluent to afford the thiolester 35a in 93% yield. The reaction

was found to be general for other substituted benzoyl ketenedithioacetals 35 b-e as well

(Scheme 26).

S C H s o SCH3 R 60Oc R

CH,

Scheme 26

34 35

Other ketenedithioactels derived froin 2-acetyl thiophene 36, cyclic ketones like

tetralone 38 and cyclohexanone 40 and aliphatic ketones like acetone 42 also reacted

smoothly giving the corresponding p-oxothiolesters in good yields (Scheme 27).

34,35 R Yield (%)

Product I R' R2 Yield (%)

Scheme 27

The reaction proceeds effectively with alkenoyl ketenedithioacetals as well. For

instance, the substituted cinnamoyl ketenedithioacetal 44c prepared by the condensation

of 4-methoxybenzaldehyde with acyl ketenedithioacetal was also treated with the resin

under the above conditions. The respective y,&unsaturated (J-oxodithioester 45c was

isolated in 87% yield (Scheme 28).

Scheme 28

Poly-N-vinyl pyrrolidone and poly-4-vinyl pyridine bromine complexes are

known to be reagents suitable for bromination of olefins and alkynes. They also effect

side chain allylic bromination. These polymer supported reagents are in fact charge-

transfer complexes of bromine with pyridine or pyrrolidone. The bromination using

polymer supported reagents are slower and hence more selective compared to the direct

bromination.

In the present case. it is not very clear, why the a-oxoketenedithioacetal did not

undergo a bromination at the a-carbon atom. Since the reaction is carried out in the

presence of water, activation of the P-position of the ketenedithioacetal by complexation

with either the pyridine-bromine complex or the pyrrolidone-bromine complex via the

intermediates 71 or 72 respectively would result in the addition of H 2 0 to the P-carbon

leading to the formation of !3-oxothiolester, after subsequent elimination of MeSH.

SMe SMe Me s'

The above method developed for the partial hydrolysis of ketenedithioacetals

using polymer supported reagents has many advantages over other procedures including

the boron trifluoride etherate assisted solvolysis described in the previous section. The

yield of the thiolester obtained is far better when the reaction was carried out using the

polymeric reagent. For example in the case of aliphatic systems like acetone, the yield

obtained in BF? assisted solvolysis was only 35% and the reaction mixture was

contaminated with several unidentified products. Nevertheless, when the corresponding

reaction was carried out using the polymer reagent, the thiolester was isolated in 98%

yield. In addition, it is to be noted that the reaction was very clean and the thiolester

was the only product formed. The reaction workup procedure needed just a filtration

and washing of the polymer reagent. Since the thiolester was formed as the only single

product, the product purification required just passing through a short column packed

with silica gel.

3.3.3 a-Oxoketenedithioacetals on Polymer Support

Combinatorial organic synthesis has emerged as an alternative to the traditional

synthetic methods to prepare large number of organic compounds in a short time span to

discover leads for specific purposes by employing fast screening techn~logies.~"he

development of strategies for the synthesis of heterocyclic compounds of potential

biological activity on the solid phase has developed as a thrust area in contemporary

scientific research owing to their importance in medicinal chemistry. Several synthetic

intermediates have been attached to polymer supports and their further manipulations

have resulted in the discovery of a number of heterocyclic compounds, which were

screened for their pharmacological activities '' For example, imines are a class of

intermediates used vastly in organic synthesis and their cycloaddition, condensation and

nucleophilic addition reactions are well studied. The attachment of imine functionality to

a polymer support involves the condensation of an aldehyde with a resin bound amine or

amino acid. This resin bound imine have been used for the synthesis of a variety of

heterocyclic libraries. 70.71.72 For instance, the resin bound amino acid 73 on condensation

with aromatic and heteroaromatic aldehydes afford the resin bound aryl imine 74. The

[3+2] cycloadditions of these imines with olefins and acetylenes result in the formation

of pyrrolidine and pyrrolin derivatives 75 (Scheme 29)''

75

Scheme 29

Resin bound amines are also used for the synthesis of dihydropyridine

derivatives. The dihydropyridine moiety is known to be the present in many biologically

active compounds and is thought to be the component responsible for the activity. The

method involves generation of a resin bound enamino ester through the condensation of

a p-ketoester 77 with a resin bound amine 76. This was treated with an aldehyde

followed by a second P-ketoester and the product formed on the polymer support is

cleaved by treatment with TFA to afford 1.4-dihydropyridines 79 (Scheme 30).74.7J.7"

79

Scheme 30

The application of resin bound p-ketoesters in combinatorial synthesis involves

the attachment of 0-ketoesters to Wang resin and its further modification in the

synthesis of quinolones.77 An illustrative example is shown in Scheme 3 1 . The p-

ketoester 80 was transesterified with Wang resin to get the resin bound p-keto ester 81

This was condensed with an amine to get the enamide, which was cyclised to quinoline

derivatives by treatment with TMG in DCM. Cleavage from the resin was affected by

treatment with TFAiDCM.

I (CH30)2CHN(CH?)2 THF.

2 R ~ N H * HN F F

Scheme 31

Acrylic ester functionalized polymer resin is used for the solid phase synthesis of

dihydropyrimidones.78 Acrylic esters of Wang resin are prepared using acryloyl chloride.

They were treated with primary amines to afford the N-substituted 13-aminoesters 87.

Addition to isocyanate followed by cyclisation of the resulting ester gave the

corresponding dihydropyrimidine-2,4-diones 89 (Scheme 32).

Scheme 32

Resin bound sulfides are being extensively used in the solid phase synthesis of

benzothiazo~ones.~~ The method involves finctionalization of Merrifield resin with 2-

carboxythiophenol to give the resin bound sulfide 92. This was converted to the amide

93 by the reaction with an amine. The sulfide link of this amine was selectively oxidized

with N-(phenylsulfonyl)-3-phenyloxaziridine. The intermediate sulfoxide bound resin on

treatment with trichloro acetic anhydride undergoes cyclative cleavage to the

benzothiazolone 94 (Scheme 33) .

0

a L s I

~ N H , BOP C Hpy I . p ~ A ' ~ ~ s o 2 ~ ~ 2 TCAA. DCM

- R- DIPEA. D m 2 , ~

R

0 0

Scheme 33

a-Oxoketenedithioacetals have been successhlly used in the synthesis of a large

variety of five and six membered heterocyclic compounds. For example, their reactions

with heterobinucleophiles like hydrazine, hydroxylamine, guanidines, amidines, etc. have

been shown to give interesting classes of heterocyclesx" Nitrogen heterocycles such as

pyrazoles, pyridazines, pyrimidines, and isoxazoles were formed by the reaction of a-

oxoketenedithioacetals with binuc~eo~hiles. '~

Considering the significance of combinatorial organic synthesis in drug discovery

as well as the potential biological activity of the heterocycles, we have made some

efforts to hnctionalize polymers with multifunctional synthones. This would make

possible the effective testing and study of compounds for their pharmacological activity,

by generating libraries of heterocycles. This may be accomplished by hnctionaliziny

properly selected polymer backbones with the polarized ketenedithioacetal functionality.

And this resin, incorporated with ketenedithioacetal, can be used to generate libraries of

heterocycles. As an initiative in this direction, we have functionalized Merrifield resin

with various a-oxoketenedithioacetals and examined some subsequent transformations.

3.3.3.1 Reaction of &Oxodithioesters with MemjTeld Resin

P-Oxodithioesters are usually prepared from active methylene ketones by

treating them with dialkyl trithiocarbonates in the presence of a base such as sodium

h~dride." We have also developed alternative facile methods for their synthesis starting

from substituted ketene dithioacetals. These results are described in Chapter 4 of this

thesis. Alkylation of 13-oxodithiocarboxylates with alkyl halides or dialkyl sulfates in the

presence of a base lead to the formation of the corresponding a-oxoketenedithioacetals.

Thus, if we have an alkylating agent on the polymer support that would react with P- oxodithiocarboxylates. the polymer attached with functionalized ketenedithioacetals can

be easily prepared. Chloromethylated polystyrene (Merrifield resin) is probably the

easiest available polymer support attached with a group that can be used for alkylation.

A solution of 0-oxodithiocarboxylate 96b (2.2 g, 10 mmol), prepared from

acetophenone, in DMF was treated with sodium hydride (50%. 1.40 g, 30 mmol) in one

portion. Merrifield resin 95 (1 g, 3 .5 mmolCl1g) was added after 15 min. and the mixture

was heated on a water bath for 15 h at about 100 "C with occasional shaking. The

mixture was transferred to a Buchner funnel and washed successively with water,

methanol and methylene chloride. The beads were then dried in a vacuum oven at 60 O C

to give the ketenedithioacetal functionalized resin 97b in 1.578 g corresponding to 97%

functionalizaion (Scheme 34).

The IR spectrum of 97b showed the carbonyl stretching frequency at 1625cm.I.

The C=C stretching appeared at 1475 cm". The spectrum superimposed over that of the

Menifield resin is shown in Figure 18. It can be seen that the C-CI stretching bands in

the Merrifield resin (B) appeared at 1260 cm-' and at 680cm.'. However, the spectrum

of the ketenedithioacetal functionalized resin (A) do not show these bands indicating

that all the CH2CI moieties have been alkylated. Hence, it is clear that hnctionalization

is almost complete. The weight increment of the beads also shows that the eficiency of

functionalization is very high.

Other substituted (3-oxodithioesters 96a and 96c-f were also allowed to react

with Merrifield resin under these conditions. Thus, the ketenedithioacetal functionalized

resins 97a and 97c-f were isolated and their IR spectra were compared with that of

Merrifield resin.

R Wt. Increment(g) %

P - C I C ~ ~ 0 700 98

C6H5 0.578 97

p-BrC6H4 0.842 97

p - C H & h 0.625 97

~ - C ~ - I ~ O C ~ H J 0.673 95

CH3 0.375 98

Scheme 34

rn rn >YE imo m (cm')

Figure 18 IR (KBr) Spectrum of ketenerlithioacetal Functionalized Resin 976 (A) and Merrifielrl Resin (B)

The ketenedithioacetal functionality was found to liberate as the P-oxothiolester

from the polymer backbone on exposure to HCI vapor. The ketenedithioacetal

functionalized resin 97b was allowed to stand overnight in presence of HCI vapor. This

resin was washed with methylene chloride and the filtrate was concentrated to get the

corresponding P-oxothiolester 35b was isolated in 53% yield (Scheme 35).

HCI vapor D

12 houn H3CS

Scheme 35

We have attempted a few reactions to examine the potential of polymer

supported acyl ketenedithioacetals in the combinatorial synthesis of heterocycles.

However, it was found that part of the heterocycle formed was liberated during the

cyclization process. This shows that there is not much selectivity, resulting from the

differences in the leaving group ability of methylthio group and the benzylthio group.

The low yields of P-oxothiolester in the partial hydrolysis also indicate that a part of the

P-oxothiol moieties remain on the polymer support as S-benzyl P-oxothiolester. This

suggests that suitable linkers should be developed to attach functionalized

ketenedithioacetals to the polymer support so that the heterocycle would not get

detached during their formation.

3.4 Experimental

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

point apparatus. Infrared spectra were measured using a Shimadzu IR-470 spectrometer

and are given as cm-I. Proton NMR spectra were recorded in CDC13 on a Jeol (90

MHz), Jeol GSX (400 MHz) or a Bruker WM 300 (300 MHz) spectrometer. Carbon- I3

NMR spectra were recorded in CDCI3 on a Jeol (22.4 MHz) or a Bruker WM 300 (75.5

MHz). Chemical shifts are reported in parts per million (ppm) downfield from internal

reference, tetramethyl silane. Coupling constants J are given in Hz. Electron impact

mass spectra (EIMS) were obtained on a Finnigen-Mat 3 12 instrument.

Commercial solvents DME and dioxane were dried before use. The ketones and

boron trifluoride etherate were purchased from Sisco-chem, Mumbai. Merrifield resin

was obtained from Aldrich Chemical Co.. USA. The polymer supported reagent, N-

vinylpyrrolidone bromine complex, used for the partial hydrolysis of a-

oxoketenedithioacetals was obtained as a gift from the research group of Professor V.

N. Rajasekharan Pillai. Details regarding the preparation and characterization of the

resin will be published elsewhere.

3.4.1 Preparation of Starting Materials

3.4:l.l General Method for the Preparation of a-Oxoketenedithioacetals

The ketenedithioacetals 34a-e, 36, 38, 40, and 42 were prepared according to

the known procedure." To a suspension of sodium 1-butoxide (19.2 g, 0.2 mol),

prepared by refluxing molecular sodium (4.6 g, 0.2 mol) in r-butanol (100 mL), and

benzene (100 mL) a mixture of the ketone (0.1 mol) and carbondisulfide (0.1 mol) was

added. The reaction mixture was stirred at room temperature for three to four hours.

Methyl iodide (28.38 g, 0.2 mol) was added slowly to a well cooled (0-5 "C) mixture

over 30 min and was stirred at room temperature for 12 h. The mixture was poured into

cold water, the benzene layer was separated and the aqueous layer was extracted with

benzene (3x50 mL) The combined extracts were washed with water, dried with sodium

sulfate and concentrated to give the crude ketenedithioacetal. This was further purified

either by crystallization or by column chromatography over silicagel. The a-

oxoketenedithioacetals prepared were characterized by comparing their spectral and

physical data with reported values.

3.4.1.2 General Procedure for the Preparation of Alkenoyl ketenedithioacetals

Cinnamoyl ketenedithioacetals 44a-e and 2-thienoyl ketenedithioacetal 46 were

prepared according to the known methodg4 Sodium ethoxide was prepared by

dissolving sodium (0.1 mol) in 20 mL of 95% ethanol. This was cooled and a solution of

a-oxoketenedithioacetal (0.05 mol) and the respective benzaldehyde (0.05 mol) in

ethanol was added with external cooling (0-5 OC) and stirring. The reaction mixture was

further stirred for two hours and was diluted with cold water. The precipitated alkenoyl

ketenedithioacetal was filtered, washed with water, dried and was purified by

recrystallization from methanol. The substituted cinnamoyl ketenedithioacetals were

characterized by comparing their spectral and physical data with the reported values.

3.4.1.3 Preparation of I,I-Bismethylthio-3-oxo-9-phenyl-l,4,6,8-nonatetraene, 48

1,1-Bismethylthio-3-0~0-9-phenyl-1,4,6.8-nonatetraene was prepared by the

base catalysed condensation of 5-phenyl-2.4-pentadienaldehyde with acyl ketene

dithioacetal. 5-Phenyl-2,4-pentadienaldehyde was obtained by a sequential reduction and

Vilsmeier-Haack reaction of benzalacetone

Benzalacetone (5.84 g, 0.04 mol) was taken in absolute ethanol (25 A).

Sodium borohydride 4.5 g (0.12 mol) was added to the mixture and was refluxed

for 7 h. The reaction mixture was cooled to room temperature and was added to a cold

saturated solution of ammonium chloride and extracted with methylene chloride

(3x50 mL) Combined organic layer was washed with brine, dried and the solvent was

removed under vacuum. The crude alcohol thus obtained was added to the Vilsmeier-

Haack reagent, prepared from 7.3 mL (0.08 mol) POCI, and DMF (50 mL), keeping the

temperature at 0-5 'C. The mixture was stirred at room temperature for 12 h and

poured over cold saturated potassium carbonate solution. The organic layer was

extracted using benzene (3x50 mL). The combined organic layer was washed with wafer

(3x50 mL), dried and the solvent was removed to get the crude aldehyde. This was

purified by column chromatography over silicagel using hexanelethylacetate (25%) as

the eluent to afford 5-phenyl-2.4-pentadienaldehyde(4.8 g, 76%).

Sodium ethoxide was prepared by dissolving 0.46 g sodium in 10 mL 95%

ethanol. This was cooled to 0-5 "C and added a solution of acyl ketenedithioacetal, 1.62

g(O.O1 mol) in ethanol followed by the 5-phenyl-2,4-pentadienaldehyde(l.58 g, 0.01

mol) and stirred at 0-5 "C for 5 h. Poured into crushed ice and the precipitated 1,l-

bismethylthio-3-0~0-9-phenyl-1.4,6.8-nonatetraene 48 was filtered, washed with water,

dried and was purified by recrystallization from methanol. ( 'H NMR (300 MHz, CDCI3)

6 = 2.41(s, 6H, SCH,), 6.07(s, IH, vinylic). 6.23(d, IH, J = 15Hz. vinylic), 640(d. IH, j

= 15Hz. vinylic), 6.61-681(m, 3H, vinylic). 7.18-7.36(m, 6H, arom & vinylic). IR(KBr)

v = 1630(C=C), 1550, 1470(C=C). 1240, and 1 1 10 cm-')

3.4.2 Boron Trifluoride Assisted Partial Hydrolysis of a-oxoketene-

dithioacetals

3.4.2.1 Reaction of a-Oxoketenedithioacetal34a with Boron Tnifluoride Etherate

in DME

Generalprocedure: The ketenedithioacetal 34a ( I0 mmol. 2.58 g) was taken in 25 mL

DME and boron trifluoride etherate (1.3 mL. 10 mmol) was added. The reaction

mixture was refluxed for 3 h with stirring. Cooled, poured into cold water, neutralized

with saturated sodium bicarbonate solution and extracted with ether. Washed with

water. dried over anhydrous sodium sulfate and concentrated to get the crude thiolester.

This was purified by column chromatography over silicagel (60-120 mesh) using

hexane-ethyl acetate (50: I) as the eluent to afford the P-ketothiolester 35a in 67% yield.

.Y-Methyl-3-oxo-3-(l-chlorophet1~~I/propaethote (35a) Obtained as a pale yellow

solid, 1.5g (67%), mp 86-87"C, by the reaction of the ketenedithioacetal, 34a in

refluxing DME for 3 h. Spectral data are given in the following section.

3.4.2.2 Reaction of a-Oxoketenedithioacetals with Boron Trifluoride Etherate in

Dioxane: Preparation of P-Oxothiolesters, 35a-e, 37, 39, 41 and 43

To acyl ketenedithioacetals (10 mmol) in dioxane, boron trifluoride etherate

(1.3 mL, 10 mmol) was added and the mixture was either refluxed or stirred at room

temperature till the reaction is complete as indicated by TLC (2-6 11.). The reaction

mixture was poured into cold water, neutralized with saturated sodium bicarbonate

solution and extracted with ether (3x50 mL). The combined organic layer was washed

with water, dried over anhydrous sodium sulfate and removed the solvent under

vacuum. The residue was column chromatographed over silicagel (60-120 mesh) using

hexane-ethyl acetate (50: 1) as the eluent.

S-Methyl-3-oxo-3-(-l-chlor~phu~ryl)prvpa~~ethivaiu (35a)

Obtained as a pale yellow solid, 2.0 g (90%). mp 86-87 "C,

by the reaction of the ketenedithioacetal, 34a in refluxing

dioxane for 1.5 h. Exists as the enol form in CDC11.(>95%),

IR (KBr); v = 1680(C=0), 1625, 1560, 1535, 1480,

1440(C=C), 1390, 1210. cm.' 'H NMR (90 MHz, CDCI?) 6 =

2.39(s, 3H, SCH?), 6.08(s, IH, vinylic, enol), 7.36(d, 2H, scti,

J=9Hz, arom), 7.71 (d, 2H. J=9Hz, arom), 13 18(s. IH, OH, ('I

CloH902CIS enol) p p m . ' 3 ~ NMR(22.4 MHz, CDC13) 6 = 10.88(SCH1, FW 228.69 enol), 11.87(SCHz, keto). 53.37(CH2, keto), 96.84(vinylic,

enol). 127.39. 128.58, 128.79, 129.92, 131.00, 137.44(arom,

keto & enol), 166.89(C-0, enol), 194.84(C=0, enol) ppm.

ElMS m/z 228 (M-, 13.6%), 181(74.3%, [C9H60~Cl]'),

139(100%, [C7&0C1]'). 1 1 1(25.8%), and 89(6.2%)

.S-Me~hyl-3-oxo-3-phe1~yIpr0~1ut1t!thiu (35b) Obtained as a S ~ I I ,

pale yellow liquid. 1.0 g (52%), by the reaction of the

ketenedithioacetal 34b in refluxing dioxane for 4.5 h, CIOHIQO~S

(keto:enol = 47:53 ), 1R (neat); v = 1660, 1600(C=O), 1560, FW 194.24

1480, 1440(C=C), and l?lO(C-0) cm-' 'H NMR (90 MHz,

CDCI,) 6 = 2.32(s, 159H, SCH3, enol), 2.40(s, 141H, SCH?,

keto), 4.22(s, 0.94H, C R , keto), 6.1 1(s, 0.53H, vinylic enol),

7.20-8.10(m, 5H, arom). 13.19(s, O.S3H, OH, enol) ppm.

NMR(22.4 MHz, CDCli) 6 = 10.88(SCH3, enol),

I1.90(SCH,, keto), 5352iCH2, keto), 96.87(vnylic, enol),

126.91, 128.43, 128.58, 131.44, 132.67, 133.59,

135.83(arom, keto & enol), 16844(C-0, enol), 191 6 8 ,

192.19(C=0, keto), 194.96(C=0, enol) ppm.. EIMS m/z

194(M*, 7.2%), 146(49.3%, [C9Hh02]'). 133(11.4%),

105(100%, [C~HSOI*).

S-Melhyl-3-oxo-3-(4-hromophe1ty5,propa1ethioaie (35c)

Obtained as an orange yellow solid. 1.61 g (59%),

mp 55-56 OC, by the reaction of the ketenedithioacetal 34c in

refluxing dioxane for 3 h, (keto:enol = 50:50), IR (KBr); v =

1610(C=O), 1600, 1570, 1490(C=C), 14 10, and 1220(C-0)

cm-I. 'H NMR (90 MHz, CDC13) 6 = 2.33 (s, 15H, SCH?,

enol), 2.4(s 1.5H, SCH1, vinylic. keto), 4.18(s, IH, CH2, SCII,

keto), 6.08(s O.SH, vinylic, enol), 7.62(m, 4H, arom), 13.13(s, 0 7

13 05H. OH, enol) ppm. C NMR(22.4 MHz, CDCI?) 6 = Cl0H9O2BrS

I 1.03(SCH3, enol) 12.04(SCH3, keto), 53.60(CH2, keto), FW 273.14

97.04(vinylic, enol), 126.10, 127.81, 129.06, 130.19, 13 1.74,

13 1.98, 13461(aroln, keto & enol). 16719(C-0, enol),

190.73, 19195(C=O, keto), 195.08(C=O, enol) ppm. EIMS

miz 273(5%, W ), 273(M7. 71), 225(49.9%, [C9&0~Br]*).

223(51.3%), 181(98.8%), 183(100%, [C~HJOB~]'), and

154(25.7%)

S-Me/hyl-3-oxo-3-(4-m~hylph~'11yI)propat1~fhioate (35d)

Obtained as a pale yellow liquid, 1.50 g (58%), by the reaction

of the ketenedithioacetal 34d in refluxing dioxane for 4 h,

(keto:enol = 65:35), IR(neat) v = 1678, 1600(C=O), 1580,

1565(C=C) and 12 15(C-0) cm-I. 'H NMR (90 MHz, CDCI;)

6 = 2.28(s, 105H, SCH?, enol). 2.34(s. I95H. SCII?, keto),

4.13(s, I3H, CH2. keto), 6.07(s, 0.35H, vinylic, enol). 7.07-

7.28(m, 2H, arom), 7.65(d, J=9Hz, 07H, arom), 7.82(d,

J=9Hz. 13H. arom), 13.22(s. 035H. OH, enol) ppm. "C

NMR(22.4 MHz, CDCI;) 6 = 10.88(SC:H1, enol),

1 1.87(SCH1, keto), 21.32, 2 1.47(CH3), 53.46(CH2, keto),

96.30(vinylic, enol), 126.26, 128.79, 129.24, 129.30, 129.84,

133.51, 142.16, 144.58(arom, keto gi enol), 168.74(C-0.

enol), 191.30, 192.31(C=O. keto), 194.79(C=O, enol) ppm..

EIMS d z 208(M'. 5.5%). 160(26.3%, [ C I O H ~ O ~ ] ) ,

134(2 1.9). 1 19(100%, [CsH70]*).

S-Methyl-3-oxo-3-(4-mefhoxy~1henyr)pr0paihoae (35e)

Obtained as a pale yellow liquid, l .OO g (48%), by the reaction

of the dithioacetal 34e in refluxing dioxane for 6 h, (keto:enol

= 75:25), IR (KBr ); v = 1650(C=O). 1595, 1575,

1498(C=C), and 1220(C-0) cm-I. 'H NMR (90 MHz, CDCI,)

6 = 2.27(s, 75H, SCH?, enol), 2.34(s, 2.25H, SCH?, keto),

3.80(s, 3H, OCH,), 4.07(s. I SH , CHZ, keto), 6.05(s, 0.25H,

vinylic, enol)), 772(d, J=9Hz. 2H, arom), 791(d, J=9Hz, 2H,

arom), 13.3 I(s, 0.25H, OH, enol) ppm. "C NMR(22.4 MHz,

CDCI?) 6 = IO.SS(SCH,, enol), 11.57(SCH3, keto),

53.07(CH2, keto), 5504(OCH3), 95.19(vinylic, enol), 124.43,

127.77, 128.64, 13073(arom), 16829(C-0, enol), 189.86,

192,19(C=O, keto), 194.22 ( G O , enol) ppm.

S-Methyl-3-0x0-3-thienylyrop~~nethioat (37) obtained as pale

yellow liquid. 0.96 g (48%), by the reaction of the ketene-

dithioacetal 36 in refluxing dioxane for 4 h, (keto:enol =

93 :07). IR(neat); v = 1650(C=O), 16 15, 1540, 1420(C=C),

1215(C-0) cm-I. 'H NMR (400 MHz CDC13) 6 = 2.22(s,

2.79H, SCH? , enol), 2.29(s, 0.21H, SCH3, keto), 4.08 (s,

186H, CHI, keto), 5.95(s, vinylic, enol), 6.89-702(m, 007H,

arom, enol), 7.02-709(m, 0.93H. arom. keto). 7.39-742(m,

0.07H. arom, enol), 7.45-7 5 1 (m, 007H. arorn, enol), 7.58-

7.62(m, 093H, arom, keto), 7.67-778(m, 0.93H. arom,

k e t o ) . " ~ M ( 1 0 0 . 4 MHz, CDCI,) 6 = 1 1 .97(SCH3, keto),

54.14(keto CHZ), 95,88(vinylic, enol), 128, 128.24, 128.57,

130.11, 133.73, 135.15, 136.41, 1429S(arom, keto & enol),

16333(C-0, enol), 184.04, 191.66(C=0, keto) ppm.

(39) Obtained as an yellow solid, 2.14 g (97%). mp 56-58 "C

from the ketenedithioacetal, 38, on refluxing in dioxane for 2

h. Exists as the enol form (>95%) in CDCI?. IR (KBr); v =

3450, 1680. 1610(C=O), 1550, 1445(C=C), 1250, and 11 10

cm'l. 'H NMR (90 MHz, CDCI,) 6 = 2.38(s, 3H. SCH,). 2.52-

295(m, 4H, CHZ), 7.08-7.35(m, 3H, CH2. arom). 7.72-

790(m, IH, arom), 13.4 (s, IH, OH, enol) ppm. "C NMR

(22.4 MHz. CDCI,) 6 = 1 I06(SCH?). 21 29 . 27.62(CHz).

61 . ~ I ( c H , keto), 105.52(vinylic, enol), 126.52, 127.15,

129.51, 130.76. 13840(arom), 16259(C-0, enol),

19610(C=O) ppm.. EIMS d z 220 (M'. 34.5%). 173(100%.

[CI 1H902]-), 145(47%, [C,oHsO]*), 1 15(90.9%), and

105(60.9%, [C7HsO]*)

S-Methyl cyclohexanone-2-lhiolcarboxylatr (41) Obiained as

pale yellow liquid, 1.10 g (64%) by the reaction of the ketene

dithioacetal 40 in dioxane for 5.5 h. Exists as the enol form

(>95%) in CDCI,. IR(neat) v = 1620(C=0), 1560,

1420(C=C), 1320, 1245, and 1160 cm.' I H NMR (90MHz

CDC13) 6 = 1.65 (m, 4H, aliph), 2.26(m. 7H. SCH? & CHz),

13.05(s, lH, OH, enol) ppm. "C NMR 6= 10.79(SCH3).

21.20, 22.28, 22.43, 29.08(CHz), 10653(vinylic, enol),

170.20(C-0, enol), 196.87(C=O) ppm

S-Methyl-3-oxobuta~~ethioate (43), Obtained as yellow liquid,

0.46 g, (35%), by the reaction of the ketenedithioacetal 42 in

dioxane at room temperature for 5.5 h. Exists as the keto form

(>95%) in CDCI3. IR(neat); v = 1710, 1670, 1640(C=O),

1550(C=C), 1210, 1090 cm-I. 'H NMR (90 MHz, CDC13) F =

2.3 1(s, 3H, SCH3), 2 44(s, 3H. CHI). 3.78(s. 2H. keto CHI)

ppm. "C NMR 6 = ll.08(SCH1, enol), I 192(SCHx, keto). CsHa02S FW 13217

21 .42(CH3, enol), 29.3 1(CH3. keto), 58. 16(CH1, keto),

100.78(vinylic, enol), 174.98(C-0, enol), 194.23(C=0) ppm.

3.4.2.3 Preparation of y, &Unsaturated P-Oxothiolcarboxylates, 45a-e, 47 and 49

To the alkenoyl ketenedithioacetals (10 mmol) in dioxane borontrifluoride

etherate (1 3 mL. 10 mmol) was added and the mixture was refluxed for 2-3 h. The

reaction mixture was poured into cold water, neutralized with saturated sodium

bicarbonate solution and extracted with ether (3x50 m L ) The combined organic layer

was washed with water, dried over anhydrous sodium sulfate and the solvent was

removed under vacuum. The residue was column chromatographed over silicagel (60-

120 mesh) using hexane-ethyl acetate (50:2) as the eluent.

S-Mefhyl-3-oxo-5-phe11yl--I-pei1fe11eth1nc~ie (45a) Obtained

as pale yellow solid, 1.91 g (87%). mp 56-58 "C, by the

reaction of the ketenedithioacetal 44a in refluxing dioxane

for 2 h, (keto:enol = 25:75), IR(KBr); v = 3400,

1635(C=0), 1580, 1440, 1415(C=C), 1260, 1170 and 1080 S('11,

cm.' 'H NMR (90 MHz CDCI2) 6= 2.35(s 3H. SCHi), Ci2H1202S

3.91(s, 0.5H. CH2, keto). 5.6(s. 075H, vinylic, enol), 64(d, FW 220.28

0.75H. J=16Hz, vinylic, enol), 6.78(d, 025H, J=16Hz,

vinylic. keto), 7.18-763(m, 6H, arom & vinylic), 12 52(s,

0.75H, enol) ppm. "C NMR(22.4, CDCl,) 6=10.64(SCH1,

enol). 11.75(SCH3. keto), 5533(CH~, keto).

101.10(vinylic, enol), 120.97, 124.73. 127.36, 128.25,

128.49, 128.61, 129.24, 130.58. 133.71, 134.85, 13813,

144 57(arom & vinylic, keto & enol), 16596(C-0, enol),

190.70. 19192(C=0, keto). 194.37 (C=O, enol) ppm..

EIMS d z = 220(M'. 19.8%), 173(79.9%, [CllH902].),

131(100%, [CgH70]'), 115(15.3%) and 103(50.4%,

[CxHl]').

S-Melhyl-3-oxo-5-(4-chIo1'oj~h~'try//-4-pet1It't1eihio~1le

(45b) Obtained as a pale yellow solid, 2.30 g (92%) mp

122-123 "C, by the reaction ofthe ketenedithioacetal 44b in

refluxing dioxane for 2 h. Exists in the en01 form in CDCI?

(>95%). IR (KBr); v = 1630(C=0), 1580, 1440(C=C),

1260. 1080 and 800 cm-'. 'H NMR (90MHz CDCl;) 6 =

2.38(s, 3H, SCH3), 5.59(s IH, vinylic, enol), 6.28(d, lH, S l l l ,

JZ16Hz, vinylic), 7.22-758(m, 5H, arom & vinylic) i.i

12.49(s, IH. OH, enol) ppm "C NMR(22.4 MHz, CDCI3) 6 ClzHrlOzClS FW 254.73

= 11.00(SCH3), 101.64(vinylic, enol), 121.87, 128.73,

129.06, 129.24, 129.68, 133.71, 135.35, 136,96(arom &

vinylic. keto & enol), 165.81(C-0, enol), 19487(C=0)

ppm.. EIMS m/z = 254(M', 12.1%). 207(58.5%,

[CI~H~O~CI]*) . 165(100%, [CgH6OCI]'). 137(28.5%,

[C,&Cl]') and 127(3.9%). 75(26.8%).

(4%) Obtained as a pale yellow solid, 1 75 g (70%). rnp 82-

83 "C, by the reaction of the ketenedithioacetal 44c in (,,,,, refluxing dioxane for 2.5 h, (keto:enol = 50:50), IR (KBr);

v = 1630(C=0), 1580, 1550(C=C), 1265, 1170 and I080 CliH1401S FW 250.3 1

I cm-' H NMR(90 MHz, C'DCli) S - 2.33(s. ;H, SCH!.

keto & enol), 3.69-3.71 (m. 6H. OCH2, keto & enol),

3.82(s, IH, CH2, keto), 5.5 1 (s, 0.5H. vinylic, enol). 618(d,

IH, J=17Hz, vinylic, keto & enol), 6.9(d, 2H. J=9Hz,

arom), 7.28-7.58(m, 3H. arom & vinylic), 12.5(s, 0.5H,

OH, enol). I3c NMR (22.4 MHz, CDCh) 6 = 1070(SCH;.

enol). 11.84(SCH1, keto). 5542(OCH3), 5556(Ct12, keto)

100.48(vinylic, enol), 11 8.56, 122.55, 126.43, 127.69,

12903, 130.16, 138.04, 144.63(arom & vinylic, keto &

enol), 160.68(C-0, enol), 166.68, 190.70(C=0, keto),

19425(C=O, enol) ppm EIMS miz = 250(M-, 27.4%)

203(64.1%, [CI~HIIO~] . ) , 16 1(100%, [CLOHPOZI*),

133(41.2%, [C9H90]'), and 13 1(8%)

S-Methyl-3-oxo-5-(4-t1itro[~het1~I)-4-~et1tet11hou1e (45d)

Obtained as an yellow solid, 1.73 y (65%). mp 159- I60 "C,

by the reaction of the ketenedithioacetal 44d in refluxing in

dioxane for 3.5 h. Exists as the en01 form in CDCI? (>95%).

1R ( K B r ) ; v = 1640(C=0), 1600, 15 1 S(C=C), 1340, 1260

cm-I. 'H NMR (90 MHz. CDCI3) 6=2.38 (s, 3H, SCHI).

5.67(s, IH, vinylic, enol), 6.46(d, IH, J=16Hz, vinylic),

7.48-835(m, 5H, arom & vinylic), 12.42(s, IH, OH, enol).

S-Met~!vl-2-methyl-3-oxo-5-phet1yl-4-per1ter1ethiouie (45)

Obtained as a pale yellow solid, 1.57g (67%) mp 67-68 "C,

by the reaction of the ketenedithioacetal 44e in refluxing

dioxane for 2 h. Exists in the enol form in CDCI3. (>95%).

1R (KBr), v = 1630(C=O), 1580, !550(C=C), 1440, and

1260, 1210 cm-I. IH NMR (90 MHz, CDCI?) 6 = 2.10 (s,

3H, CH;), 2.34(s, 3H, SCH>), 685(d, It{. J-ISHz, vinylic),

7.28-7 72(m, 6H, arom & vinylic), 13 5(s, IH, OH, e~lol)

ppm. "C NMR(22.4MHz. CDCI,) 6 = 1 1.51(CH1),

1178(SCH3), 10579(vinyIic, enol), 127.63. 128.79,

128.91. 129.36, 135.80. 13852(arom & vinylic) 16610(C-

0, enol), 198.19(C=O) ppm. EIMS m/z 234(M 21 4%).

186(86.8%, [CI~HIOOZ]'). 131(lOO?~o, [CsH70]').

128(8.7%), and 115(7.1%).

S-Methyl-3-oxo-j-thie1y-4-/1et1te11ethioute (47) Obtained as

a pale yellow solid, 2.03 g (90%), mp 62-63 OC, by the

reaction of the ketenedithioacetal 46 in refluxing dioxane

for 2 h. Exists as the enol form in CDCll (> 95%). IR

(KBr); v = 1625(C=O). 1580, 1500(C=C). 14 10. 1265,

1215, and 1080 cm-'. 'H NMR(90 MHz, CDCI,) 6 = 2.3(s.

3H, SCH3, enol). 5.5(s.lH, vinylic, enol). 6 l ( d , IH,

J=16Hz, vinylic), 6.92-778(m. 4H. arom & vinylic),

12.53(s. IH, OH, enol) ppm. C ( 2 2 . 4 MHz. CDCI?)

6 = 1070(SCH3, enol), 11.78(SCHi, keto), 5S.40(CHz,

keto), 10086(vinylic, enol), 120 02, 123.36. 127.42.

127.80, 12810, 129.42, 130.88, 13216, 136.90, 139.08,

14036(arom & vinylic, keto & enol), 165.64(C-=SO, enol),

190.07, 191.92(C=07 keto). 194. I9(C=O, enol) ppm.

ELMS miz 226(M* 12.6%), 179(47 I%, [Cr,H702S]'),

137(100%, [C7H80S]'), and 123(7.6%).

S-Melhyl-3-oxo-9-phe1yl--/, 6,8-t1o11ofrie~1elhi0nfe (49)

Obtained as an yellow solid, 2.5 g (88%), mp 108-1 10 OC,

by the reaction of the ketenedithioacetal 48 in refluxing

dioxane for 1.5 h. Exists as the en01 form in CDCI, (>95%).

IR (KBr), v = 3400(OH), 1600(C=0), 1570, 1595,

1550(C=C), 1080, and 1000 cm-I. 'H NMR(300 MHz,

CDCl,) 6 = 2.29(s, 3H, SCH,), 5.43(s, IH, vinylic, enol),

5 74(d, 15Hz. IH. vinylic), 6.30-684(m, 4H, vinylic), 7.10-

7.36 (m, 6H, arom & vinylic), 12 33(s IH. OH. enol)

p p m . l k NMR(75.47 MHz. CDCI:) G = 10.02(SCH3. enol).

I 1 50(SCH3, keto), 54.82 (CH,. keto), I 0 0 15(CH, vinylic),

125.72, 12734, 127.71. 127.98. 134.97, 138.23,

142 36(arom & vinylic). 16537(C-0, enol). 190.01,

I9157(C=O, keto), 193.54(C=0, enol) ppm.

3.4.3 Reaction of a-Oxoketenedithioacetals with Poly-(N-vinylpyrrolidone)

Bromine Complex

The ketenedithioacetal (0.01 mol) was taken in chloroform (20 mL) The

polymeric reagent, 0.04 mol (3.16 g) was added to the reaction mixture followed by a

few drops of water. The mixture was kept at 60 "C for 2-4 h with occasional shaking.

When the reaction was complete, as inferred from the TLC, the mixture was filtered and

the reagent was washed with chloroform (10 mLx3). The filtrate together with the

chloroform washings was evaporated under vacuum. The crude P-ketothiolester was

hrther purified by passing through a short column packed with silicagel using

hexanelethyl acetate (50: 1 ) as the eluent.

.Y-Methyl-3-oxo-3-(-l-chloro~~he1ry~pro1ia~1ethioute (35a), Obtained as a pale yellow

solid, 2 1 2 g (93%). mp 84-85 "C. Spectral data were discussed in the previous

section.

S-Methyl-3-0x0-3-phetylpropanethiuat~. (35b) Obtained as a pale yellow liquid, 1.80

g (93%). Speciral data were discussed in the previous section.

S-Methyl-3-oxo-3-(I-hromophe~1yI)pro~~~111ethioc1e (35c) Obtained as an orange

yellow solid, 2.33 g (86%). mp 55-57 "C. Spectral data were discussed in the

previous section.

S-Me1hyl-3-oxo-3-(I-methy~)he11y~proj1~111eth10~1 (35d) Obtained as a pale yellow

liquid. 1 74 g (84%) Spectral data were discussed in the previous section

S-Merhyl-3-oxo-3-l-/-methoxy~1he1~~~I)j11'opc111e~h1o~1te (35e) obta~ned as a pale yellow

liquid, 1 94 g (87%) Spectral data were discussed in the previous section

,S-Me/hyl-3-oxo-3-thiet1~~rup~11te1h10uIe (37) Obtained as a pale yellow liquid, I .24 g

(84%). Spectral data were discussed in the previous section.

S-Merhyl-3,-I-d~hydra-I(ZH)-t1~1~~thulet1ot1e-Z-~hio/c~1rho.~yIute (39) Obtained as a

yellow solid. 1.53 g (89% ), mp 56-57 "C. Spectral data were discussed in the

previous section.

S-Mzlhyl cyclohexarrot~e-2-thiolcarhoxyl~ (41) Obtained as pale yellow liquid. 1.10

g (74%). Spectral data were discussed in the previous section.

S-Melhyl-3-oxobzrta~1e1hion1e (43) Obtained as an yellow liquid, 1.30 g (98%).

Spectral data were discussed in the previous section.

.S-Me/hyl-3-oxo-5-(-/-meIho~~phety/)-4-~~et1tet1ethe (45a) Obtained as a pale

yellow solid, 2 1 5 g (87%) mp 83-85 "C. Spectral data were discussed in the

previous section.

3.4.4 Preparation of Ketenedithioacetal Functionalized Resins 97a-f

A solution of P-oxodithiocarboxylate (10.5 mn~ol) prepared from the respective

ketones, in DMF was treated with sodium hydride (0.03 mol), in one portion. Merrifield

resin (Ig. 3.5 mmol Cl/g) was added after 15 min. and the mixture was heated on a

water bath for 15 h at about 100 "C with occasional shaking. The mixture was

transferred to a Buchner funnel and washed successively with water, methanol and

rnethylene chloride. The beads were then dried in a vacuum oven at 60 "C to give the

ketenedithioacetal hnctionalized resin.

KelerredithioucetaIf21t1~11ot1ulized rcsitr (97a). Obtained by treating I g of Merrifield

resin (3.5 mmol CI) and 10.5 ~nmol (2.44 g) of the dithioester 96a. Increase in weight.

0.700 g(98%). IR (KBr) v = 162O(C=O), 1470, 1215. 1090, and 1010 cm-'.

Ketetredilhioacelal fut~c/iotralized resirr (97b) Obtained by treating I g of Merrifield

resin (3.5 mmol CI) and 10.5 mmol (2.10 g) of the dithioester 9 6 b Increase in weight:

0.585 g (97%). IR (KBr) v = 1625(C=O), 1475, 121 5 , 1055, and 1030cni~'

Ke~r~redi/h~oace/ul~it~cf~ot~~~/~zed reslrr (97c) Obtained by treating I g of Merrifield

resin (3.5 mmol CI) and 10.5 mmol (2.88 g) of the dithioester 96c. Increase in weight:

0.842 g (97%). IR (KBr) v = 1620(C=0), 1580. 1470,121 5, 1010, and 1070 cm-'

Ketenedithioacetalfunctior~aIized resin (97d) Obtained by treating 1 g of Merrifield

resin (3.5 mmol CI) and 10.5 mmol (2.24 g) of the dithioester 9 6 d Increase in weight:

0.63 1 g (97%). IR (KBr) v = 1620(C=O), 1600, 1475, 1230. 1050, and 1015 cm-'

Ketenedithioacetal fitnctio~iaIited resin (97e) Obtained by treating 1 g of Merrifield

resin (3.5 mmol CI) and 10.5 mmol (2.40 g) of the dithioester 96e. Increase in weight:

0.673 g (95%). IR (KBr) v = 1620(C=0), 1600, 1480. 1230, 1165. 1060, and 1025

cm"

Ketenedithioacetalfur~ctio~~alized resin (97f) Obtained by treating 1 g of Merrifield

resin (3.5 mmol CI) and 10.5 mmol (1.48 g) of the dithioester 96f Increase in weight:

0.375 g (98%). IR (KBr) v = 1625(C=0), 1480, 1410. 1200, 1050, and 1025 cm-I

3.4.4.1 Partial Hydrolysis of the Ketenedithioacetal Functionalized Resin 97a-f

The ketenedithioacetal functionalized resin was kept in a round bottomed flask

and HCl vapor was passed into it. Now the flask was closed and kept overnight. The

beads (yellow colored) were collected on a funnel and washed with methylene chloride

several times. The solvent was removed in vacuum.

.S-Merhyl-3-oxo-3-(4-chloroj~he11yl) pror~anefhioote (3%). Isolated as a pale yellow

solid, 1.40 g (61%), mp 85-87 "C. Spectral data were discussed earlier.

S-Methyl-3-0x0-3-phenylpropanethioate (35b). Isolated as pale yellow liquid, 1.0 g

(53% ). Spectral data were discussed earlier.

S-Melhyl-3-0x0-3- (4-bron~ophenyl) propanelhroate (3512). Isolated as an orange

yellow solid, 1 27 g (47%), mp 55-56 "C Spectral data were discussed earlier

S-Methyl-3-0x0-3-(+methyl phenyl)pro[)arlethioate (35d). Isolated as a pale yellow

liquid. I . I0 g (53%). Spectral data were discussed earlier.

S - M e t h y l - 3 - 0 x 0 - 3 - ( 4 - m e t h o x y p h e n y l l p , (35e). Isolated as a pale yellow

liquid, 1.12 g (50% ). Spectral data were discussed earlier.

S-Methyl-3-oxobulanelhioate (43). Isolated as an yellow liquid, 0.75 g (57%).

Spectral data were discussed earlier.

3.5 . References and Notes

Dieter, R. K. Tetrahedrotr 1986, 42, 3029; b) Junjappa, H.; Ila, H.; Asokan, C.

V. Tetrahedron 1990. 46, 5423; c) Kolb. M. Sytrthe.si.s 1990. 171

a) Dieter, R. K.; Jenkitkasemwong, L. Y . ; Dieter, J . W. .I. Org. ('hem. 1984, 49,

3183; b) Dieter, R. K.; Jenkitkasemwong, L. Y Tetrahedron Lett. 1982, 23,

3747; c) Myrboh, B.; Ila, H.; Junjappa, H. J. Org. (Them. 1983,18, 5327

Okuyama, T.; Inaoka, T.; Fueno, T. J. Org. ('hem. 1985,51,4988

Shahak, I . ; Sasson,Y, Tetrahedrotr Lett. 1973, 420

Asokan, C. V.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H. Syrrthesis 1988, 28 1

Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981,

103, 3099 and references therein; b) Hirama, M.; Masamune, S. Tetrahedron

Lett. 1979, 2225; c) Hirama, M.; Garvey, D. S.; Lu, L L . D.; Masamune S.

Teterahedron Lett. 1979, 3937; d) Evans, D. A ; Nelson, J. V.; Taber, T. R. 7vp.

Stereochem. 1982, 13, 1; e) Masamune, S. Pure and Applied ('hemistry 1981,

197. and references therein.

Baker, R. B.; Reid, E. E. J. Am. ('hem. Soc 1929. 51, 1567

Cronyn, M. W.; Chang, M. P.; Wall, R. A. .I. Am. Chem. Soc. 1955, 77, 3031

Wilson, G. E.; Hess, A. .I. Org. ('hen1 1980. 45. 2766

Liu, H. J.; Lai, H. K. 7ttrahedrot11,ett. 1979, 1193

Fox, C. M. J.; Ley, S. V. Org. Syt~th. 1987, 66, 108

Fox, C. M. J.; Ley, S. V. Org. Synth. 1987, 66, 108

Brooks, D. W.; Lu, L. D. L.; Masamune. S. Atigew. ('hem. Itit. Ed. Etigl. 1979,

18. 72

Bauer, W.; Kuhlein, K. Methoderr Org. ((%em. (Houben-Wely) 1985, L' 5, 832

Ley, S. V.; Woodward, P. R. 7'etraheu'votr ],eft. 1987, 28, 345

Bodalski, R.; Pietrusiewicz, K. M.; Monkiewiczs, J.; Koszuk, J. Tetruhedrori

Idett. 1980. 21, 2287

Kato, T. Acc. Chem. Res. 1974, 7, 265

Oikawa, Y.; Sugano, K.; Yonemitsu, 0. J. Org. .hem 1978,18, 2087

Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedrotl 1992, 18, 1145

Booth, P. M.; Fox, C. M J . ; Ley, S. V. kircrhedroti 1.eti. 1983, 5 143

Ley, S. V.; Woodward, P. R. 7ttrahedrotr Leti. 1987, 28, 3019

Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. ('hem. Soc. Perkin Trans 11987, 121

Clarke, T.; Ley, S. V. J. Chem. Soc. Perlor1 Trans 11987, 131

Fierz-David, H. E.; Ziegler. E. Hehl. Chim. Acia 1928, 11, 776; b) Hauser, C.

R.; Reynold, G. A .I. Am. ('hem. S o c 1948, 70, 2402; c) Limpach, L. ('hem.

Ber. 1931, 6-1, 970; d) Misani, F.; Bogert, M. T. J Org. ('hem. 1945, 10, 347; e)

Coffey, S.; Thomson, J. K.; Wilson, F. J. .I. Chem. S o c Chem. Commuti. 1936,

856; f) Matsuo. K.; Kimura, M.; Kinuta. T. ; Takai, N.; Tanaka. K. ('hem.

Pharm. Bull. Japati 1984, 32, 4197; g) Bestman, H. J.; Kumar, K. ('hem. Ber.

1983, 116, 2708; h) Hendi, J. F.; Hendi, S. B.; Wolfe, J. F. Synth. Commuti.

1987. 17, 13

Fox, C. M. J.; Ley, S. V.; Slawin, A. M. Z ; Williams, D. J. J. Soc. (:hem.

('ommtrri. 1985. 1805

Ley, S. V.; Smith, S. C.; Woodward, P. R. 7ttruhedrorli,eit. 1988, 29, 5829

Ley, S. V.; Smith, S. C.; Woodward, P. R. 7tircrhedrort 1.eti. 1988, 29, 5829

Asokan, C. V.; Ila, H.; Junjappa, H. lktrahedrorr Leti. 1985, 26, 1087

Asokan, C. V.; Ila, H.; Junjappa, H. ,(j/nrhesis 1987, 284

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