Chapter 5

Vilsmeier-Haack Reactions of a-Hydroxyketene Dithioacetals:

Synthesis of Substituted Pentadienethioates

5.1 Introduction

The chloromethyleneirninium salts derived from acid chlorides like POCL

and N,N-disubstituted tbrmamides such as DMF are potential intermediates

involved in the Vilsmeier-Ilaack-Arnold reaction^.'^ They have been extensively used for thc formylation of activated aromatic, heteroaromatic and fully

conjugated ~ ~ s t e m s . ~ ~ ' The broad synthetic utility of these iminium salts is not

only restricted to formylation of electron rich compounds, but also has been

widely exploited for electrophilic substitutions followed by intramolecular

cyclizations, producing a variety of heterocyclic compounds. The reactions of

Vilsmeier-Haack reagents with a-oxoketene dithioacetals have led to some facile

carbonyl transposition strategies which could be employed in the synthesis of

polyene natural products like ~arotenoids. '~,~ Our research group has recently

investigated the reactions of tr-oxoketene dithioacetals derived from benzyl

methyl ketones with Vilsmeier reagents leading to the formation of

chlorosubstituted 2,4-pentadienthioates involving a 1,5 alkylthio shift of the

iminoalkylated intermediate.": In continuation of this study, we have investigated

the reactions of a-hydroxyketene dithioacetals with chloromethyleneiminium

salts which proceeded with a 1,s methylthio shift and afforded functionalized

pentadienethioates, thereby effecting a 1,3 carbonyl group transposition.

5.1.1 Carbonyl Group Transpositions: Applications in Organic Synthesis

Despite the abundance of carbonyl group in organic compounds, its

transposition within the molecular frameworks for the realization of synthetic

objectives has not been fully exploited. Junjappa and Dieter have extensively

studied reductive and alkylative 1,3-carbonyl group transpositions involving

12-addition of organometallic reagents either on vinylogous thiolesters or on

a-oxoketene dithioacetals to form the intermediate carbinol acetals and their

subsequent acid induced transformations to a$-unsaturated thiolester~.~. '~

Simple and alkylative carbonyl group transpositions are of considerable synthetic

importance for introducing new C-C bonds in a regiospecific manner. Among the

numerous variants, 1,2- ;and 1,3-carbonyl group transpositions are by far the most

intensively investigated reactions. There are also a limited number of examples

involving l,4-transfer of carbonyl group, while those involving 1,5- and

1,6-transpositions are generally confined to intramolecular hydride shifts only."

Reports from the research group of Junjappa have shown that the sequential 1,2-

addition of NaBF-l., or Grignard reagents to polyenyl ketene dithioacetals followed

by boron triflouride etherate assisted methanolysis could lead even to 1,11-

transposed polyene e s t c r ~ . ~ " . ~

5.1.2 1,3-Carbonyl Group Transpositions: General Strategies

Wharton KI ui. have reported an elegant route for 1,3-carhonyl group

transposition which involves a rapid reaction between the epoxy ketone derived

from (+)-a-ionone 1 and hydrazine. The geometric isomers of 4 formed in the

ratio ca. 1: 1 and were oxidized to give E-a-damascone 5 and its Z counterpart

(Scheme 1 ).I2

Scheme 1

In another approach. Trost er al. have achieved the 1,3-transposition via a

[2,3] sigmatropic rearrangement (Scheme 2).13

Me OH SPh

Me

10 11 12 Scheme 2

Buchi rf ul have synthesized p-damascone 17 from the oxime 13 of

p-ionone viu an intramolecular migration of the oxygen atom of the oxime to the

remote carbon of a conjugated double bond (Scheme 3).14

16 17

Scheme 3

The carbonyl group present in cyclooct-1-en-3-one 18 was alkylatively

transposed by Dauben et ul. by the sequential Grignard reaction and pyridinium

chlorochromate mediated oxidation (Scheme 4) '

19

Scheme 4

Exan~ples of 1,3-carbonyl group transposition reactions involving

hnctionalized ketene dithioacetals would be discussed later.

5.1.3 Chloromethylenein~inium Salts: Preparation and Synthetic Applications

Chloromethyleneiminium salts, popularly known as Vilsmeier reagents,

are employed for a wide range of synthetic objectives including formylation of

electron rich substrates. The Vilsmeier-Haack reaction generally proceeds via the

attack of the carbonyl oxygen of the amide 21 to POCb to form an adduct 22,

which reacts further to give the chloromethyleneimium salt 23 (Scheme 5).la

I'OCI, R3Na40POCI~ - R, CI - , - ,ky

R7 H R2 Rz H CI 0

OPOCI,

2 1 22 23

Scheme 5

The cl1loromethyleneirninium salt generally reacts with an electron rich

substrate at its electron rich centre, leading to the formation of an intermediate

irninium salt which on basic hydrolysis affords the corresponding aldeheyde. For

example, Mekonnen el al. have reported the formylation at the 5-position of the

imidazo[2,1-hjoxazole 24 employing Vilsmeier Haack reagent (Scheme 6) . l 6

24 25

Scheme 6

In the case of carbonyl compounds like simple enolizable ketones,

chloroformylated products are obtained and the reaction involves iminoalkylation

of the en01 form of the substrate followed by hydrolysis of the iminium salt

formed.'" When multiple irninoalkylations occur on enolizable ketones like

dibenzyl ketone 26, cyclizations of the pentadienaldehyde 27 formed during

hydrolysis occurs, resulting in the formation of pyrilium salt which reacts with

water to afford substituted pyrones 28 (Scheme 7).17

26 27 Scheme 7

In continuation with the studies on reactivity of dithioketals with

Vilsmeier-Haack reagent we have observed that the iminoalkylated intermediate

derived from the dithioketal 29 also cyclizes in a similar fashion to afford 3,5

diphenyl-4H-pyran-4-one 31 (Scheme 8).8C

EMF/ POC13

16h. r t .

30 31 Scheme 8

Multiple iminoalkylated intermediates can be cyclized in the presence of

NH4CI or NH40Ac to afford substituted pyridines and napthyridines. Isobutene

32 on treatment with chloromethyleneiminium salts 33 afforded 2,7-

napthyridines 34 in good yields (Scheme 9).18

- .p CHO

Scheme 9

Studies from this laboratory have resulted in an expedient synthesis of

aryl pyridine carbaldehydes 37 from carbinols 36 derived from acetophenones 35,

by treatment with chloromethyleneiminium salts followed by quenching with

ammonium acetate (Scheme I O ) . ' ~

0 H,C OH

CH, CHJMgl -- - A']

X Ft,O 4 2 8 0 ~ ~ 1 2 h * , 3 NH40Ac

35 36 37 Scheme 10

When the same protocol was extended to aliphatic alcohols like r-butanol

38, functionalized napthyridines 39 were formed (Scheme 11).

H3C OH K 1 . POCId DMF( 6 equiv.) -.

n3c' YH:, 2. r t . , 15h 3. NH,OAG CHO

38 39 Scheme 11

Benzofused 1,4-diazepinones 40 on treatment with Vilsmeier reagent

followed by quenching with NH4CI afforded pyrido-fused benzodiazepine-2-ones

41(Scheme 12)."'

40 41

Scheme 12

4-N-(methy1formamido)pyridine underwent reaction with (COC1)x to

afford the intermediate 43, which underwent aerial oxidation to form a carbene

which then cyclized and subsequently gave 5-substituted-N-methyl isatin 47.

(Scheme 13)."

Scheme 13

Acetylation reactions under Vilsmeier-Haack reaction conditions are

usually less efficient compared to formylation reactions. However the Vilsmeier

reaction using dimethyl acetamide and POCI, was used in acylation reaction of

hexahydropyroloindolizine 48 to afford an inseparable mixture of the two

regioisomers 49a and 49b in good yields (Scheme 14).*~

a

- . ,. A,/ , I

N~ I -. I '3 q" POCl3 \ ~ ~ - \ 1

* q0 YC + CH3 48 49a 49b

Scheme 14

Triflouron~ethanesulfbnic anhydride has been used to activate DMF to

generate the iminium salt 51. which on treatment with nucleophiles like primary

and secondary alcohols. thiols etc., afforded new iminium salts 52 which were

later converted to esters 51 and 0-alkyl thiolesters 53 by hydrolysis and thiolysis 7 3 respectively (Scheme

Scheme 15

Nagarajan et 01 have observed that a ring opening of dibenzodiazepinone

ring occurs on treatment with chloromethyleneiminum salts followed by

cyclization to afford benzimidazole 56 derivatives (Scheme 16).24

POCI, IDMF -- h 0

55 56 Scheme 16

5.1.4 a-Hydroxyketene Dithioacetals: Synthetic Uses

a-Hydroxyketene dithioacetals are potent intermediates in many synthetic

transformations." T'hey are usually prepared from anxoketene dithioacetals by

reduction using NaBK, or by a 12 addition of organolithium or organomagnesium

reagents. 'The carbinol acetals 58 derived from a-oxoketene dithioacetals 57 of a

variety of cyclic and acylic active methylene ketones by 1,2-addition of Grignard

reagents. on boron triflouride etherate assisted methanolysis afforded the

a$-unsaturated S-methyl esters 59. The hydrolysis of these carhinols using

boron triflouride etherate in the presence of water gave the corresponding

a,B-unsaturated esters 60 (Scheme 1 7).yd

58

Scheme 17

5,s-Bis(methylthio)substituted pentadienaldehydes 63 were synthesized from

the a-oxoketene dithioacetals 61 employing a sequential 1,2 reduction using NaBH4

and chloromethyleneim~nium salt mediated formylation reaction (Scheme 1 8).8ab

0 SCW, NaBH, H3c ,"qH3 POCt3, L I M L HIG:cw, H329 SCH, ---' SCHl

R R R

Scheme 18

o,o)-Bis(methylthit,)substituted polyenaldehydes were prepared by a

combination of sequential aldol condensation, reduction and Vilsmeier Haack reaction.

This is exemplified by the synthesis of 9,9-bis(methy1thio) nonapentenaldehyde 67

(Scheme 19).'"'

0 SCH,

I NaOMeI MeOH MeOH R R

66 67

Scheme 19

Recent studies from our research group have developed a facile method

for the synthesis of methylthio substituted 4-aryl pyridines 70 from aryl substituted

a-hydroxyketene dithioacetals 69 via the sequential Grignard-Vilsmeier reactions,

followed by quenching with ammonium acetate (Scheme 2 0 ) . ~ ~ ~

69

Scheme 20

We envisioned that the modification of this protocol involving

1,2-addition of organomagnesium reagents followed by dehydration of the

resulting carbinol and subsequent iminoalkylation could lead to variously

functionalized polyenes and heterocycles.

5.2 Results and Discussion

The Vilsmeier-Haack reaction of the carbinols derived from tr-oxoketene

dithioacetals leads to iminoalkylated intermediates which on aqueous work up

could in principle, afford conjugated pentadienaldehydes, which could be further

used for carbonyl group transposition reactions and other synthetic

transformations. Contraty to our expectations, the iminoalkylated intermediate

underwent a 1.5-shift of one of the methylthio groups, to afford the

corresponding pentadienethioates in good yields.

5.2.1 Reactions of 4,4-Bis(methylsulfanyl)-2-phenyl-3-buten-2-o1 with Chloromethyleneiminium Salts: Synthesis of Substituted 3-Aryl-5- methylsulfanyl-2,4-pentadienethioates

The 2-(4-chlorophenyl)-4,4-bis(methylsulfanyl)-3-buten-2-ol 69a was

prepared by the Grignard reaction of the corresponding a-oxoketene dithioacetals

68a by the 1 &ddition of methyl Grignard reagent. The crude carbinol was then

treated with the chloromethyleneiminium salt derived from POC13 and DMF at

room temperature for 12 hours. Subsequent work up using aqueous K2CO3

solution, extraction with diethyl ether and column chromatography over silica gel

using hexane:cthyl acetate (9:l) as eluent afforded a yellow crystalline solid in

55% yield (Scheme 21). This compound was identified as S-methyl (2E,4E)-3-(4-

chlorophenyl)-5-(methylsulfanyl)-2,4-penatdienethioate 71a on the basis of

spectral data (Scheme 2 I).

OH SCH,

SCH, 2equiv.. 12 h, r t .

X X X

Yield (%)

60

60

60

50

45

Scheme 21

The 'H NMR spectrum (300 MHz, CDCl-,) of 71a shows two singlets for

three protons each, at 6 2.30 and 2.33 ppm, which are due to the two methylthio

groups. The singlet at 6 5.73 is due to the styryl proton. The protons of the

olefinic bond connected to one of the methylthio group appears as two doublets at

6 6.54 and 7.5 respectively, showing [runs coupling (J = 15.3 Hz). The doublets

at 6 7.15 (J = 9 Hz) and 6 7.26(5 = 9 Hz) integrating for two protons each are due

to the para substituted aromatic ring. The "C NMR (100.4 MHz, CDC13) shows

signals at 6 11.9 and 14.4 ppm due to the two methylthio groups. The aromatic

and olefinic protons appear at 119.9, 121.4, 128.6, 130.3, 134.7, 137.8, 142.1 and

149.7 ppm respectively. The carbonyl group shows peak at 6189.2 ppm. IR

spectrum (KBr) showed bands at v 1640, 1565, 1540, 1020 cm-'. EIMS of 71a

showed the molecular ion peak at m/z 284 (5 %).

The structure was further confirmed based on HMBC and C, H-COSY

experiments (Fig 1 and 2).

1 I

up-

s-

1

Fig 1. HMBC correlation spectrum of 71a

Fig 2. C,H-COSY spectrum of 71a

The HMHC spectrum shows a long range connectivity between the

protons of one of the methylthio group (-SCH3) at 2.30 ppm and the carbonyl

l . " l . b ~ , l l . l " l l . . . , l ' . l !'a4

Fig. I 'H NMR(300 MHz, CDCb) Spectrum of Compound 71a

Fig. I1 I" C NMK(75 MHz, CI)C13) Spectrum of Compound 71a

Fig. 111 IR Spectrum of Compound 71a

Fig. IV Mass Spectrum(GCMS) of Compound 71a

carbon at 190 ppm, thereby confirming the presence of the thiolester moiety in

the molecule. The protons of the second methylthio group at 2.34 ppm shows

connectivity with an sp2 carbon at 138 ppm, indicating that the second methylthio

group is attached to the alkene double bond. The alkene proton Ha at 7.6 pprn

shows connectivity to two sp2 carbons- the one a to the carbonyl group at 120 ppm

(assigned by C,H-COSY) and the one at 138 ppm could be the ring carbon. The

alkene proton Hb at 6 6.5 ppm shows connectivity to a sp3 carbon at 11.9 pprn

(-SCH3), further establishing this connectivity. This proton also shows long range

connectivity to a carbon at 6 150 ppm. The styryl proton at 6 5.7 pprn shows

connectivity to the thiolester carbonyl, indicating that it is present on the carbon

atom a to the carbonyl group. It also shows connectivity to the sp2 ring carbon at

6 138 ppm and with the olefinic carbon at 6 121 pprn.

Other a-hydroxyketene dithioacetals 69b-e under similar reaction

conditions gave the corresponding pentadienethioates 71b-e in 45-67% yields and

were characterized with the help of analytical and spectral data, which will be

discussed in the experimental section of this chapter.

The a-oxoketene dithioacetal 72 derived from a-tetralone also underwent

1,2 addition of methyl Grignard reagent to afford the corresponding carbinol 73

which on iminoalkylation afforded the pentadienethioate 74 in 60% yields

(Scheme 22).

Scheme 22

The structure of the product was confirmed by HMBC experiment (Fig. 3).

Fig 3. HMBC Spectrum of 74

One of the S-methyl carbons (6 14.84) shows connectivity with a proton

at 6 6.5 ppm indicating that this methylthio group is attached to the double bond.

The carbonyl carbon (6 194) shows connectivity with the second methylthio group

indicating the presence of the thiolester functionality in the molecule. Thus the

structure of 74 was confirmed on the basis of further assignments as shown in fig 3.

However, our efforts to extend this reaction to the a-hydroxyketene

dithioacetals derived from propiophenone afforded complex reaction mixtures.

The proposed mechanistic pathway for the formation of the pentadienethioate

involves a 1 J-shift of the methylthio group of the iminium salt intermediate 77 as well

as a 1,3-carbonyl group transposition. The chloromethyleneiminium salt mediated

dehydration of the a-hydroxyketene dithioacetal 69 would afford the corresponding

l,l-bis(methylthi0)-3-aryl-1,3-butadiene 75. The reaction of the diene 75 with

chloromethyleneiminium salt would lead to an iminoalkylated intermediate 77,

which would cyclize to form the intermediate 78. Addition of a molecule of water

triggers an intramolecular 1,s-shiA of an S-methyl group to form the thiolester

intermediate 80. Subsequent elimination of a molecule of N,N-dimethyl amine

from 80 affords the pentadienethioate 71 (Scheme 23).

OH SCH,

SCH, w -+ X

69 75

Scheme 23

Base induced intramolecular 1.3- and 1,5-shifts of alkylthio groups of

ketene dithioacetals are reported in literature. Junjappa et a1 have observed an

intermolecular thioallylic rearrangement involving a 1,3-shift of the alkylthio

group while studying a-methyl deprotonation of the a-oxoketene dithioacetals 81

using NaH as base (Scheme 24).26

r- X -

aH, SMe

SMe SMe SMe

X-

d

SMe SMe SMe SMe SMe

84 85

Scheme 24

a-Allyl ketene dithioacetals 87, under identical reaction conditions

underwent an intramolecular migration of the alkylthio group involving

1,6-conjugate addition to the mobile oxopentadienyl intermediate 88, to afford

the corresponding dienes 91 in good yields (Scheme 25).17

90 Scheme 25

A recenl report from this laboratory describes an interesting intramolecular

1,5-shift of the methylthio group of the a-oxoketene dithioacetal 92 derived from

benzyl methyl ketone, by reaction with Vilsrneier reagents leading to the formation

of the corresponding chloro substituted pentadienethiolesters 96 (Scheme 26)''

95 96

Scheme 26

5.2.2 Reactions of 1-(1,3-Dithiolan-2-yliden)-2-phenyl-2-propanos with Chloromethyleneiminium Salts

Our studies on bis(cinnamoy1) ketene dithioacetals had established that

the methylthio groups present in these substrates are more vulnerable to

hydrolysis than their cyclic analogues.28 We next attempted to examine the

reactivity patterns of the a-hydroxyketene dithioacetal 98, derived from the

addition of methyl Grignard to cyclic ketene dithioacetal 97, towards Vilsmeier-

Haack reagents. Unlike in the case of S-methyl ketene dithioacetals, the carbinol

acetal on dehydration and subsequent iminoalkylation afforded the expected

forrnyl derivative 99 in good yields (Scheme 27).

98

Scheme 27

The ' I NMK spectrum (300 MHz, CDCI,) shows a singlet for four

protons at 6 2 3 0 and 3.26 ppm due to the dithiolan moiety. The doublet at 6 6.2

(J = 9 Hz) pprn is due to the styryl proton. The proton a to the dithiolan moiety

appears as a singlet at 6 6.2 ppm. The aromatic protons appear as a multiplet for five

protons at 6 7.3 pprn and the aldeheyde proton appear as a doublet at F 9.2 pprn

(J = 9 Hz). l'he ' 3 ~ NMR (100.4 MHz, CDC13) shows signals at 6 36.2 and 41

pprn due to the two methylthio groups. The aromatic and olefinic protons appear

at 6 110.5. 115.9, 125. 127.2, 128.6, 128.9, 129, 130.2, 136.2, 154, and 159 pprn

respectively. The carbonyl group shows peak at 6 193 ppm.

As in the case of S-methyl ketene dithioacetals, the first step in the

proposed mechanism involves dehydration of the a-hydroxyketene dithioacetal 98

triggered by chloromethyleneirninium salt to afford the corresponding 2-[2-aryl-2-

propenylidenel-l,3-dithiolanes 100, which undergoes subsequent iminoalkylation

with chloromethyleneirninium salt leading to the formation of an iminoalkylated

ketene dithioacetal intermediate 101. Hydrolysis of 101 would afford the

corresponding 4-(1,3-dithiolan 2-yliden) 3 phenyl-2-butenal 99 (Scheme 2 ~ ) . ~ ' ~

102 99 Scheme 28

5.3 Experimental

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

point apparatus. lnfra red spectra were recorded on Shimadzu IR-470

spectrometer and the f'requencies are reported in cm-'. Proton NMR spectra were

recorded on a Bruker DRX-300 (300 MHz), Bruker WM 250 (250 MHz) or on a

Bruker WM 400 (400 MHz) spectrometer in CDC13. Chemical shifts are

expressed in parts per million downfield from internal tetramethyl silane.

Coupling constants .l are given in Hz. Electron impact Mass spectra were

obtained on a Finnigen --Mat 3 12 instrument.

5.3.1 General Procedure for the Synthesis of 3-Aryl pentadienethioates 71a-e

The methyl Grignard reagent was prepared from 1.41 g (10 mmol) methyl

iodide, 0.3 g (10.7 mmol) magnesium and a pinch of iodine crystals (0.10 g) in

ether. The methyl magnesium iodide was cooled to 0-5 "C and the ketene

dithioacetals (7.2 mmol) in ether was added slowly over 15 min. The mixture was

stirred at this temperature for half an hour and was poured over cold saturated

ammonium chloride solution. It was then extracted with ether (3 x 50 mL). The

combined organic layer was washed with water and dried over anhydrous sodium

sulphate. Ether was removed and the a-hydroxyketene dithioacetals formed were

used for the next step without further purification.

The Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL)

and POCl, (1.24 mL, 10 mmol). The mixture was then stirred for 15 min. at room

temperature. The crude tx-hydroxyketene dithioacetals obtained from the

Grignard reaction were dissolved in dry DMF and added in about 15 min at

0-5 "C. The reaction mixture was the stirred for 12h at room temperature, added to

cold saturated K2C-03 solution (300 mL) and extracted with diethyl ether (3 x 50 mL).

The organic laycr was washed with water, dried over anhydrous Na2S04 and

evaporated to give the crude product which was chromatographed using hexane:

ethyl acetate (98:2) as eluent to give the aryl pentadienethioates 71a-e.

C,,H,,CIOS, Ma1 Wt. 284 83

i;,3H,iBr0S2

Mol Wt 32'3 28

~'-~efhyl(2~,4E)-3-(4-chloropheny-5-

(methylsulfany1)-2.4-pentadienethioufe 71a was

obtained by the Vilsmeier reaction of 4,4-

bis(methylsulfany1)-2-phenyl-3-buten-2-01 69a (2

g, 7.2 mmol) as yellow crystalline solid. Yield 1.2

g (60%), mp 43-45 "C. IR v,,dcm ' 1640, 1565, 1540, 1020. 'H NMR (300 MHz, CDCI,) 6 2.30

(s, 3H, SMe), 2.33 (s, 3H, SMe), 5.73 (s, IH,

olefinic, HL), 6.52 (d, IH, 5 = 15.3 HZ, olefinic,

H ~ ) , 7.15 (d, 2H, J = 1 1 Hz, aromatic), 7.59

(d, l H, J = 15.3 Hz, olefinic, H" pppm. "C NMR

(75MHz , CDC13) 6 11.9, 14.4, 119.9, 121.4,

128.6, 130.3, 134.7, 137.8, 142.1, 149.7, 189.2

ppm. EIMS m/z (%) 284 (M', 5), 252 (25), 237

(96), 205 (72), 189 (30), 149 (loo), 139 (32), 113

(25), 101 (28), 75 (70).

~'-~eth~l(2E,4E)-3-(4-bromophenyI,-5-

(methylsulfanyl)-2.4-penladienethioare 71b was

obtained by the Vilsmeier reaction of

2-(4-bromopheny1)-4,4-bis(methylsu1fanyl)-3-

buten-2-01 69b (2 g, 7.2 mmol) as yellow

crystalline solid. Yield 1.2 g (60%) ; mp 60 "C. 'H

NMR (300 M H c CDCI3) 6 2.29 (s, 3H, SMe),

2.32 (s. 3H, SMe), 5.72 (s, IH, olefinic He), 6.51

(d, l H, J = 15.3 Hz, olefinic, H ~ ) , 7.08 (d, 2H, J =

8.1 Hz, aromatic), 7.41 (d, I , J = 8.1 Hz,

aromatic), 7.58 (d, IH, J = 15.3 Hz, olefinic, Ha)

ppm . liC NMR(75.47 M H z CDC13) 6 10.9, 13.4,

118.8, 120.3, 121.8, 129.8, 130.3, 130.5, 137.2,

141.1, 144.0, 148.0, 188.0ppm.

C,,HI~O~S? Mol W 280 41

C,rH,,OS,

Mol Wt 264 41

(methylsulfay~-2.4-pen/adienethioate 71c was

obtained by the Vilsmeier reaction of 2-(4-

ol 69c ( 2 g, 7.4 mmol) as yellow crystalline solid.

Yield 1.2 g (60%). IR v,,/cm-' 1595, 1470, 1420,

1240, 1165,785. 'H NMR (90 MHz, CDCI,) G 2.10

(s, :iH, SMe), 2.41 (s, 3H, SMe), 3.80 (s, 3H, OMe),

5.91 (s, IH, olefinic, Hc), 6.75 (d, IH, J = 18 Hz,

oletinic, H ~ ) , 7.15 (m, 4H, aromatic), 7.65 (d, IH, J

= 18Hz, olefinic, Ha) ppm. "C NMR (22.5 MHq

CK1l) 6 10.9, 13.4, 118.8, 120.3, 121.8, 129.8, 130.3,

130.5, 137.2, 141.1, 144.0, 148.0, 188.0 ppm. GCMS

mlz (%) 281 (S), 267 (7), 202 (8), 191 (7), 159 (lo),

145 (9), 135 (loo), 121 (25), 107 (22), 92 (25),

77 (48).

(methylsulfany1)-2,4-pentadienelhioale 71d was

obtained by the Vilsmeier reaction of 2-(4-

methylphenyl)-4.4-bis(methylsulfanyl)-3-buten-2-ol

69d ( 2g, 7.9 mmol) as deep brown oil. Yield 1 g

NMR (300 MHz, CDCI,) G 2.29 (s, 3H, SMe), 2.32

(s, 3H, SMe), 2.45 (s, 3H, Me), 5.84 (s, IH, olefinic,

H'), 6.67 (d, IH, J = 15.3 Hz, olefinic, H ~ ) , 7.18

(m, J H , aromatic), 7.76 (d, IH, J = 18 Hz, olefinic,

Ha)ppm. ''c NMR (75 MHq CDC13) 15 10.9, 13.4, 118.8, 120.3, 121.8, 129.8, 130.3, 130.5, 137.2,

141.1, 144, 148, 188 ppm. ElMS mlz (%) 264 (7),

23 1 ( 9 x 2 16 (1 00), 184 (40), 173 (3 I), 168 (77), 140

(39), 128 (52), 114 (59), 75 (32).

SCH.

'SCH:,

C,JH,,OS,

Mol Wt 250 38

2 4-pentadienethioate 71e was obtained by the

Vilsmeier reaction of 2-phenyl-4,4-

b1s(methylsulfanyl)-3-buten-2-ol 69e (2 g, 8.4

mmol) as a brown oil. Yield 1.14 g (55 %). IR

v,,/cm~' 1655, 1545, 1430, 1140, 760. ' H NMR

(90 MHz, CDCI,) F 2.31 (s, 3H, SMe), 2.40

(s. 3H, Sme), 5.90 (s, IH, oletinic, HC), 6.65 (d,

IH, J = 18 Hz, oletinic, H'), 7.45 (m, 4H,

aromatic), 7.60 (d, IH, J = 18Hz, olefinic, Ha)

ppm. GCMS m/z (%) 250 (2), 203 (loo), 160

(231, 155 (47), 130 (25), 115 (27), 102 (lo),

77 (12).

S)-~ethyl I-(( E )- (methylsulfanyl) ethenyll-3,4-

dihydro-2-napthalenecarbothioate 74 was

obtained by the Vilsmeier reaction of 2-

[bis(methylsulfanyl)methy lenel-l -methyl-l,2,3,4-

tetrahydro-I-napthalenol 73 (2 g, 7.5 mmol) as a

yellow clystalline solid. Yield 1.2 g (60%).mp

102-104 'C.'H NMR (200 MHz, CDCI3) 6 2.37

(s, 3H, SMe), 2.41 (s, 3H, SMe), 2.62 (m, 2H,

methylene), 2.74 (m, 2H, methylene), 6.52 (d, IH,

J = 16 Hz, olefinic, H'), 6.56 (d, IH, J = 16 Hz,

olefinic, Ha), 6.87 (d, IH, J = 16Hz, olefinic, H~)

7.21 (m, 3H, aromatic), 7.51 (d, IH, J = 8 Hz,

aromatic) ppm. I3C NMR (75 MHz, CDCI,) 6

12.6, 14.9, 26.1, 28.8, 30.1, 30.6, 121.3, 126.2,

126.7, 127.9, 128.8, 129.2, 130.8, 134.5, 134.6,

138.9, 140.1, 194.2 ppm.

5.3.2 General Procedure for the Synthesis of 4-(1,3-Dithiolan-2-y1iden)-3- aryl-2-butenal 99

The methyl Cirignard reagent was prepared from 1.41 g (10 mmol) methyl

iodide, 0.3 g (10.7 mmol) magnesium and a pinch of iodine crystals (0.10 g) in

ether. The methyl magnesium iodide was cooled to 0-5 O C and the cyclic ketene

dithioacetals (8.4 mmol) in ether was added slowly over 15 rnin. The mixture was

stirred at this temperature fbr half an hour and was poured over cold saturated

ammonium chloride solution. It was then extracted with ether (3 x 50 mL). The

combined organic layer was washed with water and dried over anhydrous sodium

sulfate. Ether was removed and the a-hydroxyketene dithioacetal fbrmed were

used for the next step without further purification.

The Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL)

and POC1, (1.24 mL, 10 mmol). The mixture was then stirred for 15 min. at room

temperature. The crude a-hydroxyketene dithioacetal obtained from the Grignard

reaction were dissolved in dry DMI' and added in about 15 min at 0-5°C. The

reaction mixture was stirred for 12h at room temperature, added to cold saturated

K2C03 solution (300mli) and extracted with diethyl ether (3 x 50 mL). The

organic laycr was washed with water, dried over anhydrous Na2S04 and

evaporated to give the crude product which was chromatographed using hexane:

ethyl acetate (98:2) as eluent to give 99.

99 was obtained by the Vilsmeier reaction of

1-(1,3-dithiolan-2-yliden)-2-phenyl-2-propanol 98

(2 g, 8.4 mmol) as a white crystalline solid. Yield o H c , i-) (." , .. -L .~ s 1.14 g (55%). mp 110 "C. ' H NMR (300 MHz, .-I

CDCl,) 8 3.27 (m, 4H, -SCH,-), 6.1 1 (d, l H, J =

C I ~ H I ~ O S ~ 9Hz, olefinic), 6.42 (s,lH,olefinic), 7.54 (m, 5H, Mo Wl 248 37 aromatic), 9.28 (d, IH, J = 9Hz, CHO) ppm. "C

NMR (75 MHz, CDCI,) 6 36.2, 41.0, 110.5,

115.9, 125.7, 127.2, 128.6, 128.9, 129.0, 130.2,

136.2, 154.0, 159.0, 193.0 ppm ElMS mlz (%)

248 M',(6), 222 (23), 191 (20), 172 (42), 149

(IOO), 143 (45), 115 (90), 105 (25), 85 (30).