Chapter Four

Reactions of p-0x0 thioamides 41nd P-0x0 dithioesters with 1,2-Bielectrophiles

4.1 Introduction

The P-0x0 thioamides are usually formed from the reaction of enolizable cal ,any1

compounds with aryl or alkyl isothiocyanates. The active methylene ketone may be

treated with a base to generate the enolate anion which on subsequent reaction with

isothiocyanates afford the p-0x0 thioamides. Alternatively the enamines generated from

ketones also add to isothiocyanates to afford respective hnctionalized thioamides. Often

the adducts obtained from isothiocyanates and ketones or enamines are directly t~ ,ated

with 1,2-bielectrophiles such as a-haloketones to give heterocycles such as thiophenes or

thiazoles. We have examined the reactions of various substituted acetophenones with

phenyl isothiocyanates and their subsequent alkylation with a-haloketones. 'I'he k

intermediate ketene N,S-acetal obtained by the alkylation of the adduct has got three

possible modes of cyclizations. The study was aimed at understanding the most< of

cyclization that would be preferred under these conditions.

The P-0x0 dithioesters can in principle be prepared from similar reactions of

enolate anions or enamines with carbon disulfide followed by alkylation with one

equivalent of the alkylating agent. However such approaches meet with limited success.

Therefore we have employed the method developed by Junjappa and co-workers rec,,ntly.

This method involve the reaction of enolates derived from active methylene ketones with

dimethyl trithiocarbonate. The P-0x0 dithioesters have not been extensively used for

heterocyclic synthesis. We have carried out some studies on the alkylation of the p-0x0

dithioesters with 1,2-bielectrophiles such as 1.2-dibromoethane and phenacyl bromide.

1,2-Dibromoethane gave a product which involve alkylation of two molecules of

dithioesters with one molecule of 1,2-dibromoethane The reaction with phenacyl bromide

resulted in an unusual cyclization involving the intramolecular nucleophilic displacement of

methylthio group with the carbonyl oxygen.

1.1.1 Reactions of carbanions with isothiocyanates followed by

alkylation with functionalized electrophiles

Active methylene compounds react with aryl or alkyl isothiocyanates in the

presence of base to give an intermediate thiolate anion which on subsequent alky~ation

lead to the formation of functionalized ketene-S,N-acetals 5.1.3 The intermediate thiolate

anion on hydolysis furnish functionalized thioamides 4 (Scheme 1).

Scheme 1

If the alkylation is performed by an alkylating agent which is fiinctionali. d in

such a way that the intermediate ketene-S.N-acetal obtained can undergo firther

cyclization, that could be a convenient preparative method for a variety of function;~lized

heterocycles. There are some examples in the literature which involve alkylation of a-

oxoketene-S,N-acetals on nitrogen which on subsequent cyclization leads to the formatio~i

of 3-acyl pyrroles. Thus the alkylation of a-0x0 ketene-N,S-acetal with t,.omo

acetaldehide diethyl acetal undergo cyclization in hot DMF to give the pyrrole deriv i . t. lves

9 (Scheme 2)

o\N,H MeS + EayO& Br oky=OkJ I

MeS MeS

R I R

I K

6 7 8 9

Scheme 2

A similar alkylation of acyl ketene-N,S-acetals with propargyl bromide I the

presence of cuprous bromide in dioxane also gave pyrrole derivatives. However under

these conditions the alkylation occurs at the a-position of the ketene-N.S-acetal The

proposed intermediate is an allene in the formation of pyrrole which could be obtained by

a nucleophilic attack of the ketene N,S-acetal on the triple bond of the propargyl bromide

(Scheme 3) '

RI

o k H - - oh MeS MeS I

I MeS

I CH?

R R R

10

Scheme 3

In the reactions described above alkylations are performed on a pre-fcrn~cd

ketene-S,N-acetal. Alternatively such alkylations can be carried out directly aftc the

addition of the enolate to isothiocyanates. However in such cases alkylation preferably

occur at the sulfur atom and not at the nitrogen. Thus when the enolate ions derived from

substituted acetophenones were added to phenyl isothiocyanates and the subsequent

alkylation was performed by propargyl bromide the intermediate S-propargyl ketene N,S-

acetals underwent further cyclization to afford substituted thiazole derivatives (Scheme

4)

12

Scheme 4

While the alkylation of a secondary thioamide as in the reaction mentioned above

lead to the cyclization involving nitrogen, a similar alkylation of p-0x0 thioamides with

tertiary amino group with propargyl bromide gave 2-amino-3-acyl-4-methyl thiophenes in

good yields 16 (Scheme 5 ) '

15

Scheme 5

An alternative approach to the synthesis of heterocycles through the additi~~n of

enolates to isothiocyanates employs a-haloketones as the alkylating agent. There are

reports in the literature which describes alkylation of P-0x0 dithioesters and P-0x0

thioamides with a-ha~oketones*~ These reactions involve the alkylation at the thiolate

anion followed by an intramolecular nucleophilic attack of enolates on a carbonyl group or

a nitrile. For example Gompper and Schafer have described the reaction of the dianion of

the dithioic acid derived from methyl cyanoacetate with a-chloro acetamide. The reaction

proceeds under acidic conditions and the intermediate formed from the initial S-alkylation

undergo cyclization which involves addition to the nitrile group (Scheme 616

18

Scheme 6

Y = CN, C02Me, - c - ~ e

When the alkylation of the dithiolate dianion is carried out with two equivalents of

a-halocarbonyl compounds or a-halonitriles the reaction leads to the formation of

substituted thienothiophene24. 7a.7c.S

Several substituted a-cyanoketones were treated with carbon disulfide in the

presence of base and the intermediate dithiolate anion were alkylated sequentialy with

methyl iodide and a-haloketones esters or a-halonitriles to afford the respective

thiophenes 211c,h.7 (Scheme 7).

22 23 24

R= Aryl,; Y= -CN. -C02Me, -COMe

Scheme 8

Similar reactions leading to thienothiophenes were also observed during the alkylation of

the dithiolate anion derived from acetyl acetone 1c.9 (Scheme 9).

NBu 0

CH3

25 26 27

Scheme 9

The thiolate anion derived from simple (3-0x0 dithioesters were also alkylated with

a-haloesters, bromocrotonate a-halonitriles and amides." This is exemplified by the

reaction of p-0x0 dithioesters with bromocrotonate in the presence of potassium

carbonate in refluxing acetone (Scheme 10).

8 r d Acetone R SMe OMe

28 29 30

Scheme 10

Similar reactions of 13-0x0 thioamides where the intermediate is a ketene-N,S-

acetal also lead to cyclizations to the respective 2-amino substituted thiophenes 32

(Scheme 1 I)."."

3 1 32

Scheme 11

However when the alkylation was done with ethyl bromoacetate or bromoacetyl

chloride thiazolidones 35 are the products are obtained and not the thiopl~enes

(scheme12).12

Mohareb and co-workers have examined the reaction of

active methylene reagents with phenyl isothiocynate in the presence of base and have

studied the subsequent alkylation with a variety of functionalized electrophiles. They

usually get either a poly hnctionalized thiophene or a thiozoline derivative as the product f

For example the reaction of malononitrile or ethyl cyanoacetate with phenyl

isothiocyanate in the presence of base followed by alkylation with phenacyl bromide gave

the thiazoline derivative 37 (Scheme 13).13

00 S Na

b N , P h Br-CH2-03J3

A do R

I 0 H *>Nqph R <qN R

33 34 35

Scheme 12

37

Scheme 13

Similar reactions employing bromoacetyl coumarin as the alkylating agent also

gave the respective thiazole or thiophene as the product depending on the nature of the

starting substrate. Mohareb and co-workers have examined the reaction of 1,3 dicarbonyl

co~npounds such as acetyl acetone, ethyl acetoacetate, dibenzoyl methane,and diethyl

malonate with phenyl isothiocyanate and the adduct was further alkylated with phenacyl

bromide or chloroacetone to give the respective functionalized 2,3-dihydrothiazoles. As

expected alkylation with bromoacetyl bromide gave the corresponding thiazolidinone.lJ

4.1.2 Reactions of enamines

There are several examples which involve the.reaction of electron rich substrates

such as enamines, vinyl sulfides or ketene dithioacetals with aryl or alkyl isothiocyanates

that lead to the formation of heterocycles on subsequent cyclization. For example the

reaction of phenylamino cyclohexene 38 with benzoyl isothiocyanate afford the pyrimidine

thione 39 l 5

38 39

Scheme 14

The reaction of isothiocyanates leading to the formation of heterocycles have been

reviewed by Rajappa l6 The adduct formed from enamines and other electron rich

substrates with phenylisothiocyanate may be subjected to further reaction with

functionalized electrophiles for the synthesis of thiophene derivatives and thiazole

derivatives. Rajappa's group have developed a synthesis of thiophene derivatives, which

involve the reaction of an enamine with isothiocyanate followed by alkylation with a-

haloketones."

The enaminoketone derived from I-butyl acetoactate 39 form the adduct 40 with phenyl

isothiocyanate which cyclizes to the thiophene 41 on alkylation with phenacyl bromide In.

a-Haloesters and a-haloamides are also used for similar cyclization reactions leading to

the formation of thiophene derivatives.19

Enamino nitriles also undergo similar reactions, however here the cyclization

invole nitrile group rather than the enamino fbnctionality. The enamine moiety undergo

hydrolysis to give the carbonyl group in the product (Scheme 16). 20

Ot-Bu

Ph H&,ph 0

H

41

Scheme 15

43

Scheme 16

The ketene aminals 44 derived from nitromethane also react in a similar fashion.

The adduct 45 formed from ketene aminal and aryl or alkyl isothiocyanate was alkylated

with a-haloketones to afford the corresponding substituted thiophenes 46 (Scheme 17) *'

46

Scheme 17

Alternatively alkylation of the enamine isothiocyanate adducts with

bromonitromethane also provide thiophene derivatives substituted with the nitro

Reaction of enamines with isothiocyanates afford the enaminothioamides. The

chemistry of these intermediates other than their reactions with a-haloketones to form

heterocycles, particularly thiophene derivatives remain mostly unexplored..

4.2 Results and Discussion

The reactions of the enolate anions derived from substituted acetophenones in the

presence of a base such as sodium hydride in DMF with phenyl isothiocyanate followed

by alkylation with phenacyl bromide and a-bromopropiophenone were examined first.

Similar reactions were also carried out with acetylthiophene. Reactions of enolates derived

from acetyl acetone and ethyl acetoacetate were also examined. Finally a few reactions of

benzoyl dithioacetate were also examined.

4.2.1 Reactions of Enolates with Phenyl isothiocyanate followed by

alkylation with Phenacyl bromide

The reaction of the enolates derived from substituted acetophenones with

phenylisothiocyanate after alkylation with phenacyl bromide should lead to the formation

of an intermediate ketene N,S-acetal 53 where the phenacyl moiety is substituted on

sulfur. However this intermediate cannot be isolated, it undergo further cyclization

reactions under these conditions. There are three possible modes of cyclization as shown

in scheme 19 , 20 and 21. Scheme 19 shows direct nucleophilic attack of the nitrogen on

the carbonyl group of the phenacyl moiety. Subsequent removal of water should lead to

the formation of the substituted thiazole 54..Scheme 20 shows the cyclization involving

the enolate derived from the phenacyl moiety and the carbonyl group of the starting

acetophenone. Subsequent elimination of water leads to the formation of 2-phenylamino-

5-benzoyl thiophene 57..Scheme 21 shows the third possible mode of cyclization. Here

the electron rich a-carbon of the ketene N,S-acetal functionality add to the carbonyl

group. Elimination of water and aromatization affor'd, 2-phenylamino-3-aroyl thiophene

62.

50

Scheme 18

53

Scheme 19

Scheme 20

6 1

Scheme 21

We have examined the reaction of the enolate anion generated from p-

chloroacetophenone using NaH as base in dry DMF with equimolar amount of phenyl

isothiocyanate. The reaction mixture was allowed to stir at 0-5'C for six hours,then the

~ntermediate dianion was treated with phenacyl bromide and was stirred at room

temparature overnight..Work up of thereaction and purificationof the residue by column

chromatography over silicagel using hexane ethyl acetate mixture (20: 1) as solvent. gave a

product which was identified as 2-phenylamino-3-(4'-chlorobenzoyl)-4-pheny thiophene

64d on of spectral and analytical data. The product 64d was isolated as an yellow

crystalline solid having a melting point 145-46'~.

IR Spectrum (KBr, Fig 1) shows a broad band at v 3430 cm" due to OH

group and did not clearly show a band due to the carbonyl group. Bands at v 1580, 1529,

1490 cm-' are due to delocalized C=O and C=C stretching. The band at v 1255 cm-' was

assigned to C-N stretching. Bands at v 755,725,695 cm-' could be due to C-H

deformation.

Fig. 1 IR Spectrum (KBr) of compound 65d

a H b Me c OMe d a

65a-d

Scheme 22

Proton NMR (90 Mhz CDCI,, Fig 2) showed a peak at 6 6.30 ppm due to the

proton at 5 position of the thiophene ring. The multiplet appeared between 6 6.9 - 7.5

ppm account for the fourteen aromatic protons. A broad singlet appeared at 6 11.2ppm

due to OH proton

I3c NMR (22.4 MHz, CDCI3, Fig 3) shows peaks at 106.3, 127.5, 129.6, 130.2,

136.9. 138.3, 130.4, 141.5 due to aromatic carbon atoms. The peak at 162.2 is due to C-2

carbon and at 191.4 is due to carbonyl carbon. Based on UV, IR, 'H NMR and "C NMR

spectra the structure of the product was suggested to be 2-phenylamino 3(4'

chlorobenzoyl )-4-phenyl thiophene.

The structure was further confirmed by its mass spectrum (Fig 4), which gave

molecular ion peak as the base peak at m/z 390 (100%) and peak at 357 (63.3%) due to

M* - SH and peak at 139 (74.3%) due to CIC6H4CO'' and 11 1 (37.1%) due to ClC6Hst

and 77 (41.1%) due to C~HJ.'. Thus the mass fragmentation confirmed that the carbonyl

Fig. 2 'H NMR Spectrum (90 MHz) of compound 6Sd

-

CI

0

Mii

2/0 ZOO /PO /8U 170 /60 /& /IC 1 3 120 /YO /i70 W 80 70 b0 50 4 3 9 20 /d 0 -10 20

i

Fig. 3 "C NMR Spectrum (22.4 MHz) of compound 65d

Fig. 4 Mass Spectrum (EIMS) of compound 65d

group of the starting p-chloroacetophenone was not included in cyclizaton. Absence of

carbonyl group in the IR spectrum can be attributed to the contribution of the en01

tautomer of 65 which could be stabilized by intramolecular hydrogen bonding

65d

The reaction has been shown to be general and was carried out with acetophenon

63a and other substituted acetophenones 63b and 63c. In all cases 2-phenylamino-3-

aroyl-4-phenyl thiophenes 63 were the only products obtained in moderate to good yields.

All products were characterized with the help of spectral and analytical data

(Experimental).

We.have hrther examined the alkylation of thiolate anions obtained by the addition

ofp-chloroacetophenone to phenylisothiocynate by 2-bromopropiophenone. The product

obtained was 3-p-chlorobenzoyl-5-methyl-2-phenyl amino-4-phenyl thiophene 67 in 43%

yield. The structure was confirmed by spectral and analytical data and is described in the

experimental part of this chapter. This provide hrther evidence for the confirmation of the

structures of 65a-d as well.

The results described above, suggests that the cyclization involving the a-

carbon of the ketene N,S-acetal functionality and the carbonyl group of the phenacyl

moiety is preferred. Junjappa and co-workers have shown that, in the case of S-propargyl

ketene N,S-acetals, cycliition involving the nitrogen of the secondary amino substituent

is preferred to that involving the a-carbon of the ketene N,S-acetal hnctionality.

However when the amino substituent was tertiary, thiophene could be obtained by the

nucleophilic attack of the ketene N,S-acetal hnctionality to the allene derived from the

propargyl group (Scheme 20 and Scheme 21).

CI & C H ~ F ' ~ L - N = ~ S . NaH, DMF ph$-g-r c1 A I xph CH3

Scheme 23

However similar cyclization here, involving the phenacyl group instead of allene,

favour the cyclization involving enamino group, despite the fact that the amino substituent

is secondary. The mode of cyclization shown in Scheme 20 which involve the enolate ion

derived from the phenacyl moiety and the carbonyl group a-to the ketene N,S-acetal is not

favored. The carbonyl group a-to the ketene N,S-acetal is highly delocalized because of

the electron donation from the amino substituent. Thus the electrophilic characterof the

carbonyl group is considerably reduced. As a result of this reduced electrophilicity a

cyclization involving nucleophilic attack at this carbonyl group would not be favored

However, when the intermediate thiolate anion obtained by the addition of acetyl

thiophene to phenyl isothiocyanate on alkylation with phenacyl bromide gave the thiazole

derivative 69 in 80% yield under similar reaction condition (Scheme 24).

IR Spectrum of 69 (KBr, Fig 5) shows a broad band at v 3430 cm.' due to OH

group and a band due to the carbonyl group was not clearly observed. Bands at v 16 15,

1580, cm-I are due to the delocalized C=O and C=C stretching of the aromatic ring. The

band at v 1275cm-' was assigned to C-N stretching. Bands at v 755,715,695 cm" could

be due to C-H deformation.

Proton NMR (90 MHz CDCI3, Fig 6 ) showed a multiplet appeared between 6 6 9 -

7.5 ppm account for the 15 aromatic and the vinylic protons

"C NMR (22.4 Hz, CDCI3, Fig 7) shows peak at 6 176.201 ppm which would be

due to the carbonyl carbon. Peaks at 6 164.8, 146.8, 141.2, 137.6, 130.1, 129.7, 129.2,

129.0, 128.8, 128.6, 128.3, 128.1, 127.9, 127.4, 126.7, 117.7, 106.7, 87.8 ppm are due to

the aromatic carbon atoms.

Mass spectrum(Fig 8), which gave molecular ion peak at m/z 361 (55.0%) and the base

peak at 111 (100%). Other prominent peaks are at 328 (3.1%), 250 (21.1%). 215

(13.7%), 105 (64.1%), and 77 (35.8%). Based on UV, IR, 'H NMR, I3c NMR and Mass

spectra the structure of the product was suggested to be 3,4-diphenyl-2-(2-thienoyl

methy1ene)-2,3-dihydro-1.3-thiazole 69.

69

Scheme 24

Though the structure of thiazole 69 was confirmed with the help of spectral and

analytical data it is not very clear, why acetyl thiophene favor a cyclization involving the

nitrogen and the carbonyl group of the phenacyl moiety leading to the formation of the

Fig. 5 IR Spectrum (KBr) of compound 69

Fig. 6 'H NMR Spectrum (90 MHz) of compound 69

Fig. 7 "C NMR Spectrum (22.4 MHz) of compound 69

I Fig. 8 Mass Spectrum (EIMS) of compound 69

thiazole 69 This could be attributed to the reduced contribution of the nitrogen to the

delocalization of the carbonyl group because of the electron donating character of the

thiophene.

Finally we have examined the reactions of acetyl acetone and ethyl acetoacetate

under similar conditions. Here, since the a-position of the intermediate ketene-N,S-acetal

is substituted, cycl i t ion involving the enamine hnctionality is not possible. The

products that we have isolated were identified to be the ethyl-S-benzoyl-4-methyl-2-

phenylamino thiophene-3-carboxylate 71a and 2-phenylamino-3-acetyl-4-methyl-5-

benzoyl thiophene 71b, (Scheme 27) respectively from ethyl acetoacetate and acetyl

acetone. Similarly the structure of ethyl-5-benzoyl-4-methyl-2-phenylamino thiophene-3-

carboxylate 75a, obtained from ethyl acetoactate under similar conditions was

alsoconfirmed with the help of spectral data (Experimental) The structure of 2-

phenylamino-3-acetyl-4-methyl-5-benzoyl thiophenes 71b, was confirmed with spectral

data. The IR spectrum (Fig 9) shows the band due to the OH group at v 3430 cm.'

Bands at v 1610, 1580, 1538, 1490 cm-' are due to C=O and C=C stretching of of the

aromatic ring. The band at v 1260 cm-' was assigned to C-N stretching

The proton NMR spectra (90 MHz, Fig 10) in CDCI, showed a singlet integrating

for three protons at 6 1.7 ppm, due to the acetyl group. The methyl group at the C-4 of

the thiophene ring appeared as a singlet at 6 2.6 ppm. The multiplet at 6 7.1 - 7.9 ppm was

attributed to the aromatic protons. The broad singlet at 6 12.15 ppm is due to the proton

of the secondary amine hnctionality.

the I3c NMR spectra (22.4Hz, Fig 1l)in CDCI, 6 18.4, 31.4, 120.6, 124.9, 128.3,

128.5, 129.5, 131.6, 139.4, 144.9, 164.4ppm.

The mass spectrum of 71 (Fig 12) showed the molecular ion peak at m/e 335

(57.5%). Other prominent peaks were at m/e 302 (3.2%) (W-SH), 291 (4.7%) due to

(CH,CO)', 105 (100%) (PhCO)' and 77 (75.6%) (Ph)".

Since the cyclization involving the ketene N,S-acetal moiety is not possible,

there are only two possible modes of cyclization for the intermediate ketene N,S-acetal 72.

One involves the cyclization of the enolate derived from the phenacyl moiety and the

Fig. 10 'H NMR Spectrum (90 MHz) of compound 71a

Fig. 11 "C NMR Spectrum (22.4 MHz) of compound 71a

Fig. 12 Mass Spectrum (EIMS) ofconlpound 71a

carbonyl carbon of the acyl group, leading to the formation of thiophene derivatives 76

(Scheme 26).

70a, R = CH,

b, R = OC2H5

Scheme 25

.YCH3 Ph, -

I Ph. ~y&8 Ph

Ph. R % ~ ~ ~

0

Scheme 26

The alternate mode of cyclization involves deprotonation at the nitrogen and the

direct attack of the nitrogen to the carbonyl group and subsequent elimination of water to

give the thiazole 74. Mohareb and co-workers have recently reported reactions of the

adducts obtained from 1,3-dicarbonyl compounds and phenyl isothiocyanates with a-

haloketones. They have observed that the cyclization usually involves a direct nucleophilic

addition of the nitrogen to the carbonyl group of the alkylating agent leading to the

formation of thiazole derivatives 77 (Scheme 27).23

Base 9

=CH3

R-C-CH,-Br P h - N = G S

EtO

77

Scheme 27

However under our reaction conditions, the cyclization involving the acyl group

leading to the formation of thiophene was favoured. In the literature formation of similar

thiophenes have been reported from enaminoketones derived from 1,3-dicarbonyl

compounds.u

4.2.2 Reaction of p-0x0 dithioesters with 1,2-bielectrophiles

The adducts formed from active methylene ketones and aryl or alkyl

isothiocyanates on protonation afford P-0x0 thioamides. The reaction described in the

earlier section may be considered as the reaction of thiolate anions derived from p-0x0

thioamides and 1,2-bielectrophiles. In continuation with our studies involving

thiocarbonyl compounds having a carbonyl group at the j3-position we have next examined

the reaction of a-0x0 dithioesters with 1,2-bielectrophiles. The a-0x0 dithioester was

prepared from acetophenone Acetophenone on condensation with dimethyl

trithiocarbonate in the presence of sodium hydride in refluxing ben~ene .~ '

4.2.2.1 Reaction of benzoyl dithioacetate with 1,2-dibromoethane

When the benzoyl dithioacetate 78 was allowed to react with 1,2 dibromoethane in

the presence of potassium carbonate and acetone, a crystalline solid product melting point

145-146°C. was obtained in high yield (1.83g, 82%) This product was identified to be 79

(Scheme 28)on the basis of spectral data

IR Spectra O(Br, Fig 13) shows a strong band at v 1690 cm-' showing the

presence of carbonyl group,bands at v 1596, 1560, 1480, 1428, 1340, 1300 and1210 cm"

due to C=C stretching showing the presence of unsaturation. The bands at v 850, 760 and I 700 cm" are due to the C-H deformation. H NMR (300 MHz, CDCI,, Fig 14 ) shows

multiplet at 6 7.43-7.53 ppm integrating for six aromatic protons, and at 6 7.53-7.93 ppm

integrating for four aromatic protons. There were three singlets between 6 6.80-6.97 pprn

(IH) and a singlet at 6 7.26 ppm (IH) due to vinylic protons respectively. The singlet at 6

3.41 ppm was due to the four methylene protons. There was a multiplet integrating for six

hydrogen at 6 2.51-2.58 ppm due to the methyl thio groups. Mass Spectra (Fig 15) shows

peak at m/z 224 (14.9%) due to parent ion and base peak at m/z 106 (100%) due to

PhCOt ion. Other fragments are 192 (31.1%), 165 (20.4%), 132 (33.5%), 78 (67.1%).

The peak at m/z 224 results from the cleavage of the molecule to two halves at the C-C

bond of the ethane unit.

Under suitable conditions the intermediate 79 should get transformed in to the

2,2'-bithiophene 80. We have attempted a direct reaction of the benzoyl dithioacetate 78

with 1,2-dibromoethane in the presence of sodium hydride in benzene. However we could

only isolate low yield of 79 . Under these conditions deprotonation at the methyl thio

group of ketene dithioacetals are known to afford thiophene derivatives .26 However we

could not reach a suitable reaction condition to prepare the 2,2'-bithiophene 80.

4.2.2.2 Reaction of benzoyl dithioacetate with Phenacyl bromide.

We have next examined the reaction of benzoyl dithioacetate 78 with phenacyl

bromide in the presence of a base. The reaction was carried out in the presence of sodium

hydride as base in benzene at room temperature for 24h. After usual work up and

purification by chromatography over silicagel using hexane:ethylacetate mixture (I 5:2ml)

Fig. 13 IR Spectrum (KBr) of compound 79

Fig. 14 'H NMR Spectrum (300 MHz) of compound 79

-

Fig. 15 Mass Spectrum (EIMS) of compound 79

as eluent an yellow crystalline solid was isolated in 52% yield. The compound had a nlp

of 152%. The structure of this compound was confirmed as 4-phenyl-2-(2'benzoyl

"methylene)-2,3-dihydro-l,3-oxathiole 83 on the basis of spectral data.

Br- M2 - -Br Acetone

MeS

79

Scheme 28

The IR spectrum (KBr, Fig 16) of 83 showed a band due to the carbonyl group at

v 1690 cm-'. The other prominent bands in the IR spectrum were at v 1568, 1480, 1300,

1120. 870, 760 and 700 cm". The proton NMR spectrum (300MHz. CDCI,, Fig 17 )

shows a singlet at 6 6.67 ppm integrating for one vinylic proton. The aromatic protons

appeared as multiplets integrating for two protons between 6 6.67-7.23 ppm. for five

protons between 6 7.26-7.55 ppm, for two protons between 6 7.66-7.70 ppm and for two

protons between 6 7.99-8.08 ppm. The mass spectrum of 83 ( Fig 18)showed the

molecular ion peak at m/z 280 (99%). The other prominant peaks in the mass spectra

were at 203(66.9%), 134(47.6%), 105(82.8%), 77(100%).

Fig. 16 LR Spectrum (KBr) o f compound 83

Fig. 17 'H NMR Spectrum (300 MHz) o f compound 83

100 71 2BO

69

3

63

50 /00 /SO 200 260 -rW 350

i L

Fig. 18 Mass Spectrum (EIMS) of cornpou~id 83

/05

a9

303

12-4

82 83

Scheme 29

In one of the alkylation reactions of P-0x0 dithioesters, using bromocrotonate.

Junjappa and co-workers have found that the intermediate ketene dithioacetal 90 cyclizes

to the thiophene derivative 91 (Scheme 32).17

Scheme 30

Similar reactions leading to the formation of thiophenes have been reported by

other groups as well. Alkylations of the intermediate thiolate anions formed by the

addition of thiolate anion with bromoacetate or bromoacetonitrile lead to the formation of

thiophene derivativesz8

The reaction undertook a rather unusual pathway, when the alkylation of benzoyl

dithioacetate was carried out with phenacyl bromide in the presence of sodium hydride.

The enolate ion derived from the phenacyl moiety did not favor an addition to the carbonyl

group through the carbon to form the thiazole derivative 89 (Scheme 3 1)

88 89

Scheme 31

Instead the direct conjugate attack of the enolate 91 displacing the methylthio

group lead to the formation of the oxathiole derivative (Scheme 32).

Oxathiafulvenes 85 can be prepared by nucleophilic addition of enolates to 2-

amino substituted 1,3-oxathiaolium cations. The intermediate formed on the addition of

nucleophiles to 1,3- oxathiolium cations may also lead to ring opening and subsequent

cyclization to thiophene derivatives. 29

The spectral data of oxathiol-2-yilidene derivatives 87 indicate that the

contribution of polarized structure to the resonance hybrid is small. 30 Benzoyl substituted

oxathiahlvene (89 R' = PhCO, RZ = H) showed the carbonyl peak at v 1690 cm.' which

suggests that the delocalization, involving the carbonyl group is very less.

83

Scheme 32

Scheme 33

4.3 Conclusions

The a-0x0 ketene-N,S-acetals, obtained by the alkylation of the adducts formed

from substituted acetophenones and phenyl isothiocyanate, with a-haloketones such as

phenacyl bromide or a-bromo propiophenone preferably undergo intramolecular

cyclization involving the addition of the enamine hnctionality to the carbonyl group. It is

interesting to note that cycliation involving a new carbon carbon bond formation is

preferred to the direct intramolecular addition of the nitrogen to the carbonyl group even

when the amino substituent is secondary. When the a-position of the intermediate ketene

N,S-acetal is substituted with an acyl group intramolecular aldol type condensation is

preferred to the direct addition of the nitrogen to the carbonyl group, at least under our

experimental conditions.

The formation of the thiophene derivatives rather than the thiazoles, from the P- 0x0 thioamides derived from ethyl acetoacetate and acetyl acetone illustrates that an

intramolecular aldol reaction is favored.

Alkylation of benzoyl dithioacetate with 1,2-dibromoethane lead to the formation

of substituted 1,2-bis (vinylthio) ethane which has resulted from the alkylation involving

two molecules of dithioacetate with one molecule of 1.2-dibromoetl~ane. Alkylation of the

thiolate anion derived from benzoyldithioacetate with phenacyl bromide, underwent an

unusual cyclization leading to the formation of a substituted oxathiafulvene, resulting from

the direct displacement of the methylthio group by the oxygen atom of the enolate.

The reaction of P-0x0 thioamides or P-oxodithioesters with hnctionalized

electrophiles provide valuable methods for the synthesis of heterocycles, such as thiophene

and thiazole derivatives. The results described here shines more light on the selectivity of

the reaction pathways. The unusual cyclization leading to the formation of 1,3-oxathiole

opens an easy synthesis of these heterocycles which would have important application in

synthesis, and in other areas as well.

4.4 Experimental

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

apparatus. Infrared spectra were measured with a Shimadzu IR-470 spectrometer and are

given as cm". Proton NMR spectra were recorded on a varian 390 (90 MHz), Bmker

WM 250 (250 MHz), or on a Bmker WM 200 (200 MHz) spectrometer in CDCl,

Carbon-13 NMR spectra were recorded on a Bmker WM 250 (62.9 MHz) or on a Bmker

WM 200 (50.8 MHz) spectrometer in CDCI3. Chemical shifts are reported in parts per

million (ppm) downfield from internal tetra methyl silane. Coupling constants J are given

in Hz. Electron impact mass spectra were obtained on a Finnigen-Mat 3 12 instrument..

4.4.1 Reactions of enolates from substituted acetopohenones with

phenyl isothiocyanate followed by alkylation with phenacyl bromide

3-Aroyl-2-phenylamino-4-phenylthiophenes (65a-d) To an ice cooled and well

stirred suspension of sodium hydride (480mg,lOmmol, 50%) in dry DMF (20 mL),

substituted acetophenone 63 (5mmol) was added followed by phenyl isothiocyanate

(0.67g, 5mmol) in 5ml DMF. The mixture was stirred at 0-5' C for six hours. Then

phenacyl bromide (0.96g, 5mmol) in 5ml DMF was added slowly over half an hour. The

reaction mixture was stirred overnight at room temperature and then poured over crushed

ice (250g) and extracted with diethyl ether (3x50mL). The organic layer was dried over

anhydrous sodium sulfate and was evaporated to give a brown viscous residue. The

residue was column chromatographed over silicagel (60-120 mesh) using hexane:ethyl

acetate (20: 1) as eluent to give 65 which were recrystallized from hexane:chloroform

mixture (30: 1).

3-Benzoyl-2-phenylamino-4-phenylthiophene (65a) was

obtained from the reaction of acetophenone with phenyl

isothiocyanate as an yellow crystalline solid (1.24g, 70% yield) P h mp 118-1 19 "C; IR (KBr, u cm-') 3430 (broad), 1585, 1595,

1570, 1540, 1255, 745, 735, 700; UV Lax(€) (CH3OH) 394

(17000). 249 (36700) nm; 1H NMR (CDCI,) 6 6.00 (s,lH),

6.55-7.35 (m,15H), 11.50 (s,IH) ppm; EIMS ( d z ) 355 (loo%,

M' ), 322 (44.9%), 277 (15.5%), 262 (1 5.6%), 105 (38.7%),

77 (23.5%); Anal. Calcd. for C23H17NOS (355.45) C, 77.72;

y 4.82; N, 3.94% Found C, 77.80; H, 4.97; N, 3.85%.

2-Phenylamino-3-(4'-methylbenzoy1)-4-phey thiophene

(65b) was obtained from the reaction of p-methyl

acetophenone with phenyl isothiocyanate as an yellow

crystalline solid (1.07g, 58% yield); m.p 130-31'~; IR (KBr, u

M~ mPh cm-I) 343O(broad), 1600. 1560, 1540, 255. 760, 745. 735. Ph 700; W &(E) (CH30H) 393 (18100), 297 (27900), 277

(28600). 248 (34900) nm.; 'H NMR (CDC13) 6 2.1 (s,3H), 6.1

(s,lH). 6.5-7.4 (m,14H), 11.2 (s,lH) ppm; EIMS ( d z ) 369

(75.2%, ) 336 (29.5%), 119 (83.7%), 91 (100%); 77

(98.9%).; Anal. Calcd. for C2sHI9NOS (369.12) C. 78.02; H,

5.19;N, 3.79%FoundC, 78.14;H, 5.08;N, 3.70%.

2-Phenylamino-3-(4'-methoxybenzoyl)-4-pheny thiophene

(6%) was obtained from the reaction of p-methoxy

acetophenone with phenyl isothiocyanate as an yellow

crystalline solid (1.05g, 55% yield); m.p 105-06°C; IR (KBr,u

M<O mPh cm.') 345O(broad), 1600. 1580. 1530, 1255. 745, 735. 700; [H Ph NMR (CDC13) 6 3.50 (s,3H), 6.15-7.50 (m,15H ), 11.2 (s,lH );

EIMS ( d z ) 385 (3.8%, M') 355 (21.2%), 256 (43. I%), 223

(28.7%), 106 (100%). 112 (16.6%). 77 (84.2%); Anal. Calcd.

for C ~ J H I P N O ~ S (385.1 1) C, 74.78; H, 4.97; N, 3.64% Found

C, 74.65; H, 4.86; N, 3.76%. UV Li(€) (CHIOH) 348

(36760), 262 (49782).;

2-Phenylamino-3-(4'-chlorobenzoyl)-4-phey thiophene

(654 was obtained from the reaction of p-chloro

acetophenone with phenyl isothiocyanate as an yellow

crystalline solid (1.2g, 62% yield); m.p 145-46°C; IR (KBr, u

cm-') 3430(broad), 1580, 1529, 1490, 255, 755, 725, 695; UV

CI &ph ~ ~ ) ( C H ~ O H ) 3 9 4 ( 1 3 5 0 0 ) , 2 4 0 ( 3 3 3 0 0 ) . 2 1 1 ( 3 3 7 0 0 ) n m . ; Ph IH NMR (CDCI,) 6 6.30 (s,lH ), 6.9 - 7.5 (m,14H), 11.2

(s,IH); "cNMR 6 106.3, 127.5, 129.6, 130.2, 136.9, 138.3,

130.4, 141.5, 162.2, 191.4 ppm.; EIMS (mlz) 390 (M'+I.

loo% ) 357 (63.3%), 139 (74.3%). I l l (37.1%), 77 (41.1%).;

Anal. Calcd. for CUHI~CINOS (389.46) C, 70.94; H, 4.14; N,

3.60% Found C, 71.06; H, 4.03; N, 3.49%.

4.4.2Reactions of enolates from substituted acetopohenones with phenyl

isothiocyanate followed by alkylation with a-brorno-propiophenone

3-(4'-Chlorobenzoyl)-5-methyl-4-phenyI-2-pheny1aminothiophene (66) To an

ice cooled and well stirred suspension of sodium hydride (480mg,lOmmol, 50%) in dry

DMF (20 mL), p-chloroacetophenone (0.77g, Smmol) was added followed by phenyl

isothiocyanate (0.67 g, 5mmol) in 5ml DMF. The mixture was stirred at 0-5' C for six

hours. Then the 2-bromopropiophenone (1.13g, 5mmol) in 5ml DMF was added slowly

over half an hour. The reaction mixture was stirred overnight at room temperature and

then poured over crushed ice (250g) and extracted with diethyl ether (3xSOmL). The

organic layer was dried over anhydrous sodium sulfate and was evaporated to give a

brown viscous residue. The residue was column chromatographed over silicagel (60-120

mesh) using hexane:ethyl acetate (20:l) as eluent to give the substituted thiophenes 17

which was recrystallized from hexane:chloroform mixture (30:l).

3-p-Chlorobenzoyl-5-methyl-4-phenyl-2-phenylamino

thiophene (66) was obtained from the reaction of p-chloro

acetophenone with phenyl isothiocyanate followed by alkylation

with 2-bromopropiophenone as an yellow crystalline solid

(0.86g, 43%yield); m.p: 128-29°C; IR (KBr,u cm") 1578

Ci 1540,(C-Cstr), 1275(C-Nstr) 780, 755, 735, 695(C-Hdef); UV

Ph &(E) (CH3OH) 399 (11869), 232 (32273). 208 (48889).;1H

NMR (CDCI3 6 ppm) 2.24(s,3H) 6.90-760(m,14H)

11.4(s,lH); C ( G ppm): 135.894, 130.255 ,129808.

128.435, 127.630, 123.662, 1 19.395. EIMS (mtz) 403 (loo%,

M.) 392 (5.6%), 372 (1 1.6%). 257 (39.3%), 216 (16.2%), 140

(81 7%), 106 (50.4%). 93 (17.2%). 77 (40. I%).; Anal. Calcd.

for C Z ~ H ~ ~ C ~ N O S (403.08) C, 71.45; H, 4.50; N, 3.47% Found

C, 71.33;H,4.66;N, 3.34%.

4.4.3 Reaction of the enolates from acetylthiophene with phenyl

isothiocyanate followed by alkylation with phenacylbromide

3,4-Diphenyl-2-(2-thienoyl methylene)-2,3-dihydro-1,3-thiazole (69) To an ice

cooled and well stirred suspension of sodium hydride (480mg,10mmol, 50%) in dry DMF

(20 mL), acetylthiophene (0.63g. Smmol) was added followed by phenyl isothiocyanate

(0.67 g, 5mmol) in 5ml D m . The mixture was stirred at 0-5OC for six hours. Then

phenacyl bromide (0.96g, Smmol) in 5ml DMF was added slowly over half an hour. The

reaction mixture was stirred overnight at room temperature and then poured over crushed

ice (250g) and extracted with diethyl ether (3x50mL). The organic layer was dried over

anhydrous sodium sulfate and was evaporated to give a brown viscous residue. The

residue was column chromatographed over silicagel (60-120 mesh) using hexane:ethyl

acetate (20: 1) as eluent to give the substituted thiazole 69 which was recrystallized from

hexane:chloroform mixture (30: 1).

3,4-Diphenyl-2-(2-thienoyhethylene)-2,3-dihydro-1,3-

thiazole (69) was obtained from the reaction of acetyl

thiophene with phenyl isothiocyanate followed by alkylation

with phenacyl bromide as an yellow solid (1.4g. 80% yield);

m.p 128-29°C; IR (KBr, v cm-') 3430(broad), 1615, 1580,

1275, 755, 715, 695; UV ?L,&E) (CH3OH) 396 ( 1 1900), 21 1

(25600) nm.;. lH NMR (CDCI3) 6 6.1 - 8.2 (m, 15H Aromatic

and vinylic) ppm; "C NMR 6 176.201, 164.774, 146.784,

141.175, 137.565, 130.076, 129.748, 129.151, 129.032,

128.823, 128.614, 128.286, 128.137, 127.928, 127.361,

126.675, 117.695, 106.745, 87.800 ppm; EIMS (rnlz) 361

(55%. M*) 328 (3.1%), 250 (21.1%), 215 (13.7%), 1 I l(lOO%)

105 (64.1%), 77 (35.8%).; Anal. Calcd. for C2,H~5NOS~

(361.06) C, 69.97; H, 4.19; N, 3.88% Found C, 7011; H,

4.30; N, 3.74%.

4.4.4 Reaction of the enolates from acetylacetone with phenyl

isothiocyanate followed by alkylation with phenacylbromide

5-Benzoyl-3-acetyl-4-methyl-2-phenylaminothiophene (71a)

To an ice cooled and well stirred suspension of sodium hydride (480mg,10mmol,

50%) in dry DMF (20 mL), acetyl acetone (05g, 5mmol) was added followed by phenyl

isothiocyanate (0.67 g, 5mmol) in 5ml DMF. The mixture was stirred at 0-5OC for six

hours. Then phenacyl bromide (0.96g, 5mmol) in 5ml DMF was added slowly over half

an hour. The reaction mixture was stirred overnight at room temperature and then poured

over crushed ice (250g) and extracted with diethyl ether (3x50mL). The organic layer

was dried over anhydrous sodium sulfate and was evaporated to give a brown viscous

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

hexane:ethyl acetate (20:l) as eluent to give 5-Benzoyl-3-acetyl-4-methyl-2-

phenylaminothiophene 7la"which was recrystallized from hexane:chloroform mixture

(30: 1) .

5-Benzoyl-3-acetyl-4-methyl-2-phenylamino

thiophene (71a) was obtained from the reaction of acetyl

acetone with phenyl isothiocyanate as an yellow crystalline solid

(117g. 70% yield); m.p 172-73°C; 1R (KBr,u cm")

3430(broad), 1610, 1580, 1538, 490, 1260; UV La,(€)

(CH3OH) 371 (23300), 246 (30400), 206 (38300) nm.; 1H H 0 NMR (CDCI,) 6 1.7(s,3H), 2.6(s,3H), 7.1-7.9(m, IOH).

12.15(broad-s,lH) ppm; I3c NMR 6 I!' 3, 3 1.4, 50.9, 120.6.

124.9, 127.9, 128.3, 128.5, 129.5, 131.6, 139.4, 144.9,

164.4.ppm; EIMS (mlz): 335 (57.5% M'), 302 (3.2%), 291

(4.7%). 105(100%), 77 (75.6%); Anal. Calcd. for CZOH,,NO~S

(335.10) C, 71.62; H, 5.11; N, 4.18% Found C, 71.64; H.

4.97; N. 4.12%.

4.4.5 Reaction of the enolates from ethylacetoacetate with phenyl

isothiocyanate followed by alkylation with phenacylbromide

Ethyl-5-benzoyl-4-methyl-2-phenylamino thiophene-3-carboxylate(71b) To

an ice cooled and well stirred suspension of sodium hydride (480mg, I Ommol, 50%) in dry

DMF (20 mL), ethyl acetoacetate 7b (5mmol) was added followed by phenyl

isothiocyanate (0.67 g, 5mmol) in 5ml DMF. The mixture was stirred at 0-5OC for six

hours. Then phenacyl bromide (0.96g, 5mmol) in 5ml DMF was added slowly over half

an hour. The reaction mixture was stirred overnight at room temperature and then poured

over crushed ice (250g) and extracted with diethyl ether (3xSOmL). The organic laycr

was dried over anhydrous sodium sulfate and was evaporated to give a brown viscous

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

hexane:ethyl acetate (20: 1) as eluent to give the ethyl-5-benzoyl-4-methyl-2-phenylamino

thiophene-3-carboxylate 71b~~which was recrystallized from hexane:chloroform mixture

(30: I ) .

Ethyl-5-Benzoyl-4-methyl-2-phenylamino

thiophene-3-carboxylate (71b) was obtained from the

reaction of acetyl acetone with phenyl ethylacetoacetate as an

yellow crystalline solid (1.35g, 74% yield); m.p 169°C; R ( h C i 0

~ h . KBr, u cm 'I ) 3430(broad), 1635, 1619, 1595, 1240; UV

I.,-(€) (CH30H) 375 (13900), 323 (10500). 229 (21900), 208

(23300) nm.; 1H NMR (CDCI,) 6 1.45 (d,3H J=7Hz)

24(s,3H) 4.40(q,J=7Hz) 7.00-8.00(m. l OH) 10.7(s I H) ppm.

"C NMR 6 4.3, 17.9, 60.5, 120.1, 124.5, 1281, 128.3, 128.6.

129.6, 131.5 ppm; EIMS (mlz) 365 (24.9%, M') 3 18 (41.2%),

105 (100%). 93 (38.6%), 77 (87.7%); Anal. Calcd. for

C ~ I H I ~ N O ~ S (365.11) C, 69.02; H, 5.24; N, 3.84% Found C,

69.16; H, 5.1 1; N, 3.69%.

4.4.6 Reaction of the benzoyl dithioacetate with 1,2-dibromoethane

Substituted-1,2-bis (vinylthio) ethane 79 Benzoyl dithioacetate ( lg , 5mmol)

was dissolved in acetone (20 mL) and stirred overnight at room temperature in the

presence of potassium carbonate (2.7g, 20mmol) and then poured over crushed ice (250s)

and extracted with diethyl ether (3x50mL). The organic layer was dried over anhydrous

sodium sulfate and was evaporated to give a reddish brown residue. The residue was

column chromatographed over silicagel (60-120 mesh) using hexane:ethyl acetate (10: 1 )

as eluent to give 79 which were recrystallized from hexane:chloroform mixture (25: 1).

Substituted-1,2-bis (vinylthio) ethane 79 was isolated as an

yellow crystalline solid (1.83g, 82% yield); m p 14.5-46"C;, 1R

O(Br,u cm'l) 1690, 1596, 1560, 1480, 1428, 1340, 1300, 1210,

850. 760, 700 cm-' 1H N h (300MHz. CDCI,) 6 2.51-2.58

m. 0 (m, 6H -SCH3), 3 .41 (~ , 4 H, -CH2-CHZ-). 6.80-6.98 (m, IH,

vinylic) 7.25 (s, lH, vinylic) 7.43-7.53 (m, 6H, aromatic) 7.88-

7.93 (4H, aromatic); E M S ( d z ) 224 (149%). 106 (loo%),

192 (3 I . 1%). 165 (20.4%), 132 (33.5%). 78 (67.1%)

4.4.7 Reaction of the benzoyl dithioacetate with phenacyl bromide

4-Phenyl-2-(2'-benzoylmethylene)-2,3-dihydro-l,3-oxathiole 83 To an ice

cooled and well stirred suspension of sodium hydride (480mg,10mmol, 50%) in dry

benzene (20 mL), benzoyl dithioacetate 78 (Ig, 5mmol) was added and stirred for half an

hour. Then phenacyl bromide (0.96g, 5mmol) in lOml benzene was added slowly over

half an hour. The mixture was stirred overnight at room temperature and then poured over

crushed ice (250g) and extracted with diethyl ether (3x50mL). The organic layer was

dried over anhydrous sodium sulfate and was evaporated to give a brown viscous residue.

The residue was column chromatographed over silicagel (60-120 mesh) using hexane:ethyl

acetate (15:2) as eluent to give 83 which were recrystallized from hexane:chloroform

mixture (25: 1).

oxathiole 83 was isolated as an yellow crystalline solid (0.73g.

52% yield); m.p 152°C;. IR (KBr,u cm-I) 1690, 1568, 1480.

1300, 1120, 870, 760, 700 ; IH NMR (300MHz. CDCI,) 6

6.67(-s, lH), 6.67-7.23 (m, 2H) 7.26-7.55 (ni, 5H) 7.66-7.70

(m, 2H) 7.99-8.02 (m, 2H) ppm; EIMS (mlz) 280 (99%M'),

302 (3.2%), 291 (4.7%), 105(100%), 77 (75.6%), 203(66.9%),

134(47.6%), 105(82.8%), 77(100%).

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