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.
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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
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,