Synthesis of 2,4,5-trisubstituted thiazoles via lawesson's reagent-mediated chemoselective thionation-cyclization of functionalized enamides

Article abstract of DOI:10.1021/jo401208u

An efficient route to 2-phenyl/(2-thienyl)-5-(het)aryl/(methylthio)-4- functionalized thiazoles via one-step chemoselective thionation-cyclization of highly functionalized enamides mediated by Lawesson's reagent is reported. These enamide precursors are obtained by nucleophilic ring-opening of 2-phenyl/(2-thienyl)-4-[bis(methylthio)/(methylthio)(het)arylmethylene] -5-oxazolones with alkoxides and a variety of primary aromatic/aliphatic amines or amino acid esters, leading to the introduction of an ester, an N-substituted carboxamide, or a peptide functionality in the 4-position of the product thiazoles.

Full text of DOI:10.1021/jo401208u

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Note
Synthesis of 2,4,5-Trisubstituted Thiazoles via Lawesson’s Reagent
Mediated Chemoselective Thionation-Cyclization of Functionalized Enamides
S. Vijay Kumar, G. Parameshwarappa, and Hiriyakkanavar Ila
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Jul 2013
Downloaded from http://pubs.acs.org on July 2, 2013
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Synthesis of 2,4,5ꢀTrisubstituted Thiazoles via
Lawesson’s Reagent Mediated Chemoselective
ThionationꢀCyclization of Functionalized Enamides
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S. Vijay Kumar, G. Parameshwarappa and H. Ila*
New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur,
Bangaloreꢀ560064, Karnataka, India
Eꢀmail: hila@jncasr.ac.in
O
MeS
H
N
Thienyl-2/Ph
(Het)Ar/SMe
Nu
N
Nu
O
(Het)Ar/SMe
O
Thienyl-2/Ph
MeS
O
R
OEt
Nu = Oalk, R1NH ,
Lawesson's reagent
H2N
2
chemoselective
thionation
O
O
O
Nu
H
Thienyl-2/Ph
N
N
Nu
Thienyl-2/Ph
(Het)Ar/SMe
S
S
(Het)Ar/SMe
MeS
22 examples, 60-80%
R
OEt
O
O
O
R1
N
Oalk
N
O
H
H
N
N
N
Thienyl-2/Ph
Thienyl-2/Ph
Thienyl-2/Ph
(Het)Ar/SMe
(Het)Ar/SMe
(Het)Ar
S
S
S
60-80%
62-76%
62-70%
Abstract: An efficient route to 2ꢀphenyl/(2ꢀthienyl)ꢀ5ꢀ(het)aryl/(methylthio)ꢀ4ꢀfunctionalized
thiazoles via one step chemoselective thionationꢀcyclization of highly functionalized
enamides, mediated by Lawesson’s reagent has been reported. These enamide precursors are
obtained by nucleophilic ring opening of 2ꢀphenyl/(2ꢀthienyl)ꢀ4ꢀ[bis(methylthio)/
(methylthio)(het)arylmethylene]ꢀ5ꢀoxazolones with alkoxides and a variety of primary
aromatic/aliphatic amines or amino acid esters, thus leading to the introduction of an ester, Nꢀ
substituted carboxamide or peptide functionality in the 4ꢀposition of the product thiazoles.
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Thiazoles1 are the most commonly encountered heterocycles among the compounds of
biological interest and in bioactive natural products of microbial and marine origin
(particularly non ribosomal peptides), exhibiting important biological activities,1,2a such as
antitumor, antifungal, antibiotic, antiviral, antibacterial as well as peptide mimetic2aꢀb and
enzyme inhibitors.2cꢀe In nature, thiazolium ring is chemically active centre in the coenzyme
derived from vitamin B1 (thiamine).3 Synthetic thiazoles also occupy a prominent position in
drug discovery process and this ring system is found in several marketed drugs.4 Also, these
class of compounds have found broad application as functional materials,5a liquid crystals for
ferroelectric display5b and as cosmetic sunscreens.5c Therefore, in view of the structural
diversity of complex naturally occurring thiazoles, along with broad application of synthetic
analogs in various fields, new methods continue to be developed for thiazole synthesis.1,6
The two most common approaches for substituted thiazoles consist of either
functionalization of preꢀexisting core1,7 or ring assembly from acyclic precursors.1 Among the
two, the latter route has greater potential for rapid generation of diversity in functionalized
thiazoles. Within this group, Hantzsch thiazole synthesis8 (and its modified versions)9
entailing condensation of a suitably substituted αꢀhaloketone (or its equivalents) with
thioamide has proven to be a powerful method for synthesis of 2,4,5ꢀsubstituted thiazoles.
Other methods include reaction of αꢀaminonitriles with CS2, COS, isothiocyanates and
dithiocarboxlic acids.4b,9h Thionationꢀcyclization of αꢀacylaminoketones (or related
precursors) with various thionation agents (P2S5, Lawesson’s or Belleau’s reagent, H2S)
(Gabriel synthesis) is also a promising method for the synthesis of substituted thiazoles.10
However this method is not much explored, probably due to the lack of availability of
structural variants of αꢀacylaminocarbonyl compounds. Recently, Chen and coꢀworkers have
reported synthesis of 2ꢀsubstitutedꢀ4ꢀphenylꢀ5ꢀaminothiazoles in moderate yields, involving
thionation of αꢀacylglycinamides with either Lawesson’s or Belleau’s reagent and subsequent
TFAA mediated cyclization of thioamide intermediates.11 Same workers, later on developed a
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four component Ugi reaction using ammonia as amine component, for simple one step
assembly of diamide precursors, which were transformed into 2,4ꢀsubstituted 5ꢀprimary or
secondary aminothiazoles library by thionation with Lawesson’s reagent, although in
moderate yields.12 SanzꢀCervera and coꢀworkers13 have recently described an efficient
fluorous and solution phase synthesis of small library of 2,5ꢀsubstituted thiazoleꢀ4ꢀcarboxylic
esters as potential antibacterials, involving thionation and cyclization of αꢀamidoꢀβꢀketoesters
(obtained by double acylation of protected glycinates) with Lawesson’s reagent.
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S
S
MeO
P
P
OMe
S
S
Lawesson's Reagent (LR)
Our own interest in thiazole synthesis derives from our recently reported protocol for
efficient synthesis of 2ꢀphenylꢀ5ꢀ(methylthio)/(het)arylꢀ4ꢀfunctionlized oxazoles 5-6 from
common
2ꢀphenylꢀ4ꢀ[(methylthio)ꢀhet(aryl)/bis(methylthio)methylene]ꢀ5ꢀoxazolone
precursors 1 and 2 (Scheme 1).14,15 The oxazolones 1 and 2 are shown to undergo facile ring
opening in the presence of various oxygen (alkoxides), nitrogen (primary/secondary amines)
and carbon (Grignard reagents) nucleophiles, yielding functionalized enamide precursors
such as 3 or 4, which on subsequent copper catalyzed (for 3) or silver carbonate mediated (for
4) 5ꢀendo cyclization, afford substituted oxazoles 5 or 6 respectively in high yields (Scheme
1).14a,15a In continuation of this work, along with our ongoing interest in design and
Scheme 1. Synthesis of 2,4,5-Trisubstituted oxazoles
O
O
MeS
H
N
Nu
Ph
R
Nu
N
N
Cu(I) (cat) or
Nu
O
R
Ph
R
Ph
O
O
Ag2CO3 (4 equiv)
MeS
O
5, 6
1, 2
3, 4
1, 3, 5, R= Substituted (het)aryl; 2, 4, 6, R= SMe; Nu = OAlk, NH(R1R2), R3MgX
development of new synthetic methods for small molecule heterocycles,16 we further
envisaged to utilize these enamide precursors 3 and 4 for developing synthesis of 2,4,5ꢀ
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substituted thiazoles via thionationꢀcyclization of these intermediates in the presence of
Lawesson’s reagent (Schemes 2 and 3). We now report in the present paper, successful
implementation of this strategy, providing an efficient chemoselective route for 2,4,5ꢀ
functionalized thiazoles, displaying high degree of diversity at various positions of product
thiazoles.
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Chart 1. 2-Phenyl/2-thienyl-4-[(methylthio)-(het)aryl/bis(methylthio)-methylene]-5-
oxazolone precursors 1a-j and 2
MeS
MeS
(Het)Ar
(Het)Ar
N
N
2 -Thienyl
1i, (Het)Ar= 2-thienyl
O
Ph
1a, Ar = 4-MeOC6H4
1b, Ar = 3,4-(MeO)2C6H3
O
O
O
1e, (Het)Ar = 2-furyl
1j, Ar = 3,4-(methylenedioxy)C6H3
1f, (Het)Ar = 2-thienyl
MeS
1c, Ar = 3,4-(methylenedioxy)C6H3
1d, Ar = 4-FC6H4
SMe
N
1g, (Het)Ar = 2-(N-methylpyrrolyl)
1h, (Het)Ar = 3-(N-methylindolyl)
Ph
O
O
2
The
desired
4ꢀ[(methylthio)ꢀ(het)arylmethylene]ꢀ2ꢀphenyl/(2ꢀthienyl)ꢀ5ꢀoxazolones
precursors 1a-j or the corresponding 4ꢀ[bis(methylthio)methylene] derivative 2 (Chart 1)
were obtained in good yields according to our previously reported procedure.14ꢀ15 We first
examined the synthesis of 2ꢀphenylꢀ5ꢀ(het)arylthiazoleꢀ4ꢀcarboxylates 8a-i and the
corresponding 5ꢀ(methylthio)thiazoleꢀ4ꢀcarboxylate 9 via thionationꢀcyclization of the
enamino esters 3a-i and 4 respectively, which were obtained in high yields by nucleophilic
ring opening of the corresponding oxazolones 1 or 2 with various sodium alkoxides, as
reported earlier (Scheme 2).14a,15 Thionationꢀcyclization of the enamide ester 3a to thiazoleꢀ4ꢀ
carboxylate 8a was first attempted, as model substrate for optimization of reaction conditions.
Thus, refluxing 3a with 1 equiv of Lawesson’s reagent in THF for prolonged time, yielded
only unreacted starting material with no trace of thiazole 8a (or thioamide 7a). However we
found, that higher temperature reflux in toluene for 12 h, resulted in efficient thionation as
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Scheme 2. Synthesis of 2-Phenyl/(2-thienyl)-5-(het)aryl/(methylthio)thiazole-4-
carboxylates 8a-i and 9
7
8
9
MeS
O
H
N
Thienyl-2/Ph
(Het)Ar/SMe
OR1
NaOR1
N
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O
ROH/RT
(Het)Ar/SMe
Thienyl-2/Ph
O
O
MeS
1, 2
3a-i, 4
Lawesson's reagent
(2 equiv)
Toluene/∆/2-12 h
O
O
OR1
H
Thienyl-2/Ph
OR1
N
N
Thienyl-2/Ph
S
(Het)Ar/SMe
(Het)Ar/SMe
S
MeS
8a-i, 9
7
O
O
O
O
OEt
OEt
N
OEt
O
O
N
N
X
O
N
Ph
Ph
Ph
S
S
S
Ph
S
O
OMe
F
OMe
8a, X = H, 70%
8b, X = OMe, 75%
8c, 70%
8d, 80%
8e, 75%
O
O
O
OEt
N
OEt
O
OEt
SMe
N
N
N
Ph
S
Ph
Ph
S
S
S
X
S
S
N
Me
8f, X = O, 72%
8g, X = NMe, 60%
8h, 75%
8i, 80%
9, 70%
well
as intramolecular cyclization of
3a, furnishing ethyl
2ꢀphenylꢀ4ꢀ
(methoxyphenyl)thiazoleꢀ4ꢀcarboxylate 8a in 68% yield. On the other hand, when 3a was
reacted with 2 equiv of Lawesson’s reagent in refluxing toluene, reaction was complete
within 2 h yielding 8a in 70% yield (Scheme 2). Therefore this optimized protocol (with 2
equiv of Lawesson’s reagent) for the conversion of 3a to 8a was used throughout for the
synthesis of other 5ꢀ(het)arylthiazoleꢀ4ꢀcarboxylates 8b-i as shown in the Scheme 2. Thus the
reaction was equally facile for the synthesis of other 5ꢀarylthiazoleꢀ4ꢀcarboxylates 8b-d
carrying both electron donating (8b-c) and electron withdrawing (8d) substituents on 5ꢀaryl
group. Interestingly, the thionationꢀcyclization of the enamide tꢀbutyl carboxylate 3e, also
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proceeded smoothly without any side reactions, yielding the corresponding tꢀbutyl thiazoleꢀ4ꢀ
carboxylate 8e in 75% yield. Similarly, the enaminone carboxylic esters 3f-h carrying various
het(aryl) groups, were also converted into the corresponding 2ꢀphenylꢀ5ꢀ(2ꢀfuryl)/(2ꢀNꢀ
methylpyrrolyl)/(3ꢀNꢀmethylindolyl)thiazoles 8f-h in good yields, under identical conditions,
requiring prolonged refluxing (12 h) (Scheme 2). Further diversity at the 2 and 5 positions of
the product thiazoles 8 could be achieved by synthesis of the corresponding nꢀbutyl 2,5ꢀbis(2ꢀ
thienyl)thiazoleꢀ4ꢀcarboxylate 8i in 80% yield by thionationꢀcyclization of enaminoester 3i
obtained by ring opening of 2ꢀthienylꢀ4ꢀ[methylthio(2ꢀthienyl)methylene]ꢀ5ꢀoxazolone 1h
with sodium nꢀbutoxide (Scheme 2).15b Extension of the protocol to bis(methylthio)enamide
carboxylate 4 (obtained by ring opening of 2 with sodium ethoxide) also afforded the ethyl 2ꢀ
phenylꢀ5ꢀ(methylthio)thiazoleꢀ4ꢀcarboxylate 9 in 70% yield (Scheme 2). The structures of all
these newly synthesized thiazoles were confirmed with the help of spectral and analytical
data and also by Xꢀray crystal structure analysis of thiazole ester 8b (Figure S1, Supporting
Information).
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With successful synthesis of 2,5ꢀ(het)arylthiazoleꢀ4ꢀcarboxylates 8-9 in hand, we next
investigated elaboration of this protocol, for the synthesis of 2,5ꢀ(het)arylthiazoleꢀ4ꢀ(Nꢀ
aryl/alkyl)carboxamides 13a-k and 14 by one step thionationꢀcyclization of the
corresponding enamides 10a-k or 11, bearing a secondary amide functionality, which were
readily accessible by ring opening of the corresponding oxazolones 1 or 2 with primary
aliphatic, aromatic amines or amino acid esters as reported earlier (Scheme 3).14,15 It should
be noted, that these enamideꢀamide precursors 10-11 carry two secondary amide
functionalities (though electronically different), and their transformation to the corresponding
thiazoleꢀ4ꢀ(Nꢀsubstituted)carboxamides 13-14 in the presence of Lawesson’s reagent is more
challenging, requiring chemoselective thionation of enamide benzoylamino group, leading to
the enamide monothioamide intermediates 12, which on intramolecular cyclization would
afford the desired thiazoles 13ꢀ14 (Scheme 3).
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We therefore selected enamideꢀanilide 10a as the model substrate for evaluation of optimal
conditions, for its chemoselective thionationꢀcyclization to the thiazole 13a (Scheme 3). To
begin with, the thionationꢀcyclization of 10a was conducted in refluxing toluene in the
Scheme 3. Synthesis of N-Substituted 2-phenyl/(2-Thienyl)-5- (het)aryl/(methylthio)
thiazole-4-carboxamides 13a-k and 14
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11
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MeS
O
R1
H
N
(Het)Ar/SMe
Thienyl-2/Ph
N
N
R1NH2
H
O
(Het)Ar/SMe
Thienyl-2/Ph
O
O
MeS
EtOH/Cat.AcOH
∆, 4-12h
1, 2
10a-k, 11
Lawesson's reagent
(2 equiv)
THF/∆/10-12 h
O
O
R1
R1
N
H
N
Thienyl-2/Ph
N
H
N
H
S
Thienyl-2/Ph
(Het)Ar/SMe
(Het)Ar/SMe
S
MeS
12
13a-k, 14
F
F
MeO
OMe
OMe
O
O
O
Ph
N
N
O
N
H
H
N
H
N
N
N
H
N
Ph
Ph
S
Ph
S
S
OMe
F
O
S
13a, 65%
13b, 76%
13c, 68%
S
S
13d, 75%
OMe
Ph
CO2Et
NH
O
O
OMe
O
O
N
H
N
H
N
N
N
N
H
H
N
N
Ph
Ph
O
S
S
Ph
S
S
S
N
Me
OMe
F
S
13e, 70%
13f, 75%
O
13h, 65%
13g, 62%
Ph
NH
OEt
O
N
O
CO2Et
O
N
N
H
N
N
O
H
O
N
N
H
CO2Et
N
H
O
Ph
S
S
Ph
SMe
S
S
N
O
Ph
13i, 65%
13k, 62%
S
14, 70%
Me
N
13j, 70%
Me
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presence of 2 equivalents of Lawesson’s reagent, under previously described conditions for
the conversion of enamide carboxylates 3-4 to thiazole 4ꢀcarboxylates 8-9 (Scheme 2).
However these enamideꢀ amide intermediates 10ꢀ11 were found to be insoluble in toluene
and attempted cyclization of 10a to 13a under toluene reflux for prolonged time (20 h) led
only to the unreacted starting material. On the other hand, when 10a was reacted with
Lawesson’s reagent (2 equiv) in refluxing THF for 12 h, analysis of reaction mixture revealed
exclusive formation of only one product in reasonably good yield (65%), which to our
delight, was found to be the desired 2ꢀphenyꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀthiazoleꢀ4ꢀ(Nꢀ
phenyl)carboxamide 13a on the basis of its spectral and analytical data (Scheme 3).17
Similarly, the other enamideꢀanilide precursors 10b-c, derived from ring opening of
oxazolones 1d-e with 4ꢀfluoroaniline, also underwent facile chemoselective monothionationꢀ
cyclization in the presence of Lawesson’s reagent, furnishing the corresponding 2ꢀphenylꢀ5ꢀ
(het)arylthiazoleꢀ4ꢀcarboxyanilides 13b-c in good yields (Scheme 3).The structure of these
thiazoles were further confirmed by Xꢀray crystal structure analysis of 13b (Figure Sꢀ2,
Supporting Information). Similarly, the 2,5ꢀbis(2ꢀthienyl)thiazoleꢀ4ꢀcarboxyanilide 13d could
also be obtained in 75% yield, by thionationꢀcyclization of the enamide precursor 10d
(obtained by ring opening of 2ꢀ(2ꢀthienyl)ꢀ4ꢀ[(methylthio)(2ꢀthienyl)methylene]ꢀ5ꢀoxazolone
1i with 3,4,5ꢀtrimethoxyaniline). The versatility and the scope of this chemoselective
monothionationꢀcyclization protocol was further demonstrated by efficient synthesis of 2ꢀ
phenyl/(2ꢀthienyl)ꢀ5ꢀ(het)arylthiazoleꢀ4ꢀ(Nꢀalkyl)carboxamides 13e-g in good yields from the
respective enamideꢀNꢀ(alkyl)amides 10e-g under the identical conditions (Scheme 3).
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With the successful implementation of this strategy for the synthesis of 2,5ꢀ
(het)arylthiazoleꢀ4ꢀ(Nꢀaryl/alkyl)carboxamides 13a-g, we further envisaged of interesting
extension of this work for the synthesis of thiazole based peptidomimetics such as 13h-k,
which are known to display interesting biological activity.2bꢀc We were indeed delighted to
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find that openꢀ chain peptidoenamide precursors 10h-k (obtained by ring opening of 1 with
various amino acid esters i.e., phenyalanine, valine and tryptophan) were smoothly
transformed into thiazole based peptidomimetics 13h-k, with a range of 5ꢀ(het)aryl groups, in
good yields, under these optimized reaction conditions (Scheme 3). Finally the corresponding
bis[(methylthio)methylene]enamide anilide 11 (obtained by ring opening of 4ꢀbis(methylthio)
methyleneoxazolone 2 with 4ꢀfluoroaniline) also afforded the corresponding 2ꢀphenylꢀ5ꢀ
(methylthio)thiazoleꢀ4ꢀ(Nꢀ4ꢀflurophenyl)carboxyanilide 14 in 70% yield (Scheme 2).
Interestingly, attempted thionationꢀcyclization of tertiary amide 15 (derived from ring
opening of 1a with piperidine, did not furnish the desired thiazoleꢀ5ꢀtertiaryꢀamide 16. The
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product
isolated
was
characterized
as
the
2ꢀphenlꢀ4ꢀ[(4ꢀ
methoxyarylidene)(methylthio)]oxazolone 1a formed by thermal eliminative cyclization of
14, presumably due to the steric reasons (Scheme 4).
Scheme 4. Attempted Thionation-cyclization of N-piperidino-enamide-amide 15
O
N
N
Ph
S
O
OMe
16
Lawesson's reagent
(2 equiv)
H
N
N
Ph
MeS
THF/Reflux/12 h
O
MeS
OMe
OMe
N
15
Ph
O
O
1a, 65%
In conclusion, we have devised a highly regioꢀ and chemoselective, useful protocol for the
synthesis of 2,4,5ꢀtrisubstituted thiazoles via one step thionationꢀcyclization of functionalized
enamide precursors in the presence of Lawesson’s reagent. These enamide intermediates are
readily available in high yields, by nucleophilic ring opening of a number of 4ꢀ[(methylthio)ꢀ
(het)arylmethylene]ꢀ5ꢀoxazolones with alkoxides or a variety of primary aliphatic, aromatic
amines and amino acid esters, offering wide range of functional group diversity at 4ꢀ and 5ꢀ
positions of the product thiazoles. Also, the remarkable chemoselectivity observed in the
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facile thionation of benzoylamino group (over the other secondary amide moiety) in
enamides 10-11, is particularly noteworthy, since, selective conversion of an amide to
thioamide with various thionating agents is often not feasible for substrates, comprised of
ketone, esters and amide moieties.10b,10e Additionally, thionationꢀcyclization of the aminoacid
derived enamide precursors 10h-k, provides access to a range of potentially biologically
relevant, thiazole based chiral peptidomimetics. The broad scope and operational simplicity
of the reaction, along with the diversity of compatible starting materials, makes this
methodology attractive for the synthesis of biologically important thiazoles, with option for
combinatorial synthesis.
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Although it is not possible to give a definite explanation for the observed chemoselectivity
in the thionation of enamide amides 10-11 with Lawesson’s reagent, however it appears that
enamide carbonyl group is more electrophilic (because of the delocalization of the nitrogen
lone pair on double bond), than the carbonyl group of the other secondary amide moiety, thus
undergoing faster nucleophilic attack by the dissociated Lawesson’s reagent, followed by
facile intramolecular cyclization of the resulting thioamides to the corresponding thiazoles.10b
Experimental Section
The desired oxazolone precursors 1a-j and 2 were prepared according to our earlier
procedure.14,15 Similarly, all the starting enamide esters 3a-i and 4 were obtained by ring
opening of the corresponding oxazolones 1a-e, 1g-i or 2 with appropriate alkoxides in
alkanols as reported,14a,15a whereas, the enamide amide precursors 10a-k and 11 were
prepared by ring opening of the respective oxazolones 1a,1d-j or 2 with appropriate primary
amines or amino acid esters.14,15a The known enamide esters 3a-c, 3e-f, 3h, 4 and the enamide
amides 10f, 10h, 10j and 11 were characterized by comparison of their spectral data with
those reported,14a,15a whereas the spectral and analytical data of the unknown 3g, 3i, 10a-c,
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10g and 10k is given below. A few of the enamides (3d, 10d-e and 10i) were subjected to
thionationꢀcyclization without further purification and characterization.
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(E) Ethyl 2-benzamido-3-(1-methyl-1H-pyrrol-2-yl)-3-(methylthio)acrylate (3g). brown
semisolid (268 mg, 78%): Rf 0.4 (1:3 EtOAc:hexane); IR (KBr, cm−1) 3310, 1648, 1478,
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1
1296; H NMR (400 MHz, CDCl3) δ 7.65 (br s, 1H), 7.59ꢀ7.57 (m, 2H), 7.50ꢀ7.46 (m, 1H),
7.38 (t, J = 8.0 Hz, 2H), 6.71 (t, J = 2.4 Hz, 1H), 6.19ꢀ6.17 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H),
3.59(s, 3H), 1.86 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9,
164.2, 133.5, 132.1, 130.5, 128.8, 127.3, 126.7, 124.9, 124.7, 110.5, 108.4, 61.7, 34.4, 15.9,
14.3; HRMS (ESI) m/z calcd for C18H20N2O3S [M + H]+ 345.1273, found 345.1256.
(E) Butyl 3-(methylthio)-3-(thiophen-2-yl)-2-(thiophene-2-carboxamido)acrylate (3i).
white solid (305 mg, 80%): mp 132ꢀ133 °C; Rf 0.5 (1:3 EtOAc:hexane); IR (KBr, cm−1)
1
3312, 1712, 1650, 1511, 1244; H NMR (400 MHz, CDCl3) δ 7.77 (br s, 1H), 7.51 (dd, J =
5.2 Hz, 1.2 Hz, 1H), 7.46 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.41 (dd, J = 3.6 Hz, 0.8 Hz, 1H), 7.27
(dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.11 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 7.05 (dd, J = 5.2 Hz, 3.6 Hz,
1H), 4.32 (t, J = 6.8 Hz, 2H), 2.13 (s, 3H), 1.74 (quin, J = 6.8 Hz, 2H), 1.47 (sex, J = 7.2 Hz,
2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 159.0, 138.7, 137.3,
131.7, 129.6, 128.8, 128.5, 128.2, 128.1, 128.0, 65.9, 30.6, 19.4, 17.6, 13.8; HRMS (ESI) m/z
calcd for C17H19NO3S3 [M + Na]+ 404.0425, found 404.0402.
(E)
N-(1-(4-Methoxyphenyl)-1-(methylthio)-3-oxo-3-(phenylamino)prop-1-en-2-yl)
benzamide (10a). white solid (394 mg, 85%): mp 112ꢀ113 °C; Rf 0.4 (2:3 EtOAc:hexane);
IR (KBr, cm−1) 3270, 1634, 1250; 1H NMR (400 MHz, CDCl3) δ 10.07 (br s, 1H), 9.53 (br s,
1H), 7.68 (t, J = 8.8 Hz, 4H), 7.49 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.35ꢀ7.29 (m,
13
4H), 7.05 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H), 1.89 (s, 3H); C NMR
(100 MHz, CDCl3) δ 166.0, 164.3, 159.1, 139.5, 138.5, 133.6, 131.6, 130.5, 128.6, 128.3,
127.7, 127.6, 123.2, 119.8, 113.8, 55.2, 15.7; HRMS (ESI) m/z calcd for C24H22N2O3S [M +
H]+ 419.1429, found 419.1411.
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(E/Z) N-(1-(4-Fluorophenyl)-3-(4-fluorophenylamino)-1-(methylthio)-3-oxoprop-1-en-2-
yl) benzamide (10b). (E:Z = 50:50), white solid (400 mg, 85%): mp 224ꢀ225 °C; Rf 0.5 (2:3
EtOAc:hexane); IR (KBr, cm−1) 3250, 1641, 1508; 1H NMR (400 MHz, CDCl3) δ 10.16 (br s,
0.5H), 9.86 (br s, 0.5H), 9.79 (br s, 0.5H), 9.58 (br s, 0.5H), 8.01 (d, J = 7.6 Hz, 1H), 7.73ꢀ
7.59 (m, 3H), 7.55ꢀ7.48 (m, 1.5H), 7.42ꢀ7.40 (m, 2.5H), 7.32ꢀ7.14 (m, 4H), 7.00 (t, J = 8.8
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Hz, 1H), 1.96 (s, 1.5H), 1.88 (s, 1.5H); C NMR (100 MHz, CDCl3) δ 166.1, 165.0, 164.0,
163.1, 162.9, 160.6, 160.5, 159.4, 157.0, 156.9, 138.7, 135.7, 135.4, 133.6, 133.5, 133.2,
132.1, 131.7, 131.53, 131.44, 131.2, 131.1, 130.8, 128.6, 128.3, 127.8, 127.7, 121.73, 121.66,
121.1, 121.0, 115.4, 115.3, 115.2, 115.1, 114.9; HRMS (ESI) m/z calcd for C23H18F2N2O2S
[M + Na]+ 447.0955, found 447.0938.
(E/Z) N-(3-(4-Fluorophenylamino)-1-(furan-2-yl)-1-(methylthio)-3-oxoprop-1-en-2-yl)
benzamide (10c). (E:Z = 50:50), off-white solid (382 mg, 87%): mp 120ꢀ122 °C; Rf 0.5 (2:3
1
EtOAc:hexane); IR (KBr, cm−1) 3268, 1634, 1509; H NMR (400 MHz, CDCl3) δ 9.33 (br s,
0.5H), 8.32 (br s, 0.5H), 8.17 (br s, 0.5H), 7.91ꢀ7.89 (m, 1H), 7.86ꢀ7.84 (m, 1H), 7.63ꢀ7.54
(m, 3H), 7.49ꢀ7.44 (m, 2H), 7.42 (dd, J = 2.0 Hz, 0.8 Hz, 0.5H), 7.33 (dd, J = 9.2 Hz, 4.8 Hz,
1H), 7.00 (t, J = 8.4 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.79 (d, J = 3.2 Hz, 0.5H), 6.56 (dd, J
= 3.6 Hz, 0.4 Hz, 0.5H), 6.52 (dd, J = 3.6 Hz, 1.6 Hz, 0.5H), 6.39 (dd, J = 3.6 Hz, 1.6 Hz, 0.5
H), 2.26 (s, 1.5H), 2.12 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 165.1, 164.7, 162.7, 162.5,
161.0, 158.6, 151.5, 147.6, 144.3, 143.5, 133.9, 133.8, 133.6, 133.5, 133.4, 133.0, 132.9,
132.8, 132.68, 132.65, 129.0, 128.9, 127.8, 127.7, 122.5, 122.4, 122.3, 122.2, 118.2, 115.9,
115.73, 115.66, 115.5, 113.7, 113.6, 112.9, 112.3, 111.9, 19.3, 16.0; HRMS (ESI) m/z calcd
for C21H17FN2O3S [M + Na]+ 419.0842, found 419.0833.
(E) N-(3-(3,4-Dimethoxyphenethylamino)-1-(benzo[d][1,3]dioxol-5-yl)-1-(methylthio)-3-
oxoprop-1-en-2-yl)thiophene-2-carboxamide (10g). white solid (467 mg, 80%): mp 184ꢀ
1
185 °C; Rf 0.4 (1:1 EtOAc:hexane); IR (KBr, cm−1) 3251, 1626, 1480, 1243; H NMR (400
MHz, CDCl3) δ 7.67 (br s, 1H), 7.40 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H),
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6.95 (dd, J = 4.8 Hz, 3.6 Hz, 1H), 6.80ꢀ6.72 (m, 7H), 5.93 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H),
3.61 (q, J = 7.2 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.4, 161.2, 149.1, 148.3, 147.9, 147.7, 137.7, 131.8, 131.1, 129.5, 129.0, 127.9, 126.0,
122.6, 120.9, 112.3, 111.4, 109.1, 108.7, 101.5, 56.0, 41.3, 35.1, 16.3; HRMS (ESI) m/z calcd
for C26H26N2O6S2 [M + H]+ 527.1311, found 527.1301
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(S)-Ethyl
2-(3-(benzo[d][1,3]dioxol-5-yl)-3-(methylthio)-2-(thiophene-2-carboxamido)
acrylamido)-3-phenylpropanoate (10k). offꢀwhite solid (449 mg, 75%): mp 184ꢀ185 °C; Rf
1
0.5 (1:1 EtOAc:hexane); IR (KBr, cm−1) 3403, 1735, 1665, 1511; H NMR (400 MHz,
CDCl3) δ 9.31 (br s, 1H), 7.78ꢀ7.75 (m, 2H), 7.55 (d, J = 3.2 Hz, 1H), 7.14 (s, 5H), 7.09 (dd,
J = 5.2 Hz, 1.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.98
(s, 2H), 4.57 (q, J = 6.8 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.03 (dd, J = 6.0 Hz, 4.0 Hz, 2H),
13
1.75 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 171.0, 164.6, 160.9,
146.9, 146.7, 138.8, 136.8, 131.4, 129.2, 129.1, 128.1, 127.8, 126.5, 122.6, 121.9, 108.6,
108.0, 101.1, 60.6, 53.5, 36.8, 15.9, 13.9; HRMS (ESI) m/z calcd for C27H26N2O6S2 [M + H]+
539.1311, found 539.1288.
General Procedure for the Synthesis of 2-Phenyl/(2-thienyl)-5-(het)aryl/(methylthio)
thiazole-4-carboxylates 8a-i and 9. To a solution of enamide ester 3 or 4 (0.5 mmol) in
toluene (10 mL), Lawesson’s reagent (0.4 g, 1.0 mmol) was added and the reaction mixture
was refluxed with stirring for 2ꢀ3 (for 8a-e) or 10ꢀ12 h (for 8f-i and 9) (monitored by TLC). It
was then poured into iceꢀcold water (30 mL), extracted with EtOAc (3 x 30 mL), washed
with brine (1 x 30 mL), dried over Na2SO4 and the solvent was removed under reduced
pressure to give crude thiazoles, which were purified by column chromatography over silica
gel using EtOAcꢀhexane as eluent.
Ethyl 5-(4-methoxyphenyl)-2-phenylthiazole-4-carboxylate (8a). white solid (118 mg,
1
70%): mp 126ꢀ127 °C; Rf 0.45 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1720, 1247, 1180; H
NMR (400 MHz, CDCl3) δ 7.99ꢀ7.97 (m, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.46ꢀ7.44 (m, 3H),
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6.95 (d, J = 8.8 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.6, 162.6, 160.6, 146.2, 141.1,133.1, 131.5, 130.6, 129.1,
126.9, 122.8, 113.8, 61.4, 55.5, 14.3; HRMS (ESI) m/z calcd for C19H17NO3S [M + H]+
340.1007, found 340.1008.
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Ethyl 5-(3,4-dimethoxyphenyl)-2-phenylthiazole-4-carboxylate (8b). pale yellow solid
(138 mg, 75%): mp 140ꢀ141 °C; Rf 0.45 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1720, 1261,
1186; 1H NMR (400 MHz, CDCl3) δ 7.99ꢀ7.97 (m, 2H), 7.46ꢀ7.45 (m, 3H), 7.12 (dd, J = 8.0
Hz, 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H),
13
3.93 (s, 3H), 3.92 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 165.6,
162.7, 150.1, 148.7, 146.0, 141.2, 133.0, 130.7, 129.1, 126.9, 123.0, 113.4, 110.9, 61.4, 56.2,
56.1, 14.3; HRMS (ESI) m/z calcd for C20H19NO4S [M + Na]+ 392.0932, found 392.0932.
Ethyl 5-(benzo[d][1,3]dioxol-5-yl)-2-phenylthiazole-4-carboxylate (8c). pale yellow solid
(124 mg, 70%): mp 139ꢀ140 °C; Rf 0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1720, 1477,
1
1240, 1187; H NMR (400 MHz, CDCl3) δ 7.98ꢀ7.96 (m, 2H), 7.45ꢀ7.46 (m, 3H), 7.03ꢀ7.01
(m, 2H), 6.85 (dd, J = 6.8 Hz, 1.6 Hz, 1H), 6.03 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.30 (t, J =
13
7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 165.7, 162.5, 148.7, 147.7, 145.8, 141.4, 133.0,
130.7, 129.1, 126.9, 124.2, 124.1, 110.6, 108.3, 101.7, 61.5, 14.3; HRMS (ESI) m/z calcd for
C19H15NO4S [M + Na]+ 376.0619, found 376.0618.
Ethyl 5-(4-fluorophenyl)-2-phenylthiazole-4-carboxylate (8d). white solid (130 mg, 80%):
mp 158ꢀ160 °C; Rf 0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1716, 1195; 1H NMR (400 MHz,
CDCl3) δ 7.99ꢀ7.97 (m, 2H), 7.51 (dd, J = 8.8 Hz, 5.2 Hz, 2H), 7.47ꢀ7.45 (m, 3H), 7.12 (t, J =
8.8 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.3, 164.6, 162.3, 162.2, 144.9, 141.7, 132.8, 132.0, 131.9, 130.8, 129.1, 127.0, 126.63,
126.6, 115.6, 115.3, 61.5, 14.2; HRMS (ESI) m/z calcd for C18H14FNO2S [M + H]+ 328.0808,
found 328.0803.
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t-Butyl 5-(4-methoxyphenyl)-2-phenylthiazole-4-carboxylate (8e). pale yellow solid (138
1
mg, 75%): mp 99ꢀ100 °C; Rf 0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1718, 1251, 1153; H
7
8
NMR (400 MHz, CDCl3) δ 8.00ꢀ7.98 (m, 2H), 7.45ꢀ7.41 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H),
9
13
3.86 (s, 3H), 1.42 (s, 9H); C NMR (100 MHz, CDCl3) δ 165.5, 161.8, 160.4, 144.5, 143.1,
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133.1, 131.4, 130.5, 129.0, 126.9, 123.4, 113.8, 82.1, 55.6, 28.1; HRMS (ESI) m/z calcd for
C21H21NO3S [M + H]+ 368.1320, found 368.1312.
Ethyl 5-(furan-2-yl)-2-phenylthiazole-4-carboxylate (8f). brown solid (108 mg, 72%): mp
1
69ꢀ70 °C; Rf 0.65 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1712, 1317, 1226, 1186; H NMR
(400 MHz, CDCl3) δ 7.99ꢀ7.97 (m, 2H), 7.54 (d, J = 3.2 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H),
7.47ꢀ7.43 (m, 3H), 6.56 (dd, J = 3.2 Hz, 1.6 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 162.6, 145.6, 143.9, 139.1, 136.1, 132.9,
130.7, 129.1, 126.9, 114.1, 112.8, 61.7, 14.5; HRMS (ESI) m/z calcd for C16H13NO3S [M +
Na]+ 322.0514, found 322.0508.
Ethyl 5-(1-methyl-1H-pyrrol-2-yl)-2-phenylthiazole-4-carboxylate (8g). brown semisolid
1
(94 mg, 60%): Rf 0.6 (1:3 EtOAc:hexane); IR (KBr, cm−1) 1720, 1465, 1189; H NMR (400
MHz, CDCl3) δ 8.00ꢀ7.97 (m, 2H), 7.46ꢀ7.45 (m, 3H), 6.81 (dd, J = 2.4 Hz, 2.0 Hz, 1H),
6.34 (dd, J = 3.6 Hz, 2.0 Hz, 1H), 6.22 (dd, J = 3.6 Hz, 2.4 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H),
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3.54 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 167.2, 161.9, 143.9,
136.8, 133.0, 130.8, 129.1, 127.0, 124.8, 121.0, 112.8, 108.4, 61.4, 34.7, 14.3; HRMS (ESI)
m/z calcd for C17H16N2O2S [M + H]+ 313.1011, found 313.1005.
Ethyl 5-(1-methyl-1H-indol-3-yl)-2-phenylthiazole-4-carboxylate (8h). yellow solid (135
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mg, 75%): mp 96ꢀ98 °C; Rf 0.5 (1:5 EtOAc:hexane); IR (KBr, cm−1) 1708, 1469, 1190; H
NMR (400 MHz, CDCl3) δ 8.03ꢀ8.00 (m, 2H), 7.86ꢀ7.83 (m, 2H), 7.49ꢀ7.43 (m, 3H), 7.38 (d,
J = 8.4 Hz, 1H), 7.31 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.25ꢀ7.22 (m, 1H), 4.37 (q, J = 7.2 Hz,
2H), 3.89 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.9, 163.2,
140.5, 140.2, 137.1, 133.4, 131.9, 130.3, 129.1, 127.5, 126.9, 122.7, 120.9, 120.1, 109.9,
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104.7, 61.4, 33.4, 14.4; HRMS (ESI) m/z calcd for C21H18N2O2S [M + Na]+ 385.0987, found
385.0985.
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Butyl 2,5-di(thiophen-2-yl)thiazole-4-carboxylate (8i). yellow semisolid (140 mg, 80%): Rf
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0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1716, 1464, 1186; H NMR (400 MHz, CDCl3) δ
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7.54 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 7.47ꢀ7.43 (m, 3H), 7.09 (dd, J = 4.0 Hz, 2.4 Hz, 1H), 7.08
(dd, J = 3.6 Hz, 2.4 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 1.71 (quin, J = 6.8 Hz, 2H), 1.37 (sex, J
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= 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 162.3, 159.0, 140.5,
137.9, 136.1, 130.5, 128.74, 128.69, 128.0, 127.6, 127.4, 65.5, 30.6, 19.1, 13.7; HRMS (ESI)
m/z calcd for C16H15NO2S3 [M + H]+ 350.0343, found 350.0335.
Ethyl 5-(methylthio)-2-phenylthiazole-4-carboxylate (9). yellow solid (98 mg, 70%): mp
82ꢀ83 °C; Rf 0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 1693, 1446, 1203, 1058; 1H NMR (400
MHz, CDCl3) δ 7.91ꢀ7.89 (m, 2H), 7.44ꢀ7.42 (m, 3H), 4.46 (q, J = 7.2 Hz, 2H), 2.66 (s, 3H),
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1.45 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 163.4, 162.6, 149.5, 139.4, 132.9,
130.4, 129.1, 126.6, 61.6, 20.3, 14.6; HRMS (ESI) m/z calcd for C13H13NO2S2 [M + Na]+
302.0285, found 302.0288.
General Procedure for the Synthesis of N-Substituted 2-(2-Thienyl)/phenyl-5-
(het)aryl/(methylthio)thiazole-4-carboxamides 13a-k and 14. To a solution of enamideꢀ
amide 10 or 11 (0.5 mmol) in THF (10 mL), Lawesson’s reagent (0.4 g, 1.0 mmol) was added
and the reaction mixture was refluxed with stirring for 10ꢀ12 h (monitored by TLC). It was
then concentrated under reduced pressure and the residue was diluted with water (30 mL),
extracted with EtOAc (3 x 30 mL), washed with brine (1 x 30 mL), dried over Na2SO4,
followed by removal of the solvent to give crude thiazoles, which were purified by column
chromatography over silica gel using EtOAcꢀhexane as eluent.
5-(4-Methoxyphenyl)-N,2-diphenylthiazole-4-carboxamide (13a). yellow solid (125 mg,
65%): mp 167−168 °C; Rf 0.4 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3362, 1681, 1602, 1516;
1H NMR (400 MHz, CDCl3) δ 9.56 (br s, 1H ), 7.99ꢀ7.97 (m, 2H ), 7.70 (d, J = 7.6 Hz, 2H),
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1H), 6.97 (d, J = 8.8 Hz, 2H ), 3.86 (s, 3H); C NMR (100 MHz, CDCl3) δ 164.3, 160.6,
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159.7, 141.9, 138.2, 132.9, 131.9, 130.8, 129.3, 129.1, 126.6, 124.3, 123.4, 122.5, 120.1,
113.8, 55.5; HRMS (ESI) m/z calcd for C23H18N2O2S [M + Na]+ 409.0987, found 409.0984.
N,5-Bis(4-fluorophenyl)-2-phenylthiazole-4-carboxamide (13b). pale yellow solid (148
mg, 76%): mp 208ꢀ209 °C; Rf 0.6 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3352, 1680, 1228; 1H
NMR (400 MHz, CDCl3) δ 9.51 (br s, 1H ), 7.99ꢀ7.96 (m, 2H), 7.69ꢀ7.63 (m, 4H), 7.51 (m,
3H), 7.13 (t, J = 8.8 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 165.1,
164.7, 162.2, 160.8, 159.4, 158.4, 143.5, 142.3, 134.0, 133.9, 132.6, 132.4, 132.3, 131.1,
129.3, 126.7, 126.19, 126.15, 121.9, 121.8, 115.9, 115.7, 115.6, 115.3; HRMS (ESI) m/z
calcd for C22H14F2N2OS [M + H]+ 393.0873, found 393.0854.
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N-(4-Fluorophenyl)-5-(furan-2-yl)-2-phenylthiazole-4-carboxamide (13c). brown solid
(123 mg, 68%): mp 120ꢀ122 °C; Rf 0.5 (1:3 EtOAc:hexane); IR (KBr, cm−1) 3357, 1692,
1509, 1225; 1H NMR (400 MHz, CDCl3) δ 9.53 (br s, 1H ), 7.99ꢀ7.97 (m, 2H), 7.95 (dd, J =
3.6 Hz, 0.8 Hz, 1H), 7.70 (dd, J = 8.8 Hz, 5.2 Hz, 2H), 7.52 (dd, J = 1.6 Hz, 0.8 Hz, 1H),
7.51ꢀ7.48 (m, 3H), 7.09 (t, J = 8.8 Hz, 2H), 6.58 (dd, J = 3.6 Hz, 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 64.1, 159.6, 147.9, 143.7, 134.73, 134.70, 132.4, 131.7, 131.1, 129.3, 129.0,
127.93, 127.90, 126.7, 125.74, 125.7, 116.0, 115.8, 114.0, 112.2; HRMS (ESI) m/z calcd for
C20H13FN2O2S [M + Na]+ 387.0579, found 387.0579.
2,5-Di(thiophen-2-yl)-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide (13d). yellow
semisolid (172 mg, 75%): Rf 0.4 (1:3 EtOAc:hexane); IR (KBr, cm−1) 3412, 1671, 1507,
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1128; H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H ), 7.71 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.54
(dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.48 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.46 (dd, J = 5.2 Hz, 1.2 Hz,
1H), 7.13 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 7.09 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 6.98 (s, 2H), 3.89
(s, 6H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 157.4, 153.5, 140.9, 137.3, 135.9,
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135.1, 134.0, 131.4, 130.8, 129.4, 128.9, 128.4, 128.0, 127.6, 98.2, 61.1, 56.4; HRMS (ESI)
m/z calcd for C21H18N2O4S3 [M + H]+ 459.0507, found 459.0495.
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N-Butyl-2-phenyl-5-(thiophen-2-yl)thiazole-4-carboxamide (13e). brown solid (120 mg,
70%): mp 94ꢀ95 °C; Rf 0.4 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3409, 1664, 1515; 1H NMR
(400 MHz, CDCl3) δ 7.94ꢀ7.91 (m, 2H), 7.68 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.62 (br s, 1H),
7.48ꢀ7.46 (m, 3H), 7.43 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.06 (dd, J = 4.8 Hz, 3.6 Hz, 1H), 3.46
(q, J = 7.2 Hz, 2H), 1.64 (quin, J = 7.2 Hz, 2H), 1.44 (sex, J = 7.6 Hz, 2H), 0.97 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.5, 161.9, 141.9, 136.9, 132.7, 131.4, 131.1,
130.8, 129.2, 129.1, 127.3, 126.6, 39.3, 32.0, 20.4, 14.0; HRMS (ESI) m/z calcd for
C18H18N2OS2 [M + Na]+ 365.0758, found 365.0758.
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N-(2-(1H-Indol-3-yl)ethyl)-5-(1-methyl-1H-indol-3-yl)-2-phenylthiazole-4-carboxamide
(13f). yellow solid (178 mg, 75%): mp 159ꢀ160 °C; Rf 0.4 (1:3 EtOAc:hexane); IR (KBr,
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cm−1) 3401, 3293, 1652, 1523; H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.12 (br s, 1H),
7.98 (d, J = 8.0 Hz, 1H), 7.87ꢀ7.85 (m, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.45ꢀ7.43 (m, 3H),
7.39ꢀ7.35 (m, 2H), 7.30 (td, J = 8.0 Hz, 0.8 Hz, 1H ), 7.24ꢀ7.19 (m, 2H), 7.13 (td, J = 8.0 Hz,
0.8 Hz, 1H), 7.08 (s, 1H), 3.84 (s, 3H), 3.80 (q, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 162.8, 161.8, 141.4, 137.9, 137.1, 136.5, 133.6, 133.2, 130.2,
129.1, 127.6, 127.5, 126.5, 122.4, 122.3, 122.2, 120.7, 120.0, 119.6, 119.0, 113.5, 111.3,
109.9, 104.4, 40.0, 33.3, 25.7; HRMS (ESI) m/z calcd for C29H24N4OS [M + Na]+ 499.1569,
found 499.1567.
N-(3,4-Dimethoxyphenethyl)-5-(benzo[d][1,3]dioxol-5-yl)-2-(thiophen-2-yl)thiazole-4-
carboxamide (13g). yellow semisolid (153 mg, 62%); Rf 0.4 (1:3 EtOAc:hexane); IR (KBr,
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cm−1) 3406, 1665, 1507, 1236; H NMR (400 MHz, CDCl3) δ 7.60 (br t, J = 6.0 Hz, 1H ),
7.47 (dd, J = 3.6 Hz, 1.2 Hz, 1H ), 7.43 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H),
7.11ꢀ7.08 (m, 2H), 6.85ꢀ6.78 (m, 4H), 6.0 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.62 (q, J = 6.8
Hz, 2H ), 2.86 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.4, 158.1, 149.2, 148.7,
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147.8, 147.5, 142.6, 141.8, 136.5, 131.8, 128.5, 128.2, 127.4, 124.6, 123.6, 120.9, 112.2,
111.6, 111.1, 108.1, 101.6, 56.1, 56.0, 40.9, 35.7; HRMS (ESI) m/z calcd for C25H22N2O5S2
[M + H]+ 495.1048, found 495.1017.
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(S)-Ethyl
2-(5-(4-methoxyphenyl)-2-phenylthiazole-4-carboxamido)-3-
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phenylpropanoate (13h). yellow solid (158 mg, 65%): mp 88ꢀ89 °C; Rf 0.45 (1:4
D
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EtOAc:hexane); [α]25 = +35.1 (c, 0.3, CHCl3); IR (KBr, cm−1) 3394, 1739, 1673, 1508; H
NMR (400 MHz, CDCl3) δ 8.05 (br d, J = 8.4 Hz, 1H ), 7.92ꢀ7.89 (m, 2H), 7.59 (d, J = 8.8
Hz, 2H), 7.47ꢀ7.45 (m, 3H), 7.32ꢀ7.22 (m, 5H), 6.94 (d, J = 8.8 Hz, 2H), 4.99 (dt, J = 8.4 Hz,
6.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.23 (dd, J = 14.0 Hz, 6.0 Hz, 1H), 3.19
(dd, J = 14.0 Hz, 6.0 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7,
164.2, 161.3, 160.5, 144.1, 141.5, 136.3, 132.9, 131.8, 130.6, 129.7, 129.1, 128.7, 127.2,
126.6, 122.5, 113.7, 61.5, 55.5, 53.2, 38.5, 14.2; HRMS (ESI) m/z calcd for C28H26N2O4S [M
+ Na]+ 509.1511, found 509.1512.
(2S)-Ethyl
3-methyl-2-(5-(1-methyl-1H-indol-3-yl)-2-phenylthiazole-4-
carboxamido)butanoate (13i). yellow solid (150 mg, 65%): mp 79ꢀ80 °C; Rf 0.45 (1:4
D
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EtOAc:hexane); [α]25 = +22.3 (c, 0.6, CHCl3); IR (KBr, cm−1) 3403, 1735, 1668, 1509; H
NMR (400 MHz, CDCl3) δ 8.30 (s, 1H ), 8.20 (br d, J = 8.8 Hz 1H), 8.01ꢀ7.97 (m, 3H), 7.50ꢀ
7.45 (m, 3H), 7.37ꢀ7.35 (m, 1H), 7.29 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.24 (td, J = 8.0 Hz, 1.2
Hz, 1H), 4.70 (dd, J = 9.2 Hz, 5.2 Hz, 1H), 4.29ꢀ4.20 (m, 2H), 3.87 (s, 3H), 2.36ꢀ2.28 (m,
1H), 1.31 (t, J = 7.2 Hz, 3H), 1.05 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.2,
162.5, 161.9, 140.9, 138.5, 137.1, 133.6, 133.2, 130.3, 129.1, 127.5, 126.5, 122.4, 120.8,
120.0, 109.9, 104.4, 61.3, 57.4, 33.4, 31.7, 19.3, 18.3, 14.4; HRMS (ESI) m/z calcd for
C26H27N3O3S [M + Na]+ 484.1671, found 484.1670.
(2S)-Ethyl
3-(1H-indol-3-yl)-2-(5-(1-methyl-1H-pyrrol-2-yl)-2-phenylthiazole-4-
carboxamido)propanoate (13j). brown solid (174 mg, 70%): mp 88ꢀ89 °C; Rf 0.45 (1:4
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EtOAc:hexane); [α]25 = −6.0 (c, 0.3, CHCl3); IR (KBr, cm−1) 3376, 1735, 1664, 1517; H
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NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H ), 8.03 (br d, J = 8.4 Hz 1H), 7.79ꢀ7.77 (m, 2H),
7.63 (d, J = 8.0 Hz, 1H), 7.45ꢀ7.42 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 (dt, J = 8.4 Hz, 1.2
Hz, 1H), 7.10ꢀ7.05 (m, 2H), 6.7 (dd, J = 2.8 Hz, 2.0 Hz, 1H), 6.34 (dd, J = 3.6 Hz, 2.0 Hz,
1H), 6.19 (dd, J = 3.6 Hz, 2.8 Hz, 1H), 5.03 (dt, J = 8.4 Hz, 5.6 Hz, 1H), 4.16ꢀ4.10 (m, 2H),
3.50 (s, 3H), 3.40 (dd, J = 5.6 Hz, 3.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.1, 165.7, 160.9, 144.2, 136.3, 133.9, 132.8, 130.7, 129.1, 127.9, 126.7, 125.0,
123.0, 122.3, 121.0, 119.9, 119.0, 112.7, 111.3, 110.6, 108.2, 61.5, 53.2, 34.9, 28.0, 14.2;
HRMS (ESI) m/z calcd for C28H26N4O3S [M + Na]+ 521.1623, found 521.1624.
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(2S)-Ethyl 2-(5-(benzo[d][1,3]dioxol-5-yl)-2-(thiophen-2-yl)thiazole-4-carboxamido)-3-
phenylpropanoate (13k). yellow semisolid (156 mg, 62%): Rf 0.45 (1:4 EtOAc:hexane);
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[α]25D = +47.2 (c, 0.3, CHCl3); IR (KBr, cm−1) 3391, 1737, 1672, 1502, 1250; H NMR (400
MHz, CDCl3) δ 7.92 (br d, J = 8.4 Hz, 1H ), 7.48 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.44 (dd, J =
5.2 Hz, 1.2 Hz, 1H), 7.34ꢀ7.30 (m, 2H), 7.27ꢀ7.22 (m, 3H), 7.12 (d, J = 1.6 Hz, 1H), 7.09 (dd,
J = 5.2 Hz, 3.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.0 (s, 2H), 4.95
(dt, J = 8.4 Hz, 6.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.20 (dd, J = 6.0 Hz, 4.0 Hz, 2H), 1.22
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 160.9, 158.2, 148.7, 147.5, 143.1,
141.2, 136.6, 136.2, 129.6, 128.8, 128.6, 128.1, 127.4, 127.2, 124.5, 123.5, 111.0, 108.1,
101.6, 61.5, 53.3, 38.5, 14.2; HRMS (ESI) m/z calcd for C26H22N2O5S2 [M + H]+ 507.1048,
found 507.1046.
N-(4-Fluorophenyl)-5-(methylthio)-2-phenylthiazole-4-carboxamide (14). offꢀwhite solid
(120 mg, 70%): mp 185ꢀ186 °C; Rf 0.5 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3374, 1664,
1509; 1H NMR (400 MHz, CDCl3) δ 9.1 (br s, 1H ), 7.89ꢀ7.87 (m, 2H), 7.69 (dd, J = 8.8 Hz,
13
4.8 Hz, 2H), 7.47ꢀ7.45 (m, 3H), 7.05 (dd, J = 8.6 Hz, 8.8 Hz, 2H), 2.66 (s, 3H); C NMR
(100 MHz, CDCl3) δ 162.9, 160.7, 160.3, 158.2, 146.1, 140.9, 134.1, 134.0, 132.7, 130.6,
129.3, 126.2, 121.5, 121.4, 115.9, 115.6, 20.4; HRMS (ESI) m/z calcd for C17H13FN2OS2 [M
+ Na]+ 367.0351, found 367.0354.
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5-(4-Methoxyphenyl)-N,2-diphenylthiazole-4-carbothioamide (17). red solid (132 mg,
66%): mp 130ꢀ132 °C; Rf 0.6 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3440, 1594, 1550, 1244;
1H NMR (400 MHz, CDCl3) δ 14.85 (br s, 1H ), 7.90 (d, J = 8.8 Hz, 2H), 7.81ꢀ7.78 (m, 2H),
7.50ꢀ7.48 (m, 4H), 7.40ꢀ7.39 (m, 3H), 7.30ꢀ7.27 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 3.89 (s,
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55
56
57
58
59
60
13
3H); C NMR (100 MHz, CDCl3) δ 207.7, 163.6, 161.5, 145.8, 141.7, 141.2, 140.2, 133.1,
131.8, 130.1, 130.0, 129.1, 126.7, 126.3, 121.4, 112.6, 55.6; HRMS (ESI) m/z calcd for
C23H18N2OS2 [M + H]+ 403.0939, found 403.0920.
Acknowledgements. We thank Prof. C. N. R. Rao, FRS, for encouragement, the Council of
Scientific and Industrial Research (CSIR, New Delhi) for research fellowship (to S.V.K) and
JNCASR, Bangalore, for research associateship (to G.P) and the Indian National Science
Academy, New Delhi, for an INSA Senior Scientist position (to H.I). We also thank Dr.
Sebastian C. Peter, Mr. Abishek Kannan Iyer and Mr. Arpan Hazra for their help in Xꢀray
crystal structure determination of compounds 8b and 13b.
Supporting Information. Figures giving 1H NMR and 13C NMR spectra and ORTEP Xꢀray
crystal structure displays and CIF files giving crystallographic data for 8b and 13b. This
material is available free of charge via the Internet at http://pubs.acs.org.
References:
1. Reviews: (a) Metzger, J. V. Comprehensive Heterocyclic Chemistry; Katritzky, A. R.;
Rees, C. W. Eds.; Pergamon: New York, 1984, Vol 6, 235. (b) Dondoni, A.; Merino, P;
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Eds; Elsevier, NY, 1996, Vol 3, p 373.(c) Chen, B.; Heal, W. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R.
J. K. Eds; Elsevier: Oxford, 2008, Vol 4, pp 635. (d) Wipf, P. Chem. Rev. 1995, 95, 2115.
(e) Wu, Y.ꢀ J.; Yang, B. V. Five membered ring systems: with N and S (Se, Te) atoms, in
progress in Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A. Eds.; Elsevier, Oxford,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
2007, Vol 18, p 247. (f) Jin, Z. Nat. Prod. Rep. 2009, 26, 382. (g) Mustafa, S. M.; Nair, V.
A.; Chittoor, J. P.; Krishnapillai S. MiniꢀRev. Org. Chem. 2004, 1, 375.
7
8
9
2. (a) Umkehrer, M.; Kolb, J.; Burdack, C.; Hiller, W. Synlett. 2005, 79 and references
therein. Peptidomimetics: (b) Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A.
Tetrahedron Lett. 1993, 34, 1901. Enzyme Inhibitor: (c) Desroy, N.; Moreau, F.; Briet, S.;
Le Fralliec, G.; Floquet, S.; Durant, L; Vongsouthi, V.; Gerusz, V.; Denis, A.; Escaich, S.
Biorg. Med. Chem. 2009, 17, 1276. (d) Heng, S.; Gryncel. K. R.; Kantrowitz, E. R. Biorg.
Med. Chem. 2009, 17, 3916. (e) Bey, E.; MarchaisꢀOberwinkler, S.; Werth, R.; Negri, M.;
AlꢀSoud, Y. A.; Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.; Hartmann, R. W. J. Med.
Chem. 2008, 51, 6725.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
4. (a) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Discovery Dev. 2005, 8, 723. (b)
Thomae, D.; Perspicace, E.; Xu, Z.; Henryon, D.; Schnieder, S.; Hesse, S.; Kirsch, G.;
Seck, P. Tetrahedron 2009, 65, 2982 and references therein. (c) Qaio, Q.; Dominique, R.;
Goodnow, Jr. R. Tetrhedron Lett. 2008, 49, 3682 and references therein. (d) Potewar, T.
M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron 2007, 63, 11066 and references therein.
5. (a) Mori, A.; Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548. (b) Kiryanov, A. A.; Sampson,
P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925 (c) Bach, T.; Heuser, S. Tetrahedron Lett.
2000, 41, 1707.
6. (a) Pfeiffer, W. ꢀD. Science of Synthesis 2002, 11, 627.(b) Kazmaier, U.; Ackermann, S.
Org. Biomol. Chem. 2005, 3, 3184.
7. Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911 and references therein.
8. (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20, 3118. (b) Eicher, T.;
Hauptmann, S. The Chemistry of Heterocycles. Structure, Reactions, Syntheses and
Applications, WileyꢀVCH, Weinheim 2nd ed, 2003.
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
9. (a) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004. (b) Miyamoto, K.; Nishi, Y.;
Ochiai, M. Angew. Chem., Int. Ed. 2005, 44, 6896. (c) Donohoe, T. J.; Kabeshov, M. A.;
Rathi, A, H.; Smith, I. E. D. Org. Biomol. Chem. 2012, 10, 1093 and references therein.
(d) Yoshimatsu, M.; Yamamoto, T.; Sawa, A.; Kato, T.; Tanabe, G.; Muraoka, O. Org.
Lett. 2009, 11, 2952. (e) Gao, X.; Pan, Y.ꢀm.; Lin, M.; Chen, L.; Zhan, Z.ꢀp. Org. Biomol.
Chem. 2010, 8, 3259. (f) Murai, T.; Hori, F.; Maruyama, T. Org. Lett. 2011, 13, 1718. (g)
Shi, B.; Blake, A. J.; Lewis, W.; Campbell, I. B.; Judkins, B. D.; Moody, C. J. J. Org.
Chem. 2005, 75, 152. (h) Cook, A. H.; Heilbron, I.; Macdonald, S. F.; Mahadevan, A. P.;
J. Chem. Soc. 1949, 1064.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. Lawesson’s reagent: (a) Shabana, R.; Scheibye, S.; Clausen, K.; Olesen S. O.; Lawesson,
S.ꢀO. Nouv. J. Chim. 1980, 4, 47. (b) Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde,
B.; Andersen, T. P.; Lawesson, S. ꢀO. Chem. Lett. 1983, 6, 809. (c) Review: Jesberger,
M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929. (d) Kaleta, Z.; Makowski, B. T.; Soos,
T.; Dembinski, R. Org. Lett, 2006, 8, 1625. (e) Belleau’s reagent: Lajoie, G.; Lepine, F.;
Maziak, L.; Belleau, B. Tetrahedron Lett. 1983, 24, 3815. (f) Josse, O.; Labar, D.;
MarchandꢀBrynaert, J. Synthesis, 1999, 406.
11. Thompson, M. J.; Chen, B. Tetrahedron Lett. 2008, 49, 5324 and references therein.
12. Thompson, M. J.; Chen. B. J. Org. Chem. 2009, 74, 7084.
13. SanzꢀCervera, J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibanez, I.; Murguia, M.; Fustero,
S. J. Org. Chem. 2009, 74, 8988.
14. (a) Misra, N. C.; Ila, H. J. Org. Chem. 2010, 75, 5195. (b) Amareshwar, V.; Misra, N. C.;
Ila, H. Org. Biomol. Chem. 2011, 9, 5793.
15. (a) Vijay Kumar, S.; Saraiah, B.; Misra, N. C.; Ila, H. J. Org. Chem. 2012, 77, 10752.
(b) Yugandar, S.; Acharya, A.; Ila, H. J. Org. Chem. 2013, 78, 3948.
16. (a) Ila, H., Junjappa, H. Chimia 2013, 67,17 and references therein. (b) Vijay Kumar, S.;
Yadav, S. K.; Raghava, B.; Saraiah, B.; Ila, H.; Rangappa, K. S.; Hazra, A. J. Org.
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Chem. 2013, 78, 4960. (c) Singh, P. P.; Yadav, A. K.; Ila, H., Junjappa, H. Eur. J. Org.
Chem. 2011, 4001.
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17. In the case of thionationꢀcyclization of all the enamideꢀ amides 10a-k and 11 with
Lawesson’s reagent, formation of some polymeric product was observed, along with the
corresponding product thiazole ꢀ4ꢀ carboxamides 13a-k and 14.
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When the enamideꢀanilide 10a was reacted with excess of Lawesson’s reagent (5 equiv) in
refluxing THF for prolonged time (18 hr), monitoring of reaction showed initial
formation of thiazoleꢀ4ꢀanilide 13a, which was slowly converted to the thiazole ꢀ4ꢀ
thioanilide 17 in 66% yield. Similarly, when the thiazole 13a was reacted with
Lawesson’s reagent (2 equiv) for 8 hr in refluxing THF, the thioanilide 17 was obtained
in 65 % yield.
S
O
O
Lawesson's reagent
(5 equiv)
H
N
N
N
N
Ph
H
H
H
N
N
THF/Reflux/18 h
O
Ph
Ph
S
S
MeS
OMe
OMe
OMe
17, 66%
10a
13a
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