A concise, greener, solvent-free novel one-pot synthesis of trisubstituted thiophenes

Article abstract of DOI:10.1016/j.tetlet.2012.10.022

Herein, we report a concise, greener, solvent-free, and novel one pot method for the synthesis of 2-morpholino-3-aryl-5-aroyl thiophenes using 1-morpholino-2-arylethanethione, N,N′-dimethyl formamide dimethyl acetal, and various phenacyl bromides. The driving force for this reaction is the removal of N,N′-dimethylamine from 3-(dimethylamino)-1-morpholino-2- arylprop-2-ene-1-thione resulting in various trisubstituted thiophenes (2-morpholino-3-aryl-5-aroyl thiophenes).

Full text of DOI:10.1016/j.tetlet.2012.10.022

Tetrahedron Letters 53 (2012) 6927–6930
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A concise, greener, solvent-free novel one-pot synthesis of
trisubstituted thiophenes q
⇑
Hitesh B. Jalani, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, V. Sudarsanam, Kamala K. Vasu
Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054,
Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report a concise, greener, solvent-free, and novel one pot method for the synthesis of 2-mor-
pholino-3-aryl-5-aroyl thiophenes using 1-morpholino-2-arylethanethione, N,N0-dimethyl formamide
dimethyl acetal, and various phenacyl bromides. The driving force for this reaction is the removal of
N,N0-dimethylamine from 3-(dimethylamino)-1-morpholino-2-arylprop-2-ene-1-thione resulting in var-
ious trisubstituted thiophenes (2-morpholino-3-aryl-5-aroyl thiophenes).
Received 8 August 2012
Revised 3 October 2012
Accepted 5 October 2012
Available online 12 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Trisubstituted thiophenes
DMF–DMA
Phenacyl bromides
Solvent-free
One pot reaction
Syntheses of small molecules, especially five-membered ring
heterocycles have always attracted the scientific community, be-
cause of their vivid therapeutic importance. In addition to this,
small heterocyclic scaffolds are present in more than 50% of phar-
maceutical substances and allow various interactions with the bio-
logical targets due to the presence of side chains or various polar
bonds, which are not accessible in carbocyclic scaffolds. It is also
revealed that the diversity of synthetic methods used by the phar-
maceutical industries to generate heterocycles containing products
is based on only five-membered aromatic heterocycles represent-
ing more than top 200 best selling drugs.1
Thiophene is an important structural motif in medicinal chem-
istry and it is considered as a classical bioisostere for the benzene
ring and due to its small ring structure it is found in many thera-
peutically active substances (Fig. 1) such as Raloxifene, Olanzepine,
Clopidogrel, Tiamenidine, Tiaprofenic acid, Suprofen, Raniliate
strontium, potent PI3K inhibitors etc. One of the common methods
for the synthesis of 2-morpholino thiophene is the Willgerodt–
Kindler2 reaction of acetophenone, sulfur, and morpholine which
gives the intermediate 1-morpholino-2-arylethanethione. This
1-morpholino-2-arylethanthione intermediate on reaction with
morpholine and triethyl orthoformate gives the dimorpholide
compounds which on reaction with various aryl, aroyl halides re-
sult in 2-morpholino thiophenes.3,4 In addition to this, recently,
Huang et al. developed a multi-step synthesis of 2-morpholino
thiophene compound known for its PI3K activity.5 It has also been
observed that the 2-aminothiophene compounds are well docu-
mented in the literature,6,7 but the most popular Gewald method,8
involves the multicomponent condensation of carbonyl com-
pounds, cyanoacetates or malanonitrile, and elemental sulfur.
The above mentioned processes are associated with drawbacks
such as multistep reactions (except Gewald), harsh reaction condi-
tions, complex and tedious experimental procedures, and lower
yields. After a careful literature search, we realized that there is
still a need to develop efficient and concise methods for the
synthesis of thiophenes.
In continuation of our work on the synthesis of various bioac-
tive heterocyclic compounds using N,N0-dimethyl formamide
dimethyl acetal (DMF–DMA),9,10 we were interested to explore 1-
morpholino-2-arylethanethione intermediate resulting from the
Willgerodt–Kindler reaction of various acetophenones, sulfur, and
morpholine. We envisaged that this intermediate could be useful
for the synthesis of thiophenes. We have developed an efficient,
concise, greener, and novel sequential one-pot method for the syn-
thesis of trisubstituted thiophenes from 1-morpholino-2-
arylethanethione, DMF–DMA, and various phenacyl bromides
resulting in various 2-morpholino-3-aryl-5-aroyl (trisubstituted)
thiophenes. This method neither requires any reagent for the cycli-
zation nor the solvents (Scheme 1) which is reported herein. To the
best of our knowledge, the formation of 2-morpholino-3-aryl-5-
aroyl (trisubstituted) thiophenes using N,N’-dimethyl formamide
dimethyl acetal (DMF–DMA) has not been reported so far.
q
Communication Ref. No.: PERD-080712.
⇑
Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail address: kamkva@gmail.com (K.K. Vasu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.022

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H. B. Jalani et al. / Tetrahedron Letters 53 (2012) 6927–6930
Figure 1. Select examples of biologically active thiophenes.
Scheme 1. One pot synthesis of trisubstituted thiophenes.
In order to check this hypothesis, we started our efforts by carry-
by gaining the aromatic property by the removal of dimethyl
amine and hydrogen bromide resulting in the desired trisubsti-
tuted thiophenes 4. During the course of the study, it was observed
that the reaction of electron withdrawing groups present in phena-
cyl bromide furnished good yields (4a, b, e, and m), while the
electron rich phenacyl bromide resulted in comparatively lower
yields (4d, j, and l) and the reaction of intermediate 1-morpho-
lino-2-arylethanethione containing electron withdrawing group
with phenacyl bromide containing electron releasing groups elic-
ited lower yields (4h, j, and k) as shown in Table 1.
In conclusion, we have demonstrated a novel, concise, efficient,
and greener one-pot method for the synthesis of trisubstituted
thiophenes from simple starting materials like 1-morpholino-2-
arylethanethione, N,N0-dimethylformamide dimethyl acetal, and
various phenacyl bromides to elicit the tri-substituted thiophenes
in good to excellent yields. The present method is attractive due to
its facile conditions suggesting this protocol could be an alternative
to other protocols (harsh conditions). The product can be isolated
very easily without the use of chromatography. Furthermore, the
present protocol can be useful in future for the generation of com-
pound libraries of thiophene compounds incorporating various
cyclic amines like piperazine, pyrrolidine, and N-methyl piperazine
at the 2nd position of thiophenes. Further exploration for the syn-
thesis of thiophene compounds incorporating various halogen
partners using this methodology is under development.
ing out the sequential reaction of 1-morpholino-2-phenylethan-
ethione 1a and DMF–DMA 2 at 80–85 °C temperature which
allows the removal of methanol to give the intermediate 3-(dimeth-
ylamino)-1-morpholino-2-phenylprop-2-ene-1-thione 5. This
intermediate 5 was then reacted with p-chloro phenacyl bromide
3a at ambient temperature giving the desired trisubstituted thio-
phene 4a, which was showing fluorescence spot in UV–visible spec-
troscopy. Further work-up of this reaction gave the yellowish
solid.12 The structure of this compound was confirmed by 1H
NMR, and Mass spectroscopy (Table 1). In addition to this, the pres-
ent protocol is useful for the construction of variety of trisubstituted
thiophenes with morpholine at the 2nd position of thiophene. The
present protocol is novel, quite efficient (high yield), concise (one
pot), and greener (no use of excess solvent as well as one of the sub-
strate morpholines) as compared to our earlier reported method3 in
which a harsh condition (more than 130 °C temperature) is required
to furnish the formation of di-morpholine compound in the second
step.
The plausible reaction mechanism for the formation of these tri-
substituted thiophenes is described in (Scheme 2). The synthesis of
1-morpholino-2-arylethanethione is well documented in the liter-
ature.4 Subsequent reaction of 1-morpholino-2-arylethanethione 1
with DMF–DMA 2 at elevated temperatures resulted in the forma-
tion of intermediate 5. The mechanism for the formation of inter-
mediate 5 is reported in the literature.11 The intermediate 5 is
versatile in nature and has one dominant nucleophilic (C@S) site
and one electrophilic (C–NMe2) site. The highly polar C–Br bond
of phenacyl bromide is facile toward the nucleophilic attack of sul-
fur to give species 6. The double bond resulted from keto-enol tau-
tomerism attacks the electron deficient imine carbon (to which
electron pulling quaternary nitrogen is attached, which makes this
carbon a strong electrophile) to give the intermediate 8 in a 5-exo-
trig cyclization manner. This intermediate now could be stabilized
Acknowledgments
We gratefully acknowledge the financial support for this work
from B.V. Patel PERD centre. HBJ thanks Industrial Commissioner
(IC) of Gujarat for the grant provided to carry out research work.
We thank Dr. Manish Nivsarkar and Prof. C.J. Shishoo Directors of
B.V. Patel PERD centre, for their constant encouragement and
support.

H. B. Jalani et al. / Tetrahedron Letters 53 (2012) 6927–6930
6929
Table 1
Synthesis of trisubstituted thiophenes from 1-morpholino-2-arylethanethione, DMF–DMA, and phenacyl bromides
Cl
O
O
O
O
Br
N
N
N
S
H
Cl
S
O
O
SO2Me
NHCOCH3
O
Br
N
S
H
MeO2S
S
O
O
O
O
O
Br
N
N
N
S
H3COCHN
S
O
H
O
O
O
Br
N
N
S
S
S
O
H
NO2
O
O
Br
N
O
S
O2N
Cl
O
H
N
O
Cl
O
Br
N
S
H
S
S
Cl
Cl
O
Cl
SO2Me
O
O
O
O
Br
Br
N
N
S
MeO2S
H3COCHN
Cl
O
H
Cl
Cl
NHCOCH3
O
O
N
N
S
S
Cl
O
H
Cl
O
O
O
Br
N
N
S
S
MeO2S
O
H
MeO2S
OMe
O
O
O
O
N
N
Br
N
S
S
MeO2S
MeO2S
MeO
O
H
MeO2S
MeO2S
NHCOCH3
O
O
Br
N
S
S
H3COCHN
O
H
O
O
O
N
Br
N
S
S
H3COCHN
O
H
H3COCHN
NO2
O
O
O
N
Br
N
S
S
O2N
O
H
a
Yields refer to isolated products. Melting points of compounds are uncorrected.
LC-MS analysis M+1 at m/z.
b

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H. B. Jalani et al. / Tetrahedron Letters 53 (2012) 6927–6930
Scheme 2. Plausible reaction mechanism for trisubstituted thiophene formation.
11. Abu-Shanab, F. A.; Sherif, S. M.; Mousa, S. A. S. J. Heterocycl. Chem. 2009, 46, 801.
12. General experimental procedure for the preparation of 2-morpholino-3aryl-5aroyl
thiophenes: In hot air dried flask, 1-morpholino-2-arylethanethione
(1.0 mmol) and dimethylformamide dimethyl acetal (1.5 mmol) were
References and notes
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mixed together and heated to 80–85 °C for 6–10 h. Progress of the reaction
was monitored by TLC using ethyl acetate/hexane (4:6), showing the
consumption of both the starting materials. The reaction was then allowed
to be at ambient temperature and phenacyl bromide 3 (1.0 mmol) was added
with stirring. The reaction was then again maintained at same conditions for
another 3–6 h. After completion of the reaction, the reaction mixture was then
evaporated (50–60 °C) on Buchi rotavapor to remove the volatiles and then
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anhydrous magnesium sulfate and concentrated under reduced pressure. The
residues were treated with hexane and/or ether to give the pure compounds
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