Access to 2-Amino-3-Arylthiophenes by Base-Catalyzed Redox Condensation Reaction Between Arylacetonitriles, Chalcones, and Elemental Sulfur

Article abstract of DOI:10.1002/adsc.201901235

A straightforward access to 2-amino-3-arylthiophenes has been developed via one-pot two-step three-component reaction of arylacetonitriles, chalcones and elemental sulfur. The first step consists of a DBU-catalyzed formation of Michael adduct between aryl

Full text of DOI:10.1002/adsc.201901235

Title: Access to 2-Amino-3-arylthiophenes by Base-catalyzed Redox
Condensation Reaction between Arylacetonitriles, Chalcones,
and Elemental Sulfur
Authors: Thi Thu Tram Nguyen, Van Anh Le, pascal retailleau, and
Thanh Binh Nguyen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901235
Link to VoR: http://dx.doi.org/10.1002/adsc.201901235

10.1002/adsc.201901235
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Access to 2-Amino-3-arylthiophenes by Base-Catalyzed Redox
Condensation Reaction between Arylacetonitriles, Chalcones,
and Elemental Sulfur
Thi Thu Tram Nguyen,b Van Anh Le,a Pascal Retailleau,a and Thanh Binh Nguyena,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1
avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Email: thanh-binh.nguyen@cnrs.fr
Department of Chemistry, Faculty of Science, Can Tho University of Medicine and Pharmacy, Vietnam
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
with antiperoxidative properties. Osseor or strontium
ranelate is used to treat osteoporosis. Raltitrexed is
used in cancer chemotherapy by inhibiting thymidylate
synthase. Brotizolam used in the short-term treatment
of insomnia.
Another attractive feature of 2-aminothiophenes is
their ability to act as starting points for the synthesis of
Abstract. A straightforward access to 2-amino-3-
arylthiophenes has been developed via one-pot two-step
three-component reaction of arylacetonitriles, chalcones
and elemental sulfur. The first step consists of a DBU-
catalyzed formation of Michael adduct between
arylacetonitriles and chalcones. The second step is a
cascade of DABCO-catalyzed sulfuration of the Michael
adduct with elemental sulfur followed by an oxidative
cyclization to afford thiophenes. Compared to the
Gewald reactions and related transformations which are
limited in acetonitriles bearing a methylene group
activated by an -substituted electron withdrawing
group as substrates, our method can be applied to a wide
range of arylacetonitriles and requires only catalytic
amounts of DBU and DABCO. The developed reaction
opens an access to 3-aryl-2-aminothiophenes
complementary to classical Gewald reactions with high
degree of structural diversity and atom efficiency.
bioactive
thiophene-containing
heterocycles,
conjugates and hybrids.[10]
In general, various synthetic pathways developed by
Gewald in 1960s[11] have become key approach
employed in the synthesis of Gewald 2-
aminothiophenes (Scheme 1).[12]
Keywords: sulfur; 2-aminothiophene; chalcone,
arylacetonitrile; oxidative sulfuration
Substituted 2-aminothiophenes occupy an important
place in thiophene chemistry because of their
fascinating biological activities[1] such as antiviral,[2]
anticancer,[3]
anti-tubercular,
antimicrobial,[4,5]
antioxidants,[6] kinase inhibitors,[7] as well as various
beneficial effects on neurological disorders.[8]
Olanzapine, sold under the trade name Zyprexa among
others, is an atypical antipsychotic primarily used to
treat schizophrenia and bipolar disorder. Bentazepam
possesses anxiolytic, anticonvulsant, sedative and
skeletal muscle relaxant properties.
Figure 1. Selected examples of 2-aminothiophene drugs
In this series of reactions, -sulfanyl carbonyl
compounds B, which can exist as dimeric forms A
were allowed to react with acetonitriles C -
substituted by an electron withdrawing group in the
presence of a basic catalyst (usually secondary or
tertiary amine such as Et3N or piperidine).
A large number of 2-aminothiophene-containing
molecules with promising pharmacological effects
have been approved by the FDA (Figure 1). For
example, T-62, which is fused 2-amino-3-
benzoylthiophene analog, is a selective allosteric
enhancer of the adenosine A receptor[9] whereas
Tinoridine is a non-steroidal anti-inflammatory drug
1
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10.1002/adsc.201901235
Advanced Synthesis & Catalysis
Alternatively, ,-unsaturated nitrile -substituted Claisen-Schmidt condensation of acetophenones and
by an electron withdrawing group E were treated sulfur benzaldehydes. To the best of our knowledge, this type
and amine. In a one-pot three-component version, E of sulfur-involved multicomponent access to 2-amino-
was obtained in situ from the Knoevenagel-Cope 3-arylthiophenes has never been explored.
condensation of carbonyl compounds D with nitriles C.
At the outset of this study, we performed an
Other methods were also developed based on exploratory reaction of chalcone 1a with
reaction conditions optimization[13] or extension of phenylacetonitrile 2a and elemental sulfur. Given the
substrate scope[14] of the Gewald reaction or as fact that the preparation of Michael adducts from
alternative
approaches
to
2-aminothiophene phenylacetonitrile and chalcone and the subsequent
derivatives starting from organosulfur compounds.[15]
sulfuration require both a base catalyst, it was assumed
that there is an opportunity for combining both the
reactions in one-pot using only one basic catalyst.
Based on our previous experience with elemental
sulfur, we initially chose DABCO[18] as a basic catalyst
and DMSO as an oxidant additive.[19] To our delight,
heating a mixture of phenylacetonitrile 1a and
chalcone 2a with elemental sulfur (2 equiv) and
DABCO (20 mol %) DMSO at 80 °C for 16 h led to
the desired product 3aa in moderate yield. The low
efficiency of this seminal trial was inarguably due to
the competing formation of side products issued from
direct attack of elemental sulfur on 1a and 2a (Scheme
2).
Scheme 1. 2-Aminothiophenes by Gewald reaction
However, it should be noted that the Gewald
reaction as well as all of its variations and most of the
alternative synthetic methods of 2-aminothiophenes
have an intrinsic limitation: the obtained 2-
aminothiophene products should have an electron
withdrawing group (EWG) in the position 3 of the
thiophene ring such as ester, amide, thioamide, cyano,
ketone etc.
Mechanistically, the first step is a Knoevenagel
condensation between the carbonyl compounds B (or
D) and the acetonitriles C to produce the substituted
acrylonitriles
F (or E, respectively). Such a
Scheme 2. Initial three-component synthesis of 3aa
condensation is feasible if the methylene group of the
cyano compounds B (or D) is more acidic than that of
the acetonitriles C to avoid the competing formation of
carbanion during this step as well as the use of stronger
bases for deprotonation. This explains why the
presence of an EWG on the cyano compound C plays
a central role to the success of the Gewald reaction.
Consequently, the amount of structural diversity these
methods can generate is inherently limited.
To avoid this limitation, we envisioned an
alternative approach in which we could install a neutral
functional group in the position 3 of the thiophene ring
such as aryls. More importantly, the high degree of
structural diversity should be supported by using
starting materials that are readily available in a wide
range of structures.
As part of our goal to discover new reactivities of
elemental sulfur in organic synthesis,[16] our attention
was drawn to the development of strategy for direct
incorporation of sulfur atom from elemental sulfur to
organic scaffolds.[17] We report here a versatile
synthesis of 2-amino-3-arylbenzothiophenes via base-
catalyzed three-component reaction of sulfur with
readily available arylacetonitriles and chalcones. It is
worth noting that chalcones are very readily available
as commercialized chemicals or via synthesis from
Trimer 4 was isolated in 25% yield (based on 1a)
was identified as one of the side products.[18] A radical
solution for this issue is to transform as completely as
possible both organic substrates 1a and 2a into
Michael adduct A prior to the addition of elemental
sulfur. For this purpose, we optimized the reaction
conditions for the C-C bond formation step with some
selected results presented in Table 1.
Gratifyingly, this initial step proceeded at 80 °C
with significant rate (entry 1) and accomplished after 4
h (entry 2) when DABCO was used as a base. However,
DABCO was shown to be catalytically inactive at rt.
At this stage, we considered the possibility to replace
DABCO by a more performant base catalyst. This
catalyst should not only promote efficiently the C-C
bond formation step but also not have any detrimental
impact on the subsequent sulfurating cyclization.
Among the nitrogen bases (N-methylpiperidine, N-
methylmorpholine, pyridine, triethylamine, DIPEA,
DBU) tested in catalytic amounts (20 mol %), we
quickly identified DBU as an excellent candidate since
this catalyst could promote the expected reaction even
at rt with a catalyst loading as low as 1 mol % in only
30 min (entries 4-6). Other bases were shown to be
2
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10.1002/adsc.201901235
Advanced Synthesis & Catalysis
either less efficient than DABCO (N-methylpiperidine,
With the optimized conditions (Table 1, entry 5) for
N-methylmorpholine, pyridine, triethylamine, DIPEA) two-step one-pot reaction, we set out to explore the
or totally absent of catalytic activity (pyridine) but all scope of the arylacetonitriles 1 (Scheme 4). The
of them were totally inactive at rt.
reaction worked with arylacetonitriles bearing a wide
We noted also that replacing DMSO in this reaction range of substituents including methyl (3ab-3ad),
by other additives (DMF, DMAc, N-methylpiperidone, methoxy (3ae-3ah), halogen (3ai-3an) in different
THF, dioxane, CH2Cl2) or performing the reaction in position of the aromatic ring with moderate[20] to good
the absence of DMSO led to significantly lower yields. Notably, the presence of an ortho-substituent
reactivity. For practical reasons, the set of conditions was not problematic (3ad, 3ag, 3ak, 3an). Substrate
in entry 5 was applied for all subsequent reaction with bearing an electron withdrawing groups such as
chalcones. In most cases, Michael adduct A was trifluoromethyl or nitro or 2-pyridyl ring reacted in the
formed as a mixture of two diastereomers in a 2:3 ratio. same manner and gave the expected products in
Since both newly for stereocenters will be destroyed reasonable yields.
after the formation of thiophene ring, this low
diastereoselectivity had no impact on the next step
although a slight difference in reactivity could occur.
Table 1. Optimization of the initial Michael additiona
Entry Base (x mol %) T (°C)
t
A (%)b
50
100
0
1
2
3
DABCO (20)
DABCO (20)
DABCO (20)
80
80
25
20 min
4 h
16 h
4
5
6
DBU (20)
DBU (5)
DBU (1)
25
25
25
10 min
30 min
30 min
100
100
100
a
Reaction conditions: phenylacetonitrile 1a (0.6 mmol),
chalcone 2a (0.5 mmol), DMSO (0.1 mL, 1.5 mmol) and
base (x mol %). b Yield determined by 1H NMR of the crude
reaction mixture.
Scheme 4. Reaction of nitriles 1 with chalcone 2a and S8
At this stage, we were ready to evaluate the
subsequent sulfuration by adding powder sulfur to the
reaction mixture and heating at 80 °C for 16 h (Scheme
3). Contrary to our expectations, the mixture of
Michael adducts remained unchanged, potentially due
to strong interaction of elemental sulfur with DBU to
such an extent that this base was not available to
deprotonate cyanoketone A. At this point, we turned
our attention to add DABCO (20 mol %) as a basic
catalyst for this second step. To our delight, 2-
aminothiophene 3aa was formed in good yield. Other
bases (N-methylpiperidine, N-methylmorpholine,
pyridine, triethylamine, DIPEA, pyridine) were shown
to be less efficient.
Next, we further evaluated the scope of the
chalcones 2 by varying both aryl groups of this
component (Scheme 5). Functional groups such as
methyl, methoxy or chloro did not influence
significantly on the efficiency of the reaction, the
expected products could be obtained in good yields in
all these cases (3ba-3ha).
We witnessed the same outcome with chalcones
bearing an electron with drawing group such as cyano
(product 3ia) and nitro (products 3ja and 3ka).
It should be noted that hydrogen sulfide, a possible
by-product of the oxidative sulfuration step could
attack these EWG including addition to the cyano
group to provide thioamide and reduction of the nitro
group to lower oxidation state nitrogen derivatives.
However, such undesirable reactions were avoided in
all these cases, unarguably due to the presence of
DMSO which could act as a hydrogen sulfide
scavenger by oxidizing H2S into starting elemental
sulfur.[19]
Similarly, thienyl derivatives 3la-3na could be
obtained in the same manner as for phenyl analogs.
Finally, reaction with alkylated conjugated enones
such as cyclohexanone or benzylideneacetone
followed the same pathway and led to the expected
Scheme 3. Access to 3aa - optimization of the second step
3
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10.1002/adsc.201901235
Advanced Synthesis & Catalysis
thiophenes 3oa-3pa, despites in lower yields,
potentially due to side reactions relating to enolization
of the alkyl moieties.
Scheme 6. Reaction of nitrile 5 with chalcone 2a and S8
While details of the oxidative sulfuration and
cyclization steps were not fully understood, we
proposed
a plausible mechanism (Scheme 7).
Sulfuration of Michael adduct A occurred via its
carbanion B and complex C between DABCO and
sulfur to provide cyanopolysulfide D. Desulfurative
cyclization of cyano D would lead to thioimine E,
which could undergo
a
tautomerization into
thioenamine F. Dehydrogenation of F could be
achieved via DABCO-catalyzed formation of
carbanion G stabilized by the benzoyl group and could
involve activated sulfur species C via a sequence of
sulfuration of carbanion G to H and elimination of
hydrogen (poly)sulfide from H.
Scheme 5. Reaction of nitrile 1a with enones 2 and S8
We were curious to see whether this process would
extend to a classical cyanoacetate derivative 5 (Scheme
6). To our surprise, while the first steps of Michael
addition and sulfurative cyclization proceeded without
any difficulty, the aromatization could not be achieved
despite more drastic conditions (heating at 100 °C,
prolonging the reaction time up to 72 h). The structure
of the obtained product 7 was determined as a trans-
dihydrothiophene by X-ray crystallography. This may
be explainable based on a less favorable conformation
of the 4-phenyl and 5-benzoyl group. Indeed, due to a
stronger conjugation between the 2-amino and 3-ester
groups in 7 compared to 2-amino and 3-phenyl groups
in 3aa, dehydrogenation step would be more difficult
for 3aa.
Scheme 7. Proposed mechanism
In conclusion, we have developed a three-
component synthesis of 2-aminothiophenes involving
arylacetonitriles 1, chalcones 2 and elemental sulfur.
This one-pot transformation consists of two steps: (i)
initial formation of Michael adduct A catalyzed by
DBU; and (ii) oxidative sulfuration and cyclization of
adduct A with elemental sulfur catalyzed by DABCO.
4
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10.1002/adsc.201901235
Advanced Synthesis & Catalysis
Compared to the previous approaches based on [4] a) S. Al-Mousawi, M. El-Apasery, H. Mahmoud,
Gewald reactions which required acetonitrile
substrates bearing an -substituted EWG, our method
could be applied successfully to arylacetonitriles,
opening a convenient and complementary access to 3-
aryl-2-aminothiophenes. Moreover, unlike most of the
previous syntheses based on Gewald reactions using
stoichiometric amount or in excess base additive, only
catalytic amounts of DBU and DABCO were needed
in our reaction. In term of atom efficiency, the global
transformation of our method consists of a removal of
only two hydrogen atoms.
Once again, this reaction showcased elemental
sulfur as a versatile tool for organic synthesis of
organosulfur compounds in an inexpensive and
straightforward manner. We hope that this method will
attract the attention of both medicinal and material
chemists.
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Experimental Section
General procedure for the synthesis of 2-
aminothiophenes 3 and dihydrothiophene 7
A mixture of acetonitrile 1 (0.6 mmol, 1.2 equiv),
chalcone 2 (0.5 mmol, 1 equiv) and DBU (4 mg, 0.025
mmol, 5 mol %), and DMSO (0.1 mL, 1.5 mmol, 3
equiv) was stirred at rt for 30 min in a 7-mL tube.
Sulfur (32 mg, 1 mmol) and DABCO (0.1 mmol) was
next added to the tube and the resulting mixture was
stirred and heated at 80 °C for 16 h. The reaction
mixture was purified by column chromatography on
silica gel (CH2Cl2 to CH2Cl2:EtOAc) to afford the
product as a yellow solid.
[8] C. Ballatore, A. B. Smith, V. M. Y. Lee, J. Q.
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1977, 26, 11.
[10] a) T. Nasr, S. Bondock, S. Eid, Eur. J. Med. Chem.
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B. França, J. P. N. Silva, E. O. Barreto, E. B. Silva, R. S.
Ferreira, C. C. Gatto, D. R. M. Moreira, J. L. Siqueira-
Neto, F. J. B. Mendonça-Júnior, M. C. A. Lima, J. H.
Bortoluzzi, M. T. Scotti, L. Scotti, M. R. Meneghetti, T.
M. Aquino, J. X. Araújo-Júnior, Bioorg. Med. Chem.
2016, 24, 4228.
CCDC-1951373 and CCDC-1951374 (compounds 7 and
3aa
respectively)
contain
the
supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
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Hentschel, J. Prak. Chem. 1972, 314, 303.
Acknowledgements
We thank ICSN-CNRS and Dr. A. Marinetti (ICSN-CNRS) for
helpful support.
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[20] The yields described here were the result of a two-step
sequence and obviously depended on the first step. If the
conversion of the first step was not complete, i.e.
arylacetonitriles and chalcones were not consumed
totally, these two compounds could react with sulfur to
give many products. One of these, resulting from an
oxidative trimerization of arylacetonitriles, was
previously described (ref. 18) by our group. The
separation of all these side products from the principal
products was shown to be not easy and this could lower
the overall yield.
6
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10.1002/adsc.201901235
Advanced Synthesis & Catalysis
COMMUNICATION
Access to 2-Amino-3-arylthiophenes by Base-
catalyzed Redox Condensation Reaction between
Arylacetonitriles, Chalcones, and Elemental Sulfur
Adv. Synth. Catal. Year, Volume, Page – Page
Thi Thu Tram Nguyen,b Van Anh Le,a Pascal
Retailleau,a and Thanh Binh Nguyena,
7
This article is protected by copyright. All rights reserved.