New approach to 3-aminothiophene-2-carboxylic acid derivatives: Access to 5-aryl-4-(ethylsulfanyl) compounds

Article abstract of DOI:10.1080/00397910701198922

Treatment of DMSO/water solutions of β-bromo-α-(ethylsulfanyl) cinnamonitriles with sodium sulphide and α-halo acetic acids derivatives followed by cyclization in a potassium carbonate/acetone/DMSO mixture gave the expected 3-amino-5-aryl-4-(ethylsulfanyl

Full text of DOI:10.1080/00397910701198922

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New Approach to 3‐Aminothiophene‐
2‐carboxylic Acid Derivatives: Access to
5‐Aryl‐4‐(ethylsulfanyl) Compounds
Frédéric Lassagne a , Francis Pochat a & Sourisak Sinbandhit b
a Laboratoire de Chimie Organique , Université de Rennes 1 , Rennes,
France
b Centre Régional de Mesures Physiques de l'Ouest, Université de Rennes 1 ,
Rennes, France
Published online: 13 Oct 2010.
To cite this article: Frédéric Lassagne , Francis Pochat & Sourisak Sinbandhit (2007) New Approach to
3‐Aminothiophene‐ 2‐carboxylic Acid Derivatives: Access to 5‐Aryl‐4‐(ethylsulfanyl) Compounds, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:7,
1133-1140, DOI: 10.1080/00397910701198922
To link to this article: http://dx.doi.org/10.1080/00397910701198922
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Synthetic Communicationsw, 37: 1133–1140, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701198922
New Approach to 3-Aminothiophene-
2-carboxylic Acid Derivatives: Access to
5-Aryl-4-(ethylsulfanyl) Compounds
´ ´
Frederic Lassagne and Francis Pochat
´
Laboratoire de Chimie Organique, Universite de Rennes 1, Rennes
France
Sourisak Sinbandhit
´
Centre Regional de Mesures Physiques de
´
l’Ouest, Universite de Rennes 1, Rennes, France
Abstract: Treatment of DMSO/water solutions of b-bromo-a-(ethylsulfanyl)cinna-
monitriles with sodium sulphide and a-halo acetic acids derivatives followed by
cyclization in a potassium carbonate/acetone/DMSO mixture gave the expected
3-amino-5-aryl-4-(ethylsulfanyl)thiophene-2-carboxylic acids derivatives in fair
yields.
Keywords: 3-amino-5-aryl-4-(ethylsulfanyl)thiophene-2-carboxylic acids deriva-
tives, b-bromo-a-(ethylsulfanyl)cinnamonitriles, (ethylsulfanyl)acetonitrile, methyl
3-amino-5-aryl-4-bromothiophene-2-carboxylate, sodium sulphide
INTRODUCTION
Several examples described syntheses of fused heterocycles using alkyl
3-aminothiophene-2-carboxylate[1] or carboxamide as starting materials.
These synthons react easily to give structural analogues of pharmacophores.[2]
Received in Poland June 12, 2006
´ ´
Address correspondence to Frederic Lassagne, Laboratoire de Chimie Organique,
´
Universite de Rennes 1, Bat 7, Campus de Beaulieu, 35042 Rennes, France. E-mail:
frederic.lassagne@univ-rennes1.fr
1133

1134
F. Lassagne, F. Pochat, and S. Sinbandhit
Scheme 1. R55CN: R155R255H;R155OMe, R255H. R55CO2Me: R155Cl, R255H;
R155OMe, R255H; R1, R255OCH2O. R55CONH2: R155R255H; R155Cl, R255H; R1,
R255OCH2O.
Following our ongoing interest in new biologically active molecules, we
propose here an easy access to a new series of thiophenes 3 starting from
b-bromo-a-(ethylsulfanyl)cinnamonitriles b-substituted by an aryl group 2
as depicted in Scheme 1.
In our investigation, the 3-amino-5-aryl-4-(ethylsulfanyl)thiophene-2-
carboxylic acids derivatives 3 were obtained in a four-step procedure
starting from (ethylsulfanyl)acetonitrile.[3] Condensation with benzaldehydes
followed by bromination afforded the b-bromo-a-(ethylsulfanyl)cinnamoni-
triles 1, which were isolated as Z/E mixtures in good yields ranging from
70 to 80%.[4]
When treated with a slight excess of sodium sulphide in a DMSO/water
mixture at room temperature, the compounds 1 were converted to the corre-
sponding sodium thienolate, which was immediately trapped with various
a-haloacetic acids derivatives (chloroacetonitrile, methyl bromoacetate,
chloroacetamide). The resulting condensation products 2 were obtained in
good yields (Table 1) and could be further used as such (the analysis of the
1H NMR spectra showed that the crude products contained less than 5% of
the starting compounds 1).
The final cyclization using a K2CO3/acetone/DMSO mixture furni-
shed the new family of 3-amino-5-aryl-4-(ethylsulfanyl)thiophene-2-
carboxylic acids derivatives 3a to 3c in fair yields varying between 56
and 73%.
Furthermore, in the case of methyl 3-amino-5-aryl-4-(ethylsulfanyl)thio-
phene-2-carboxylate 3a, we have observed that the ethylsulfanyl group could
be replaced by a halogen,[5] bromine, using N-bromosuccinimide as reagent.
Indeed, methyl 3-amino-5-aryl-4-bromothiophene-2-carboxylates, 4a1 could
be obtained from the corresponding thiophenes 3a1, using N-Bromosuccinimide
(NBS) excess in refluxing acetonitrile/water, as exemplified in Scheme 2.

3-Aminothiophene-2-carboxylic Acid
1135
Table 1. Synthesis of compounds 2 from b-bromo-a-(ethylsulfanyl)cinnamonitriles 1
and a-haloacetic acids derivatives
a-Haloacetic
acids
derivatives
Products 2
(Z/E mixture)
Substrate 1 (Z/E mixture)
Yield (%)
98
a
a1
BrCH2CO2Me
BrCH2CO2Me
a
a2
94
a
BrCH2CO2Me
ClCH2CN
a3
98
97
a
b1
a
b2
ClCH2CN
96
a
ClCH2CONH2
ClCH2CONH2
ClCH2CONH2
c1
96
94
93
b
c2
b
c3
aProducts 2 were yellow to red colored oils.
bCompounds 2 were crystalline products: mp (2c2) 118–1228C, mp (2c3)
112–1168C.

1136
F. Lassagne, F. Pochat, and S. Sinbandhit
Scheme 2.
CONCLUSION
This article described a simple and efficient method for preparation of a new
thiophene family, involving the use of a single starting material in a four-step
procedure. The versatility of these synthons could be of interest for preparing
novel heterocyclic systems and consequently access to new compounds poten-
tially endowed with biological properties.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker Advance 500-MHz spec-
trometer using chloroform-d as solvent, and chemical shifts refer to TMS on a
d scale. Melting points were determined on a Kofler apparatus and are uncor-
rected. Mass spectra were recorded in the electron impact (EI) mode on a
Varian Mat 311. Elemental analyses were performed on a Carlo Erba Instru-
˚
ment EA-1112. Acetone and dimethyl sulphoxide were stored over a type 4A
molecular sieve. (Ethylsulfanyl)acetonitrile, and b-bromo-a-(ethylsulfanyl)-
cinnamonitriles 1 were prepared according to described procedures.[3,4]
Sodium sulphide nonahydrate, anhydrous potassium carbonate, chloroacetoni-
trile, methyl bromoacetate, and a-chloroacetamide were purchased from
Aldrich. Analytical thin-layer chromatography (TLC) was performed on
Merck silica-gel-coated plates (60F254).
General Procedure for the Conversion of b-Bromo-a-
(ethylsulfanyl)cinnamonitriles 1 into Compounds 2
To a stirred solution of starting compounds 1 (4.83 mmol) in DMSO (8 mL)
.
cooled to 168C, a solution of Na2S 9H2O, (5.82 mmol, 1.40 g) in 1.5 mL
of H2O was rapidly added. After 25 min, a solution of the appropriate
a-haloacetic acid derivative (8.21 mmol) in DMSO (2 mL) was added in
one drop to the resulting red mixture and stirred for a 1 h. The reaction was
quenched with water (50 mL) and extracted with diethyl ether (compounds
2a1, 2a2, 2a3, 2b1, 2b2) or dichloromethane (compounds 2c1, 2c2, 2c3). The
organic layer was washed twice with water and brine and dried with

3-Aminothiophene-2-carboxylic Acid
1137
Na2SO4. The solvents and the excess of liquid a-haloacetic acid derivative
were removed under reduced pressure, yielding the sufficiently pure precur-
sors 2 as Z/E mixture (Table 1).
General Procedure for the Preparation of 3-Amino-5-aryl-4-
(ethylsulfanyl)thiophene-2-carboxylic Acids Derivatives (3)
A mixture of precursors 2 (3.05 mmol), anhydrous potassium carbonate
(3.05 mmol), acetone (8 mL), and DMSO (2 mL) was vigorously stirred and
refluxed under nitrogen. The reaction was monitored by TLC using CH2Cl2
as eluent. When the reaction was finished (reaction time 1 to 4 h), the
cooled mixture was filtered over celite and concentrated under reduced
pressure. The resulting residue was dissolved in CH2Cl2 (25 mL) and
washed with 1 N aqueous HCl solution to give the crude product. The pure
3-amino-5-aryl-4-(ethylsulfanyl)thiophene-2-carboxylic acids derivative 3
was isolated after recrystallization (the solvent is given in the product
description).
Methyl 3-Amino-5-(4-chlorophenyl)-4-(ethylsulfanyl)thiophene-2-
carboxylate (3a1)
Reaction time 1 h; this compound was obtained in 73% yield as pale yellows
crystals, mp 122–1248C (CH3CN/H2O). 1H NMR (500 MHz, CDCl3):
d ¼ 1.00 (3H, t, CH3, J 7.3 Hz), 2.52 (2H, q, CH2, J 7.3 Hz), 3.85 (3H, s,
CO2CH3), 5.97 (2H, br s, NH2), 7.38 (2H, d, H30 2 50, J 8.5 Hz), 7.64 (2H,
d, H20 2 60, J 8.5 Hz). 13C NMR (75.5 MHz, CDCl3): d ¼ 14.77 (CH3),
29.35 (CH2), 51.44 (OCH3), 98.47 (C-2), 117.37 (C-4), 128.72 (C-30 2 50),
130.49 (C-20 2 60), 131.88 (C-10), 135.13 (C-40), 150.97 (C-5), 155.08 (C-3),
164.61 (C55O). Anal. calcd. for C14H14ClNO2S2: C, 51.29; H, 4.30; N, 4.27;
S, 19.56. Found: C, 51.44; H, 4.26; N, 4.64; S, 19.74. EIMS: m/z calcd. for
C14H14ClNO2S2: 327.01545. Found 327.0144 (Mþ).
Methyl 3-Amino-4-(ethylsulfanyl)-5-(-40-methoxyphenyl)thiophene-
2-carboxylate (3a2)
Reaction time 4 h; this compound was obtained in 63% yield as orange
needles, mp 80–828C (CH3OH). 1H NMR (500 MHz, CDCl3): d ¼ 1.01
(3H, t, CH3, J 7.4 Hz), 2.51 (2H, q, CH2 J 7.4 Hz), 3.83 (3H, s, OCH3),
3.84 (3H, s, CO2CH3) 5.98 (2H, br s, NH2), 6.93 (2H, d, H30 2 50, J
8.8 Hz), 7.66 (2H, d, H20 2 60, J 8.8 Hz). 13C NMR (75.5 MHz, CDCl3):
d ¼ 14.72 (CH3), 29.23 (CH2), 51.28 (CO2CH3), 55.29 (OCH3), 97.50
(C-2), 113.84 (C-30 2 50), 116.13 (C-4), 125.84 (C-10), 130.47 (C-20 2 60),

1138
F. Lassagne, F. Pochat, and S. Sinbandhit
152.53 (C-5), 155.26 (C-3), 160.26 (C-40), 164.67 (C55O). Anal. calcd. for
C15H17NO3S2: C, 55.70; H, 5.30; N, 4.33; S, 19.83. Found: C, 51.59; H,
5.26; N, 4.40; S, 19.98. EIMS: m/z calcd. for C15H17NO3S2: 323.06499.
Found 323.06420 (Mþ).
Methyl 3-Amino-5-(1,3-benzodioxol-5-yl)-4-(ethylsulfanyl)-
thiophene-2-carboxylate (3a3)
Reaction time 2 h; this compound was obtained in 67% yield as red needles,
mp 106–1088C (CH3OH). 1H NMR (500 MHz, CDCl3): d ¼ 1.04 (3H, t, CH3,
J 7.4 Hz), 2.53 (2H, q, CH2, J 7.4 Hz), 3.84 (3H, s, CO2CH3), 5.97 (2H, br s,
NH2), 6.02 (2H, s, OCH2O), 6.85 (1H, d, H-50, J 8.1 Hz), 7.18 (1H, dd, H-60, J
8.1, 1.7 Hz), 7.25 (1H, d, H-20, J 1.7 Hz). 13C NMR (75.5 MHz, CDCl3):
d ¼ 14.75 (CH3), 29.25 (CH2), 51.32 (OCH3), 97.60 (C-2), 101.45
(OCH2O), 108.31 (C-50), 109.55 (C-20), 116.44 (C-4), 123.32 (C-60), 127.17
(C-10), 147.61 (C-30), 148.36 (C-40), 152.24 (C-5), 155.15 (C-3), 164.64
(C55O). Anal. calcd. for C15H15NO4S2: C, 53.39; H, 4.48; N, 4.15; S,
19.01. Found: C, 51.44; H, 4.37; N, 4.43; S, 19.15.
3-Amino-4-(ethylsulfanyl)-5-(-4-methoxyphenyl)thiophene-2-
carbonitriles (3b1)
Reaction time 1.5 h; this compound was obtained in 56% yield as yellow
1
needles, mp 1308C (CH3CN). H NMR (500 MHz, CDCl3): d ¼ 1.03 (3H, t,
CH3, J 7.4 Hz), 2.51 (2H, q, CH2, J 7.4 Hz), 3.85 (3H, s, OCH3), 5.06 (2H,
br s, NH2), 6.95 (2H, d, H-30 2 50, J 8.8 Hz), 7.62 (2H, d, H-20 2 60, J
8.8 Hz). 13C-NMR (75.5 MHz, CDCl3): d ¼ 14.69 (CH3), 29.37 (CH2),
55.36 (OCH3), 77.25 (C-2), 114.02 (C-20 2 60), 115.27 (CN), 116.01 (C-4),
124.90 (C-10), 130.40 (C-30 2 50), 152.93 (C-3), 156.75 (C-5), 160.54
(C-40). Anal. calcd. for C14H14N2OS2: C, 57.90; H, 4.86; N, 9.65; S, 22.08.
Found: C, 57.81.; H, 4.75; N, 9.71; S, 22.23.
3-Amino-4-(ethylsulfanyl)-5-phenylthiophene-2-carbonitriles (3b2)
Reaction time 1 h; this compound was obtained in 59% yield as pale yellow
1
needles, mp 1248C (CH3CH2OH). H NMR (500 MHz, CDCl3): d ¼ 1.01
(3H, t, CH3, J 7.4 Hz), 2.51 (2H, q, CH2, J 7.4 Hz), 5.10 (2H, br s, NH2),
7.42–7.43 (3H, m, H-30 2 40 2 50), 7.64–7.65 (2H, m, H-20 2 60). 13C NMR
(75.5 MHz, CDCl3): d ¼ 14.67 (CH3), 29.42 (CH2), 78.05 (C-2), 115.11
(CN), 116.95 (C-4), 128.59 (C-30 2 50), 129.11 (C-20 2 60), 129.47 (C-40),
132.47 (C-10), 152.89 (C-5), 156.69 (C-3). Anal. calcd. for C13H12N2S2: C,

3-Aminothiophene-2-carboxylic Acid
1139
59.97; H, 4.65; N, 10.76; S, 24.63. Found: C, 59.98.; H, 4.62; N, 10.75; S,
24.75. EIMS: m/z calcd. for C13H12N2S2: 260.04419. Found 260.0447 (Mþ).
3-Amino-5-(4-chlorophenyl)-4-(ethylsulfanyl)thiophene-2-
carboxamide 3c1
Reaction time 1.5 h; this compound was obtained in 62% yield as yellow
crystals, mp 156–1588C (CCl4). 1H NMR (500 MHz, CDCl3): d ¼ 1.01
(3H, t, CH3, J 7.4 Hz), 2.53 (2H, q, CH2, J 7.4 Hz), 5.72 (2H, br s,
CONH2), 6.18 (2H, br s, NH2), 7.39 (2H, d, H-30 2 50, J 8.4 Hz), 7.63 (2H,
d, H-20 2 60, J 8.4 Hz). 13C NMR (75.5 MHz, CDCl3): d ¼ 14.75 (CH3),
29.26 (CH2), 99.52 (C-2), 118.62 (C-4), 128.69 (C-30 2 50), 130.51 (C-
20 2 60), 131.64 (C-10), 135.04 (C-40), 145.36 (C-5), 154.45 (C-3), 166.55
(C ¼ O). Anal. calcd. for C13H13ClN2OS2: C, 49.91; H, 4.19; N, 8.95; S,
20.50. Found: C, 49.88; H, 4.11; N, 8.83; S, 20.61.
3-Amino-5-(1,3-benzodioxol-5-yl)-4-(ethylsulfanyl)thiophene-2-
carboxamide 3c2
Reaction time 1.5 h; this compound was obtained in 60% yield as white
1
needles, mp 1228C (CH3CN). H NMR (500 MHz, CDCl3): d ¼ 1.04 (3H, t,
CH3, J 7.4 Hz), 2.54 (2H, q, CH2, J 7.4 Hz), 5.77 (2H, br s, CONH2), 6.02
(2H, s, OCH2O), 6.17 (2H, br s, NH2), 6.84 (1H, d, H-50, J 8.1 Hz), 7.15
(1H, dd, H-60, J 1.7-8.1 Hz), 7.23 (1H, d, H-20, J 1.7 Hz). 13C-NMR
(75.5 MHz, CDCl3): d ¼ 14.77 (CH3), 29.19 (CH2), 98.79 (C-2), 101.46
(OCH2O), 108.31 (C-50), 109.61 (C-20), 117.65 (C-4), 123.36 (C-60), 126.96
(C-10), 147.58 (C-30), 148.28 (C-40), 148.66 (C-5), 154.46 (C-3), 166.69
(C55O). Anal. calcd. for C14H14N2O3S2: C, 52.16; H, 4.38; N, 8.69, S,
19.89. Found: C, 52.10; H, 4.31; N, 8.77; S, 20.25. EIMS: m/z calcd. for
C14H14N2O3S2: 322.04459. Found 322.04570 (Mþ).
3-Amino-4-(ethylsulfanyl)-5-phenylthiophene-2-carboxamide 3c3
Reaction time 1.5 h; this compound was obtained in 70% yield as yellow
crystals, mp 104–1068C (CCl4). 1H NMR (500 MHz, CDCl3): d ¼ 1.00
(3H, t, CH3, J 7.3 Hz), 2.52 (2H, q, CH2, J 7.3 Hz), 5.81 (2H, br s,
CONH2), 6.18 (2H, br s, NH2), 7.39–7.40 (3H, m, H-30 2 40 2 50), 7.67
(2H, d, H-20 2 60, J 6.6 Hz). 13C NMR (75.5 MHz, CDCl3): d ¼ 14.71
(CH3), 29.21 (CH2), 99.50 (C-2), 118.20 (C-4), 128.39 (C-30 2 50), 128.95
(C-40), 129.27 (C-20 2 60), 133.19 (C-10), 148.90 (C-5), 154.42 (C-4),
166.75 (C55O). Anal. calcd. for C13H14N2OS2: C, 56.09; H, 5.07; N, 10.06;
S, 23.04. Found: C, 56.01; H, 5.05; N, 10.4.98; S, 23.15.

1140
F. Lassagne, F. Pochat, and S. Sinbandhit
Procedure for the Preparation of Methyl 3-Amino-4-bromo-5-
(4-chloro-phenyl)thiophene-2-carboxylate (4a1)
To a stirred solution of methyl 3-amino-4-(ethylsulfanyl)-5-(4-chlorophenyl)
thiophene-2-carboxylate 3a1, (0.500 g, 1.52 mmol) in a mixture of acetonitrile
(6 mL) and water (0.5 mL), N-bromosuccinimide (0.680 g, 3.82 mmol) was
added in small portions. The mixture was then heated under reflux for 1 h and
cooled, and the solid was filtered. Recrystallization from acetonitrile yielded
65% (0.345 g) of pure bromothiophene 4a1 as a white needles. Mp 152–1548C
(CH3CN). 1H NMR (500 MHz, CDCl3): d ¼ 3.86 (3H, s, CO2Me), 5.74 (2H, br
s, NH2), 7.4 (2H, d, H-30 2 50, J 8.6 Hz), 7.56 (2H, d, H-20 2 60, J 8.6 Hz).
13CNMR (75.5 MHz, CDCl3): d ¼ 51.61 (OCH3), 99.28 (C-2), 100.51 (C-4),
128.96 (C-30 2 50), 130.09 (C-20 2 60), 130.91 (C-10), 135.44 (C-40), 141.93
(C-5), 151.00 (C-3), 164.09 (C55O). Anal. calcd. for C12H9BrClNO2S: C,
41.68; H, 2.62; N, 4.04; S, 9.25. Found: C, 41.65; H, 2.55; N, 4.23; S, 9.45.
EIMS: m/z calcd for C12H9BrClNO2S: 344.92259. Found 344.9239 (Mþ).
ACKNOWLEDGMENTS
The authors are grateful to F. Mongin for many helpful discussions and to
P. Guenot for recording mass spectra.
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