Thiophene-2,5-dicarboxylic acid bis-aryl(alkyl) amides

Article abstract of DOI:10.1002/hc.20153

A base-catalyzed condensation of diacetamido sulfides [(RNHCOCH ₂)₂S)] with glyoxal affording thiophene-2,5-dicarboxylic acid bis-aryl-(alkyl) amides has been accomplished under mild conditions. Excellent results were readily obtaine

Full text of DOI:10.1002/hc.20153

Heteroatom Chemistry
Volume 16, Number 6, 2005
Thiophene-2,5-dicarboxylic Acid
Bis-aryl(alkyl) Amides
Metin Koparır, Ahmet Cansız, and Ahmet C¸ etin
Chemistry Department, Faculty of Arts and Sciences, Firat University, 23119 Elazıg˘ , Turkey
Received 15 July 2004; revised 13 April 2005
or aryl) is so far unreported in spite of a mention
ABSTRACT: A base-catalyzed condensation of di-
of this possibility by Hinsberg in his first paper [7].
acetamido sulfides [(RNHCOCH2)2S)] with glyoxal
On the other hand, several successful condensations
affording thiophene-2,5-dicarboxylic acid bis-aryl-
of diketo sulfides with vicinal dialdehydes afford-
(alkyl)amides has been accomplished under mild con-
ing thiepin derivatives or the corresponding sulfur-
ditions. Excellent results were readily obtained when
eliminated aromatized products after sulfur extru-
R was a substituted 3-nitrophenyl, 4-nitrophenyl, 4-
sion are known [8,9]. It was expected, therefore, that
chlorophenyl group, but the yield was poor when R
the condensation of diketo sulfides with glyoxal, the
was cyclohexyl. Unknown compounds were character-
simplest dialdehyde, affording the more stable thio-
ized by elemental analyses, IR, 1H, and 13C NMR tech-
phene ring, might be more facile.
ꢀ
C
niques. 2005 Wiley Periodicals, Inc. Heteroatom Chem
While in the Hinsberg reaction, strong bases
in high concentrations can and must be used [10]
in the reaction of diketo sulfides possessing very
16:503–506, 2005; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20153
reactive methylene and carbonyl groups in the
same molecule, the use of strong basic conditions
INTRODUCTION
has brought about extensive self-condensation. The
Cannizzaro reaction of glyoxal may also occur as ev-
idenced by the immediate precipitation of sodium
glycolate upon addition of sodium alkoxide to a so-
lution of glyoxal in alcohol. In preference to these
side reactions, the desired condensations were found
to be performed efficiently by carrying out the re-
action under mild conditions: thus, when a dilute
solution of sodium methoxide was slowly added
to a stirred solution of a diacetamido sulfide and
glyoxal in methanol and, if necessary, a co-solvent
such as dioxane at room temperature, thiophene-2,5-
dicarboxylic acid bis-aryl(alkyl)amides 3a–e began
to precipitate generally in just a few minutes. In or-
der to obtain pure products in high yields, the base
must be added very slowly, especially at the begin-
ning of the reaction when most of the starting mate-
rials are still present.
During the past two decades, much progress has
been made in the synthetic chemistry of thiophenes
[1]. 3-Thiapentane-1,5-diones have been recently
used as the starting materials in some syntheses
[2–5].
Diketo sulfides of the type RCOCH2SCH2COR
have two methylene groups activated by both a car-
bonyl and a sulfide group, and are considered to be
suitable for condensation with 1,2-dicarbonyl com-
pounds providing a thiophene nucleus. When R is O-
alkyl, i.e. thiodiacetic acid ester, the reaction is the
well-known Hinsberg thiophene synthesis and has
been used extensively to prepare 3,4-disubstituted
thiophene derivatives [6]. However, the extension of
the Hinsberg reaction to diketo sulfides (R = alkly
In light of studies on the synthetic chemistry of
thiophenes during the last 15 years, we have partly
contributed to this progress by developing a new
Correspondence to: Metin Koparır; e-mail: mkoparir@hotmail.
com.
2005 Wiley Periodicals, Inc.
c
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503

504 Koparır, Cansız, and C¸etin
thiophene synthesis. Finally, we have also partly con-
tributed to this progress by obtaining a thiophene
derivative, which involves formamide groups.
recorded on Varian Gemini 200 MHz and Jeol FX-
90Q spectrometers and are reported in ppm (δ) rela-
tive to tetramethylsilane as the internal standard (1H)
or deuterochloroform (13C NMR 75.5, 49.5, and 22.4
MHz). Elemental analyses were done on a LECO-
CHNS-938. Starting chemicals were obtained from
Merck or Aldrich.
RESULTS AND DISCUSSION
The synthesis of compounds 1–3 is outlined in
Scheme 1. When chloroacetyl chloride was added
to amines in the presence of potassium carbonate,
1a–e were obtained. Reaction of 1a–e with Na2S in
ethanol gives the cyclohexyl- or aryl-substituted diac-
etamido sulfides 2a–e, respectively. Thiophene-2,5-
dicarboxylic acid bis-aryl(alkyl)amides 3a–e were
then obtained from the reaction of 2a–e with glyoxal
in methanol in mild condition.
The yield of 3a was very poor. The reason for this
could be the lack of conjugation between n-electrons
on nitrogen atom with cyclohexyl in 2a. On the other
hand, yields of 3b–e were somewhat more satisfac-
tory, because of an effective conjugation they have
with the aromatic ring in 2b–e. In addition, higher
yields were found in the presence of substituents
with higher electron attractive power.
General Procedure for the Synthesis of 1
To an ice-cooled solution of R-NH2 (0.05 mol) in
acetone was added chloroacetylchloride (0.05 mol
in acetone) dropwise, and the solution was kept for
2 h at room temperature. The resulting mixture was
poured in ice-cold water, and the shiny crystalline
product was collected. Then it was filtered.
2-Chloro-N-cyclohexylacetamide 1a. White
solid; yield 77%, mp 156–157◦C. IR (KBr) υ: 3288
(NH), 1670, 1570, 1410 (N C O, amide I, II, and III
bands) cm−1. 1H NMR (CDCl3) δ 7.31 (br, 1H, NH),
4.00 (s, 2H, CH2 Cl), 1.25–1.75 (m, 11H, cyclohexyl
CH2 ). Anal. Calcd for C8H14ClNO (175): C, 54.70;
H, 8.03; N, 7.97. Found: C, 54.55; H, 8.01; N, 8.01.
In the IR spectrum of 3a–e, the most charac-
teristic absorptions are at 1640–1683 cm−1 ν (C O),
3263–3290 cm−1 ν( NH). The data for all compounds
are given in the Experimental section.
2-Chloro-N-(3-nitro-phenyl)acetamide 1b. Yel-
low solid; yield 78%, mp 159–160◦C. IR (KBr) υ:
1
1680 (C O), 3278 (NH) cm−1. H NMR (CDCl3) δ
7.57–8.62 (m, 5H, Ar-H, and NH), 4.22 (s, 2H,
CH2 Cl). Anal. Calcd for C8H7ClN2O3 (214): C,
44.77; H, 3.29; N, 13.05. Found: C, 44.71; H, 3.24; N,
13.09.
EXPERIMENTAL
Melting points were determined on a Thomas Hov-
ver melting point apparatus and are uncorrected, but
checked by differential scanning calorimetry (DSC).
The IR spectra were registered with a Mattson 1000
FT-IR spectrophotometer. The NMR spectra were
2-Chloro-N-(4-nitro-phenyl)acetamide 1c. Yel-
low solid; yield 82%, mp 161–162◦C. IR (KBr) υ:
1
1683 (C O), 3277 (NH) cm−1. H NMR (CDCl3) δ
7.59–8.66 (m, 5H, Ar-H, and NH), 4.24 (s, 2H,
CH2 Cl), Anal. Calcd for C8H7ClN2O3 (214): C,
44.77; H, 3.29; N, 13.05. Found: C, 44.68; H, 3.11; N,
13.00.
2-Chloro-N-(4-chloro-phenyl)acetamide
1d.
White solid; yield 65%, mp 182–183◦C. IR (KBr) υ:
1
1670 (C O), 3263 (NH) cm−1. H NMR (CDCl3) δ
8.27 (br, 1H, NH), 7.23–7.82 (m, 4H, Ar-H,), 4.21
(s, 2H, CH2 Cl), Anal. Calcd for C8H7Cl2NO (204):
C, 47.09; H, 3.46; N, 6.86. Found: C, 44.98; H, 3.40;
N, 6.81.
2-Chloro-N-phenylacetamide 1e. Yellow solid;
yield 65%, mp 149–150◦C. IR (KBr) υ: 1669 (C O),
1
3283 (NH) cm−1. H NMR (CDCl3) δ 7.36–7.91 (m,
6H, Ar-H, and NH), 4.23 (s, 2H, CH2 Cl), Anal.
Calcd for C8H8ClNO (169): C, 56.65; H, 4.75; N, 8.26.
Found: C, 56.61; H, 4.73; N, 8.19.
SCHEME 1

Thiophene-2,5-dicarboxylic Acid Bis-aryl(alkyl) Amides 505
NMR (CDCl3) δ 11.05 (br, 2H, NH), 7.13–7.36 (m,
10H, Ar-H), 3.28 (s, 4H, CH2 S), Anal. Calcd for
C16H16N2O2S (300): C, 63.98; H, 5.37; N, 9.33; S,
10.67. Found: C, 63.91; H, 5.28; N, 8.29; S, 10.63.
General Procedure for the Synthesis of 2
To a stirred, refluxing solution of the haloacetamido
compounds 1a–e (0.2 mole) in 200 mL of ethanol,
solution of sodium sulfide nonahydrate (0.1 mole) in
65 mL of water was added dropwise over a period of
25 min; the solution was added more slowly toward
the end to prevent orange coloration. After refluxing
for an additional 25 min, the solution was allowed to
cool slowly to directly obtain pure crystals of 2a–e.
General Procedure for the Synthesis of 3
A solution of glyoxal was prepared by refluxing a mix-
ture of 168 mg (0.8 mmole, 2.4 mmole as a monomer)
of glyoxal trimer dihydrate and 15 mL of methanol
for 1 h under magnetical stirring. The diacetoamido
sulfide 2a–e, (2.0 mmol) was dissolved in the solu-
tion by application of heat and, if necessary, addi-
tion of the appropriate amount of a co-solvent such
as dioxane (benzene and dichloromethane may also
be used) to keep the diacetamido sulfide in solu-
tion. To the still warm solution (ca. 40–50◦), a so-
lution of sodium methoxide (50 mg of sodium dis-
solved in 5 mL of methanol) was added dropwise via
a hypodermic syringe over a period of 5–10 min. In
course of the addition, crystals began to precipitate
and thick slurry was formed rapidly. After stirring for
30 min, the crystals were collected by filtration and
washed with methanol. The filtrate was diluted with
water, and the precipitate was collected and recrys-
tallized.
N-Cyclohexyl-2-[(cyclohexylcarbamoyl)methyl-
sulfanyl]acetamide 2a. Shiny white solid; yield
69%, mp 207–208◦C. IR (KBr) υ: 3280 (NH), 1655,
1570, 1410 (N C O, amide I, II, and III bands)
1
cm−1. H NMR (CDCl3) δ 6.85 (br, 2H, NH), 3.20
(s, 4H, CH2 S), 1.25–1.83 (m, 22H, cyclohexyl
CH2 , and CH ). Anal. Calcd for C16H28N2O2S
(312): C, 61.50; H, 9.03; N, 8.96; S, 10.26. Found: C,
61.44; H, 9.13; N, 8.78; S, 10.45.
N-(3-Nitrophenyl)-2-[(3-nitrophenylcarbamolyl)-
methylsulfanyl]acetamide 2b. Light yellow solid;
yield 60%, mp 223–224◦C. IR (KBr) υ: 3276 (NH)
1682, 1568, 1407 (N C O, amide I, II, and III
bands) cm−1. 1H NMR (CDCl3) δ 10.30 (br, 2H, NH),
7.43–8.56 (m, 8H, Ar-H), 3.57 (s, 4H, CH2 S), Anal.
Calcd for C16H14N4O6S (390): C, 49.23; H, 3.61; N,
14.35; S, 8.21. Found: C, 49.09; H, 3.52; N, 14.20; S,
8.33.
Thiophene-2,5-dicarboxylic Acid Bis(cyclohexyl-
amide) 3a. White solid; yield 45%, mp 237–238◦C.
IR (KBr) υ: 3285 (NH) 1648, 1487, 1378 (N C O,
1
amide I, II, and III bands) cm−1. H NMR (CDCl3) δ
N-(4-Nitrophenyl)-2-[(4-nitrophenylcarbamolyl)-
methylsulfanyl]acetamide 2c. Light yellow solid;
yield 68%, mp 220–221◦C. IR (KBr) υ: 3280 (NH)
1679, 1568, 1398 (N C O, amide I, II, and III
bands) cm−1. 1H NMR (CDCl3) δ 10.27 (br, 2H, NH),
7.45–8.54 (m, 8H, Ar-H), 3.57 (s, 4H, CH2 S), Anal.
Calcd for C16H14N4O6S (390): C, 49.23; H, 3.61; N,
14.35; S, 8.21. Found: C, 49.29; H, 3.59; N, 14.21; S,
8.31.
7.13–7.93 (m, 4H, thiophene CH, and NH), 1.24–
1.83 (m, 22H, cyclohexyl CH2). 13C NMR peaks
(CDCl3, TMS, δ ppm): 169.08, 156.11, 50.80, 36.91,
26.01, 25.51 Anal. Calcd for C18H26N2O2S (334): C,
64.64; H, 7.84; N, 8.38; S, 9.59. Found: C, 64.60; H,
7.64; N, 8.11; S, 9.52.
Thiophene-2,5-dicarboxylic Acid Bis[(3-nitrophe-
nyl)amide] 3b. Yellow solid; yield 60%, mp 253–
254◦C. IR (KBr) υ: 3271 (NH) 1655, 1570, 1398
1
(N C O, amide I, II, and III bands) cm−1. H NMR
N-(4-chlorophenyl)-2-[(4-chlorophenylcarbamo-
lyl)methylsulfanyl]acetamide 2d. Shiny white solid;
yield 74%, mp 271–272◦C. IR (KBr) υ: 3268 (NH)
1661, 1549, 1401 (N C O, amide I, II, and III
(CDCl3) δ 10.42 (br, 2H, NH), 7.39–8.21 (m, 10H,
Ar-H, and thiophene CH). 13C NMR peaks (CDCl3,
TMS, δ ppm): 169.05, 159.26, 156.18, 154.00, 138.01,
129.91, 127.01. Anal. Calcd for C18H12N4O6S (412): C,
52.43; H, 2.93; N, 13.59; S, 7.78. Found: C, 52.40; H,
2.90; N, 13.55; S, 7.72.
1
bands) cm−1. H NMR (CDCl3) δ 9.98 (br, 2H, NH),
7.40–7.70 (m, 8H, Ar-H), 3.54 (s, 4H, CH2 S), Anal.
Calcd for C16H14Cl2N2O2S (369): C, 52.04; H, 3.82;
N, 7.59; S, 8.68. Found: C, 52.01; H, 3.79; N, 7.51; S,
8.59.
Thiophene-2,5-dicarboxylic Acid Bis[(4-nitrophe-
nyl)amide] 3c. Yellow solid; yield 65%, mp 249–
250◦C. IR (KBr) υ: 3280 (NH) 1649, 1570, 1402
N-Phenyl-2-[(phenylcarbamolyl)methylsulfanyl]-
acetamide 2e. Light yellow solid; yield 70%, mp
213–214◦C. IR (KBr) υ: 3286 (NH) 1665, 1561,
1
(N C O, amide I, II, and III bands) cm−1. H NMR
(CDCl3) δ 10.41 (br, 2H, NH), 7.41–8.20 (m, 10H,
1
1398 (N C O, amide I, II, and III bands) cm−1. H
Ar-H, and thiophene CH). 13C NMR peaks (CDCl3,

506 Koparır, Cansız, and C¸etin
TMS, δ ppm): 169.05, 159.27, 156.17, 154.01, 139.00,
129.90, 127.02. Anal Calcd for C18H12N4O6S (412): C,
52.43; H, 2.93; N, 13.59; S, 7.78. Found: C, 52.41; H,
2.90; N, 13.57; S, 7.70.
ppm): 169.05, 159.28, 156.10, 153.99, 130.05, 129.91,
126.95. Anal Calcd for C18H14N2O2S (322): C, 67.06;
H, 4.38; N, 8.69; S, 9.95. Found: C, 66.98; H, 4.31; N,
8.63; S, 9.95.
Thiophene-2,5-dicarboxylic Acid Bis[(4-chloro-
phenyl)amide] 3d. White solid; yield 65%, mp 201–
302◦C. IR (KBr) υ: 3265 (NH) 1655, 1570, 1411
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1
(N C O, amide I, II, and III bands) cm−1. H NMR
(CDCl3) δ 10.49 (br, 2H, NH), 7.41–8.22 (m, 10H,
Ar-H, and thiophene CH). 13C NMR peaks (CDCl3,
TMS, δ ppm): 169.05, 158.92, 156.11, 153.82, 129.99,
128.81, 125.91. Anal Calcd for C18H12Cl2N2O2S (391):
C, 55.25; H, 3.09; N, 7.16; S, 8.19. Found: C, 55.20;
H, 3.07; N, 7.12; S, 8.11.
[6] Chadwick, D. J.; Chamvers, J.; Meakins, D.; Snowden,
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Thiophene-2,5-dicarboxylic Acid Bis(phenyl-
amide) 3e. Yellow solid; yield 60%, mp 243–244◦C.
IR (KBr) υ: 3280 (NH) 1640, 1559, 1417 (N C O,
1
amide I, II, and III bands) cm−1. H NMR (CDCl3)
δ 10.93 (br, 2H, NH), 7.36–7.93 (m, 12H, Ar-H, and
thiophene CH). 13C NMR peaks (CDCl3, TMS, δ