Reactions of ketene dithioacetal for a new versatile synthesis of 4,5-substituted 3-aminothiophene-2-carboxylate derivatives

Article abstract of DOI:10.1080/17415993.2016.1156117

ABSTRACT: Poly substituted 3-aminothiophenes were successfully synthesized in good yields by using a one-pot protocol via ketene S,S-acetal as an intermediate in basic medium (K₂CO₃/N,N-dimethylformamide) followed by Dieckmann condensation with ethyl bromoacetate. Further, chemistry of thiophenes was explored using active functional groups such as C₃–NH₂, C₄–CN and C₅–SCH₃ on the thiophene nucleus. Synthesis of ethyl 3-acetamido-4-cyano-5-(methylthio)thiophene-2-carboxylate derivatives and ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate derivatives.

Full text of DOI:10.1080/17415993.2016.1156117

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Reactions of ketene dithioacetal for a new
versatile synthesis of 4,5-substituted 3-
aminothiophene-2-carboxylate derivatives
Satish M. Chavan, Raghunath B. Toche, Vasant M. Patil, Pankaj B. Aware &
Poonam S. Patil
To cite this article: Satish M. Chavan, Raghunath B. Toche, Vasant M. Patil, Pankaj B. Aware &
Poonam S. Patil (2016): Reactions of ketene dithioacetal for a new versatile synthesis of 4,5-
substituted 3-aminothiophene-2-carboxylate derivatives, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2016.1156117
To link to this article: http://dx.doi.org/10.1080/17415993.2016.1156117
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Date: 29 March 2016, At: 01:13

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1156117
Reactions of ketene dithioacetal for a new versatile synthesis
of 4,5-substituted 3-aminothiophene-2-carboxylate
derivatives
Satish M. Chavana,b , Raghunath B. Tochea , Vasant M. Patila
Pankaj B. Awarea and Poonam S. Patila
,
aOrganic Chemistry Research Center, Department of Chemistry, K.R.T. Arts, B.H. Commerce and A.M. Science
College, Savitribai Phule Pune University, Nashik, Maharashtra, India; bDepartment of Chemistry, R.N.C. Arts,
J.D.B. Commerce and N.S.C. Science College, Savitribai Phule Pune University, Nashik, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received 31 October 2015
Accepted 16 February 2016
Poly substituted 3-aminothiophenes were successfully synthesized
in good yields by using a one-pot protocol via ketene S,S-acetal as
an intermediate in basic medium (K2CO3/N,N-dimethylformamide)
followed by Dieckmann condensation with ethyl bromoacetate. Fur-
ther, chemistry of thiophenes was explored using active functional
groups such as C3–NH2, C4–CN and C5–SCH3 on the thiophene
nucleus.
Synthesisofethyl3-acetamido-4-cyano-5-(methylthio)thiophene-
2-carboxylate derivatives and ethyl 3-amino-4-carbamoyl-5-(methylt
hio)thiophene-2-carboxylate derivatives.
KEYWORDS
Ketene dithioacetals; poly
substituted 3-amino
thiophene; ethyl
bromoacetate;
cyanothiophene-2-
carboxylate;
thiocarbamoylthiophene-2-
carboxylate
O
NH-R
NH-R
COOEt
H2N
NH2
NC
S
COOEt
NC
S
S
O
S
COOEt
S
O
S
NH
Ar
NH
Ar
Ar = C6H5, 4-MeOC6H4, 4-ClC6H4
R = H, Acetyl, chloroacetyl, pyrrolyl
1. Introduction
Malononitrile dithioacetals are versatile intermediates for organic synthesis.[1–3] Their
ease of preparation and extensive synthetic applications make them attractive synthons for
the synthesis of functionalized heterocycles.[3,4] Nucleophiles, like aliphatic and aromatic
amines or hydrazines can replace the methylthio (SCH3) group and assist intermediate
CONTACT Raghunath B. Toche
raghunath_toche@rediffmail.com
Organic Chemistry Research Center,
Department of Chemistry, K.R.T. Arts, B.H. Commerce and A.M. Science College, Savitribai Phule Pune University, Nashik422
002, Maharashtra, India
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1156117
© 2016 Taylor & Francis

2
S. M. CHAVAN ET AL.
CN
CN
NH2
NC
S
CN
S
NC
S
CN
Ethyl bromoacetate
i. NaOH/DMF
CS2
Na2S. 9H2O/DMF
80oC, 1.15 hr
NC
K2CO3 /DMF, 800C, 1.5 hr
COOEt
ii. DMS, 0oC , 2 hr
SNa
S
S
2
1
85%
1a
79%
Scheme 1. Synthesis of ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2).
in situ cyclization.[3] Ketene dithioacetals could be used in reactions with various nucle-
ophiles leading to synthesis of a variety of nitrogen heterocycles like pyridines, pyridones,
pyrimidines, quinolines, pyrroles, pyrazoles and imidazoles.[1,2,5–11] They are used in the
synthesis of sulfur containing heterocycles like thiophenes, thiopyrans and other bioactive
molecules like cyclopentanoids, polyenes, etc.[1–11]
Thiophenes form a major class of bioactive heterocycles. They show a broad
spectrum of biological response such as antibacterial,[12–14] anti-leishmanial,[1]
antifungal,[1,12–15] antimicrobial,[12–15] antitumor,[16,17] anticancer,[16,17] anti-
inflammatory,[13,14] antiproliferative,[18] molluscicidal[19] and anticonvulsant
activity.[20] A literature survey showed that amongst the substituted thiophenes, poly sub-
stituted 3-amino thiophenes in particular need to be studied. Hence, we have focused our
plan towards the synthesis of poly substituted 3-amino thiophenes.
2. Results and discussion
The synthetic strategies adopted for the synthesis of intermediates and target com-
pounds are depicted in 1–6. The active methylene moiety of malononitrile reacted
with carbon disulfide in N,N-dimethyl formamide with a small excess of equimo-
lar potassium hydroxide to yield the non-isolable intermediate potassium sulfide salt.
This salt in situ reacted with dimethyl sulfate (DMS) and furnished ketene dithioac-
etal, i.e. 2-(bis(methylthio)methylene) malononitrile 1 in 85% yields.[2,21,22] Earlier
Ram et al. [1] and Castano et al. [2] reported the synthesis of ethyl 3-amino-4-
cyano-5-(methylthio)thiophene-2-carboxylate (2) starting from ketene dithioacetal, i.e. 2-
bis((methylthio)methylene) malononitrile (1) and ethyl mercaptoacetate in basic medium
with 60–65% yield. These methods need conventional reagents such as ethyl mercap-
toacetate, N,N-dimethylformamide (DMF), KOH [1]; ethyl mercaptoacetate, ethanol or
triethylamine.[2] Ethyl mercaptoacetate is an expensive and hazardous starting material.
Our change to the above methods involves an inexpensive and non-hazardous reagent,
sodium sulfide (Na2S·9H2O), as the nucleophile. Sodium sulfide selectively replaces one
of the methylthio (SCH3) groups and gives the sodium thiolate intermediate (1a). Fur-
thermore, in situ reaction of 1a with ethyl bromoacetate gave the S-alkylation product via
a Dieckmann condensation under basic conditions (K2CO3/DMF) as a new key step to
furnish ethyl-3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2) in 79% yield.
The merits of our method are clean mild reaction conditions and easy aqueous work up,
and excellent yields of the products. The structure of compound 2 was verified using the
published spectral and analytical data.[1,2]
Ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2) reacted with 1:1
mixture of acetic anhydride and glacial acetic acid at 80°C for 15–20 min gave
ethyl 3-acetamido-4-cyano-5-(methylthio)thiophene-2-carboxylate (3) with 85% yield.

JOURNAL OF SULFUR CHEMISTRY
3
O
NH2
H2N
Conc.H2SO4
COOEt
S
stirr, RT,
5 hr
S
O
NH2
HN
S
70%
4
NC
S
NC
S
Ac2O/ glac. AcOH
Heat, 80oC, 15 min
COOEt
COOEt
S
S
S
NH2
P4S10 / EtOH
H2N
3
2
85 %
COOEt
60%
S
reflux, 80o
7-8 hr
5
Scheme 2. Synthesis of ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate derivatives
(3, 4, 5).
O
Cl
NH2
HN
O
i) TEA/ toluene, 0oC, 0.5 hr
ii) Heat, 110 oC, 2 hr
Cl
Cl
R = H, OMe,Cl
R
R
6a-c 80-85%
Scheme 3. Synthesis of 4-substituted 2-chloro-N-phenylacetamide (6a–c).
Compound (2) stirred in conc.H2SO4, furnished 3-amino-4-carbamoyl-5-(methylthio)
thiophene-2-carboxylate (4) in 70% yield. Further, conversion of compound (2) to thio-
carbamide (5) with 60% yield was achieved by using phosphorus pentasulfide (P4S10) at
reflux temperature in absolute ethanol. The structures of the isolated products explained
on the basis of their IR, 1H NMR and MS. (Scheme 2).
The various 4-substituted 2-chloro-N-acetamides 6a–c were prepared in good yields
by reaction of chloroacetyl chloride with corresponding anilines in toluene using catalytic
amounts of triethylamine at 0°C. After attaining room temperature reaction mixture was
heated at reflux temperature.[23] (Scheme 3).
Ethyl 3-acetamido-4-cyano-5-(methylthio)thiophene-2-carboxylate 3 reacted with
equimolar sodium sulfide (Na2S 9H2O) and 4-substituted 2-chloro-N-phenylacetamide
6a–c in N,N-dimethyl formamide at 80°C afforded ethyl 5-((4-substituted phenylcarba
moyl)methylthio)-3-acetamido-4-cyanothiophene-2-carboxylate derivatives 7a–c with
65–78% yields. The structural illustrations of compounds 7a–c are explained on analyt-
ical and spectroscopic data. For example, IR spectrum displayed stretching frequencies at
3462, 3284, 2226, 1740, 1678, 1640 cm−1 which were assigned for NH, CN, CO and COOEt
groups (Scheme 4).
The ethyl 5-(4-substituted phenylcarbamoyl)methylthio)-3-amino-4-carbamoyl-
thiophene-2-carboxylate derivatives 8a–c were achieved with 70–80% yields by reacting
ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate (4) with equimolar

4
S. M. CHAVAN ET AL.
O
O
NH
O
NH
NC
S
NC
Ar
Cl
COOEt
Na2S.9H2O
H
N
N
H
+
COOEt
S
DMF , 80oC
2 hr
Ar
S
S
O
3
6 a-c
7 a-c 65 - 78%
Ar = C6H5 ,4-OMeC6H4, 4-ClC6H4
Scheme 4. Synthesis of ethyl 5-((4-phenyl substituted carbamoyl)methylthio)-3-acetamido-4
cyanothiophene-2-carboxylate (7a–c).
O
NH2
O
S
NH2
H2N
O
O
Na2S. 9H2O
COOEt
H
N
H2N
Ar
Cl
S
+
S
COOEt
N
H
Ar
DMF, 80OC
2 hr
S
4
6 a-c
8 a-c 70-80%
Ar = C6H5 , 4-OMeC6H4 , 4-ClC6H4
Scheme 5. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-amino-4-carba
moylthiophene-2-carboxylate derivatives (8a–c).
OMe
O
S
O
S
NH2
O
N
O
NHCOCH2Cl
COOEt
MeO
i) TEA/ toluene, 0oC, 0.5 hr
ii) Heat, 110 oC, 2 hr
O
H2N
O
H2N
O
Cl
H2N
O
+
COOEt
COOEt
H
N
Cl
H
N
glac. AcOH, reflux, 4hr
10 a-c
S
S
H
N
Ar
Ar
S
S
Ar
9 a-c
60-75%
8 a-c
Ar = C6H5 , 4-OMeC6H4 ,4-ClC6H4
70-75%
Scheme 6. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-(2-chloroacetamido)-
4-carbamoylthiophene-2-carboxylate derivatives (9a–c) and ethyl 5-((4-substituted phenylcar
bamoyl)methylthio)-4-carbamoyl-3-(1H-pyrrol-1-yl)thiophene-2-carboxylate derivatives (10a–c).
amount of sodium sulfide (Na2S 9H2O) and 4-substituted 2-chloro-N-phenylacetamide
6a–c in DMF at 70–80°C. The assignments of the structures of compounds 8a–c were
based on analytical and spectroscopic data. For example, IR spectrum showed stretching
frequencies at 3462, 3284, 1740, 1678, 1640 cm−1 assignable to NH2, NH, CONH2 and
COOEt groups. The 1H NMR spectra of compound 8a showed triplet at δ 1.23, quartet at
δ 4.20, singlet at δ 6.61, singlet at δ 7.52–7.67 and singlet at δ 10.18 were assigned to CH3,
OCH2, NH2, amide NH2 and NH groups (Scheme 5).
Ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-(2-chloroacetamido)-4-carba
moylthiophene-2-carboxylate derivatives 9a–c were achieved with 69–76% yields by
reacting ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate (4) with
equimolar amount of chloroacetyl chloride in toluene as a solvent at 70–80°C.

JOURNAL OF SULFUR CHEMISTRY
5
In the same way, ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-4-carbamoyl-3-
(1H-pyrrol-1-yl)thiophene-2-carboxylate derivatives 10a–c was obtained on reaction with
2,5-dimethoxytetrahydrofuran with 70–76% yields. The assignments of the structures of
compounds 9a–c and 10a–c were based on analytical and spectroscopic data. Therefore, IR
spectrum showed stretching frequencies at 3462, 3284, 1740, 1678, 1640 cm−1 assignable
to NH2, NH, CONH2 and COOEt groups.
3. Conclusion
We have explored a facile and efficient protocol for the synthesis of poly substituted 3-
aminothiophene derivatives 7a–c to 10a–c with good yields. Particularly valuable features
of the present method include broad substrate scope, short reaction time, straightforward
procedure and easy aqueous work up that facilitated 80–85% recovery of pure product and
use of inexpensive chemicals and reagents.
4. Experimental
All the chemicals and solvents have been purified by standard literature procedures and
moisture was removed from the glass apparatus using CaCl2 drying tubes. The melting
points determined in open capillary tubes with Gallenkamp melting point apparatus and
are uncorrected. FT-IR spectra recorded on Bruker FTIR-TENSOR II spectrophotometer
1
using Platinum attenuated total reflection (ATR) discs. H NMR spectra of synthesized
compounds were recorded on a Bruker Ascend 500 NMR spectrophotometer at 500 MHz
frequency in CDCl3 or in dimethyl sulfoxide (DMSO-d6) using tetramethylsilane as inter-
nal standard. Chemical shifts recorded in δ ppm and multiplicities are given as s (singlet),
bs (broad singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). Mass spectra were
recorded on a Shimadzu LC-MS QP 2010A mass spectrometer with an ionization potential
of 70 eV. Elemental analyses were performed on Thermo Quest Flash 1112 Series EA ana-
lyzer. Reactions monitored by thin layer chromatography using 0.2 mm silica gel 60 F254
(Merck) plates using UV light (254 and 366 nm) for detection. Common reagent grade
available chemicals were utilized without further purification or prepared by standard
literature procedures. All the compounds have been synthesized by conventional methods.
4.1. Synthesis of 2-(bis(methylthio)methylene)malononitrile (1)
The reaction mixture of potassium hydroxide (0.2 mol, 27.0 g) in water (8 ml), DMF 25 ml
was cooled at 0°C. To this mixture, malononitrile (0.1 mol, 6.60 g) was added and the
resultant solution stirred at the room temperature for 2 h. Carbon disulfide (0.22 mol,
15.20 ml) was then added dropwise through dropping funnel for 0.5 h. The reaction mix-
ture was raised and kept for 1 h at room temperature. DMS (0.2 mol, 24.4 ml) was added
dropwise at 0–5°C and the reaction mixture stirred for 4 h at room temperature (TLC
check, n-hexane:ethyl acetate, 8:2). The reaction mass was quenched by adding crushed ice
with stirring, the solid was filtered and washed with water, dried and recrystallized from
ethanol to give a faint yellow solid. Yield 85%; 14 g, m.p. 80°C; m.p. Lit [2,21,22] 80–81°C.
The structure of compound 1 was determined on the basis of spectral and analytical data
and compared to literature values.[2,21,22]

6
S. M. CHAVAN ET AL.
4.2. Synthesis of ethyl 3-amino-4-cyano-5-(methylthio)
thiophene-2-carboxylate (2)
The 2-(bis(methylthio)methylene)malononitrile (1) (1.703 g, 0.01 mol) was added to a
solution of sodium sulfide, (Na2S 9H2O; 1.561 g, 0.02 mol) in 15 ml of DMF at room
temperature and the reaction mixture was heated at 70°C for 1.25 h. Ethyl bromoacetate
(1.671 g, 0.01 mol) was added dropwise and then reaction mixture was heated at 70°C for
1.5 h. Anhydrous potassium carbonate (1.382 g, 0.01 mol) was added and heated for 2 h
at 70°C (TLC check, n-hexane:ethyl acetate, 8:2). The solution was poured into cold water
and the solid isolated by filtration under vacuum, dried and recrystallized from ethanol
as faint yellow solid. Yield 79%, 1.85 g, m.p. 144–146°C m.p. Lit [2] 146°C; The struc-
ture of compound 2 established on the basis of spectral and analytical data found as per
literature.[1,2]
4.3. Synthesis of ethyl 3-acetamido-4-cyano-5-(methylthio)thiophene-2-
carboxylate (3)
Ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2) (2.42 g, 0.01 mol) was
added to (10 ml, 1:1) mixture of glac. AcOH and Ac2O and heated at the reflux temper-
ature for 20 min. The reaction mixture was cooled to room temperature. The mixture
was then poured into crushed ice and the solid got isolated by filtration under vacuum,
dried and recrystallized from ethanol as faint yellow solid. Yield 65%, 1.85 g, m.p. 170°C;
1
IR (Platinum ATR) vmax: 3273, 1696, 1670, 2226 cm−1; H NMR (CDCl3) δ 1.33–1.41
(t, 3H, J = 7 Hz, CH3), 1.65 (s, 3H, CH3), 2.70 (s, 3H, SCH3), 4.27–4.32 (q, 2H, J = 7 Hz
& J = 14 Hz, OCH2), 6.5 (s, 2H, NH2), 7.51 (s, 1H, NH); 13C NMR (CDCl3) 14.8, 18.1,
62.8, 74.3, 115.6, 158.4,192.8 δ ppm; MS m/z (%): 284.03 (100), 285.03 (14.4), 286.02 (9.0),
287.03 (1.1) Anal. Calcd. for C11H12N2O3S2: C, 46.46; H, 4.25; N, 9.85; Found: C, 46.25; H,
4.36; N, 9.81.
4.4. Synthesis of ethyl 3-amino-4-carbamoyl-5-(methylthio)
thiophene-2-carboxylate (4)
Ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2) (2.42 g, 0.01 mol) was
stirred in 5 ml Conc.H2SO4 at the room temperature for 4–5 h. The reaction mixture was
poured into cold water and the solid got isolated by filtration under vacuum, dried and
recrystallized from ethanol as pale yellow solid. Yield 85%, 2.9 g, m.p. 206°C; IR (Platinum
ATR) vmax: 3471, 3346, 3174, 2976, 2915, 1670, 1639 cm−1; 1H NMR (500 MHz CDCl3) δ
1.33–1.36 (t, 3H, J = 7.5 Hz, CH3), 2.64–2.65 (s, 3H, CH3), 4.26 (s, 3H, SCH3), 4.27–4.30
(q, 2H, J = 7.5 Hz & J = 14 Hz, OCH2), 6.5 (s, 2H, NH2); 7.05 (s, 2H, CONH2); 13C NMR
(CDCl3) 15.5, 18.4, 64.5, 75.1, 114.6, 158.1, 194.1 δ ppm; MS m/z (%):260.03 (M+1,100),
261.03 (12.2), 262.02 (9); Anal. Calcd. for C9H12N2O3S2: C, 41.52; H, 4.65; N, 10.76; Found:
C, 41.49; H, 4.65; N, 10.83.
4.5. Synthesis of ethyl 3-amino-5-(methylthio)-4-thiocarbamoylthiophene-2-
carboxylate (5)
Ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (2) (2.42 g, 0.01 mol)
dissolved in 10 ml ethanol and stirred at the room temperature. Phosphorous pentasulfide

JOURNAL OF SULFUR CHEMISTRY
7
(P4S10; 2.23 g, 0.01 mol) was added to the reaction mixture and stirred at the reflux tem-
perature for 7–8 h. (TLC check, n-hexane:ethyl acetate, 7:3). The excess ethanol evaporated
by vacuum and the solid separated was washed with little ethanol. The solid product thus
got isolated by filtration under vacuum, dried and recrystallized from ethanol as yellow
crystals.[24] Yield 60%, 1.66 g, m.p. 146°C; IR (Platinum ATR) vmax: 3421, 3310, 3269,
1
2322, 1741, 1672 cm−1; H NMR (500 MHz CDCl3) 1.35–1.38 (t, J = 7 Hz, 3H, CH3),
2.65 (s, 3H, SCH3), 4.29–4.33 (q, J = 7 Hz & J = 14 Hz, 2H, OCH2,) 6.95 (s, 2H, NH2),
7.67 (s, 2H, CSNH2); MS m/z (%): 276.01 (M+1,100), 278.00 (13.6), 277.01 (12.4); Anal.
Calcd. for C9H12N2O2S3: C, 39.11; H, 4.38; N, 10.14; O, 11.58; S, 34.80; Found: C, 39.11;
H, 4.38; N, 10.14; O, 11.58; S, 34.80.
4.6. General procedure for synthesis of 4-substituted 2-chloro-N-
phenylacetamides (6a–c)
Chloroacetyl chloride, (0.03 mol) and 2–3 drops of triethylamine were added in toluene
and the mixture stirred in water bath for 10 min. The mixture of aryl amine (0.02 mol) in
toluene was added dropwise and refluxed for 2 h. Reaction mixture cooled to room tem-
perature and the white precipitate got was filtered, washed with toluene and recrystallized
from ethanol to give compounds 6a–c in 80–85% yield.[23]
4.7. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-
acetamido-4-cyanothiophene-2-carboxylate (7a–c)
Ethyl-3-acetamido-4-cyano-5-(methylthio)thiophene-2-carboxylate (3) (2.84 g, 0.01 mol)
was added to the solution of sodium sulfide, (Na2S 9H2O; 1.561 g, 0.01 mol) in 15 ml
DMF at the room temperature and the reaction mixture heated at 70°C for 1.15 h. The
4-substituted 2-chloro-N-phenylacetamide (0.01 mol) was slowly added and then the reac-
tion mixture heated at 70°C for 1.5 h. (TLC check, n-hexane:ethyl acetate, 8:2). The solution
was then poured into cold water and the solid got isolated by filtration under vacuum, dried
and recrystallized from ethanol–DMF (9:1) to give the compounds 7a–c.
4.7.1. Ethyl 5-((phenylcarbamoyl)methylthio)-3-amino-4-cyanothiophene-2-
carboxylate (7a)
White solid, Yield 65%, 2.62 g, m.p. 170°C; IR (Platinum ATR)vmax: 3461, 3284, 2290, 1741,
1648 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 1.26 (t, J = 7 Hz, 3H, CH3), 2.64–2.89 (s,
2H, SCH2), 3.51 (s, 3H, CH3), 3.55–3.65 (q, J = 7 Hz & J = 14 Hz, 2H, OCH2), 7.08–7.07
(t, J = 7 Hz, 2H, ArH), 7.29–7.32 (m, J = 7 Hz & J = 1.5 Hz, 2H, ArH), 7.58–7.59 (t,
J = 0.7 Hz, 1H, ArH), 10.17 (s, 1H, NH); 13C NMR (DMSO-d6); 14.8, 18.1, 62.8, 74.3,
115.6, 158.4,192.8 δ ppm δ; MS m/z (%): 403.07 (M+1,100), 404.07 (21.4), 405.06 (9.1);
Anal.Calcd.for C18H17N3O4S2: C, 53.58; H, 4.25; N, 10.41; Found: C, 53.70; H, 4.28; N,
10.38.
4.7.2. Ethyl 5-((4-methoxyphenylcarbamoyl)methylthio)-3-acetamido-4-
cyanothiophene-2-carboxylate (7b)
Gray solid, Yield 73%, 3.16 g, m.p. 182°C; IR (Platinum ATR) vmax: 3377, 3246, 2226, 1741,
1
1677 cm−1; H NMR (500 MHz, DMSO-d6) δ 1.28 (t, J = 7 Hz, 3H, CH3), 2.09 (s,3H,
OCH3), 3.35 (s, 3H, CH3), 4.20 (s, 2H, SCH2), 4.23–4.27 (q, J = 7 Hz & J = 14 Hz, 2H,

8
S. M. CHAVAN ET AL.
OCH2), 6.87–6.89 (d, J = 9 Hz, 2H, ArH), 6.91 (s, 1H, NH), 7.506–7.254 (d, J = 9 Hz,
2H, ArH); 13C NMR (DMSO-d6) 14.8, 18.1, 62.8, 74.3, 115.6, 158.4,192.8 δ ppm; MS m/z
(%): 456.8 (M+1,100), 434.08 (22.6, 435.07 (9); Anal. Calcd. for C19H19N3O5S2: C, 52.64;
H, 4.42; N, 9.69; Found: C, 52.60; H, 4.45; N, 9.75.
4.7.3. Ethyl 5-((4-chlorophenylcarbamoyl)methylthio)-3-acetamido-4-
cyanothiophene-2-carboxylate (7c)
Yellowish brown solid, Yield 78%, 3.42 g, m.p.124°C; IR (Platinum ATR) vmax: 3459, 3280,
2280, 1743, 1668 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 1.26 (t, J = 7 Hz, 3H, CH3),
2.01–2.12 (s, 3H, COCH3), 3.35 (s,3H, CH3), 3.74 (s, 2H, SCH2), 4.25–4.28 (q, J = 7 Hz &
J = 14 Hz, 2H, OCH2), 6.40–6.43 (d, J = 9.5 Hz, 2H, ArH), 6.90 (s, 1H, NH), 7.503–7.522
(d, J = 9.5 Hz, 2H, ArH), 10.20–10.27 (s, 1H, NH); MS m/z (%): 437.03 (M+1,100), 439.02
(41), 438.03 (21.4), 440.03 (9.4); Anal. Calcd. for C18H16ClN3O4S2: C, 49.37; H, 3.68; N,
9.60; Found: C, 49.43; H, 3.58; N, 9.80.
4.8. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-amino-4-
carbamoylthiophene-2-carboxylate derivatives (8a–c)
Ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate (4) (2.60 g, 0.01 mol)
was added to the mixture of sodium sulfide, (Na2S 9H2O; 1.561 g, 0.01 mol) in 15 ml DMF
at the room temperature. Reaction mass heated at 70°C for 1.15 h. Then 4-substituted
2-chloro-N-phenylacetamide 6a–c (0.01 mol) added dropwise and heated at 70°C for
1.5 h. (TLC check, n-hexane:ethyl acetate, 8:2). Reaction mass was then poured into cold
water and the solid got isolated by filtration under vacuum, dried and recrystallized from
ethanol–DMF (9:1) to give the compounds 8a–c.
4.8.1. Ethyl 5-((phenylcarbamoyl)methylthio)-3-amino-4-carbamoylthiophene-2-
carboxylate (8a)
Faint gray solid, Yield 70%, 2.66 g, m.p. 198°C; IR (Platinum ATR) vmax: 3461, 3284, 3198,
1
2290, 1741, 1648 cm−1; H NMR (500 MHz, DMSO-d6) δ 1.20–1.23 (t, J = 7 Hz, 3H,
CH3), 4.05 (s, 2H, SCH2), 4.20 (q, J = 7 Hz & J = 14 Hz, 2H, OCH2), 6.60 (s, 2H, NH2),
7.06–7.09 (t, J = 8 Hz, 1H, ArH), 7.52–7.67 (s, 2H, NH2), 7.53–7.54 (t, J = 8 Hz, 4H,
ArH), 7.77 (s, 2H, CONH2), 10.32 (s, 1H, CONH); MS m/z (%): 379.07 (100), 380.07 (19.3),
381.06 (9.1); Anal. Calcd. for C16H17N3O4S2: C, 50.64; H, 4.52; N, 11.07; Found: C, 50.68;
H, 4.42; N, 11.17.
4.8.2. Ethyl 5-((4-methoxyphenylcarbamoyl)methylthio)-3-amino-4-
carbamoylthiophene-2-carboxylate (8b)
Faint gray solid, Yield 77.5%, 3.17 g, m.p. 232°C; IR (Platinum ATR) vmax: 3491, 3464, 3385,
1
1741, 1671 cm−1; H NMR (500 MHz, DMSO-d6) δ 1.23–1.27 (t, J = 7 Hz, 3H, CH3),
2.11 (s, 3H, CH3), 4.05 (s, 2H, SCH2), 4.20–4.22 (q, J = 7 Hz & J = 14 Hz, 2H, OCH2),
6.63 (s, 2H, NH2), 6.90–6.91 (d, J = 7 Hz, 2H, ArH), 7.47–7.48 (d, J = 7 Hz, 2H, ArH),
7.79 (s, 2H, CONH2), 10.20 (s, 1H, NH); 13C NMR (DMSO-d6) 18.1, 65.8, 75.5, 120.6,
162.4,193.8 δ ppm; MS m/z (%): 409.08 (100), 410.08 (20.4), 411.07 (9.1); Anal. Calcd. for
C17H19N3O5S2: C, 49.86; H, 4.68; N, 10.26; Found: C, 49.76; H, 4.78; N, 10.33.

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9
4.8.3. Synthesis of ethyl 5-((4-chlorophenylcarbamoyl)methylthio)-3-amino-4-
carbamoylthiophene-2-carboxylate (8c)
White solid, Yield 80%, 3.31 g, m.p. 210°C; IR (Platinum ATR) vmax: 3462, 3274, 3195,
1
2280, 1741, 1648 cm−1; H NMR (500 MHz, DMSO-d6) δ 1.20–1.23 (t, J = 7 Hz, 3H,
CH3), 4.05 (s, 2H, SCH2), 4.15–4.19 (q, J = 7 Hz & J = 14 Hz, 2H, OCH2), 6.59 (s, 2H,
NH2), 7.36–7.38 (d, J = 7 Hz, 2H, ArH), 7.56–7.57 (t, J = 7 Hz, 2H, ArH), 7.75 (bs, 2H,
CONH2),10.46 (s, 1H, CONH); 13C NMR (DMSO-d6) 18.1, 63.8, 75.1, 119.6, 160.4,189.8
δ ppm; MS m/z (%): 413.03 (M+1,100), 415.02 (41), 414.03 (19.2), 416.03 (7.4); Anal.
Calcd. for C16H16ClN3O4S2: C, 46.43; H, 3.90; N, 10.15; Found: C, 46.53; H, 3.87; N, 10.25.
4.9. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-3-
(2-chloroacetamido)-4-carbamoylthiophene-2-carboxylate derivatives (9a–c)
In toluene, chloroacetyl chloride, (0.5 ml) and 2–3 drops of triethylamine were added
and stirred in water bath for 10 min. The mixture of ethyl 5-((4-substituted phenyl-
carbamoyl) methylthio)-3-amino-4-carbamoylthiophene-2-carboxylate 8a–c (0.200 mg)
in toluene was added dropwise and refluxed for 2 h. Reaction mixture cooled to room
temperature, white precipitate got filtered, washed with benzene and recrystallized from
ethanol–DMF (9:1) to give compounds 9a–c in 72–76% yields.
4.9.1. Ethyl 5-((phenylcarbamoyl)methylthio)-3-(2-chloroacetamido)-4-
carbamoylthiophene-2-carboxylate (9a)
Brown solid, Yield 72%, 0.173 g, m.p. 228°C; IR (Platinum ATR) vmax: 3395, 3289, 1740,
1697, 1651 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 1.18–1.25 (t, J = 7 Hz, 3H, CH3), 2.51
(s, 3H, CH3), 4.01 (s, 2H, SCH2), 3.72–3.73 (s, 2H, NCH2), 4.22 (m, J = 7 Hz & J = 14 Hz,
2H, OCH2), 7.41 (s, 2H, NH2), 7.52–7.67 (s, 2H, NH2), 6.90–6.91 (t, J = 0.9 Hz, 1H, ArH),
7.30–7.32 (t, J = 8 Hz,2H, ArH), 7.52–7.54 (t, J = 8 Hz, 2H, ArH), 10.25–10.27 (s, 1H,
CONH), 10.71 (s, 1H, NH); 13C NMR (DMSO-d6) 22.1, 66.8, 78.1, 129.6, 164.4,192.8
δ ppm; MS m/z (%): 455.04 (M+1,100), 457.03 (41), 456.04 (21.5), 458.04 (8.2); Anal.
Calcd. for C18H18ClN3O5S2: C, 47.42; H, 3.98; N, 9.22; Found: C, 47.55; H, 3.93; N, 9.35.
4.9.2. Ethyl 5-((4-methoxyphenylcarbamoyl)methylthio)-3-(2-chloroacetamido)-4-
carbamoylthiophene-2-carboxylate (9b)
Gray solid, Yield 73%, 0.187 g, m.p. 204°C; IR (Platinum ATR) vmax: 3395, 3289, 1740,
1697, 1651 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 1.18–1.25 (t, J = 7 Hz, 3H, CH3), 2.5
(s, 3H, CH3) 3.72 (s, 2H, NCH2), 4.01 (s, 2H, SCH2), 4.23–4.28 (m, J = 7 Hz & J = 14 Hz,
2H, OCH2), 6.89–6.91 (d, J = 9 Hz, 2H, ArH), 7.47–7.48 (d, J = 9 Hz, 2H, ArH), 7.53 (s,
2H, CONH2), 10.12–10.27 (s, 1H, CONH), 10.71 (s, 1H, CONH); 13C NMR (DMSO-d6)
22.9, 66.1, 77.1, 131.6, 167.4,195.8 δ ppm; MS m/z (%): 485.05 (M+1,100), 487.05 (35.8),
486.05 (23.7), 487.04 (9.5%), 488.05 (8.9); Anal. Calcd.for C19H20ClN3O6S2: C, 46.96; H,
4.15; N, 8.65; Found: C, 46.96; H, 4.11; N, 8.70.
4.9.3. Ethyl 5-((4-chlorophenylcarbamoyl)methylthio)-3-(2-chloroacetamido)-4-
carbamoylthiophene-2-carboxylate (9c)
Faint yellow solid, Yield 76%, 0.197 g, m.p. 228°C; IR (Platinum ATR) vmax: 3395, 3289,
1
1740, 1697, 1651 cm−1; H NMR (500 MHz, DMSO-d6) δ 1.18–1.25 (t, J = 7 Hz, 3H,

10
S. M. CHAVAN ET AL.
CH3), 3.05 (s, 2H, CH2Cl), 4.07 (s, 2H, SCH2), 4.22–4.32 (m, J = 7 Hz & J = 14 Hz, 2H,
OCH2), 4.32 (s, 2H, CH2), 7.37–7.39 (d, J = 8.5 Hz, 2H, ArH), 7.48 (s, 2H, CONH2),
7.62–7.64 (d, J = 8.5 Hz, 2H, ArH), 10.13 (s, 1H, CONH), 10.27 (s, 1H, NH), 10.71
(s, 1H, CONH); MS m/z (%): 490.00 (M+1,100), 501.70 (M+3) ; Anal. Calcd. for
C18H17Cl2N3O5S2: C, 44.09; H, 3.49; N, 8.57; Found: C, 44.19; H, 3.43; N, 8.60.
4.10. Synthesis of ethyl 5-((4-substituted phenylcarbamoyl)methylthio)-4-
carbamoyl-3-(1H-pyrrol-1-yl)thiophene-2-carboxylate derivatives (10a–c)
The 25 ml round flask was charged with glac. AcOH (4 mL), ethyl 5-((4-substi
tuted phenylcarbamoyl)methylthio)-3-amino-4-carbamoylthiophene-2-carboxylate 8a–c
(1 mmol) and 2,5-dimethoxytetrahydrofuran (0.132 g, 1 mmol) added. The reaction mix-
ture was heated under reflux for 4–6 h at 117°C. After completion of reaction (TLC check,
n-hexane:ethyl acetate 6:4), the reaction mixture cooled, poured into 25 g crushed of ice.
The resulting light brown solid was collected by vacuum filtration, washed with cold water
and recrystallized from ethanol–DMF (9:1) to afford pure compounds 10a–c.
4.10.1. Ethyl 5-((phenylcarbamoyl)methylthio)-4-carbamoyl-3-(1H-pyrrol-1-yl)
thiophene-2-carboxylate (10a)
Brown solid, Yield 70%, 0.30 g, m.p.132°C; IR (Platinum ATR) vmax: 3461, 33197, 3198,
1739, 1661, cm−1; 1H NMR (500 MHz, DMSO-d6) δ 1.25–1.27 (t, J = 7 Hz, 3H, CH3),
4.07–4.11 (s, 2H, SCH2), 4.15–4.23 (m, J = 7 Hz & J = 14 Hz, 2H, OCH2), 7.04–7.10 (m,
J = 2.5 Hz, 4H, pyrrolyl), 7.24–7.29, (d, J = 0.8 Hz, 1H, ArH), 7.31–7.33 (d, J = 8 Hz,
2H, ArH), 7.42–7.52 (t, J = 8 Hz, 2H, ArH), 7.60 (s, 2H, CONH2), 10.39–10.47 (s, 1H,
CONH); MS m/z (%): 429.08 (M+1,100), 430.09 (25), 431.08 (11.7); Anal. Calcd. for
C20H19N3O4S2: C, 55.93; H, 4.46; N, 9.78; Found: C, 56.03; H, 4.49; N, 9.88.
4.10.2. Ethyl 5-((phenylcarbamoyl)methylthio)-4-carbamoyl-3-(1H-pyrrol-1-yl)
thiophene-2-carboxylate (10b)
Brown solid, Yield 70.5%, 0.3 g, m.p. 178°C; IR (Platinum ATR) vmax: 3462, 3317, 3194,
1
1737, 1661, cm−1; H NMR (500 MHz, DMSO-d6) δ 1.25 (t, J = 7 Hz, 3H, CH3), 1.91
(s, 3H, OCH3), 4.07 (s, 2H, SCH2), 4.12–4.24 (m, J = 7 Hz & J = 14 Hz, 2H, OCH2),
7.37–7.39 (m, 4H, pyrrolyl), 7.40–7.43 (d, J = 8.5 Hz, 2H, ArH), 7.57–7.61 (d, J = 8.5 Hz,
2H, ArH), 7.62 (s, 2H, CONH2), 10.53–10.54 (s, 1H, NH); MS m/z (%): 459.09 (M+1,100),
460.10 (23), 461.09 (10.3); Anal. Calcd. for C21H21N3O5S2: C, 54.89; H, 4.61; N, 9.14;
Found: C, 54.79; H, 4.67; N, 9.17.
4.10.3. Ethyl 5-((phenylcarbamoyl)methylthio)-4-carbamoyl-3-(1H-pyrrol-1-yl)
thiophene-2-carboxylate (10c)
Brown solid, Yield 76%, 0.324 g, m.p. 144–146°C; IR (Platinum ATR) vmax: 3485, 3350,
1
3321, 1741, 1676, cm−1; H NMR (500 MHz, DMSO-d6) δ 1.25–1.27 (t, J = 7 Hz, 3H,
CH3), 4.02–4.07 (s, 2H, SCH2), 4.20–4.24 (m, J = 7 Hz & J = 14 Hz, 2H, OCH2), 7.39 (m,
4H, pyrrolyl), 6.87–6.92 (d, J = 0.8 Hz, 1H, ArH), 7.48 (t, J = 8 Hz, 2H, ArH), 7.49–7.50
(t, J = 8 Hz, 2H, ArH), 7.51 (s, 2H, CONH2), 10.26–10.28 (m, 1H, CONH); 13C NMR
(DMSO-d6) 23.9, 66.1, 77.1, 117.1,138.6, 167.4, 195.8 δ; MS m/z (%): 463.04 (M+1,100),

JOURNAL OF SULFUR CHEMISTRY
11
465.04 (41.3), 464.05 (22), 466.04 (10); Anal. Calcd. for C20H18ClN3O4S2: C, 51.77; H, 3.91;
N, 9.06; Found: C, 51.87; H, 3.87; N, 9.11.
Acknowledgements
Satish M. Chavan thanks to UGC, WRO-Pune for teacher fellowship (F. No. 34-38/14 (WRO) Dt.
10/7/2014); CIF, SPPU, Pune for spectral analysis; Secretary, Gokhale Education Society, Nashik
422 005; Principal, R.N.C. Arts, J.D.B. Commerce and N.S.C. Science College, Nashik 422 101 and
Principal, K.R.T. Arts, B.H. Commerce & A.M. Science College, Nashik 422 002, (MS), India for
facilities.
ORCID
Satish M. Chavan http://orcid.org/0000-0002-7581-0644
Raghunath B. Toche http://orcid.org/0000-0001-9555-9277
Vasant M. Patil http://orcid.org/0000-0002-7677-9335
Pankaj B. Aware http://orcid.org/0000-0003-4082-9406
Poonam S. Patil http://orcid.org/0000-0001-6762-9872
References
[1] Ram VJ, Goel A, Shukla PK, Kapil A. Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones
as antileishmanial and antifungal agents. Bioorg Med Chem Lett. 1997;7(24):3101–3106.
[2] Castano MAM, Dominguez-Manzanares E, Escribano AM, et al. Thiophene and furan com-
pounds. United States Patent WO 2,005,070,916 A1 (EP 1706395 B1, 2012 Apr 4).
[3] Sommen G, Comel A, Kirsh G. An easy access to variously substituted thieno[2,3-b]pyrroles
by using isothiocyanates. Syn Lett. 2001;11:1731–1734.
[4] Thomae D, Perspicace E, Henryon D, et al. One-pot synthesis of tetrasubstituted thiophenes
and selenophenes. Tetrahedron. 2009;65:10453–10458.
[5] Sommen G, Comel A, Kirsh G. An improved method for the synthesis of aminothiophenes
precursors of thieno[2,3-b]pyrrole. Tetrahedron Lett. 2002;43:257–259.
[6] Hassan SM, Emam HA, Abdelall MM. Heteroaromatization with ketene dithiacetals: Part
I. Synthesis of some novel 5-amino-1-(1,3,4-thiadiazol-2-yl) and 1-(1,3,4-thiadiazin-2-yl)
pyrazole-4-carbonitriles. J Chem Res (S). 2000:544–545; J Chem Res (M). 2000:1301–1315.
[7] Hassan SM, Emam HA, Abdelall MM. An improved method for the synthesis of aminothio-
phenes precursors of thieno[2,3-b]pyrrole. Tetrahedron Lett. 2002;43:257–259.
[8] Hassan SM, Emam HA, Abdelall MM. Heteroaromatization with ketene dithiacetals: Part
II. Synthesis of some novel 5-aminopyrazole-3-carbonitrile, 3-carboximide and pyrazolo[3,4-
d]pyrimidin-4-one derivatives as antimicrobial agents.Phosphorus Sulfur Silicon Relat Elem.
2001;175:109–127.
[9] Bakavoli M, Beyzaie H, Rahimizadeh M, Eshghi H, Takjoo R. Regioselective synthesis of new
2-(E)-cyano(thiazolidin-2-ylidene)thiazoles. Molecules. 2009;14:4849–4857.
[10] Bakavoli M, Beyzaie H, Rahimizadeh M, Eshghi H. Regioselective synthesis of 2-[(E)-
benzo[d]thiazol-2-(3H)-ylidene)(cyano)methyl] thiazoles. Heterocycl Commun. 2011;17
(3–4):151–154.
[11] Sommen G, Comel A, Kirsh G. Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-
acetals. Tetrahedron. 2003;59:1557–1564.
[12] Al-Adiwish WM, Yaacob WA, Adan D, Nazlina I. Synthesis and antibacterial activity of
thiophenes. Int J Adv Sci Eng Inform Technol. 2012;2(4):27–30.
[13] Khalifa ME, Gobouri AA. In vitro Biological activity of some synthesized monoazo hete-
rocycles based on thiophene and thiazolyl-thiophene analogs. Int J Biol Biomol Agr Food
Biotechnol Eng. 2014;8(4):384–391.

12
S. M. CHAVAN ET AL.
[14] Asif M, Iqbal C, Satyndra D, et al. Synthesis and antimicrobial screening of some novel
substituted thiophenes. Hygeia J Drug Med. Aug. 2012–Sep. 2012;4(1):112–118.
[15] Abo-Salem HM, El-Sawy ER, Fathy A, Mandour AH. Synthesis, antifungal activity and molec-
ular docking study of some novel highly substituted 3-indolylthiophene derivatives. Egypt
Pharm J. 2014;13:71–86.
[16] Wang W, Shangguan S, Qiu N, Hu C, Zhang L, Hu Y. Design, synthesis and biological evaluation
of 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 1. Bioorg
Med Chem. 2013;21(11):2879–2885.
[17] Wang W, Shangguan S, Qiu N, Hu C, Zhang L, Hu Y. Design, synthesis and biological evaluation
of 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 2. Bioorg
Med Chem. 2013;21(11):2886–2894.
[18] Martorana A, Gentile C, Perricone U, et al. Synthesis, antiproliferative activity and insil-
ico insights of new 3-benzoylamino-benzo[b]thiophene derivatives. Eur J Med Chem.
2015;90:537–546.
[19] Kanwade SB, Toche RB, Patil SP, Desai AE, Bhamare SS. Aminothiophenedicarboxaimides and
dicyanothiopheneacetamides as effective synthetic molluscicides against Indoplanorbis exustus
snail. Eur J Med Chem. 2011;45:4682–4686.
[20] Pavan Kumar K, Venkanteswara Rao J, Mukkanti K. Madhusudhanreddy Induri. Anticonvul-
sant activity of some Mannich bases of 2-aminothiophenes having indole-3-carboxaldehyde
against strychnine, picrotoxin, lithium pilocarpine-induced seizures. Der Pharmacia Lettre.
2012;4(3):968–971.
[21] Lee S, Lee D, Song K-S, Liu K-H, Gong Y-D, Lee T. Parallel synthesis of 2,4,5-
trisubstituted thiophene-3-carbonitrile derivatives on traceless solid support. Tetrahedron.
2014;70:9183–9190.
[22] Mohan S, Ananthan S. A new approach for the synthesis of some novel sulfur bridged pyrazoles
and their characterization. J Chem Pharm Res. 2011;3(1):402–413.
[23] Parekh NM, Juddhawala KV. Microbial studies of N-chloro aryl acetamide substituted thiazole
and 2,4-thiazolidine dione derivatives. J Chem Pharm Res. 2012;4(9):4149–4155.
[24] Kaboudin B, Elhamifar D. Phosphorus pentasulfide: a mild and versatile reagent for the
preparation of thioamides from nitriles. Synthesis. 2006;2:0224–0226.