Influence of solvent and substituents on the reaction of N-alkylthioacetamides with dimethyl acetylenedicarboxylate: Synthesis of functionalized thiophenes containing an exocyclic double bond

Article abstract of DOI:10.1016/j.tetlet.2013.06.127

The reaction of thioacetamides with dimethyl acetylenedicarboxylate affords 3-oxothien-2-ylidene or 4-oxothiazol-2,5-ylidene derivatives based on the structure of the thioacetamides and the solvent employed. The structural features of the 3-oxothien-2-yli

Full text of DOI:10.1016/j.tetlet.2013.06.127

Tetrahedron Letters 54 (2013) 4876–4879
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Influence of solvent and substituents on the reaction of
N-alkylthioacetamides with dimethyl acetylenedicarboxylate:
synthesis of functionalized thiophenes containing an exocyclic
double bond q
a
a
b
Konstantin L. Obydennov a, , Elena L. Klimareva , Marya F. Kosterina , Pavel A. Slepukhin ,
⇑
Yury Yu. Morzherin a
a Ural Federal University, Mira 19, Ekaterinburg 620002, Russia
b I. Postovsky Institute of Organic Synthesis, Kovalevskoy 22, Ekaterinburg 620090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of thioacetamides with dimethyl acetylenedicarboxylate affords 3-oxothien-2-ylidene or 4-
oxothiazol-2,5-ylidene derivatives based on the structure of the thioacetamides and the solvent
employed. The structural features of the 3-oxothien-2-ylidenes are discussed.
Received 30 April 2013
Revised 16 June 2013
Accepted 26 June 2013
Available online 3 July 2013
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Acetylenedicarboxylate
Thioacetamide
Thiophene
Thiazole
Exocyclic double bond
Thiophenes containing double bonds attract attention as photo-
–A (donor–
In the present work we report that reactions between
cyanothioacetamides 1a–d and DMAD 2 proceed via different
pathways depending on the structure of 1 and the solvent. To
establish the influence of the solvent, heterocyclization reactions
were conducted in ethanol or acetic acid (Scheme 2).
Thiophenes 5c,d were formed as the major products from cya-
nothioacetamides with bulky substituents on nitrogen 1c,d.12–14
However, in the case of the cyanothioacetamides 1c,d it was shown
that the main products were (2-cyanomethylen-4-oxothiazolidin-
5-ylidene)acetic acid methyl esters 4c,d when the reaction was
conducted in ethanol (Table 1). The thiazoles 4 and thiophenes 5
were easily separated by recrystallization from acetic acid. With
cyanothioacetamides 1a,b the formation of thiophene derivatives
was not observed.15,16
chromic molecular switches1 and as models of D–
p
spacer–acceptor) systems.2 There are a number of methods in the
literature for the preparation of thiophenes containing exocyclic
double bonds (Scheme 1). In general, these compounds are synthe-
sized from isothiocyanates (pathway A)3,4 or by the oxidation of
thiophenes (pathway B).5–7
In this Letter, we report a method for the preparation of the
thiophenes containing exocyclic double bonds by reaction of N-
monosubstituted thioacetamides with dimethyl acetylenedicar-
boxylate (DMAD) (pathway C). In reactions of N,N-disubstituted
thioacetoamides with DMAD the formation of thiazoles does not
occur, as was reported previously by us.8 Although there are a
number of possible pathways for the reaction between acetylen-
edicarboxylates and N-substituted thioamides,9–11 formation of
thiophenes is now reported.
The percentage increase in the formation of the thiophenes can
be due to the formation of iminium intermediate 3 when acetic
was used as the solvent.
At the same time N,N0-dialkylmalonodithioamides 6a–d react
with DMAD to afford only 3-oxothien-2(3H)-ylidene derivatives
8a–d (Scheme 3) in 40–65% yields.17–19 This result is additional to
earlier work when the reaction was carried out in acetone and only
the formation of thiazoles was observed.11 Malonothioacetamides
6a–d are more reactive in comparison with cyanothioacetamides
1a–d, therefore the reaction proceeds even at room temperature.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding author. Tel./fax: +7 8 (343) 375 48 18.
E-mail address: k.l.obydennov@ustu.ru (K.L. Obydennov).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.127

K. L. Obydennov et al. / Tetrahedron Letters 54 (2013) 4876–4879
4877
Table 1
R1
R1
Synthesis of thiazoles 4 and thiophenes 5
N
N
C
C
R
Solventa
Product ratio 4:5b
Yieldc (%)
S
S
R2
O
(a) Me
EtOH
CH3COOH
EtOH
CH3COOH
EtOH
CH3COOH
EtOH
1:0
1:0
1:0
1:0
4:1d
2:3
2:1d
1:3
50
51
62
56
37
75
57
53
R1
NH
O
S
OEt
X
(b) Bn
(c) Cy
(d) i-Pr
R2
H
R2
OEt
EWG
O
A
EWG
O
EWG
O
CH3COOH
X
O
a
All reactions were carried out using equimolar amounts of each compound in
R1
R1
10 ml of solvent, 70 °C, 8 h.
b
R2
Ratio of the thiazole 4 and thiophene 5.
R2
S
S
c
Isolated yield of the thiazoles 4 and thiophenes 5.
d
Ratio determined from the 1H NMR spectrum of the crude product.
B
It is worth noting that the second thioamide group was unaf-
fected even when 2 equiv of DMAD were used. Presumably the
reaction route is governed by formation of iminium derivative 7
as a result of intermolecular hydrogen bond formation thanks to
the presence of the second thioamide group (see Scheme 3).
According to X-ray crystal data20 the thiophene 8a has a planar
structure which is stabilized by two intramolecular hydrogen
bonds (N2–H2ꢀ ꢀ ꢀS2 and N1–H1ꢀ ꢀ ꢀO2), and three weak interactions
exist due to the presence of nearby located heteroatoms: O3 and
MeOOC
O
MeOOC
2
R
H
S
R
N
H
S
N
O
1
MeO
EWG
EWG
EWG = CN, C(S)NHAlk
C
Scheme 1. General pathways toward thiophenes containing exocyclic double
bonds.
MeO
H
O
N
S
N
H
O
R
R
HN
OMe
N
R
S
4a-d
70 oC, 8 h
HN
S
N
O
O
O
O
CH3COOH or
MeO
H
EtOH
O
OMe
OMe
MeO
1a-d
2
R
S
3
NH
O
N
5c,d
1,3,4: R= Me (a), Bn (b), Cy (c), i-Pr (d),
Scheme 2. Synthesis of thiazoles 4 and thiophenes 5.
H
R
S
S
N
OMe
O
R
R
i
S
HN
N
O
O
R
O
H
N
H
S
OMe
OMe
MeO
6a-d
7
MeO
H
O
R
H
S
N
O
H
S
N
R
8a-d
6,7,8: R = Me (a), Bn (b), Pr (c), i-Pr (d)
Scheme 3. Reagents and conditions: (i) CH3COOH or EtOH + 1 equiv CH3COOH, rt, 40 °C, 4 h.

4878
K. L. Obydennov et al. / Tetrahedron Letters 54 (2013) 4876–4879
Figure 2. Spectra of the exocyclic double bond hydrogen atom in thiophene 5d at
different temperatures.
Figure 1. Molecular structure and selected geometric parameters (Å) of compound
8a.
novel 3-oxo-3H-thien-2-ylidenes were prepared. It was shown that
formation of 3-oxo-3H-thien-2-ylidenes in acetic acid was favored
due to the hindered substituent at nitrogen and the presence of a
second thioamide group. The thioamide group leads to a planar
stable structure of 2-[4-(methylcarbamothioyl)-3-oxothien-
2(3H)-ylidene]acetate. It was revealed that 2-[2-(cyanomethyl-
MeO
H
O
MeO
H
O
S
S
N
N
H
6.65
6.72
HO
O
ene)-4-oxothiazolidin-5-ylidene]acetates exist in
together with the hydroxy forms as a result of tautomerism.
a
solution
N
N
5d-hydroxy
5d-keto
Acknowledgments
MeO
O
The research was carried out in terms of Ural Federal University
development program with the financial support of young
scientist.
S
H
N
X
O
X =O, CH2, -
N
References and notes
9
1. Bren, V. A.; Dubonosov, A. D.; Minkin, V. I.; Tsukanov, A. V.; Gribanova, T. N.;
Shepelenko, E. N.; Revinsky, Y. V.; Rybalkin, V. P. J. Phys. Org. Chem. 2007, 20,
917–928.
Scheme 4. The equilibrium of thiophene 5b in solution.
2. Manzhos, S.; Segawa, H.; Yamashita, K. Chem. Phys. Lett. 2012, 527, 51–56.
3. Knieb, A.; Gruner, M.; Mayer, R. Monatsh. Chem. 1996, 127, 1173–1187.
4. Khmel’nitskaya, E. Yu.; Grigor’ev, N. B.; Ryabova, S. Yu.; Trofimkin, Yu. I.;
Azimov, V. A.; Granik, V. G. Chem. Heterocycl. Compd. 2002, 38, 1357–1362.
5. Takekuma, S.-I.; Sonoda, K.; Minematsu, T.; Takekuma, H. Tetrahedron 2008, 64,
3802–3812.
6. Marin, L.; Van Mierloo, S.; Zhang, Y.; Robeyns, K.; Champagne, B.; Adriaensens,
P.; Lutsen, L.; Vanderzande, D.; Maes, W. Tetrahedron 2013, 69, 2260.
7. Bromby, A. D.; Jansonius, R. P.; Sutherland, T. C. J. Org. Chem. 2013, 78, 1612–
1620.
8. Kosterina, M. F.; Morzherin, Yu. Yu.; Tkachev, A. V.; Rybalova, T. V.; Gatilov, Yu.
V.; Bakulev, V. A. Russ. Chem. Bull. 2002, 51, 653.
9. Danilkina, N. A.; Mikhailov, L. E.; Ivin, B. A. Russ. J. Org. Chem. 2006, 42, 783–814.
10. Britsun, V. N.; Esipenko, A. N.; Lozinskii, M. O. Chem. Heterocycl. Compd. 2008,
44, 1429–1459.
S1, N2 and S2, O2 and N1 (see Fig. 1). In all probability, intramolec-
ular hydrogen bonds exist in intermediate 7 that similarly facilitate
the direction of further condensation.
The thiophenes 8a–d have groups which can undergo further
heterocyclizations to form bicyclic heterocyclic system.21–24
In the 1H NMR spectra of thiazoles 4a–d and thiophenes 5c,d,
we observed doubling of the signals of all groups, including the
signals assigned to the exocyclic double bond hydrogen atoms
(5–7 ppm), which indicates that isomers were formed, unlike with
thiophenes 8a–d. The tautomeric equilibrium of (2-methylen-4-
oxo-thiazolidin-5-ylidene)acetic acid ethers has been described
previously.25 In the earlier work, tautomerism of (Z)-methyl 2-
[4-cyano-5-(dialkylamino)-3-oxothien-2(3H)-ylidene]acetic acids
esters 9 was not observed.8 We propose that isomerization of
thiophenes 5c,d could occur via tautomerism (Scheme 4).
An additional 1H NMR experiment in which the spectra of thio-
phene 5d were recorded over a temperature range from rt to 100 °C
(Fig. 2) was done. In the 1H NMR spectra of compound 5b recorded
in DMSO-d6 at 80 °C and 100 °C the doubling of the signals disap-
peared, while in the spectra 8c recorded in CDCl3, doubling of the
signals was not observed, even on cooling to ꢁ60 °C. Hence, isom-
erization is via tautomerism and not the formation of regioisomers
during cyanothioacetamides heterocyclization with DMAD.
In summary, we have developed a novel pathway for N-
substituted thioacetamide heterocyclization with DMAD. Several
11. Obydennov, K. L.; Kosterina, M. F.; Klimareva, E. L.; Bakulev, V. A.; Morzherin,
Yu. Yu. Russ. Chem. Bull. 2011, 5, 1016–1018.
12. General procedure. To a suspension of cyanthioacetomide (1.2 mmol) in 20 ml
of glacial AcOH was added (0.095 ml, DMAD, 1.2 mmol) at 40 °C. The mixture
was stirred at 70 °C for 8 h. The resulting precipitate was filtered to give the
pure solid product. Thiazole derivatives were obtained by dilution of the
filtrate with water, filtration, and recrystallization from ethanol if neccesary.
13. (Z)-Methyl
2-[4-cyano-5-(isopropylamino)-3-oxothien-2(3H)-ylidene]acetate
(5d). Yield 34%, yellow crystals; mp 270–271 °C. 1H NMR (400 MHz, DMSO-
d6, 25 °C): (the keto-form (61%)) 1.32 (s, 6H, CH3), 3.79 (s, 3H, CH3), 3.89–3.97
(m, 1H, CH), 6.72 (s, 1H, @CH), 10.43 (s, 1H, NH); hydroxy-form (39%) 1.30 (s,
6H, CH3), 3.78 (s, 3H, CH3), 4.40–4.48 (m, 1H, CH), 6.65 (s, 1H, @CH), 10.28 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6, 25 °C): (mixture of isomers) 21.91,
22.31, 48.52, 50.99, 52.58, 77.00, 78.10, 114.04, 114.11, 115.26, 115.49, 144.42,
145.30, 165.87, 166.05, 170.66, 173.90, 180.77, 182.81. Anal. calcd for
C
11H12N2O3S: C, 52.37; H, 4.79; N, 11.10; S, 12.71; found: C, 52.10; H, 4.70;
N, 11.15; S, 12.85. MS (EI, 70 eV), m/z (%): 252 [M]+ (83).
14. (Z)-Methyl 2-[(Z)-2-(cyanomethylene)-3-cyclohexyl-4-oxothiazolidin-5-
ylidene]acetate (5c). Yield 30%, pale yellow powder; mp 259–261 °C. 1H NMR

K. L. Obydennov et al. / Tetrahedron Letters 54 (2013) 4876–4879
4879
(400 MHz, DMSO-d6, 25 °C): 1.36–1.19 (3H, m, CHCy), 1.80–1.59 (5H, m,
CHCy), 2.14–2.10 (2H, m, CHCy), 3.78 (3H, s, OCH3), 4.09 (1H, m, CHCy), 6.04
(1H, s, CH), 6.74 (1H, s, @CH). 13C NMR (100 MHz, DMSO-d6, 25 °C): 24.97,
25.70, 27.99, 115.06, 53.09, 56.89, 74.28, 117.25, 140.63, 154.87, 164.23,
166.60. Anal. calcd for C14H16N2O3S: C, 57.52; H, 5.52; N, 9.58; S, 10.97; found:
C, 57.55; H, 5.50; N, 9.60; S, 10.92. MS (EI, 70 eV), m/z (%): 292 [M]+ (60).
149 °C. 1H NMR (400 MHz, CDCl3, 25 °C): 3.85 (s, 3H, CH3), 4.81 (d, 2H, J = 6.4,
CH2), 4.89 (d, 2H, J = 5.2, CH2), 3.82 (s, 3H, CH3), 6.94 (s, 1H, @CH), 7.29–7.43
(m, 10H, 2Ph), 11.83 (s, 1H, NH); 13.68 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6, 25 °C): 46.30, 49.57, 52.01, 101.36, 115.85, 126.88, 127.08, 127.27, 127.59,
128.09, 128.43, 135.01, 136.64, 143.19, 165.40, 177.24 (S@C), 181.36 (COOMe),
184.99 (C@O). Anal. calcd for C22H20N2O3S2: C, 66.24; H, 4.75; N, 6.60; S, 15.11;
found: C, 66.25; H, 4.80; N, 6.60; S, 15.10. MS (EI, 70 eV), m/z (%): 424 [M]+ (33).
19. (Z)-Methyl 2-[5-(isopropylamino)-4-(isopropylcarbamothioyl)-3-oxothien-2(3H)-
ylidene]acetate (8d). Yield: 0.2 g (65%), yellow crystals; mp 140–142 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): 1.31 (d, J = 6,4 Hz, 6H, CH3), 1.46 (d, J = 6,4 Hz,
6H, CH3), 3.86 (s, 3H, OCH3), 3.92–4.04 (m, 1H, CH), 4.62–4.73 (m, 1H, CH), 6.92
(s, 1H, @CH), 11.52 (s, 1H, NH), 13.52 (s, 1H, NH. 13C NMR (100 MHz, CDCl3,
25 °C): d 21.58, 22.97, 44.88, 50.43, 52.53, 101.41, 115.95, 114.93, 166.92,
176.33, 182.31, 184.12. Anal. calcd for C14H20N2O3S2: C, 51.19; H, 6.14; N, 8.53;
S, 19.53; found: C, 51.20; H, 6.10; N, 8.50; S, 19.55. MS (EI, 70 eV), m/z (%): 328
[M]+ (30).
20. The structure of compound 7a was deposited with the Cambridge
Crystallographic Data Centre (No. CCDC 930944; deposited@ccdc.cam.ac.uk
or http://www.ccdc.cam.ac.uk/data_request/cif).
21. Guo, Y.; Yan, Y.; Zhi, X.; Yang, C.; Hu, H. Bioorg. Med. Chem. Lett. 2013, 3382–
3384.
22. Mérour, J.-Y.; Chichereau, L.; Desarbre, E.; Gadonneix, P. Synthesis 1996, 519–
524.
23. Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron 2009, 1119–1124.
24. Palluotto, F.; Campagna, F.; Carotti, A.; Ferappi, M.; Rosato, A.; Vitali, C., II
Farmaco 2002, 63–69.
15. General procedure. To
a suspension of N-substituted cyanothioacetamide
(1.1 mmol) in 20 ml of glacial AcOH was added (0.160 ml, DMAD, 1.1 mmol)
at room temperature. The mixture was stirred at temperature 70 °C for 8 h,
then diluted with ice-cold water (20 ml), stirred for 30 min, and filtered. The
precipitate was dried over P2O5 under reduced pressure.
16. (Z)-Methyl 2-(2-(cyanomethylene)-3-benzyl-4-oxothiazolidin-5-ylidene)acetate
(4b). Yield: 0.2 g (63%); mp 119–120 °C, pale yellow powder. 1H NMR
(400 MHz, DMSO-d6, 25 °C): 3.82 (s, 3H, OCH3), 5.00 (s, 2H, CH2), 5.82 (s, 1H,
CH), 6.90 (s, 1H, CH), 7.38–7.29 (m, 5H, Ar-H); Anal. calcd for C15H12N2O3S: C,
60.02; H, 4.02; N, 9.33; S, 10.58; found: C, 59.99; H, 4.03; N, 9.33; S, 10.68. MS
(EI, 70 eV), m/z (%): 300 [M]+ (8.9).
17. General procedure. To a suspension of malonthioamide (1.2 mmol) in 20 ml of
glacial AcOH was added (0.095 ml, DMAD, 1.2 mmol) at 40 °C. The mixture was
stirred at 40 °C for 4 h. In the cases of thiophenes 4a,b, filtration gave
compound as yellow fibers after washing with AcOH (10 ml) and then of
distilled water (50 ml). The precipitate was dried over P2O5 under reduced
pressure. In the cases of thiophenes 4c,d, the mixture was diluted with of ice-
cold water (20 ml) then mixture was stirred for 30 min and filtered. The
precipitate was recrystallized from ethanol, filtered, washed with ethanol 1 ml,
and dried over P2O5 under reduced pressure.
18. (Z)-Benzyl
2-[5-(benzylamino)-4-(methylcarbamothioyl)-3-oxothien-2(3H)-
25. Berseneva, V. S.; Tkachev, A. V.; Morzherin, Yu. Yu.; Dehaen, W.; Luyten, I.;
Toppet, S.; Bakulev, V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2133–2136.
ylidene]acetate (8b). Yield: 0.18 g (65%), yellow fibrous precipitate; mp 148–