Cyanoethylation and carboxyethylation of 5-benzofuryl-4-substituted 4H-1,2,4-triazole-3-thiols

Article abstract of DOI:10.1134/S1070363217060317

Base-catalyzed reactions of 5-benzofuryl-4-substituted 4H-1,2,4-triazole-3-thiols with acrylonitrile and acrylic acid afforded 2-(2-cyanoethyl)- or 2-(2-carboxyethyl)triazoline-3-thiones. Attempts to obtain the corresponding sulfanyl derivatives failed.

Full text of DOI:10.1134/S1070363217060317

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 6, pp. 1317–1320. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Kaldrikyan, N.S. Minasyan, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 6, pp. 1045–1048.
LETTERS
TO THE EDITOR
Cyanoethylation and Carboxyethylation
of 5-Benzofuryl-4-substituted 4H-1,2,4-Triazole-3-thiols
M. A. Kaldrikyana and N. S. Minasyanb*
a Mnjoyan Institute of Fine Organic Chemistry, Scientific and Technological Center of Organic and Pharmaceutical
Chemistry of the National Academy of Sciences of Armenia, Yerevan, Armenia
b Molecular Structure Research Center, National Academy of Sciences of the Republic of Armenia,
Azatutyan pr. 26, Yerevan, 0014 Armenia
*e-mail: nunemin@gmail.com
Received February 27, 2017
Abstract—Base-catalyzed reactions of 5-benzofuryl-4-substituted 4H-1,2,4-triazole-3-thiols with acrylonitrile
and acrylic acid afforded 2-(2-cyanoethyl)- or 2-(2-carboxyethyl)triazoline-3-thiones. Attempts to obtain the
corresponding sulfanyl derivatives failed.
Keywords: benzofuryl-1,2,4-triazole-3-thiol, acrylonitrile, cyanoethylation, acrylic acid, carboxyethylation,
S-alkylation
DOI: 10.1134/S1070363217060317
Triazole is one of the five-membered heterocycles
that are present in many natural products and
medications. A number of 1,2,4-triazole-based drugs is
currently known. Thus, ribavirin shows a strong
antiviral effect [1, 2]; rizatriptan is effective for the
treatment of migraine headaches [3]; anastrozole is an
antitumor drug [4]. Synthesis, reactions, and biological
activity of a number of 1,2,4-triazole derivatives
containing various pharmacophore fragments in the
positions 3, 4, and 5 of the heterocycle have been
reported, some of which have a pronounced or
moderate antitumour or antibacterial activity, and the
ability to influence DNA methylation [5–8]. These
results and data on previously synthesized 1,2,4-
triazole derivatives showing significant antitumor
activity [9–12] confirm the practical importance and
scientific significance of continuing a targeted search
for biologically active compounds among the new
triazole derivatives.
alkaline medium [9–11]. Cyanoethylation and carboxy-
ethylation of 1,2,4-triazole-3-thiols with acrylonitrile
and acrylic acid were carried out in the presence of
triethylamine or NaOH as a catalyst.
Alkylation and cyanoethylation of 1,2,4-triazole-3-
thiols are of interest due to the search for new
biologically active triazole derivatives. However, data
on the structure of the products of alkylation and
cyanoethylation are not consistently reliable and
sometimes contradictory [13, 14]. We have previously
shown that the reaction of 5-(4-alkoxyphenyl)-4-
phenyl(benzyl)-4H-triazole-3-thiol with acrylonitrile in
the presence of triethylamine resulted in the formation
of the corresponding 2-N-(2-cyanoethyl)triazole-3-
thiones. We did not succeed in obtaining the 3-cyano-
ethylsulfanyl derivative [13]. However, the reaction of
acrylonitrile with 1,2,4-triazole-3-thiol in a 2% NaOH
solution afforded 3-(2-cyanoethylsulfanyl)-1,2,4-tri-
azole as a sole product, whose formation was proven
only by elemental analysis data [14]. In this regard, we
performed the cyanoethylation reaction of triazole-3-
thiols 2a–2h with acrylonitrile in the presence of both
triethylamine and NaOH [14]. It was found that in both
cases the reaction proceeded exclusively with the
formation of 2-N-cyanoethyltriazoline-3-thiones 3a–3h
(Scheme 1). Structure of the compounds obtained was
Here we studied the reactions of cyanoethylation
and carboxyethylation of 5-benzofuryl-4-substituted
4H-1,2,4-triazole-3-thiols.
The starting 1,2,4-triazole-3-thiols 2a–2h were
obtained by intramolecular cyclization of the corres-
ponding 1,4-disubstituted thiosemicarbazides 1 in an
1317

1318
KALDRIKYAN, MINASYAN
Scheme 1.
R1
CONHNHCSNHR2
O
1a_1h
R1
R1
N
N
N
N
NCH2CH2CN
S
O
N
O
SH
R2
R2
2a_2h
3a_3h
R1
R1
N
N
N
N
N
NCH2CH2COOH
S
O
O
SCH2CH2COOH
R2
R2
4a, 4b, 4d
5a, 5b
R1 = H, R2 = C6H5 (a); R1 = H, R2 = CH2C6H5 (b); R1 = H, R2 = C6H11 (c); R1 = H, R2 = CH2 = CHCH2 (d); R1 = СH3, R2 =
C6H5 (e); R1 = СH3, R2 = СН2C6H5 (f); R1 = СH3, R2 = C6H11 (g); R1 = СH3, R2 = CH2=CHCH2 (h); R1 = H, R2 = C6H5 (a);
R1 = H, R2 = CH2C6H5 (b); R1 = H, CH2=CHCH2 (d).
1
confirmed by 1H and 13C NMR spectra. Thus, in the 1H
NMR spectrum of compound 3a there were triplet
signals of the CH2CN and NCH2 groups at 3.10 and
4.59 ppm, respectively. The 13C NMR spectrum of
compound 3a contained the signal of the NCH2 moiety
(44.6 ppm) and no signal of the SCH2 group, which
elemental analysis, H and 13C NMR spectroscopy
data.
5-Benzofuryl-4-substituted 2-cyanoethyl-2H-1,2,4-
triazole-3-thiones 3a–3h (general procedure). A
mixture of the corresponding 1,2,4-triazole-3-thiol 2
(0.01 mol), 10 mL of freshly distilled acrylonitrile,
20 mL of triethylamine, and 20 mL of water or 40 mL
of a 2% solution of NaOH was refluxed for 8–10 h.
Excess of acrylonitrile was distilled off, then 40 mL of
water was added. The crystals formed were filtered off
and dried.
would appear in
a
stronger field when S-
cyanoethylation occurs.
In a similar manner, acrylic acid reacted with
triazole-3-thiols 2a, 2b, and 2d in the presence of tri-
ethylamine to give exclusively 2-(2-carboxyethyl)tri-
azoline-3-thiones 4a, 4b, and 4d. The sructure of the
resulting compounds was additionally confirmed by an
authentic synthesis of 4a from nitrile 3a. The melting
point of a mixture of two samples obtained was not
depressed. We did not succeed in isolating 3-(2-car-
boxyethyl)sulfanyl derivatives 5a, 5b, and 5d.
Attempts to alkylate triazole-3-thiols 2a, 2b, and 2d
with 2-chloropropionic and 2-bromopropionic acids in
both alcoholic and aqueous KOH solution were not
successful (Scheme 1).
5-Benzofuryl-4-phenyl-2-(2-cyanoethyl)-2H-1,2,4-
triazole-3(4H)-thione (3a). Yield 94.5%, mp 174–
175°C, Rf 0.73. 1H NMR spectrum, δ, ppm: 3.16 t (2H,
CH2CN, J = 6.7 Hz), 4.58 t (2H, NCH2, J = 6.7 Hz),
6.30 d (1H, =CH, J = 0.8 Hz), 7.22 d.d.d (1H, C6H4,
J = 8.0, 7.3, 0.9 Hz), 7.35 d.d.d (1H, C6H4, J = 8.2, 7.3,
1.4 Hz), 7.45–7.51 m (4H, C6H4 + C6H5), 7.62–7.68 m
(3H, C6H5). Found, %: N 17.26; S 9.42. C19H14N4OS.
Calculated, %: N 16.17; S 9.25.
5-Benzofuryl-4-benzyl-2-(2-cyanoethyl)-2H-1,2,4-
triazole-3(4H)-thione (3b). Yield 90%, mp 126–127°C,
Rf 0.68. 1H NMR spectrum, δ, ppm: 3.14 t (2H, CH2CN,
The purity, individuality, and structure of the
synthesized compounds were confirmed by TLC,
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CYANOETHYLATION AND CARBOXYETHYLATION
1319
J = 6.6 Hz), 4.58 t (2H, NCH2, J = 6.6 Hz), 5.67 s (2H,
NCH2), 7.18–7.32 m (6H, C6H4 and C6H5), 7.36 d (1H,
=CH, J = 0.8 Hz), 7.39 d.d.d (1H, C6H4, J = 8.3, 7.2,
1.2 Hz), 7.56 d.d.d (1H, C6H4, J = 8.3, 1.6, 0.8 Hz),
7.65 br.d (1H, C6H4, J = 7.8 Hz). Found, %: N 15.75; S
8.56. C20H16N4OS. Calculated, %: N 15.54; S 8.29.
5-(5-Methylbenzofuryl)-4-cyclohexyl-2-(2-cyano-
ethyl)-2H-1,2,4-triazole-3(4H)-thione (3g). Yield
1
97.0%, mp 123–124°C, Rf 0.70. H NMR spectrum, δ,
ppm: 1.14–1.26 m (2H, C6H11), 1.35–1.52 m (2H,
C6H11), 1.66–1.92 m (4H, C6H11), 2.02–2.16 m (2H,
C6H11), 2.49 s (3H, CH3), 3.06 t (2H, CH2CN, J =
6.7 Hz), 4.49 t (2H, NCH2, J = 6.7 Hz), 4.70–4.82 m
(1H, C6H11), 7.24 d.d (1H, C6H3, J = 8.5, 1.9 Hz), 7.30
d (1H, =CH, J = 0.8 Hz), 7.49 d (1H, C6H3, J =
8.5 Hz), 7.51 d.d (1H, C6H3, J = 1.9, 0.8 Hz). 13C
NMR spectrum, δC, ppm: 15.6 (CH2), 20.7 (CH2), 24.4
(CH2), 25.3 (2CH2), 28.9 (2CH2), 44.4 (NCH2), 57.8
(NCH), 110.3 (CH), 110.5 (CH), 116.3 (CN), 121.4
(CH), 126.7 (C), 127.3 (CH), 140.8 (C), 141.4 (C),
152.9 (C), 166.7 (C). Found, %: N 15.52; S 8.96.
C20H22N4OS. Calculated, %: N 15.28; S 8.74.
5-Benzofuryl-4-cyclohexyl-2-(2-cyanoethyl)-2H-
1,2,4-triazole-3(4H)-thione (3c). Yield 85.7%, mp
194–195°C, Rf 0.67. 1H NMR spectrum, δ, ppm: 1.10–
1.27 m (2H), 1.36–1.53 m (2H), 1.66–1.93 m (4H,
C6H11), 2.04–2.21 m (2H, C6H11), 3.07 t (2H, CH2CN,
J = 6.7 Hz), 4.71–4.83 m (1H, NCH, C6H11), 7.34 t.d
(1H, C6H4, J = 7.5, 1.1 Hz), 7.40 d (1H, =CH, J =
0.8 Hz), 7.41–7.47 m (1H, C6H4), 7.60–7.64 m (1H,
C6H4), 7.75 d.d (1H, C6H4, J = 7.7, 1.3 Hz). 13C NMR
spectrum, δC, ppm: 15.6 (CH2), 24.4 (CH2), 25.3
(2CH2), 28.9 (2CH2), 44.4 (NCH2), 57.8 (NCH), 110.5
(CH), 110.9 (CH), 126.6 (C), 140.8 (C), 141.3 (C),
154.4 (C). Found, %: N 15.68; S 9.28. C19H20N4OS.
Calculated, %: N 15.89; S 9.09.
4-Allyl-5-(5-methylbenzofuryl)-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (3h). Yield 90.5%,
1
mp 102–103°C, Rf 0.74. H NMR spectrum, δ, ppm:
2.47 s (3H, CH3), 3.09 t (2H, CH2CN, J = 6.6 Hz),
4.52 t (2H, NCH2, J = 6.6 Hz), 5.04 d.t (2H, NCH2, J =
5.3, 1.5 Hz), 5.16–5.24 m (2H, =CH2), 5.97 d.d.t (1H,
=CH, J = 17.0, 10.5, 5.3 Hz), 7.22 d.d (1H, C6H3, J =
8.4, 1.7 Hz), 7.40 d (1H, =CH, J = 0.8 Hz), 7.45–7.49
m (2H, C6H3). Found, %: N 17.48; S 9.62. C17H16N4O6.
Calculated, %: N 17.27; S 9.88.
4-Allyl-5-benzofuryl-2-(2-cyanoethyl)-2H-1,2,4-
triazole-3(4H)-thione (3d). Yield 85.5%, mp 109–
110°C, Rf 0.72. 1H NMR spectrum, δ, ppm: 3.10 t (2H,
CH2CN, J = 6.6 Hz), 4.53 t (2H, NCH2, J = 6.6 Hz),
5.06 d.t (2H, NCH2, J = 5.3, 1.5 Hz), 5.17–5.25 m (2H,
=CH2), 5.99 d.d.t (1H, =CH, J = 17.0, 10.5, 5.3 Hz),
7.31 d.d.d (1H, C6H4, J = 7.8, 7.3, 1.0 Hz), 7.42 d.d.d
(1H, C6H4, J = 8.2, 7.3, 1.3 Hz), 7.51 d (1H, =CH, J =
0.9 Hz), 7.61 br.d (1H, C6H4, J = 8.2 Hz), 7.72 br.d
(1H, C6H4, J = 7.8 Hz). Found, %: N 18.26; S 10.57.
C16H14N4OS. Calculated, %: N 18.05; S 10.33.
5-Benzofuryl-4-substituted 2-(2-carboxyethyl)-
1,2,4-triazole-3(4H)-thiones 4a, 4b, 4d (general
procedure). A mixture of 1,2,4-triazole-3-thiol 2a, 2b
or 2d (0.001 mol), 2 mL of acrylic acid, 4 mL of
triethylamine and 4 mL of water was refluxed for 15–
20 h. Water was added to quench the reaction. Upon
cooling, the formed crystals were filtered off, washed
with water and dried.
5-(5-Methylbenzofuryl)-4-phenyl-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (3e). Yield 97.2%, mp
1
161–162°C, Rf 0.72. H NMR spectrum, δ, ppm: 2.39
br.s (3H, CH3), 3.16 t (2H, CH2CN, J = 6.7 Hz), 4.58 t
(2H, NCH2, J = 6.7 Hz), 6.20 d (1H, =CH, J = 0.9 Hz),
7.15 br.d.d (1H, C6H3, J = 8.4, 1.6 Hz), 7.25–7.27 m
(1H, C6H3), 7.34 br.d (1H, C6H3, J = 8.4 Hz), 7.44–
7.49 m (2H, C6H5), 7.60–7.68 m (3H, C6H5). Found,
%: N 15.31; S 8.58. C20H16N4OS. Calculated, %: N
15.54; S 8.89.
5-Benzofuryl-4-phenyl-2-(2-carboxyethyl)-2H-
1,2,4-triazole-3(4H)-thione (4a). Yield 72%, mp 171–
172°C, Rf 0.56. 1H NMR spectrum, δ, ppm: 2.92 t (2H,
CОCH2, J = 7.5 Hz), 4.50 t (2H, NCH2, J = 7.5 Hz),
6.26 d (1H, =CH, J = 0.7 Hz), 7.17–7.24 m (1H,
C6H4), 7.34 t.d (1H, C6H4, J = 7.8, 1.3 Hz), 7.42–7.50
m (4H, C6H4 + C6H5), 7.60–7.67 m (3H, C6H4), 12.25
br.s (1H, COOH). Found, %: N 11.64; S 8.92.
C19H15N3O3S. Calculated, %: N 11.50; S 8.77.
5-(5-Methylbenzofuryl)-4-benzyl-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (3f). Yield 74.0%, mp
148–149°C, Rf 0.60. 1H NMR spectrum, δ, ppm: 2.44 s
(3H, CH3), 3.13 t (2H, CH2CN, J = 6.6 Hz), 4.57 t (2H,
NCH2, J = 6.6 Hz), 5.65 s (2H, NCH2C6H5), 7.17–7.31
m (7H) and 7.40–7.45 m (2H, C6H5, C6H3, Hfuryl).
Found, %: N 14.75; S 8.74. C21H18N4OS. Calculated,
%: N 14.96; S 8.56.
5-Benzofuryl-4-benzyl-2-(2-carboxyethyl)-2H-
1,2,4-triazol-3(4H)-thione (4b). Yield 65.8%, mp 85–
1
86°C, Rf 0.51. H NMR spectrum, δ, ppm: 2.87 t (2H,
CОCH2, J = 7.5 Hz), 4.50 t (2H, NCH2, J = 7.5 Hz),
5.65 s (2H, CH2C6H5), 7.19–7.32 m (7H), 7.38 d.d.d
(1H, C6H4, J = 8.3, 7.9, 1.2 Hz), 7.55 d.d (1H, C6H4,
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KALDRIKYAN, MINASYAN
2. Sidwell, R.W., Bailey, K.W., Wong, M.H., Bernard, D.L.,
and Smee, D.F., Antiviral Res., 2005, vol. 68, no. 1,
p. 10. doi 10.1016/j. antiviral.2005.06.003
3. Williamson, D.J., Hill, R.G., Shepheard, S.J., and
Hargreaves, R.J., Br. J. Pharmacol., 2001, vol. 133,
p. 1029. doi 10.1038/sj.bjp. 0704162
4. Coombes, R.C., Wynne, C.H., and Dowse, A.M.,
Endocrine-Related Cancer, 1999, vol. 6, p. 259. doi
10.1677/erc.0.0060259
5. Ovsepyan, T.R., Arsenyan, F.G., Nersesyan, L.E.,
Aharonyan, A.S., Danielyan, I.S., Paronikyan, R.V., and
Melik-Ohanjanyan, R.G., Pharm. Chem. J., 2015,
vol. 49, p. 251. doi 10.1007/s11094-015-1261-5
6. Ovsepyan, T.R., Dilanyan, S.V., Minasyan, N.S., and
Melik-Ohanjanyan, R.G., Russ. J. Org. Chem., 2014,
vol. 50, p. 736. doi 10.1134/s1070428014050194
7. Ovsepyan, T.R., Grboyan, S.V., Arsenyan, F.G., and
Melik-Ohanjanyan, R.G., Pharm. Chem. J., 2012,
vol. 45, p. 705. doi 10.1007/s11094-012-0706-3
8. Ovsepyan, T.R., Melik-Ogandzhanyan, R.G., Pano-
syan, G.A., Arsenyan, F.G., and Garibdzhanyan, B.T.,
Pharm. Chem. J., 2009, vol. 43, no. 12, p. 645. doi
10.1007/s11094-010-0371-3
9. Kaldrikyan, M.A., Grigoryan, L.A., Melik-Ohanjanyan, R.G.,
and Arsenyan, F.G., Pharm. Chem. J., 2009, vol. 43,
no. 5, p. 242. doi 10.1007/s11094-009-0287-y
J 8.3, 1.2 Hz), 7.64 d.d (1H, C6H4, J = 7.9, 1.5 Hz),
12.27 br.s (1H, COOH). Found, %: N 13.35; S 8.67.
C20H17N3O3S. Calculated, %: N 13.07; S 8.45.
4-Allyl-5-benzofuryl-2-(2-carboxyethyl)-2H-1,2,4-
triazole-3(4H)-thione (4d). Yield 74.5%, mp 148–
149°C, Rf 0.52. 1H NMR spectrum, δ, ppm: 2.83 t (2H,
CH2OH, J = 7.5 Hz), 4.44 t (2H, NCH2, J = 7.5 Hz),
5.04 d.t (2H, NCH2, J = 5.3, 1.5 Hz), 5.18 d.q (1H,
=CH2, J = 17.1, 1.5 Hz), 5.20 d.q (1H, =CH2, J = 10.2,
1.5 Hz), 5.98 d.d.t (1H, =CH, J = 17.1, 10.2, 5.3 Hz),
7.31 d.d.d (1H, C6H4, J = 8.2, 7.2, 1.1 Hz), 7.41 d.d.d
(1H, C6H4, J = 7.8, 7.2, 1.1 Hz), 7.51 d (1H, =CH, J =
0.9 Hz), 7.60 br.d (1H, C6H4, J = 8.2 Hz), 7.71 br.d
(1H, C6H4, J = 7.8 Hz). Found, %: N 12.56; S 9.46.
C16H15N3O3S. Calculated, %: N 12.75; S 9.73.
5-Benzofuryl-4-phenyl-2-(2-carboxyethyl)-2H-
1,2,4-triazol-3(4H)-thione (4a) (authentic synthesis).
A mixture of 2-(2-cyanoethyl)-1,2,4-triazole-3-thione
3a (0.001 mol) and 5 mL of conc. hydrochloric acid
was refluxed for 8–10 h. After cooling, water was
added, and the mixture was kept overnight. The
formed crystals were filtered off, washed with water,
and dried. Yield 55.5%, mp 171–172°C (no melting
point depression was observed in a mixed sample with
above described compound 4a).
10. Kaldrikyan, M.A., Grigoryan, L.A., Melik-Ohanjanyan, R.G.,
and Arsenyan, F.G., Pharm. Chem. J., 2011, vol. 45,
no. 4, p. 211. doi 10.1007/s11094-011-0596-9
11. Kaldrikyan, M.A., Melik-Ohanjanyan, R.G., and
Arsenyan, F.G., Pharm. Chem. J., 2013, vol. 47, no. 4,
p. 191. doi 10.1007/s11094-013-0924-3
12. Kaldrikyan, M.A., Minasyan, N.S., and Melik-
Ohanjanyan, R.G., Russ. J. Org. Chem., 2013, vol. 49,
no. 10, p. 1550. doi 10.1134/s1070428013/00254
1H and 13C NMR spectra (DMSO-d6) were recorded
on a Mercury-300 spectrometer, internal reference
TMS. Melting points were measured on a Boetius
apparatus. TLC analysis was performed on Silufol UV-
254 plates, eluent benzene–acetone, 1 : 0.25 (3а–3h)
or benzene–acetone–ethanol, 1 : 1 : 0.1 (4а, 4b, 4d).
13. Kaldrikyan, M.A., Minasyan, N.S., and Melik-
Ohanjanyan, R.G., Russ. J. Gen. Chem., 2016, vol. 86,
no. 2, p. 305. doi 10.1134/s10736321602017
14. Azaryan, A.S., Iradyan, N.S., and Aroyan, A.A., Arm.
Khim. Zh., 1975, vol. 28, no. 9, p. 709.
REFERENCES
1. Sidwell, R.W., Hofman, J.H., Khore, G.P., Allen, L.B.,
Witkowski, J.T., and Robins, R.K., Science, 1972,
vol. 177, no. 4050. p. 705. doi 10.1126/science.177.4050.705
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