Transamination of cyanothioacetamide with morpholine. molecular and crystal structure of 3-(morpholin-1-yl)-3-thioxopropanenitrile and 3-(morpholin-1-yl)- 3-thioxopropanethioamide

Article abstract of DOI:10.1134/S1070363212040184

Transamination of cyanothioacetamide with equimolar amount of morpholine resulted in the formation of 3-(morpholin-1-yl)-3-thioxopropanenitrile, and with twofold excess of morpholine 3-(morpholin-1-yl)-3-thioxopropanethioamide was obtained. By the alkylation of the resulting products 2-[2-(morpholin-1-yl)-2- thioxoethylidene]thiazolidin-4-one, 3-amino-N-(4-acetylphenyl)-5-(morpholin-1- yl)-thiophene-2-carbox-amide, 3-amino-3-methylthio-1-morpholinoprop-2-ene-1- thione, (2E,4E)-2-(morpholin-4-yl)thiocarbonyl)-5-phenylpenta-2,4- dienothioamide, and 3-{2′-[2″-(molrpholin-1-yl)-2-thioxoethyl] thiazol-4′-yl}-2H-chromen-2-one were synthesized. The 3-(morpholin-1-yl)- 3-thioxopropanenitrile and 3-(morpholin-1-yl)-3-thioxopropane-thioamide structures were studied by the X-ray diffraction.

Full text of DOI:10.1134/S1070363212040184

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 4, pp. 720–724. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.D. Dyachenko, A.N. Chernega, S.V. Dyachenko, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 4, pp. 634–638.
Transamination of Cyanothioacetamide
with Morpholine. Molecular and Crystal Structure
of 3-(Morpholin-1-yl)-3-thioxopropanenitrile
and 3-(Morpholin-1-yl)-3-thioxopropanethioamide
V. D. Dyachenkoa, A. N. Chernegab, and S. V. Dyachenkoa
a Taras Shevchenko Lugansk National University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: dvd_lug@online.lg.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received February 8, 2011
Abstract—Transamination of cyanothioacetamide with equimolar amount of morpholine resulted in the
formation of 3-(morpholin-1-yl)-3-thioxopropanenitrile, and with twofold excess of morpholine 3-(morpholin-
1-yl)-3-thioxopropanethioamide was obtained. By the alkylation of the resulting products 2-[2-(morpholin-1-
yl)-2-thioxoethylidene]thiazolidin-4-one, 3-amino-N-(4-acetylphenyl)-5-(morpholin-1-yl)-thiophene-2-carbox-
amide, 3-amino-3-methylthio-1-morpholinoprop-2-ene-1-thione, (2E,4E)-2-(morpholin-4-yl)thiocarbonyl)-5-
phenylpenta-2,4-dienothioamide, and 3-{2'-[2''-(molrpholin-1-yl)-2-thioxoethyl]thiazol-4'-yl}-2H-chromen-2-
one were synthesized. The 3-(morpholin-1-yl)-3-thioxopropanenitrile and 3-(morpholin-1-yl)-3-thioxopropane-
thioamide structures were studied by the X-ray diffraction.
DOI: 10.1134/S1070363212040184
It was shown previously that cyanothioacetamide
(I) was transaminated with morpholine affording 3-
(morpholin-1-yl)-3-thioxopropanenitrile (II) and 1-
amino-3-(morpholin-1-yl)-1,3-propanedithione (III) [1].
Formerly only one example of the thioacetamide trans-
amination with piperidine was known [2], as confirm
surveys [3–6].
In this study compounds II and III were studied by
XRD and their alkylation and condensation with
cinnamic aldehyde was studied.
The general view of molecules II and III, and the
main bond lengths and bond angles are shown in Figs. 1
and 2, respectively. In both molecules, the con-
formation of the morpholine substituent N1O1C1–4 is
almost undistorted chair: the torsion angles in the ring
vary in a narrow range (54.7°–58.7° in the structure II
and 54.3°–60.3° in the structure III), the angular
fragments O1C1C4 and N1C2C3 form dihedral angles
with the C1–4 plane 128.1° and 129.1° in compound II
and 126.1° and 130.0° in compound III, respectively.
The N1 atom has planar-trigonal configuration of its
bonds (the sums of bond angles at the N1 atom in II
Fig. 1. General view of molecule II and numbering of
atoms. Selected bond lengths (Å) and bond angles (deg):
S1–C5 1.663(3), N1–C2 1.471(3), N1–C3 1.460(3), N1–C5
1.324(3), N2–C7 1.138(4), C5–C6 1.515(4), C6–C7 1.456(3),
C2N1C3 110.6(2), C2N1C5 125.6(2), C3N1C5 123.7(2),
S1C5N1 125.2(2), S1C5C6 120.3(2), N1C5C6 114.5(2),
N2C7C6 174.2(3).
720

TRANSAMINATION OF CYANOTHIOACETAMIDE WITH MORPHOLINE
and III are 359.9(6)° and 360.0(9)°. The system of
721
N1–C5(=S1)–C6 bonds is almost coplanar with N1C2C3
group: the respective dihedral angle is only 7.5° in the
molecule II and 1.5° in III. This conformation is quite
favorable for the effective conjugation between the
lone electron pair of atom N1 and the C5=S1 π-system.
Indeed, the N1–C5 bond transmiting this interaction
[1.324(3) Å in II and 1.330(5) Å in III] is significantly
shorter than the value of 1.45 Å, typical for an ordinary
single N(sp2)–C(sp2) bond [7, 8]. Similarly, in the
molecule III the n(N2)–π(C7=S2) interaction results in
the shortening of the N2–C7 bond to 1.315 (5) Å.
Note that the reaction of cyanothioacetamide I with
the equimolar amount of morpholine at 20°C in
ethanol proceeds along the transamination path [9] to
form compound II. Use of a twofold excess of
morpholine under the same conditions results in the
formation of the dithioamide III. This may be due to
the presence in the reaction mixture of hydrogen
sulfide eliminated from the cyanothioacetamide I
under the action of morpholine. It is known that the
addition of hydrogen sulfide to nitriles in basic
Fig. 2. General view of molecule III and numbering of
atoms. Selected bond lengths (Å) and bond angles (deg):
S1–C5 1.683(4), S2–C7 1.661(4), N1–C2 1.474(5), N1–C3
1.473(6), N1–C5 1.330(5), N2–C7 1.315(5), C5–C6 6 1.524
(5), C2N1C3 111.9 (3), C2N1C5 122.4(3), C3N1C5 125.7(3),
S1C5N1 124.2(3), S1C5C6 118.2(3), N1C5C6 117.7(3),
S2C7N2 122.1(3), S2C7C6 121.4(3), N2C7C6 116.5(3).
Ph
O
O
N
N
O
H2N
MeS
N
H2N
N
S
S
S
O
O
S
S
VII
VI
VIII
O
O
Ph
Br
CHO
_KI,
_H2O
O
_HBr,
_H2O
_H2O
OEt
MeI / KOH
Cl
O
H
O
HN
O
2
N
O
NH2
N
H2N
S
N
O
NC
_NH3,
_CH2(CN)2
_HCl,
_EtOH
S
S
S
S
I
IX
III
O
N
NH
NH2
Cl
C
S
_NH3
HN
O
O
O
N
S
N
O
O
Me , 2 KOH
O
NH
O
NH
N
_KCl,
_H2O
NC
O
S
O
Me
Me
II
V
IV
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

722
DYACHENKO et al.
Main crystallographic parameters of compounds II and III,
the conditions of the diffraction experiments and the details
of structure refinement
medium is a reversible process [10]. Further addition
of hydrogen sulfide to compound II just leads to the
formation of dithiodiamide III.
The alkylation of 3-(morpholin-1-yl)-3-thioxopro-
panenitrile II with α-chloro-4-acetylacetanilide in
DMF in the presence of a twofold excess of KOH gave
3-amino-2-(4-acetylphenylcarbamoyl)-5-morpholino-
thiophene (IV). The reaction path involves, apparently,
the formation of thioester V which is unstable in these
conditions and readily undergoes the intramolecular
cyclization to form the substituted thiophene IV, a pro-
mising intermediate for designing drugs with antitumor
[11–13] and antidiabetic activity [14, 15].
Parameter
II
III
Empirical formula
C7H10N2OS
170.23
C7H12N2OS2
204.31
М
Crystal system
Orthorhombic Monoclinic
Space group
Pbca
Pc
a, Å
9.204(2)
7.435(2)
24.518(3)
90.0
5.981(1)
5.604(2)
14.756(3)
99.44(1)
487.8
2
b, Å
Compound III enters the Knoevenagel condensation
with cinnamic aldehyde as a CH component, forming
the corresponding alkene VI. The alkylation of
dithiodiamide III with methyl iodide in DMF in the
presence of KOH leads to thioether VII. The use in
this reaction of α-halocarbonyl compounds bromacetyl-
coumarin or ethyl monochloroacetate as alkylating
agents resulted in the synthesis of substituted Hantzsch
thiazole VIII and thiazolidone IX, respectively.
c, Å
β, deg
V, Å3
1677(6)
8
Z
dcalc, g cm–3
1.35
1.39
μ, cm–1
29.31
724.2
4.82
F(000)
216.5
The structures of the obtained compounds IV, VI–
1
Crystal size, mm
Diffraction angle limits θ, deg
Spheric segment
0.19×0.34×0.42 0.19×0.22×0.34
65 27
0 < h < 10, 0 < h < 7,
IX were confirmed by mass spectrometry, IR and H
1
NMR spectroscopy (see Experimental). For the H
NMR spectra the presence is characteristic of the
proton signals of morpholine fragment as multiplets at
δ 3.11–4.25 ppm, and the characteristic signals of
protons of aromatic substituents in the corresponding
regions of the δ scale.
0 < k < 8,
0 < l < 28
0 < k < 7,
–18 < l < 18
Number of reflections:
measured
EXPERIMENTAL
1692
1428
1292
1071
X-ray diffraction investigation of single crystals of
compounds II and III was carried out at room
temperature on an automatic four-circle Enraf-Nonius
CAD-4 diffractometer (graphite monochromator, ratio
of scanning rates ω/2θ = 1.2). The extinction in the
crystal was accounted for by the method of azimuthal
scanning [16]. Both structures were solved by the
direct method and refined by the full-matrix least-
squares procedure in an anisotropic approximation
using a program package CRYSTALS [17]. In both
these structures all the hydrogen atoms were revealed
from a difference synthesis of electron density. In
compound II all H atoms were refined isotropically, in
the structure III only the atoms H1 and H2 associated
with the N2 atom were refined, while the remaining H
atoms were included in the refinement with fixed
positional and thermal parameters. In the refinement
independent
in least-squares calc.
1031 [> 3σ(I)] 843 [> 3σ(I)]
Number of refined parameters 140
117
7.2
Number of reflections per
parameter
7.4
Divergence factors:
R
0.044
0.049
1.077
0.033
0.034
1.164
Rw
GOOF
Weighting factors
2.44, 1.91, 2.34, 0.66, 0.17, 0.52,
0.45, 0.51
0.04, 0.11
Residual electron
density Δρ, е Å–3
0.30; –0.32
0.19; –0.17
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

TRANSAMINATION OF CYANOTHIOACETAMIDE WITH MORPHOLINE
723
we used the Chebyshev weight scheme [18]. The
absolute configuration of III was determined by the
Flack method [19], the enantipole parameter p was
refined to the value of 0.01 from 926 reflections with
non-averaged Friedel equivalents. The crystallographic
data of the studied compounds and conditions of the
diffraction experiments are given in the table.
acetylchloroacetanilide, the mixture was stirred for 1 h
and the same amount of the alkali was added again, the
stirring was continued for 2 h and the mixture was left
for one day. Then the reaction mixture was diluted
with an equal volume of water and the resulting
precipitate was filtered off, washed with water, ethanol
and hexane. Yield 2.45 g (71%), white powder, mp
199–200°C (BuOH). IR spectrum, ν, cm–1: 3242, 3297,
The IR spectra were recorded on an IKS-40
1
3425 (NH2), 1680 (C=O), 1657 [CONH, δ (NH2)]. H
1
instrument from the samples in mineral oil. The H
NMR spectrum, δ, ppm: 2.50 s (3H, Me), 3.17 m (4H,
CH2NCH2), 3.75 m (4H, CH2OCH2), 5.67 s (1H, C4H
thiophene), 6.68 br.s (2H, NH2), 7.80 br.s (4H, C6H4),
br.s 8.87 (1H, CONH). Found, %: C 58.87, H 5.32, N
12.30. C17H19N3O3S. Calculated, %: C 59.11, H 5.54,
N 12.16.
NMR spectra were recorded on a Gemini-200 spectro-
meter (199.975 MHz) for compounds II and IV and a
Bruker DR-500 (500.13 MHz) instrument for com-
pounds III, VI–IX, solvent DMSO-d6, reference TMS.
The mass spectra were recorded on a Kratos MS-890
instrument (70 eV) with direct introduction of sub-
stance III into the ion source, and Crommas GC/MS-
Hewlett-Packard 5890/5972 instrument, column HP-5
MS (70 eV), compounds VI, VII, and IX were taken
as solutions in CH2Cl2. Melting points were deter-
mined on a Koeffler block. Monitoring of the reaction
progress and of the purity of the compounds was
performed by TLC (Silufol UV-254, acetone-hexane,
3:5, development in iodine vapor and UV irradiation).
(2E,4E)-2-(Morpholin-4-ylthiocarbonyl)-5-phenyl-
pentyl-2,4-dienethioamide (VI). To a stirred suspend-
sion of 2.04 g (10 mmol) of the CH-acid III in 20 ml
of ethanol was added 1.26 ml (10 mmol) of cinnamic
aldehyde and 3 drops of triethylamine, the mixture was
stirred for 2 h and left standing for 48 h. The pre-
cipitate formed was filtered off, washed with ethanol
and hexane. Yield 2.1 g (66%), colorless crystals, mp
193–195°C (EtOH). IR spectrum, ν, cm–1: 3290, 3433
1
3-(Morpholin-1-yl)-3-thioxopropanenitrile (II).
To a stirred suspension of 1.0 g (10 mmol) of cyano-
thioacetamide I in 15 ml of ethanol at 20°C was added
0.87 ml (10 mmol) of morpholine. The mixture was
stirred for 30 min and left for a day. The precipitate
was then filtered off, washed with ethanol and hexane.
Yield 1.3 g (76%), yellow crystals, mp 89°C (EtOH)
(published 91–92°C [20], 95°C [21]).
(NH2). H NMR spectrum, δ, ppm: 3.11–4.09 m (8H,
morpholine), 4.91 d (1H, C3H, J 9.2 Hz), 5.08 m (1H,
C4H), 6.4 d (1H C5H, J 9.4 Hz), 7.19 m (2H, Ph, J
6.94 Hz), 7.22 m (1H, Ph, J 6.94 Hz), 7.31 q (2H, Ph, J
7.09 Hz), 10.42 br.s (2H, NH2). Mass spectrum, m/z
(Irel, %): 319 (100) [M + 1]+. Found, %: C 60.22, H
5.61, N 8.68. C16H18N2OS2. Calculated, %: C 60.35, H
5.70, N 8.80.
1-Amino-3-(morpholin-1-yl)-1,3-propanedithione
(III) was prepared analogously to compound II using
1.74 ml (20 mmol) of morpholine. Yield 0.8 g (39%),
yellow crystals, mp 143–150°C (decomp.). IR spec-
trum, ν, cm–1: 3190, 3278, 3356 (NH2).1H NMR spec-
trum, δ, ppm: 3.70 m (4H, CH2NCH2), 3.91 s (2H,
CH2), 4.42 m (4H, CH2OCH2), 8.87 and 9.43 br.s (1H,
NH2). Mass spectrum, m/z (Irel, %): 206(6) [M + 2]+,
205 (7) [M + 1]+, 204 (55) [M]+, 171 (8) [M – SH]+,
144 (9), 119 (22), 110 (20), 101 (8), 86 (100)
[morpholinyl]+, 60 (39), 54 (18), 42 (23). Found, %: C
40.93, H 6.07, N 13.58. C17H12N2OS2. Calculated, %:
C 41.15, H 5.92, N 13.71.
3-Amino-3-methylthio-1-(morpholin-1-yl)prop-2-
ene-1-thione (VII). To a stirred suspension of 2.04 g
(10 mmol) of dithiodiamide III in 15 ml of DMF was
added sequentially 5.6 ml (10 mmol) of 10% aqueous
solution of KOH and 0.62 ml (10 mmol) of methyl
iodide, the mixture was stirred for 5 h and diluted with
an equal volume of water. The precipitate was filtered
off, washed with water, ethanol, and hexane. Yield 1.05 g
(48%), brown powder, mp 102–103°C (EtOH). IR
spectrum, ν, cm–1: 3178, 3326 (NH2), 1650 [δ(NH2)].
1H NMR spectrum, δ, ppm: 2.41 s (3H, Me), 3.58 m
(4H, CH2NCH2), 3.89 m (4H, CH2OCH2), 5.31 s (1H,
=CH), br.s 9.35 (2H, NH2). Mass spectrum, m/z (Irel,
%): 219 (100) [M + 1]+. Found, %: C 43.92, H 66.02,
N 12.77. C8H14N2OS2. Calculated, %: C 44.01, H
66.13, N 12.83.
3-Amino-2-(4-acetylphenylcarbamoyl)-5-(mor-
pholin-4-yl)thiophene (IV). To a stirred solution of
1.7 g (10 mmol) of compound II in 15 ml of DMF was
added sequentially 5.6 ml (10 mmol) of 10% aqueous
solution of KOH and 2.12 g (10 mmol) of 4-
3-[2'-(2''-(Morpholin-1-yl)-2-thioxoethyl)thiazol-
4'-yl]-2H-chromen-2-one (VIII). A mixture of 2.04 g
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

724
DYACHENKO et al.
5. Litvinov, V.P., Usp. Khim., 1999, vol. 68, no. 9, p. 817.
6. Jagodzinski, T.S., Chem. Rev., 2003, vol. 103, no. 1,
(10 mmol) of compound III and 2.67 g (10 mmol) of
bromoacetylcoumarine in 15 ml of DMF was stirred
for 5 h and then diluted with equal volume of water.
The precipitate formed was filtered off, washed with
water, ethanol and hexane. Yield 2.68 g (72%), yellow
powder, mp 222–224°C (BuOH). IR spectrum, ν, cm–1:
p. 197.
7. Burke-Laing, M. and Laing, M., Acta Cryst., Part B,
1976, vol. 32, no. 12, p. 3216.
8. Allen, F.H., Kennard, O., Watson, D.G., Brammer, L.,
Orpen, A.G., and Tailor, R., J. Chem. Soc., Perkin
Trans. 2, 1987, no. 12, p. S1.
9. Mishchenko, G.L. and Vatsuro, K.V., Sinteticheskie
metody organicheskoi khimii (Synthetic Methods in
Organic Chemistry), Moscow: Khimiya, 1982, p. 297.
1
1714 (C=O). H NMR spectrum, δ, ppm: 3.62 t (2H,
CH2N, J 4.42 Hz), 3.71 t (2H, NCH2, J 4.42 Hz), 3.99 t
(2H, OCH2, J 4.42 Hz), 4.25 t (2H, OCH2, J 4.42 Hz),
4.74 s (2H, CH2), 7.41 t (1H, Harom, J 8.01 Hz), 7.44 d
(1H, Harom, J 8.01 Hz), 7.63 t (1H, Harom, J 8.01 Hz),
7.92 d (1H, Harom, J 8.01 Hz), 8.36 s (1H, C5H,
thiazole), 8.73 s (1H, C5H, coumarine). Found, %: C
57.92, H 4.27, N 7.42. C18H16N2O3S2. Calculated, %: C
58.05, H 4.33, N 7.52.
10. Zil’berman, E.N., Reaktsii nitrilov (Reactions of Nit-
riles), Moscow: Khimiya, 1972.
11. USA Patent no. 6414013, 2002, Ref. Zh. Khim., 2003.
03.04 – 19O.63P.
12. USA Patent no. 7179836, 2007, Ref. Zh. Khim., 2007.
2-[2-(Morpholin-1-yl)-2-thioxoethylidene)thiazol-
idine-4-one (IX) was prepared analogously to com-
pound VII with 1.06 ml (10 mmol) of ethyl chloro-
acetate as alkylating agent. Yield 1.51 g (62%), yellow
crystals, mp 206–208°C (PrOH). IR spectrum, ν, cm–1:
07.21 – 19O.83P.
13. USA Patent no. 7423061, 2008, Ref. Zh. Khim., 2009.
09.04 – 19O.56P.
14. USA Patent no. 7138529, 2006, Ref. Zh. Khim., 2007.
07.21 – 19O.84P.
1
3302 (NH), 1700 (C=O). H NMR spectrum, δ, ppm:
15. Surikova, T.P., Zakharova, V.D., Mochalov, S.S., and
3.48 s (2H, SCH2), 3.68 m (4H, CH2NCH2), 3.92 m
(4H, CH2OCH2), 6.41 s (1H, CH=), 11.1 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 245 (100) [M + 1]+.
Found, %: C 44.13, H 4.81, N 11.32. C9H12N2O2S2.
Calculated, %: C 44.24, H 4.95, N 11.47.
Shabarov, Yu.S., Khim.-Farm. Zh., 1989, no. 7, p. 840.
16. North, A.C.T., Phillips, D.C., Scott, F., and Mathews, F.S.,
Acta Cryst., Part A, 1968, vol. 24, no. 2, p. 351.
17. Watkin, D.J., Prout, C.K., Carruthers, J.R., and
Betteridge, P.W., Crystals, no. 10, Oxford: University
of Oxford 1996.
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