Synthesis of N-aryl- and N,N-diethyl-9-methyl-11-sulfanylidene-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxamides

Article abstract of DOI:10.1134/S1070428016070174

Three-component condensation of N-aryl- and N,N-diethyl-3-oxobutanamides with salicylaldehyde and thiourea in ethanol in the presence of sodium hydrogen sulfate afforded N-aryl- and N,N-diethyl-9-methyl-11-sulfanylidene-8-oxa-10,12-diazatricyclo[7.3.1.0

Full text of DOI:10.1134/S1070428016070174

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 7, pp. 1022–1025. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © T.M. Zamaraeva, V.L. Gein, N.A. Buzmakova, M.V. Dmitriev, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 7, pp. 1028–1031.
Synthesis of N-Aryl- and N,N-Diethyl-9-methyl-
11-sulfanylidene-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-
2,4,6-triene-13-carboxamides
T. M. Zamaraevaa,* V. L. Geina, N. A. Buzmakovaa, and M. V. Dmitrievb
a Perm State Pharmaceutical Academy, Ministry of Health Protection of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
b Perm State National Research University, ul. Bukireva 15, Perm, 614990 Russia
Received March 10, 2016
Abstract—Three-component condensation of N-aryl- and N,N-diethyl-3-oxobutanamides with salicylaldehyde
and thiourea in ethanol in the presence of sodium hydrogen sulfate afforded N-aryl- and N,N-diethyl-9-methyl-
11-sulfanylidene-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxamides. Reaction of the
same compounds in the absence of a catalyst under solvent-free conditions gave N-aryl-6-(2-hydroxyphenyl)-4-
methyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimidine-5-carboxamides.
DOI: 10.1134/S1070428016070174
It is known that dihydropyrimidinones(thiones)
possessing an aryl substituent with a hydroxy group in
the ortho position can be converted into tricyclic struc-
tures with an oxygen bridge connecting the heterocycle
and the aryl substituent [1–4]. The formation of
9-methyl-11-oxo(sulfanylidene)-8-oxa-10,12-diazatri-
cyclo[7.3.1.02,7]trideca-2,4,6-triene derivatives to-
gether with 4-(2-hydroxyphenyl)pyrimidines in reac-
tions of β-ketoesters with salicylaldehyde and urea
(thiourea) in the presence of NaHSO4 was reported [5].
Three-component condensation of acetylacetone with
salicylaldehyde and urea (thiourea) in the presence of
NaHSO4 under microwave irradiation or on heating in
boiling ethanol in the presence of MnCl2 as catalyst led
to the formation of 13-acetyl-9-methyl-11-oxo(sul-
fanylidene)-8-oxa-10,12-diazatricyclo[7.3.1.02,7]tri-
deca-2,4,6-trienes as the only products [6, 7].
N-Aryl- and N,N-diethyl-3-oxobutanamides were
not involved in analogous three-component condensa-
tions. In some cases, N-aryl-3-oxobutanamides behave
differently from 3-oxobutanoic acid esters and acetyl-
acetone in multi-component reactions [9]. Further-
more, amide group is a pharmacophoric fragment [10].
While continuing studies in this line, N-aryl- and
N,N-diethyl-3-oxobutanamides were brought into
three-component condensation with salicylaldehyde
and thiourea on heating in ethanol (reaction time 1 h)
in the presence of sodium hydrogen sulfate as catalyst.
As a result, we isolated N-aryl- and N,N-diethyl-9-
methyl-11-sulfanylidene-8-oxa-10,12-diazatricyclo-
[7.3.1.02,7]trideca-2,4,6-triene-13-carboxamides 1a–1e
(Scheme 1). When the reaction was carried out under
the conditions described in [11, 12], we isolated
N-aryl-6-(2-hydroxyphenyl)-4-methyl-2-sulfanylidene-
1,2,3,6-tetrahydropyrimidine-5-carboxamides 2a–2d.
We failed to isolate analogous N,N-diethyl derivative
in the reaction with N,N-diethyl-3-oxobutanamide.
Biological screening of 9-methyl-11-oxo(sulfanyli-
dene)-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-
2,4,6-triene derivatives showed prospects of using
them as calcium channel blockers with prolonged anti-
arrhythmic and antianginal effects on cardiac muscle
and antihypertensive and spasmolytic effects on brain
vessels [1, 8]. Therefore, synthesis of new potentially
biologically active compounds of this series seems to
be important.
Compounds 1a–1e and 2a–2d are colorless or
slightly colored crystalline substances soluble in DMF,
DMSO, acetic acid, and acetone and insoluble in
water. Unlike 2a–2d, compounds 1a–1e showed
a negative color test for enolic hydroxy group on treat-
ment with an alcoholic solution of iron(III) chloride.
1022

SYNTHESIS OF N-ARYL- AND N,N-DIETHYL-9-METHYL-11-SULFANYLIDENE-...
1023
Scheme 1.
O
Me
8
O
9
R1R2N
10NH
NaHSO4, EtOH
78°C, 1 h
7
11
12
1
6
N
H
S
2
3
5
O
O
S
4
CHO
OH
1a–1e
R1
+
+
Me
N
H2N
NH2
O
Me
R2
R1R2N
No solvent
120–150°C, 5–10 min
OH
NH
N
H
S
2a–2d
R1 = H, R2 = Ph (a), 2-MeC6H4 (b), 2-MeOC6H4 (c), 2-ClC6H4 (d); R1 = R2 = Et (e).
introduced as solutions in water–acetonitrile–formic
acid (49.95:50:0.05); electrospray ionization, positive
ion detection; 150°C; capillary voltage 3500–4000 V;
cone voltage 20–80 V. The elemental analyses were
obtained on a Perkin Elmer 2400 analyzer. The melting
points were determined on an M-565 melting point
apparatus.
The mass spectra of 1a–1d contained the molecular ion
peaks with m/z values consistent with the proposed
structures (see Experimental).
The structure of 1e was determined by X-ray
analysis of a single crystal which was obtained by slow
crystallization from ethanol (see figure). Compound 1e
crystallized in centrosymmetric space group belonging
to the monoclinic crystal system. All bond lengths and
bond angles in molecule 1e are close to the corre-
sponding reference values. The dihydropyran and
hexahydropyrimidine rings appear in sofa conforma-
tion. The dihedral angle formed by the two planar
fragments C7C1C2O1C9 and C7N1C11N2C9 is 69.6°, and
the angles between the C7N1C11N2C9 and C7C8C9
planes and between the C7C1C2O1C9 and C7C8C9
planes are 52.4 and 58.2°, respectively. Molecules 1e
in crystal are linked through intermolecular hydrogen
bonds N1–H1···O2 [x, 0.5 – y, 0.5 + z; N1–H1 0.82(2),
N1 ···O2 2.805(2), H1 ···O2 2.16(2) Å, ∠N1H1O2
136(2)°] to form infinite chains along the c crystallo-
graphic axis. The X-ray diffraction data for compound
1e were deposited to the Cambridge Crystallographic
Data Centre (entry no. CDDC 1 453 995) and are
available at www.ccdc.cam.ac.uk.
The X-ray diffraction data for compound 1e were
acquired on an Xcalibur R diffractometer with a CCD
detector [MoKα radiation, 295(2) K, ω-scanning with
a step of 1°] according to standard procedure [13].
C14
C16
C13
C15
N3
C6
C12
N1
C7
C5
O2
C1
C8
C9
C4
C11
C2
S1
N2
C3
EXPERIMENTAL
O1
C10
The IR spectra were recorded in KBr on a Specord
1
M-80 spectrometer. The H NMR spectra were
measured on a Bruker 500 instrument at 500.13 MHz
using DMSO-d6 as solvent and tetramethylsilane as
internal standard. The mass spectra were obtained
using a Waters Acquity UPLC I-Class instrument
equipped with a Xevo TQD detector; samples were
Structure of the molecule of N,N-diethyl-9-methyl-11-sul-
fanylidene-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-
triene-13-carboxamide (1e) according to the X-ray diffrac-
tion data. Non-hydrogen atoms are shown as thermal vibra-
tion ellipsoids with a probability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

ZAMARAEVA et al.
1024
A correction for absorption was applied by the
SCALE3 ABSPACK algorithm [13]. Monoclinic
crystal system, space group P21/c; unit cell parameters:
a = 9.6764(13), b = 18.556(3), c = 9.1490(13) Å; β =
95.519(13)°; V = 1635.1(4) Å3; Z = 4. The structure
was solved by the direct method and was refined by
the full-matrix least-squares method in anisotropic
approximation for all non-hydrogen atoms. Hydrogen
atoms were placed in geometrically calculated posi-
tions and were refined according to the riding model in
isotropic approximation with dependent thermal
parameters, except for NH hydrogens which were
refined independently in isotropic approximation. The
structure was solved and refined using SHELXS and
SHELXL packages [14]. Final divergence factors:
R1 = 0.0419, wR2 = 0.1101 [3267 reflections with
I > 2σ(I)]; R1 = 0.0502, wR2 = 0.1157 (3845 indepen-
dent reflections); goodness of fit S = 1.049; Δρ =
0.285/–0.341 ēÅ–3.
N-(2-Methoxyphenyl)-9-methyl-11-sulfanyli-
dene-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-
2,4,6-triene-13-carboxamide (1c). Yield 2.98 g
(81%), mp 200–202°C. IR spectrum, ν, cm-1: 3300,
1
3270, 3200 (NH), 1670 (C=O), 1608 (C=C). H NMR
spectrum, δ, ppm: 1.75 s (3H, 9-CH3), 3.38 m (1H,
13-H), 3.74 s (3H, CH3O), 4.46 d.d (1H, 1-H, J = 2.8,
2.7 Hz), 6.66–7.15 m (8H, Harom), 8.90 s (1H, 10-H),
9.04 d (1H, 12-H, J = 2.7 Hz), 9.25 s (1H, CONH).
Mass spectrum: m/z 369 [M]+. Found, %: C 61.66,
61.89; H 5.08, 5.26; N 11.25, 11.50. C19H19N3O3S.
Calculated, %: C 61.77; H 5.18; N 11.37.
N-(2-Chlorophenyl)-9-methyl-11-sulfanylidene-
8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-
triene-13-carboxamide (1d). Yield 3.39 g (91%),
mp 239–240°C. IR spectrum, ν, cm–1: 3352, 3250,
1
3200 (NH), 1672 (C=O), 1592 (C=C). H NMR spec-
trum, δ, ppm: 1.75 s (3H, 9-CH3), 3.37 m (1H, 13-H),
4.60 d.d (1H, 1-H, J = 2.8, 3.0 Hz), 6.72–7.42 m (8H,
9-Methyl-N-phenyl-11-sulfanylidene-8-oxa-
10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-
carboxamide (1a). A mixture of 0.01 mol of 3-oxo-N-
phenylbutanamide, 0.01 mol of salicylaldehyde,
0.01 mol of thiourea, and 0.008 mol of sodium hydro-
gen sulfate in 15 mL of ethanol was refluxed for 1 h.
After cooling, the precipitate was filtered off and re-
crystallized from ethanol. Yield 2.98 g (88%), mp 214–
216°C. IR spectrum, ν, cm–1: 3312, 3208 (NH), 1672
(C=O), 1590 (C=C). 1H NMR spectrum, δ, ppm: 1.76 s
(3H, 9-CH3), 3.17 m (1H, 13-H), 4.60 d.d (1H, 1-H,
J = 2.8, 3.1 Hz), 6.74–7.54 m (9H, Harom), 8.97 s (1H,
10-H), 8.92 d (1H, 12-H, J = 2.7 Hz), 10.06 s (1H,
CONH). Mass spectrum, m/z: 339 [M]+, 262 [M – Ph]+.
Found, %: C 63.57, 63.82; H 4.97, 5.14; N 12.24,
12.51. C18H17N3O2S. Calculated, %: C 63.70; H 5.05;
N 12.38.
H
arom), 8.94 s (1H, 10-H), 9.67 d (1H, 12-H, J =
2.8 Hz), 9.70 s (1H, CONH). Mass spectrum: m/z 373
[M]+. Found, %: C 57.72, 57.96; H 4.22, 4.40; N 11.12,
11.37. C18H16ClN3O2S. Calculated, %: C 57.83;
H 4.31; N 11.24.
N,N-Diethyl-9-methyl-11-sulfanylidene-8-oxa-
10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-
carboxamide (1e). Yield 2.05 g (64%), mp 225–
227°C. IR spectrum, ν, cm–1: 3300, 3280 (NH), 1670
(C=O), 1590 (C=C). 1H NMR spectrum, δ, ppm: 1.06 t
and 1.13 t (3H each, CH3CH2, J = 6.8 Hz), 3.38 m
(4H, CH3CH2), 1.69 s (3H, 9-CH3), 3.28 m (1H,
13-H), 4.40 d.d (1H, 6-H, J = 2.0, 3.2 Hz), 6.83–
7.19 m (4H, Harom), 9.05 s (1H, 10-H), 9.10 d (1H,
12-H, J = 2.8 Hz). Found, %: C 60.04, 60.29; H 6.54,
6.70; N 13.03, 13.28. C16H21N3O2S. Calculated, %:
C 60.16; H 6.63; N 13.15.
Compounds 1b–1e were synthesized in a similar
way.
6-(2-Hydroxyphenyl)-4-methyl-N-phenyl-2-sul-
fanylidene-1,2,3,6-tetrahydropyrimidine-5-carbox-
amide (2a). A mixture of 0.01 mol of acetoacetanilide,
0.01 mol of salicylaldehyde, and 0.01 mol of thiourea
was heated for 5–10 min at 120–150°C until gas no
longer evolved. The mixture was cooled and treated
with ethanol, and the precipitate was filtered off and
recrystallized from ethanol. Yield 2.58 g (76%),
mp 261–263°C. IR spectrum, ν, cm–1: 3290, 3200
9-Methyl-N-(2-methylphenyl)-11-sulfanylidene-
8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-
triene-13-carboxamide (1b). Yield 3.00 g (85%),
mp 262–264°C. IR spectrum, ν, cm–1: 3200, 3296,
1
3280 (NH), 1664 (C=O), 1580 (C=C). H NMR spec-
trum, δ, ppm: 1.76 s (3H, 9-CH3), 2.21 s (3H,
CH3C6H4), 3.35 m (1H, 13-H), 4.61 d.d (1H, 1-H, J =
2.7, 3.1 Hz), 6.74–7.39 m (8H, Harom), 8.95 s (1H,
10-H), 9.02 d (1H, 12-H, J = 2.7 Hz), 9.41 s (1H,
CONH). Mass spectrum: m/z 353 [M]+. Found, %:
C 64.46, 64.69; H 5.34, 5.52; N 11.76, 12.02.
C19H19N3O2S. Calculated, %: C 64.57; H 5.42; N 11.89.
1
(NH), 3150 (OH), 1670 (C=O), 1590 (C=C). H NMR
spectrum, δ, ppm: 1.75 s (3H, 4-CH3), 4.60 d (1H, 6-H,
J1,6 = 2.8 Hz), 6.74–7.53 m (10H, Harom, OH), 8.88 d
(1H, 1-H, J1,6 = 2.8 Hz), 8.94 s and 8.95 s (1H, 3-H,
2-SH), 10.03 s (1H, CONH). Found, %: C 63.57,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

SYNTHESIS OF N-ARYL- AND N,N-DIETHYL-9-METHYL-11-SULFANYLIDENE-...
1025
63.83; H 4.95, 5.13; N 12.26, 12.49. C18H17N3O2S.
Calculated, %: C 63.70; H 5.05; N 12.38.
3-H, 2-SH), 9.69 s (1H, CONH). Found, %: C 57.70,
57.94; H 4.23, 4.41; N 11.11, 11.36. C18H16ClN3O2S.
Calculated, %: C 57.83; H 4.31; N 11.24.
Compounds 2b–2d were synthesized in a similar
way.
REFERENCES
6-(2-Hydroxyphenyl)-4-methyl-N-(2-methyl-
phenyl)-2-sulfanylidene-1,2,3,6-tetrahydropyrimi-
dine-5-carboxamide (2b). Yield 2.58 g (73%),
mp 260–262°C. IR spectrum, ν, cm–1: 3400, 3380,
3210 (NH), 3096 (OH), 1664 (C=O), 1592 (C=C).
1H NMR spectrum, δ, ppm: 1.76 s (3H, 4-CH3), 2.21 s
(3H, CH3C6H4), 4.63 d (1H, 6-H, J1,6 = 2.8 Hz), 6.75–
1. El-Hamouly, W.S., El-Khamry, A.-M.A., and
Abbas, E.M.H., Indian J. Chem., Sect. B, 2006, vol. 45,
p. 2091.
2. Kappe, C.O., Tetrahedron, 1993, vol. 49, p. 6937.
3. Rehani, R., Shah, A.C., and Arya, V.P., Indian J. Chem.,
Sect. B, 1994, vol. 33, p. 775.
7.41 m (9H, Harom, OH), 8.93 d (1H, 1-H, J1,6
=
4. Kurbanova, M.M., Russ. J. Org. Chem., 2010, vol. 46,
2.8 Hz), 8.95 s and 8.96 s (1H, 3-H, 2-SH), 9.40 s (1H,
CONH). Found, %: C 64.44, 64.68; H 5.33, 5.50;
N 11.77, 12.00. C19H19N3O2S. Calculated, %: C 64.57;
H 5.42; N 11.89.
p. 599.
5. Cheng Qingfang, Wang Qifa, Xu Xingyou, Ruan
Mingjie, Yao Hailun, and Yang Xujie, J. Heterocycl.
Chem., 2010, vol. 47, p. 624.
6. Cheng Qingfang, Wang Qifa, Tan Tin, Chen Na, and
6-(2-Hydroxyphenyl)-N-(2-methoxyphenyl)-
4-methyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimi-
dine-5-carboxamide (2c). Yield 2.58 g (70%),
mp 247–249°C. IR spectrum, ν, cm–1: 3390, 3340,
3200 (NH), 3150 (OH), 1672 (C=O), 1590 (C=C).
1H NMR spectrum, δ, ppm: 1.73 s (3H, 4-CH3), 3.78 s
(3H, CH3O), 4.51 d (1H, 6-H, J1,6 = 2.1 Hz), 6.73–
Shuai Mei, J. Heterocycl. Chem., 2012, vol. 49, p. 1352.
7. Kulakov, I.V., Talipov, S.A., Shulgau, Z.T., and
Seilkhanov, T.M., Chem. Heterocycl. Compd., 2014,
vol. 50, no. 10, p. 1477.
8. Baldwin, J.J., Claremon, D.A., and McClure, D.E., US
Patent no. 4609494, 1986.
9. Gein, V.L., Yankin, A.N., Nosova, N.V., Dmitriev, M.V.,
and Nasakin, O.E., Russ. J. Gen. Chem., 2016, vol. 86,
p. 58.
7.96 m (9H, Harom, OH), 8.92 d (1H, 1-H, J1,6
=
2.1 Hz), 8.94 s and 8.96 s (1H, 3-H, 2-SH), 9.41 s (1H,
CONH). Found, %: C 61.65, 61.87; H 5.10, 5.28;
N 11.24, 11.49. C19H19N3O3S. Calculated, %: C 61.77;
H 5.18; N 11.37.
10. Mashkovskii, M.D., Lekarstvennye sredstva (Medi-
cines), Moscow: Novaya Volna, 2012, 16th ed.
11. Gein, V.L., Zamaraeva, T.M., Zorina, A.A., and Vakh-
N-2-(Chlorophenyl)-6-(2-hydroxyphenyl)-
4-methyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimi-
dine-5-carboxamide (2d). Yield 2.94 g (79%),
mp 225–227°C. IR spectrum, ν, cm–1: 3360, 3280,
3200 (NH), 3025 (OH), 1680 (C=O), 1600 (C=C).
1H NMR spectrum, δ, ppm: 1.76 s (3H, 4-CH3), 4.62 d
(1H, 6-H, J1,6 = 1.9 Hz), 6.75–7.71 m (9H, Harom, OH),
8.93 d (1H, 1-H, J1,6 = 1.9 Hz), 8.95 s and 8.96 s (1H,
rin, M.I., Russ. J. Org. Chem., 2009, vol. 45, p. 1581.
12. Gein, V.L., Kholkin, I.V., Zamaraeva, T.M., Vakh-
rin, M.I., and Voronina, E.V., Pharm. Chem. J., 2012,
vol. 46, no. 2, p. 114.
13. CrysAlisPro, Version 1.171.37.33 (release 27-03-2014
CrysAlis171 .NET), Agilent Technologies.
14. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008,
vol. 64, p. 112.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016