Synthesis of N-Aryl- and N,N-diethyl-2-methyl-3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazocine-11-carboxamides

Article abstract of DOI:10.1134/S1070428017010158

N-Aryl- and N,N-diethyl-3-oxobutanamides reacted with salicylaldehyde and N-phenylthiourea in ethanol in the presence of sodium hydrogen sulfate as catalyst to give the corresponding N-substituted 2-methyl-3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,

Full text of DOI:10.1134/S1070428017010158

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 1, pp. 86–89. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, N.A. Buzmakova, M.V. Dmitriev, O.E. Nasakin, M. I. Kazantseva, 2017, published in Zhurnal
Organicheskoi Khimii, 2017, Vol. 53, No. 1, pp. 90–93.
Synthesis of N-Aryl- and N,N-Diethyl-2-methyl-
3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-
1,3,5-benzoxadiazocine-11-carboxamides
V. L. Gein,a* T. M. Zamaraevaa, N. A. Buzmakovaa, M. V. Dmitrievb,
O. E. Nasakinc, and M. I. Kazantsevac
a Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
b Perm National State Research University, ul. Bukireva 15, Perm, 614990 Russia
c I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
Received June 4, 2016
Abstract—N-Aryl- and N,N-diethyl-3-oxobutanamides reacted with salicylaldehyde and N-phenylthiourea in
ethanol in the presence of sodium hydrogen sulfate as catalyst to give the corresponding N-substituted
2-methyl-3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazocine-11-
carboxamides.
DOI: 10.1134/S1070428017010158
It is known that some N-substituted dihydropyri-
midin-2-ones and -thiones exhibit a higher biological
activity than their N-unsubstituted analogs [1]. Cardio-
vascular agents promising as antihypertensive drugs
and vasodilators were found among 3-substituted dihy-
dropyrimidines, in particular 3-alkyl, 3-acyl [2, 3], and
3-sulfanyl derivatives [4]. 3-Phenacyl-substituted dihy-
dropyrimidines showed anti-inflammatory activity [5],
and 3-carbamoyl derivatives were reported to exhibit
high antimalarial activity [6]. 1-Alkyl-substituted dihy-
dropyrimidines are known as antitumor and antiviral
agents [7–10], while 1-aryl- [11] and 1-methyl deriva-
tives [12] displayed antimycobacterial activity.
Although a large number of compounds possessing
practically important properties have been found in the
series of N-substituted dihydropyrimidines, the synthe-
sis of new potentially biologically active represen-
tatives of this class of compounds remains topical.
Cheng et al. [13, 14] described the three-component
reaction of acetylacetone (β-keto esters) with salicylal-
dehyde and N-phenylurea in the presence of NaHSO4,
which afforded 9-methyl-10-phenyl-11-oxo-8-oxa-
10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene
derivatives (2-methyl-4-oxo-3-phenyl-3,4,5,6-tetra-
hydro-2H-2,6-methano-1,3,5-benzoxadiazocines).
While continuing studies in this line we examined the
three-component condensation of N-aryl- and N,N-di-
ethyl-3-oxobutanamides with salicylaldehyde and
N-phenylthiourea. The reactions were carried out by
heating the reactants in boiling ethanol for 1 h in the
presence of NaHSO4 as catalyst. The only products
were N-substituted 2-methyl-3-phenyl-4-sulfanyli-
Scheme 1.
O
1
O
Me
O
O
CHO
OH
R1R2N
2
NaHSO4
S
3N
R1
11
+
+
6
4
Me
N
5
N
H
10
H2N
N
S
R2
H
7
9
8
1a–1f
R1 = H, R2 = Ph (a), 2-MeC6H4 (b), 2,4-Me2C6H3 (c), 2-MeOC6H4 (d), 2-ClC6H4 (e); R1 = R2 = Et (f).
86

SYNTHESIS OF N-ARYL- AND N,N-DIETHYL-2-METHYL-3-PHENYL-...
87
dene-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benz-
oxadiazocine-11-carboxamides 1a–1f (Scheme 1).
C16
C17
C15
C14
Compounds 1a–1f were isolated as colorless or
weakly colored crystalline solids which were soluble
in DMF, DMSO, acetic acid, and acetone and insoluble
in water. The IR spectra of 1a–1f contained absorption
bands due to stretching vibrations of the amide
carbonyl group (1664–1680 cm–1), N–H bonds (3150–
3392 cm–1), and C=C bonds (1588–1600 cm–1). Apart
from signals of protons in the aromatic rings and sub-
stituents therein, compounds 1a–1f characteristically
C18
C19
C13
N1
O3
C12
O1
N2
C4
C3
S1
1
showed in the H NMR spectra a singlet at δ 1.35–
C5
1.45 ppm from the 2-methyl group, a multiplet signal
at δ 3.50–3.74 ppm from 11-H, a doublet of doublets at
δ 4.42–4.75 ppm (J = 1.0–2.7, 1.8–3.8 Hz) from 6-H,
a doublet at δ 9.13–9.37 ppm (J = 2.8–5.6 Hz) from
5-H, a singlet at δ 9.12–9.85 ppm from the amide NH
proton (1a–1e), and multiplet signals at about δ 1.11
and 3.41 ppm due to ethyl groups on the amide nitro-
gen atom of 1f. Compounds 1a–1f showed a negative
color test for enolic hydroxy group on treatment with
a solution of iron(III) chloride. In the mass spectrum of
1e we observed the molecular ion peak with m/z 450,
which is consistent with the proposed structure.
C1
N3
C21
C11
C10
C20
C22
C7
C2
C3
C25
O2
C23
C9
C8
C24
Structure of the molecule of N-(2-methoxyphenyl)-2-methyl-
3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-
methano-1,3,5-benzoxadiazocine-11-carboxamide (1d) ac-
cording to the X-ray diffraction data.
N–H···S and N–H···O intermolecular hydrogen
bond system.
The structure of 1d in crystal was unambiguously
determined by X-ray analysis of its single crystal
obtained by slow crystallization from a solution in
ethanol (see figure). Compound 1d crystallized in
centrosymmetric space group belonging to the mono-
clinic crystal system with a unit cell containing four
crystallographically independent molecules. Figure
shows one independent molecule; atoms of the other
molecules are numbered with an additional index, A,
B, or C. The pyran and pyrimidine rings in all indepen-
dent molecules adopt a conformation intermediate
between sofa and half-chair. The C5 and C1 atoms
deviate from the plane formed by the other four atoms
of the pyran ring by 0.63–0.67 and 0.15–0.18 Å,
respectively, in opposite directions. Likewise, the py-
rimidine atoms C5 and C4 deviate from the C1N1C6N2
plane by 0.52–0.56 and 0.24–0.29 Å, respectively, in
opposite directions. The phenyl substituent is turned
through an angle of ~90° with respect to the pyrimi-
dine ring plane. The arylcarbamoyl substituents are not
planar: the absolute values of the torsion angle
C12N3C13C14 which characterize rotation of the me-
thoxyphenyl group with respect to the carbamoyl frag-
ment range from 39 to 43°. Molecules 1d in crystal are
linked to form infinite two-dimensional networks
parallel to the (001) plane through a developed
The X-ray diffraction data for compound 1d were
deposited to the Cambridge Crystallographic Data
Centre (www.ccdc.cam.ac.uk; CCDC entry
no. 1479266).
EXPERIMENTAL
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 on
a Waters Acquity UPLC I-Class instrument coupled
with a Xevo TQD detector (electrospray ionization,
positive ion detection, capillary voltage 3500–4000 V,
cone voltage 20–80 V, temperature 150°C; samples
were introduced as solutions in water–acetonitrile–
formic acid, 49.95:50.00:0.05). The elemental com-
positions were determined with a Perkin Elmer 2400
analyzer. The melting points were measured on
an M-565 melting point apparatus.
The X-ray diffraction data for compound 1d were
acquired on an Xcalibur R single crystal diffractometer
(monochromatized MoKα radiation, ω-scanning) from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017

GEIN et al.
88
a fragment of a colorless plate crystal using
CrysAlisPro software package [15]. Monoclinic crystal
system, space group P21/n; C25H23N3O3S; unit cell
parameters: a = 20.986(3), b = 18.1649(17), c =
25.727(3) Å; β = 110.099(15)°; V = 9210(2) Å3;
M 445.52; dcalc = 1.285 g/cm3; Z = 16. Total of 69535
reflection intensities were measured, including 22602
independent reflections and 12265 reflections with
I > 2σ(I). A correction for absorption was applied
empirically by the SCALE3 ABSPACK algorithm
[15]. The structure was solved by the direct method
and was refined by the full-matrix least-squares
method in anisotropic approximation for all non-hy-
drogen atoms. Hydrogen atoms of the NH groups were
localized from the difference Fourier maps, and their
positions were refined independently in isotropic
approximation. The other hydrogens were refined
according to the riding model in isotropic approxima-
tion. All calculations were performed using SHELXL
[16] and OLEX2 [17]. Final divergence factors: R1 =
0.0688, wR2 = 0.1492 [reflections with I > 2σ(I)]; R1 =
0.1395, wR2 = 0.1942 (all independent reflections);
goodness of fit S = 1.028.
C 69.80, 70.02; H 5.31, 5.50; N 9.66, 9.91.
C25H23N3O2S. Calculated, %: C 69.91; H 5.40; N 9.78.
N-(2,4-Dimethylphenyl)-2-methyl-3-phenyl-4-
sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-
1,3,5-benzoxadiazocine-11-carboxamide (1c). Yield
3.50 g (79%), mp 230–232°C. IR spectrum, ν, cm–1:
1
3272, 3150 (NH), 1664 (C=O), 1592 (C=C). H NMR
spectrum, δ, ppm: 1.42 s (3H, 2-CH3), 2.21 s and
2.25 s (3H each, Me2C6H3), 3.50 m (1H, 11-H),
4.70 d.d (1H, 6-H, J = 1.8, 1.0 Hz), 6.87–7.23 m
(12H, Harom), 9.29 d (1H, 5-H, J = 2.8 Hz), 9.42 s
(1H, CONH). Found, %: C 70.29, 70.52; H 5.60, 5.77;
N 9.36, 9.60. C26H25N3O2S. Calculated, %: C 70.40;
H 5.68; N 9.47.
N-(2-Methoxyphenyl)-2-methyl-3-phenyl-4-sul-
fanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-
1,3,5-benzoxadiazocine-11-carboxamide (1d). Yield
3.38 g (76%), mp 214–215°C. IR spectrum, ν, cm–1:
1
3392, 3200 (NH), 1680 (C=O), 1600 (C=C). H NMR
spectrum, δ, ppm: 1.39 s (3H, 2-CH3), 3.79 s (3H,
CH3O), 3.74 m (1H, 11-H), 4.65 d.d (1H, 6-H, J = 2.8,
1.8 Hz), 6.83–8.05 m (13H, Harom), 9.28 d (1H, 5-H,
J = 4.6 Hz), 9.56 s (1H, CONH). Found, %: C 67.29,
67.52; H 5.12, 5.29; N 9.31, 9.56. C25H23N3O3S. Cal-
culated, %: C 67.40; H 5.20; N 9.43.
Compounds 1a–1f (general procedure). A mixture
of 10 mmol of acetoacetamide, 10 mmol of salicyl-
aldehyde, and 15 mmol of N-phenylthiourea in 15 mL
of ethanol containing 8 mmol of sodium hydrogen
sulfate was heated for 1 h under reflux. After cooling,
the precipitate was filtered off and recrystallized from
ethanol.
N-(2-Chlorophenyl)-2-methyl-3-phenyl-4-sul-
fanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-
1,3,5-benzoxadiazocine-11-carboxamide (1e). Yield
4.00 g (89%), mp 225–227°C. IR spectrum, ν, cm–1:
1
3384, 3190 (NH), 1680 (C=O), 1588 (C=C). H NMR
2-Methyl-N,3-diphenyl-4-sulfanylidene-3,4,5,6-
tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazo-
cine-11-carboxamide (1a). Yield 3.49 g (84%),
mp 210–212°C. IR spectrum, ν, cm–1: 3304, 3200
(NH), 1672 (C=O), 1596 (C=C). 1H NMR spectrum, δ,
ppm: 1.41 s (3H, 2-CH3), 3.71 m (1H, 11-H), 4.66 d.d
(1H, 6-H, J = 1.8, 3.8 Hz), 6.89–8.08 m (14H, Harom),
9.32 d (1H, 5-H, J = 5.6 Hz), 9.59 s (1H, CONH).
Found, %: C 69.25, 69.50; H 5.00, 5.17; N 10.00,
10.24. C24H21N3O2S. Calculated, %: C 69.38; H 5.09;
N 10.11.
spectrum, δ, ppm: 1.43 s (3H, 2-CH3), 3.64 m (1H,
11-H), 4.74 d.d (1H, 6-H, J = 2.7, 1.9 Hz), 6.82–
7.77 m (13H, Harom), 9.35 d (1H, 5-H, J = 4.6 Hz),
9.85 s (1H, CONH). Found, %: C 63.95, 64.18;
H 4.38, 4.57; N 9.22, 9.47. C24H20ClN3O2S. Calculat-
ed, %: C 64.06; H 4.48; N 9.34.
N,N-Diethyl-2-methyl-3-phenyl-4-sulfanylidene-
3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxa-
diazocine-11-carboxamide (1f). Yield 2.46 g (62%),
1
mp 196–198°C. H NMR spectrum, δ, ppm: 1.11 m
(6H, CH3CH2), 3.41 m (4H, CH3CH2), 1.35 s (3H,
2-CH3), 3.59 m (1H, 11-H), 4.42 d.d (1H, 6-H, J = 1.7,
2.1 Hz), 6.87–7.27 m (9H, Harom), 9.13 d (1H, 5-H,
J = 3.8 Hz). Found, %: C 66.36, 66.59; H 6.77, 6.94;
N 10.46, 10.70. C22H27N3O2S. Calculated, %: C 66.47;
H 6.85; N 10.57.
2-Methyl-N-(2-methylphenyl)-3-phenyl-4-sul-
fanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-
1,3,5-benzoxadiazocine-11-carboxamide (1b). Yield
3.48 g (81%), mp 226–228°C. IR spectrum, ν, cm–1:
1
3328, 3240 (NH), 1680 (C=O), 1592 (C=C). H NMR
spectrum, δ, ppm: 1.45 s (3H, 2-CH3), 2.25 s (3H,
CH3C6H4), 3.55 m (1H, 11-H), 4.75 d.d (1H, 6-H, J =
2.7, 2.8 Hz), 6.82–7.47 m (13H, Harom), 9.37 d (1H,
5-H, J = 5.5 Hz), 9.54 s (1H, CONH). Found, %:
This study was performed under financial support
by the Russian Science Foundation (project no. 15-13-
10029).
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SYNTHESIS OF N-ARYL- AND N,N-DIETHYL-2-METHYL-3-PHENYL-...
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9. Wisen, S., Androsavch, J., Evans, C.G., Chang, L., and
Gestwickli, J.E., Bioorg. Med. Chem. Lett., 2008,
vol. 18, p. 60.
REFERENCES
1. Cho, H., Ueda, M., Shima, K., Mizuno, A., Hayashi-
matsu, M., Ohnaka, Y., Takeuchi, Y., Hamaguchi, M.,
Aisaka, K., Hidaka, T., Kawai, M., Takeda, M., Ishi-
hara, T., Funahashi, K., Satoh, F., Morita, M., and
Noguchi, T., J. Med. Chem., 1989, vol. 32, p. 2399.
2. Atwal, K.S., Rovnyak, G.C., Kimball, S.D., Floyd, D.M.,
Moreland, S., Swanson, B.N., Gougoutas, J.Z.,
Schwartz, J., Smillie, K.M., and Malley, M.F., J. Med.
Chem., 1990, vol. 33, p. 2629.
10. Fewell, S.W., Smith, C.M., Lyon, M.A., Dumit-
rescu, T.P., Wipf, P., Day, B.W., and Brodsky, J.L.,
J. Biol. Chem., 2004, vol. 279, p. 51131.
11. Zalavadiya, P., Tala, S., Akbari, J., and Joshi, H., Arch.
Pharm. Chem. Life Sci., 2009, vol. 342, p. 469.
12. Zamaraeva, T.M., Odegova, T.F., Fedotov, A.Yu.,
Tomilov, M.V., Gein, V.L., and Slepukhin, P.A., Russ. J.
Gen. Chem., 2014, vol. 84, p. 1950.
3. Atwal, K.S., Swanson, B.N., Unger, S.E., Floyd, D.M.,
Moreland, S., Hedberg, A., and O’Reilly, B.C., J. Med.
Chem., 1991, vol. 34, p. 806.
13. Cheng, Q.F., Wang, Q.F., Xu, X.Y., Ruan, M.J.,
Yao, H.L., and Yang, X.J., J. Heterocycl. Chem., 2010,
vol. 47, p. 624.
4. Atwal, K., US Patent no. 4684656, 1987.
14. Cheng, Q.F., Wang, Q.F., Tan, T., Chen, N.,
and Shuai, M., J. Heterocycl. Chem., 2012, vol. 49,
p. 1352.
5. Chikhale, R.V., Bhole, R.P., Khedekar, P.B., and
Brusari, K.P., Eur. J. Med. Chem., 2009, vol. 44, p. 3645.
6. October, N., Watermeyer, N.D., Yardley, V., Egan, T.J.,
Ncokazi, K., and Chibale, K., MedChemMed, 2008,
vol. 3, p. 1649.
15. CrysAlisPro, Version 1.171.37.33 (release 27-03-2014
CrysAlis171.NET), Agilent Technologies.
16. Sheldrick, G.M., Acta Crystallogr., Sect. C, 2015,
7. Prokopcova, H., Dallinger, D., Uray, G., Kaan, H.Y.K.,
Ulaganathan, V., Kozielski, F., Laggner, C., and
Kappe, C.O., ChemMedChem, 2010, vol. 5, p. 1760.
8. Evans, C.G., Wisen, S., and Gestwickli, J.E., J. Biol.
Chem., 2006, vol. 281, p. 33182.
vol. 71, p. 3.
17. Dolomanov, O.V., Bourhis, L.J., Gildea, R.J.,
Howard, J.A.K., and Puschmann, H., J. Appl.
Crystallogr., 2009, vol. 42, p. 339.
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