Ring formation and ring opening reactions of a dihydrothiadiazine cycle fused to 1,2,4-triazole

Article abstract of DOI:10.1016/j.mencom.2008.09.008

A new method of dihydrothiadiazine cycle annelation to 1,2,4-triazole derivatives is suggested and a ring opening reaction of the obtained dihydrothiadiazine cycle is found, leading to a substituted desoxybenzoine; the structures of both reaction products are supported by X-ray analysis.

Full text of DOI:10.1016/j.mencom.2008.09.008

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 253–254
Ring formation and ring opening reactions of
a dihydrothiadiazine cycle fused to 1,2,4-triazole
Alexandra A. Kolodina,*a Alexandr V. Lesina and Yulia V. Nelyubinab
a Department of Chemistry, Southern Federal University, 344090 Rostov-on-Don, Russian Federation.
E-mail: lexandra@inbox.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2008.09.008
A new method of dihydrothiadiazine cycle annelation to 1,2,4-triazole derivatives is suggested and a ring opening reaction of the
obtained dihydrothiadiazine cycle is found, leading to a substituted desoxybenzoine; the structures of both reaction products are
supported by X-ray analysis.
Recently,1 we reported a new intramolecular cyclization of
S-methylene derivatives of N-imidazolylimines giving 3,4-di-
hydro-2H-imidazo[2,1-b][1,3,4]thiadiazines through the C–C
bond formation at thiadiazine ring closing. Here we show that
a similar reaction with 4-amino-3-nitrobenzylthio-1,2,4-triazole
derivatives can be used as a new route for the synthesis of
6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines. High
interest in the fused triazolo[3,4-b][1,3,4]thiadiazine systems
is stimulated by their broad biological activity, whereas their
syntheses are mainly based on the cyclocondensation of 5-sub-
stituted 4-amino-1,2,4-triazole-3-thiones with α-halocarbonyl
compounds.2
By the condensation of 5-substituted 4-amino-3-nitrobenzyl-
thio-1,2,4-triazoles 1a–c† with benzaldehydes under base catalysis
conditions, triazolo[3,4-b][1,3,4]thiadiazines 2‡ were obtained
(Scheme 1). This method of formation of 6,7-dihydro-5H-
1,2,4-triazolo[3,4-b][1,3,4]thiadiazines has not been described
before.
The structure of compound 2b was confirmed by X-ray
analysis§ (Figure 1). According to X-ray diffraction (XRD)
studies, 2b crystallizes in centrosymmetric space group (C2/c)
with a different configuration of the asymmetric atoms resulting
in the presence of two corresponding enantiomers in the crystal.
The examination of molecular geometry revealed that the bond
lengths and angles do not significantly deviate from the typical
values accepted for them. The conformation of the thiadiazine
cycle in 3 can be described as a slightly distorted sofa with the
C(6) atom deviating by 0.64 Å from the plane formed by other
atoms of the cycle. The aromatic substituents at the chiral C(6)
and C(7) atoms are both in the equatorial position relative to
the mean plane of the thiadiazine fragment; the angles between
the latter and the C(6)–C(16) and C(7)–C(23) bond lines are
91(1) and 114(1)°, respectively.
‡
General procedure for the synthesis of 2a–c. Equimolar quantities
(5 mmol) of compound 1 and aromatic aldehyde were refluxed for 1–1.5 h
in EtOH (10 ml) in the presence of NaOH (5 mmol). The precipitate was
filtered and recrystallized from MeCN.
N
6-(4-Chlorophenyl)-7-(4,5-dimethoxy-2-nitrophenyl)-3-phenyl-6,7-dihydro-
5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine 2a: yield 81%, mp 305 °C.
1H NMR ([2H6]DMSO) d: 3.77, 3.90 (2s, 3H, OMe), 5.22 [dd, 1H,
C(6)H, J 10.3 and 10.4 Hz], 5.71 [d, 1H, C(7)H, J 10.0 Hz], 7.24 (d, 2H,
4-ClC6H4, J 8.8 Hz), 7.33 (d, 3H, 4-ClC6H4, J 8.8 Hz), 7.44–7.49 (m,
4H, Ph, HAr), 7.25 (d, 1H, NH, J 11.1 Hz), 7.87–7.97 (m, 2H, Ph).
MS, m/z (%): 463 (17), 326 (4), 258 (1), 196 (5), 177 (70), 152 (13), 136
(48), 103 (100), 77 (63). Found (%): C, 56.32; H, 3.44; N, 13.29. Calc.
for C24H20ClN5O4S (%): C, 56.52; H, 3.95; N, 13.73.
6-(4-Chlorophenyl)-7-(4-nitrophenyl)-3-phenyl-6,7-dihydro-5H-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazine 2b: yield 58%, mp 285 °C. 1H NMR
([2H6]DMSO) d: 4.97 [dd, 1H, H(6), J 10.1 and 10.2 Hz], 5.19 [d, 1H,
H(7), J 9.8 Hz], 7.29 (s, 4H, Ar), 7.42–7.45 (d, 3H, Ph), 7.49 (d, 1H, NH,
J 10.5 Hz), 7.68 (d, 2H, Ar, J 8.8 Hz), 7.92 (m, 2H, Ph), 8.08 (d, 2H, Ar,
J 8.8 Hz). MS, m/z (%): 310 (3), 273 (10), 259 (11), 192 (14), 177 (29),
152 (41), 138 (34), 103 (85), 89 (100), 77 (86). Found (%): C, 58.84; H,
3.91; N, 15.41. Calc. for C22H16ClN5O2S (%): C, 58.73; H, 3.58; N, 15.57.
3-(2-Furyl)-6-(3-nitrophenyl)-7-(4-nitrophenyl)-6,7-dihydro-5H-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazine 2c: yield 45%, mp 248–250 °C. 1H NMR
([2H6]DMSO) d: 5.24 [dd, 1H, C(6)H, J 9.2 and 10.2 Hz], 5.37 [d, 1H,
C(7)H, J 10.5 Hz], 6.63 (dd, 1H, Hfuryl, J 0.8 and 1.8 Hz), 7.04 (d, 1H,
R
N
Ar
EtOH, NaOH
N
N
N
O
H
N
S
R
S
N
6
7
Ar
H
Ar1
NH2
H
Ar1
1a–c
2a–c
a R = Ph, Ar = 4-ClC6H4, Ar1 = 4,5-(MeO)2-2-NO2C6H2
b R = Ph, Ar = 4-ClC6H4, Ar1 = 4-NO2C6H4
c R = 2-furyl, Ar = 3-NO2C6H4, Ar1 = 4-NO2C6H4
Scheme 1
1
The H NMR spectra of thiadiazines 2 contain two single-
proton doublets of the N(5)H and C(7)H at 7.6 and 5.2 ppm, as
well as a doublet of doublets of the C(6)H group at 5.0 ppm.
The spin–spin coupling constant of H(6) and H(7) (J 10 Hz)
evidences their pseudoaxial trans-position with respect to the
thiadiazine cycle. Good resolution of all signals and the absence
of doubling suggest that thiadiazines 2 constitute a racemic
compound and not a mixture of the four possible stereoisomers
due to the presence of the two asymmetric centers C(6) and
C(7). Thus, the reaction of the thiadiazine cycle formation is
diastereoselective.
H
furyl, J 3.3 Hz), 7.57 (dd, 1H, 3-NO2C6H4, J 8.3 and 7.9 Hz), 7.67 (d,
1H, NH, J 9.7 Hz), 7.73 (d, 3H, 4-NO2C6H4, 3-NO2C6H4, J 8.8 Hz),
7.89 (s, 1H, Hfuryl), 8.09 (d, 1H, 3-NO2C6H4, J 7.8 Hz), 8.12 (d, 2H,
4-NO2C6H4, J 8.3 Hz), 8.29 (s, 1H, 3-NO2C6H4). MS, m/z (%): 228 (2),
210 (3), 176 (4), 165 (16), 133 (11), 121 (15), 109 (16), 93 (100), 89 (50),
77 (63). Found (%): C, 53.57; H, 3.71; N, 18.22. Calc. for C20H14N6O5S
(%): C, 53.33; H, 3.13; N, 18.66.
†
Initial 4-amino-5-R-1,2,4-trialoze-3-thiones and their benzylthio deriva-
tives 1a–c were obtained according to known methods.3,4
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 253–254
O(31)
C(12)
O(4)
C(27)
C(28)
N(29)
O(30)
S(8)
C(23)
C(20)
C(4)
S(1)
C(10)
C(6)
C(24)
C(19)
N(1)
C(3)
C(5)
O(2)
Cl(1)
C(26)
C(25)
C(22)
C(21)
C(7)
C(23)
C(3)
O(3)
C(9)
N(5)
N(2)
C(9)
C(8)
C(24)
C(21)
C(20)
C(19)
N(4)
C(7)
O(1)
N(1)
N(2)
C(6)
C(2)
N(5)
C(11)
C(10)
N(4)
C(16)
C(15)
C(14)
N(3)
C(1)
C(11)
C(17)
C(18)
C(17)
C(12)
C(18)
C(13)
C(14)
C(15)
C(13)
Cl(22)
C(16)
Figure 1 General view of compound 2b. Hydrogen atoms are omitted for
clarity.
Figure 2 General view of compound 3 in representation of atoms via
thermal ellipsoids (P = 50%). Hydrogen atoms are omitted for clarity.
In the course of our investigations of 2a, a dihydrothiadiazine
ring opening reaction going through the S–C bond cleavage
has been found, which led to the formation of compound 3
(Scheme 2).¶ The 1H NMR spectrum of 3 contains an AB-quartet
of the prochiral methylene group at 4.3–4.9 ppm. The structure
of 3 was confirmed by X-ray analysis§ (Figure 2). In line with
XRD data, the geometrical parameters for the molecule of 3 are
also close to the standard ones for this type of compounds. The
mutual disposition of the heterocyclic and nitroaryl residues is a
cisoid one. Although the smallest interatomic distance between
them was found to be approximately 3.0 Å, the corresponding
dihedral angle of 23(1)° prevents them from exhibiting the
stacking interaction. On the other hand, such an arrangement of
substituents results in the formation of centrosymmetric dimers
via H-bonding between the NH group of the heterocycle and
the oxygen atom of the methoxy group [N···O 3.037(2) Å,
NHO 171(1)°].
NO2
CH2Br
N
N
Ph
Ph
NH
S
N
S
N
N
N
N
NO2
2a
NO2
NO2
§
Crystallographic data. Crystals of 2b (C22H16ClN5O2S, M = 349.91)
are monoclinic, space group C2/c, at 100 K: a = 27.4221(12), b =
= 8.6924(5) and c = 20.7520(12) Å, b = 124.784(5)°, V = 4062.6(4) Å3,
Z = 8 (Z' = 1), dcalc = 1.471 g cm–3, m(MoKα) = 3.22 cm–1, F(000) = 1856.
MeO
MeO
OMe
OMe
Cl
Cl
3
4
Crystals of 3 (C24H20ClN5O4S, M = 509.96) are triclinic, space group
–
P1, at 100 K: a = 8.4216(6), b = 11.0433(8) and c = 12.4718(9) Å, a =
O
= 93.573(2), b = 90.349(2), g = 96.911(2)°, V = 1149.13(14) Å3, Z = 2
(Z' = 1), dcalc = 1.474 g cm–3, m(MoKα) = 3.00 cm–1, F(000) = 528. Intensities
of 18241 (2b) and 15115 (3) reflections were measured with a Bruker
SMART APEX2 CCD diffractometer [l(MoKα) = 0.71072 Å, w-scans,
2q < 60°] and 5399 independent reflections [Rint = 0.0352] for 2b and
6679 [Rint = 0.0319] for 3 were used in a further refinement. The struc-
tures were solved by a direct method and refined by the full-matrix least-
squares technique against F2 in the anisotropic–isotropic approximation.
Hydrogen atoms of NH groups were located from the Fourier synthesis
of the electron density. Positions of H(C) atoms were calculated. All
hydrogen atoms were refined in the isotropic approximation in riding
model. For 2b the refinement converged to wR2 = 0.1094 and GOF = 1.007
for all independent reflections [R1 = 0.0366 was calculated against F for
4430 observed reflections with I > 2s(I)]. For 3 the refinement converged
to wR2 = 0.0978 and GOF = 1.010 for all independent reflections [R1 =
= 0.0411 was calculated against F for 5041 observed reflections with
I > 2s(I)]. All calculations were performed using SHELXTL PLUS 5.0.5
CCDC 701622 and 701623 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
NO2
NO2
N
H+, H2O
Ph
N
+
N
S
MeO
OMe
H2N
Cl
5
6
Scheme 2
The thio group alkylation of compound 3 by p-nitrobenzyl-
bromide leads to the formation of corresponding sulfide 4,¶ the
hydrolysis of which results in desoxybenzoine 5 and 4-amino-
3-(4-nitrobenzylthio)-5-phenyl-1,2,4-triazole 6, which is identical
to initial substance 1b in physico-chemical and spectral charac-
teristics.
Therefore, the formation and further thiadiazine ring opening
reactions enable obtaining desoxybenzoine derivatives from initial
aromatic aldehyde and benzylhalogenide by their addition to
the 5-substituted 4-amino-3-thio-1,2,4-triazole functional groups.
¶
Online Supplementary Materials
4-[1-(4-Chlorophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethylideneamino]-
Supplemetary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.09.008.
2,4-dihydro-3H-5-phenyl-1,2,4-triazole-3-thione 3. Thiadiazine 2a (1 mmol)
was dissolved in 5 ml DMF and added dropwise the EtONa solution
(4 mmol) in 3 ml EtOH. After 15 min, the reaction mixture was diluted
with water and neutralized with dilute AcOH. Recrystallized from MeOH,
yield 62%, mp 236 °C.
N-[1-(4-Chlorophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethylideneamino]-
3-(4-nitrobenzyl)thio-4H-5-phenyl-1,2,4-triazole-4-amine 4. Triazolethione
3 was alkylated analogously to the obtaining method of compounds 1.
Recrystallized from the mixture of benzene/hexane (3:1). Yield 67%,
mp 127 °C.
1-(4-Chlorophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethanone 5. Com-
pound 4 was refluxed for 2 h in 40% HCl solution. Extracted with CHCl3,
evaporated to dryness. The substance was isolated by column chromato-
graphy [Al2O3 (III); eluent, CHCl3]. Yield 30%, mp 185 °C.
For spectral characteristics of compounds 3–5, see Online Supplementary
Materials.
References
1 A. A. Kolodina, N. I. Gaponenko and A. V. Lesin, Khim. Geterotsikl.
Soedin., 2007, 1415 [Chem. Heterocycl. Compd. (Engl. Transl.), 2007,
43, 1202].
2 R. M. Shaker and A. A. Aly, Phosphorus Sulfur Silicon Relat. Elem.,
2006, 181, 2577.
3 J. R. Reid and N. D. Heindel, J. Heterocycl. Chem., 1976, 13, 925.
4 X. Y. Liu, W. F. Xu and N. Hou, Acta Academica Med. Shandong, 2001,
39, 112.
5 G. M. Sheldrick, SHELXTL v. 5.10, Structure Determination Software
Suite, Bruker AXS, Madison, Wisconsin, USA, 1998.
Received: 6th June 2008; Com. 08/3152
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