Fused polycyclic nitrogen-containing heterocycles 13. Synthesis of 6-phenyl-2-phenylimino-6H-1,3,4-thiadiazine-5-carboxylic acid and its intermolecular cyclodehydration accompanied by sulfur extrusion to form dipyrazolo[1,5-a,1′,5′d]pyrazine

Article abstract of DOI:10.1007/s11172-005-0270-z

Condensation of methyl phenylchloropyruvate with 4-phenylthiosemicarbazide proceeds as the Bose reaction to form 5-methoxycarbonyl-6-phenyl-2-phenylimino- 6H-1,3,4-thiadiazine, which is hydrolyzed to give carboxylic acid. In the presence of polyphosphoric

Full text of DOI:10.1007/s11172-005-0270-z

Russian Chemical Bulletin, International Edition, Vol. 54, No. 2, pp. 441—444, February, 2005
441
Fused polycyclic nitrogenꢀcontaining heterocycles
13.* Synthesis of 6ꢀphenylꢀ2ꢀphenyliminoꢀ6Hꢀ1,3,4ꢀthiadiazineꢀ5ꢀcarboxylic
acid and its intermolecular cyclodehydration accompanied by sulfur extrusion
to form dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazine
ꢀ
V. A. Mamedov, I. Z. Nurkhametova, A. T. Gubaidullin, I. A. Litvinov, and Ya. A. Levin
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843 2) 73 2253. Eꢀmail: mamedov@iopc.kcn.ru
Condensation of methyl phenylchloropyruvate with 4ꢀphenylthiosemicarbazide proceeds
as the Bose reaction to form 5ꢀmethoxycarbonylꢀ6ꢀphenylꢀ2ꢀphenyliminoꢀ6Hꢀ1,3,4ꢀthiaꢀ
diazine, which is hydrolyzed to give carboxylic acid. In the presence of polyphosphoric acid,
the latter undergoes intermolecular cyclodehydration accompanied by sulfur extrusion to yield
dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazine.
Key words: phenylchloropyruvates, 4ꢀphenylthiosemicarbazide, 5ꢀmethoxycarbonylꢀ6ꢀpheꢀ
nylꢀ2ꢀphenyliminoꢀ6Hꢀ1,3,4ꢀthiadiazine, Bose reaction, dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazine.
Earlier, we have demonstrated that the reactions of
phenylchloropyruvic acid esters and amides with N,N´ꢀdiꢀ
phenylthiourea produce 4ꢀhydroxythiazolidines, which are
stable intermediates of the Hantzsch reaction,2,3 whereas
their reactions with thiosemicarbazide afford stable interꢀ
mediates of the Bose reaction,4 viz., 5ꢀhydroxyperhydroꢀ
thiadiazines.5,6
carboxylic acid 8 prepared by hydrolysis of ester 7
(Scheme 2).
Like intramolecular dehydration of 2ꢀsubstituted
5ꢀphenylthiazoleꢀ4ꢀcarboxylic acids with polyphosphoric
acid,7 the Friedel—Crafts reaction of acid 8 under these
conditions would be expected to give indeno[2,1ꢀe]ꢀ1,3,4ꢀ
thiadiazine 9. However, the reaction afforded a sulfurꢀ
free product rather than indenothiadiazine 9. Based on
the results of elemental analysis and spectroscopy, we
assigned structure 10 to this product. Structure 10 correꢀ
sponds to the dehydration product of pyrazolecarboxylic
acid 11, which can be derived from acid 8 through sulfur
extrusion (Scheme 3). This result is consistent with the
wellꢀknown instability of 1,3,4ꢀthiadiazines in acidic meꢀ
dium. Under these conditions, the latter are transꢀ
formed into pyrazoles with sulfur extrusion and ring conꢀ
traction.6—9
Xꢀray diffraction study of compound 10 confirmed its
structure (Fig. 1). Compound 10 crystallizes in the triꢀ
clinic space group. The unit cell contains DMSO solvate
molecules. In the crystal, molecule 10 occupies a speꢀ
cial position (see Fig. 1), so that there are four DMSO
molecules per molecule 10. The tricyclic fragment of
the molecule is planar, and the phenyl substituent
(C(21)—C(26) atoms) lies virtually in the plane of the
tricyclic system (the dihedral angle between the planes
is 4.8°). The second phenyl substituent is twisted with
respect to the plane of the molecule by 57.1°. The moꢀ
lecular packing in the crystal is characterized by an extenꢀ
sive system of intermolecular interactions involving the
In this connection, the reaction of methyl phenylꢀ
chloropyruvate (1) with 4ꢀphenylthiosemicarbazide conꢀ
taining fragments of both N,N´ꢀdiphenylthiourea and
thiosemicarbazide would be expected to give either
thiazolidine derivatives 2 and 3 or thiadiazine derivaꢀ
tives 4. However, it appeared that the reaction affords one
product regardless of the nature of the solvent, acidity of
the reaction mixture, the order of addition of the reꢀ
agents, temperature, etc., including the known condiꢀ
tions.2—6 The elemental composition of this product corꢀ
responds to isomeric structures 5—7, which are dehydraꢀ
tion products of compounds 2—4, respectively. However,
1
the H NMR spectrum shows a singlet for the methine
proton at δ 5.63, which unambiguously supports strucꢀ
ture 7 and argues against structures 5 and 6 (Scheme 1).
Therefore, the reaction of 4ꢀphenylthiosemicarbazide with
chloroketone 1 proceeds as the Bose reaction rather than
as the Hantzsch reaction.
Taking into account the presence of the ester and
phenyl groups at the adjacent C atoms in heterocycle 7,
we examined the possibility of indenoannelation of
* For Part 12, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 432—435, February, 2005.
1066ꢀ5285/05/5402ꢀ0441 © 2005 Springer Science+Business Media, Inc.

442
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Mamedov et al.
Scheme 1
Reagents and conditions: i. 5% aqueous NaHCO3 solution.
Scheme 2
azines, are available in the literature. For example, two
3ꢀchlorocarbonylꢀ5ꢀmethoxycarbonylꢀ4ꢀtrimethylsilylꢀ
pyrazole molecules eliminate two HCl molecules to form
the dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazine system.10 The reꢀ
action of 3ꢀcarboxyꢀ4ꢀ(αꢀhydroxybenzyl)pyrazole proꢀ
ceeds analogously and gives rise to the pyrazinedione ring
accompanied by elimination of two water molecules.11
3ꢀFormylpyrazoles also undergo dimerization to diꢀ
pyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazines.11—14 An analogous beꢀ
havior was observed for 5ꢀacylꢀ2ꢀpyrazolines.15,16
solvate molecules. The molecular and supramolecular
structures of compounds 7 and 10 in the crystals will be
described in detail elsewhere.
Experimental
The pyrazinedione ring in tricyclic structure 10 is
formed through two nucleophilic substitutions involving
the carboxy group of one molecule of biphilic pyrazoleꢀ
carboxylic acid 11 and the nucleophilic N atom of the
pyrazole fragment of another molecule 11. Data on cyꢀ
clization of pyrazoles containing the carbonyl group at
position 3, which affords dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrꢀ
The melting points were determined on a Boetius hotꢀstage
microscope. The IR spectra were recorded in Nujol mulls on a
URꢀ20 spectrometer. The H NMR spectra were recorded on a
Bruker MWꢀ250 spectrometer (250 MHz). Methyl phenylꢀ
chloropyruvate (1) was prepared according to a known proꢀ
cedure.17
1
Scheme 3
PPA is polyphosphoric acid

Synthesis of dipyrazolo[1,5ꢀa,1´,5´ꢀd]pyrazine
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
443
C(24)
C(23)
C(22)
C(25)
C(26)
C(21)
N(1)
N(10)
O(9)
N(2)
S(2B)
C(27)
C(9)
C(3A)
C(2)
O(18)
C(32)
C(29)
O(24)
C(3)
C(31)
C(36)
C(35)
C(33)
C(34)
S(1)
C(28)
C(45)
Fig. 1. Molecular structure of compound 10 in the crystal.
5ꢀMethoxycarbonylꢀ6ꢀphenylꢀ2ꢀphenyliminoꢀ6Hꢀ1,3,4ꢀthiaꢀ
diazine (7). A solution of chloropyruvate 1 (2.12 g, 0.01 mol) in
CH2Cl2 (10 mL) was added carefully dropwise to a solution of
4ꢀphenylthiosemicarbazide (1.67 g, 0.01 mol) in CH2Cl2 (30 mL)
under argon at 0 2 °C. The reaction mixture was stirred at this
temperature for 3 h, warmed to ~20 °C, and poured into water.
The organic layer was separated, and the aqueous solution was
extracted with CH2Cl2 (3×15 mL). The organic layer and the
extract were combined and dried with MgSO4. The solvent was
removed, the residue was treated with a 5% aqueous NaHCO3
solution, and the precipitate was filtered off and recrystallized
from MeOH. Compound 7 was obtained in a yield of 2.75 g
(84.6%) as paleꢀyellow crystals, m.p. 209—210 °C. Found (%):
C, 62.70; H, 4.75; N, 12.65; S, 9.97. C17H15N3O2S. Calcuꢀ
a yield of 0.8 g (61%), m.p. >360 °C. Found (%): C, 73.42;
H, 4.05; N, 16.14. C32H22N6O2. Calculated (%): C, 73.57;
H, 4.21; N, 16.09. IR, ν/cm–1: 3250 (br), 1700, 1600, 1550,
1510, 1485, 1380, 1345, 1290, 1250. 1H NMR (CD3OD), δ: 6.95
(br.t, 1 H, H(4´), NPh, J = 7.85 Hz); 7.10—7.58 (m, 9 H, NPh,
CPh); 7.90 (br.s, 1 H, NH). Crystals suitable for Xꢀray diffracꢀ
tion study were prepared by recrystallization from DMSO.
Found (%): C, 57.32; H, 5.81; N, 9.76; S, 15.05. C32H22N6O2•
•4Me2SO. Calculated (%): C, 57.56; H, 5.51; N, 10.07; S, 15.36.
Xꢀray diffraction study of compound 10 was performed on an
automated fourꢀcircle EnrafꢀNonius CADꢀ4 diffractometer. Red
plateletꢀlike crystals are triclinic, C32H22N6O2•4Me2SO, crysꢀ
tal dimensions 0.1×0.2×0.3 mm. At 20 °C, a = 6.142(6) Å, b =
13.392(8) Å, c = 14.4580(10) Å, α = 65.53(2)°, β = 85.34(4)°,
lated (%): C, 62.78; H, 4.61; N, 12.92; S, 9.86. IR, ν/cm–1
:
γ = 87.77(6)°, V = 1079(1) Å3, Z = 1, dcalc = 1.29 g cm–3, space
–
3286 (NH), 1714 (C=O), 1590 (C=N). 1H NMR (DMFꢀd7), δ:
3.80 (s, 3 H, Me); 5.63 (s, 1 H, CH); 6.70 (dd, 1 H, pꢀH (NPh),
J = 7.05 Hz, J = 7.43 Hz); 7.01—7.44 (m, 9 H, Ph, 2 oꢀH,
2 mꢀH (NPh)); 7.63 (br.s, 1 H, N(3)H).
group P1. The unit cell parameters and the intensities of
1514 reflections, of which 1443 reflections were with I ≥ 2σ,
were measured at 20 °C (λ(CuꢀKα), graphite monochromator,
ω/2θ scanning technique, θ < 73.7°). The intensities of three
check reflections showed no decrease in the course of Xꢀray data
collection. The absorption correction was applied (µ(Cu) =
23.98 cm–1). The structure was solved by direct methods using
the SIR program18 and refined first isotropically and then anisoꢀ
tropically using the SHELXLꢀ97 program package.19 Subseꢀ
quently, the position of the H atom at the N(1) atom was reꢀ
vealed from difference electron density maps. The coordinates
of other H atoms were calculated based on stereochemical criteꢀ
ria and refined using a riding model. The final R factors were
R = 0.065, Rw = 0.168 using 1443 reflections with F 2 > 4σ. All
calculations were carried out using the MolEN20 and WinGX21
program packages. The figure was drawn using the PLATON
program.22
6ꢀPhenylꢀ2ꢀphenyliminoꢀ6Hꢀ1,3,4ꢀthiadiazineꢀ5ꢀcarboxylic
acid (8). 1,3,4ꢀThiadiazine 7 (2.9 g, 0.01 mol) was refluxed in
20% hydrochloric acid (25 mL) for 2 h. The hot reaction mixꢀ
ture was filtered and the crystals that precipitated upon cooling
were filtered off and recrystallized from PriOH. Acid 8 was
isolated in a yield of 2.7 g (97%), m.p. 227—229 °C. Found (%):
C, 62.51; H, 4.25; N, 13.65; S, 10.27. C16H13N3O2S. Calcuꢀ
lated (%): C, 61.74; H, 4.18; N, 13.50; S, 10.30. IR, ν/cm–1
:
3380, 3340 (NH); 3060 (C(5)H); 1685 (C=O); 1640 (C=N).
1H NMR (CD3OD), δ: 5.68 (s, 1 H, CH); 7.01—7.45 (m,
10 H, 2 Ph).
3,8ꢀDiphenylꢀ2,7ꢀdiphenyliminoꢀ1H,6Hꢀdipyrazoꢀ
lo[1,5ꢀa,1´,5´ꢀd]pyrazine (10). A mixture of P2O5 (35 g) and
H3PO4 (10 mL) was heated with stirring at 240 °C for 1.5 h.
Then polyphosphoric acid that formed was cooled, and acid 8
(2.05 g, 0.01 mol) was dissolved in polyphosphoric acid with
stirring. The reaction mixture was kept at 100—140 °C for 1.5 h,
cooled, and diluted with water. The crystals that precipitated
were filtered off and dried in air. Compound 10 was obtained in
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 03ꢀ03ꢀ32865
and 02ꢀ03ꢀ32280) and the Charity Foundation for Supꢀ
port of Russian Science.

444
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Mamedov et al.
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11. J. Bastide, J. Lematre, and J. Soulier, C. R. Acad. Sci.,
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Received May 26, 2004;
in revised form August 4, 2004