Addition of hydrazine to 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines: Hydrazine derivatives of 4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1002/jhet.218

(Chemical Equation Presented) The 7-aryl-4,7-dihydro[1,2,4]triazolo[1,5-a] pyrimidines 1a-c can undergo addition of hydrazine to the enamine double bond leading to hydrazine derivatives of tetrahydrotriazolopyrimidines 2a-c; the process is usually accompa

Full text of DOI:10.1002/jhet.218

November 2009
Addition of Hydrazine to 4,7-Dihydro[1,2,4]triazolo[1,5-
a]pyrimidines: Hydrazine Derivatives of 4,5,6,7-
Tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine
1413
Sergey A. Komykhov,a* Konstantin S. Ostras,a Kyryl M. Kobzar,b
Vladimir I. Musatov,a and Sergey M. Desenkoa
aScientific and Technological Corporation, ‘‘The Institute for Single Crystals’’, National Academy
of Science of Ukraine, Lenin Avenue 60, Kharkiv 61001, Ukraine
bBruker BioSpin GmbH, Silberstreifen 4, Rheinstetten 76287, Germany
*E-mail: komykhov@isc.kharkov.com
Received January 18, 2006
DOI 10.1002/jhet.218
Published online 10 November 2009 in Wiley InterScience (www.interscience.wiley.com).
The 7-aryl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines 1a-c can undergo addition of hydrazine to the
enamine double bond leading to hydrazine derivatives of tetrahydrotriazolopyrimidines 2a-c; the process
is usually accompanied by partial opening of pyrimidine ring leading to 3a,b.
J. Heterocyclic Chem., 46, 1413 (2009).
INTRODUCTION
enced by aryl ring. The investigated dihydroazolopyrimi-
dine contains supposedly only one reaction center for
nucleophile attack, namely the C-5 carbon. The most
appropriate nucleophilic reagent for this case, in our
opinion, could be hydrazine. The earlier described reac-
tions of analogous acetyl derivatives with hydrazine or
hydroxylamine [2] (Scheme 1) were accompanied by het-
erocyclizations leading to only one stereoisomer (a pair
of enantiomers) in both cases; the stereochemistry of het-
erocyclization products was consistent with nucleophilic
attack of the enamine double bond from the sterically
less hindered side of the dihydroazolopyrimidine system.
1,4-Dihydroazines are compounds which are very im-
portant in biological processes. According to the avail-
able data about the structure–activity relationship for
1,4-dihydropyridines [1], the phenyl substituent at posi-
tion 4 of dihydropyrimidine ring is the most suitable for
showing physiological activity. However, the stereo-
chemistry of addition processes for 4-aryl-1,4-dihydroa-
zines was not widely investigated, in spite of their
simplicity and their similarity to chemical processes in
nature [2]. It is also known that dihydroazines fused
with azole ring possess a relatively stable dihydro struc-
ture (in comparison with nonfused 1,4-dihydroazines,
such as 1,4-dihydropyridine and 1,6-dihydropyrimidine).
This makes them convenient models for studying many
theoretical problems of organic chemistry, e.g. tautome-
rization, stereochemistry, and chemical reactivity [3]. In
addition, there are many compounds with various types
of physiological activity exactly among dihydroazolo-
pyrimidines [4].
RESULTS AND DISCUSSION
We studied the reaction of dihydroazolopyrimidines
1a-c with hydrazine by heating in dioxane. The products
1
obtained from 1a,b were showed in the NMR H spec-
trum in the presence of two groups of signals (com-
pounds 2a,b and 3a,b, respectively). In case of 3-nitro-
phenyl derivative (1c), the presence of only one
compound was observed (2c). Pure compound 3b was
isolated by fractional crystallisation of the obtained mix-
ture 2b and 3b; the attempts to isolate either 2a or 3a in
analogous way were fully unsuccessful.
Only several adducts of dihydroazolopyrimidines
(namely hydrates) are described; they were formed ei-
ther by attempt of preparation of corresponding dihy-
droazolopyrimidine [5], or directly from previously pre-
pared dihydroazolopyrimidine in attempts of its salt for-
mation with HCl (as side product without isolation) [6].
The aim of this work was to investigate the ability of
the enamine fragment of the 7-aryl-5-methyl-4,7-dihy-
dro[1,2,4]triazolo[1,5-a]pyrimidine to react with nucleo-
phile and to study the stereochemistry of nucleophilic
addition to dihydroazine ring which should be influ-
The elemental analysis for pure 3b and 2c and for
obtained mixtures showed that compounds 2 and 3 are
isomers, and their composition corresponded to addition
of one molecule of hydrazine to azolopyrimidine 1.
1
The H NMR spectra of 2a–c, 3a,b in DMSO-d6 (Ta-
ble 1) were similar and showed signals of ABX systems
C
V
2009 HeteroCorporation

1414
S. A. Komykhov, K. S. Ostras, K. M. Kobzar, V. I. Musatov, and S. M. Desenko
Vol 46
Table 1
1
The H NMR data for 2a-c, 3a,b (d/ ppm).
Coupling
constants / Hz
Aliphatic protons
Compound
Substituent
Ph
NH
–
ArH
HX (7-H)
5.25
HB (2-H)
2.43
HA (2-H)
1.85
CH3
1.30
3JBX
3JAX
2JAB
2a (in mixture
with 3a)
2b (in mixture
with 3b)
7.14–7.57
4.6
4.9
5.0
11.3
15.0
13.8
11.8
4-CH3OC6H4
3- O2NC6H4
–
6.80–7.35
5.14
5.40
2.36
2.49
1.83
1.87
1.28
1.30
11.6
11.6
2c
7.37 (1H, s)
8.16 (1H, m),
8.09 (1H, s),
7.60–7.72 (2H, m),
7.42 (1H, m)
7.14–7.57
3a (in mixture
with 2a)
3b
Ph
6.10, 5.53
6.10, 5.51
5.55
5.51
3.11
3.03
2.84
2.79
1.50
1.55
8.8
8.6
5.8
6.1
15.0
14.7
4-CH3OC6H4
7.29–7.31 (2H, m),
7.29 (1H, s),
6.81–6.85 (2H, m)
(the signals of 3 were shifted downfield in comparison
with 2), singlets of CH3 groups, and multiplets of aro-
matic rings. Compound 3b also showed broad signals of
two NH2 groups, but in the spectrum of 2c only one sig-
nal of NH protons was observed in the aromatic region.
The 13C NMR spectra of 2c and 3b were allowed to
make the structure assignment. Both compounds showed
signals of aliphatic CH and CH2 carbons, but compound
2c showed signal of quaternary carbon in the aliphatic
region, at 69.2 ppm, which was consistent with the pro-
posed structure of cyclic adduct. In contrast, the spec-
trum of 3b contained an additional signal downfields, at
ꢀ159.0 ppm, which was assigned to imine carbon.
Thus, compound 3b has the opened, noncyclic structure,
as shown in Scheme 2. Two series of signals were
observed in the spectrum of 3b. The minor signals had
low intensity and probably represented the stereoisomers
of 3b which had different configuration of the
C¼¼NANH2 fragment. The assignment of signals in 13C
NMR spectrum of 3b was based on HSQC experiment.
The reaction can be described by Scheme 2:
the same direction from the plane of the azolopyrimi-
dine system. Thus, compounds 2 have the stereochemis-
try as shown in Scheme 2.
3
The J values between HX and HA in 2a–c were 11.3–
11.6 Hz (Table 1) indicating that HX and HA are both
axial. Such contradiction between coupling data and
NOE results could be explained by equilibrium between
conformers of 2a–c (Scheme 3).
Thus, 7-aryl derivatives of 4,7-dihydro[1,2,4]tria-
zolo[1,5-a]pyrimidines can add nucleophiles directly,
and their nucleophilic attack occurs from the side oppo-
site to the orientation of aryl substituent. Compounds
2a–c, 3a, b were quite unstable in DMSO-d6 solutions
undergoing partial elimination of hydrazine (for 2), par-
tially full decomposition in about 0.5–1.0 h at room
temperature.
EXPERIMENTAL
The melting points, determined on a Kofler apparatus, are
1
uncorrected. The H and 13C NMR spectra were obtained on a
Varian Mercury VX-200 or Bruker DMX 600 in DMSO-d6
with TMS as a internal standard. The EI mass spectra were
measured on a Varian 1200L at 70 eV.
4,7-Dihydro-5-methyl-7-aryl[1,2,4]triazolo[1,5-a]pyrimidines
(1b,c). General procedure. Compounds 1b,c were prepared by
the procedure described in ref. 7 for 1a. A mixture of commer-
cially available 3-amino-1,2,4-triazole (0.84 g, 10 mmol) and
the corresponding substituted benzylideneacetone (10.0 mmol)
Two stereoisomers are possible for compounds 2, but
in their NMR spectra the signals of only one stereoiso-
mer were observed. The stereochemistry of 2 was inves-
tigated by NOE measurements. The irradiation of CH3
showed enhancement for ortho protons of aromatic ring
which proved proximity of the protons and showed that
methyl group and aryl substituent are both oriented in
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Addition of Hydrazine to 4,7-Dihydro[1,2,4]triazolo[1,5-a]pyrimidines:
Hydrazine Derivatives of 4,5,6,7-Tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine
1415
Scheme 3
40% of 3a. Anal. Calcd. for C12H16N6 (244.3): 59.00% C,
6.60% H, 34.40% N. Found: 58.87% C, 6.54% H, 34.35% N.
Compounds 2b,c and 3b were prepared in analogous way
from 1b and 1c, respectively. In case of 1c, the precipitate
formed contained only pure 2c.
A mixture of 2b and 3b was isolated in 96% yield and
contained, according to the 1H NMR data, 65% of 2b and
35% of 3b.
Pure compound 3b was isolated by careful crystallization of
the obtained mixture from dioxane-diethyl ether; m.p. 175–
177ꢁC. 13C NMR (DMSO-d6), for major stereoisomer: 14.5
(CH3), 44.1 (CH2), 55.6 (OCH3), 56.4 (CH), 114.1, 129.0 (m-
and o-CAr), 133.2 (i-CAr), 144.2 (C-5 of triazole), 148.6 (CH
of triazole), 155.1 (AC¼¼NA), 159.0 (p-CAr); for minor stereo-
isomer: 22.8 (CH3), 34.8 (CH2), 54.8 (OCH3), 55.6 (CH),
114.2, 128.6 (m- and o-CAr), 133.1 (i-CAr), 145.3 (C-5 of tria-
zole), 148.9 (CH of triazole), 155.4 (AC¼¼NA), 159.2 (p-CAr).
Anal. Calcd. for C13H18N6O (274.3): 56.92% C, 6.61% H,
30.64% N. Found: 56.83% C, 6.55% H, 30.71% N.
Compound 2c, m.p. 153–154ꢁC, was isolated in yield 73%.
13C NMR (DMSO-d6) d, ppm: 24.2 (CH3), 41.2 (C-6),
55.7 (C-7), 69.2 (C-5), 122.6 (p-CAr), 123.1 (o-CAr), 130.5
(m0-CAr), 134.6 (o0-CAr), 143.3 (i-CAr), 148.3 (m-CAr), 149.3
(C-2), 154.7 (C-3a). Anal. Calcd. for C12H15N7O2 (289.3):
49.82% C, 5.23% H, 33.89% N. Found: 49.69% C, 5.14% H,
33.97% N.
in DMF (1 mL) was refluxed for 30 min. The reaction mixture
was cooled to 20ꢁC, mixed with benzene (20 mL) and the pre-
cipitate formed was collected by filtration and crystallized
from DMF-methanol mixture.
4,7-Dihydro-5-methyl-7-(4-methoxyphenyl)[1,2,4]triazolo
[1,5-a]pyrimidine (1b). 4,7-Dihydro-5-methyl-7-(4-methoxy-
phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (1b) was isolated with
yield 58% and melted at 215–216ꢁC (from mixture of DMF
1
and methanol). The H NMR signals were found in DMSO-d6
at 1.85 s, 3H (4-CH3), 3.70 s, 3H (OCH3), 4.50 d, 1H (6-H),
3
5.09 d, 1H, J ¼ 2.0 (7-H), 6.86 m, 2H (m-ArH), 7.11 m, 2H
(o-ArH), 7.51 s, 1H (2-H), 9.52 br.s, 1H (NH). The 13C NMR
signals were measured in DMSO-d6 at d, ppm: 18.9 (5-CH3),
55.8 (OCH3), 59.6 (C-7), 96.1 (C-6), 114.5 (m-CAr), 128.8 (o-
C
Ar), 132.4 (i- CAr), 135.3 (C-5), 149.6 (C-3a), 149.8 (C-2),
159.5 (p-CAr). The ei ms spectrum showed peaks at m/z
(%)242 (87) [Mþ], 227 (57) [Mþ-15], 214 (34) [Mþ-28], 200
(40) [Mþ-42], 135 (100) [Mþ-107]. Anal. Calcd. for
C13H14N4O (242.3): 64.45% C, 5.82% H, 23.13% N. Found:
64.39% C, 5.71% H, 23.05% N.
REFERENCES AND NOTES
[1] (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew Chem 1981,
93, 755; (b) Goldmann, S.; Stoltefuß, J. Angew Chem 1991, 103, 1587.
[2] Desenko, S. M.; Komykhov, S. A.; Orlov, V. D.; Meier, H.
J Heterocycl Chem 1998, 35, 989.
4,7-Dihydro-5-methyl-7-(3-nitrophenyl)[1,2,4]triazolo[1,5-a]
pyrimidine (1c). Yield 52%; m.p. 249–250ꢁC (ethanol). 1H
NMR (DMSO-d6): 1.88 s, 3H (CH3), 4.61 m, 1H (6-H), 6.23
m, 1H (7-H), 7.60 s, 1H (2-H), 7.62–7.67 m, 2H (5,6-ArH),
8.03 m, 1H (2-ArH), 8.12–8.18 m, 1H (4-ArH), 9.73 br.s, 1H
(NH). 13C NMR (DMSO-d6): 19.0 (5-CH3), 59.3 (C-7), 94.9
(C-6), 121.9 (2-CAr), 123.5 (4-CAr), 131.0 (5-CAr), 133.5 (6-
CAr), 134.1 (C-5), 145.2 (1-CAr), 148.6 (3-CAr), 149.9 (C-3a),
150.4 (C-2). MS [EI, m/z (rel. %)]: 257 (78) [Mþ], 242 (25)
[Mþ-15], 210 (14) [Mþ-47], 135 (100) [Mþ-122], 128 (13)
[Mþ-129]. Anal. Calcd. for C12H11N5O2 (257.3): 56.03% C,
4.31% H, 27.22% N. Found: 55.92% C, 4.24% H, 27.18% N.
5-Methyl-7-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]
pyrimidin-5-yl)hydrazine (2a) and 2-(3-hydrazono-1-phenyl-
butyl)[1,2,4]triazol-3-amine (3a). A solution of 1a [7] (1.40
g, 6.6 mmol) and 85% hydrazine hydrate (1.66 g, 30 mmol) in
dioxane (7 mL) was heated for 60 min and the solvent was
evaporated under reduced pressure. The residue was triturated
with diethyl ether (10 mL) and allowed to stand for 2 days.
The formed precipitate (1.51 g) was filtered off. It contained,
[3] (a) Desenko, S. M. Khim Geterotsikl Soedin 1995, 147; (b)
Desenko, S. M. Chem Heterocycl Compd (Engl Transl) 1995, 31, 125.
[4] (a) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.; Naka-
mura, T. (Yoshitomi Pharmaceutical Industries), U.S. Pat. 4,918,074
(1990); Chem Abstr 114, 81, 873 (1991); (b) Tsuda, N.; Mishina, T.; Obata,
M.; Araki, K.; Inui, A.; Nakamura, T. (Yoshitomi Pharmaceutical Indus-
tries), Jpn. Pat. 63,101,383 (1988); Chem Abstr 109, 128, 988 (1988); (c)
Desenko, S. M.; Orlov, V. D.; Lipson, V. V.; Gorbenko, N. I.; Pivovarevich,
L. P.; Ryndina, E. N.; Moroz, V. V.; Varavin, V. P. Khim Farm Zhurn
1995, 29, 37; Desenko, S. M.; Orlov, V. D.; Lipson, V. V.; Gorbenko, N. I.;
Pivovarevich, L. P.; Ryndina, E. N.; Moroz, V. V.; Varavin, V. P. Chem
Abstr 1996, 124, 239; (d) Atwal, K. S.; Moreland, S. Bioorg Med Chem
Lett 1991, 1, 291.
[5] Desenko, S. M.; Gladkov, E. S.; Nenaydenko, V. G.; Shish-
kin, O. V.; Shishkina, S. V. Khim Geterotsikl Soedin 2004, 71.
¨
[6] Abou El Ella, D.; Goßnitzer, E.; Wendelin, W. J Heterocycl
Chem 1996, 33, 373.
[7] Desenko, S. M.; Orlov, V. D.; Lipson, V. V. Khim Geterot-
sikl Soedin 1990, 1638; Chem Heterocycl Compd (Engl. Transl.) 1990,
26, 1362.
1
according to the H NMR data (Table 1) about 60% of 2a and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet