Hydrazine-1-carbonitriles: New synthesis approach to and reactions with carbonyl compounds

Article abstract of DOI:10.1007/s00706-009-0184-9

A series of 1-(pyrimidin-2-yl)hydrazine-1-carbonitriles was synthesized by base-catalyzed condensation of 3,4-diamino-1,2,4-triazole hydrobromide with several 1,3-dinucleophilic compounds. These final products were formed by ring opening of the 1,2,4-tria

Full text of DOI:10.1007/s00706-009-0184-9

Monatsh Chem (2009) 140:1337–1342
DOI 10.1007/s00706-009-0184-9
ORIGINAL PAPER
Hydrazine-1-carbonitriles: new synthesis approach
to and reactions with carbonyl compounds
Boris V. Paponov Æ Oleg V. Shihkin Æ
Svetlana V. Shishkina Æ Yulia A. Kovach Æ
Sergey A. Kravchenko Æ Andrey O. Doroshenko
Received: 26 November 2008 / Accepted: 2 September 2009 / Published online: 29 September 2009
Ó Springer-Verlag 2009
Abstract A series of 1-(pyrimidin-2-yl)hydrazine-1-car-
bonitriles was synthesized by base-catalyzed condensation
of 3,4-diamino-1,2,4-triazole hydrobromide with several
1,3-dinucleophilic compounds. These final products were
formed by ring opening of the 1,2,4-triazolium ring via inter-
mediate 3-amino[1,2,4]triazolo[1,5-a]pyrimidinium bromides.
Up to present time, the only synthetic approach to
hydrazine-1-carbonitriles was developed via interaction of
organic hydrazines with BrCN (Scheme 1).
Although this reaction was known from the very
beginning of the twentieth century, it could be applied only
to a limited number of alkyl- [8] and arylhydrazones
[9, 10], whose organic moieties are inert to BrCN. Parti-
cularly there was no evidence concerning the synthesis of
1-hetarylhydrazine-1-carbonitriles.
Keywords Triazolopyrimidinium salts Á Ring opening Á
Dehydrobromination Á Azoles Á X-Ray structure
determination
In this paper we are reporting an effective route for the
synthesis of 1-(pyrimidin-2-yl)hydrazine-1-carbonitriles—
the first representatives of 1-hetarylhydrazine-1-carboni-
triles. It is based on the opening of the five-membered ring
of 3-amino[1,2,4]triazolo[1,5-a]pyrimidinium bromides. In
our opinion this should enlarge the field of application of
ring-opening reactions in practical organic chemistry [11].
The proposed method allows to synthesize hydrazine-1-
carbonitriles substituted in position 1 with residues sensi-
tive to BrCN. It also avoids the usage of highly toxic
hydrazines and halogen cyanides, which were needed for
the traditional synthesis of the title compounds.
Introduction
Substituted hydrazines are important substrates in the
synthesis of pyrazole [1, 2], indole [3–5], pyridazine [6, 7]
and other heterocyclic systems demonstrating a wide
spectrum of pharmaceutical activity. However, the syn-
thesis of 1-substituted hydrazine-1-carbonitriles has not
been developed, and the potential of these compounds as
building blocks for drug design has not yet been studied.
Results and discussion
B. V. Paponov (&) Á Y. A. Kovach Á S. A. Kravchenko Á
A. O. Doroshenko
Department of Organic Chemistry,
V.N. Karazin Kharkov National University,
4 Svobody sq., Kharkov 61077, Ukraine
e-mail: paponov@univer.kharkov.ua
In one of our previous papers we reported the synthesis of
2,3-diamino-5,7-diaryl[1,2,4]triazolo[1,5-a]pyrimidinium
salts by the reaction of 3,4,5-triamino-1,2,4-triazole with
a,b-dibromochalcones (1,3-diaryl-2,3-dibromopropan-1-
ones) [12, 13]. Introduction of 3,4-diamino-1,2,4-triazole
as a nucleophilic compound into the same reaction results
in the formation of a hardly separable mixture of products.
However, we succeeded in obtaining a series of 1-(4,6-
diarylpyrimidin-2-yl)hydrazine-1-carbonitriles 3a–3g in
good yields by the interaction of 3,4-diamino-1,2,4-triazole
A. O. Doroshenko
e-mail: andrey.o.doroshenko@univer.kahrkov.ua
O. V. Shihkin Á S. V. Shishkina
STC ‘‘Institute for Single Crystals’’,
60 Lenin ave., Kharkov 61001, Ukraine
123

1338
B. V. Paponov et al.
Table 1 Compounds 3a–3g and 4d–4g; substituents and yields
H
CN
N
BrCN
R1; R2
4 Yield (%)
3 Yield (%)
R
NH2
R N
NH2
C6H5; C6H5
–
3a, 65
3b, 63
3c, 62
3d, 93b
3e, 91b
3f, 89b
3g, 92b
R = Alk, Ar
4-BrC6H4; C6H5
-
4-ClC6H4; C6H5
-
Scheme 1
C6H5; 4-NO2C6H4
4-BrC6H4; 4-NO2C6H4
4-ClC6H4; 4-NO2C6H4
4-CH3OC6H4; 4-NO2C6H4
4d, 87a
4e, 89a
4f, 83a
4g, 88a
hydrobromide 1 with 1,3-diaryl-2,3-dibromopropan-1-ones
2a–2g in the presence of sodium acetate in a molar ratio of
1:1:3. All newly synthesized compounds were identified by
their H- and 13C-NMR spectra as well as a typical inten-
sive IR absorption in the range of 2,200 cm-1 (Scheme 2;
1
a
Twofold excess of NaOAc
b
Obtained on treatment of the salts 4d–4g with excess of
triathylamine
Table 1).
In the case of 1-aryl-3-(4-nitrophenyl)-2,3-dibromopro-
pan-1-ones 2d–2g acting as the electrophilic components
of the discussed reaction, 3-amino-7-(4-nitrophenyl)-5-
aryl[1,2,4]triazolo[1,5-a]pyrimidinium bromides 4d–4g
were found in the reaction mixture together with the final
nitriles 3d–3g. We have to consider 4d–4g as intermediates
in the synthesis of the title products, which is supported by
the fact that in the presence of a twofold excess of sodium
acetate the salts 4d–4g became the only products of the
interaction of 1 with 2d–2g. The treatment of 4d–4g with
an excessive quantity of triethylamine results in the for-
mation of nitriles 3d–3g in excellent yields.
pair on atom 2 of the triazolopyrimidinium moiety into the
new chemical bond [17]. Such reactions are typical to
triazoloazine systems having no substituents in position 2
[18–20], whereas in the case of 2-substituted systems
opening of the six-membered ring was reported [21].
Theopeningofthefive-memberedringwasstudiedalsofor
the model 3-amino-5,7-dimethyl[1,2,4]triazolo[1,5-a]pyri-
midinium bromide (5), which was synthesized according to
[22]. Treatment of 5 with an excess of triethylamine results
in 1-(4,6-dimethylpyrimidin-2-yl)hydrazine-1-carbonitrile
(6) in good yield (Scheme 3). This fact supports our statement
concerning the intermediate formation of 3-amino[1,2,4]
triazolo[1,5-a]pyrimidinium salts inreactions of3,4-diamino-
1,2,4-triazole with 1,3-dinucleophilic agents while synthe-
sizing 1-(pyrimidin-2-yl)hydrazine-1-carbonitriles.
Evidently the formation of nitriles 3d–3g was undergone
as dehydrobromination of the triazolopyrimidinium salts
4d–4g in the basic acetate medium. Elimination of a proton
from position 2 of the triazolopyrimidinium intermediate
and formation of a zwitterionic triazolium species should
take place in the discussed case. The latter compound was
not separated; however, the formation of analogous inter-
mediates was reported in the classical work on the
chemistry of thiamine [14–16].
1-(Pyrimidin-2-yl)hydrazine-1-carbonitrile 6 readily reacts
with the carbonyl compounds under the conditions described in
[8]: by heating of nitrile 6 with aromatic aldehydes in toluene,
hydrazones 7a–7d were formed in good yields (Scheme 3).
The molecular structure of 7a–7d was confirmed by IR
(vꢀCꢀN * 2,200 cm-1), 1H-NMR, and 13C-NMR spectra and
X-ray investigation of compound 7b (Fig. 1).
The subsequent opening of the five-membered cycles
was undergone as transformation of the unshared electron
Scheme 2
R2
Br
R2
BrHC
N N
*HBr
NH2
N
N
N
CHBr
R1
HC
R1
O
N
NaOAc 3 eq.
EtOH, reflux
N
NH2
1
H2N
4a-4g
2a-2g
-HBr
R2
N
R2
N
C
N
N
N
N
C
N
R1
R1
N
NH2
H2N
3a-3g
123

Hydrazine-1-carbonitriles
1339
Scheme 3
Br
N
N
NEt3
N
N
C
N
N
N
H2N
N
6
5
NH2
O
R1
CHO
R2
C
R
H2
NH2
N
N
R1
R2
N
N
N
C
R
N
N
N
N
8a, R1 = Ac, R2= CH3 (68%)
8b,
7a, R = C6H5 (72%)
R1 = R2 = -[CH2]4- (76%)
7b, R = 4-CH3OC6H4 (78%)
7c, R = 4-BrC6H4 (69%)
7d, R = 2-HOC6H4 (71%)
Experimental
Melting pointsweremeasured ona Kofler hot stage apparatus.
Elemental analyses for C, H and N were conducted using a
Perkin–Elmer C, H, N Analyzer; their results were found to be
in good agreement with the calculated values. IR spectra were
recorded on a NICOLET Avatar-360 spectrophotometer in
1
KBr pellets. The H-NMR spectra were performed on a
BRUKER DRX-400 (400 MHz) and Varian VXR-200 Mer-
cury (200 MHz) spectrometer in DMSO-d6 solution with
Me4Si as the internal standard. The 13C-NMR spectra were
recorded on a BRUKER DRX-400 spectrometer at 100 MHz
in DMSO-d6 solution with Me4Si as the internal standard. The
purity of all obtained compounds was checked by TLC on
SilufolUV254plates; spotswerevisualizedwith iodinevapor
and UV light.
Fig. 1 X-ray molecular structure of (E)-1-(4,6-dimethylpyrimidin-2-
yl)-2-((4-methoxyphenyl)methylene)hydrazine-1-carbonitrile (7b)
In the case of pentane-2,4-dione and cyclohexanone,
carbonyl compounds with active a-methylene groups, the
discussed reaction did not stop on the hydrazone formation
stage. The following attack of the a-methylenic moiety to
the nitrile group of 6 leads to 3,4-disubstituted 1-(4,6-
dimethylpyrimidin-2-yl)-5-aminopyrazoles 8a and 8b,
which are isomeric to the corresponding hydrazones
(Scheme 3). Our hypothesis of the formation of a pyrazole
ring is supported by the disappearance of the C:N bond
vibrations (vꢀCꢀN * 2,200 cm-1) and the appearance of
simply recognizable bands of the primary 5-amino group
1-(4,6-Diarylpyrimidin-2-yl)hydrazine-1-carbonitriles 3a–3c
2,3-Dibromo-1,3-diarylpropan-1-one 2a–2c (2.5 mmol)
was added to a solution of 0.45 g 3,4-diamino-1,2,4-
triazole hydrobromide (1, 2.5 mmol) and 0.615 g dry
sodium acetate (7.5 mmol) in 20 cm3 ethanol. 1-(4,6-
Diarylpyrimidin-2-yl)hydrazine-1-carbonitriles 3a–3c sep-
arated as white amorphous solids after refluxing the
reaction mixture for 18 h. The crude products were purified
by recrystallization from ethanol.
vibrations (vꢀNH * 3,370, 3,250 cm-1) in the IR spectra of
2
1
8a and 8b. The H- and 13C-NMR spectral data of 8a, 8b
1-(4,6-Diphenylpyrimidin-2-yl)hydrazine-1-carbonitrile
(3a, C17H13N5)
also confirmed our hypothesis and did not contradict to
similar data of the 1-alkyl-5-aminopyrazole derivative
described by Viehe [8].
Yield 65%; colorless needles. M.p.: 174–176 °C (EtOH);
IR (KBr): vꢀ = 3,429, 3,321 (NH2), 2,242 (C:N), 1,612,
123

1340
B. V. Paponov et al.
1
1,598 (C=N, C=C) cm-1; H-NMR (400 MHz, DMSO-d6,
20 °C): d = 5.84 (s, 2 H), 7.58–7.60 (m, 6 H), 8.34 (s, 1
H), 8.38–8.40 (m, 4 H) ppm; 13C-NMR (100 MHz, DMSO-
d6, 20 °C): d = 107.8, 112.9, 128.0, 129.4, 132.2, 136.0,
160.7, 166.1 ppm.
3-Amino-5-(4-bromophenyl)-7-(4-nitrophenyl)-3H-
[1,2,4]triazolo[1,5-a]pyrimidinium bromide
(4e, C17H12Br2N6O2)
Yield 89%; orange solid. M.p.: 213–215 °C; IR (KBr):
vꢀ = 3,431, 3,233 (NH2), 1,637, 1,584 (C=N, C=C), 1,531,
1,349 (NO2) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
1-(4-(4-Bromophenyl)-6-phenylpyrimidin-2-yl)
hydrazine-1-carbonitrile (3b, C17H12BrN5)
20 °C): d = 7.12 (s, 2 H), 7.96–7.98 (d, J = 8.8 Hz, 2
H), 8.44–8.46 (d, J = 8.8 Hz, 2 H), 8.53–8.55 (d,
J = 8.8 Hz, 2 H), 8.55–8.57 (d, J = 8.8 Hz, 2 H), 8.89
(s, 1 H), 9.86 (s, 1 H) ppm; 13C-NMR (100 MHz, DMSO-
d6, 20 °C): d = 112.9, 124.3, 128.8, 131.3, 132.6, 133.2,
133.5, 133.6, 147.8, 148.8, 149.1, 150.2, 165.4 ppm.
Yield 63%; colorless needles. M.p.: 176–178 °C (EtOH);
IR (KBr): vꢀ = 3,432, 3,327 (NH2), 2,244 (C:N), 1,616,
1
1,602 (C=N, C=C) cm-1; H-NMR (400 MHz, DMSO-d6,
20 °C): d = 5.86 (s, 2 H), 7.58–7.60 (m, 3 H), 7.79–7.81
(d, J = 8.8 Hz, 2 H), 8.36–8.37 (d, J = 8.3 Hz, 2 H) 8.38
(s, 1 H), 8.39–8.41 (d, J = 8.8 Hz, 2 H) ppm; 13C-NMR
(100 MHz, DMSO-d6, 20 °C): d = 107.7, 112.8, 126.1,
128.1, 129.4, 130.0, 132.3, 132.4, 135.3, 135.9, 160.7,
164.9, 166.3 ppm.
3-Amino-5-(4-chlorophenyl)-7-(4-nitrophenyl)-3H-
[1,2,4]triazolo[1,5-a]pyrimidinium bromide
(4f, C17H12BrClN6O2)
Yield 83%; orange solid. M.p.: 211–213 °C; IR (KBr):
vꢀ = 3,440, 3,231 (NH2), 1,640, 1,593 (C=N, C=C), 1,525,
1,352 (NO2) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
1-(4-(4-Chlorophenyl)-6-phenylpyrimidin-2-yl)
hydrazine-1-carbonitrile (3c, C17H12ClN5)
20 °C): d = 7.14 (s, 2 H), 7.82–7.84 (d, J = 8.3 Hz, 2
H), 8.45–8.47 (d, J = 8.3 Hz, 2 H), 8.56–8.57 (d,
J = 8.3 Hz, 2 H), 8.63–8.64 (d, J = 8.3 Hz, 2 H), 8.90
(s, 1 H), 9.87 (s, 1 H) ppm; 13C-NMR (100 MHz, DMSO-
d6, 20 °C): d = 113.0, 124.3, 130.2, 131.3, 132.6, 133.2,
133.6, 139.5, 147.8, 148.9, 149.1, 150.1, 165.2 ppm.
Yield 62%; colorless needles. M.p.: 180–182 °C; IR (KBr):
vꢀ = 3,434, 3,323 (NH2), 2,239 (C:N), 1,611, 1,600 (C=N,
C=C) cm-1
;
1H-NMR (400 MHz, DMSO-d6, 20 °C):
d = 5.87 (s, 2 H), 7.58–7.60 (m, 3 H), 7.66–7.68 (d,
J = 8.3 Hz, 2 H), 8.38 (s, 1 H), 8.40–8.42 (d, J = 8.8 Hz,
2 H), 8.44–8.46 (d, J = 8.3 Hz, 2 H) ppm; 13C-NMR
(100 MHz, DMSO-d6, 20 °C): d = 107.8, 112.8, 128.1,
129.4, 129.5, 129.9, 132.3, 134.9, 135.9, 137.1, 160.7,
164.8, 166.3 ppm.
3-Amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)-3H-
[1,2,4]triazolo[1,5-a]pyrimidinium bromide
(4g, C18H15BrN6O3)
Yield 88%; orange solid. M.p.: 206-208 °C; IR (KBr):
vꢀ = 3,426, 3,244 (NH2), 1,607, 1,595 (C=N, C=C), 1,549,
3-Amino-5-aryl -7-(4-nitrophenyl)-3H-[1,2,4]
triazolo[1,5-a]pyrimidinium bromides 4d–4g
1,347 (NO2) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 7.03 (s, 2 H), 7.25–7.27 (d, J = 8.3 Hz, 2
H), 8.42–8.43 (d, J = 7.8 Hz, 2 H), 8.54–8.55 (d,
J = 8.3 Hz, 2 H), 8.60–8.61 (d, J = 7.8 Hz, 2 H), 8.76
(s, 1 H), 9.76 (s, 1 H) ppm; 13C-NMR (100 MHz, DMSO-
d6, 20 °C): d = 56.4, 112.1, 115.6, 124.3, 126.6, 131.8,
132.5, 133.8, 147.8, 148.3, 150.1, 164.6, 165.8 ppm.
2,3-Dibromo-1-aryl-3-(4-nitrophenyl)propan-1-one 2d–2g
(2.5 mmol) was added to solution of 0.45 g 3,4-diamino-
1,2,4-triazole hydrobromide (1, 2.5 mmol) and 0.41 g dry
sodium acetate (5 mmol) in 50 cm3 ethanol. The mixture
was refluxed for 40 min, and the bright orange solid of
3-amino-7-(4-nitrophenyl)-5-aryl-3H-[1,2,4]triazolo[1,5-a]
pyrimidinium bromide 4 was filtered off and washed twice
with hot ethanol on a glass filter. Compounds 4d–4g were
used without further purification.
1-(6-Aryl-4-(4-nitrophenyl)pyrimidin-2-yl)hydrazine-1-
carbonitriles 3d–3g (from 3-amino-5-aryl-7-(4-nitrophenyl)-
3H-[1,2,4]triazolo[1,5-a]pyrimidinium bromides 4d–4g)
Triethylamine (0.21 cm3, 1.75 mmol) was added to
3-amino-5-aryl-7-(4-nitrophenyl)-3H-[1,2,4]triazolo[1,5-a]
pyrimidinium bromide 4d–4g (1.45 mmol) in 15 cm3
ethanol and refluxed for 10 min. White solids precipitated
after cooling the reaction mixture were filtered off and
washed twice with cold ethanol on a glass filter. 1-(6-Aryl-
4-(4-nitrophenyl)pyrimidin-2-yl)hydrazine-1-carbonitriles
3d–3g were separated as white amorphous powders.
3-Amino-7-(4-nitrophenyl)-5-phenyl-3H-[1,2,4]triazolo
[1,5-a]pyrimidinium bromide (4d, C17H13BrN6O2)
Yield 87%; orange solid. M.p.: 210–212 °C; IR (KBr):
vꢀ = 3,396, 3,201 (NH2), 1,630, 1,593 (C=N, C=C), 1,525,
1,354 (NO2) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 7.12 (s, 2 H), 7.73–7.74 (d, J = 7.3 Hz, 2
H), 7.77–7.79 (t, J = 7.3 Hz, 1 H), 8.45–8.47 (d,
J = 8.8 Hz, 2 H), 8.55–8.57 (d, J = 8.8 Hz, 2 H), 8.60–
8.61 (d, J = 7.3 Hz, 2 H), 8.87 (s, 1 H), 9.85 (s, 1 H) ppm;
13C-NMR (100 MHz, DMSO-d6, 20 °C): d = 112.9,
124.3, 129.5, 130.1, 132.6, 133.7, 134.3, 134.4, 147.8,
148.7, 148.9, 150.2, 166.5 ppm.
1-(4-(4-Nitrophenyl)-6-phenylpyrimidin-2-yl)hydrazine-1-
carbonitrile (3d, C17H12N6O2)
Yield 93%; white amorphous powder. M.p.: 218–220 °C;
IR (KBr): vꢀ = 3,439, 3,333 (NH2), 2,243 (C:N), 1,617,
123

Hydrazine-1-carbonitriles
1341
1
1,588 (C=N, C=C), 1,536, 1,353 (NO2) cm-1; H-NMR
(400 MHz, DMSO-d6, 20 °C): d = 5.91 (s, 2 H), 7.60–
7.62 (m, 3 H), 8.41–8.44 (m, 4 H), 8.52 (s, 1 H), 8.65–8.67
(d, J = 8.3 Hz, 2 H) ppm; 13C-NMR (400 MHz, DMSO-
d6, 20 °C): d = 109.0, 112.7, 124.5, 128.2, 129.4, 129.5,
132.5, 135.7, 142.0, 149.7, 160.8, 163.8, 166.8 ppm.
116 °C; IR (KBr): vꢀ = 3,411, 3,322 (NH2), 2,225 (C:N),
1
1,591 (C=N, C=C) cm-1; H-NMR (400 MHz, DMSO-d6,
20 °C): d = 2.43 (s, 6 H), 5.28 (s, 2 H), 6.58 (s, 1 H) ppm;
13C-NMR (100 MHz, DMSO-d6, 20 °C): d = 23.5, 111.7,
141.9, 159.0, 167.8 ppm.
Products 7a–7d and 8a, 8b were obtained under reaction
conditions described in Ref. [4a] for 1-alkylhydrazine-
1-carbonitriles by heating of 1-(4,6-dimethylpyrimidin-
2-yl)hydrazine-1-carbonitrile (6) and the appropriate
carbonyl compounds in toluene.
1-(6-(4-Bromophenyl)-4-(4-nitrophenyl)pyrimidin-2-
yl)hydrazine-1-carbonitrile (3e, C17H11BrN6O2)
Yield 91%; white amorphous powder. M.p.: 223–225 °C;
IR (KBr): vꢀ = 3,435, 3,332 (NH2), 2,242 (C:N), 1,619,
1
1,589 (C=N, C=C), 1,533, 1,349 (NO2) cm-1; H-NMR
1-(4,6-Dimethylpyrimidin-2-yl)-2-(phenylmethylene)hydra-
zine-1-carbonitrile (7a, C14H13N5)
(400 MHz, DMSO-d6, 20 °C): d = 5.92 (s, 2 H), 7.82–
7.84 (d, J = 8.3 Hz, 2 H), 8.38–8.40 (d, J = 8.8 Hz, 2 H),
8.42–8.44 (d, J = 8.3 Hz, 2 H), 8.55 (s, 1 H), 8.65–8.67 (d,
J = 8.8 Hz, 2 H) ppm; 13C-NMR (100 MHz, DMSO-d6,
20 °C): d = 109.0, 112.6, 124.5, 126.5, 129.4, 130.1,
132.5, 135.0, 141.9, 149.8, 160.8, 164.0, 165.6 ppm.
Yield 72%; white amorphous powder. M.p.: 178–180 °C;
IR (KBr): vꢀ = 2,234 (C:N), 1,631 (C=N), 1,603, 1,590
(C=N, C=C) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 2.52 (s, 6 H), 7.11 (s, 1 H), 7.52–7.55 (m, 3
H), 7.69–7.91 (d, J = 7.8 Hz, 2 H), 8.34 (s, 1 H) ppm; 13C-
NMR (100 MHz, DMSO-d6, 20 °C): d = 23.9, 105.9,
117.5, 128.6, 129.4, 131.7, 132.8, 149.7, 156.8,
169.4 ppm; MS (EI, 70 eV): m/z (rel. intensity) = 251
(M?, 18), 174 (19), 148 (100), 121 (15), 107 (54), 90 (20).
1-(6-(4-Chlorophenyl)-4-(4-nitrophenyl)pyrimidin-2-
yl)hydrazine-1-carbonitrile (3f, C17H11ClN6O2)
Yield 89%; white amorphous powder. M.p.: 219–221 °C;
IR (KBr): vꢀ = 3,434, 3,334 (NH2), 2,243 (C:N), 1,615,
1
1,588 (C=N, C=C), 1,534, 1,351 (NO2) cm-1; H-NMR
1-(4,6-Dimethylpyrimidin-2-yl)-2-((4-methoxy-
phenyl)methylene)hydrazine-1-carbonitrile
(7b, C15H15N5O)
(400 MHz, DMSO-d6, 20 °C): d = 5.91 (s, 2 H), 7.81–
7.83 (d, J = 8.8 Hz, 2 H), 8.38–8.40 (d, J = 8.3 Hz, 2 H),
8.43–8.45 (d, J = 8.8 Hz, 2 H), 8.55 (s, 1 H), 8.65–8.67 (d,
J = 8.3 Hz, 2 H) ppm; 13C-NMR (100 MHz, DMSO-d6,
20 °C): d = 109.0, 112.5, 124.4, 129.4, 129.5, 130.0,
134.6, 137.4, 141.9, 149.8, 160.8, 164.0, 165.5 ppm.
Yield 78%; white amorphous powder. M.p.: 174–176 °C;
IR (KBr): vꢀ = 2,227 (C:N), 1,618 (C=N), 1,599, 1,591
(C=N, C=C) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 2.45 (s, 6 H), 7.04 (s, 1 H), 7.14–7.16 (d,
J = 7.3 Hz, 2 H), 7.55–7.57 (d, J = 7.3 Hz, 2 H), 8.31 (s,
1 H) ppm; 13C-NMR (100 MHz, DMSO-d6, 20 °C):
d = 23.9, 56.1, 105.9, 117.3, 121.2, 130.6, 131.9, 140.6,
156.9, 169.4 ppm; MS (EI, 70 eV): m/z (rel. inten-
sity) = 281 (M?, 27), 266 (12), 250 (45),174 (17), 148
(100), 107 (84).
1-(6-(4-Methoxyphenyl)-4-(4-nitrophenyl)pyrimidin-2-
yl)hydrazine-1-carbonitrile (3g, C18H14N6O3)
Yield 93%; white amorphous powder. M.p.: 210–212 °C;
IR (KBr): vꢀ = 3,439, 3,333 (NH2), 2,234 (C:N), 1,609,
1
1,588 (C=N, C=C), 1,536, 1,353 (NO2) cm-1; H-NMR
(400 MHz, DMSO-d6, 20 °C): d = 3.86 (s, 3 H), 5.87 (s, 2
H), 7.12–7.14 (d, J = 8.8 Hz, 2 H), 8.39–8.41 (m, 5 H),
8.62–8.64 (d, J = 8.3 Hz, 2 H) ppm; 13C-NMR (100 MHz,
DMSO-d6, 20 °C): d = 56.0, 108.1, 112.7, 114.8, 124.4,
128.0, 129.3, 130.0, 142.2, 149.6, 160.7, 163.0, 163.3,
166.3 ppm.
2-((4-Bromophenyl)methylene)-1-(4,6-dimethylpyrimidin-
2-yl)hydrazine-1-carbonitrile (7c, C14H12BrN5)
Yield 78%; white amorphous powder. M.p.: 194–196 °C;
IR (KBr): vꢀ = 2,237 (C:N), 1,632 (C=N), 1,606, 1,592
(C=N, C=C) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 2.43 (s, 6 H), 7.09 (s, 1 H), 7.71–7.73 (d,
J = 7.8 Hz, 2 H), 7.79–7.81 (d, J = 7.8 Hz, 2 H), 8.41 (s,
1 H) ppm; 13C-NMR (100 MHz, DMSO-d6, 20 °C):
d = 23.9, 105.7, 117.6, 125.2, 130.4, 132.1, 148.5, 156.7,
169.5 ppm; MS (EI, 70 eV): m/z (rel. intensity) = 331
(M?, 5), 174 (6), 157 (8), 148 (100), 107 (37), 90 (22).
1-(4,6-Dimethylpyrimidin-2-yl)hydrazine-1-carbonitrile
(6, C7H9N5)
Triethylamine (2.1 cm3, 17.5 mmol) was added to a
solution of 3.5 g 3-amino-5,7-dimethyl[1,2,4]triazolo[1,5-
a]pyrimidin-8-ium bromide (14.3 mmol) in 20 cm3 water
and refluxed for 20 min. The hot reaction mixture was
extracted with tetrachloromethane (3 9 15 cm3), and the
crude 1-(4,6-dimethylpyrimidin-2-yl)hydrazine-1-carboni-
trile (2 g, 12.4 mmol) was filtered off from the
tetrachloromethane extract. The crude product was purified
by recrystallization from tetrachloromethane to afford
white needles. Yield 87%; colorless needles. M.p.: 114–
1-(4,6-Dimethylpyrimidin-2-yl)-2-((2-hydroxyphenyl)meth-
ylene)hydrazine-1-carbonitrile (7d, C14H13N5O)
Yield 71%; white amorphous powder. M.p.: 191–193 °C;
IR (KBr): vꢀ = 3,567 (OH), 2,231 (C:N), 1,628 (C=N),
1,600, 1,587 (C=N, C=C) cm-1 1H-NMR (400 MHz,
;
DMSO-d6, 20 °C): d = 2.42 (s, 6 H), 6.94–6.96 (m, 2 H),
123

1342
B. V. Paponov et al.
7.04 (s, 1 H), 7.12–7.13 (dd, J = 7.3 Hz, 1 H), 7.26–7.27
(dd, J = 7.3 Hz, 1 H), 7.85–7.86 (d, J = 7.3 Hz, 1 H),
8.47 (s, 1 H), 10.21 (s, 1 H) ppm; 13C-NMR (100 MHz,
DMSO-d6, 20 °C): d = 23.9, 105.6, 117.4, 118.4, 120.1,
129.1, 133.3, 147.5, 156.6, 157.7, 169.5 ppm; MS (EI,
70 eV): m/z (rel. intensity) = 267 (M?, 40), 239 (5), 226
(8), 149 (100), 107 (76), 91 (25).
using the SHELXTL package [23]. Positions of hydrogen
atoms were located from electron density difference maps and
refined in isotropic approximation. Full-matrix least-squares
refinement against F2 in anisotropic approximation using
4,087 reflections was converged to wR2 = 0.146 [R1 = 0.055
for 3,045 reflections with F[4r(F), S = 1.070]. Atomic
coordinates and crystallographic parameters have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC-647644).
1-(5-Amino-1-(4,6-dimethylpyrimidin-2-yl)-3-meth-
ylpyrazol-4-yl)ethanone (8a, C12H15N5O)
Yield 68%; white amorphous powder. M.p.: 242–244 °C;
IR (KBr): vꢀ = 3,383, 3,277 (NH2), 1,698 (C=O), 1,637,
1,610, 1,593 (C=N, C=C) cm-1 1H-NMR (400 MHz,
;
References
DMSO-d6, 20 °C): d = 2.34 (s, 3 H), 2.37 (s, 3 H), 2.44 (s,
6 H), 7.16 (s, 1 H), 8.18 (s, 2 H) ppm; 13C-NMR
(100 MHz, DMSO-d6, 20 °C): d = 16.1, 23.9, 29.7, 104.0,
117.3, 150.0, 153.7, 156.8, 168.8, 192.3 ppm; MS (EI,
70 eV): m/z (rel. intensity) = 245 (M?, 90), 230 (100), 163
(19), 123 (28), 107 (37).
1. Makino K, Kini HS, Kurasawa Y (1999) J Heterocycl Chem
36:321
2. Wiley RH, Hexner PE (1963) Org Synth Coll 4:351
3. Gribble GW (2000) J Chem Soc Perkin Trans 1:1045
4. Robinson B (1969) Chem Rev 69:227
5. Robinson B (1963) Chem Rev 63:373
6. Tisler M, Stanovnik B (1990) Adv Heterocycl Chem 49:385
7. Lutz RE, King SM (1952) J Org Chem 17:1519
8. Rykmans T, Viehe HG, Feneau-Dupont G, Tinat B, Declerq GP
(1997) Tetrahedron 53:1729
2-(4,6-Dimethylpyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-
indazol-3-amine (8b, C13H17N5)
Yield 76%; white amorphous powder. M.p.: 227–229 °C;
IR (KBr): vꢀ = 3,362, 3,241 (NH2), 1,622, 1,608, 1,592
9. Pellizari G (1907) Gazz Chim Ital 37:620
10. Pilgram KH, Skiles RD (1983) J Heterocycl Chem 20:1533
11. Maiboroda DA, Babaev EV (1995) Chem Heterocycl Compd
(Engl Transl) 1445
(C=N, C=C) cm-1
;
1H-NMR (400 MHz, DMSO-d6,
20 °C): d = 1.74 (s, 4 H), 2.44 (s, 6 H), 2.49 (s, 2 H),
2.52 (s, 2 H), 7.16 (s, 1 H), 8.78 (s, 2 H) ppm; 13C-NMR
(100 MHz, DMSO-d6, 20 °C): d = 23.6, 27.9, 28.1, 43.6,
43.8, 104.6, 142.1, 143.6, 148.7, 158.8, 168.2 ppm; MS
(EI, 70 eV): m/z (rel. intensity) = 243 (M?, 84), 215 (100),
149 (7), 134 (7), 121 (5), 107 (21).
12. Kolos NN, Orlov VD, Paponov BV, Shishkin OV, Baumer SV,
Kvashnitskaya NA (1999) Chem Heterocycl Compd (Engl
Transl) 708
13. Kolos NN, Orlov VD, Paponov BV, Shishkin OV (2001) Chem
Heterocycl Compd (Engl Transl) 338
14. Breslow R (1957) J Am Chem Soc 79:1762
15. Breslow R (1958) J Am Chem Soc 80:3719
16. Gallo AA, Sable HZ (1974) J Biol Chem 249:1382
17. Gilchrist TL (1987) Adv Heterocycl Chem 41:41
18. Revankar GR, Robins RK, Tolman RL (1974) J Org Chem
39:1256
19. Hori M, Tanaka K, Kataoka T, Shimizu H, Imai E, Kimura K,
Hashimoto Y (1985) Tetrahedron Lett 26:1321
20. Konyukhov VN, Dianova LN, Koksharova TG, Volkova NV,
Bakulev VA, Anisimova OS (1985) Chem Heterocycl Compd
(Engl Transl) 335
21. Hori M, Tanaka K, Kataoka T, Shimizu H, Imai E, Kimura K,
Hashimoto Y (1985) J Chem Soc Perkin Trans 1:2333
22. Pashinnik VE, Golubushina GM, Chuiguk VA (1973) Ukr Khim
Zh (Russ Ed) 39:1040
23. Sheldrick GM, SHELXTL PLUS. PC Version (1998) A system of
computer programs for the determination of crystal structure from
X-ray diffraction data, Rev 5.1
X-ray structure determination of 7b
˚
Crystals of 7b are monoclinic. a = 11.041(1) A, b =
˚
˚
9.167(1) A, c = 14.908(2) A, b = 10.62(1)°, V = 1,412.1(3)
3
A , Mr = 281.32, Z = 4, space group P21/c, Dcalc
1.323 g cm-3
˚
=
, , F(000) = 592;
l(MoKa) = 0.088 mm-1
crystal size ca. 0.11 9 0.18 9 0.32 mm3. All crystallo-
graphic measurements were performed at 100 K. Intensities
of 13,143 reflections (4,139 independent, Rint = 0.046) were
measured on the ‘‘Xcalibur-3’’ diffractometer (graphite
monochromated MoKa radiation, CCD detector, x-scans,
2Hmax = 60°). The structure was solved by direct methods
123