Cyanoacetylation of 5-Aminopyrazole: Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile derivatives

Article abstract of DOI:10.1515/znb-2009-0712

N1-Substituted-5-amino-4-cyanopyrazoles were cyanoacetylated with a mixture of cyanoacetic acid and acetic anhydride. Cyclization with POCl3 gave 4-chloro-pyrazolo[3,4-d]pyrimidine derivatives. From the reaction with hydrazine and arylhydrazines, the hydrazinyls and their oxidized forms, the azo products, were obtained. The structure of the compounds obtained has been confirmed by ¹H and ¹³C NMR spectroscopy.

Full text of DOI:10.1515/znb-2009-0712

Cyanoacetylation of 5-Aminopyrazole: Synthesis of 2-(1-Aryl-4-
substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
Abdellatif M. Salaheldin
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
Present address: Centro de Qu´ımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga,
Portugal
Reprint requests to Dr. A. M. Salaheldin. E-mail: amsalaheldin@yahoo.com,
salaheldin@quimica.uminho.pt
Z. Naturforsch. 2009, 64b, 840 – 846; received March 19, 2009
N1-Substituted-5-amino-4-cyanopyrazoles were cyanoacetylated with a mixture of cyanoacetic
acid and acetic anhydride. Cyclization with POCl3 gave 4-chloro-pyrazolo[3,4-d]pyrimidine deriva-
tives. From the reaction with hydrazine and arylhydrazines, the hydrazinyls and their oxidized forms,
the azo products, were obtained. The structure of the compounds obtained has been confirmed by 1H
and 13C NMR spectroscopy.
Key words: Cyanoacetylations, Cyanopyrazoles, Pyrazolo[3,4-d]pyrimidines, Acetonitrile Derivatives
Introduction
olo[3,4-d]pyrimidine derivatives as antioxidants [12].
With the objective of synthesizing members of this
class of compounds we started from the key intermedi-
ates 5a – c (2-cyano-N-(1-aryl-4-cyano-1H-pyrazol-5-
yl)acetamides). These compounds are readily prepared
from 3 using a synthetic strategy depicted in Scheme 1.
Pyrazole and pyrimidine derivatives received con-
siderable attention from organic chemists due to their
biological and chemotherapeutic importance. Pyr-
azolopyrimidines and related fused heterocycles are
of interest as potential bioactive molecules. They are
known to function as CNS (Central Nervous Sys-
tem) depressants [1], neuroleptic agents [2], and tu-
berculostatic agents [3]. Pyrazolo[3,4-d]pyrimidines
were identified as a general class of adenosine recep-
tors [4, 5]. Moreover, a series of [1-aryl-1H-pyrazolo
[3,4-d]pyrimidin-4-yl]arylhydrazoneswere discovered
as novel inhibitors of glycogen synthase kinase-3
(GSK-3) [6].
Heterocycles containing a cyanoacetyl group are
relatively unexplored. Most of the reported prepa-
rations involved nucleophilic displacement of halide
in haloacetyl derivatives by cyanide [7], or of an
alkyl carboxylates using acetonitrile in the presence
of a strong base, like sodium amide [8]. The cy-
anoacetylating reagent (acetic anhydride and cyano-
acetic acid under heating) has been used in the syn-
thesis of 6-aminouracils via urea [9] and N-acetyla-
tion and C-acetylation of enamines [10]. Other acti-
vation procedures, such as conversion to cyanoacet-
yl chloride, have also been described, although this
reagent has the tendency to self-polymerize (particu-
larly when heated) [11]. We have concentrated our at-
tention on ortho-aminocyanopyrazolesand their pyraz-
Result and Discussions
The N1-substituted 5-amino-4-cyanopyrazoles 3
[13] were used as starting materials as they contain an
amino and a cyano group in adjacent positions, which
is required for the synthesis of the condensed systems
including pyrimidine [14 – 16]. When compound 3a
was heated in refluxing acetic anhydride, the diacetyl
derivative 4 was obtained. In order to get cyanoacetyl-
ation, the pyrazoles 3a – c were poured onto a solution
of the cyanoacetylating reagent (cyanoacetic acid and
◦
acetic anhydride) and heated to 95 C for 30 min. N-
Substituted 2-cyanoacetamide derivatives 5a – c were
isolated as solid products by simple filtration, and no
C-acetylation products were isolated. The structures
of 5a – c were confirmed by elemental analyses and
1
spectral (MS, IR and H NMR) data (see Experimen-
1
tal Section). For example, their H NMR spectra in
[D6]DMSO revealed, in each case, a characteristic sig-
nal in the region δ = 4.0 – 4.2 assignable to the –CH2–
protons, at δ = 8.1 – 8.3 for the pyrazole 3-H and at δ =
10.9 – 11.1 for the NH proton. The IR spectra showed
the characteristic band for the N–H stretch of the NH
c
0932–0776 / 09 / 0700–0840 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
841
Scheme 1.
group in the region 3350 – 3180 cm−1 and character- 4-aminopyrazolo[3,4-d]pyrimidine derivatives 8a, b
istic bands for the C=O stretch in the region 1700– were obtained [14].
1730 cm−1
.
When compounds 7a, b were treated with hydrazine
When any of the 2-cyanoacetamide derivatives 5a – hydrate in ethanol at reflux temperature, they afforded
c was refluxed in acetic acid, it cyclized into the the corresponding hydrazinyl derivatives 9a, b, respec-
corresponding 4-hydroxypyrazolopyrimidine deriva- tively. The 1H NMR spectrum of compound 9a showed
tive (6a – c). The structures of 6a – c were confirmed a signal at δ = 4.94 ppm (s, 2H, NH2, exchange-
by spectral and elemental analysis. Heating of com- able with D2O), and a signal at δ = 9.32 ppm (s,
pounds 6a – c in POCl3 afforded the 4-chloro deriva- 1H, NH, exchangeable with D2O). Compound 10 was
tives 7a – c. Compounds 7 can be prepared via the one- prepared by condensation of the hydrazinyl derivative
pot reaction of compounds 5 with POCl3. The products 9b with the p-methoxybenzaldehyde [6] (Scheme 2).
isolated were the 4-chloropyrazolo[3,4-d]pyrimidine The structure of hydrazone 10 was confirmed based
derivatives 7a – c, whose spectral characteristics were on spectroscopic and elemental analysis data. The
completely coincident with the samples obtained be- 1H NMR spectrum of compound 10 revealed a signal
fore (Scheme 1).
at δ = 8.34 ppm for the N=CH proton and a signal at
Moreover, recently we described the reaction of δ = 12.15 ppm (s, 1H, NH, exchangeable with D2O).
compounds 3a, b with malononitrile form which the
Similarly, when 7a – c were reacted with phenylhy-
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A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
Scheme 2.
drazine derivatives under reflux condition, the arylhy- tered on a Perkin Elmer FTIR-1600 instrument using Nujol
emulsions between NaCl plates. 1H NMR (300 MHz) and
drazinyl derivatives 11a – c were obtained. All these
13C NMR (75.4 MHz) spectra were recorded in [D6]DMSO
hydrazinyls have not been reported hitherto. Their
or CDCl3 on a Varian Unity Plus spectrometer using tetra-
structures were confirmed by their elemental and spec-
tral analyses (MS, IR and 1H, 13C NMR) data (see Ex-
methylsilane (TMS) as an internal reference, and results
are expressed as δ values. Double resonance HMQC and
perimental Section). For example, the 1H NMR spectra
of compound 11b revealed two singlet signals at δ =
8.30 and 10.0 ppm for the two NH groups.
Treatment of the hydrazinyl derivatives 11a – c with
2 equivalents of iron(III) chloride in ethanol for 2 h
HMBC experiments were carried out for complete assign-
ment of proton and carbon signals in the NMR spectra, when-
ever possible. Mass spectra were performed on a Shimadzu
GCMS-QP 1000 Ex mass spectrometer at 70 eV. Elemen-
tal analyses were obtained on a Leco CHNS-932 instrument.
at r. t. gave, in each case, the corresponding azo prod-
uct, as evidenced by TLC analysis. Elemental analy-
ses and mass spectra revealed that each of the isolated
products has two hydrogens less than the respective
hydrazinyl derivative. This finding was confirmed by
Compounds 3a – c were prepared as previously reported by
us [14, 15].
N-Acetyl-N-(4-cyano-1-phenyl-1H-pyrazol-5-yl)acetamide
(4)
1
the H NMR spectra, which indicated the absence of
A mixture of 5-amino-4-cyano-1-phenylpyrazole (3a)
(0.01 mol) and 20 mL of acetic anhydride was heated under
reflux for 7 h and then evaporated under reduced pressure.
The residue was treated with ethanol, and the solid product so
formed was collected by filtration, washed with ethanol and
the two NH protons. On the basis of this finding, the
isolated products were assigned the diazenyl structures
12a – c (Scheme 2). Moreover, compound 12 could be
converted into compound 11 by reduction using zinc in
acetic acid. Compound 8 was not obtained. These re-
sults also prove the correct structures of compounds 11
and 12, as suggested in Scheme 2.
◦
crystallized from EtOH. M. p. 132 – 134 C. Yield: 72 %. –
IR (Nujol): ν = 2210 (CN), 1688 (C=O), cm−1. – 1H NMR
◦
(300 MHz, CDCl3, 25 C, TMS): δ = 2.28 (s, 6H, 2CH3),
7.35 – 7.38 (m, 2H, Ar-H), 7.50 – 7.52 (m, 3H, Ar-H), 8.07
Experimental Section
(s, 1H, 3-H). – MS (EI, 70 eV): m/z (%) = 268 (74) [M]+. –
Melting points were determined on a Gallenkamp melting C14H12N4O2 (268.27): calcd. C 62.68, H 4.51, N 20.88;
point apparatus and are uncorrected. IR spectra were regis- found C 62.78, H 4.55, N 20.64.
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A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
843
General procedure for the preparation of 2-cyano-N-
reduced pressure. The residue was treated with water, and the
(4-cyano-1-substituted-1H-pyrazol-5-yl)acetamides 5a – c
solid product so formed was collected by filtration, washed
with ethanol and crystallized from EtOH-DMF (2 : 1).
Pyrazole derivatives 3a – c (0.02 mol) were added to a
mixture of cyanoacetic acid (0.03 mol) and Ac2O (30 mL)
and heated at 95 ◦C for 30 min. The mixture was allowed to
cool and poured on ice. The precipitate formed was collected,
washed with EtOH and dried.
2-[4-Hydroxy-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]
acetonitrile (6a)
◦
M. p. 299 – 301 C. Yield: 86 %. – IR (KBr): ν = 3327
(OH), 2227 (CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 ◦C, TMS): δ = 4.25 (s, 2H, CH2), 7.40 (t, 1H, J =
7.9 Hz, 4ꢀ-H), 7.56 (t, 2H, J = 7.9 Hz, 3ꢀ, 5ꢀ-H), 8.03 (d,
2H, J = 7.6 Hz, 2ꢀ, 6ꢀ-H), 8.32 (s, 1H, 3-H), 12.62 (s, 1H,
OH). – 13C NMR (75.4 MHz, [D6]DMSO): δ = 24.42 (CH2),
106.21 (C-3a), 115.34 (CN), 121.34 (C-2ꢀ,6ꢀ), 127.15 (C-4ꢀ),
129.25 (C-3ꢀ,5ꢀ), 136.06 (C-3), 138.23 (C-1ꢀ), 151.46 (C-7a),
152.58 (C-6), 157.37 (C-4). – MS (EI, 70 eV): m/z (%) = 251
(68) [M]+. – C13H9N5O (251.24): calcd. C 62.15, H 3.61,
N 27.87; found C 62.24, H 3.57, N 27.74.
2-Cyano-N-(4-cyano-1-phenyl-1H-pyrazol-5-yl)acetamide
(5a)
M. p. 160 – 161 ◦C (EtOH). Yield: 75 %. – IR (Nujol): ν =
3202 (NH), 2227, 2215 (CN), 1737 (C=O) cm−1. – 1H NMR
(300 MHz, [D6]DMSO, 25 ◦C, TMS): δ = 3.99 (s, 2H, CH2),
7.52 – 7.54 (m, 5H, Ar-H), 8.29 (s, 1H, 3-H), 11.04 (s, 1H,
NH). – 13C NMR (75.4 MHz, [D6]DMSO): δ = 25.94 (CH2),
89.45 (C-4), 112.50 (CN), 115.16 (CN), 124.05 (C-2ꢀ,6ꢀ),
128.99 (C-4ꢀ), 129.59 (C-3ꢀ,5ꢀ), 137.08 (C-1ꢀ), 139.58 (C-5),
142.61 (C-3), 162.27 (CO). – MS (EI, 70 eV): m/z (%) = 251
(77) [M]+. – C13H9N5O (251.24): calcd. C 62.15, H 3.61,
N 27.87; found C 61.97, H 3.69, N 27.79.
2-[1-(4-Chlorophenyl)-4-hydroxy-1H-pyrazolo[3,4-d]-
pyrimidin-6-yl]acetonitrile (6b)
◦
M. p. 308 – 310 C. Yield: 81 %. – IR (KBr): ν = 3330
(OH), 2225 (CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 ◦C, TMS): δ = 4.27 (s, 2H, CH2), 7.61 (d, 2H, J = 9.3 Hz,
3ꢀ, 5ꢀ-H), 8.26 (d, 2H, J = 9.3 Hz, 2ꢀ, 6ꢀ-H), 8.38 (s, 1H, 3-H),
12.70 (s, 1H, OH). – 13C NMR (75.4 MHz, [D6]DMSO): δ =
27.18 (CH2), 100.32 (C-3a), 117.36 (CN), 121.18 (C-2ꢀ,6ꢀ),
129.82 (C-3ꢀ,5ꢀ), 130.23 (C-4ꢀ), 135.63 (C-3), 137.78 (C-1ꢀ),
153.90 (C-7a), 158.69 (C-6), 159.93 (C-4). – MS (EI, 70 eV):
m/z (%) = 285 (81) [M, 35Cl]+, 287 (19) [M, 37Cl]+. –
C13H8ClN5O (285.69): calcd. C 54.65, H 2.82, N 24.51;
found C 54.79, H 2.98, N 24.64.
N-[1-(4-Chlorophenyl)-4-cyano-1H-pyrazol-5-yl]-2-cyano-
acetamide (5b)
M. p. 216 – 217 ◦C (EtOH). Yield: 70 %. – IR (Nujol): ν =
3220 (NH), 2228, 2211 (CN), 1724 (C=O) cm−1. – 1H NMR
(300 MHz, [D6]DMSO, 25 ◦C, TMS): δ = 4.0 (s, 2H, CH2),
7.43 – 7.59 (m, 4H, Ar-H), 8.31 (s, 1H, 3-H), 11.05 (s, 1H,
NH). – MS (EI, 70 eV): m/z (%) = 285 (90) [M, 35Cl]+, 287
(26) [M, 37Cl]+. – C13H8ClN5O (285.69): calcd. C 54.65,
H 2.82, N 24.51; found C 54.72, H 3.09, N 24.70.
2-[4-Hydroxy-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]
2-Cyano-N-(4-cyano-1-p-tolyl-1H-pyrazol-5-yl)acetamide
acetonitrile (6c)
(5c)
◦
◦
M. p. 312 – 314 C. Yield: 80 %. – IR (KBr): ν = 3320
M. p. 212 – 214 C (EtOH). Yield: 79 %. – IR (Nujol):
(OH), 2216 (CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 ◦C, TMS): δ = 2.30 (s, 3H, CH3), 4.21 (s, 2H, CH2), 7.53
(d, 2H, J = 8.8 Hz, 3ꢀ, 5ꢀ-H), 8.08 (d, 2H, J = 8.8 Hz, 2ꢀ,
6ꢀ-H), 8.35 (s, 1H, 3-H), 12.58 (s, 1H, OH). – 13C NMR
(75.4 MHz, [D6]DMSO): δ = 27.77 (CH2), 100.13 (C-3a),
117.61 (CN), 124.66 (C-2ꢀ,6ꢀ), 129.54 (C-3ꢀ,5ꢀ), 134.14
(C-3), 136.45 (C-4ꢀ), 138.86 (C-1ꢀ), 153.75 (C-7a), 158.34
(C-6), 159.76 (C-4). – MS (EI, 70 eV): m/z (%) = 265
(76) [M]+. – C14H11N5O (265.27): calcd. C 63.39, H 4.18,
N 26.40; found C 63.54, H 4.30, N 26.54.
ν = 3198 (NH), 2237, 2219 (CN), 1723 (C=O) cm−1. –
1H NMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ =
2.36 (s, 3H, CH3), 3.98 (s, 2H, CH2), 7.32 – 7.42 (m, 4H,
Ar-H), 8.27 (s, 1H, 3-H), 10.97 (s, 1H, NH). – 13C NMR
(75.4 MHz, [D6]DMSO): δ = 20.62 (CH3), 25.88 (CH2),
89.27 (C-4), 112.51 (CN), 115.13 (CN), 122.93 (C-2ꢀ,6ꢀ),
129.92 (C-3ꢀ,5ꢀ), 134.63 (C-4ꢀ), 138.68 (C-1ꢀ), 139.44 (C-5),
142.40 (C-3), 162.22 (CO). – MS (EI, 70 eV): m/z (%) = 265
(80) [M]+. – C14H11N5O (265.27): calcd. C 63.39, H 4.18,
N 26.40; found C 63.47, H 3.99, N 26.29.
General procedure for the preparation of 2-(1-aryl-4-
hydroxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetonitriles
6a – c
General procedure for the preparation of 2-(1-aryl-4-chloro-
1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetonitriles 7a – c
A mixture of 4-hydroxypyrazolopyrimidines 6a – c or
A mixture of 5a – c (0.01 mol) and acetic acid (20 mL) cyanoacetamide derivatives 5a – c (0.01 mol) and phosphorus
was heated under reflux for 6 h and then evaporated under oxychloride (25 mL) was refluxed for 7 h. After completion
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A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
◦
of the reaction, the excess of phosphorus oxychloride was re- [D6]DMSO, 25 C, TMS): δ = 4.14 (s, 2H, CH2), 4.94 (s,
moved under vacuum. The cooled reaction mixture was then 2H, NH2), 7.29 – 7.35 (m, 1H, 4ꢀ-H), 7.50 – 7.56 (m, 2H, 3ꢀ,
added to crushed ice (25 g). The resulting solid was filtered, 5ꢀ-H), 8.19 – 8.22 (m, 2H, 2ꢀ, 6ꢀ-H), 8.57 (s, 1H, 3-H), 9.32
washed with sodium bicarbonate (5 % w/v) followed by cold (s, 1H, NH). – MS (EI, 70 eV): m/z (%) = 265 (76) [M]+. –
water, dried, and crystallized from ethanol and chloroform C13H11N7 (265.27): calcd. C 58.86, H 4.18, N 36.96; found
(8 : 2 v/v).
C 58.80, H 4.25, N 37.20.
2-[4-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-
acetonitrile (7a)
2-[1-(4-Chlorophenyl)-4-hydrazinyl-1H-pyrazolo[3,4-d]-
pyrimidin-6-yl]acetonitrile (9b)
◦
M. p. 138 – 139 C. Yield: 72 %. – IR (KBr): ν = 2221
◦
M. p. 256 – 258 C. Yield: 73 %. – IR (KBr): ν = 3420 –
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 4.61 (s, 2H, CH2), 7.42 – 7.47 (m, 1H, 4ꢀ-H),
7.58 – 7.65 (m, 2H, 3ꢀ, 5ꢀ-H), 8.15 – 8.18 (m, 2H, 2ꢀ, 6ꢀ-H),
8.78 (s, 1H, 3-H). – 13C NMR (75.4 MHz, [D6]DMSO): δ =
25.24 (CH2), 107.14 (C-3a), 116.62 (CN), 121.04 (C-2ꢀ,6ꢀ),
126.80 (C-4ꢀ), 129.44 (C-3ꢀ,5ꢀ), 137.14 (C-3), 138.89 (C-1ꢀ),
152.19 (C-7a), 153.10 (C-4), 158.98 (C-6). – MS (EI, 70 eV):
m/z (%) = 269 (77) [M, 35Cl]+, 271 (20) [M, 37Cl]+. –
C13H8ClN5 (269.69): calcd. C 57.90, H 2.99, N 25.97; found
C 57.81, H 2.85, N 26.15.
1
3325 (NH, NH2), 2215 (CN) cm−1. – H NMR (300 MHz,
◦
[D6]DMSO, 25 C, TMS): δ = 4.18 (s, 2H, CH2), 4.96 (s,
2H, NH2), 7.59 (d, 2H, J = 9.0 Hz, Ar-H), 8.30 (d, 2H,
J = 9.0 Hz, Ar-H), 8.58 (s, 1H, 3-H), 9.38 (s, 1H, NH). –
MS (EI, 70 eV): m/z (%) = 299 (68) [M, 35Cl]+, 301 (14)
[M, 37Cl]+. – C13H10ClN7 (299.72): calcd. C 52.10, H 3.36,
N 32.71; found C 52.22, H 3.49, N 32.89.
2-[1-(4-Chlorophenyl)-4-(2-(4-methoxybenzylidene)hydra-
zinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]acetonitrile (10)
2-[4-Chloro-1-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-
To a mixture of 4-hydrazinopyrazolo[3,4-d]pyrimidine 9b
(2 mmol) and p-methoxy benzaldehyde (3 mmol) in ethanol
(30 mL), a few drops of acetic acid were added and the re-
action mixture refluxed for 2 h and then cooled. The pre-
cipitate, formed upon cooling, was filtered off, washed with
water and then with ethanol and finally crystallized from
dioxane to give the hydrazone derivative 10. M. p. 268 –
288 ◦C. Yield: 81 %. – IR (KBr): ν = 3265 (NH), 2229
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 3.81 (s, 3H, OCH3), 4.15 (s, 2H, CH2), 7.04
(d, 2H, J = 8.8 Hz, 3ꢀꢀ,5ꢀꢀ-H), 7.62 (d, 2H, J = 9.0 Hz,
3ꢀ,5ꢀ-H), 7.77 (d, 2H, J = 9.0 Hz, 2ꢀ,6ꢀ-H), 8.27 (d, 2H, J =
8.8 Hz, 2ꢀꢀ,6ꢀꢀ-H), 8.34 (s, 1H, N=CH), 8.61 (s, 1H, 3-H),
12.15 (s, 1H, NH). – 13C NMR (75.4 MHz, [D6]DMSO):
δ = 25.94 (CH2), 55.31 (OCH3), 100.69 (C-3a), 114.54
(C-3ꢀꢀ,5ꢀꢀ), 115.89 (CN), 122.14 (C-2ꢀ,6ꢀ), 146.58 (C-1ꢀꢀ),
128.69 (C-3ꢀ,5ꢀ), 129.17 (C-2ꢀꢀ,6ꢀꢀ), 130.21 (C-4ꢀ), 136.98
(C-3), 137.68 (C-1ꢀ), 146.18 (N=CH), 153.97 (C-7a), 156.04
(C-6), 156.96 (C-4), 160.83 (C-4ꢀꢀ). – MS (EI, 70 eV):
m/z (%) = 417 (71) [M, 35Cl]+, 419 (21) [M, 37Cl]+. –
C21H16ClN7O (417.85): calcd. C 60.36, H 3.86, N 23.46;
found C 60.21, H 3.69, N 23.54.
pyrimidin-6-yl]acetonitrile (7b)
◦
M. p. 123 – 125 C. Yield: 61 %. – IR (KBr): ν = 2227
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 4.71 (s, 2H, CH2), 7.54 (d, 2H, J = 8.7 Hz, 3ꢀ,
5ꢀ-H), 8.20 (d, 2H, J = 8.7 Hz, 2ꢀ, 6ꢀ-H), 8.88 (s, 1H, 3-H). –
C13H7Cl2N5 (304.13): calcd. C 51.34, H 2.32, N 23.03;
found C 51.50, H 2.58, N 23.19.
2-[4-Chloro-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-
acetonitrile (7c)
◦
M. p. 145 – 146 C. Yield: 70 %. – IR (KBr): ν = 2224
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 2.29 (s, 3H, CH3), 4.60 (s, 2H, CH2), 7.37 (d,
2H, J = 9.0 Hz, 3ꢀ, 5ꢀ-H), 7.90 (d, 2H, J = 9.0 Hz, 2ꢀ, 6ꢀ-H),
8.62 (s, 1H, 3-H). – MS (EI, 70 eV): m/z (%) = 283 (85) [M,
35Cl]+, 285 (22) [M, 37Cl]+. – C14H10ClN5 (283.72): calcd.
C 59.27, H 3.55, N 24.68; found C 59.39, H 3.41, N 24.85.
General procedure for the preparation of 4-hydrazino
derivatives 9a – c
Compound 7a,b (3 mmol) was dissolved in 20 mL of ab-
solute ethanol, then 2 mL of hydrazine hydrate (99 %) was
added, and the reaction mixture was heated at reflux tem-
perature for 3 h, evaporated under reduced pressure, and the
residue was recrystallized from dioxane.
General procedure for the preparation of 11a – c
To a solution of 4-chloropyrazolo[3,4-d]pyrimidines 7a –
c (0.01 mol) in ethanol (20 mL) was added the phenylhydr-
azine derivative (0.01 mol) and a catalytic amount of triethyl-
amine. The reaction mixture was heated under reflux for 3 h,
left to cool to r. t. and then poured onto ice. The solid formed
2-[4-Hydrazinyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-
6-yl]acetonitrile (9a)
◦
M. p. 246 – 248 C. Yield: 80 %. – IR (KBr): ν = 3420 – was filtered off and crystallized from EtOH to produce the
3307 (NH, NH2), 2215 (CN) cm−1. – H NMR (300 MHz, product as a white powder.
1
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A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
845
2-[4-(2-(4-Methoxyphenyl)hydrazinyl)-1-phenyl-1H-
2-[4-((4-Methoxyphenyl)diazenyl)-1-phenyl-1H-pyrazolo-
pyrazolo[3,4-d]pyrimidin-6-yl]acetonitrile (11a)
[3,4-d]pyrimidin-6-yl]acetonitrile (12a)
◦
◦
M. p. 224 – 225 C. Yield: 76 %. – IR (KBr): ν = 3240
M. p. 168 – 170 C. Yield: 70 %. – IR (KBr): ν = 2210
(NH), 2204 (CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, (CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
◦
25 C, TMS): δ = 3.85 (s, 3H, OCH3), 3.96 (s, 2H, CH2), TMS): δ = 3.88 (s, 3H, OCH3), 3.99 (s, 2H, CH2), 7.28 (d,
6.01 (brs, 1H, NH), 7.25 (d, 2H, J = 9.0 Hz, Ar-H), 2H, J = 9.0 Hz, Ar-H), 7.44 (m, 1H, Ar-H), 7.52 – 7.57 (m,
7.31 – 7.75 (m, 1H, Ar-H), 7.51 – 7.65 (m, 5H, Ar-H, NH), 2H, Ar-H), 7.65 (d, 2H, J = 9.0 Hz, Ar-H), 8.21 – 8.26 (m,
8.20 – 8.25 (m, 2H, Ar-H), 8.28 (s, 1H, 3-H). – MS (EI, 2H, Ar-H), 8.30 (s, 1H, 3-H). – MS (EI, 70 eV): m/z (%) =
70 eV): m/z (%) = 371 (68) [M]+. – C20H17N7O (371.40): 369 (76) [M]+. – C20H15N7O (369.38): calcd. C 65.03,
calcd. C 64.68, H 4.61, N 26.40; found C 64.54, H 4.70, H 4.09, N 26.54; found C 64.95, H 4.15, N 26.61.
N 26.32.
2-[1-(4-Chlorophenyl)-4-(p-tolyldiazenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-6-yl]acetonitrile (12b)
2-[1-(4-Chlorophenyl)-4-(2-p-tolylhydrazinyl)-1H-
pyrazolo[3,4-d]pyrimidin-6-yl]acetonitrile (11b)
◦
M. p. 202 – 204 C. Yield: 68 %. – IR (KBr): ν = 2223
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 2.30 (s, 3H, CH3), 4.20 (s, 2H, CH2), 7.43 (d,
2H, J = 8.7 Hz, Ar-H), 7.55 (d, 2H, J = 8.7 Hz, Ar-H), 8.10
(d, 2H, J = 8.8 Hz, Ar-H), 8.29 (d, 2H, J = 8.8 Hz, Ar-H),
8.66 (s, 1H, 3-H). – MS (EI, 70 eV): m/z ( %) = 387 (91) [M,
35Cl]+, 389 (27) [M, 37Cl]+. – C20H14ClN7 (387.83): calcd.
C 61.94, H 3.64, N 25.28; found C 62.11, H 3.55, N 25.34.
◦
M. p. 238 – 240 C. Yield: 77 %. – IR (KBr): ν = 3310,
3230 (NH), 2218 (CN) cm−1. – 1H NMR (300 MHz,
◦
[D6]DMSO, 25 C, TMS): δ = 2.29 (s, 3H, CH3), 4.0 (s,
2H, CH2), 6.08 (s,1H, NH), 6.34 (d, 2H, J = 8.8 Hz, 2ꢀꢀ,6ꢀꢀ-
H), 7.11 (d, 2H, J = 8.8 Hz, 3ꢀꢀ,5ꢀꢀ-H), 7.48 (d, 2H, J =
8.7 Hz, 3ꢀ,5ꢀ-H), 8.17 (d, 2H, J = 8.7 Hz, 2ꢀ,6ꢀ-H), 8.28
(s, 1H, NH), 8.39 (s, 1H, 3-H). – 13C NMR (75.4 MHz,
[D6]DMSO): δ = 20.55 (CH3), 27.64 (CH2), 99.71 (C-3a),
112.40 (C-2ꢀꢀ,6ꢀꢀ), 116.70 (CN), 122.20 ꢀꢀ(C-2ꢀ,6ꢀ), 128.71
(C-4ꢀꢀ), 129.15 (C-3ꢀ,5ꢀ), 129.69 (C-3ꢀꢀ,5 ), 130.73 (C-4ꢀ),
136.43 (C-3), 137.26 (C-1ꢀ), 139.90 (C-1ꢀꢀ), 154.55 (C-7a),
157.33 (C-6), 161.21 (C-4). – MS (EI, 70 eV): m/z (%) =
389 (84) [M, 35Cl]+, 391 (24) [M, 37Cl]+. – C20H16ClN7
(389.84): calcd. C 61.62, H 4.14, N 25.15; found C 61.48,
H 4.25, N 25.04.
2-[4-((4-Bromophenyl)diazenyl)-1-p-tolyl-1H-pyrazolo-
[3,4-d]pyrimidin-6-yl]acetonitrile (12c)
◦
M. p. 230 – 231 C. Yield: 69 %. – IR (KBr): ν = 2220
(CN) cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 2.28 (s, 3H, CH3), 4.18 (s, 2H, CH2), 7.37 (d,
2H, J = 9.0 Hz, Ar-H), 7.90 (d, 2H, J = 9.0 Hz, Ar-H), 8.09
(d, 2H, J = 8.9 Hz, Ar-H), 8.32 (d, 2H, J = 8.9 Hz, Ar-H),
8.63 (s, 1H, 3-H). – C20H14BrN7 (432.28): calcd. C 55.57,
H 3.26, N 22.68; found C 55.66, H 3.19, N 22.57.
2-[4-(2-(4-Bromophenyl)hydrazinyl)-1-p-tolyl-1H-pyrazolo-
[3,4-d]pyrimidin-6-yl]acetonitrile (11c)
Conversion of compounds 12 to 11
◦
M. p. 198 – 200 C. Yield: 74 %. – IR (KBr): ν = 3320 –
To a solution of diazenyl derivatives 12 (0.01 mol) in
glacial acetic acid (15 mL), Zn dust (1 g) was added. The
reaction mixture was refluxed for 2 h during which time the
color turned to pale yellow. The reaction mixture was filtered
while hot, left to cool to r. t. and then poured onto crushed ice
(25 g). The precipitated solid was collected by filtration and
recrystalized from EtOH-CHCl3 to afford the correspond-
ing hydrazinyl derivative which was found identical in all
respects with that obtained from the above reaction (TLC,
m. p., NMR). (11a, 70 % yield, 11b, 52 % yield, 11c, 65 %
yield).
3240 (NH), 2219 (CN) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 2.14 (s, 3H, CH3), 4.05
(s, 2H, CH2), 6.20 (s, 1H, NH), 6.83 (d, 2H, J = 9.0 Hz,
Ar-H), 7.38 (d, 2H, J = 9.0 Hz, Ar-H), 7.49 (d, 2H, J =
8.9 Hz, Ar-H), 8.16 (d, 2H, J = 8.9 Hz, Ar-H), 8.20
(s, 1H, NH), 8.40 (s, 1H, 3-H). – C20H16BrN7 (434.29):
calcd. C 55.31, H 3.71, N 22.58; found C 55.45, H 3.94,
N 22.37.
General procedure for the preparation of 12a – c
To a solution of the appropriate hydrazinyl derivatives
11a – c (1 mmol) in ethanol (25 mL) was added a solution
of ferric chloride (2 M, 2 mL), and the mixture was stirred
at r. t. for 2 h. The precipitated solid was filtered off, washed
with water and then with ethanol and finally crystallized from
DMF-EtOH to give 12a – c as an orange powder.
Acknowledgements
We thank Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT-
Portugal) for a fellowship grant, Prof. A. M. Campos for hos-
pitality and continuous help, and Miss Elisa Pinto for obtain-
ing the NMR and elemental analyses data.
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846
A. M. Salaheldin · Synthesis of 2-(1-Aryl-4-substituted pyrazolo[3,4-d]pyrimidin-6-yl)acetonitrile Derivatives
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