Synthesis, bioactivities, and X-ray structure analysis of 2-cyano-5-methylpyrazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1007/s10870-005-3475-y

The title compound crystallizes in the monoclinic space group P2 ₁/c with unit cell parameters a = 3.8380(12), b = 11.994(4), and c = 16.245(5) A, β = 90.743(5)°, V = 747.7(4) A³, and Z = 4. The final reliability index is 0.0409 for 1088 observed reflections. All the non-hydrogen atoms in the title compound are almost coplanar, the largest deviation from the mean plane being 0.030(2) A for atom C5. The crystal cohesion is accentuated by C-H...N hydrogen bond. The X-ray crystallography analysis indicates that the methyl group is at the 5-position of the compound 4 rather than at the 7-position of the isomer 4-1. The preliminary biological test shows that the title compound has moderate herbicidal activity.

Full text of DOI:10.1007/s10870-005-3475-y

ꢀC
Journal of Chemical Crystallography, Vol. 35, No. 9, September 2005 ( 2005)
DOI: 10.1007/s10870-005-3475-y
Synthesis, bioactivities, and X-ray structure analysis
of 2-cyano-5-methylpyrazolo[1,5-a]pyrimidine
Ming Li,(1)∗ Shuwen Wang,(1) Lirong Wen,(1) Xiuli Zhang,(2) and Ziqin Ke(3)
Received November 22, 2004; accepted February 3, 2005
The title compound crystallizes in the monoclinic space group P21/c with unit cell pa-
◦
˚
rameters a = 3.8380(12), b = 11.994(4), and c = 16.245(5) A, β = 90.743(5) , V =
3
˚
747.7(4) A , and Z = 4. The final reliability index is 0.0409 for 1088 observed reflections.
All the non-hydrogen atoms in the title compound are almost coplanar, the largest deviation
˚
from the mean plane being 0.030(2) A for atom C5. The crystal cohesion is accentuated
---
by C H· · ·N hydrogen bond. The X-ray crystallography analysis indicates that the methyl
group is at the 5-position of the compound 4 rather than at the 7-position of the isomer
4-1. The preliminary biological test shows that the title compound has moderate herbicidal
activity.
KEY WORDS: Pyrazolo[1,5-a]pyrimidine; crystal structure; mechanism; bioactivities.
Introduction
In continuation of our work on the
structure–activity relationship of pyrazolo[1,5-a]-
pyrimidine derivatives,11,12 we have obtained a
yellow crystalline compound 4, which is the prod-
uct of the reaction of 4-N,N-dimethylamino-3-
butene-2-one and 5-amino-4-cyano-1H-pyrazole.
The procedure of syntheses is shown in Scheme 1.
Theoretically, the condensation of enam-
Pyrazolo[1,5-a]pyrimidine derivatives have
showed various biological activities in the terms
of antibacterial, antischistosomal and xanthine
oxidase inhibitor.1–5 The enaminones are highly
reactive intermediates and have been extensively
used as building block in organic synthesis, es-
pecially in the heterocyclic compounds.6–8 In ad-
dition, a great deal of interest has been focused
on the synthesis of pyrazolo[1,5-a]pyrimidine
through versatile enaminones because of their
synthetic and biological potentialities.9,10
inones with 5-amino-4-cyano-1H-pyrazole in
acetic acid can be generated in two possible
ways, as shown in Scheme 2. Path 1 involves
the usual condensation between ketones and
aminopyrazole to form a Schiff base A, the latter
then cyclizes to form 4. Path 2 involves an initial
Michael-type addition of the nucleophilic amino
group in the aminopyrazole to the enaminones,
followed by the elimination of the dimethylamino
group to form B, which then cyclizes and dehy-
drates to form 4-1. IR and 1H NMR studies were
insufficient to confirm the structure of the title
compound, whether the methyl group is located
(1) College of Chemistry and Molecular Engineering, Qingdao Uni-
versity of Science and Technology, Qingdao 266042, P.R. China.
(2) Marine Drug and Food Institute, Ocean University of China, No. 5,
Yushan Road, Qingdao 266003, P.R. China.
(3) Department of Chemistry, Xinjiang Normal University, Urumuqi
830054, P.R. China.
∗To whom correspondence should be addressed; e-mail:
liming928@263.net.
667
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C
1074-1542/05/0900-0667/0 2005 Springer Science+Business Media, Inc.

668
Li, Wang, Wen, Zhang, and Ke
Scheme 1. Route of synthesis.
Experimental
at the 5- or 7-position of the pyrazolo[1,5-
a]pyrimidine skeleton. The structure of 4 was
resolved using single-crystal X-ray diffraction.
Compared with the early report,12 in com-
pound 4, the methyl group is at 5-position of the
pyrazolo[1,5-a]pyrimidine skeleton. This prove
that when R is a large group, such as aryl group,
the substituent will be probably at 7-position
of the pyrazolo[1,5-a]pyrimidine skeleton, while
when R is a small group, such as methyl group,
the substituent will be at 5-position.
Infrared spectra were obtained on a Nico-
let 510P FT-IR instrument with the compound in
a KBr disc matrix. The H NMR spectra were
obtained with a Bruker AC-300 instrument. Sam-
ples were dissolved in DMSO referenced to TMS.
The elemental analysis was performed by Perkin-
Elmer 240. Melting point was determined with
RK1 microscopic melting point apparatus and
corrected.
1
Scheme 2. The proposed reaction mechanism.

Synthesis of a pyrazolo[1,5-a]pyrimidine derivative
669
Table 1. Crystal Data and Structure Refinement
The intermediates 1, 2, and 3 were syn-
thesized according to the references.13,14 The
title compound 3-cyano-5-methylpyrazolo[1,5-
a]pyrimidine (4) was prepared as follows: Into
a 50 mL flask containing 15 mL of glacial
acetic acid, 4-N,N-dimethylamino-3-butene-2-
one (3) (0.23 g, 2 mmol) and 4-cyano-5-amino-
1H-pyrazole (2) (0.22 g, 2 mmol) were intro-
duced. It was stirred at room temperature for about
12 h, then dried in vacuum to give a yellow solid
(0.26 g, yield 83%) which was recrystallized from
ethanol to give yellow needle crystals, melting at
176–178◦C. Single crystals of 4 suitable for X-ray
diffraction analysis were obtained by slow evapo-
ration from ethanol. Anal. Calcd. (%) for C8H6N4:
C, 60.74; H, 3.83; N, 35.44. Found: C, 60.62;
H, 3.84; N, 35.54. 1H NMR (DMSO-d6) δ: 2.65 (s,
3H, CH3), 7.28 (d, 1H, J = 7.2 Hz, H-2), 8.74 (s,
1H, H-1), 9.22 (d, 1H, J = 7.2 Hz, H-3). IR (KBr)
υ: 3100, 2927, 2231, 1633, 1556, 1422, 1383.
A light yellow crystal of the title compound
Chemical formula
CCDC deposit no.
Color/shape
C8 H6 N4
254798
Yellow/prism
158.17
Formula weight
Temperature (K)
293(2)
˚
Wavelength (A)
0.71073
Crystal system, space group
Monoclinic, P21/c
˚
Unit cell dimensions (A)
a
b
c
3.8380(12)
11.994(4)
16.245(5)
90.743(5)
747.7(4)
4
1.405
0.093
2.11–26.36
β (◦)
3
˚
Volume (A )
Z
Density (calculated) (mg/m3)
Absorption coefficient (mm−1
θ range for data collection (◦)
Limiting indices
)
−4≤ h ≥4
−9 ≤ k ≥ 14
−17 ≤ l ≥ 20
Reflections collected/unique
Absorption correction
4246/1523 (Rint = 0.0291)
Semi-empirical from
equivalents
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
0.991, 0.957
1523/0/110
1.030
4 having dimensions of 0.20 mm × 0.16 mm ×
0.10 mm was mounted on a glass fiber in a random
orientation. The data were collected at 293(2) K
on a BRUKER SMART 1000 CCD diffractometer
using graphite-monochromated Mo Kα radiation
Final R indices [I > 2σ(I)]
R indices (all data)
R1 = 0.0409, wR2 = 0.1017
R1 = 0.0654, wR2 = 0.1151
Largest diff. peak and hole
−3
˚
(e.A
F (000)
)
0.191, −0.225
328
˚
(λ = 0.71073 A). A summary of the crystal data
is presented in Table 1.
The intensity data were corrected for Lp fac-
tors and empirical absorption. The structure was
solved by direct methods and expanded by using
Fourier difference techniques with SHELXS97.15
Refinements were made by full-matrix least
squares on all F2 data using SHELXL97.16 All
non-hydrogen atoms were anisotropically refined.
All hydrogen atoms were added according to the
theoretical models.
labeling (thermal ellipsoids drawn at 50% proba-
bility) is shown in Fig. 1.
In compound 4, the interatomic distances for
˚
˚
---
---
C3 N2 [1.332 A] and C6 N4 [1.321 A] are re-
markablyshorterthanthenormalcarbon–nitrogen
single bonds, but close to the typical carbon–
nitrogen double bonds,17 which indicate the elec-
tron density of the ring has considerable delocal-
˚
---
ization. The length of C1 N1 bond is 1.132 A,
indicating that it is a normal triple bond. In
--- ---
--- ---
addition, the angels of C3 N2 N3, N2 N3 C8,
--- ---
--- ---
--- ---
C2 C8 N3, C3 C2 C8 and C8 N4 C6 are
much smaller than 120◦ aquired by sp2 hybridiza-
tion, which indicates that the pyrazolopyrimi-
dine ring has strong tensile force. From this re-
sult, we assumed that the pyrazolopyrimidine ring
might be an important active site of this series of
compounds.
Results and discussion
Precise crystal data and other structure re-
finement parameters of the title compound are
presented in Table 1. Selected bond lengths, bond
angles, and torsional angles are summarized in
Table 2. General view of the molecule with atomic

670
Li, Wang, Wen, Zhang, and Ke
◦
˚
Table 2. Select Geometric Parameters (A and )
˚
Bond lengths (A)
----
----
C(1) C(2)
N(1) C(1)
1.132(2)
1.322(2)
1.3698(19)
1.355(2)
1.3782(19)
1.321(2)
1.423(2)
1.390(2)
1.400(2)
1.348(2)
1.417(2)
1.491(2)
----
----
N(2) C(3)
----
C(2) C(8)
----
C(2) C(3)
N(2) N(3)
----
----
N(3) C(4)
----
C(4) C(5)
----
C(5) C(6)
N(3) C(8)
----
----
N(4) C(6)
C(6) C(7)
----
N(4) C(8)
1.347(2)
Bond angles (◦)
----
----
----
----
----
----
C(3) N(2) N(3)
103.63(13)
125.96(14)
121.06(14)
112.98(12)
116.99(14)
178.6(2)
105.38(14)
126.74(15)
127.88(16)
N(2) C(3) C(2)
113.11(16)
119.99(15)
122.22(15)
117.90(15)
119.87(15)
122.23(14)
132.87(14)
104.90(13)
----
----
C(4) N(3) N(2)
---- ----
C(4) C(5) C(6)
---- ----
C(4) N(3) C(8)
---- ----
N(4) C(6) C(5)
---- ----
N(2) N(3) C(8)
---- ----
N(4) C(6) C(7)
---- ----
C(6) N(4) C(8)
---- ----
C(5) C(6) C(7)
---- ----
N(1) C(1) C(2)
---- ----
N(4) C(8) N(3)
---- ----
C(8) C(2) C(3)
---- ----
N(4) C(8) C(2)
---- ----
N(3) C(8) C(2)
C(8) C(2) C(1)
----
----
C(3) C(2) C(1)
Torsional angles (◦)
----
----
----
----
----
----
C(3) N(2) N(3) C(4) −179.44(15) C(4) C(5) C(6) N(4)
−1.3(2)
177.74(16)
1.0(2)
---- ---- ---- ---- ---- ----
C(3) N(2) N(3) C(8) 0.09(17) C(4) C(5) C(6) C(7)
---- ---- ---- ---- ---- ----
N(1) C(1) C(2) C(8) 168(8) C(6) N(4) C(8) N(3)
---- ---- ---- ---- ---- ----
N(1) C(1) C(2) C(3)
---- ---- ----
−11(8) C(6) N(4) C(8) C(2) −179.70(16)
----
----
----
N(3) N(2) C(3) C(2)
---- ---- ----
−0.02(18) C(4) N(3) C(8) N(4)
−1.1(2)
179.36(13)
179.44(14)
−0.12(17)
---- ---- ----
C(8) C(2) C(3) N(2)
---- ---- ----
−0.1(2) N(2) N(3) C(8) N(4)
---- ---- ----
C(1) C(2) C(3) N(2)
---- ---- ----
179.46(16) C(4) N(3) C(8) C(2)
---- ---- ----
N(2) N(3) C(4) C(5)
---- ---- ----
179.43(15) N(2) N(3) C(8) C(2)
---- ---- ----
C(8) N(3) C(4) C(5)
---- ---- ----
−0.1(2) C(3) C(2) C(8) N(4) −179.30(16)
----
----
----
N(3) C(4) C(5) C(6)
---- ---- ----
1.2(2) C(1) C(2) C(8) N(4)
1.2(3)
---- ---- ----
C(8) N(4) C(6) C(5)
---- ---- ----
0.2(2) C(3) C(2) C(8) N(3)
---- ---- ----
0.10(17)
C(8) N(4) C(6) C(7)
−178.88(14) C(1) C(2) C(8) N(3) −179.42(15)
All the non-hydrogen atoms in compound 4
of torsion angles (maximum value of torsion for
◦
--- --- ---
are coplanar, and the largest deviation from the
the N1 C1 C2 C3 bond is −11(8) ). This is
expected due to the steric hindrance of the cyano
group at C2.(Fig. 1)
˚
mean plane is 0.030(2) A for atom C5. And this
planarity is further confirmed by the magnitude
There is a potential weak intermolecular in-
---
teraction (C H· · ·N hydrogen bond) in the crystal
---
lattice. N1 atom forms potential weak C H· · ·N
intermolecular interaction with the C4 atom, the
˚
donor and the acceptor distance is 3.285(2) A. The
bond angle of the hydrogen bond is 138.7◦,with
the symmetric codes: x + 1, −y + 1/2,
z + 1/2.
The preliminary biological test showed that
the title compound exhibits some inhibiting
activity against four fungi, Gibberrella zeave, Al-
ternaria solani, Phoma asparagi and Cercosporsa
arachidicola hori. Its inhibiting rates are 36.4,
45.1, 28.7, 39.6% at 50 µg/mL, respectively. In
addition, the preliminary herbicidal activities have
been determined at the concentration of 100 and
Fig . 1. General view of the molecule with thermal ellipsoids
drawn at 50% probability level.

Synthesis of a pyrazolo[1,5-a]pyrimidine derivative
671
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The authors are very grateful to the Natural
Science Foundation of Shandong Province (No.
Y2003B01) and the National Science Foundation
of China (No. 20172031) for financial supports.
Supplementary material CCDC 254798 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data request/cif,
by e-mailing data request@ccdc.cam.ac.uk, or by contacting
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