Synthesis and structural characterization of pyrazol-1′-ylpyrazolo[1,5-a]pyrimidines by multinuclear NMR spectroscopy

Article abstract of DOI:10.1016/j.molstruc.2009.06.021

3(5)-Amino-5(3)-hydrazinopyrazole dihydrochloride (8) reacts with pentane-2,4-dione (9a) to afford 2-(3′,5′-dimethylpyrazol-1′-yl)-5,7-dimethylpyrazolo[1 ,5-a]pyrimidine (10a) instead of the 3-(3′,5′-dimethylpyrazol-1′-yl)-4,6-dimethyl-1H-pyrazo lo[3,4-b]

Full text of DOI:10.1016/j.molstruc.2009.06.021

Journal of Molecular Structure 934 (2009) 96–102
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and structural characterization of pyrazol-10-ylpyrazolo[1,5-a]pyrimidines
by multinuclear NMR spectroscopy
a
b
b,
c
Ranjana Aggarwal a, , Garima Sumran , Rosa M. Claramunt , Dionisia Sanz , J. Elguero
*
*
a Department of Chemistry, Kurukshetra University, Kurukshetra-136 119, India
b Departamento de Química y Bio-orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain
c Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2009
Received in revised form 10 June 2009
Accepted 17 June 2009
Available online 23 June 2009
3(5)-Amino-5(3)-hydrazinopyrazole dihydrochloride (8) reacts with pentane-2,4-dione (9a) to afford
2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (10a) instead of the 3-(30,50-dim-
ethylpyrazol-10-yl)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine isomer (11). Similarly, the reaction of 8
with phenyl-1,3-butanedione (9b) resulted into the formation of 2-(30-methyl-50-phenylpyrazol-10-yl)-
5-methyl-7-phenylpyrazolo[1,5-a]pyrimidine (10b) out of the four possible regioisomers. The structure
of the reaction products 10a and b was established by analysis of high-resolution 1H NMR spectra. Com-
plete spectral analysis has been achieved utilizing (1H–13C) HMQC as well as (1H–13C) and (1H–15N)
HMBC experiments.
Keywords:
Pyrazol-10-ylpyrazolo[1,5-a]pyrimidines
1,3-Diketones
Ó 2009 Elsevier B.V. All rights reserved.
Regioisomerism
HMQC and HMBC experiments
Coupling constants
1. Introduction
that the CH3 group of 3-(4-fluorophenyl)-2-(4-methyl-sulfonyl-
phenyl)-5-methylpyrazolo[1,5-a]pyrimidine (6) at position-5 res-
Amino-1H-pyrazoles are useful synthons and building blocks
for many heterocyclic products particularly for pyrazolo[1,5-
a]pyrimidines. The presence of both primary and secondary amine
functionalities in 3-amino-1H-pyrazoles is conveniently utilized in
making pyrazolo[1,5-a]pyrimidines via reacting them with biden-
tate electrophiles [1–10]. Formation of exclusively one isomeric
pyrazolo[3,4-b]pyridine has been reported by us when several
unsubstituted 5-aminopyrazoles were reacted with trifluoro-
methyl-b-diketones [11]. Joshi et al. [12] have also reported the
formation of two isomeric products, 1H-pyrazolo[3,4-b]pyridines
(3) and pyrazolo[1,5-a]pyrimidines (4), when 5-amino-3-aryl-1H-
pyrazoles (1) were treated with 1-(40-fluorophenyl)-butane-1,3-
dione (2) (Scheme 1).
onates upfield, at 2.63 ppm, as compared to CH3 group at
position-7 of 3-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-7-
methylpyrazolo[1,5-a]pyrimidine (7) at 2.88 ppm, respectively
(Scheme 2).
Thus, having the above reported uncertainties in mind and in
continuation of our efforts to synthesize pyrazolo[1,5-a]pyrimi-
dines [13] with potential biological activity, we become interested
in investigating and establishing the structure of the reaction
products obtained by the condensation of 3(5)-amino-5(3)-hydra-
zinopyrazole dihydrochloride (8) with symmetrical and unsym-
metrical b-diketones.
Reaction of 3(5)-amino-5(3)-hydrazinopyrazole dihydrochlo-
ride (8) with pentane-2,4-dione (9a) resulted in exclusive forma-
Furthermore, a perusal of literature reveals that where there is
clear evidence of the exclusive formation of pyrazolo[1,5-
a]pyrimidines, there are contradictory reports [3,4] about the po-
sition of CH3 group at position-5 and/or -7. Novinson et al. [3]
have reported peaks at 2.56 (C7–CH3) and 2.73 ppm (C5–CH3) in
the 1H NMR spectrum of 5,7-dimethylpyrazolo[1,5-a]pyrimidine
(5) (Scheme 2). On the contrary, Almansa et al. [4] have described
tion of a single isomer that may have structures either of
pyrazol-10-ylpyrazolo[1,5-a]pyrimidine (10a) or pyrazol-10-ylpy-
razolo[3,4-b]pyridine (11) (Scheme 3). The challenge was to differ-
entiate and determine its structure by NMR spectroscopy.
Similarly, phenyl-1,3-butanedione (9b) on reaction with 8 afforded
a single isomer of fused pyrazolo[1,5-a]pyrimidine which may
have one of the four possible regioisomeric structures (Scheme
4). To assign the structure of isolated regioisomers unambiguously
and to solve the discrepancy reported in the literature [3,4], we
have made use of high-resolution 1H NMR as well as multinuclear
* Corresponding authors.
E-mail addresses: ranjana67in@yahoo.com (R. Aggarwal), dsanz@ccia.uned.es (D.
Sanz).
(
13C and 15N) NMR spectroscopy.
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.06.021

R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
97
H
Ar'
N
N
N
H
N
AcOH
O
O
N
N N
and/or
H3C
Ar
+
Ar
N
H2N
Ar
Ar'
CH3
H3C
Ar'
2
4
1
3
Ar = C6H5, 4-FC6H4
Ar' = 4-FC6H4
Scheme 1. Synthesis of compounds 3 and 4 [12].
2.73
2.63 (26.51)
8.46 (d)
= 4 Hz
4
N
4
N
4
N
Ar
3
Ar
3
J
H3C
H3C
3
5
6
5
6
5
6
Ar'
Ar'
2
2
2
N
N
N
N
1
N
N
1
7
7
7
1
6.58
CH3
CH3
6.80 (d)
6.78 (d)
8.56 (d,
J
= 7.2 Hz)
2.56
5
2.88 (18.53)
7
Ar = 4-FC6H4
Ar' = 4-CH3SO2C6H4
6
Scheme 2. Literature results (in parentheses 13C chemical shifts).
H
O
O
N N
+
H3C
CH3
HCl·H2N-HN
NH2·HCl
9a
8
EtOH:H2O (1:1)
or H2O
Reflux
2
N
1
N
H
CH3
CH3
1'
N
N2'
CH3
5'
1
N
5'
7
7a
4'
4'
3'
7a
N 7
6
N
3
N
3a
2
N
5
3a N
CH3
3'
H3C
H3C
3
4
H3C
4
CH3
6
5
11
10a
Scheme 3. Synthesis of 10a.
and excess of H2O was distilled off under reduced pressure and
the residue was recrystallized from EtOH–H2O.
2. Experimental
M.p. 128–130 °C; yield1 0.96 g, 80%. IR (cmꢀ1): 2921, 1629,
Melting points were determined in open capillaries and are
uncorrected. The IR spectra were recorded on a Buck Scientific IR
1
0
1573, 1533, 1424. H NMR (400 MHz) (CDCl3, d): 2.31 (s, 3H, C3 –
4
0
M-500 spectrophotometer in KBr pellets (m
max in cmꢀ1). High-
CH3), 2.54 (s, 3H, C5–CH3), 2.57 (d, 3H, J = 0.8 Hz, C5 –CH3), 2.70
4
0
(d, 3H, J = 1.0 Hz, C7–CH3), 5.99 (bs, 1H, C4 –H), 6.55 (q, 1H,
4J = 1.0 Hz, C6–H), 6.69 (s, 1H, C3–H). HRMS (m/z): 241.1329 (M+)
(C13H15N5 requires 241.1327). Elemental Analysis: Found: C,
64.81; H, 6.45; N, 29.01%; C13H15N5 requires C, 64.73; H, 6.22, N,
29.04%.
resolution mass spectra (HRMS) were measured in EI mode on a
Kratos MS-50 spectrometer. The reactions were monitored by the
TLC carried out on pre-coated silica gel glass plates. Pentane-2,4-
dione and 1-phenyl-1,3-butanedione are commercially available.
The required 3(5)-amino-5(3)-hydrazinopyrazole dihydrochloride
(8) was synthesized by treating one equivalent of malononitrile
with two equivalents of hydrazine hydrate according to literature
procedure [14].
2.2. Synthesis of 2-(30-methyl-50-phenylpyrazol-10-yl)-5-methyl-7-
phenylpyrazolo[1,5-a]pyrimidine (10b)
2.1. Synthesis of 2-(30,50-dimethylpyrazol-10-yl)-5,7-
dimethylpyrazolo[1,5-a]pyrimidine (10a)
To H2O (20 mL) was added 3(5)-amino-5(3)-hydrazinopyrazole
dihydrochloride (8) (0.93 g, 0.005 mol) and 1-phenyl-1,3-butane-
dione (9b) (0.81 g, 0.005 mol) and the reaction mixture was boiled
under reflux for 4 h. The progress of reaction mixture was moni-
A solution of 3(5)-amino-5(3)-hydrazinopyrazole dihydrochlo-
ride (8) (0.93 g, 0.005 mol) and pentane-2,4-dione (9a) (0.5 g,
0.005 mol) in H2O (20 mL) was heated under reflux for 4 h. After
the reaction was complete (from TLC), the mixture was cooled
1
Theoretically 1 eq. of 8 is reacting with 2 eq. of 9a and b. However, yields are
calculated assuming 1 eq. of diketone.

98
R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
D
H
O
O
N N
+
CH3
x
y
HCl·H2N-HN
NH2·HCl
C
A
B
9b
8
H2O (reflux)
CH3
7
CH3
7
CH3
5'
5'
N
N
N
N
N
N
N
N
5
N
5
N
3'
3'
H3C
II (Bx+Cx or Ay+Dy)
I (Ax+Cx or By+Dy)
CH3
7
7
5'
5'
N
N
N
N
N
N
N
N
5
CH3
5
N
N
CH3
3'
3'
H3C
IV (Ax+Cy or By+Dx)
III (Bx+Cy or Ay+Dx)
Scheme 4. Synthesis of 10b (framed the real structure).
tored by TLC. The mixture was extracted with EtOAc (2 ꢁ 50 mL)
and the combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated to give a residual
mass. The residue obtained on cooling was found to be a mixture of
products as predicted by TLC and 1H NMR spectra. The residue was
column chromatographed over silica gel (100–200 mesh) using
mixtures of petroleum ether/CHCl3 of increasing polarity as eluent
to yield three compounds – benzoic acid, m.p. 120–121 °C (Lit. [15]
m.p. 121–123 °C); yield 0.02 g, 3% in the first fraction, 3-methyl-5-
phenyl-1H-pyrazole, m.p. 129–130 °C (Lit. [16,17] m.p. 128 °C);
yield 0.07 g, 8% in second fraction and finally 2-(30-methyl-50-
phenylpyrazol-10-yl)-5-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine
(10b). Thus, all the signals seen in the 1H NMR spectrum of crude
reaction mixture have been accounted for by the isolation of these
three components.
tected heteronuclear shift correlation spectra, (1H–13C) gs-HMQC,
(1H–13C) gs-HMBC and (1H–15N) gs-HMBC, were acquired and
processed using standard Bruker NMR software and in non-
phase-sensitive mode. Gradient selection was achieved through a
5% sine truncated shaped pulse gradient of 1 ms. Selected parame-
ters for (1H–13C) gs-HMQC and gs-HMBC spectra were spectral
width 3200 Hz for 1H and 12.0 kHz for 13C, 1024 ꢁ 256 data set,
number of scans 2 (gs-HMQC) or 4 (gs-HMBC) and relaxation delay
1 s. The FIDs were processed using zero filling in the F1 domain and
a sine-bell window function in both dimensions was applied prior
to Fourier transformation. In the gs-HMQC experiments GARP
modulation of 13C was used for decoupling. Selected parameters
for (1H–15N) gs-HMBC spectra were spectral width 3200 Hz for
1H and 12.5 kHz for 15N, 1024 ꢁ 512 data set, number of scans 4,
relaxation delay 1 s, 37–50 ms delay for the evolution of the
15N–1H long-range coupling. The FIDs were processed using zero
filling in the F1 domain and a sine-bell window function in both
dimensions.
M.p. 179–180 °C; yield 1.4 g, 76%. IR (cmꢀ1): 3038, 2924, 1616,
1
0
1519, 1414. H NMR (CDCl3, d): 2.39 (s, 3H, C3 –CH3), 2.61 (s, 3H,
0
C5–CH3), 6.28 (s, 1H, C4 –H), 6.61 (s, 1H, C3–H), 6.75 (s, 1H, C6–
H), 7.31–7.46 (m, 8 H, Ph-H), 7.63 (m, 2H, Ph-Ho). MS (m/z): 365
(M+). Elemental Analysis: Found: C, 75.82; H, 5.57; N, 19.51%;
C23H19N5 requires C, 75.59; H, 5.24; N, 19.16%.
3. Results and discussion
Typically, treatment of 8 with 9a resulted in the exclusive for-
mation of a single crystalline compound (TLC and 1H NMR) in
about 70–80% yields in various solvent systems (EtOH–H2O or
H2O) and under diverse conditions (stirring at room temperature
or refluxing) for 4 h. In principle, two isomeric structures, namely
2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrim-
idine (10a) or 3-(30,50-dimethylpyrazol-10-yl)-4,6-dimethyl-1H-
pyrazolo[3,4-b]pyridine (11) are possible for the product on the
basis of elemental analysis and HRMS data of the crystalline prod-
uct having molecular formula C13H15N5 (2 4 1) and molecular ion
peak at m/z = 241.132 (calcd for 241.132) (Scheme 3).
The structure of the product was unambiguously established
by IR, 1H, 13C and 15N NMR spectroscopy. The IR spectrum of
the product was found to be transparent in the region of NH
stretch ꢂ3250 cmꢀ1, thus, supporting the structure of the com-
pound to be 10a rather than structure 11. The 1H NMR spectrum
of the product revealed the presence of four methyl signals at
2.31, 2.54, 2.57 and 2.70 ppm, the presence of three signals of
one proton intensity at 5.99, 6.55 and 6.69 ppm which are char-
2.3. NMR spectroscopy [18]
Solution NMR spectra of 10a and b were recorded on a Bruker
DRX 400 (9.4 Tesla, 400.13 MHz for 1H, 100.62 MHz for 13C and
40.56 MHz for 15N) spectrometer with a 5-mm inverse-detection
H–X probe equipped with a z-gradient coil, at 300 °K. Chemical
shifts (d in ppm) are given from internal solvent, CDCl3 7.26 for
1H and 77.0 for 13C and for 15N NMR nitromethane (0.0) was used
as an external standard. Typical parameters for 1H NMR spectra
were spectral width 3200 Hz and pulse width 7.5 ls at an attenu-
ation level of 0 dB and resolution 0.15 Hz per point, in order to res-
olution enhancement Lorentzian-Gaussian multiplication was
applied (lb = ꢀ2.5, gb = 0.55). Typical parameters for 13C NMR
spectra were spectral width 21 kHz, pulse width 10.6 ls at an
attenuation level of ꢀ6 dB, resolution 0.6 Hz per point and relaxa-
tion delay 2 s; WALTZ-16 was used for broadband proton decou-
pling; the FIDS were multiplied by an exponential weighting
(lb = 2 Hz) before Fourier transformation. 2D inverse proton de-

R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
99
CH3-5
CH3-7
CH3-5’
4J=1.0
4J=0.8
CH3-3’
H-6
4J =1.0
H-3
6.56
6.54
2.64
H-4’
(ppm)
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
1
Fig. 1. High-resolution H NMR spectrum of 2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (10a) in CDCl3.
acteristic protons for pyrazole-40-H, pyrimidine-6-H and pyra-
zole-3-H, respectively, and absence of any signal corresponding
to NH protons (Fig. 1). Furthermore, there is no change in the
integration of the aromatic protons on shaking with D2O, thus
completely eliminating the presence of any exchangeable hydro-
gen in the molecule.
[19a] and 4J = 1.0 Hz (CH3-7, H-6), respectively. Similarly, two sig-
nals of one proton intensity for pyrazole-40-H and pyrimidine-6-H
appeared as a broad singlet (not resolved) at 5.99 and a quartet at
6.55 ppm (4J = 1.0 Hz) (CH3-7, H-6), respectively [19b]. Conse-
quently, the signals at 2.32 and d 2.54 ppm have been assigned
to CH3-30 and CH3-5, respectively. Thus, the good resolution of
the doublet and the coupling constant provided additional support
in distinguishing the 30-CH3 and 50-CH3 in the case of 2-(30,50-dim-
ethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine. This
observation is in consonance with the earlier findings from our lab-
oratory [20,21] and provides a conclusive proof that the methyl
groups located at position-3 of pyrazole moiety resonates upfield
in comparison to those at position-5 (ꢂ2.7 ppm). The structural
In order to solve the discrepancy reported in literature [3,4] for
the regiochemical assignment of methyl substituents on the
pyrimidine ring, high-resolution 1H NMR (Fig. 1) and two-dimen-
sional NMR spectra of 10a were examined. It is interesting to note
that in high-resolution 1H NMR spectrum of 10a two methyl
groups at 2.57 and d 2.70 ppm appeared as doublets due to allylic
4
couplings having coupling constants of J = 0.8 Hz (CH3-50, H-40)
CH3-7
CH3-5’CH3-5
CH3-3’
H-3
H-6
H-4’
(ppm)
(ppm)
CH3-5’
CH3-3’
C-3
88
14.0
16.0
18.0
20.0
22.0
24.0
92
CH3-7
96
100
104
108
C-4’
C-6
CH3-5
(ppm)
(ppm)
2.72
2.64
2.56
2.48
2.40
2.32
2.24
6.60
6.40
6.20
6.00
Fig. 2. 1H–13C gs-HMQC of 2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (10a) in CDCl3.
H-3
H-6
H-4’
CH3-7
CH3-5’ CH3-5
CH3-3’
(ppm)
140
(ppm)
C-4
C-6
C-5’
C-7
112
120
128
136
144
152
160
144
148
152
156
160
C-3a
C-3’
C-2
C-5’
C-7
C-3’
C-5
(ppm)
C-5
(ppm)
6.60
6.40
6.20
6.00
2.72
2.64
2.56
2.48
2.40
2.32
2.24
Fig. 3. 1H–13C gs-HMBC of 2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (10a) in CDCl3.

100
R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
H-3
CH3 -7
CH3-5’ CH3-5
CH3-3’
H-6
H-4’
(ppm)
(ppm)
-176
-172
-168
-164
-177.5: N-1’
-165.2: N-7a
N-1’
-160
-140
-120
-100
-113.7: N-4
-83.1: N-2’
N-7a
(ppm)
6.60
6.40
6.20
6.00
2.72
2.64
2.56
2.48
2.40
2.32
(ppm)
Fig. 4. 1H–15N gs-HMBC of 2-(30,50-dimethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (10a) in CDCl3.
identity of 10a was definitely established by multinuclear (1H–13C)
HMQC, (1H–13C) HMBC and (1H–15N) HMBC techniques: Figs. 2–4.
Table 1 contains the complete and unambiguous assignment of
all 1H, 13C and 15N NMR signals of 10a based on the three 2D NMR
techniques mentioned above. The four signals at 13.2, 13.6, 16.9
and 24.6 ppm were attributed to CH3-50, CH3-30, CH3-7 and CH3-
5, respectively, by performing a HMQC experiment (Fig. 2). The
13C chemical shifts of CH3-7 and CH3-5 of the pyrimidine moiety
CH3-5, CH3-7, CH3-30, CH3-50 can be observed provided they are
connected by not more than four bonds. The different chemical
shifts of the nitrogen atoms N-4 and N-7a, consistent with the lit-
erature findings [13,19c], are thus key to assign the chemical shift
of protons of pyrazolo[1,5-a]pyrimidine ring. Also, the chemical
shifts of N-10 and N-20 show two well-separated ranges, which
can be used to the unambiguous assignment of the proton shifts
of pyrazole moiety. The long-range connectivities in the 1H–15
N
are different enough (
D
d ꢂ 8 ppm) to distinguish between them,
HMBC are seen from CH3-5 to N-4; H-3, H-6, CH3-7 to N-7a; H-
as previously established by Chimichi et al. [19b]. Long-range con-
nectivities are accessible from the 1H–13C–HMBC spectra (Fig. 3).
An examination of 13C NMR of this compound revealed signals at
150.5, 108.2 and 140.9 ppm, which are in excellent agreement with
the values recorded for carbon atoms C-30, C-40 and C-50 of
N-substituted 3,5-dimethylpyrazoles [21].
40, CH3-50 to N-10 and CH3-30 to N-20. In compound 10a, N1 is not
3
observed, because in N-substituted pyrazoles JH4N1 ꢂ 6 Hz
> 3JH4N2 ꢂ 1 Hz [22].
Encouraged by the successful characterization of 2-(30,50-dim-
ethylpyrazol-10-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine
(10a),
we carry out the reaction of 3(5)-amino-5(3)-hydrazino-pyrazole
dihydrochloride (8) with the unsymmetrical b-diketone phenyl-1,3-
butanedione (9b). In principle, the reaction of 3(5)-amino-5(3)-hydra-
zinopyrazole dihydrochloride (8) with 9b might result in the
formation of four regioisomeric pyrazol-10-ylpyrazolo[1,5-a]pyrimi-
dines- (30-phenyl-50-methyl pyrazol-10-yl-5-phenyl-7-methyl-) (I),
(30-methyl-50-phenyl pyrazol-10-yl-5-phenyl-7-methyl-) (II), (30-
methyl-50-phenyl pyrazol-10-yl-5-methyl-7-phenyl-) (III) and (30-
phenyl-50-methyl pyrazol-10-yl-5-methyl-7-phenyl-) (IV) (Scheme
4). The proportion of regioisomers depends on the substrate, the nat-
ure of the reagent, factors governing regioselectivity [23] such as reac-
tion conditions [24] and the mechanism of cyclization [25], due to
competitive reactivity of different nucleophilic(A, B, C and D) and elec-
trophilic centers (x and y) through the pathways depicted in Scheme 4.
However, the TLC and 1H NMR examination of the crude reac-
tion mixture revealed that the condensation of phenyl-1,3-butane-
dione (9b) with 8 in water resulted in the formation of a single
isomer of a fused pyrazol-10-ylpyrazolopyrimidine 10b that may
have the structures I, II, III or IV (Scheme 4), along with 3-
methyl-5-phenyl-1H-pyrazole as the byproduct obtained by C–N
bond cleavage of 8 as reported previously by Singh et al. [26] and
a minute amount of benzoic acid (3%) by the hydrolysis of 1,3-dike-
tone 9b in aqueous acidic medium as described in the past by Ad-
kin et al. [27]. IR, 1H and 13C NMR spectra of 10b are in good
agreement with the proposed structure.
The HMBC experiments show all the connectivities which are
needed to assign also the nitrogen chemical shifts. Fig. 4 shows
the 1H–15N HMBC of compound 10a. Cross peaks for nitrogen
atoms (N-4, N7a, N-10 and N-20) and the protons H-3, H-6, H-40,
Table 1
Assignment, chemical shifts and coupling constant in compound 10a.
d
Assign.
Coupling
HMQC
HMBC
constant (Hz)
6.69
6.55
5.99
2.70
2.57
2.54
2.31
159.0
153.4
150.5
148.6
145.2
140.9
108.4
H3
H6
H40
CH3-7
CH3-50
CH3-5
CH3-30
C5
C2
C30
C3a
C7
C50
–
87.4
108.4
108.2
16.9
13.2
24.6
13.6
–
–
–
–
–
C2, C3a, N7a
4J = 1.0
C5, C7, CH3-5, CH3-7, N7a
C30, C50, CH3-50, N10
C6, C7, N7a
C50, C40, N10
C5, C6, N4
C30, C40, N20
6.55(H6), 2.54(Me-5)
6.69(H3)
5.99(H40), 2.31(Me-30)
6.69(H3)
6.55(H6), 2.70(Me-7)
5.99(H40), 2.57(Me-50)
2.70(Me-7), 2.54(Me-5)
NR
4J = 1.0
4J = 0.8
–
–
2JCH3 = 6.2
–
2JCH3
=
JH4 = 6.1
2
0
2J = 6.2
m, NR
m, NR
–
6.55
C6
1J = 166.9,
3JCH3-5
=
3JCH3-7 = 3.9
108.2
C40
1J = 173.2,
5.99
2.57(Me-50), 2.31(Me-30)
3
0
JCH3-5
=
In particular, the 1H NMR spectrum of 10b revealed the pres-
ence of a characteristic singlet at 2.39 ppm of three protons inten-
sity of a methyl group. A comparison of the chemical shift of
methyl protons of 10b with those of 10a confirms that in 10b
the methyl group is located at position-30 of the pyrazole ring. This
observation immediately ruled out structures I and IV, which are
expected to exhibit signal at a chemical shift downfield than
2.39 ppm. Thus, the product may have structures II or III having
a methyl group located at position-5 or -7 of the pyrazolo[1,5-
a]pyrimidine moiety. The most convincing diagnostic data for the
regiochemical assignment of the methyl group on the pyrimidine
3
0
JCH3-3 = 3.2
87.4
24.6
16.9
C3
CH3-5
CH3-7
1J = 184.1
1J = 127.6
1J = 130.5,
3JH6 = 3.3
1J = 127.3
1J = 129.6
6.69
2.54
2.70
–
6.55(H6)
6.55(H6)
13.6
13.2
ꢀ83.1
ꢀ113.7
ꢀ165.2
ꢀ177.5
CH3-30
CH3-50
N20
N4
N7a
N10
2.31
2.57
–
5.99(H40)
2.31(Me-30)
2.54(Me-5)
6.69(H3), 6.55(H6), 2.70(Me-7)
5.99(H40), 2.57(Me-50)
NR, not resolved.

R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
101
Table 2
CH3-5 CH3-3’
1H, 13C and 15N chemical shifts (d, ppm) and coupling constants (J, Hz) for compound
10b in CDCl3.
H-3
H-4
H-6
(ppm)
-180
N-1’
N-7a
d
Assign.
Coupling constants
(Hz)
HMQC HMBC
-160
-140
-120
-100
-80
7.63 (m, 2H)
7.46–7.31
6.75
Ho
Aromatic
H6
–
108.4
C5, C7, Ci-7, CH3-5,
N7a
N-4
6.61
6.28
2.61
2.39
159.4
152.8
150.8
H3
–
–
–
–
89.2
108.8
24.8
13.7
–
C2, C3a, N7a
C30, C5, Ci-50
C5, C6, N4
C30, C40, N20
2.61 (CH3-5), 6.75
6.61(H3)
H40
CH3-5
CH3-30
C5
C2
C30
N-2’
(ppm)
6.4
5.6
4.8
4.0
3.2
2.4
–
–
–
Fig. 6. 1H–15N gs-HMBC-NMR of 5-methyl-2-(30-methyl-50-phenyl-1H-pyrazol-10-
yl)-7-phenylpyrazolo[1,5-a]pyrimidine (10b) in CDCl3.
6.28(H40),
2.39(CH3-30)
6.61(H3)
6.75(H6), 7.63(Ho)
6.28(H40), m Ar
6.75(H6)
149.6
145.7
145.0
131.3
130.8
130.4
129.1/129.06/
128.4
/128.16/128.06
108.8
C3a
C7
C50
Ci-7
Co
Ci-50
Co, 2Cm,
–
–
–
–
sence of any quartet signal for H-6 due to allylic coupling with
CH3 protons at high resolution revealed that CH3 is present at posi-
tion-5 in pyrazolo[1,5-a]pyrimidine moiety and the value of this
methyl signal at 2.61 ppm. The other protons H-40, H-3 and H-6
in 10b are usually observed as sharp singlets at 6.28 (H-40), 6.61
(H-3) and 6.75 ppm (H-6) [28].
7.63
6.28(H40)
–
2Cp
C40
1J = 174.8,
3JCH3-3 = 2.8
1J = 167.3,
3JCH3-3 = 2.8
1J = 185.1
1J = 128.1
1J = 127.4
6.28
6.75
2.39
2.61
Furthermore, the presence of methyl groups at position-30 and -
5 finds additional evidence by the study of 13C NMR spectral data
of compound 10b. The spectrum exhibits the presence of methyl
group at 13.7 and 24.8 ppm assignable to CH3-30 and CH3-5,
respectively, in agreement with 10a spectral results. The com-
pound displayed C-30, C-40 and C-50 signals of pyrazole ring reso-
nated at 150.8, 108.8 and 145.0 ppm, respectively [20,29].
It is worthwhile to mention that the 13C NMR spectrum of 10b
shows resonance signal for C-50 at 145.0 ppm (Table 2) relatively
108.4
C6
89.2
24.8
13.7
ꢀ78.9
ꢀ110.7
ꢀ170.6
ꢀ181.1
C3
6.61
2.61
2.39
–
6.75
–
CH3-5
CH3-30
N20
2.39 (Me-30)
2.61 (Me-5)
6.75(H6),6.61 (H3)
6.28 (H40)
N4
N7a
N10
downfield,
D
d 4.3, as compared to C-50 at 140.9 ppm (Table 1) in
case of 10a. Such a deshielding of C-50 in compound 10b may be
attributed to the presence of a phenyl group at position-50 of the
pyrazole ring than at C-30, in accordance with results previously re-
ported [20].
ring came from 1H and 13C NMR spectral data of 10a which was
used as a reference for the structural elucidation of compound
10b. The methyl groups at position-5 and -7 in 10a displayed pro-
ton shifts of 2.54 and 2.70 ppm, respectively and carbon shifts of
24.6 and 16.9 ppm, respectively. In 1H NMR spectra of 10a, it has
been observed that C-7 methyl resonates downfield as compared
to C-5 methyl group. This downfield shift generally observed for
the 7- over the 5-substituted derivatives allowed the identification
of the pyrazol-10-ylpyrazolo[1,5-a]pyrimidine 10b. The regioiso-
meric structures were assigned on the basis of the coupling con-
stants of 1H NMR spectra.
Moreover, a conclusive evidence for the proposed structure III
was obtained through HMQC and HMBC experiments on 10b
(Fig. 5) and (Fig. 6). The complete assignments of all the 1H, 13C,
15N signals of 10b thus obtained are given in Table 2.
The position of CH3 group on C-5 in compound 10b is unambig-
uously determined by the 3J (CH3-5, N-4) coupling of its protons
with nitrogen atom N-4 (Fig. 6). Further, the coupling 5J (CH3-5,
N-7a) of the structure 10b (bearing the CH3 group on C-5) is not
visible in the spectrum. If 10b would have alternative structure II
(bearing the CH3 group on C-7), strong correlation between the
CH3-7 and N-7a must be appeared via 3J coupling in the spectrum.
On the other hand, signal for N-7a in 10b with two 3J (H-6, N-7a), 3J
Structure II for 10b could also be ruled out on the basis of 1H
NMR spectrum of the isolated pyrazol-10-ylpyrazolo[1,5-a]pyrimi-
dine which revealed a singlet (3 H) at 2.61 ppm for a methyl group
and a singlet (1 H) at 6.75 ppm which was assigned for H-6. Ab-
H-6 H-3
H-4’
CH3-5 CH3-3’
CH3-3’
CH3-5
(a)
(b)
H-6
H-3
ppm
88
ppm
12
H-4’
(ppm)
148
C-5’
C-7
CH3-3’
CH3-5
C-3
16
20
24
28
C-3a
C-3’
96
152
156
160
C-2
104
112
C-6
C-4’
C-5
(ppm)
7.2
6.4
5.6
4.8
4.0
3.2
2.4
ppm
ppm
6.7 6.6 6.5 6.4 6.3 6.2
2.64 2.48 2.32
Fig. 5. 1H–13C gs-HMQC (a) and 1H–13C gs-HMBC–NMR (b) of 5-methyl-2-(30-methyl-50-phenyl-1H-pyrazol-10-yl)-7-phenylpyrazolo[1,5-a]-pyrimidine (10b) in CDCl3.

102
R. Aggarwal et al. / Journal of Molecular Structure 934 (2009) 96–102
(H-3, N-7a) has now become smaller on comparison with the sig-
nal for N-7a in 10a, thus ruling out structure II.
the Mass Spectrometry Facility, University of California, San Fran-
cisco, USA for running the mass spectra and SAIF, CDRI, Lucknow
for elemental analysis.
It is also worth mentioning here that the formation of regio-
isomer 10b (III) having methyl substituents at position-30 on pyr-
azole ring and at position-5 in pyrazolo[1,5-a]pyrimidine ring is
the most reasonable. This can be attributed to the fact that the car-
bonyl carbon of acetyl group is more reactive towards nucleophilic
reaction than the carbonyl carbon adjacent to phenyl ring in phe-
nyl-1,3-butanedione and the unsubstituted nitrogen of hetero-
arylhydrazine 8 is involved in the initial reaction in agreement
with our previous findings [20], that is, the mechanism is Ay+Dx.
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a doublet
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Acknowledgments
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The authors are thankful to University Grants Commission, New
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