Carbon-Carbon Bond Cleavage Reaction: Synthesis of Multisubstituted Pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1021/acs.joc.5b00933

A new carbon-carbon bond cleavage reaction was developed for the efficient synthesis of multisubstituted pyrazolo[1,5-a]pyrimidines. This base induced reaction of 1,3,5-trisubstituted pentane-1,5-diones and substituted pyrazoles afforded good yields of the pyrazolo[1,5-a]pyrimidines.

Full text of DOI:10.1021/acs.joc.5b00933

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Note
Carbon-Carbon Bond Cleavage Reaction: Synthesis
of Multi-Substituted Pyrazolo[1,5-a]pyrimidines
Pallabi Saikia, Sanjib Gogoi, and Romesh Chandra Boruah
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 17 Jun 2015
Downloaded from http://pubs.acs.org on June 17, 2015
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Carbon-Carbon Bond Cleavage Reaction: Synthesis of Multi-
Substituted Pyrazolo[1,5-a]pyrimidines
Pallabi Saikia, Sanjib Gogoi,* Romesh C Boruah*
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Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India, Fax: +913762370011 Tel.: +91
3762372948;
skgogoi1@gmail.com;rc_boruah@yahoo.co.in
______________________________________________________________________________________________________
Abstract: A new carbon-carbon bond cleavage reaction was developed for the efficient synthesis
of multi-substituted pyrazolo[1,5-a]pyrimidines. This base induced reaction of 1,3,5-
trisubstituted pentane-1,5-diones and substituted pyrazoles afforded good yields of the
pyrazolo[1,5-a]pyrimidines.
_
_____________________________________________________________________________
The cleavage of carbon-carbon bond is a significant issue in organic chemistry due to the inert
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nature of the C−C bond. Although, the importance of this C−C bond cleavage had already
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resulted different methodologies for the cleavage of C−C, C=C and C≡C bonds, the
development of new routes for selective cleavage of C−C bond still remains as an important and
challenging goal for the chemists and biologists.
The pyrazole fused heterocycle pyrazolo[1,5-a]pyrimidine, is the key structural motif of
several drugs and pesticides. For example, the hypnotic drugs zaleplon and indiplon, the
anxiolytic drug ocinaplon and the fungicide pyrazophos, have this central motif of pyrazolo[1,5-
a]pyrimidine (Figure 1). The pyrazolo[1,5-a]pyrimidines I-III (Figure 1) are found to possess
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high affinity for translocator protein (TSPO), which is revealed as an attractive target in anti-
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cancer therapy. The pyrazolo[1,5-a]pyrimidine derivatives are also known for their wide range
of biological activities such as antimicrobial, antibacterial, antitrichomonal, antischistosomal,
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anticancer, antitumor etc. Some of the pyrazolo[1,5-a]pyrimidine derivatives are found to have
potent and selective Pim-1 inhibitory activity, excellent activity against wild-type HIV-1 and
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CK2 Kinase inhibitory activity. The importance of these pyrazolo[1,5-a]pyrimidines has led to
the development of new methods for the synthesis of these molecules, typically by the
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condensation reaction of (i) aminopyrazole with 1,2-allenic ketones, (ii) aminopyrazole with
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enaminonitriles or enaminones, (iii) aminopyrazole with 1, 3-dicarbonyl compounds or α,β-
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unsaturated carbonyl compounds . Recently, we also reported the synthesis of pyrazolo[1,5-
a]pyrimidines by the regioselective palladium catalyzed reaction of β-halovinyl aldehydes with
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-aminopyrazoles. In spite of the presence of methods for the synthesis of pyrazolo[1,5-
a]pyrimidines, due to the tremendous biological profile of these heterocycles, new efficient
methods which can accommodate a broad range of substituents on the heterocyclic scaffold
Figure 1. Examples of drugs/biologically active pyrazolo[1,5-a]pyrimidines
are still highly desirable. In continuation of our work on search for novel methods for the
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syntheses of important heterocycles, herein, we report an unprecedented reaction of 1,3,5-
trisubstituted pentane-1,5-diones with substituted 3-amino pyrazoles in the presence of base,
which proceeds via C-C bond cleavage for the easy construction of multi-substituted
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pyrazolo[1,5-a]pyrimidines. Initially, we selected 1,5-diketone 1a and 3-amino-1H-pyrazole (2a)
as the model substrates for the synthesis of compound 3a (Table 1). Refluxing a mixture of 1a
and 2a in anhydrous ethanol in the presence of two equivalents of NaOMe for twelve hours
furnished pyrazolo[1,5-a]pyrimidine 3a in 57% yield (entry 1, Table 1). The product 3a was
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identified from H NMR, C NMR and mass spectral data. To determine the ideal base and
solvent for this base induced reaction, we studied this model reaction with some other bases and
solvents as shown in Table 1. The bases such as KOMe, NaH and KOH led to lower yield of 3a
t
t
(entries 2 & 7-8). Gratifyingly, when we used NaO Bu and KO Bu as the bases (two equivalents)
Table 1. Optimization of the reaction conditions for 3a
a
b
Entry
Base
NaOMe EtOH
KOMe EtOH
NaO Bu EtOH
Solvent Yield (%)
1
2
3
4
57
62
78
84
71
62
33
24
0
t
t
KO Bu
KO Bu
KO Bu DMSO
NaH
KOH
-
EtOH
DMF
c
t
5
6
c
t
7
8
9
toluene
ethanol
ethanol
a
b
c
Two equivalents of the base was used.
Yield of the isolated
Reaction was performed at 120 C.
poroduct.
in the above reaction, the reaction afforded 78% and 84% yields of 3a respectively in ethanol
t
(
entries 3-4). Further studies of KO Bu induced cyclization reaction in high boiling solvents
DMF and DMSO could not improve the yield of the product 3a (entries 5-6) and in the absence
of the base, the reaction could not afford the product 3a (entry 9). The reaction of 1a and 2a with
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one equivalent of the base KO Bu, under the optimized reaction condition provided less yield of
a (76%). With the optimized reaction conditions in hand (Table 1, entry 4), we then explored
the substrate scope of the reaction with some representative 1,5-dicarbonyls (1a-h) and 3-amino-
H-pyrazoles (2a-g) which are shown in Table 2. The base induced cyclization reaction of 1,5-
3
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dicarbonyl 1a with various 3-amino-1H-pyrazoles (2a-g) without substituents and with
substituents such as methyl, t-butyl, phenyl and 4-fluorophenyl, present in the pyrazole ring
reacted smoothly to afford pyrazolo[1,5-a]pyrimidines 3a-f in 70-84% yields under the
optimized reaction conditions. Similarly, the reaction of 1a and 5-(thiophen-2-yl)-3-amino-1H-
pyrazole (2g) afforded pyrazolo[1,5-a]pyrimidine 3g in 67% yield. Next, the reaction of 5-
methyl-3-amino-1H-pyrazole (2b) with various symmetrical and unsymmetrical 1,5-dicarbonyls
with electron donating and electron-withdrawing groups present in the aromatic rings were
studied to extend the substrate scope. Symmetrical 1,5-dicarbonyls with methyl and chloro
groups present in the aromatic rings 1b-c, reacted efficiently with 2b to give the corresponding
substituted pyrazolo[1,5-a]pyrimidines 3h-i in good yields (77−80%). Similarly, the cyclization
reactions of 2b with symmetrical 1,5-dicarbonyls such as 3-phenyl-1,5-di-p-tolylpentane-1,5-
dione (1d), 3-phenyl-1,5-di-p-chlorophenylpentane-1,5-dione (1e), 1,5-diphenyl-3-(p-
tolyl)pentane-1,5-dione (1f) and 3-(p-chlorophenyl)-1,5-diphenylpentane-1,5-dione (1g)
proceeded very easily under the optimized condition to afford pyrazolo[1,5-a]pyrimidines 3j-m
in 71-80% yields. In addition, the reaction of 1f with 2a afforded 78% yield of pyrazolo[1,5-
a]pyrimidine 3n, whose single X-ray crystallography studies (Figure 2) confirmed the structure
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of compound 3. The reaction of unsymmetrical 1-phenyl-3,5-di-p-tolylpentane-1,5-dione (1h)
with 2b afforded a mixture of pyrazolo[1,5-a]pyrimidines 3l (41%) and 3h (32%) under the
standard condition. Similarly, the condensation reaction of unsymmetrical 1-(4-chlorophenyl)-3-
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phenyl-5-(p-tolyl)pentane-1,5-dione (1i) with 2b afforded a mixture of pyrazolo[1,5-
a]pyrimidines 3j (44%) and 3k (25%) under the standard condition. This result indicated that
phenyl ring substituted with electron withdrawing group eliminated preferentially from the 1,5-
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a
Table 2. Synthesis of various substituted pyrazolo[1,5-a]pyrimidines
a
Reaction conditions: 1,5-dicarbonyl (1.0 mmol), 3-amino pyrazole (1.0 mmol)
t
o
and KO Bu (2.0 mmol) in ethanol (3.0 mL) was heated at 120 C for 12 hours;
Isolated yields.
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Figure 2. X-ray crystal structure of 3n
dicarbonyl compound providing better yield of compound 3j. The starting 1,5-dicarbonyl
compounds were already used by different research groups for the construction of various
1
3a-b
important scaffolds
and they were easily prepared by refluxing a mixture of acetophenone
13c
with chalcone following known procedure.
A probable mechanism for the formation of compound 3 is shown in Scheme 1. First,
condensation of ketone 1 with 3-amino pyrazole 2, followed by deprotonation of the formed
imine derivative in the presence of base potassium tert-butoxide generates the pyrazolide anion
4
a. Tautomerization of the imine 4a to the enamine 4b, followed by intramolecular nuclephilic
attack of pyrazolide anion on the benzylic/allylic carbon (C3) affords intermediate 4e by
elimination of one molecule of acetophenone derivative 4d. Finally, aerial oxidation of the
1
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resulting dihydropyrazolo[1,5-a]pyrimidine 4e affords compound 3. To prove the mechanism,
the GC-MS data of the crude reaction mixture of 1d and 2b was recorded (see SI), as well as, the
Scheme 1. Proposed reaction mechanism
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side product of the reaction was isolated. The side product was found to be 4-
methylacetophenone, which proved the proposed mechanism for the formation of 3 from
intermediate 4b (Scheme 1). The substrate 1d on treatment with potassium tert-butoxide alone
under standard condition did not provide the base promoted eliminated product 4-
methylacetophenone which further suggested the reaction mechanism depicted in Scheme 1.
In conclusion, we have developed a novel base induced reaction of 1,3,5-trisubstituted
pentane-1,5-diones with substituted pyrazoles for the construction of poly substituted
pyrazolo[1,5-a]pyrimidines via C-C/C-N bond cleavage reaction. The methodology has
advantages such as wide substrate scope, easily available starting materials, high yields and
simple reaction procedure.
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EXPERIMENTAL SECTION
General information
Melting points were uncorrected. IR spectra were recorded using chloroform. NMR spectra were
recorded on a 300 MHz or 500 MHz spectrometer using tetramethylsilane (TMS) as an internal
standard. Mass spectra were recorded on GCMS instrument. All the commercially available
regents were used as received. All experiments were monitored by thin layer chromatography
(TLC). TLC was performed on pre-coated silica gel plates. Column chromatography was
performed on silica gel (100-200 mesh).
General procedure for the synthesis of pyrazolo[1,5-a]pyrimidines derivatives 3a-n: A
t
mixture of 1,5-diketone 1 (1.0 mmol), 3-amino-1H-pyrazole 2 (1.0 mmol) and KO Bu (2.0
mmol) in anhydrous ethanol was refluxed for 12 hours. After completion of the reaction, the
solvent was removed from the reaction mixture, water was added into it and then it was extracted
with ethyl acetate. The ethyl acetate layer was then washed with brine and water. Finally, it was
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dried over anhydrous Na SO and the solvent was removed under vacuo. The crude product
2
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obtained was purified by column chromatography over silica gel (100-200 mesh) using
EtOAc/Hexane as the eluant.
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,7-diphenylpyrazolo[1,5-a]pyrimidine (3a): Yellow solid (228 mg, 84%); mp: 88-90 C. H
NMR (CDCl , 300 MHz) δ 6.81 (s, 1H), 7.34 (s, 1H), 7.51 (d, J = 6.5 Hz, 2H), 7.56-7.59 (m,
3
1
3
3
1
H), 8.06 (d, J = 3.4 Hz, 2H), 8.11-8.17 (m, 4H); C NMR (CDCl , 75 MHz) δ 97.2, 105.2,
3
27.3, 128.4, 128.7, 128.9, 129.3, 130.3, 130.9, 131.6, 137.5, 145.2, 146.9, 156.2; IR (CHCl3,
-1
+
cm ): 760, 1028, 1222, 1377, 1491, 1549, 1607, 2924; MS (EI, m/z): 271 [M ]. Anal. calcd. for
C H N : C, 79.68; H, 4.83; N, 15.49. Found: C, 79.55; H, 4.99 N, 15.68.
18
13
3
2
-methyl-5,7-diphenylpyrazolo[1,5-a]pyrimidine (3b): Yellow solid (231 mg, 81%); mp: 115-
o
1
117 C; H NMR (CDCl , 500 MHz) δ 2.53 (s, 3H), 6.57 (s, 1H), 7.48-7.50 (m, 6H), 7.55 (d, J =
3
13
4
.2 Hz, 2H), 8.06-8.10 (m, 3H); C NMR (CDCl , 125 MHz) δ 14.8, 96.4, 104.3, 127.1, 128.6,
3
-1
1
28.8, 129.2, 130.0, 130.8, 131.6, 137.6, 146.1, 150.6, 155.4, 155.7; IR (CHCl , cm ): 771,
3
+
1
017, 1218, 1373, 1490, 1554, 1608, 2924; MS (EI, m/z): 285 [M ]. Anal. calcd. for C H N :
1
9
15
3
C, 79.98; H, 5.30; N, 14.73. Found: C, 79.81; H, 5.59; N, 14.89.
1
2-tert-butyl-5,7-diphenylpyrazolo[1,5-a]pyrimidine (3c): Gum (242 mg, 74%); H NMR
(
CDCl , 500 MHz) δ 1.43 (s, 9H), 6.65 (s, 1H), 7.45-7.48 (m, 4H), 7.50-7.54 (m, 3H), 8.09 (d, J
3
1
3
=
4.8 Hz, 2H), 8.20 (d, J = 5.7 Hz, 2H); C NMR (CDCl , 125 MHz) δ 30.4, 32.9, 93.0, 104.0,
3
127.1, 128.3, 128.8, 129.4, 129.9, 130.7, 131.6, 137.8, 145.9, 150.4, 155.4, 168.0; IR (CHCl3,
-1
+
cm ): 762, 1017, 1239, 1490, 1551, 1606, 2960; MS (EI, m/z): 327 [M ]. Anal. calcd. for
C H N : C, 80.70; H, 6.46; N, 12.83. Found: C, 80.96; H, 6.61; N, 12.55.
22 21
3
o
3
,5,7-triphenylpyrazolo[1,5-a]pyrimidine (3d): Yellow solid (250 mg, 72%); mp: 175-177 C;
1
H NMR (CDCl , 500 MHz) δ 7.40 (s, 1H), 7.50-7.56 (m, 7H), 7.60 (d, J = 6.6 Hz, 2H), 8.06 (d,
3
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J = 5.9 Hz, 2H), 8.21-8.25 (m, 4H), 8.49 (s, 1H); C NMR (CDCl , 125 MHz) δ 105.1, 110.6,
3
1
26.0, 126.3, 127.3, 128.6, 128.8, 129.2, 130.3, 130.9, 132.3, 137.3, 142.9, 145.9, 146.9, 155.8;
-1
+
IR (CHCl , cm ): 691, 761, 1028, 1189, 1377, 1491, 1562, 1607, 2923; MS (EI, m/z): 347 [M ].
3
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Anal. calcd. for C H N : C, 82.97; H, 4.93; N, 12.10. Found: C, 82.68; H, 4.75; N, 12.39.
2
4
17
3
3-(4-fluorophenyl)-5,7-diphenylpyrazolo[1,5-a]pyrimidine (3e): Yellow solid (256 mg, 70%);
o
1
mp: 159-161 C; H NMR (CDCl , 500 MHz) δ 7.19 (d, J = 5.4 Hz, 2H), 7.41 (s, 1H), 7.55 (d, J
3
1
3
=
8.4 Hz, 4H), 7.57 (s, 1H), 7.60 (d, J = 3.3 Hz, 1H), 8.07-8.24 (m, 6H), 8.44 (s, 1H); C NMR
(CDCl , 125 MHz) δ 105.1, 109.8, 115.4, 115.6, 127.2, 127.7, 127.8, 128.7, 128.9, 129.2, 130.4,
3
-1
1
30.9, 131.3, 137.2, 142.6, 146.9, 155.9. IR (CHCl , cm ): 750, 835, 1227, 1492, 1565, 1613,
3
+
2
924; MS (EI, m/z): 365 [M ]. Anal. calcd. for C H FN : C, 78.89; H, 4.41; N, 11.50. Found:
24 16
3
C, 78.90; H, 4.62; N, 11.71.
o
1
2
,5,7-triphenylpyrazolo[1,5-a]pyrimidine (3f): Yellow solid (246 mg, 71%); mp 161-162 C. H
NMR (CDCl , 500 MHz) δ 7.10 (s, 1H), 7.36 (s, 1H), 7.45-7.61 (m, 8H), 8.02 (d, J = 3.1 Hz,
3
1
3
1
1
H) 8.14-8.22 (m, 6H); C NMR (CDCl , 125 MHz) δ 93.7, 104.9, 126.5, 127.2, 128.2, 128.5,
3
-1
28.6, 128.8, 129.4, 130.2, 130.9, 131.4, 137.5, 146.3, 150.9, 156.0, 156.2; IR (CHCl , cm ):
3
+
759, 845, 1027, 1233, 1490, 1552, 1607, 2926; MS (EI, m/z): 347 [M ]. Anal. calcd. for
C H N : C, 82.97; H, 4.93; N, 12.10. Found: C, 82.78; H, 4.81; N, 12.34.
24
17
3
5
,7-diphenyl-2-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine (3g): Yellow solid (237 mg, 67%);
o
1
mp: 182-184 C; H NMR (CDCl , 500 MHz) δ 6.96 (s, 1H), 7.09-7.58 (m, 10H), 8.12 (d, J = 5.4
3
13
Hz, 2H), 8.18 (d, J = 4.8 Hz, 2H); C NMR (CDCl , 125 MHz) δ 93.5, 105.0, 125.7, 126.2,
3
1
27.2, 127.6, 128.5, 128.8, 129.4, 130.2, 130.9, 137.4, 146.2, 150.9, 151.5, 156.2; IR (CHCl3,
-1
+
cm ): 762, 1017, 1218, 1490, 1565, 1606, 2923; MS (EI, m/z): 353 [M ]. Anal. calcd. for
C H N S: C, 74.76; H, 4.28; N, 11.89. Found: C, 74.59; H, 4.55; N, 11.67.
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-methyl-5,7-di-p-tolylpyrazolo[1,5-a]pyrimidine (3h): Gum (251 mg, 81%); H NMR (CDCl ,
3
5
00 MHz) δ 2.42 (s, 3H), 2.46 (s, 3H), 2.52 (s, 3H), 6.54 (s, 1H), 7.21 (s, 1H), 7.31 (d, J = 4.8
1
3
Hz, 2H), 7.37 (d, J = 4.5 Hz, 2H), 7.86 (d, J=4.9 Hz, 2H), 7.97-7.99 (m, 2H); C NMR (CDCl ,
3
0
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0
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25 MHz) δ 14.8, 21.5, 96.1, 103.8, 127.0, 129.3, 129.5, 134.6, 140.3, 141.2, 155.2, 155.7. IR
-1
+
(CHCl , cm ): 762, 826, 1176, 1478, 1610, 2937; MS (EI, m/z): 313 [M ]. Anal. calcd. for
3
C H N : C, 80.48; H, 6.11; N, 13.41. Found: C, 80.16; H, 6.32; N, 13.66.
21
19
3
5
,7-bis(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (3i): Yellow solid (272 mg, 77%);
o
1
172-175 C; H NMR (CDCl , 500 MHz) δ 2.54 (s, 3H), 6.59 (s, 1H), 7.19 (s, 1H), 7.49 (d, J =
3
13
4
2
.8 Hz, 4H), 7.56 (d, J = 5.1 Hz, 4H), 8.06 (d, J = 5.9 Hz, 2H); C NMR (CDCl , 125 MHz) δ
3
9.6, 96.7, 103.7, 128.4, 129.0, 129.8, 135.8, 136.4, 137.1, 145.0, 150.4, 154.3, 155.7; IR
-1
+
(CHCl , cm ): 774, 817, 1013, 1090, 1486, 1593, 1607, 2924; MS (EI, m/z): 353 [M ]. Anal.
3
calcd. for C H Cl N : C, 64.42; H, 3.70; N, 11.86. Found: C, 64.79; H, 3.84; N, 11.62.
1
9
13
2
3
1
2
-methyl-7-phenyl-5-p-tolylpyrazolo[1,5-a]pyrimidine (3j): Brown Gum (227 mg, 76%); H
NMR (CDCl , 500 MHz) δ 2.43 (s, 3H), 2.53 (s, 3H), 6.55 (s, 1H), 7.22 (s, 1H), 7.31 (d, J = 7.8
3
13
Hz, 2H), 7.55-7.58 (m, 2H), 8.01 (d, J = 4.2 Hz, 2H), 8.06-8.09 (m, 3H); C NMR (CDCl , 125
3
MHz) δ 14.8, 21.3, 96.2, 104.2, 127.0, 128.6, 129.2, 129.5, 130.8, 131.6, 134.7, 140.4, 146.1,
-1
1
50.5, 155.3, 155.7; IR (CHCl , cm ): 765, 817, 1180, 1492, 1606, 2924; MS (EI, m/z): 299
3
+
[
M ]. Anal. calcd. for C H N : C, 80.24; H, 5.72; N, 14.04. Found: C, 80.02; H, 5.84; N, 13.98.
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17
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5-(4-chlorophenyl)-2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine (3k): Brown solid (230 mg,
o
1
7
7
1
7
2%); mp: 132-134 C; H NMR (CDCl , 500 MHz) δ 2.54 (s, 3H), 6.57 (s, 1H), 7.20 (s, 1H),
3
1
3
.49 (s, 1H), 7.56-7.58 (m, 3H), 8.05-8.08 (m, 5H); C NMR (CDCl , 125 MHz) δ 14.9, 96.6,
3
-1
04.0, 128.5, 128.7, 129.1, 129.3, 131.0, 131.5, 136.4, 146.4, 154.5, 155.7; IR (CHCl , cm ):
3
+
64, 827, 1013, 1488, 1556, 1594, 2924; MS (EI, m/z): 319 [M ]. Anal. calcd. for C H ClN :
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C, 71.36; H, 4.41; N, 13.14. Found: C, 71.59; H, 4.65; N, 13.01.
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1
7
-methyl-5-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidine (3l): Brown solid (239 mg, 80%); mp:
o
1
09-111 C; H NMR (CDCl , 500 MHz) δ 2.46 (s, 3H), 2.53 (s, 3H), 6.58 (s, 1H), 7.21 (s, 1H),
3
10
11
12
13
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60
13
.24 (s, 2H), 7.49-7.52 (m, 3H), 7.99-8.11 (m, 4H); C NMR (CDCl , 125 MHz) δ 14.9, 21.6,
3
96.2, 96.4, 103.9, 104.1, 127.3, 128.9, 129.2, 129.4, 129.6, 130.1, 141.3, 146.4, 155.3, 155.8; IR
-1
+
(
CHCl , cm ): 772, 1019, 1463, 1596, 1661, 2922; MS (EI, m/z): 299 [M ]. Anal. calcd. for
3
C H N : C, 80.24; H, 5.72; N, 14.04. Found: C, 80.46; H, 5.44; N, 14.27.
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17
3
7-(4-chlorophenyl)-2-methyl-5-phenylpyrazolo[1,5-a]pyrimidine (3m): Gum (227 mg, 71%);
1
H NMR (CDCl , 500 MHz) δ 2.54 (s, 3H), 6.58 (s, 1H), 7.51 (s, 2H), 7.56-7.59 (m, 3H), 8.08-
3
1
3
8
.12 (m, 5H); C NMR (CDCl , 125 MHz) δ 14.9, 96.5, 104.5, 127.3, 128.7, 128.9, 129.3,
3
-1
130.1, 130.9, 139.0, 143.9, 154.8, 155.0; IR (CHCl , cm ): 763, 1028, 1217, 1373, 1490, 1554,
3
+
1
607, 2923; MS (EI, m/z): 319 [M ]. Anal. calcd. for C H ClN : C, 71.36; H, 4.41; N, 13.14.
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9
14
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Found: C, 71.12; H, 4.69; N, 13.35.
o
5
-Phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidine (3n): White solid (222 mg, 78%); mp: 110-112 C;
1
H NMR (CDCl , 300 MHz) δ 2.47 (S, 3H), 6.79 (s, 1H), 7.33 (s, 1H), 7.35-7.55 (m, 4H), 7.96
3
13
(d, J = 3.4 Hz, 2H), 8.11-8.16 (m, 4H); C NMR (CDCl , 75 MHz) δ 21.6, 97.1, 104.9, 127.3,
3
-1
1
28.6, 128.9, 129.2, 129.4, 130.3, 137.6, 141.4, 145.1, 146.9, 156.2, 161.3; IR (CHCl , cm ):
3
+
2
924, 1610, 1550, 1369, 1220, 1028, 761; MS (EI, m/z): 285 [M] . Anal. calcd. for C H N : C,
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79.98; H, 5.30; N, 14.73. Found: C, 79.65; H, 4.91 N, 14.55.
Acknowledgements
P. S. thanks UGC, New Delhi for the award of senior research fellowship (UGC-JRF). Authors
thank CSIR, New Delhi, for financially supporting us with CSIR-ORIGIN (CSC-0108), CSIR-
OSDD (HCP-0001) and CSIR-ACT (CSC0301) projects. We are grateful to the Director, CSIR-
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NEIST for his keen interests.
Supporting Information:
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Copies of H NMR and C NMR spectra for 3a-n and X-ray crystallographic data (CIF file) for
n. This material is available free of charge via the Internet at http://pubs.acs.org.
References
0
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0
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2
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6
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0
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3
(
1) For recent reviews on the C-C bond cleavage, see: (a) Murakami, M.; Matsuda, T. Chem.
Commun. 2011, 47, 1100. (b) Tobisu, M.; Chatani, N. Chem. Soc. Rev. 2008, 37, 300. (c) Jun,
C.-H. Chem. Soc. Rev. 2004, 33, 610.
2
. For selected examples of the cleavage of C-C single bonds, see (a) Tobisu, M.; Kinuta, H.;
Kita, Y.; Mond, E. R.; Chatani, N. J. Am. Chem. Soc. 2012, 134, 115. (b) Li, L.; Zhang, J.
Org. Lett. 2011, 13, 5940. (c) Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang X.; Shi, Z.-J. J.
Am. Chem. Soc. 2011, 133, 15244. (d) Herbert, D. E.; Gilroy, J. B.; Staubitz, A.; Haddow, M.
F.; Harvey J. N.; Manners, I. J. Am. Chem. Soc. 2010, 132, 1988.
3
4
. For selected examples of C=C bond cleavages, see: a) Miyamoto, K.; Tada, N.; Ochiai, M. J.
Am. Chem. Soc. 2007, 129, 2772. (b) Lin, R.; Chen, F.; Jiao, N. Org. Lett. 2012, 14, 4158. (c)
Sattler, A.; Parkin, G. Nature 2010, 463, 523.
. For selected examples of the cleavage of C≡C bonds, see: (a) Shen, T.; Wang, T.; Qin C.;
Jiao, N. Angew. Chem. 2013, 125, 6809. (b) Wang, A.; Jiang, H. J. Am. Chem. Soc. 2008,
130, 5030. (c) Wang, L.-J.; Zhu, H.-T.; Lu, L.; Yang, F.; Liu X.-Y.; Liang, Y.-M. Org. Lett.
2
012, 14, 1990.
. Crossley, E. L.; Issa, F.; Scarf, A. M.; Kassiou, M.; Rendina, L. M. Chem. Commun. 2011,
7, 12179.
5
4
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2
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3
4
5
6
7
8
9
6
. (a) Al-Adiwish, W. M.; Tahir, M. I. M.; Siti-Noor-Adnalizawati, A.; Hashim, S. F.; Ibrahim
N.; Yaacob, W. A. Eur. J. Med. Chem. 2013, 64, 464. (b) Selleri, S.; Bruni, F.; Costagli, C.;
Costanzo, A.; Guerrini, G.; Ciciani, G.; Gratteri, P.; Besnard, F.; Costa, B.; Montali, M.;
Martini, C.; Fohlin, J.; Siena G. D.; Aiello, P. M. J. Med. Chem. 2005, 48, 6756. (c) Kamal,
A.; Tamboli, J. R.; Nayak, V. L.; Adil S. F.; Vishnuvardhan, M. V. P. S. Bioorg. Med. Chem.
Lett. 2013, 23, 3208. (d) Ahmed, O. M.; Mohamed, M. A.; Ahmed, R. R.; Ahmed, S. A. Eur.
J. Med. Chem. 2009, 44, 3519. (e) Reynolds, A.; Hanani, R.; Hibbs, D.; Damont, A.; Da
Pozzo, E.; Selleri, S.; Dolle, F.; Martini, C.; Kassiou, M. Bioorg. Med. Chem. Lett. 2010, 20,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
799. (f) James, M. L.; Fulton, R. R.; Vercoullie, J.; Henderson, D. J.; Garreau, L.; Chalon,
S.; Dolle, F.; Costa, B.; Guilloteau, D.; Kassiou, M. J. Nucl. Med. 2008, 49, 814. (g) Senga,
K.; Novinson, T.; Springer, R. H.; Rao, R. P.; O’Brien, D. E.; Robins, R. K.; Wilson, H. R. J.
Med. Chem. 1975, 18, 312.
7
. (a) Xu, Y.; Brenning, B. G.; Kultgen, S. G.; Foulks, J. M.; Clifford, A.; Lai, S.; Cha, A.;
Merx, S.; McCullar, M. V.; Kanner, S. B.; Ho, K.-K. ACS Med. Chem. Lett. 2015, 6, 63. (b)
Tian, Y.; Du, D.; Rai, D.; Wang, L.; Liu, H.; Zhan, P.; De Clercq, E.; Pannecouque, C.; Liu,
X. Bioorg. Med. Chem. 2014, 22, 2052. (c) Dowling, J. E.; Alimzhanov, M.; Bao, L.; Block,
M. H.; Chuaqui, C.; Cooke, E. L.; Denz, C. R.; Hird, A.; Huang, S.; Larsen, N. A. et al. ACS
Med. Chem. Lett. 2013, 4, 800.
8. Zhang, X.; Song, Y.; Gao, L.; Guo, X.; Fan, X. Org. Biomol. Chem. 2014, 12, 2099.
9
. (a) Ahmetaj, S.; Velikanje, N.; Grošelj, U.; Šterbal, I.; Prek, B.; Golobič, A.; Kočar, D.;
Dahmann, G.; Stanovnik, B.; Svete, J. Mol. Divers. 2013, 17, 731. (b) Ivachtchenko, A. V.;
Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Tkachenko, S. E.; Okun, I. M.
J. Med. Chem. 2011, 54, 8161. (c) Khalil, K. D.; Al-Matar, H. M.; Al-Dorri, D. M.; Elnagdi,
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M. H. Tetrahedron 2009, 65, 9421. (d) Haider Behbehani, Ibrahim H. H. M.; Makhseed, S.
Arkivoc 2010, ii, 267.
1
0. (a) Compton, D. R.; Sheng, S.; Carlson, K. E.; Rebacz, N. A.; Lee, I. Y.; Katzenellenbogen
B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2004, 47, 5872. (b) Gregg, B. T.;
Tymoshenko, D. O.; Razzano D. A.; Johnson, M. R. J. Comb. Chem. 2007, 9, 507. (c)
Abed, H. B.; Mammoliti, O.; Lommen, G. V.; Herdewijn, P. Tetrahedron Lett. 2013, 54,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
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9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
612. (d) Quiroga, J.; Portilla, J.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2007, 48, 6352. (e) Yin, L.; Liebscher, J. Synthesis 2004, 2329.
1
1. (a) Shekarrao, K.; Kaishap, P. P.; Gogoi S.; Boruah, R. C. Adv. Synth. Catal. 2015, 357,
1
187. (b) Prakash, R.; Shekarrao, K.; Saikia, P.; Gogoi, S.; Boruah, R. C. RSC Adv. 2015, 5,
21099. (c) Shekarrao, K.; Kaishap, P. P.; Saddanapu, V.; Addlagatta, A.; Gogoi, S.; Boruah,
R. C. RSC Adv. 2014, 4, 24001.
1
2. CCDC 1007775 contains the supplementary crystallographic data for the compound 3n.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. (a) Schmidt, E. Yu.; Bidusenko, I. A.; Protsuk, N. I.; Ushakov, I. A.; Trofimov, B. A. Eur. J.
Org. Chem. 2013, 2453. (b) Schmidt, E. Yu.; Trofimov, B. A.; Bidusenko, I. A.;
Cherimichkina, N. A.; Ushakov, I. A.; Protzuk, N. I.; Gatilov, Y. V. Org. Lett. 2014, 16,
4040. (c) Xia, Y.; Liu, Z.; Xiao, Q.; Qu, P.; Ge, R.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2012, 51, 5714.
1
4. Mahesh Kumar, P.; Siva Kumar, K.; Mohakhud, P. K.; Mukkanti, K.; Kapavarapu, R.;
Parsa, K. V. L.; Pal, M. Chem. Commun. 2012, 48, 431.
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