Highly facile and regio-selective synthesis of pyrazolo[1,5-a]pyrimidines via reactions of 1,2-allenic ketones with aminopyrazoles

Article abstract of DOI:10.1039/c3ob42445f

An efficient procedure for the syntheses of pyrazolo[1,5-a]pyrimidines through reactions of 1,2-allenic ketones with aminopyrazoles under extremely mild conditions without using any catalyst or promoter has been developed. The reactions showed excellent regio-selectivity with all the allenic ketone substrates except for those bearing an alkyl group at the internal position of the allene moiety. The reason behind this regio-selectivity dissimilarity has been explored with the aid of the B3LYP/6-31G* level of density functional theory. Moreover, this novel procedure has been successfully applied in the preparation of nucleoside-pyrazolo[1,5-a]pyrimidine chimeras with potent antiviral activities.

Full text of DOI:10.1039/c3ob42445f

Organic &
Biomolecular Chemistry
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Highly facile and regio-selective synthesis of
pyrazolo[1,5-a]pyrimidines via reactions of
1,2-allenic ketones with aminopyrazoles†
Cite this: Org. Biomol. Chem., 2014,
12, 2099
Xinying Zhang,* Yunping Song, Lin Gao, Xiaojie Guo and Xuesen Fan*
An efficient procedure for the syntheses of pyrazolo[1,5-a]pyrimidines through reactions of 1,2-allenic
ketones with aminopyrazoles under extremely mild conditions without using any catalyst or promoter has
been developed. The reactions showed excellent regio-selectivity with all the allenic ketone substrates
except for those bearing an alkyl group at the internal position of the allene moiety. The reason behind
this regio-selectivity dissimilarity has been explored with the aid of the B3LYP/6-31G* level of density
functional theory. Moreover, this novel procedure has been successfully applied in the preparation of
nucleoside-pyrazolo[1,5-a]pyrimidine chimeras with potent antiviral activities.
Received 6th December 2013,
Accepted 23rd January 2014
DOI: 10.1039/c3ob42445f
www.rsc.org/obc
and antischistosomal7 activities, and have been examined as
TSPO PET ligands,8 hepatitis C virus inhibitors,9 estrogen
Introduction
Heterobiaryls have attracted significant attention from the receptor ligands,10 CRFantagonists,11 COX-2 inhibitors,12 and KDR
scientific community due to their relevance to various bio- kinase inhibitors.13 These promising biological properties
logical activities. Among them, pyrazolo[1,5-a]pyrimidine have prompted the development of efficient synthetic strat-
forms the central core of a plethora of pharmaceuticals and egies toward pyrazolo[1,5-a]pyrimidine derivatives. So far, the
pesticides, such as Zaleplon, a hypnotic drug; Ocinaplon, available synthetic methods for pyrazolo[1,5-a]-pyrimidines
an anxiolytic drug; and Pyrazophos,
a fungicide and have mostly involved the condensation of aminopyrazole with
insecticide (Fig. 1). Moreover, some pyrazolo[1,5-a]pyrimidine 1,3-dicarbonyl or α,β-unsaturated carbonyl compounds,10–14
derivatives were found to possess anticancer,1 antitumor,2 enaminonitriles, or enaminones.15 While these methods are
anxiolytic,3 antimicrobial,4 antibacterial,5 antitrichomonal,6 generally reliable, they are usually carried out in refluxing
acetic acid and often suffer from poor regio-selectivity, tedious
procedures, and/or low yield. Although microwave16 and ultra-
sound irradiation17 have recently been successfully used to
shorten the reaction period and/or improve the yield, low
regio-selectivity still remains an unsolved problem in the
preparation of pyrazolo[1,5-a]pyrimidines by using classical
synthetic protocols.
In recent years, 1,2-allenic ketones are emerging as a power-
ful tool in forming carbon–carbon and carbon–heteroatom
bonds.18 In particular, they are highly reactive as nucleophilic
addition acceptors and usually prefer to undergo conjugate
Fig. 1 Examples of the drugs with a pyrazolo[1,5-a]pyrimidine scaffold.
addition rather than direct addition due to their intriguing
structural features.
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical
Based on the above facts and as a continuation of our
Media and Reactions, Ministry of Education, Collaborative Innovation Center of
study on the synthetic applications of functionalized allene
Henan Province for Green Manufacturing of Fine Chemicals, Henan Normal
derivatives,19 we hypothesized that an efficient and practical
University, Xinxiang, Henan 453007, P. R. China. E-mail: xinyingzhang@htu.cn,
synthesis of pyrazolo[1,5-a]pyrimidines derivatives with
improved regio-selectivity might be achieved by using 1,2-
allenic ketones as the required 1,3-bielectrophile reagents.
Herein, we would like to report our preliminary result in this
regard.
xuesen.fan@htu.cn
†Electronic supplementary information (ESI) available: Experimental details;
characterization data; copies of the 1H NMR and 13C NMR spectra of 3a–ll, 4ii–ll,
7, 8, 11, 12; and the X-ray crystal structures of 3jj and 4jj. CCDC 975574 and
975575. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ob42445f
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Table 2 Preparation of pyrazolo[1,5-a]pyrimidine (I)a
Results and discussion
Our study was initiated by reacting 1-phenylbuta-2,3-dien-
1-one (1a) with 1H-pyrazol-3-amine (2a) in ethanol. We were
pleased to find that the reaction of 1a and 2a took place
rapidly at ambient temperature in the absence of any catalyst
or promoter to afford the desired pyrazolo[1,5-a]pyrimidine
with high efficiency. More interestingly, the reaction exhibited
excellent regio-selectivity in that 5-methyl-7-phenylpyrazolo-
[1,5-a]pyrimidine (3a) was obtained in a yield of 85% while its
regio-isomer, 7-methyl-5-phenylpyrazolo[1,5-a]pyrimidine (4a),
was formed only in a trace amount (Table 1, entry 1). To
further improve the yield, the reaction was then tried in
different solvents, and among the solvents screened, acetone
gave the best yield of 3a (entries 1–7). Following studies
showed that increasing the amount of 2a (entries 7–9) or ele-
vating the reaction temperature (entries 7 and 10–11) resulted
in a decrease of the yield. Thus, the optimum reaction
conditions are: treating 1a (1 equiv.) and 2a (1 equiv.) at rt in
acetone for 2 h. Under these conditions, 3a was obtained in a
yield of 91% (entry 7).
Entry
R1
R2
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
H
CH3
2
2
2
2
2
2
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
87
86
82
84
90
79
91
88
85
89
87
p-CF3C6H4
p-BrC6H4
p-CH3OC6H4
p-CH3C6H4
m-ClC6H4
o-FC6H4
1-Naphthyl
2-Thienyl
Benzyl
9
10
11
12
3j
3k
3l
Phenylethyl
C6H5
a Reagents and conditions: 1 (1 mmol), 2a (1 mmol), acetone (4 mL),
rt. b Isolated yield.
corresponding products in excellent yields. Moreover, diverse
functional groups, such as trifluoromethyl, halides, methoxy,
and methyl group, were well tolerated under the reaction con-
ditions. Further studies showed that 1-alkyl, such as 1-benzyl,
or 1-phenethyl substituted allenic ketones could take part in
this reaction efficiently (entries 10 and 11). 1-Phenylpenta-2,3-
dien-1-one, an allenic ketone with a substituent at the terminal
position of the allene moiety, is also a suitable substrate (entry
12). Importantly, it should be noted herein that in all the
above cases, the reactions showed excellent regio-selectivity to
give one of the two possible isomers dominantly.
In the next stage, the suitability of substituted aminopyra-
zoles (2) for this pyrazolo[1,5-a]pyrimidine synthesis was
studied. The results listed in Table 3 showed that both alkyl-
and aryl-substituted aminopyrazoles are suitable substrates for
this reaction. It was also observed that while aryl-substituted
aminopyrazoles (Table 3, entries 21 and 22) are less reactive
and need a longer period to complete the reaction than alkyl-
substituted ones (entries 1–20); both of them exhibited excel-
lent regio-selectivity, thus resulting in a rapid and efficient pro-
tocol for the preparation of pyrazolo[1,5-a]pyrimidines with
diverse substitution patterns.
With the optimized reaction conditions in hand, we then
examined the generality of the synthetic protocol toward pyr-
azolo[1,5-a]pyrimidines. Firstly, various 1-substituted and 1,4-
disubstituted allenic ketones 1 were reacted with 1H-pyrazol-
3-amine (2a) under standard conditions. The results listed in
Table 2 showed that 1-aryl-substituted allenic ketones with
various substituents on the aryl ring reacted smoothly with 2a
to afford the corresponding pyrazolo[1,5-a]pyrimidines in good
to excellent yields (Table 2, entries 1–9). While electron-donat-
ing or electron-withdrawing substituents on the aryl ring have
little effect on the reaction, ortho-substituted substrate gave
a relatively lower yield (entry 7). Naphthyl (entry 8) and
thienyl (entry 9) substituted allenic ketones afforded the
Table 1 Optimization of the conditions for the reaction of 1a and 2aa
Yieldb (%)
To further explore the scope of the reaction, allenic ketones
bearing a methyl or ethyl group on the internal position of the
allene moiety were prepared, and reacted with different amino-
pyrozoles. To our surprise, under similar conditions, the reac-
tions were much more sluggish and showed dramatically
diminished regio-selectivity in that the two possible isomers
were obtained in ratios within the range of 1 : 1 to 2 : 1
(Table 4). The structures of the two isomers were unambigu-
ously confirmed by their spectroscopic data together with
X-ray diffraction analysis (Fig. 2 and 3).20
Entry 2a (equiv.) Solvent
Temp. (°C) Time (h) 3a
4a
1
2
3
4
1
1
1
1
EtOH
CH2Cl2
CH3CN
MeOH
THF
rt
rt
rt
rt
rt
rt
2
2
2
2
2
2
2
2
2
2
2
85 Trace
80 Trace
83 Trace
85 Trace
86 Trace
73 Trace
91 Trace
83 Trace
78 Trace
82 Trace
77 Trace
5
1
6
7
8
9
10
11
1
1
1.2
1.5
1
DMF
Acetone rt
Acetone rt
Acetone rt
Acetone 40
Acetone 60
1
Plausible pathways accounting for the formation of 3 and 4
are speculated in Scheme 1. An initial conjugate addition of
the amino group of 2 on the central carbon of the allene unit
a Reagents and conditions: 1a (0.5 mmol), solvent (2 mL). b Isolated
yield.
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Table 3 Preparation of pyrazolo[1,5-a]pyrimidine (II)a
Entry
R1
R2
R
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
o-FC6H4
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
C6H5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
3z
3aa
3bb
3cc
3dd
3ee
3ff
3gg
3hh
87
80
89
91
90
79
78
92
90
83
85
86
85
83
89
75
84
88
90
89
65
60
m-ClC6H4
p-BrC6H4
p-CF3C6H4
p-CH3C6H4
m,p-Di-CH3OC6H3
1-Naphthyl
2-Thienyl
Benzyl
Phenylethyl
C6H5
C6H5
m-ClC6H4
p-CH3OC6H4
p-CNC6H4
2-Thienyl
Benzyl
Phenylethyl
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
H
CH3
H
H
C6H5
p-BrC6H4
C6H5
a Reagents and conditions: 1 (1 mmol), 2 (1 mmol), acetone (4 mL), rt. b Isolated yield.
Table 4 Preparation of pyrazolo[1,5-a]pyrimidine (III)a
Entry
R1
R2
R3
R
Time (h)
Product
Yieldb (%)
1
2
3
4
C6H5
C6H5
C6H5
C6H5
H
H
H
H
CH3
CH3
CH3
CH3CH2
H
CH3
Cyclopropyl
CH3
4
4
4
4
3ii + 4ii (2 : 1)
73
92
81
55
3jj + 4jj (1.2 : 1)
3kk + 4kk (1 : 1)
3ll + 4ll (1.4 : 1)
a Reagents and conditions: 1 (1 mmol), 2 (1 mmol), acetone (4 mL), rt. b Isolated yield of two products.
in 1 followed by an intramolecular cyclization would give 3. On atoms in different allenic ketone substrates, 1-phenylbuta-
the other hand, a direct addition of the amino group of 2 on 2,3-dien-1-one (1a), 1-phenylpenta-2,3-dien-1-one (1b) and
the carbonyl group of 1 followed by an intramolecular 6-π 2-methyl-1-phenylbuta-2,3-dien-1-one (1c), were calculated with
electrocyclization and tautomerization affords 4.
the aid of the B3LYP/6-31G* level of density functional theory.
According to the proposed mechanism, factors favouring a The calculation results listed in Fig. 4 revealed that for com-
conjugated addition will benefit the formation of 3. Otherwise, pounds 1a and 1b, the positive charge of the central carbon of
the selectivity toward 3 will decrease. While the competition the allene unit (C3) is much higher than that of the carbonyl
between 1,4- and 1,2-addition can be influenced by a multi- carbon (C1). Therefore, the amino group of 2 would prefer to
plicity of different factors, the electronic nature of the nucleo- attack on C3 rather C1 to form 3 as the dominating product.
philic addition acceptor can have a predominant influence in On the other hand, the difference of the positive charge
many cases. To figure out, at least in part, the reason behind between C3 and C1 in 1c, which has a methyl group attached
the big difference in regio-selectivity of the reactions starting on the internal position of the allenic moiety, is much smaller
from allenic ketones with or without a substituent on the compared with those of 1a and 1b, thus resulting in a dramati-
internal position of the allenic moiety, the Mulliken charges of cally diminished selectivity in the formation of 3 and 4. As a
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Fig. 3 The X-ray crystal structure of 4jj.
In this regard, we have an ongoing program on the design and
synthesis of novel 5-substituted pyrimidine nucleosides as
potential antiviral and antimicrobial agents.22 With the novel
method developed in this paper, we were interested in the
preparation of hybrid compounds combining both pyrimidine
nucleoside and pyrazolo[1,5-a]pyrimidine units to get new enti-
ties with potential synergetic biological activities. For this
purpose, pyrimidine nucleoside derivatives bearing an allenic
ketone moiety on the 5-position of the pyrimidine base (6 and
10) were prepared from the corresponding 5-methyl substi-
tuted nucleosides 5 and 9, respectively.23 Treatment of 6 with
1H-pyrazol-3-amine (2a) in acetone at rt for 2 h afforded 7 in a
yield of 80%. The following aminolysis of 7 with NH3·H2O gave
product 8 in a yield of 82%. Similarly, reacting 10 with
5-methyl-1H-pyrazol-3-amine (2b) in acetone at rt for 4 h fol-
lowed by treatment with NH3·H2O led to a novel cytidine-pyr-
azolo[1,5-a]pyrimidine hybrid (12) in a total yield of 62% with
excellent regio-selectivity (Scheme 2). The structures of 7, 8, 11
and 12 were fully characterized by their spectral data of
1H NMR, 13C NMR, and HRMS. Screening these novel
Fig. 2 The X-ray crystal structure of 3jj.
further aspect, the reason for the difference of the positive
charge of C3 in 1a, 1b and 1c might be attributed to the follow-
ing facts. In 1c, due to the repulsion between the carbonyl
oxygen and its neighbouring methyl group, the carbonyl group
could not be as coplanar with the C2–C3 olefin as those in 1b
and 1c, which would dramatically decrease the positive charge
on its C3 position.
Next, to showcase the utility of the synthetic method develo-
ped herein, we continued our study by exploring the reaction
on a larger scale. Thus, 1.01 g of 1-phenylbuta-2,3-dien-1-one
(1a, 7 mmol) and 0.68 g of 5-methyl-1H-pyrazol-3-amine (2b,
7 mmol) were added to 20 mL of acetone. It was then stirred at
rt for 3 h. From the resulting mixture, 2,5-dimethyl-7-phenyl-
pyrazolo[1,5-a]pyrimidine (3m) was obtained in a yield of 78%.
Furthermore, it is well known that structural modifications
of naturally occurring pyrimidine nucleosides have resulted
in a large number of therapeutic agents for various diseases.21
Scheme 1 Plausible pathway towards 3 and 4.
Fig. 4 Mulliken charges of some selected atoms in 1-phenylbuta-2,3-dien-1-one (1a), 1-phenylpenta-2,3-dien-1-one (1b) and 2-methyl-1-phenyl-
buta-2,3-dien-1-one (1c) with the most stable conformation computed at the B3LYP/6-31G* level of DFT.
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Scheme 2 Preparation of hybrids of 5-substituted pyrimidine nucleosides and pyrazolo[1,5-a]pyrimidines.
5-substituted pyrimidine nucleosides as potential antiviral under vacuum. The residue was purified by chromatography
agents is currently underway.
on silica gel to afford the title product.
5-Methyl-7-phenylpyrazolo[1,5-a]pyrimidine (3a): yellow
solid. 1H NMR (400 MHz, CDCl3) δ: 2.60 (s, 3H), 6.61 (d, J =
2.0 Hz, 1H), 6.71 (s, 1H), 7.51 (t, J = 3.2 Hz, 3H), 7.94–7.97 (m,
2H), 8.07 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 24.8, 95.9, 108.3, 128.7, 129.2, 130.9, 131.2, 144.7, 146.1,
149.5, 158.7. HRMS calcd for C13H12N3: 210.1031 [M + H],
found: 210.1037.
Conclusions
In summary, an efficient procedure for the syntheses of pyr-
azolo[1,5-a]pyrimidines through cyclocondensation reactions
of 1,2-allenic ketones with
a variety of aminopyrazoles
5-Methyl-7-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine
(3b): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 3H),
6.59 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H),
8.02–8.06 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.7, 96.2,
108.6, 119.6, 122.3, 125.0, 125.5, 125.5, 125.6, 125.6, 127.8,
129.6, 132.0, 132.3, 132.6, 132.9, 134.6, 144.4, 144.7, 149.4,
158.8. HRMS calcd for C14H11F3N3: 278.0905 [M + H], found:
278.0911.
without using any catalyst or promoter has been developed.
The methodology provided herein has advantages such as
high yields, extremely mild conditions, a simple procedure
and excellent regio-selectivity. Moreover, this novel procedure
has been successfully applied in the preparation of nucleoside-
pyrazolo[1,5-a]pyrimidine chimeras with potent antiviral
activities.
7-(4-Bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (3c):
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.57 (s, 3H), 6.58 (d,
J = 2.0 Hz, 1H), 6.66 (s, 1H), 7.59 (dd, J1 = 6.4 Hz, J2 = 2.0 Hz,
2H), 7.82 (dd, J1 = 6.4 Hz, J2 = 2.0 Hz, 2H), 8.02 (d, J = 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 24.8, 96.0, 108.1, 125.4,
129.9, 130.7, 131.9, 144.6, 144.8, 149.5, 158.6. HRMS calcd for
C13H11BrN3: 288.0136 [M + H], found: 288.0145.
7-(4-Methoxyphenyl)-5-methylpyrazolo[1,5-a]pyrimidine (3d):
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.53 (s, 3H), 3.78 (s,
3H), 6.54 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.95 (d, J = 8.8 Hz,
2H), 7.93 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 24.7, 55.4, 95.6, 107.4, 114.0, 123.2, 130.9,
144.4, 145.8, 149.6, 158.6, 161.6. HRMS calcd for C14H14N3O:
240.1137 [M + H], found: 240.1131.
Experimental
General methods
All the commercial reagents and solvents were used without
further purification. 1H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively. Splitting patterns
are designated s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br. (broad). High-resolution mass spectra
(HRMS) were obtained by using a MicrOTOF mass spectro-
meter. All reactions were monitored by thin-layer chromato-
graphy (TLC) using silica gel plates (silica gel 60 F254
0.25 mm) and components were visualized by observation
under UV light.
5-Methyl-7-p-tolylpyrazolo[1,5-a]pyrimidine (3e): yellow
1
solid. H NMR (400 MHz, CDCl3) δ: 2.42 (s, 3H), 2.60 (s, 3H),
General procedure for the preparation of pyrazolo[1,5-a]-
pyrimidines 3, 4, 7 and 11
6.61 (d, J = 2.0 Hz, 1H), 6.71 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H),
7.88 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 2.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 21.6, 24.7, 95.7, 108.0, 128.2, 129.1, 129.3,
141.3, 144.6, 146.3, 149.5, 158.7. HRMS calcd for C14H14N3:
224.1188 [M + H], found: 224.1181.
A mixture of 1,2-allenic ketone (1 mmol) and aminopyrazole 2
(1 mmol) in acetone (4 mL) was stirred at rt. Upon completion
as indicated by TLC, the resulting mixture was concentrated
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7-(3-Chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (3f): 128.6, 129.3, 130.8, 131.4, 145.6, 150.3, 154.9, 158.2. HRMS
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.56 (s, 3H), 6.58 (d, calcd for C14H14N3: 224.1188 [M + H], found: 224.1185.
J = 2.4 Hz, 1H), 6.67 (s, 1H), 7.38–7.44 (m, 2H), 7.82 (d, J =
7-(2-Fluorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (3n):
7.6 Hz, 1H), 7.93 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H); 13C NMR yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.44 (s, 3H), 2.57 (s,
(100 MHz, CDCl3) δ: 24.8, 96.1, 108.4, 127.3, 129.2, 129.9, 3H), 6.40 (s, 1H), 6.64 (s, 1H), 7.20 (t, J = 9.2 Hz, 1H), 7.26 (t,
130.9, 132.7, 134.6, 144.4, 144.7, 149.5, 158.7. HRMS calcd for J = 8.0 Hz, 1H), 7.44–7.48 (m, 1H), 7.75–7.78 (m, 1H); 13C NMR
C13H11ClN3: 244.0642 [M + H], found: 244.0651.
(100 MHz, CDCl3) δ: 14.8, 24.7, 95.4, 109.3, 109.3, 116.3, 116.5,
7-(2-Fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (3g): 119.4, 119.5, 124.3, 124.3, 131.2, 131.2, 132.4, 132.4, 140.6,
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.63 (s, 3H), 6.64 (d, 149.9, 154.9, 157.9, 158.7, 161.2. HRMS calcd for C14H13FN3:
J = 2.4 Hz, 1H), 6.76 (s, 1H), 7.26 (t, J = 9.2 Hz, 1H), 7.31 (t, J = 242.1094 [M + H], found: 242.1099.
7.2 Hz, 1H), 7.50–7.54 (m, 1H), 7.75 (td, J1 = 7.6 Hz, J2 = 1.6 Hz,
7-(3-Chlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine
1H), 8.07 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: (3o): yellow solid. 1H NMR (400 MHz, CDCl3) δ; 2.50 (s, 3H),
24.8, 96.1, 110.2, 110.2, 116.3, 116.6, 119.2, 124.4, 124.4, 131.1, 2.61 (s, 3H), 6.43 (s, 1H), 6.66 (s, 1H), 7.47–7.51 (m, 2H), 7.92
131.1, 132.6, 132.6, 141.3, 144.7, 149.1, 158.4, 158.7, 161.2. (d, J = 7.2 Hz, 1H), 8.01 (s, 1H); 13C NMR (100 MHz, CDCl3) δ;
HRMS calcd for
228.0945.
C
13H11FN3: 228.0937 [M
+
H], found: 14.8, 24.7, 95.5, 107.6, 127.4, 129.3, 129.9, 130.9, 133.0, 134.7,
144.1, 150.2, 155.2, 158.3. HRMS calcd for C14H13ClN3:
5-Methyl-7-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidine (3h): 258.0798 [M + H], found: 258.0805.
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.63 (s, 3H), 6.69 (d,
7-(4-Bromophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine
J = 2.0 Hz, 1H), 6.72 (s, 1H), 7.36–7.38 (m, 2H), 7.45–7.49 (m, (3p): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.42 (s, 3H),
1H), 7.55 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.89 (d, J = 2.52 (s, 3H), 6.35 (s, 1H), 6.56 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H),
8.4 Hz, 1H), 7.98 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H); 13C NMR 7.84 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.8,
(100 MHz, CDCl3) δ: 24.8, 95.9, 110.6, 125.1, 125.2, 126.5, 24.7, 95.4, 107.2, 125.3, 130.1, 130.8, 131.8, 144.2, 150.2, 154.9,
127.0, 127.9, 128.7, 129.3, 130.7, 131.0, 133.6, 144.9, 146.0, 158.2. HRMS calcd for C14H13BrN3: 302.0293 [M + H], found:
149.3, 158.6. HRMS calcd for C17H14N3: 260.1188 [M + H], 302.0299.
found: 260.1182.
2,5-Dimethyl-7-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]-
5-Methyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine
(3i): pyrimidine (3q): yellow solid. 1H NMR (400 MHz, CDCl3) δ:
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.61 (s, 3H), 6.61 (d, 2.46 (s, 3H), 2.58 (s, 3H), 6.41 (s, 1H), 6.64 (s, 1H), 7.76 (d, J =
J = 2.0 Hz, 1H), 7.05 (s, 1H), 7.21 (t, J = 4.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
4.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H); CDCl3) δ: 14.7, 24.7, 95.6, 107.8, 119.7, 122.4, 125.1, 125.5,
13C NMR (100 MHz, CDCl3) δ: 24.7, 95.8, 104.7, 127.6, 131.2, 125.6, 125.6, 125.6, 127.9, 129.7, 131.9, 132.2, 132.6, 132.9,
131.5, 131.9, 139.4, 144.3, 149.5, 158.0. HRMS calcd for 134.8, 143.9, 150.3, 155.1, 158.3. HRMS calcd for C14H13F3N3:
C11H10N3S: 216.0595 [M + H], found: 216.0587.
292.1062 [M + H], found: 292.1068.
7-Benzyl-5-methylpyrazolo[1,5-a]pyrimidine (3j): yellow
2,5-Dimethyl-7-p-tolylpyrazolo[1,5-a]pyrimidine (3r): yellow
1
1
solid. H NMR (400 MHz, CDCl3) δ: 2.45 (s, 3H), 4.42 (s, 2H), solid. H NMR (400 MHz, CDCl3) δ: 2.42 (s, 3H), 2.48 (s, 3H),
6.19 (s, 1H), 6.56 (d, J = 2.4 Hz, 1H), 7.27–7.33 (m, 5H), 8.06 (d, 2.58 (s, 3H), 6.39 (s, 1H), 6.63 (s, 1H), 7.32 (d, J = 7.6 Hz, 2H),
J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 24.7, 36.2, 95.9, 7.91 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.9,
107.7, 127.4, 128.9, 129.7, 134.8, 144.3, 148.1, 148.6, 158.5. 21.6, 24.7, 95.1, 107.1, 128.4, 129.2, 129.3, 141.2, 145.7, 150.3,
HRMS calcd for C14H14N3: 224.1188 [M + H], found: 224.1192.
154.8, 158.2. HRMS calcd for C15H16N3: 238.1344 [M + H],
5-Methyl-7-phenethylpyrazolo[1,5-a]pyrimidine (3k): yellow found: 238.1341.
1
solid. H NMR (400 MHz, CDCl3) δ: 2.46 (s, 3H), 3.10 (t, J = 7.6
7-(3,4-Dimethoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyri-
1
Hz, 2H), 3.35 (t, J = 7.6 Hz, 2H), 6.36 (s, 1H), 6.53 (d, J = 2.4 Hz, midine (3s): yellow solid. H NMR (400 MHz, CDCl3) δ: 2.44
1H), 7.13–7.23 (m, 5H), 8.04 (d, J = 2.0 Hz, 1H); 13C NMR (s, 3H), 2.53 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 6.34 (s, 1H),
(100 MHz, CDCl3) δ: 24.7, 31.9, 32.2, 95.7, 107.4, 126.4, 128.4, 6.60 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.59 (dd, J1 = 8.4 Hz,
128.6, 140.1, 144.2, 147.8, 148.6, 158.3. HRMS calcd for J2 = 1.6 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H); 13C NMR (100 MHz,
C15H16N3: 238.1344 [M + H], found: 238.1341.
CDCl3) δ: 14.8, 24.6, 55.9, 56.0, 94.9, 106.7, 110.8, 112.1,
5-Ethyl-7-phenylpyrazolo[1,5-a]pyrimidine (3l): yellow solid. 122.6, 123.5, 145.2, 148.5, 150.4, 151.1, 154.6, 158.1. HRMS
1H NMR (400 MHz, CDCl3) δ: 1.41 (t, J = 8.0 Hz, 3H), 2.93 (q, calcd for C16H18N3O2: 284.1399 [M + H], found: 284.1403.
J = 7.6 Hz, 2H), 6.68 (s, 1H), 6.79 (s, 1H), 7.56 (s, 3H), 8.01 (d,
2,5-Dimethyl-7-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidine
J = 3.6 Hz, 2H), 8.12 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: (3t): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.37 (s, 3H),
13.1, 31.5, 96.0, 107.4, 128.7, 129.2, 130.9, 131.4, 144.7, 144.8, 2.59 (s, 3H), 6.48 (s, 1H), 6.60 (s, 1H), 7.33–7.37 (m, 1H),
149.6, 163.6. HRMS calcd for C14H14N3: 224.1188 [M + H], 7.42–7.47 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 6.4 Hz,
found: 224.1185.
1H), 7.87 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H); 13C NMR
2,5-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine
(3m): (100 MHz, CDCl3) δ: 14.9, 24.7, 95.4, 109.9, 125.3, 125.3, 126.4,
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.49 (s, 3H), 2.60 126.9, 127.9, 128.6, 129.4, 130.7, 130.8, 133.6, 145.3, 150.0,
(s, 3H), 6.41 (s, 1H), 6.66 (s, 1H), 7.53 (t, J = 2.8 Hz, 3H), 8.00–8.03 155.1, 158.1. HRMS calcd for C18H16N3: 274.1344 [M + H],
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.8, 24.6, 95.2, 107.5, found: 274.1341.
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2,5-Dimethyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine (3u): 150.2, 158.3, 161.8, 161.8. HRMS calcd for C17H15N4: 275.1297
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.55 (s, 3H), 2.60 (s, [M + H], found: 275.1295.
3H), 6.40 (s, 1H), 6.98 (s, 1H), 7.21–7.23 (m, 1H), 7.65 (d, J =
2-Cyclopropyl-5-methyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyri-
4.4 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, midine (3cc): yellow solid; 1H NMR (400 MHz, CDCl3) δ:
CDCl3) δ: 14.9, 24.7, 95.1, 103.9, 127.6, 131.3, 131.6, 131.8, 0.98–1.07 (m, 4H), 2.12–2.15 (m, 1H), 2.53 (s, 3H), 6.27 (s, 1H),
138.8, 150.3, 154.8, 157.5. HRMS calcd for C12H12N3S: 6.91 (s, 1H), 7.15 (t, J = 4.0 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H),
230.0752 [M + H], found: 230.0758.
8.19 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 9.7, 10.2,
7-Benzyl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (3v): yellow 24.7, 92.0, 103.3, 127.3, 130.9, 131.6, 131.9, 138.5, 150.1, 157.4,
1
solid. H NMR (400 MHz, CDCl3) δ: 2.37 (s, 3H), 2.47 (s, 3H), 161.0. HRMS calcd for C14H14N3S: 256.0908 [M + H], found:
4.36 (s, 2H), 6.03 (s, 1H), 6.32 (s, 1H), 7.22–7.30 (m, 5H); 13C 256.0903.
NMR (100 MHz, CDCl3) δ: 14.7, 24.6, 36.1, 95.2, 106.7, 127.3,
7-Benzyl-2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidine
128.8, 129.8, 134.9, 147.6, 149.3, 154.4, 158.1. HRMS calcd for (3dd): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 0.90–0.94 (m,
C15H16N3: 238.1344 [M + H], found: 238.1345.
2H), 1.01–1.06 (m, 2H), 2.11–2.15 (m, 1H), 2.41 (s, 3H), 4.38 (s,
2,5-Dimethyl-7-phenethylpyrazolo[1,5-a]pyrimidine
(3w): 2H), 6.06 (s, 1H), 6.20 (s, 1H), 7.26–7.35 (m, 5H); 13C NMR
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.42 (s, 3H), 2.46 (s, (100 MHz, CDCl3) δ: 9.3, 10.2, 24.6, 36.1, 91.5, 106.5, 127.3,
3H), 3.08 (t, J = 8.0 Hz, 2H), 3.31 (t, J = 8.0 Hz, 2H), 6.26 (s, 128.8, 129.9, 135.0, 147.6, 149.2, 158.1, 161.0. HRMS calcd for
1H), 6.31 (s, 1H), 7.13–7.24 (m, 5H); 13C NMR (100 MHz, C17H18N3: 264.1501 [M + H], found: 264.1505.
CDCl3) δ: 14.7, 24.6, 31.8, 32.0, 95.0, 106.3, 126.4, 128.4, 128.5,
140.2, 147.3, 149.3, 154.3, 157.9. HRMS calcd for C16H18N3: (3ee): yellow solid. H NMR (400 MHz, CDCl3) δ: 0.90–0.91 (m,
2-Cyclopropyl-5-methyl-7-phenethylpyrazolo[1,5-a]pyrimidine
1
252.1501 [M + H], found: 252.1509.
2H), 1.02 (d, J = 8.4 Hz, 2H), 2.09–2.12 (m, 1H), 2.44 (s, 3H),
5-Ethyl-2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine
(3x): 3.10 (t, J = 8.4 Hz, 2H), 3.31 (t, J = 8.0 Hz, 2H), 6.18 (s, 1H),
1
yellow solid. H NMR (400 MHz, CDCl3) δ: 1.38 (t, J = 8.0 Hz, 6.28 (s, 1H), 7.17 (d, J = 6.8 Hz, 2H), 7.25 (t, J = 6.8 Hz, 3H); 13
C
3H), 2.50 (s, 3H), 2.87 (q, J = 8.0 Hz, 2H), 6.44 (s, 1H), 6.69 (s, NMR (100 MHz, CDCl3) δ: 9.4, 10.2, 24.6, 31.8, 32.1, 91.3,
1H), 7.54 (t, J = 3.2 Hz, 3H), 8.02 (d, J = 4.0 Hz, 2H); 13C NMR 106.2, 126.4, 128.4, 128.5, 140.4, 147.2, 149.3, 157.9, 160.9.
(100 MHz, CDCl3) δ: 13.2, 14.8, 31.5, 95.3, 106.5, 128.6, 129.2, HRMS calcd for C18H19N3: 278.1657 [M + H], found: 278.1653.
130.8, 131.5, 145.9, 150.3, 154.9, 163.2. HRMS calcd for
C15H16N3: 238.1344 [M + H], found: 238.1348.
2-Cyclopropyl-5-ethyl-7-phenylpyrazolo[1,5-a]pyrimidine
(3ff): yellow solid. H NMR (400 MHz, CDCl3) δ: 0.86–0.90 (m,
1
2-Cyclopropyl-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidine 2H), 1.01–1.06 (m, 2H), 1.37 (t, J = 7.6 Hz, 3H), 2.11–2.15 (m,
1
(3y): yellow solid. H NMR (400 MHz, CDCl3) δ: 0.85–0.87 (m, 1H), 2.86 (q, J = 7.6 Hz, 2H), 6.24 (s, 1H), 6.68 (s, 1H), 7.54 (t,
2H), 0.95–0.99 (m, 2H), 2.06–2.10 (m, 1H), 2.50 (s, 3H), 6.20 (s, J = 7.6 Hz, 3H), 8.04–8.06 (m, 2H); 13C NMR (100 MHz, CDCl3)
1H), 6.56 (s, 1H), 7.44 (d, J = 2.4 Hz, 3H), 7.97–7.98 (m, 2H); δ: 9.4, 10.2, 13.2, 31.4, 91.1, 106.3, 128.5, 129.3, 130.8, 131.5,
13C NMR (100 MHz, CDCl3) δ: 9.3, 10.2, 24.6, 91.2, 107.2, 145.7, 150.3, 161.6, 163.1. HRMS calcd for C17H18N3: 264.1501
128.4, 129.3, 130.7, 131.3, 145.2, 150.4, 158.2, 161.3. HRMS [M + H], found: 264.1508.
calcd for C16H16N3: 250.1344 [M + H], found: 250.1341.
5-Methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine (3gg): yellow
7-(3-Chlorophenyl)-2-cyclopropyl-5-methylpyrazolo[1,5-a]- solid. 1H NMR (400 MHz, CDCl3) δ: 2.61 (s, 3H), 6.71 (s, 1H),
pyrimidine (3z): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 6.94 (s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H),
0.81–0.85 (m, 2H), 0.96–1.00 (m, 2H), 2.04–2.08 (m, 1H), 2.51 7.53–7.56 (m, 3H), 8.00–8.02 (m, 2H), 8.11–8.14 (m, 2H); 13C
(s, 3H), 6.18 (s, 1H), 6.55 (s, 1H), 7.33–7.41 (m, 2H), 7.84 (d, J = NMR (100 MHz, CDCl3) δ: 24.8, 92.5, 108.2, 126.6, 128.5, 128.7,
7.2 Hz, 1H), 7.98 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 9.5, 128.8, 129.5, 130.9, 131.1, 133.1, 145.6, 150.8, 155.6, 158.6.
10.2, 24.6, 91.4, 107.3, 127.4, 129.3, 129.7, 130.7, 132.9, 134.4, HRMS calcd for C19H16N3: 286.1344 [M + H], found: 286.1348.
143.6, 150.2, 158.2, 161.5. HRMS calcd for C16H15ClN3:
284.0955 [M + H], found: 284.0953.
7-(4-Bromophenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimi-
dine (3hh): yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.62
2-Cyclopropyl-7-(4-methoxyphenyl)-5-methylpyrazolo[1,5-a]- (s, 3H), 6.71 (s, 1H), 6.92 (s, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.44
pyrimidine (3aa): yellow solid. 1H NMR (400 MHz, CDCl3) δ: (t, J = 8.0 Hz, 2H), 7.68–7.70 (m, 2H), 7.96–7.98 (m, 2H),
0.81–0.84 (m, 2H), 0.93–0.97 (m, 2H), 2.03–2.08 (m, 1H), 2.46 8.01–8.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 24.8, 92.7,
(s, 3H), 3.75 (s, 3H), 6.14 (s, 1H), 6.50 (s, 1H), 6.91 (d, J = 107.9, 125.4, 126.5, 128.7, 128.9, 129.9, 131.0, 131.8, 132.9,
8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, 144.5, 150.7, 155.7, 158.6. HRMS calcd for C19H15BrN3:
CDCl3) δ: 9.3, 10.2, 24.6, 55.3, 90.9, 106.3, 113.8, 123.3, 130.9, 364.0449 [M + H], found: 364.0455.
144.9, 150.4, 158.0, 161.1, 161.5. HRMS calcd for C17H18N3O:
280.1450 [M + H], found: 280.1453.
5,6-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine (3ii): yellow
solid. H NMR (400 MHz, CDCl3) δ: 2.14 (s, 3H), 2.62 (s, 3H),
1
4-(2-Cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)- 6.58 (d, J = 2.0 Hz, 1H), 7.45–7.47 (m, 2H), 7.53–7.57 (m, 3H),
1
benzonitrile (3bb): yellow solid. H NMR (400 MHz, CDCl3) δ: 7.95 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 15.1,
0.81–0.83 (m, 2H), 0.97–1.01 (m, 2H), 2.03–2.07 (m, 1H), 2.56 24.1, 95.5, 114.9, 128.9, 129.4, 129.9, 130.9, 144.0, 147.4, 159.6.
(s, 3H), 6.20 (s, 1H), 6.64 (s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 8.13 HRMS calcd for C14H14N3: 224.1188 [M + H], found: 224.1185.
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 9.5, 10.2,
2,5,6-Trimethyl-7-phenylpyrazolo[1,5-a]pyrimidine
(3jj):
24.7, 91.8, 107.7, 114.2, 118.2, 129.9, 132.2, 135.6, 143.0, 143.0, yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.08 (s, 3H), 2.39 (s,
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3H), 2.57 (s, 3H), 6.35 (s, 1H), 7.44–7.54 (m, 5H); 13C NMR (400 MHz, CDCl3) δ: 1.54 (s, 3H), 2.00 (s, 3H), 2.13–2.20 (m,
(100 MHz, CDCl3) δ: 14.9, 15.1, 24.1, 94.8, 113.9, 128.8, 129.6, 1H), 2.32 (s, 3H), 2.42 (s, 3H), 2.49 (s, 3H), 2.71–2.77 (m, 1H),
129.8, 131.0, 143.5, 148.2, 154.0, 159.1. HRMS calcd for 4.17 (d, J = 2.8 Hz, 2H), 4.23–4.25 (m, 1H), 5.12–5.13 (m, 1H),
C15H16N3: 238.1344 [M + H], found: 238.1342.
6.21 (t, J = 6.8 Hz, 1H), 6.30 (s, 1H), 6.70 (s, 1H), 8.28 (s, 1H);
2-Cyclopropyl-5,6-dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine 13C NMR (100 MHz, CDCl3) δ: 13.5, 14.6, 20.0, 20.8, 24.6, 38.8,
1
(3kk): yellow solid. H NMR (400 MHz, CDCl3) δ: 0.74–0.77 (m, 63.5, 74.0, 82.9, 87.3, 95.9, 107.7, 109.6, 137.9, 141.6, 149.7,
2H), 0.93–0.96 (m, 2H), 2.01–2.03 (m, 1H), 2.08 (d, J = 1.2 Hz, 152.1, 154.8, 157.9, 169.9, 170.2, 176.4. HRMS calcd for
3H), 2.55 (d, J = 2.0 Hz, 3H), 6.11 (s, 1H), 7.45–7.54 (m, 5H); C22H26N5O6S: 488.1604 [M + H], found: 488.1609.
13C NMR (100 MHz, CDCl3) δ: 9.4, 10.2, 15.1, 24.0, 90.0, 113.7,
General procedure for the preparation of nucleoside-pyrazolo-
[1,5-a]pyrimidine chimeras 8 and 12
128.6, 129.7, 129.7, 130.9, 143.4, 148.2, 159.0, 160.7. HRMS
calcd for C17H18N3: 264.1501 [M + H], found: 264.1498.
6-Ethyl-2,5-dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine (3ll):
A
sealed tube (50 mL) containing compound 7 or 11
1
yellow solid. H NMR (400 MHz, CDCl3) δ: 1.05 (t, J = 7.6 Hz,
(0.5 mmol), i-PrOH (5 mL), NH3·H2O (1 mL) and a magnetic
stirring bar was heated to 90 °C for 8 h. The resulting mixture
was then concentrated under vacuum, and the residue was
purified by chromatography on silica gel to afford the nucleo-
side-pyrazolo[1,5-a]pyrimidine chimera 8 or 12.
4-Amino-1-butyl-5-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)-
pyrimidin-2(1H)-one (8): white solid. 1H NMR (400 MHz,
DMSO) δ: 0.88 (t, J = 7.2 Hz, 3H), 1.22–1.30 (m, 2H), 1.55–1.62
(m, 2H), 2.52 (s, 3H), 3.70 (t, J = 7.6 Hz, 2H), 6.58 (s, 1H), 6.94
(s, 1H), 8.09 (s, 1H), 8.13 (s, 1H); 13C NMR (100 MHz, DMSO)
δ: 14.1, 19.7, 24.7, 31.3, 49.1, 95.9, 98.1, 111.0, 140.3, 144.4,
149.0, 149.1, 155.2, 158.8, 162.8. HRMS calcd for C15H19N6O:
299.1620 [M + H], found: 299.1656.
4-Amino-5-(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)-
1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-
pyrimidin-2(1H)-one (12): white solid. 1H NMR (400 MHz,
DMSO) δ: 2.02–2.08 (m, 1H), 2.18–2.22 (m, 1H), 2.35 (s, 3H),
2.48 (s, 3H), 3.46–3.54 (m, 2H), 3.77 (s, 1H), 4.19 (s, 1H), 4.90
(t, J = 4.4 Hz, 1H), 5.22 (d, J = 2.8 Hz, 1H), 6.18 (t, J = 6.0 Hz,
1H), 6.37 (s, 1H), 6.69 (br., 1H), 6.81 (s, 1H), 7.48 (br., 1H),
8.28 (s, 1H); 13C NMR (100 MHz, DMSO) δ: 14.9, 24.7, 41.2,
61.5, 70.5, 85.8, 87.9, 95.2, 99.3, 110.1, 139.8, 143.7, 149.8,
153.7, 154.5, 158.5, 162.5. MS: m/z 373 (MH)+. HRMS calcd for
C17H21N6O4: 373.1624 [M + H], found: 373.1628.
3H), 2.39 (s, 3H), 2.47 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 6.36 (s,
1H), 7.41–7.43 (m, 2H), 7.53–7.56 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ: 14.8, 14.8, 21.7, 23.2, 94.7, 120.7, 128.9, 129.1, 129.6,
131.1, 143.9, 148.1, 154.3, 158.6. HRMS calcd for C16H18N3:
252.1501 [M + H], found: 252.1503.
6,7-Dimethyl-5-phenylpyrazolo[1,5-a]pyrimidine (4ii): yellow
1
solid. H NMR (400 MHz, CDCl3) δ: 2.32 (s, 3H), 2.86 (s, 3H),
6.67 (d, J = 2.0 Hz, 1H), 7.46–7.53 (m, 5H), 8.10 (d, J = 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ; 14.1, 15.5, 96.7, 113.4,
128.4, 128.7, 128.7, 128.9, 139.7, 144.0, 146.9, 159.5. HRMS
calcd for C14H14N3: 224.1188 [M + H], found: 224.1181.
2,6,7-Trimethyl-5-phenylpyrazolo[1,5-a]pyrimidine
(4jj):
yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.26 (s, 3H), 2.52 (s,
3H), 2.80 (s, 3H), 6.43 (s, 1H), 7.43–7.51 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ: 14.2, 14.7, 15.5, 95.8, 112.5, 128.3, 128.6,
128.7, 139.7, 143.4, 147.6, 154.2, 159.1. HRMS calcd for
C15H16N3: 238.1344 [M + H], found: 238.1351.
2-Cyclopropyl-6,7-dimethyl-5-phenylpyrazolo[1,5-a]pyrimidine
1
(4kk): yellow solid. H NMR (400 MHz, CDCl3) δ: 0.88–0.92 (m,
2H), 1.02–1.07 (m, 2H), 2.12–2.16 (m, 1H), 2.24 (s, 3H), 2.79 (s,
3H), 6.25 (s, 1H), 7.40–7.50 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ: 9.2, 10.2, 14.1, 15.5, 91.8, 112.3, 128.3, 128.6, 128.7,
139.8, 143.4, 147.6, 159.0, 160.8. HRMS calcd for C17H18N3:
264.1501 [M + H], found: 264.1505.
6-Ethyl-2,7-dimethyl-5-phenylpyrazolo[1,5-a]pyrimidine (4ll):
1
yellow solid. H NMR (400 MHz, CDCl3) δ: 1.06 (t, J = 7.2 Hz,
Acknowledgements
3H), 2.54 (s, 3H), 2.68 (q, J = 7.2 Hz, 2H), 2.84 (s, 3H), 6.44 (s,
1H), 7.44–7.47 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 13.9,
14.7, 15.1, 21.6, 95.8, 119.1, 128.2, 128.3, 128.5, 139.9, 143.3,
147.4, 154.4, 159.3. HRMS calcd for C16H18N3: 252.1501
[M + H], found: 252.1504.
The authors are grateful to the National Natural Science
Foundation of China (NSFC) (grant numbers 21172057 and
21272058), the Research Fund for the Doctoral Program of
Higher Education (RFDP) (grant number 20114104110005),
and the Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT) (IRT 1061) for financial
support.
1-Butyl-5-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)-4-(methyl-
1
thio)pyrimidin-2(1H)-one (7): yellow solid. H NMR (400 MHz,
CDCl3) δ: 0.90 (t, J = 8.0 Hz, 3H), 1.35 (sext, J = 7.2 Hz, 2H),
1.73 (quint, J = 7.2 Hz, 2H), 2.47 (s, 3H), 2.58 (s, 3H), 3.86 (t,
J = 7.2 Hz, 2H), 6.57 (d, J = 2.4 Hz, 1H), 6.86 (s, 1H), 7.99 (d, J =
2.4 Hz, 1H), 8.00 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 13.5,
13.7, 19.7, 24.8, 30.8, 51.2, 96.6, 107.1, 110.6, 138.5, 144.5,
146.9, 149.1, 153.1, 158.4, 175.6. HRMS calcd for C16H20N5OS:
330.1389 [M + H], found: 330.1382.
((2R,3S,5R)-3-Acetoxy-5-(5-(2,5-dimethylpyrazolo[1,5-a]pyri-
midin-7-yl)-4-(methylthio)-2-oxopyrimidin-1(2H)-yl)tetrahydro-
furan-2-yl)methyl acetate (11): yellowish solid. 1H NMR
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