Reactivity of the -C(Cl){double bond, long}C-C{double bond, long}N- moiety towards AlCl3-induced C-C bond forming reactions: a new synthesis of 7-(hetero)aryl-substituted pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2008.11.010

The reactivity of the -C(Cl){double bond, long}C-C{double bond, long}N- moiety towards an AlCl₃-induced C-C bond forming reaction was investigated through the reaction of 7-chloro-5-phenyl-pyrazolo[1,5-a]pyrimidine with arenes and heteroarenes.

Full text of DOI:10.1016/j.tetlet.2008.11.010

Tetrahedron Letters 50 (2009) 354–358
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of the –C(Cl)@C–C@N– moiety towards AlCl3-induced C–C bond
forming reactions: a new synthesis of 7-(hetero)aryl-substituted
pyrazolo[1,5-a]pyrimidines
Arumugam Kodimuthali a,b, Nishad T. C. a, Padala Lakshmi Prasunamba b, Manojit Pal a,
*
a New Drug Discovery, R&D Center, Matrix Laboratories Ltd, Anrich Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andra Pradesh 502 325, India
b Department of Chemistry, University College of Science, Osmania University, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactivity of the –C(Cl)@C–C@N– moiety towards an AlCl3-induced C–C bond forming reaction
was investigated through the reaction of 7-chloro-5-phenyl-pyrazolo[1,5-a]pyrimidine with arenes and
heteroarenes. This study furnished a novel and highly selective methodology for the preparation of
7-(hetero)aryl substituted-pyrazolopyrimidines in good to excellent yields under mild reaction
conditions.
Received 1 September 2008
Revised 29 October 2008
Accepted 5 November 2008
Available online 7 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Z
We first describe the AlCl3-induced C–C bond forming reaction
between 7-chloro-5-phenyl-pyrazolo[1,5-a]pyrimidine and (het-
ero)arenes, such reactions being only known for using transition-
metal catalysts.
R1
N
Ph
N
N
N
N
N
Over the last 20 years, the pyrazolo[1,5-a]pyrimidine frame-
work, a member of [5,6]-fused bicyclic heterocycles, has been a
versatile scaffold for various pharmacological studies.1–8 Apart
from their utility for several disease targets, pyrazolo[1,5-a]pyrim-
idines have shown enormous synthetic value in the preparation of
various drugs and bio-active molecules. This is exemplified by the
usage of 3-cyanomethyl and 3-cyano derivatives of 7-(hetero)aryl-
pyrazolo[1,5-a]pyrimidines (A and B, Fig. 1) as key intermediates
in the synthesis of a number of drugs.9–12 Also, 3-bromo-7-(het-
ero)aryl-pyrazolo[1,5-a]pyrimidines (C, Fig. 1) have been a key
Aryl /
R2
hetero
aryl
X
X = CH / N; R1 = alkyl / aryl
R2 = NH2, OMe, CONHR etc.
A; Z = CH2CN
B; Z = CN
D
C; Z = Br
Figure 1. Examples of pyrazolopyrimidine precursors for the synthesis of various
drugs.
synthetic precursor for
x-functionalized 3-alkynylpyrazolo[1,5-a]-
pyrimidines.13 Because of their wide pharmaceutical and synthetic
importance, a number of methods have been developed for the
synthesis of appropriately substituted pyrazolo[1,5-a]pyrimi-
dines.14–19 However, none of these methods were found to be con-
venient and general for the preparation of 7-(hetero)aryl
pyrazolopyrimidines (D, Fig. 1). Recently, transition metal-medi-
ated C–C bond forming reactions have become a powerful tool in
organic synthesis. Accordingly, 7-chloro-5-phenyl-pyrazolo[1,5-a]-
pyrimidine was coupled with (a) arylboronic acids under Suzuki
conditions or (b) an organometallic reagent such as ArZnI in the
presence of a Pd-catalyst to afford the compound D.20 While these
methodologies afforded D in good yields, they often required the
use of expensive catalysts and reagents. Additionally, in many
cases the required boronic acids or organo-zinc reagents are either
not available commercially or their preparations often require
cumbersome procedures. More recently, AlCl3-induced heteroary-
lation of arenes and heteroarenes has been reported as an alterna-
tive but less expensive strategy for the synthesis of various
nitrogen containing heterocyclic compounds.21–23 This strategy in-
volved the construction of a C–C bond via exploiting the reactivity
of a chloro group attached to the azomethine carbon [e.g., @C–
C(Cl)@N–] in the presence of AlCl3. While a variety of heteroaryl
chlorides containing the @C–C(Cl)@N– moiety have been utilized
successfully earlier,24,25 to the best of our knowledge the reactivity
of a chloride containing the –C(Cl)@C–C@N– moiety towards an
AlCl3-induced C–C bond forming reaction has not been examined.
We anticipated that the complexation of AlCl3 with the nitrogen
of the –C(Cl)@C–C@N– moiety would activate the chloro group
* Corresponding author. Tel.: +91 08458279301; fax: +91 08458279305.
E-mail addresses: manojitpal@rediffmail.com, Manojit.Pal@matrixlabsindia.com
(M. Pal).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.010

A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 354–358
355
to facilitate a nucleophilic attack by arenes or heteroarenes at the
chlorine bearing carbon atom. Herein, we report the first (het-
ero)arylation of 7-chloro-5-phenyl-pyrazolo[1,5-a]pyrimidine in
the presence of AlCl3 amenable for the preparation of compounds
of potential pharmacological interest.
N
OMe
N
N
AlCl3
N
+
solvent
OMe
RT
MeO
OMe
N
N
MeO
The key compound that is, 7-chloro-5-phenyl-pyrazolo[1,5-
a]pyrimidine (1) required for our study was prepared via the reac-
tion of 3-aminopyrazole with ethyl benzoylacetate in acetic acid
under reflux for 3 h followed by chlorination of the resulting com-
pound (i.e., 5-phenyl-4H-pyrazolo[1,5-a]pyrimidin-7-one) in POCl3
in the presence of pyridine at room temperature for 3 days.26 In our
initial approach 1,3,5-trimethoxybenzene 2a, chosen as an arene
component was reacted with 1 (Scheme 1) and the results of our
initial studies are summarized in Table 1. Thus a mixture of 1
(1.0 equiv), 2a (1.0 equiv) and AlCl3 (1.2 equiv) in dichloroethane
(5 ml) was stirred at room temperature (25 °C). Both the reactants
were consumed completely after 15 h and the desired 5-phenyl-7-
(2,4,6-trimethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine 3a was iso-
lated in 89% yield (Table 1, entry 1,). Encouraged by this result,
we then decided to examine the effect of time, temperature and
solvents on this heteroarylation process. It was observed that the
longer reaction time (48 h) did not improve the product yield (data
not shown) whereas the reaction was completed within 2 h when
Cl
3a
2a
1
OMe
Scheme 1. AlCl3-induced heteroarylation of 1,3,5-trimethoxybenzene (2a) with 1.
Table 1
Heteroarylation of 2a with 1 under various conditions
Entry
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
ClCH2CH2Cl
CH2Cl2
CHCl3
15
48
54
24
32
12
72
89
74
70
74
77
62
CH3CN
EtOAc
THFb
Toluene
No reaction
a
Yield of isolated products.
The reaction was carried out at 60 °C.
b
Table 2
Synthesis of 7-(hetero)aryl-substituted pyrazolo[1,5-a]pyrimidines (3)
S. No
Reactant (2)
Product (3)
Conditions
Yielda (%)
MeO
OMe
N
1
rt 15 h
80 °C 2 h
89
87
N
N
OMe
3a
MeO
OMe
2a
OMe
N
OH
Me
OH
N
N
3b
2
3
4
rt 20 h
80 °C 7 h
86
83
HO
Me
2b
2c
2d
OH
N
OH
N
N
3c
rt 20 h
80 °C 13 h
84
82
HO
OH
OH
N
OH
N
3d
N
rt 16 h
80 °C 10 h
84
82
HO
OMe
(continued on next page)
OMe

356
A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 354–358
Table 2 (continued)
S. No
Reactant (2)
Product (3)
Conditions
Yielda (%)
OMe
5
rt 13 h
80 °C 8 h
86
85
N
N
OMe
N
3e
2e
MeO
OMe
N
OH
N
N
3f
6
rt 36 h
80 °C 24 h
32
80
2f
OH
N
OMe
N
N
3g
7
rt 24 h
80 °C 9 h
45
84
2g
OMe
N
N
8
rt 21 h
80 °C 3 h
87
85
N
N
H
3h
2h
NH
N
N
N
N
3i
9
rt 16 h
80 °C 3 h
90
89
Me
2i
N
Me
N
N
3j
N
10
rt 33 h
80 °C 20 h
35
88
N
N
H
2j
N
NH
a
Yield of isolated products.
carried out at 80 °C (see later, Table 2). Nevertheless, in order to
maintain the milder nature of reaction conditions we decided to
continue our studies at room temperature. To identify the best
suitable solvent, the heteroarylation of 2a was carried out in a vari-
ety of solvents without changing other factors and conditions as
shown in Scheme 1. Reactions proceeded well in dicholorome-

A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 354–358
357
thane, chloroform, acetonitrile, ethylacetate and THF but required
Br
varied reaction times for completion (Table 1, entries 2–6). Yields
of isolated products were found to be comparable in all these sol-
vents except THF. Toluene was found to be ineffective for the reac-
tion of 1 with 2a (Table 1, entry 7). Thus, dichloroethane was found
to be the best solvent for the heteroarylation of 2a with 1.
N
2a, AlCl3
dichloroethane
N
Br
N
N
NBS
1
MeO
OMe
RT, 20 h
dichloromethane
RT, 1 h
N
N
Having established the optimum condition, we then decided to
examine the reactivity of heteroaryl chloride 1 with other arenes
and heteroarenes. Accordingly, a number of arenes were reacted
with 1 (Scheme 2) and the results are summarized in Table 2. Are-
nes such as 2-methyl-benzene-1,3-diol (2b), benzene-1,3-diol (2c),
3-methoxy-phenol (2d), 1,3-dimethoxybenzene (2e), 1-naphthol
(2f) and 1-methoxynaphthalene (2g) were employed successfully
to afford the desired products 3b–3g (Table 2, entries 2–7) in good
yields.27,28 While the reactions were carried out at room tempera-
ture in most cases, the heteroarylation of naphthalene derivatives
for example, 2f and 2g however required a higher temperature that
is, 80 °C (Table 2, entry 6 and 7). The free phenolic hydroxyl group
was well tolerated in the case of 2b, 2c, 2d and 2f (Table 2, entries
2–4 and 6) and heteroarylation occurred at the ring carbon rather
than oxygen. The use of heteroarenes such as indole (2h), N-meth-
ylindole (2i) and imidazole (2j) afforded the corresponding prod-
ucts 3h, 3i and 3j in good yields (Table 2, entries 8–10).
Cl
OMe
5
4
COOH
COOH
B(OH)2
N
N
N
MeO
OMe
Na2CO3, Pd(PPh3)4
DMF, 90 oC, 18 h
OMe
6
Scheme 3. Synthesis of compound 6.
We have shown that 7-chloro pyrazolo[1,5-a]pyrimidine partic-
ipated in AlCl3-induced C–C bond forming reactions smoothly with
a variety of commercially available arenes and heteroarenes. Be-
sides the preparation of 3f, 3g and 3j, which require elevated tem-
peratures, the reaction proceeds equally well at room temperature
or 80 °C. In order to extend the scope and application of this pro-
cess, 3-bromo-7-chloro-5-phenyl pyrazolo[1,5-a]pyrimidine (4),
prepared by treating compound 1 with NBS26 in dichloromethane
was reacted with trimethoxybenzene (2a) in the presence of AlCl3
at rt (Scheme 3). The chloro group was replaced by the arene
smoothly without affecting the bromo group affording the corre-
sponding product 5 in good yield (79%). The observed selectivity
of the AlCl3-induced heteroarylation reaction towards chloro over
bromo is remarkable and allows the preparation of appropriate
bromo derivatives amenable for further functionalizations.13 Thus,
compound 5 was coupled with 4-carboxyphenylboronic acid under
the Suzuki reaction condition to afford compound 6 in 67% yield
(Scheme 3), demonstrating the potential of the present process
for the preparation of diversity based pyrazolopyrimidine ana-
logues of potential pharmacological interest.
Mechanistically, the present C–C bond forming reaction seems
to proceed via complexation of the nitrogen of the six-membered
ring with AlCl3 to activate the chloro group. This facilitates a nucleo-
philic attack by arenes or heteroarenes at the chlorine bearing
carbon atom (Fig. 2). However, the reactivity of the chloro group
seemed to have been enhanced further by the adjacent nitrogen
present at the junction of the 6- and 5-membered ring (Fig. 2). This
perhaps explains the fact that unlike other heteroaryl halides21–23
the reaction of 1 with 2 proceeds at room temperature.
AlCl3
N
AlCl3
N
Ph
Ph
N
N
N
N
Cl
Cl
A
B
AlCl3
Ph
N
RH
3
N
N
AlCl3
HCl
R
Figure 2. Proposed mechanism for AlCl3-induced heteroarylation of 2 with 1.
reaction often observed with transition-metal-catalyzed reactions
and therefore may have advantages over the transition-metal-
mediated process for the synthesis of 7-(hetero) aryl-pyrazolo-
[1,5-a]pyrimidines especially on a large scale. We believe that
the methodology would find wide applications in the synthesis
of diversity-based pyrazolopyrimidines of potential medicinal
value.
Acknowledgements
The authors thank the management of Matrix Laboratories
Limited for their continuous support and encouragement.
In conclusion, the methodology described above illustrates the
usefulness of 7-chloropyrazolo[1,5-a]pyrimidine as an efficient
heteroarylating agent for arenes and heteroarenes in the presence
of AlCl3 in a one-pot reaction. The methodology is free from the
formation of homocoupled products as byproducts, a common side
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.010.
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Scheme 2. AlCl3-induced heteroarylation of 2 with 1.

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(s, 6H, OCH3); m
max (KBr, cmÀ1): 1621, 1587; Mass (ESI method, i-butane): 362
(M++1, 100%); 13C NMR (75 MHz, DMSO-d6) 162.9, 158.8 (2C), 154.3, 148.4,
144.3, 142.3, 136.7, 130.3, 128.9 (2C), 127.1 (2C), 107.8, 101.9, 96.1, 91.0 (2C),
55.8 (2C, OCH3), 55.5 (OCH3); HPLC purity 98.90%; compound 3b: yellow solid;
mp 197.1 °C; 1H NMR (300 MHz, CDCl3) d 10.06 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H),
8.14–8.11 (m, 2H), 7.57–7.51 (m, 3H), 7.43 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.83
(d, J = 2.5 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.22 (s, 1H), 2.29 (s, 3H, CH3); mmax
(KBr, cmÀ1): 1604, 1549; Mass (ESI method, i-butane):318.1 (M++1, 100%); 13
C
NMR (75 MHz, CDCl3) 158.4, 157.2, 156.6, 150.0, 147.9, 144.7, 137.3, 130.5,
129.3, 129.0 (2C), 127.5 (2C), 115.1, 113.0, 109.0, 106.9, 97.8, 8.7; HPLC purity
99.16%; compound 3g: light brown solid; mp 153.9 °C; 1H NMR (300 MHz,
CDCl3) d 8.39 (d, J = 8.3 Hz, 1H), 8.16–8.08 (m, 3H), 7.73 (d, J = 7.8 Hz, 1H),
7.52–7.39 (m, 7H), 6.98 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 4.09 (s, 3H,
OCH3); m
max (KBr, cmÀ1): 1606, 1584, 1545; Mass (ESI method, i-butane):352.3
(M++1, 100%); 13C NMR (75 MHz, DMSO-d6) 156.7, 154.9, 148.7, 146.4, 144.9,
136.7, 131.2, 130.4, 129.2 (2C), 128.9 (2C), 127.3 (2C), 125.7, 125.2, 124.6,
121.9, 121.6, 107.0, 103.9, 96.7, 55.9; HPLC purity 99.91%.