Pyrazoloquinazolinones and pyrazolopyridopyrimidinones by a sequential N-acylation-SNAr reaction

Article abstract of DOI:10.1016/j.tetlet.2015.01.146

An efficient synthesis of pyrazolo[1,5-a]quinazolin-5(4H)-ones and pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-ones is reported from the reaction of 2-haloaroyl chlorides with 5-amino-1H-pyrazoles. The reaction takes advantage of the 1,3-disposition of el

Full text of DOI:10.1016/j.tetlet.2015.01.146

Tetrahedron Letters 56 (2015) 1367–1369
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Tetrahedron Letters
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Pyrazoloquinazolinones and pyrazolopyridopyrimidinones
by a sequential N-acylation–S Ar reaction
N
⇑
Krishna Kumar Gnanasekaran, N. Prasad Muddala, Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of pyrazolo[1,5-a]quinazolin-5(4H)-ones and pyrazolo[1,5-a]pyrido[3,2-e]pyrimi-
din-5(4H)-ones is reported from the reaction of 2-haloaroyl chlorides with 5-amino-1H-pyrazoles. The
reaction takes advantage of the 1,3-disposition of electrophilic centers in the acid chloride and the similar
arrangement of nucleophilic sites in the pyrazole to form the central six-membered ring. Initial acylation
of the C5 amino group of the pyrazole is performed in DMF at À10 °C, and subsequent heating to 140 °C,
Received 9 December 2014
Accepted 21 January 2015
Available online 29 January 2015
Keywords:
Pyrazolo[1,5-a]quinazolin-5(4H)-ones
Pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-
in the same reaction vessel, completes the synthesis via an S
and the 2-haloarylamide. The reaction gives yields of 66–93% for the two-step sequence.
Ó 2015 Elsevier Ltd. All rights reserved.
N
Ar ring closure between N1 of the pyrazole
5
(4H)-ones
Sequential reaction
N-acylation–S Ar reaction
N
Heterocycle synthesis
A recent report from this laboratory described an approach to
by a three-step conversion to the target. Thus, a need exists to
develop a more efficient approach to the synthesis of these
systems.
isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones via a
1
sequential N-acylation–S
N
Ar reaction. This two-step process joins
a 2-haloaroyl chloride having a 1,3-arrangement of electrophilic
centers with a b-enaminoester incorporating two nucleophilic
centers in a similar arrangement to efficiently annulate a six-
membered heterocycle to the aromatic ring. Transformations of
this type are sometimes possible as tandem reactions,2 but more
commonly as sequential processes due to the higher temperature
Over the past decade, pyrazolo[1,5-a]quinazolin-5(4H)-ones
have received considerable attention as potential pharmaceuticals
since they exhibit a wide variety of medicinal properties. Recently,
derivatives 1 and 2 have been identified as potent inhibitors of
9–11
poly(ADP-ribose)polymerase-1 (PARP-1)
and topoisomerase I
1
2
(top1), respectively, which can be used to control various can-
cers. Shutting down these enzymes abolishes the ability of cancer
cells to repair damaged DNA, precipitating apoptosis, and cell cycle
arrest. Additionally, compounds such as 3 can act as dual inhibitors
N
required for the final S Ar ring closure. In either case, this strategy
dramatically shortens the synthesis without the need for catalysts
or special reagents. The current report describes the application of
this protocol to the synthesis of pyrazolo[1,5-a]quinazolin-5(4H)-
ones and pyrazolo[1,5-a]-pyrido[3,2-e]pyrimidin-5(4H)-ones.
Our literature search revealed that few methods are available
for the synthesis of these heterocycles, and most entail multistep
of the metabotropic glutamate receptors 2 and 3 (mGlu
2
and
mGlu ), and thus, may be useful for the amelioration of neurode-
3
generative diseases such as schizophrenia, depression, and
5
anxiety. Though these receptors are currently not well under-
3
procedures. The earliest approach, reported by Michaelis involved
stood, pyrazoloquinazolinones appear to act as negative allosteric
modulators to diminish the signaling that causes depression.
Several of these compounds are pictured in Figure 1.
a four-step synthesis of 5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-
one followed by heating with aqueous ammonia under pressure.
Nearly 60 years later, Wright4 reported a second approach from
substituted 2-hydrazinobenzoic acids and unsaturated nitriles, a
method that has been further modified to proceed under micro-
Our study began by focusing on the reaction of 2-fluorobenzoyl
chloride (4a) with 5-amino-1H-pyrazole (5a) to give 6a. This
transformation should permit assessment of the viability of this
approach to the target compounds and optimization of the process.
The reaction was initially attempted by acylation of the pyrazole
(1.3 equiv) with the acid chloride (1 equiv) at 23 °C in the presence
of 3.0 equiv of triethylamine in 1,2-dichloroethane (DCE).
Subsequent heating at 84 °C resulted in ca. 15% conversion to the
heterocycle with numerous side products. To better control the
5
wave conditions. A third synthesis, designed to give the 2-
amino-4-methyl derivatives, required the preparation of 2-(3-
methyl-4-oxo-3,4-dihydroquinazolin-2-yl)acetonitrile6–8 followed
⇑
Corresponding author. Tel.: +1 405 744 5952; fax: +1 405 744 6007.
E-mail address: rab@okstate.edu (R.A. Bunce).
http://dx.doi.org/10.1016/j.tetlet.2015.01.146
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

1
368
K. K. Gnanasekaran et al. / Tetrahedron Letters 56 (2015) 1367–1369
O
N
NH(CH
2
)
2
N(CH
3
)
2
Table 2
Pyrazolo[1,5-a]quinazolin-5(4H)ones 6 from 4 and 5
NH
O
N
O
O
N
6 4
C H -4-Cl
2
H N
N
N
2
X
R2
R1
X
N
Cl
NH
K CO
2
3
1
N
N
CH
+
HN
3
(
PARP-1
(top1 inhibitor)
F
N
DMF
R
2
inhibitor)
O
N
N
4
a (X = H)
5
6
CH
3
R1
N
4b (X = NO )
2
4
3 6 4
-CH O-C H
4
5
R1
H
R2
Product
Yield (%)
N
3
C
6
H
4
-3-F
a: X = H
a
b
c
d
e
f
a
b
c
d
g
e
f
H
H
H
H
H
CN
H
H
H
H
H
H
CN
6a
6b
6c
6d
6e
6f
6g
6h
6i
81
75
79
77
89
93
82
78
76
78
80
92
88
(
dual Glu
2 3
/Glu
CH
3
inhibitor)
a
c-C
3
H
5
4-CH
3
Ph
Figure 1. Biologically active pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives.
CO
H
2
Et
b: X = NO
2
H
initial acylation, we performed this step at 10 °C in DMSO
containing 3.0 equiv of K CO and obtained cleaner formation of
the monoacylated product. We then proceeded to optimize the
conditions for the final S Ar cyclization and found that direct
heating of this mixture at 150 °C for 30 min gave complete
conversion to the pyrazoloquinazolinone. Using this procedure,
however, isolation of the heterocycle proved troublesome as it
was only sparingly soluble in common organic solvents and DMSO
CH
3
a
2
3
c-C
3
H
5
4-CH
2-Thienyl
3
Ph
6j
6k
6l
N
CO
H
2
Et
6m
a
3 5
c-C H = cyclopropyl.
(
bp 189 °C) was difficult to remove under vacuum. Thus, only 45%
Table 3
Pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-ones 8 from 7 and 5
of the product was isolated in pure form using this solvent. Other
media, such as dichloroethane (DCE), acetonitrile (ACN) and tetra-
hydrofuran (THF), were found to be unsatisfactory due to solubility
problems and low boiling points. Finally, the entire sequence was
repeated in DMF (bp 153 °C), the solvent was removed by rotary
evaporation, and the yield was improved to 81%. Further refine-
O
O
Cl
K
2
CO
DMF
3
NH
+
5
R2
N
N
N
Cl
N
ment of the conditions revealed that 2.0 equiv of K
2
CO
3
was suffi-
7
8
R1
cient to promote product formation, while <2 equiv dramatically
lowered the yield (see Table 1). Similar results were observed
when 2-fluoro-5-nitrobenzoyl chloride and 2-chloronicotinoyl
chloride were used as substrates.
5
R1
R2
Product
Yield (%)
a
b
c
d
f
H
CH
c-C
4-CH Ph
H
H
H
H
H
8a
8b
8c
8d
8f
66
71
78
82
87
3
Our results for the synthesis of pyrazolo[1,5-a]quinazolin-
a
3
H
5
5
(4H)-ones 6 from 4a and 4b are shown in Table 2. The initial acyl-
ation was performed in DMF using 2 equiv of K CO
at À10 °C for
5 min. The reaction was then warmed to room temperature and
3
CN
2
3
1
a
3 5
c-C H = cyclopropyl.
stirred for an additional 15 min. The final ring closure was accom-
plished by heating this mixture at 140 °C, in the same flask, for a
period of 30–60 min. Work-up consisted of removing the solvent
under vacuum, slurrying the crude product in water to remove
the base, filtering the solid, and washing with methanol/ether
(2:1). Some cases required chromatographic purification, and this
was accomplished on a short silica gel column eluted with metha-
nol/chloroform (1:9). Employing this standard protocol, yields
were consistently between 75–93%, regardless of the level of aro-
matic activation.
Our yields for the preparation of pyrazolo[1,5-a]pyrido[3,2-
e]pyrimidin-5(4H)-ones 8 from 2-chloronicotinoyl chloride (7)
N
and 5 are shown in Table 3. These reactions are terminated by S -
Table 1
Reaction optimizationa
O
O
N
2
H N
Cl
K
2
CO
3
NH
+
Ar addition to a 2-chloropyridine moiety, and though the leaving
group is less reactive, the polarized C@N bond and secondary acti-
vation by the ortho amide carbonyl facilitate the final ring closure.
HN
DMF
F
N
N
4a
5a
6a
1
3
Only the ester-substituted pyrazole 5e failed to give the hetero-
cyclic product in good yield. In this case, the reaction produced an
inseparable mixture of three products, which included the desired
ester and the corresponding acid as the major components. In this
reaction, the ester group underwent facile hydrolysis during
workup of the fused pyrazolopyridopyrimidinone product, which
required more basic conditions for isolation. Attempts to remove
the acid by extraction, even with mild base, led to additional ester
cleavage. Apart from this one setback, the yields (66–87%) were
similar to those achieved with the above fluoroaromatic substrates
and the experimental details were essentially the same.
Basec
Expt No
Equiv
T (°C)
Solvent
Yield (%)
1
2
3
4
5
6
7
TEA
DBU
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
84
84
150
150
81
DCE
DCE
DMSO
DMSO
ACN
15
20
35
45
Trace
Trace
81
81
Trace
Na
2
CO
3
K
K
K
K
2
CO
2
CO
2
CO
2
CO
3
3
3
3
66
THF
140
140
140
DMF
DMF
DMF
b
8
K
2
CO
CO
3
9
K
2
3
a
b
c
Mole ratio of reactants 4:5 (1.0:1.3).
Optimized conditions.
Anhydrous Na CO and K CO were used.
2 3 2 3
The presumed mechanism for the process is illustrated in
Scheme 1 for the formation of 6a. Initial amide formation by the

K. K. Gnanasekaran et al. / Tetrahedron Letters 56 (2015) 1367–1369
1369
O
F
O
O
Acknowledgments
.
.
Cl H N
2
NH
NH
The authors wish to express their appreciation to the OSU Col-
lege of Arts and Sciences for funds to upgrade our departmental FT-
IR instruments and for a new 400 MHz NMR.
.
.
HN
N
H
N
HN
F
F
N
N
4
5a
9
10
O
N
O
N
Supplementary data
NH
NH
F–
–HCO
3
–
–
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01.146.
H
N
N
2–
CO
3
1
1
6a
References and notes
Scheme 1. Presumed mechanism.
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ido[3,2-e]pyrimidin-5(4H)-ones using a sequential acylation–S Ar
N
reaction. The strategy involves reaction of the 1,3-disposed electro-
philic sites in the 2-haloaroyl chlorides with the similarly disposed
nucleophilic sites in the 5-amino-1H-pyrazole reactants to
construct the central six-membered ring of the fused heterocyclic
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