A facile one-step synthesis of 5-chloro-imidazo[1,5-a]quinazoline by microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.08.054

A new and facile method has been developed for the one-step synthesis of 5-chloro-imidazo[1,5-a]quinazoline by cyclization of N-acylanthranilic acid A with 2-amino acetamide B1 or 2-amino-acetonitrile B2 in the presence of POCl₃ under microwave

Full text of DOI:10.1016/j.tetlet.2009.08.054

Tetrahedron Letters 50 (2009) 6048–6052
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile one-step synthesis of 5-chloro-imidazo[1,5-a]quinazoline
by microwave irradiation
b
a
a
c
Guo Li a, , Ramesh Kakarla , Samuel W. Gerritz , Annapurna Pendri , Baoqing Ma
*
a Early Discovery Chemistry, Bristol Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA
b PTC Therapeutics Inc., 100 Corporate Ct, South Plainfield, NJ 07080, USA
c Merial Limited, 631 Route 1, North Brunswick, NJ 08902, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and facile method has been developed for the one-step synthesis of 5-chloro-imidazo[1,5-a]qui-
nazoline by cyclization of N-acylanthranilic acid A with 2-amino acetamide B1 or 2-amino-acetonitrile
B2 in the presence of POCl3 under microwave irradiation. 5-chloro-imidazo[1,5-a]quinazolines can be
further functionalized by displacement of 5-Cl group.
Received 4 June 2009
Revised 3 August 2009
Accepted 18 August 2009
Available online 21 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Imidazoquinazoline
4-Quinazolinone
Microwave
1. Introduction
Cl
Cl
Cl
4-Quinazolinones are of interest to medicinal chemists due to
their anticancer, antiviral, antimicrobial, anticonvulsant, and
anti-inflammatory activities.1 Fusing an imidazo moiety with
the quinazoline ring affords imidazoquinazolines; two imidazo-
quinazoline-based drugs, anagrelide and quazinone, are used
clinically as anti-thrombotic and cardiotonic agents.2 Structural
variants of imidazoquinazolines can provide new compounds
for evaluation against a variety of biological targets. The imi-
dazo[1,5-a]quinazolines NNC 14-0185 and NNC 14-0189 have
been reported to show promising anticonvulsant profile in rats
and mice.3 In spite of the interesting pharmacological properties
of imidazo[1,5-a]quinazolines, there are few reports of their syn-
thesis and the known methods require multi-step synthesis from
quinazolines.4
N
N
O
O
N
N
N
N
H
H
Anagrelide
Quazinone
O
N
F
N
N
N
F
N
N
O
N
N
O
N
N
N
N
Anthranilic acid and its derivatives are well-precedented5
building blocks for the synthesis of quinazolinones. Grimmel re-
ported6 the synthesis of quinazolinones by heating N-acetylanthra-
nilic acids with anilines in the presence of condensing reagents,
such as phosphorus trichloride, phosphorus oxychloride, or thionyl
chloride. Xue et al. improved7 the yield for the synthesis of C2, N3-
disubstituted-quinazolinones from anilines and N-acylanthranilic
acids by using acetonitrile as a solvent, but they noted that no
4-quinazolinone was produced in the reactions involving an alkyl-
NNC 14-0185
NNC 14-0189
amine. The present study emerged from optimizing the reaction
conditions for the synthesis of quinazolinones from N-acylanthra-
nilic acids and 2-amino acetamides: we discovered the formation
of a new tricyclic product 5-chloroimidazo[1,5-a]quinazoline when
POCl3 was used as a condensing reagent. In this Letter, we report
the first one-step synthesis of 5-chloroimidazo[1,5-a]quinazolines
by the cyclization of N-acylanthranilic acid with 2-amino aceta-
mides or 2-amino-acetonitriles in the presence of condensing re-
agent POCl3 and utilizing microwave irradiation.
* Corresponding author. Tel.: +1 203 6775611; fax: +1 203 6776984.
E-mail address: Guo.Li@bms.com (G. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.054

G. Li et al. / Tetrahedron Letters 50 (2009) 6048–6052
6049
O
O
N
OH
NH
PCl3, acetonitrile
NH2
NH2
N
+
Microwave
N
160oC, 30mins
O
O
1
Scheme 1.
Cl
N
O
O
N
N
OH
POCl3, acetonitrile
NH2
NH2
+
+
N
N
NH
Microwave
150oC, 60mins
N
O
O
1
2
Scheme 2.
is activated as an acetimidoyl chloride. The formation of the qui-
nazolinone and imidazoquinazoline products can be explained by
the amino moiety of 2-amino-2-phenylacetamide attacking two
different sites in the activated intermediate of 2-acetamidobenzoic
acid: route (a) proceeds via amide formation and carboxamide
dehydration to afford a quinzolinone, and route (b) proceeds via
amidine formation, carboxamide dehydration, and stepwise cycli-
zation to afford an imidazoquinazoline. During this one-pot cycli-
zation three new bonds were formed.
Utilizing POCl3 as the condensing reagent, we next conducted a
substrate survey as shown in Table 1. Varying R3 on the 2-position
of 2-amino acetamide strongly influenced the yield of the imidazo-
quinazoline product, with a general trend of Me > Ph > H (Table 1,
entries 1–3). The introduction of an electron-withdrawing group
(R2) at the 5-position of the 2-acetamidobenzoic acid improved
the yield for the formation of the imidazoquinazoline (Table 1, en-
tries 4–9). When R2 is an electron-donating group, for example, a
methoxy group, only a trace amount of the desired imidazoquinaz-
oline was observed in a complex product mixture. In most cases,
the main reaction byproduct was the corresponding 2-acetoni-
trile-4-quinazolinone. The yield ratio of the imidazoquinazoline
product to the corresponding quinazolinone of each reaction is
shown in Table 1.
2. Results and discussion
Our initial attempts at the formation of imidazo[1,5-a]quinazo-
lines were unsuccessful, providing instead the undesired 4-quinaz-
olinone. For example, in the reaction of 2-acetamidobenzoic acid
with 2-amino-2-phenylacetamide in the presence of 3 equiv of
PCl3 under microwave irradiation, we observed formation of the
4-quinazolinone with concomitant carboxamide dehydration to af-
ford the 2-acetonitrile-4-quinazolinone 1 as shown in Scheme 1.8
Further investigation of this reaction by surveying different
condensing reagents, such as PCl3, POCl3, PCl5, and SOCl2, indicated
that the condensing reagents played a crucial role in determining
the product distribution. While SOCl2 gave no cyclized product,
PCl5 provided some quinazolinone but in very poor yield, and
PCl3 afforded exclusively the quinazolinone product 1 in reason-
able yield. Interestingly, when POCl3 was used, we obtained a 1:1
mixture of the desired imidazoquinazoline 2 and the quinazoli-
none 1 (Scheme 2).9
The assigned structures for 5-chloro-1-methyl-3-phenylimi-
dazo[1,5-a]quinazoline
2
and 2-(2-methyl-4-oxoquinazolin-
3(4H)-yl)-2-phenylacetonitrile 1 were confirmed by single crystal
X-ray crystallography (Fig. 1).10
Our mechanistic proposal for the formation of the quinazoli-
none and imidazoquinazoline products is shown in Scheme 3. Both
carbonyl groups in 2-acetamidobenzoic acid can be activated by
POCl3, the acid is activated as an acid chloride while the acetamide
Because the carboxamide was dehydrated to a cyano group in
the quinazolinone product, we surmised that the nitrile intermedi-
ate was formed prior to cyclization. This led us to substitute 2-
Figure 1. X-ray structure of (a) 5-chloro-1-methyl-3-phenylimidazo[1,5-a]quinazoline 2 and (b) 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-2-phenylacetonitrile 1.

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G. Li et al. / Tetrahedron Letters 50 (2009) 6048–6052
(a)
+
O
O
N
O
O
N
OH
NH
POCl3
Cl
H2N
N
N
N
H
N
(a)
N
O
NH2
O
Cl
(b)
Cl
1
(b)
O
O
Cl
O
N
Cl
Cl
N
NH
N
N
NH2
N
NH
N
N
N
N
2
Scheme 3.
Table 1
Formation of the imidazoquinazoline under microwave irradiation
R3
Cl
N
O
O
R3
R1
NH2
H2N
N
POCl3, acetonitrile
OH
R2
N
CN
O
R2
B1
+
+
R2
R3
NH
R1
Microwave
N
R3
150oC, 60mins
N
R1
O
H2N
N
A
C
D
B2
Entry
Substrate A
Substrate B1
Substrate B2
Product C
Yield of Ca (%)
Yield ratio C:D
NH2
Cl
N
NH2
COOH
O
O
1
30
56
50:50
84:16
NH2
N
N
N
H
N
Cl
N
NH2
COOH
O
H2N
O
2
3
39
41
68:32
73:27
N
N
N
H
H2
N
N
Cl
N
NH2
COOH
O
H2N
O
0
21
0:100
31:69
N
N
N
H
H2
N
N
NH2
O
NH2
Cl
Br
COOH
Br
O
N
4
36
50
65:35
79:21
N
NH2
N
N
H
N
Cl
N
NH2
Br
Br
COOH
O
H2N
Br
N
O
5
6
40
43
73:27
83:17
N
H
N
H2
N
N
Cl
N
NH2
COOH
O
H2N
Br
N
O
18
26
32:68
42:58
N
H
H2
N
N
N

G. Li et al. / Tetrahedron Letters 50 (2009) 6048–6052
6051
Table 1 (continued)
Entry
Substrate A
Substrate B1
Product C
Yield of Ca (%)
Yield ratio C:D
Substrate B2
NH2
Cl
N
NH2
O2N
COOH
O
O2
N
N
O
7
45
78
82:18
100:0
NH2
N
H
N
N
Cl
N
NH2
O2N
O2N
COOH
O
H2N
O2
N
N
O
8
9
51
69
86:14
92:8
N
H
N
H2
N
N
Cl
N
NH2
COOH
O
H2N
O2
N
N
O
38
46
58:42
68:32
N
H
H2
N
N
N
Cl
N
NH2
COOH
H2
N
N
O
O
10
25
43
48:52
64:36
N
N
H
H2
N
N
Cl
N
COOH
O
NH2
N
H2
N
O
11
10
11
63:37
62:38
N
H
N
H2
N
N
a
Yields of the isolated products.
aminoacetonitriles for the corresponding 2-amino acetamides, and
we found that 2-aminoacetonitriles improved the yield of the de-
sired imidazoquinazolines. For example, the cyclization of 2-acet-
amido-5-nitrobenzoic acid with 2-amino-2-phenylacetonitrile
afforded exclusively the imidazoquinazoline product in 78% yield
(Table 1, entry 7). When 2-aminoacetonitrile was used, the corre-
sponding 5-chloro-imidazoquinazoline was isolated as the major
product in nearly every case (exceptions: Table 1, entries 3, 6,
and 11) with yields ranging from 41% to 78%. When R1 is a phenyl
group, the yield of the imidazoquinazoline is significantly lower
than when R1 is an alkyl group (Table 1, entry 11).
which can be explored for their pharmacology properties. The
structure of the tricyclic imidazoquinazoline was confirmed by
X-ray crystal structure analysis.
Acknowledgments
The authors thank Dieter Drexler and Joseph Cantone for the
HRMS study of all the new compounds.
Supplementary data
Finally, it should be noted that the 5-chloro-1-methyl-3-pheny-
limidazo[1,5-a]quinazoline can be further functionalized by dis-
placement of 5-Cl with alkyl amines. For example, the 5-Cl of 2
was displaced by piperidine to afford 3 in 83% yield (Scheme 4).11
In conclusion, we have developed a new method for the one-
step synthesis of imidazo[1,5-a]quinazoline. In this method, the
cyclization of N-acylanthranilic acid with 2-amino acetamide or
2-amino-acetonitrile in the presence of POCl3 afforded the 5-chlo-
roimidazo[1,5-a]quinazolines under microwave irradiation. The
yield of imidazoquinazoline was improved by introducing an elec-
tron-withdrawing group at the 5-position of 2-acetamidobenzoic
acid. This route provided ready access to imidazoquinazolines
Supplementary data (experimental procedures, spectroscopic
data for all new compounds, selected 1H and 13C NMR spectra
and X-ray crystallography data for 5-chloro-1-methyl-3-phenyl-
imidazo[1,5-a]quinazoline and 2-(2-methyl-4-oxoquinazolin-
3(4H)-yl)-2-phenyl-acetonitrile) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.08.054.
References and notes
1. (a) Raghavendra, N. M.; Thampi, P.; Gurubasavarajaswamy, P. M.; Sriram, D.
Archiv der Pharmazie 2007, 340, 635; (b) Gao, X.; Cai, X.; Yan, K.; Song, B.; Gao,
L.; Chen, Z. Molecules 2007, 12, 2621; (c) Pereira, M. D. F.; Chevrot, R.; Rosenfeld,
E.; Thiery, V.; Besson, T. J. Enzyme Inhib. Med. Chem. 2007, 22, 577; (d) Abu-
Shady, H. A.; Michael, A. N.; Abbas, S. E.; Abu-Youssef, H. E. Egyptian J. Chem.
2007, 50, 313; (e) Kumar, A.; Rajput, C. S.; Bhati, S. K. Bioorg. Med. Chem. 2007,
15, 3089.
2. (a) Spence, C. M.; Bergden, R. N. Drugs 1994, 47, 809; (b) Venuti, M. C.;
Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988,
31, 2136.
3. Jackson, H. C.; Hansen, H. C.; Kristiansen, M.; Suzdak, P. D.; Klitgaard, H.; Judge,
M. E.; Swedberg, M. D. B. Eur. J. Pharmacol. 1996, 308, 21.
4. (a) Hansen, H. C.; Kristiansen, M. US005371080A, 1994.; (b) Singh, B. D.;
Chaudhury, D. N. J. Indian Chem. Soc. 1969, 46, 21.
5. Hisano, T. Org. Prep. Proced. Int. 1973, 5, 145.
H
N
N
N
Cl
N
N
N
100oC
N
N
6. Grimmel, H. W.; Guenther, A.; Morgan, J. F. J. Am. Chem. Soc. 1946, 68, 539.
7. Xue, S.; McKenna, J.; Shieh, W. C.; Pepic, O. J. Org. Chem. 2004, 69, 6474.
8. Procedure for the Preparation of 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-2-
2
3
Scheme 4.
phenylacetonitrile 1 using PCl3 as condensing reagent: In
a 0.5–2 ml glass

6052
G. Li et al. / Tetrahedron Letters 50 (2009) 6048–6052
microwave vessel were placed 2-acetamidobenzoic acid (27 mg, 0.15 mmol), 2-
J = 7.7 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.80 (ddd, J = 8.8, 7.3, 1.5 Hz, 1H), 8.13 (d,
J = 8.8 Hz, 1H), 8.22 (dd, J = 8.1, 1.5 Hz, 1H), 8.30–8.38 (m, 2H). 13C NMR
(500 MHz, CDCl3) d: 19.4, 115.8, 118.3, 126.0, 126.7, 127.2, 128.5, 128.6, 130.0,
131.6, 133.3, 133.7, 135.6, 137.4, 145.2. HRMS (M+H) calcd for C17H13N3Cl:
294.0793; found: 294.0790.
amino-2-phenylacetamide (33.8 mg, 0.225 mmol), acetonitrile (1 ml), followed
by trichlorophosphine (62 mg, 0.45 mmol). The reaction mixture was heated
under microwave irradiation using an EmrysTM Optimizer at 160 °C for 30
minutes. The solvent was removed and the residue was purified by PrepHPLC
to give the product in 54% yield. 1H NMR (500 MHz, CDCl3) d: 2.51 (s, 3H), 7.37–
7.48 (m, 5H), 7.52 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.80 (ddd, J = 8.3,
7.1, 1.4 Hz, 1H), 7.94 (br s, 1H), 8.32 (d, J = 8.3 Hz, 1H). 13C NMR (500 MHz,
CDCl3) d: 23.9, 45.8, 115.8, 119.6, 125.8, 127.3, 127.5, 127.7, 129.5, 129.7, 131.6,
135.5, 147.0, 152.9, 161.8. HRMS (M+H) calcd for C17H14N3O: 276.1131; found:
276.1127.
10. Crystallographic data (excluding structure factors) for the structures in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 734596 and 734597.
11. Procedure for the preparation of 5-piperidinoimidazo[1,5-a]quinazoline 3: In a
20 ml scintillation vial were placed 5-chloro-1-methyl-3-phenyl-imidazo[1,5-
a]quinazoline (29 mg, 0.1 mmol) and piperidine (0.5 ml, neat). The reaction
mixture was heated at 100 °C. The reaction completed after 1 h as indicated by
LCMS. The piperidine was removed and the residue was purified by PrepHPLC
to give 5-chloro-1-methyl-3-phenyl-imidazo[1,5-a]quinazoline 3 in 83% yield.
1H NMR (400 MHz, CDCl3) d: 1.67–1.96 (6H, m), 3.04 (3H, s), 3.34–3.51 (4H, m),
7.22 (1H, t, J = 7.3 Hz), 7.35–7.52 (3H, m), 7.70 (1H, td, J = 7.9, 1.5 Hz), 7.98 (1H,
dd, J = 7.9, 1.3 Hz), 8.10 (1H, d, J = 8.5 Hz), 8.42 (2H, dd, J = 8.3, 1.3 Hz). 13C NMR
(500 MHz, CDCl3) d: 19.5, 24.9, 26.0, 51.9, 115.5, 116.1, 124.6, 125.5, 125.7,
125.8, 127.6, 128.4, 131.9, 133.1, 134.8, 135.5, 136.7, 156.3. HRMS (M+H) calcd
for C22H22N4: 343.1917; found: 343.1918.
9. Procedure for the preparation of 5-chloro-1-methyl-3-phenyl-imidazo[1,5-
a]quinazoline
2 using POCl3 as condensing reagent: In a 0.5–2 ml glass
microwave vessel were placed 2-acetamidobenzoic acid (27 mg, 0.15 mmol),
2-amino-2-phenylacetamide (33.8 mg, 0.225 mmol), acetonitrile (1 ml),
followed by phosphoryl trichloride (69 mg, 0.45 mmol). The reaction mixture
was heated under microwave irradiation using an EmrysTM Optimizer at 150 °C
for 60 min. The solvent was removed and the residue was purified by PrepHPLC
to give 5-chloro-1-methyl-3-phenyl-imidazo[1,5-a]quinazoline 2 in 30% yield.
1H NMR (300 MHz, CDCl3) d: 3.06 (s, 3H), 7.29 (t, J = 7.5 Hz, 1H), 7.45 (t,