Direct synthesis of N-aryl derivatives of quinazolin-4(3H)-ones employing arylboronic acids in the presence of Cu(OAc)2

Article abstract of DOI:10.1055/s-0029-1219385

Copper-promoted N-arylation of quinazolin-4(3H)-ones with boronic acid at room temperature in the presence of air has been investigated. This method is general and can be applied to synthesizing derivatives of quinazolin-4(3H)-one with medicinal values. G

Full text of DOI:10.1055/s-0029-1219385

LETTER
721
Direct Synthesis of N-Aryl Derivatives of Quinazolin-4(3H)-ones Employing
Arylboronic Acids in the Presence of Cu(OAc)2
Synthesis of
N
-
Ary
i
l
Deriv
n
atives of
Q
u
t
inazoli
a
3
H
)-on
l
es i Sreeramamurthy, Ettam Ashok, Velisoju Mahendar, Gourishetti Santoshkumar, Parthasarathi Das*
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, AP, India
Fax +91(40)23045438; E-mail: parthads@yahoo.com
Received 7 September 2009
Initial studies investigated reaction between 7-fluoro-
Abstract: Copper-promoted N-arylation of quinazolin-4(3H)-ones
with boronic acid at room temperature in the presence of air has
been investigated. This method is general and can be applied to syn-
thesizing derivatives of quinazolin-4(3H)-one with medicinal val-
ues.
quinazolin-4(3H)-one1c and phenylboronic acid in the
presence of Cu(OAc)2 (1 equiv) at room temperature un-
der air.18 The desired N-aryl quinazolinone was isolated in
good yield and, with this encouraging result, we investi-
gate the scope with different boronic acids and quinazo-
lin-4(3H)-ones, the results of which are listed in Table 1.
Key words: Cu(OAc)2, boronic acid, quinazolin-4(3H)-one
O
O
Quinazolin-4(3H)-one derivatives are of considerable in-
terest because of their broad spectrum of biological ef-
fects.1 These include kinase inhibition,2 anticancer,3 anti-
inflammatory,4 antidiabetes, and anti-obesity activity.5 In
addition more than 40 alkaloids containing a quinazolin-
4(3H)-one moiety have been isolated from natural
source.6 Some of these also have interesting biological
features such as antimalarial activity7, biofungicide,8 and
diuretic properties.
R2
B(OH)2
R2
NH
N
R1
R1
Cu(OAc)2, air, Et3N
r.t., 24–70 h
N
N
55–80% yield
Scheme 1
Arylboronic acids with chloro-, fluoro-, and trifluorome-
thyl substitution gave good yields in shorter reaction times
(Table 1, entries 2, 4, and 6) compared to the methoxy de-
rivative (Table 1, entry 10). Reaction with benzodioxol-
boronic acid (Table 1 entry 3) and benzodioxinboronic
acid (Table 1 entry 7) proceeded more slowly and in mod-
erate yield. Having demonstrated the generality of this re-
action, we explore the possibility in synthesizing kinase
inhibitor analogues by following the same methodology.
For this purpose 6-methoxy-7-(3-morpholinopropoxy)-
quinazolin-4(3H)-one19 was synthesized and treated with
various arylboronic acids in the presence of Cu(OAc)2 at
ambient temperature to yield N-substituted quinazolin-4-
(3H)-one derivatives (Table 2). As expected chloro- and
fluoro-substituted arylboronic acids resulted in good
yields (Table 2, entries 2 and 3) in shorter reaction times
compared to the methoxy-substituted arylboronic acid
(Table 2, entries 4 and 5).20
The most common methods for the preparation of
quinazolinones involve the amidation of 2-aminobenzo-
nitrile or 2-aminobenzoic acid or its derivatives followed
by oxidative ring closure under basic conditions.9 Other
methods involve cycloaddition of anthranilic acid deriva-
tives with a diverse range of substrates including imidates
and iminohalides.10 Recent reports reveal that quinazolin-
4(3H)-ones have been prepared by using silica sulfuric ac-
12
id,11 PCl3, low-valent titanium,13 and under microwave
irradiation.14 However, there is still a need to develop ef-
ficient, mild, and direct methods for the synthesis of N-
aryl quinazolin-4(3H)-one derivatives.
Copper-promoted carboncnitrogen (C–N) and carbon–
oxygen (C–O) oxidative coupling reactions of NH/OH-
containing substrates with arylboronic acids have
emerged as a powerful synthetic methodology.15 This
novel methodology is characterized by the mild reaction
conditions (r.t., weak base, in air) and extensions and ap-
plications of this new methodology have been report-
ed.16,17 In connection with a drug discovery program, we
recently required an efficient protocol for N-aryl substitu-
tion of quinazolin-4(3H)-ones and herein we report cop-
per(II) acetate promoted C–N bond formation with
arylboronic acids under mild, room-temperature condi-
tions (Scheme 1).
In summary, we have developed a general mild, efficient,
and direct method for synthesizing the N-aryl derivatives
of quinazolin-4(3H)-ones, and this method has been ap-
plied to the synthesis of quinazolinone derivatives of
pharmaceutical interest.
Acknowledgment
We thank Dr. Reddy’s Laboratories Ltd. for financial support and
encouragement. Help from the analytical department in recording
spectroscopic data is highly appreciated.
SYNLETT 2010, No. 5, pp 0721–0724
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Advanced online publication: 10.02.2010
DOI: 10.1055/s-0029-1219385; Art ID: D24609ST
© Georg Thieme Verlag Stuttgart · New York

722
K. Sreeramamurthy et al.
LETTER
Table 1 Reactions between 7-Fluoroquinazolin-4(3H)-ones and Phenylboronic Acids in the Presence of Cu(OAc)2
Entry Substrate
Boronic acid
Producta
Time (h) Yield (%)b
O
O
B(OH)2
1
26
25
68
74
NH
NH
N
F
N
O
F
N
O
Cl
F
Cl
B(OH)2
2
N
N
F
F
N
O
F
F
N
O
O
O
B(OH)2
B(OH)2
O
3
72
24
56
80
NH
NH
NH
O
F3C
F3CO
F
F
N
O
N
O
CF3
OCF3
F
4
N
N
F
N
O
F
N
O
B(OH)2
5
26
24
68
26
72
75
60
72
F
N
F
N
O
O
B(OH)2
Cl
6
Cl
NH
N
N
O
N
O
O
O
O
O
B(OH)2
Cl
7
Cl
NH
N
N
N
O
O
B(OH)2
MeO
MeO
MeO
8
NH
NH
N
MeO
N
O
N
O
F
B(OH)2
MeO
9
35
60
68
60
MeO
MeO
N
N
F
MeO
N
O
N
O
OMe
B(OH)2
MeO
10
MeO
MeO
NH
MeO
MeO
N
N
a Characterized by IR, 1H NMR, 13C NMR, and MS.
b Isolated yield.
Podanyi, B.; Szasz, G. Heterocycles 1994, 37903. (d) For
review on quinazolinone, see: Mhaske, S. B.; Argade, N. P.
Tetrahedron 2006, 62, 9787.
References and Notes
(1) (a) Armarego, W. L. F. Quinazolines; Brown, D. J., Ed.;
John Wiley and Sons: London, 1967. (b) Ellis, G. P.
Synthesis of Fused Heterocycles, Vol. 47; John Wiley and
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A. R.; Ruan, F.; Treiberg, J. WO 2005113556, 2005-6, US
16778, 2005; Chem. Abstr.2006, 144, 22759.
Synlett 2010, No. 5, 721–724 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Aryl Derivatives of Quinazolin-4(3H)-ones
723
Table 2 Reactions between 6-Methoxy-7-(3-morpholinopropoxy)-uinazolin-4(3H)-ones with Various Arylboronic Acids in the Presence of
Cu(OAc)2
Entry Substrate
Boronic acid
Producta
Time Yield
(h)
(%)b
O
N
O
N
O
N
O
N
O
N
O
N
B(OH)2
MeO
O
MeO
O
NH
NH
NH
NH
N
N
1
30
65
N
N
O
O
F
B(OH)2
MeO
O
MeO
O
2
28
28
65
70
72
60
N
N
O
F
O
Cl
B(OH)2
O
MeO
O
MeO
O
N
3
N
N
N
O
O
Cl
O
OMe
B(OH)2
MeO
O
MeO
O
N
4
N
N
N
O
OMe
OMe
O
OMe
OMe
O
N
O
N
MeO
O
NH
MeO
O
5
70
55
N
N
B(OH)2
N
O
OMe
O
a Characterized by IR, 1H NMR, 13C NMR, and MS.
b Isolated yield.
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Bondar, G.; Chen, L.; Chuang, C.-Y.; Claus, T. H.; Fathi, Z.;
Fu, W.; Khire, U. R.; Kristie, J. A.; Liu, X.-G.; Lowe, D. B.;
McClure, A. C.; Michels, M.; Ortiz, A. A.; Ramsden, P. D.;
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Sweet, L. J.; Bullock, W. H. J. Med. Chem. 2007, 50, 5202.
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Rajesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2006, 47,
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Synlett 2010, No. 5, 721–724 © Thieme Stuttgart · New York

724
K. Sreeramamurthy et al.
LETTER
(12) Xue, S.; McKenna, J.; Shieh, W. C.; Repi, O. J. Org. Chem.
2004, 69, 6474.
(13) Shi, D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H.
Tetrahedron Lett. 2003, 44, 3199.
7.80–7.78 (m, 1 H), 7.62–7.60 (m, 2 H), 7.42–7.45 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 159.0, 147.6, 146.4, 134.6,
131.6, 129.8, 129.6, 125.2, 116.2, 115.7. ESI-MS: 275 [M +
H]+. ESI-HRMS: m/z calcd for C14H9ClFN2O [M + H]+:
275.0387; found: 275.0383.
(14) (a) Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.;
Ramana, A. V. Tetrahedron Lett. 2004, 45, 6–517.
(b) Kalusa, A.; Chessum, N.; Jones, K. Tetrahedron Lett.
2008, 49, 5840.
(15) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.;
Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
(c) Chan, D. M. T.; Lam, P. Y. S. Recent Advances in
Copper-Promoted C-Heteroatom Bond Cross-Coupling
Reaction with Boronic Acids and Derivatives, In Boronic
Acids: Preparation and Application in Organic Synthesis
and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
2005, 205.
(16) (a) Lam, P. Y. S.; Deudon, S.; Averil, K. M.; Li, R.; He, M.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122,
7600. (b) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G.
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S. Tetrahedron Lett. 2003, 44, 3863.
Table 1, Entry 7
Brown solid; mp 194–196 °C. IR (KBr): 3066, 2981, 2939,
2727, 1681, 1556 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 8.32 (s, 1 H), 8.17–8.15 (m, 1 H), 7.97–7.95 (m, 1 H)
7.76–7.73 (m, 1 H), 7.12–7.10 (m, 1 H), 7.03–6.98 (m, 2 H),
4.30 (s, 4 H). 13C NMR (50 MHz, CDCl3): d = 159.0, 147.7,
146.3, 143.7, 143.2, 134.5, 131.4, 130.2, 129.4, 125.2,
123.1, 120.1, 117.0, 116.3, 64.0. ESI-MS: 315 [M + H]+.
ESI-HRMS): m/z calcd for C16H12ClN2O3 [M + H]+:
315.0536; found: 315.0529.
Table 1, Entry 8
Brown solid; mp 190–192 °C. IR (KBr): 3086, 3026, 2962,
2654, 1739, 1610 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 8.24 (s, 1 H), 7.58–7.48 (m, 6 H,), 7.20–7.18 (m, 1 H),
3.94 (s, 3 H), 3.89 (s, 3 H). 13C NMR (50 MHz, CDCl3):
d = 159.2, 154.6, 148.9, 145.6, 143.8, 137.7, 129.1, 128.5,
127.4, 114.8, 108.0, 105.4, 56.0, 55.7. ESI-MS: m/z = 283
[M + H]+. ESI-HRMS: m/z calcd for C16H15N2O3 [M + H]+:
283.1083; found: 283.1081.
(17) (a) Evans, D. A.; Katz, J. L.; Peterson, G. S.; Hinterman, T.
J. Am. Chem. Soc. 2001, 123, 12411. (b) Collman, J. P.;
Zhong, M.; Zhang, C.; Costanzo, S. Org. Lett. 2001, 66,
7892. (c) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2002, 4, 4309. (d) Bakkestuen, A. K.; Gundersen, L.-L.
Tetrahedron Lett. 2003, 44, 3359. (e) Strouse, J. J.;Jeselnik,
M.; Tapaha, F.; Jonsson, C. B.; Parker, W. B.; Arterburn,
J. B. Tetrahedron Lett. 2005, 46, 5699. (f) Benard, S.;
Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441.
(g) Guy, C. S.; Jones, T. C. Synlett 2009, 2253.
(18) General Procedure for N-Arylation of 4 (3H)-
Quinazolinone
Table 1, Entry 9
Brown solid; mp 243–245 °C. IR (KBr): 3433, 3060, 2962,
2837, 1683, 1610, 1502 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 8.22 (s, 1 H), 7.49–7.47 (m, 1 H), 7.46–7.44 (m, 1
H), 7.39–7.37 (m, 2 H), 7.19–7.17 (m, 1 H), 3.94 (s, 3 H),
3.88 (s, 3 H), 2.30 (s, 3 H). 13C NMR (50 MHz, CDCl3):
d = 161.4, 159.2, 154.68, 148.99, 145.64, 143.84, 133.65,
130.68, 126.9, 125.3, 115.6, 114.7, 108.0, 105.3, 56.02,
55.75, 14.07. ESI-MS: m/z 315 [M + H]+. ESI-HRMS: m/z
calcd for C17H16FN2O3 [M + H]+: 315.1145; found:
315.1143.
(19) Ple, P. A.; Green, T. P.; Hennequin, L. F.; Curwen, J.;
Fennel, M.; Allen, J.; van der Brempt, C. L.; Costello, G.
J. Med. Chem. 2004, 47, 871.
A mixture of the requisite 4 (3H)-quinazolinone (1.0 mmol),
phenylboronic acid (1.5 mmol), anhyd Cu(OAc)2 (1.0
mmol) and Et3N (2.0 mmol) in dry CH2Cl2 (10–15 mL) was
stirred at ambient temperature under air for 24–70 h.
Progress of the reaction was monitored by TLC. The
reaction mixture was filtered through Celite, the filtrate
concentrated in vacuo, and the resulting mixture purified by
chromatography on silica gel (CH2Cl2–MeOH) to yield the
corresponding N-substituted quinazolin-4 (3H)-one.
Selected Spectroscopic Data
(20) Selected Spectroscopic Data
Table 2, Entry 2
Brown solid; mp 125–127 °C. IR (KBr): 3429, 3076, 2954,
2495, 2854 2445, 1678 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 8.22 (s, 1 H), 7.60–7.58 (m, 2 H,), 7.56–7.54 (m, 1
H), 7.40–7.36 (m, 2 H), 7.20–7.18 (m, 1 H), 4.20–4.18 (m, 2
H), 3.85 (s, 3 H), 3.60–3.58 (m, 4 H), 2.46–2.38 (m, 6 H),
1.96–1.94 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 164.0,
159.0, 153.9, 149.0, 145.5, 143.7,134.0, 133.8, 129.7, 129.5,
116.0, 115.6, 114.6, 108.6, 105.5, 66.9, 64.8, 55.7, 54.6,
53.0, 25.4. ESI-MS: 414 [M + H]+. ESI-HRMS: m/z calcd
for C22H25FN3O4 [M + H]+: 414.1829; found: 414.1830.
Table 1, Entry 6
Brown solid; mp 221–223 °C. IR (KBr): 3105, 3043, 2976,
2495, 1928 1614 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 8.37 (s, 1 H), 8.14–8.12 (m, 1 H,), 7.95–7.93 (m, 1 H),
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