Tandem palladium-catalyzed addition cyclocarbonylation: An efficient synthesis of 2-heteroquinazolin-4(3H)-ones

Article abstract of DOI:10.1021/ol902924x

Chemical Equation Presented A highly practical and efficient method for the synthesis of 2-heteroquinazolin-4(3H)-ones has been developed by a palladium-catalyzed tandem reaction. Under mild reaction conditions (80 °C, 100 psi), a wide variety of 2-heteroquinazolin-4(3H)-ones were obtained in good to excellent yields.

Full text of DOI:10.1021/ol902924x

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1188-1191
Tandem Palladium-Catalyzed Addition/
Cyclocarbonylation: An Efficient
Synthesis of
2-Heteroquinazolin-4(3H)-ones
Fanlong Zeng and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
howard.alper@uottawa.ca
Received December 19, 2009
ABSTRACT
A highly practical and efficient method for the synthesis of 2-heteroquinazolin-4(3H)-ones has been developed by a palladium-catalyzed tandem
reaction. Under mild reaction conditions (80 °C, 100 psi), a wide variety of 2-heteroquinazolin-4(3H)-ones were obtained in good to excellent
yields.
2-Heteroquinazolin-4(3H)-ones have recently attracted con-
siderable attention due to their diverse biological and
pharmacological activities.1 For example, 2-aminoquinazolin-
4(3H)-one derivatives have shown high activities as dopam-
ine agonists,2 histamine H4 receptor inverse agonists,3 anti-
inflammatory,4 antitumor,5 antihypertentive,6 anticonvulsant,7
antihyperglycemic,8 and antibacterial9 agents.
A number of synthetic methods for the preparation of
2-heteroquinazolin-4(3H)-ones have been developed. In
general, the synthetic methods to such compounds can be
classified into the following five categories: (1) alkylation
of 2,4-quinazolinediones10 or 2-thioxoquinazolin-4-ones;11
(2) the direct substitution of 2-chloroquinazolin-4(3H)-
ones12 or its analogues such as 2-alkylthioquinazolin-
4(3H)-ones,13 2-cyanoquinazolin-4(3H)-ones14 by nucleo-
philes; (3) amidation of 2-aminobenzoic acid15 and its
(1) (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153. (b) Ismail, M. A. H.; Barker, S.; Abou El
Ella, D. A.; Abouzid, K. A. M.; Toubar, R. A.; Todd, M. H. J. Med. Chem.
2006, 49, 1526.
(2) Grosso, J. A.; Nichols, E. D.; Kohli, J. D.; Glock, D. J. Med. Chem.
1982, 25, 703.
(3) Smits, R. A.; de Esch, I. J. P.; Zuiderveld, O. P.; Broeker, J.; Sansuk,
K.; Guaita, E.; Coruzzi, G.; Adami, M.; Haaksma, E.; Leurs, R. J. Med.
Chem. 2008, 51, 7855.
(4) (a) Alagarsamy, V.; Dhanabal, K.; Parthiban, P.; Anjana, G.; Deepa,
G.; Murugesan, B.; Rajkumar, S.; Beev, A. J. J. Pharm. Pharmacol. 2007,
59, 669. (b) Alagarsamy, V.; Muthukumar, V.; Pavalarani, N.; Vasantha-
nathan, P.; Revathi, R. Biol. Pharm. Bull. 2003, 26, 557.
(5) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson,
D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860.
(6) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.; Gutcait, A.; Liu, S.-W.; Yen,
M.-H.; Chien, S.-L.; Rong, J.-K. J. Med. Chem. 1998, 41, 3128.
(7) Zappala`, M.; Grasso, S.; Micale, N.; Zuccala`, G.; Menniti, F. S.;
Ferreri, G.; Sarroc, G. D.; Michelid, C. D. Bioorg. Med. Chem. Lett. 2003,
13, 4427.
(9) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.; Duch,
D. S.; Ferone, R.; Hall, W. R.; Humphrey, J.; Kelly, J. M.; Wilson, D. C.
J. Med. Chem. 1993, 36, 2279.
(10) Schneller, S. W.; Ibay, A. C.; Christ, W. J.; Brunst, R. F. J. Med.
Chem. 1989, 32, 2247.
(11) Azev, Yu. A.; Golomolzin, B. V.; Dyulcks, T.; Klyuev, N. A.;
Yatluk, Yu. G. Chem. Heterocycl. Compd. 2007, 43, 356.
(12) De Ruiter, J.; Brubaker, A. N.; Millen, J.; Riley, T. N. J. Med.
Chem. 1986, 29, 625.
(13) Gruner, M.; Rehwald, M.; Eckert, K.; Gewald, K. Heterocycles
2000, 53, 2363.
(8) Ram, V. J.; Farhanullah; Tripathib, B. K.; Srivastavab, A. K. Bioorg.
Med. Chem. 2003, 11, 2439.
(14) Lee, H.-S.; Chang, Y.-G.; Kim, K. J. Heterocycl. Chem. 1996, 61,
659.
10.1021/ol902924x  2010 American Chemical Society
Published on Web 02/25/2010

derivatives, i.e., 2-aminobenzonitrile,16 2-aminobenzoate,17
and isatoic anhydride;18 (4) reaction of nucleophiles, i.e.,
guanidines, with o-fluorobenzoyl derivatives;19 (5) the
tandem aza-Witting reaction of iminophosphorane.20
Table 1. Optimization of the Reaction Conditions for the
Reaction of N-(2-Iodophenyl)-N′-phenylcarbodiimide with
Piperidinea
These procedures often suffer from certain drawbacks
such as multistep reactions, harsh reaction conditions, and
low yields. Recently, several new synthetic methods have
been reported including copper-catalyzed amination of
2-halobenzyl acids,21 solid-supported synthesis,22 micro-
wave irradiation,23 and synthesis from aromatic amines
through Friedel-Crafts reaction.24 We have been inter-
ested in the one-step synthesis of carbonyl-containing
heterocycles by carbonylation reactions, which provide
convenient and efficient approaches to potentially useful
carbonyl-containing heterocyclic compounds.25 One of us
reported that the palladium-catalyzed cyclocarbonylation
of o-iodoanilines with heterocumulenes afforded quinazo-
lin-4(3H)-ones.26 Herein, we report a novel and efficient
protocol to synthesize various 2-heteroquinazolin-4(3H)-
ones under mild conditions.
entry
[Pd]
base
PCO (psi) solvent yieldb (%)
1
2
3
4
5
6
7
8
Pd2(dba)3 Cs2CO3
Pd2(dba)3 Et3N
Pd2(dba)3 K2CO3
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
500
500
500
500
500
500
300
100
100
100
100
100
THF
THF
THF
THF
THF
PhMe
PhMe
PhMe
THF
THF
THF
THF
92
85
88
93
86
92
91
87
93
90c
86d
92e
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
Initially, the reaction of N-(2-iodophenyl)-N′-phenyl-
carbodiimide (1a)27 with piperidine (2a) was chosen as
the model reaction to optimize the reaction conditions
which included the catalyst, solvent, and base under car-
bon monoxide pressure (Table 1). Using Pd2(dba)3·
CHCl3-PPh3-Cs2CO3 as the catalytic system, the desired
product 3a was obtained in 92% yield (entry 1). Lower
product yields were obtained when Et3N (86%) or K2CO3
(88%) was used instead of Cs2CO3 (entries 2 and 3).
However, using the Pd(OAc)2-K2CO3 catalytic system
under the same reaction conditions gave 3a in 93%
isolated yield (entry 4). The reaction system was not
sensitive to the solvent and the pressure of carbon
monoxide (entries 4 and 6-9). Even at 100 psi of CO,
the desired product 3a was isolated in 93% yield (entry
9). The product yields decreased slightly as the amount
of palladium was reduced (entries 9-11). On the basis of
the results, the Pd(OAc)2 (4%)-K2CO3-CO (100 psi)
catalytic system was chosen as the optimal reaction
conditions (entry 9). It should be noted that using 2.0 equiv
of piperidine as the nucleophile afforded no byproducts
(entry 12), which indicated that the intramolecular car-
bonylation is very regioselective to form quinazolin-4(3H)-
one (3a).
a All reactions were carried out using 0.5 mmol of 1a, 0.55 mmol of
2a, [Pd]/PPh3/1a ) 4:8:100, 2.0 equiv of base, 6 mL of solvent, 80 °C,
15 h. b Isolated yield. c [Pd]/PPh3/1a ) 3:6:100. d [Pd]/PPh3/1a ) 2:4:100.
e 1. 0 mmol of 2a.
methyl group which is closest to the nitrogen atom has
no major effect on the reaction (entries 1-3).
In a similar fashion, reaction of carbodiimide (1a) with
diethylamine (2h) and diisopropylamine (2i) afforded the
corresponding quinazolin-4(3H)-ones in 93% and 91%
yields, respectively (entries 11 and 15). Using N-methyl-
aniline instead of aliphatic amines as the N-nucleophile,
the analogous product (3p) was obtained in 55% yield.
The electronic effect of the substituents on the aromatic
rings of carbodiimides (1) was also investigated. This
cyclization process tolerates both electron-donating (p-
MeO) and electron-withdrawing (p-Cl) groups on the
aromatic rings of carbodiimides (entries 6-9 and 11-14).
(19) Fray, M. J.; Mathias, J. P.; Nichols, C. L.; Po-Ba, Y. M.; Snow, H.
Tetrahedron Lett. 2006, 47, 6365.
(20) (a) Ding, M.-W.; Zeng, G.-P.; Wu, T.-J. Synth. Commun. 2000,
30, 1599. (b) Makino, S.; Okuzumi, T.; Tsuji, T.; Nakanishi, E. J. Comb.
Chem. 2003, 5, 756.
(21) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem. Int. Ed.
2009, 48, 348. (b) Huang, X.; Yang, H.; Fu, H.; Qiao, R.; Zhao, Y. Synthesis
2009, 16, 2679.
Using the optimized reaction conditions, the scope of
this reaction was extended to a variety of carbodiimides
and nucleophiles, and the results are summarized in Table
2. The reaction of N-(2-iodophenyl)-N′-phenyldicarbodi-
imide (1a) with piperidine (2a), 2-methylpiperidine (2b),
and 2,6-dimethylpiperidine (2c) gave the products in 93%,
94%, and 92% yields, respectively, indicating that the
(22) (a) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002,
67, 5831. (b) Kundu, B.; Partani, P.; Duggineni, S.; Sawant, D. J. Comb.
Chem. 2005, 7, 909.
(23) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69.
(24) Zeghida, W.; Debray, J.; Chierici, S.; Dumy, P.; Demeunynck, M.
J. Org. Chem. 2008, 73, 2473.
(25) (a) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 4903. (b) Vieira, T. O.;
Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008, 10, 4899. (c) Chouhan,
G.; Alper, H. Org. Lett. 2008, 10, 4987. (d) Zheng, Z.; Alper, H. Org. Lett.
2008, 10, 829. (e) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10,
5281.
(15) Somers, F.; Ouedraogo, R.; Antoine, M.-H.; de Tullio, P.; Becker,
B.; Fontaine, J.; Damas, J.; Dupont, L.; Rigo, B.; Delarge, J.; Lebrun, P.;
Pirotte, B. J. Med. Chem. 2001, 44, 2575.
(26) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773.
(27) The carbodiimdes 1a-d were efficiently prepared by the known
metathesis reactions of corresponding isocyanates with N-(2-iodophenyl)-
triphenyliminophosphorane, and the latter was synthesized in 98% yield
by the reaction of 2-iodoaniline with PPh3 in precence of Et3N and
C2Cl6.
(16) Wilson, L. J. Org. Lett. 2001, 3, 585.
(17) Hess, H.-J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968, 11,
130.
(18) (a) Yang, R.-Y.; Kaplan, A. Tetrahedron Lett. 2000, 41, 7005. (b)
Gopalsamy, A.; Yang, H. J. Comb. Chem. 2000, 2, 378.
Org. Lett., Vol. 12, No. 6, 2010
1189

Table 2. One-Step Synthesis of 2-Heteroquinozalin-4(3H)-onesa
a All reactions were carried out using 0.5 mmol of 1, 0.55 mmol of 2, [Pd]/PPh3/1 ) 4:8:100, 2.0 equiv of base, 6 mL of solvent, under 100 psi
of CO, 80 °C, for 15 h. b Isolated yield.
The yields of products 3i and 3n decreased slightly due
to the 1-naphthyl group on the nitrogen atom of the
carbodiimide (1d), which affects steric hindrance in the
first-step addition reaction. When phenol and 2-naphthol
were used as nucleophiles, the desired products were
formed in reasonable yields (entries 18-21). When
thiophenol was used as the nucleophile, product (3v) was
not formed. A possible reason why 3v was not formed is
because the palladium active species is blocked by the in
situ fromed intermediate. For the same reason, reaction
of carbodiimide 1a with pyrazole did not afford the
corresponding product.
The cyclocarbonylation reaction appears to proceed through
in situ generation of isomeric guanidines (4a and 4b, Scheme
1) from an intermolecular addition of the nucleophile (2) to
o-iodoarylcarbodiimides (1). Oxidative addition of the inter-
mediate 4 to the in situ generated palladium(0) species28 leads
to complex 5, which is followed by the formation of aroyl-
palladium iodide complex 6 via carbon monoxide insertion into
the aryl carbon-palladium bond of 5. Thus, base-catalyzed
intramolecular cyclization of 6 gives a palladacycle 7,
(28) MaCrindle, R.; Ferguson, G.; Arsenault, G. J.; McAlees, A. J.;
Stephenson, D. K. J. Chem. Res., Synop. 1984, 360.
1190
Org. Lett., Vol. 12, No. 6, 2010

which undergoes reductive elimination affording the quinazolin-
4(3H)-one 3 with regeneration of the palladium(0) species.
Scheme 1. Possible Reaction Mechanism
In summary, we have demonstrated a simple and efficient
strategy for the one-step synthesis of potentially important
2-heteroquinazolin-4(3H)-one derivatives by palladium-cata-
lyzed intermolecular addition and intramolecular cyclocarbo-
nylation cascade reaction protocol. A large number of 2-ami-
noquinazolin-4(3H)-ones and 2-phenoxyquinazolin-4(3H)-ones
were obtained in good to excellent yields.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
support of this research.
Supporting Information Available: Experimental proce-
1
dures, spectroscopic data, and copies of H and 13C NMR
spectra for the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902924X
Org. Lett., Vol. 12, No. 6, 2010
1191