Palladium-catalyzed cyclocarbonylation of o-lodoanilines with Imidoyl Chlorides to produce quinazolin-4(3H)-ones

Article abstract of DOI:10.1021/ol7029454

A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields by the palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides and carbon monoxide. The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones.

Full text of DOI:10.1021/ol7029454

ORGANIC
LETTERS
2008
Vol. 10, No. 5
829-832
Palladium-Catalyzed Cyclocarbonylation
of o-Iodoanilines with Imidoyl Chlorides
to Produce Quinazolin-4(3H)-ones
Zhaoyan Zheng and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
howard.alper@uottawa.ca
Received December 5, 2007
ABSTRACT
A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63−91% yields by the palladium-catalyzed cyclocarbonylation of o-iodoanilines
with imidoyl chlorides and carbon monoxide. The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative
addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones.
Quinazolin-4(3H)-ones are an important class of fused
heterocyclic compounds known as the core structural skeleton
in a variety of natural products and synthetic drugs.1 They
exhibit a wide range of biological activities such as anti-
cancer,2 antidiabetic,3 antiinflammatory,4 antimicrobial,5 an-
ticonvulsant,6 antibacterial,7 antimalarial,8 antiallergy,9 and
analgesic10 properties. There are a number of synthetic
methods available for the preparation of quinazolin-4(3H)-
ones.11 The most common synthetic route involves the
amidation of 2-aminobenzoic acid or its derivatives, i.e.,
2-aminobenzonitrile, 2-aminobenzoate, and 2-arylnitrilium
salts, followed by oxidative ring closure.12,13 Other synthetic
pathways include the cyclization of anthranilamides with
aldehydes,14 and with ketones or acid chlorides under acidic
or basic conditions.15 These traditional methods often suffer
from low yields, multistep reactions, or harsh reaction
conditions. Recently, several new synthetic methods were
reported including solid-phase synthesis,16 microwave ir-
radiation,17 and ionic liquid as a medium.18 A few examples
(1) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.; Thou,
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Chem. Nat. Comput. 1997, 33, 221. (c) Michael, J. P. Nat. Prod. Rep. 2004,
21, 650. (d) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
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Borror, A. L. J. Am. Chem. Soc. 1960, 82, 3152. (e) Bogentoft, C.; Kronberg,
L.; Danielessan, B. Acta Pharm. Suec. 1969, 6, 485.
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Boll. Chim. Farm. 1995, 134, 503. (b) Ibrahim, S. S.; Abdel-Halim, A. M.;
Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. J. Chem. Res., Synop. 1997,
154.
(6) (a) Mannscherck, A.; Koller, H.; Stuhler, G.; Davis, M. A.; Traber,
J. Eur. J. Med. Chem. 1984, 19, 381. (b) Hori, M.; Iemura, R.; Hara, H.;
Ozaki, A.; Sukamoto, T.; Ohtaka, H. Chem. Pharm. Bull. 1990, 38, 1286.
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Ecker, D. J. J. Med. Chem. 1999, 42, 4705.
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A. F.; Baruth, H. W.; Yaremko, B. J. Med. Chem. 1983, 26, 420.
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Med. Chem. 1985, 28, 568. (b) Segarra, V.; Crespo, M. I.; Pujol, F.; Belata,
J.; Domenech, T.; Miralpix, M.; Palacios, J. M.; Castro, A. Bioorg. Med.
Chem. Lett. 1998, 8, 505. (c) Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga,
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10.1021/ol7029454 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

of transition metal-catalyzed routes to quinazolin-4(3H)-ones
have appeared in the literature, including the use of PdCl2-
(PPh3)2 and SnCl2 catalysis.19 Quinazolin-4(3H)-ones were
also synthesized employing dicobalt octacarbonyl,20 ruthe-
nium or platinum complexes,21 and titanium reagents22 as
catalysts. One of us has developed a palladium-catalyzed
reaction of o-iodoanilines with heterocumulenes to afford
quinazolin-4(3H)-ones derivatives.23
2-Substituted-4H-3,1-benzoxazin-4-ones derivatives were
isolated from the Pd-catalyzed cyclocarbonylation of o-
iodoanilines with acid chlorides and carbon monoxide.24
Herein, we reported an effective palladium-catalyzed three-
component reaction of o-iodoanilines, imidoyl chlorides, and
carbon monoxide affording substituted quinazolin-4(3H)-ones
bearing a variety of functional groups.
of Pd(OAc)2 and 0.07 mmol of 1,4-bis(diphenylphosphino)-
butane (dppb), or 1,4-bis (diphenylphosphino)propane (dppp)
and 2.1 mmol of Et3N in 10 mL of THF, at 110 °C for 48
h afforded trace amounts of 2,3-diphenyl-quinazoline-4(3H)-
one (3a) (Table 1, entries 1 and 2). Performing the same
reaction using 0.135 mmol of triphenylphosphine (PPh3)
instead of bidentate phosphine ligands resulted in the
isolation of 3a in 74% yield (Table 1, entry 3). When
employing the bulky and electron-rich monophosphine Xphos
(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), the
yield of product 3a was reduced to 46% (Table 1, entry 4).
Thus, the choice of ligand is important for this transforma-
tion. The use of Pd(PPh3)4 instead of Pd(OAc)2 combined
with PPh3 gave a similar result (Table 1, entry 5). Pd2(dba)3
(tris(dibenzylideneacetone)-dipalladium(0)-chloroform ad-
duct) can be used for this reaction, but it is not as effective
as Pd(OAc)2 (Table 1, entries 6 and 7). We selected Pd-
(OAc)2 and PPh3 to use as the catalytic system for the
reaction of a variety of imidoyl chlorides with o-iodoanilines
and CO.
The reaction of o-iodoaniline 1a with N-phenylbenzimi-
doyl chloride 2a was chosen as a model system (Table 1).
Table 1. Optimization of the Reaction Conditions for the
Reaction of o-Iodoaniline with N-(Phenyl)benzimidoyl Chloridea
Other reaction parameters were also examined. Shorter
reaction times, lower pressures of carbon monoxide, or lower
temperatures, resulted in incomplete consumption of starting
materials (Table 1, entries 8-10). A slight increase in the
yield was observed by increasing the reaction temperature
to 140 °C (Table 1, entry 11).
The scope of the reaction was explored by treating a
variety of imidoyl chlorides with o-iodoanilines under the
optimized reaction conditions. The results are summarized
in Table 2.
time
(h)
temp
(oC)
CO
(psi)
yield
(%)b
entry
catalyst system
1
2
3
4
5
6
7
8
9
Pd(OAc)2/dppb
Pd(OAc)2/dppp
Pd(OAc)2/PPh3
Pd(OAc)2/x-phos
Pd(PPh3)4
Pd2(dba)3/PPh3
Pd2(dba)3/x-phos
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
48
48
48
48
48
48
48
24
48
48
48
110
110
110
110
110
110
110
110
110
80
500
500
500
500
500
500
500
500
300
500
500
trace
trace
74
46
72
63
40
48
62
Reaction of 1a with an imidoyl chloride containing
4-methoxyphenyl (2b) or 4-methylphenyl (2c-e) substituents
gave 2,3-disubstituted quinazolin-4(3H)-ones 3b-e in 70-
91% yields (Table 2, entries 2-5), while the use of imidoyl
chlorides having a 4-chlorophenyl group afforded the
products 3f and 3g in 67% and 65% yields, respectively
(Table 2, entries 6 and 7). The reaction occurs more slowly
when an imidoyl chloride containing two 4-chlorophenyl
groups was used as the reactant with 3h formed in 63% yield
after 72 h (Table 2, entry 8). An electron-donating group
increases the reactivity of the imidoyl chloride to give a better
product yield. Treatment of 1a with imidoyl chlorides bearing
alkyl groups also afforded the expected products 3i-k in
81-90% yields (Table 2, entries 9-11). The molecular
structure of 3i was confirmed by an X-ray crystallographic
determination (Figure 1).
10
11
54
75
140
a Reaction conditions: o-iodoaniline 1a (1.0 mmol), N-(phenyl) benz-
imidoyl chloride 2a (1.0 mmol), Pd cat. (0.03 mmol), PPh3 or Xphos (0.135
mmol), or dppp or dppb, (0.07mmol), Et3N (2.1 mmol), CO 300 or 500
psi, THF (10 mL). b Isolated yield.
Initially, treatment of 1a (1.0 mmol) and 2a (1.0 mmol) at
500 psi of carbon monoxide, in the presence of 0.03 mmol
The annulation method could be extended to an imidoyl
chloride bearing a furan substituent. It was noteworthy that,
under the standard conditions, the expected quinazoline-
4(3H)-one 3l was obtained in 13% yield, while amidine 4
was isolated as a major product in 55% yield (Scheme 1).
The structure of compound 4 was confirmed by X-ray
diffraction (Figure 2). A beneficial effect of increasing the
reaction temperature on the reaction was observed. The yield
of 3l increased to 87% when the temperature was raised to
(16) (a) Gouilleux, L.; Fehrentz, J. A.; Winternitz, F.; Martinez, J.
Tetrahedron Lett. 1996, 37, 7031. (b) Buckman, B. O.; Mohan, R.
Tetrahedron Lett. 1996, 37, 4439.
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McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241. (b) Montazeri,
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Tetrahedron Lett. 2006, 47, 3561.
(19) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J. Orga-
nomet. Chem. 1995, 494, 229.
(20) Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816.
(21) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1993, 58,
310.
(22) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.; Wang, X. S;
Hu, H. W. Synth. Commun. 2004, 34, 1759.
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830
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Synthesis of Quinazolin-4(3H)-ones via
Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines 1
with Imidoyl Chlorides 2a
Figure 1. Perspective view of compound 3i.
150 °C (Table 2, entry 12). A more extensive investigation
of the reaction showed that amidine 4 could be obtained
Scheme 1
nearly quantitatively, in the presence of Et3N without a Pd
catalyst. Further treatment of the amidine 4 could give 3l in
good yield using the Pd(OAc)2/PPh3 catalytic system at
150 °C (Scheme 1). This result suggests that the cyclocar-
bonylation reaction may proceed via formation of amidine
4.
Figure 2. Perspective view of compound 4.
The palladium-catalyzed carbonylation reaction was also
successfully extended to o-iodoanilines possessing various
substituents to afford 2,3,6-trisubstitued quinazolin-4(3H)-
ones in 66-74% yields (Table 2, entries 13-15).
A possible reaction mechanism for the formation of
quinazolin-4(3H)-ones 3 is outlined in Scheme 2. Reaction
of the imidoyl chloride with the amino group of the
a o-Iodoaniline 1 (1.0 mmol), imidoyl chloride 2 (1.0 mmol), Pd(OAc)2
(0.03 mmol), PPh3(0.135 mmol), Et3N (2.1 mmol), CO 500 psi, THF (10
mL), 110 °C, 48 h. b Isolated yield. c 72 h. d 150 °C.
Org. Lett., Vol. 10, No. 5, 2008
831

monoxide insertion into the aryl carbon-palladium bond of
5 affords the aroylpalladium iodide complex 6. Base-
catalyzed intramolecular cyclization of 6 gives a palladacycle
7 which undergoes reductive elimination affording quinazo-
lin-4(3H)-one 3 with regeneration of palladium(0).
Scheme 2. Proposed Reaction Mechanism
In conclusion, we have demonstrated an effective approach
for the one-step synthesis of quinazolin-4-(3H)-ones from
readily available imidoyl chlorides and o-iodoanilines by a
palladium-catalyzed three-component process. The method
tolerates a range of functional groups, and substituted
quinazoline-4(3H)-ones were formed in 63-91% yields.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
for support of this research.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra and the crystal structure analysis of 3i and 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
o-iodoaniline in the presence of base, following a process
of NH tautomerism, could give the amidine intermediate 4.
Oxidative addition of 4 to the in situ generated palladium-
(0) species25 leads to a palladium complex 5. Carbon
OL7029454
(25) MaCrindle, R.; Ferguson, G.; Arsenault, G. J.; McAlees, A. J.;
Stephenson, D. K. J. Chem. Res., Synop. 1984, 360.
832
Org. Lett., Vol. 10, No. 5, 2008