Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines with Heterocumulenes: Regioselective Preparation of 4(3H)-Quinazolinone Derivatives

Article abstract of DOI:10.1021/jo991922r

A catalyst system comprising palladium acetate - bidentate phosphine is effective for the cyclocarbonylation of o-iodoanilines with heterocumulenes at 70-100°C for 12-24 h to give the corresponding 4(3H)-quinazolinone derivatives in good yields. Utilizing o-iodoaniline with isocyanates, carbodiimides, and ketenimines for the reaction, 2,4-(1H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones were obtained, respectively. The nature of the substrates including the electrophilicity of the carbon center of the carbodiimide, and the stability of the ketenimine, influence the product yields of this reaction. Urea-type intermediates are believed to be generated first in situ from the reaction of o-iodoanilines with heterocumulenes, followed by palladium-catalyzed carbonylation and cyclization to yield the products.

Full text of DOI:10.1021/jo991922r

J . Org. Chem. 2000, 65, 2773-2777
2773
P a lla d iu m -Ca ta lyzed Cycloca r bon yla tion of o-Iod oa n ilin es w ith
Heter ocu m u len es: Regioselective P r ep a r a tion of
4(3H)-Qu in a zolin on e Der iva tives
Chitchamai Larksarp and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received December 16, 1999
A catalyst system comprising palladium acetate-bidentate phosphine is effective for the cyclocar-
bonylation of o-iodoanilines with heterocumulenes at 70-100 °C for 12-24 h to give the
corresponding 4(3H)-quinazolinone derivatives in good yields. Utilizing o-iodoaniline with isocy-
anates, carbodiimides, and ketenimines for the reaction, 2,4-(1H,3H)-quinazolinediones, 2-amino-
4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones were obtained, respectively. The nature of
the substrates including the electrophilicity of the carbon center of the carbodiimide, and the stability
of the ketenimine, influence the product yields of this reaction. Urea-type intermediates are believed
to be generated first in situ from the reaction of o-iodoanilines with heterocumulenes, followed by
palladium-catalyzed carbonylation and cyclization to yield the products.
In tr od u ction
compounds. The main synthetic routes to such com-
pounds utilize 2-aminobenzoic acid or its derivatives,11
2-aminobenzonitrile,12 isatoic anhydride,13 2-carbomethoxy-
phenyl isocyanate,14 N-arylnitrilium salts,15 and 4H-3,1-
benzoxazinones.16 Recently, the solid-phase synthesis of
2,4-(1H, 3H)-quinazolinediones have been reported.17 The
direct ortho substitution of N-(tert-butoxycarbonyl)aniline
by a lithium reagent was also described.18 Transition
metals were utilized in the preparation of these com-
pounds; e.g., Akazome et al.19 described the use of
ruthenium and platinum complexes for the catalytic
reduction N-heterocyclization of N-(2-nitrobenzoyl)a-
mides under carbon monoxide pressure. A 2,4-(1H,3H)-
quinazolinedione was synthesized by the reaction of
azobenzene with a stoichiometric amount of dicobalt
octacarbonyl under CO pressure at 230 °C.20 The reaction
of aromatic 2-carbamoylaniline with carbon monoxide
4(3H)-Quinazolinone derivatives are of considerable
interest because of their pharmacological properties;1 e.g.,
protein tyrosine kinase inhibitor,2 cholecystokinin inhibi-
tor,3 antimicrobial,4 anticonvulsant,5 sedative and hy-
potensive,6 antidepressant and antiinflammatory,7 as
well as antiallergy.8 In addition, more than 40 alkaloids
comprised of a 4(3H)-quinazolinone moiety were isolated
from natural sources.9 Some of these have interesting
biological properties such as antimalarial activity and
biofungicide10 and diuretic properties. There are a num-
ber of methods described for the preparation of the
(1) (a) Armarego, W. L. F. Quinazolines; Brown, D. J ., Ed.; J ohn
Wiley & Sons, Ltd: London, 1967. (b) Ellis, G. P. Synthesis of Fused
Heterocycles; J ohn Wiley & Sons Ltd.: Chichester, 1987; Vol. 47. (c)
Hermecz, I.; Ko¨ko¨si, J .; Poda´nyi, B.; Sza´sz, G. Heterocycles 1994, 37,
903.
(2) Wagner, G.; Wunderlich, I. Pharmazie 1978, 33, 15.
(3) (a) Yu, M. J .; McCowan, J . R.; Mason, N. R.; Deeter, J . B.; G.,
M. L. J . Med. Chem. 1992, 35, 2534. (b) Padia, J . K.; Field, M.; Hinton,
J .; Meecham, K.; Pablo, J .; Pinnock, R.; Roth, B. C.; Singh, L.; Suma-
Chauhan, N.; Trivedi, B. K.; Webdale, L. J . Med. Chem. 1998, 41, 1042.
(4) (a) Habib, O. M.; Moawad, E. B.; Girges, M. M.; El-Shafei, A. M.
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.
(5) (a) Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.;
Ohtaka, H. Chem. Pharm. Bull. 1990, 38, 1286. (b) Wenzel, D. G. J .
Am. Pharm. Assoc. 1955, 44, 550.
(6) (a) Hayao, S.; Havera, H. J .; Strycker, W. G.; Leipzig, T. J .; Kulp,
R. A.; Hartzler, H. E. J . Med. Chem. 1965, 8, 807. (b) Havera, H. J . J .
Med. Chem. 1979, 22, 1548.
(7) Lowe, J . A., III; Archer, R. L.; Chapin, D. S.; Cheng, J . B.;
Helweg, D.; J ohnson, J . L.; Koe, B. K.; Lebel, L. A.; Moore, P. F.;
Nielsen, J . A.; Russo, L. L.; Shirley, J . T. J . Med. Chem. 1991, 34, 624.
(8) LeMahieu, R. A.; Carson, M.; Nason, W. C.; Parrish, D. R.;
Welton, A. F.; Baruth, H. W.; Yaremko, B. J . Med. Chem. 1983, 26,
420.
(11) (a) Lalezari, I.; Stein, C. A. J . Heterocycl. Chem. 1984, 21, 5.
(b) Kornet, M. J .; Varia, T.; Beaven, W. J . Heterocycl. Chem. 1984, 21,
1533. (c) Maillard, J .; Vincent, M.; Benard, M.; J olly, R.; Morin, R.;
Menillet, C. Chim. Ther. 1968, Mar-Apr, 100. (d) Papadopoulos, E.
P.; Torres, C. D. J . Heterocycl. Chem. 1982, 19, 269. (e) Dean, W. D.;
Papadopoulos, E. P. J . Heterocycl. Chem. 1982, 19, 1117. (f) Mayoral,
J .; Melendez, E.; Mercha´n, F.; Sanchez, J . Synthesis 1981, 962. (g)
Couture, A.; Cornet, H.; Grandclaudon, P. Synthesis 1991, 1009. (h)
Paster, G.; Blanchard, C.; Montginoul, C.; Torreilles, E.; Giral, L. Bull.
Soc. Chim. Fr. 1974, 1331. (i) Herlinger, H. Angew. Chem., Int. Ed.
Engl. 1964, 3, 378. (j) Garin, J .; Melendez, E.; Mercha´n, F. L.; Tejero,
T.; Villarroya, E. Synthesis 1963, 406.
(12) (a) Taylor, E. C.; Shvo, Y. J . Org. Chem. 1968, 33, 1719. (b)
Papadopoulos, E. P. J . Heterocycl. Chem. 1981, 18, 515. (c) Papadopou-
los, E. P. J . Heterocycl. Chem. 1980, 17, 1553.
(13) Minami, T.; Ogata, M.; Hirao, I. Synthesis 1982, 231.
(14) Canonne, P.; Aksssira, M.; Dahdouh, A.; Kasmi, H.; Boumzebra,
M. Heterocycles 1993, 36, 1305.
(15) Al-Talib, M.; J ochims, J . C.; Hamed, A.; Wang, Q.; Ismail, A.
E. Synthesis 1992, 697.
(9) (a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry. The Structure, Reaction, synthesis and uses of Heterocyclic
Compounds. Part 2B; Pergamon Press: New York, 1984; Vol. 3. (b)
Pelletier, S. W. Alkaloids: Chemical and Biological Prospective; J ohn
Wiley & Sons Ltd.: New York, 1983; Vol. 1.
(10) (a) Tsantrizos, Y. S.; Xu, X.-J . Can. J . Chem. 1993, 71, 1362.
(b) Wang, H.; Genesan, A. J . Org. Chem. 1998, 63, 2432. (c) He, F.;
Snider, B. B. J . Org. Chem. 1999, 64, 1397. (d) Sugimori, T.; Okawa,
T.; Egushi, S.; Kakehi, A.; Yashima, E.; Okamoto, Y. Tetrahedron 1998,
54, 7997.
(16) (a) Errede, L. A.; Oien, H. T.; Yarian, D. R. J . Org. Chem. 1977,
42, 12. (b) Doleschall, G.; Lempert, K. J . Monatsh. Chem. 1964, 95,
1068.
(17) (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.
(18) Muchowski, J . M.; Venuti, M. C. J . Org. Chem. 1980, 45, 4798.
(19) Akazome, M.; Kondo, T.; Watanabe, Y. J . Org. Chem. 1993, 58,
310.
(20) Murahashi, S.; Horiie, S. J . Am. Chem. Soc. 1956, 78, 4816.
10.1021/jo991922r CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/04/2000

2774 J . Org. Chem., Vol. 65, No. 9, 2000
Larksarp and Alper
Ta ble 1. Deter m in a tion of th e Effect of Ba se on th e
P a lla d iu m -Ca ta lyzed Cycloca r bon yla tion Rea ction of 1a
w ith 2a a
and a stoichiometric or excess amount of selenium in the
presence of N-methylpyrrolidine afforded 2,4-(1H,3H)-
quinazolinediones in fine yields.21 A combination of PdCl2-
(PPh3)2 and SnCl2 was reported for the intermolecular
reductive N-heterocyclization of 2-nitrobenzamide to give
the corresponding quinazolines.22
Palladium-catalyzed carbonylation reactions can serve
as effective tools for the synthesis of heterocyclic-contain-
ing carbonyl moieties. The palladium-catalyzed carbo-
nylation of aniline derivatives afforded 4H-3,1-benzox-
azinones.23 We recently examined the utility of palladium
catalysts for the preparation of benzo[e]-1,3-oxazin-4-one
derivatives from o-iodophenols with heterocumulenes and
carbon monoxide (eq 1).24
entry
base (1.5 mmol)
isolated yieldb (%)
1
2
3
4
(iPr)2NEt
Et3N
K2CO3
Na2CO3
72
63
75
60
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), base (1.5
Palladium-catalyzed carbonylation of a mixture of
o-iodoanilines and lactams resulted in 3-52% yields.25
Encouraged by the usefulness of 4(3H)-quinazolinone
derivatives, we decided to explore the preparation of the
title compounds by palladium catalyzed cyclocarbonyla-
tion reactions of o-iodoanilines with heterocumulenes.
We now wish to report a convenient method for the
synthesis of 4(3H)-quinazolinone derivatives by treat-
ment of o-iodoanilines with heterocumulenes such as
isocyanates, carbodiimides, and ketenimines in the pres-
ence of a palladium catalyst under carbon monoxide
pressure.
mmol), Pd(OAc)2 (0.02 mmol), dppb (0.02 mmol), THF (5 mL), 300
psi CO, 80 °C, 12 h. Isolated yield by silica gel column chroma-
tography.
b
and 2a (2 mmol) in the presence of 0.02 mmol each of
Pd(OAc)2 and dppb under 300 psi CO in THF, and the
results are summarized in Table 1. Potassium carbonate
(entry 2) gave results similar to those obtained by using
diisopropylethylamine (entries 1 and 3), while slightly
lower yields of 3a resulted from the reaction using
triethylamine and sodium carbonate as the base (entries
2 and 4).
Similar yields of 3a were observed in the reaction of
1a with 2a and K2CO3 under 300 psi CO, in the presence
of 2 mol % Pd(OAc)2 in THF, using PCy3 (71%) compared
to the same reaction employing dppb as the added ligand.
Higher yields of 3a were obtained from the reaction
employing PPh3 (85%) or 1,1′-bis(diphenylphosphino)
ferrocene (dppf) (88%) as the ligand. It is worth noting
that the use of dppb and dppf in some cases gave the
same isolated product yield. Therefore, dppb and dppf
were chosen to use as added ligands in this study.
A variety of 3-substituted 2,4-(1H,3H)-quinazolinedi-
ones (3) can be prepared in moderate to good yields by
the reaction of o-iodoanilines (1) with isocyanates (2)
under carbon monoxide pressure in the presence of 2 mol
% Pd(OAc)2-bidentate phosphine (dppb or dppf) catalyst
and 1.5 mol % K2CO3 in THF at 70-80 °C for 12 h (see
Table 2 for results). Two equivalents of isocyanates to
o-iodoaniline was used since lower product yields may
be obtained if 1 equiv is used.26 Isocyanates containing
either electron-withdrawing or electron-donating groups
on the aromatic ring react with o-iodoaniline to form
3-substituted 2,4-(1H,3H)-quinazolinediones (3) in good
yields. o-Iodoaniline (1a ), p-chloro-o-iodoaniline (1b), and
p-methyl-o-iodoaniline (1c) were converted to 3 in this
reaction. However, none of the desired product was
isolated, using o-iodoaniline with a hydroxyl group
Resu lts a n d Discu ssion
Treatment of o-iodoaniline, 1a (1 mmol), and p-chlo-
rophenylisocyanate, 2a (2 mmol),26 with 300 psi CO in
benzene, in the presence of 0.02 mmol of Pd(OAc)2, 0.02
mmol of 1,4-bis(diphenylphosphino)butane (dppb), and (i-
Pr)2NEt for 12 h at 80 °C afforded 3-(p-chlorophenyl)-
2,4-(1H,3H)-quinazolinedione (3a ) in 44% isolated yield
(eq 2). Performing the same reaction but using THF
instead of benzene resulted in the isolation of 3a in 72%
yield. Lower product yields were obtained when using
DMF (56%) or DME (54%) as the solvent.
Using the Pd2(dba)3‚CHCl3-dppb catalytic system un-
der the same reaction conditions in THF furnished 3a
in 72% isolated yield. The effect of base used in the
reaction was investigated in the reaction of 1a (1 mmol)
(21) Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. Bull. Chem. Soc.
J pn. 1987, 60, 1793.
(22) Akazome, M.; Yamamoto, J .; Kondo, T.; Watanabe, Y. J .
Organomet. Chem. 1995, 494, 229.
(23) (a) Larock, R. C.; Fellows, C. A. J . Org. Chem. 1980, 45, 363.
(b) Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1996, 997. (c) Larksarp,
C.; Alper, H. Organic Lett. 1999, 1, 1619.
(25) Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Heterocycles 1985,
23, 2803.
(26) As reported in ref 24, using 2 mol equiv of isocyanate in the
reaction with 1 mol of o-iodophenol gave better product yields than
performing the reaction using a 1:1 ratio, possibly because dimerization
or trimerization of the isocyanate may occur in the presence of base.
See: (a) Hofmann, A. W. Ber 1860, 3, 761. Snape, H. L. J . Chem. Soc.
1886, 49, 254. (b) Hofmann, A. W. Ber 1885, 18, 764.
(24) Larksarp, C.; Alper, H. J . Org. Chem. 1999, 64, 9194.

Pd-Catalyzed Cyclocarbonylation of o-Iodoanilines
J . Org. Chem., Vol. 65, No. 9, 2000 2775
Ta ble 2. Cycloca r bon yla tion Rea ction s of o-Iod oa n ilin e
(1) w ith Isocya n a tes (2) Ca ta lyzed by
Ta ble 3. 2-Am in o-(3H)-qu in a zolin -4-on es (5) fr om th e
P a lla d iu m -Ca ta lyzed Rea ction of o-Iod oa n ilin es (1) w ith
Ca r bod iim id es (4) a n d Ca r bon Mon oxid ea
P d (OAc)2-Bid en ta te P h osp h in e Com p lexesa
R′NdCdO, 2, R′ ) product isolated yieldb (%)
entry
1
R′′NdCdNR′′, 4, R′′ ) product isolated yieldb (%)
entry
1
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1a
1c
1d
1a
1c
1a
1c
p-ClC6H4, 2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
88d
68d
72c
68d
80d
90c
0d
1
2
3
4
5
6
7
8
9
1
p-ClC6H4, 4a
5a
5b
5c
5d
5e
5f
5g
5h
5i
75
67
55
90
64
64
78
2a
2a
1b
1c
1d
1a
1b
1d
1e
1a
1a
1a
1b
4a
4a
4a
p-BrC6H4, 2b
p-CH3OC6H4, 2c
C6H5, 4b
4b
2c
2c
C6H5, 2d
2d
4b
4b
87d
89d
83c
77c
74
p-BrC6H4, 4c
p-CH3C6H4, 4d
C6H11, 4e
iC3H7, 4f
73 (61)c
10
11
p-CH3C6H4, 2e
2e
3j
3k
10
11
12
0
0
0
a
Reaction conditions: 1/2/K2CO3/Pd(OAc)2/bidentate phosphine
ligand, 1:2:1.5:0.02:0.02 mmol in 5 mL of THF, 70-80 °C, 300 psi
a
Reaction conditions: refer to the Experimental Section for the
b
CO, 12 h. Isolated yield by silica gel column chromatography.
general procedure for the cyclocarbonylation of o-iodoanilines (1)
c dppb was used in this reaction. dppf was used in this reaction.
d
b
with carbodiimides (4). The products (5) were purified by silica
gel column chromatography. c The yield in parentheses was
obtained from the reaction using dppb as the ligand.
substituted at the C-4 of the phenyl ring (1d ) in reaction
with p-methoxyphenylisocyanate (2c) (entry 7). The latter
may be due to competitive reactions of the hydroxyl and
amine groups with the isocyanate, or to differences in
the electrophilicity of the central carbon in isocyanates
vs carbodiimides.
Sch em e 1
2-Amino-4(3H)-quinazolinones (5) can be prepared in
moderate to good yields by utilizing the developed method
with o-iodoaniline (1, 1 mmol), carbodiimide (4, 1 mmol),
and 300 psi carbon monoxide, catalyzed by 2 mol % Pd-
(OAc)2 and dppf in the presence of 1.5 mmol K2CO3 in
THF at 100 °C for 24 h (Table 3).
Using o-iodoanilines with electron-withdrawing or
electron-donating groups substituted on the phenyl ring
does not have any effect on the selectivity of the reaction.
The reaction tolerates nitrile as well as hydroxyl func-
tional groups of o-iodoanilines (entries 4, 7, and 8). In
contrast, using carbodiimides containing an electron-
donating substituent on nitrogen, such as 4d -f, gave
recovered starting material (entries 10-12).
A possible mechanism for the palladium-catalyzed
cyclocarbonylation reaction of o-iodoanilines (1) with
isocyanates (2) or carbodiimides (4) is outlined in Scheme
1. Initial reaction of o-iodoaniline with an isocyanate or
carbodiimide can give a urea (6a ) or a guanidine (6b).
Oxidative addition of the palladium catalyst to the C-I
bond of 6a or 6b would afford 7. Carbonyl insertion into
the latter and possible coordination of the NHR′′ moiety
to the metal would afford the aroylpalladium intermedi-
ate 8. Reductive elimination would result in the forma-
tion of 3-substituted-4(3H)-quinazolinone derivatives.
When carbodiimides are used as reactants, 4(3H)-
quinazolinone-2-imine intermediates 9 may be generated
that, on rearrangement, would afford the more stable
2-amino-4(3H)-quinazolinones 5 (eq 3). Evidence for this
process came from the reaction of N-methyl-o-iodoaniline
(1f) with bis(p-chlorophenyl)carbodiimide (4a ), which
under the same reaction conditions afforded 1-methyl-
3-(p-chlorophenyl)-N-(p-chlorophenyl)-4(3H)-quinazolinone-
2-imine (9j) in 61% isolated yield (eq 4). Rearrangement
did not occur here, since such a process would require a
methyl rather than a hydrogen transfer.
2-Alkyl-4(3H)-quinazolinone derivatives can be syn-
thesized by using ketenimines rather than carbodiimides
in the reaction with o-iodoanilines and CO. Treatment
of o-iodoaniline (1) with an equimolar amount of a
ketenimine (10) at 300 psi CO, in the presence of 2 mol
% each of Pd(OAc)2 and dppf, gave 2-alkyl-4(3H)-
quinazolinones (11) in good to excellent isolated yields
(see Table 4 for results). Ketenimines 10a -c are quite

2776 J . Org. Chem., Vol. 65, No. 9, 2000
Larksarp and Alper
Ta ble 4. P a lla d iu m -Ca ta lyzed Cycloca r bon yla tion
Sch em e 2
Rea ction s of o-Iod oa n ilin es (1) w ith Keten im in es (10)a
Isolated yieldb
entry
1
1
10
product
(%)
1a PhNdCdC(CH3)(COOEt)
11a
98
10a
2
3
4
5
6
1b
1c
1d
1e
10a
10a
10a
10a
11b
11c
11d
11e
11f
87
99
45
47
72
1a nBuNdCdC(CH3)(COOEt)
10b
7
8
1c
1a
10b
11g
11h
74
95
PhNdCdC(CH3)(COPh)
10c
9
10
11
12
1c
1a
1b
1b
10c
PhNdCdC(COOEt)2
10d
PhNdCdC(Ph)2
10e
11i
11j
11k
95
71
94
0
tuted with aromatic groups, do not react with o-iodo-
anilines (entries 12 and 13).
The palladium-catalyzed cyclocarbonylation reaction of
ketenimines with o-iodoanilines may proceed in a path-
way similar to that of isocyanates and carbodiimides.
There are two conceivable amidine intermediates that
can be formed in situ from the reaction of an o-iodoaniline
with a ketenimine, namely 12 and 13. If 12 is formed,
oxidative addition and carbonyl insertion followed by
coordination of the amine unit to palladium, and subse-
quent reductive elimination would afford 14. Rearrange-
ment of 14 would form the more stable 2-alkyl-4(3H)-
quinazolinone (11). An alternate pathway to 11 may
involve oxidative addition and carbonyl insertion of 13
to give 15 Base-catalyzed intramolecular cyclization of
15 would form 11.
13
1b
p-tolylNdCdC(Ph)2
10f
0
a
Reaction conditions: refer to the Experimental Section for the
general procedure for the cyclocarbonylation of o-iodoanilines (1)
with ketenimines (10). The products (11) were purified by silica
gel column chromatography.
b
In summary, the research reported herein constitutes
simple methods for the synthesis of 2,4(1H,3H)-quinazo-
linediones, 2-amino-4(3H)-quinazolinones, and 2-alkyl-
4(3H)-quinazolinone derivative by palladium-catalyzed
cyclocarbonylation reaction of o-iodoanilines with isocy-
anates, carbodiimides, and ketenimines, respectively.
Exp er im en ta l Section
Gen er a l Met h od s. Pd(OAc)2, phosphine ligands, o-iodo-
aniline (1a ), dicyclohexylcarbodiimide (4e), diisopropylcarbo-
diimide (4f), and isocyanates (2) were purchased from com-
mercial sources and were used as received. Carbodiimides
(4a -d ),27 p-chloro-o-iodoaniline (1b),28 p-methyl-o-iodoaniline
(1c),28 p-hydroxy-o-iodoaniline (1d ),29 p-cyano-o-iodoaniline
(1e),30 N-methyl-o-iodoaniline (1f),31 ketenimines (10a -c,32
stable and can be used in the reaction to obtain high
product yields. However, ketenimine 10d is not stable
in air and should be kept under nitrogen at low temper-
ature at all times. Therefore, freshly prepared 10d gave
better product yields than a sample that was kept for
more than 1 month. For example, 11k was obtained in
94% isolated yield (entry 11) when freshly prepared 10d
was used and in 60% yield using 10d prepared 1 month
earlier. Note that ketenimines, which are fully substi-
(27) Campbell, T. W.; Monagle, J . J .; Foldi, V. J . Am. Chem. Soc.
1962, 84, 3673.
(28) Brewster, R. Q. In Organic Syntheses; Blatt, A. H., Ed.; J ohn
Wiley & Sons: New York, 1943; Collect. Vol. II, p 347.
(29) Kvalnes, D. E. J . Am. Chem. Soc. 1934, 56, 667.
(30) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J .; Cottrell, I. F.; Houghton, P. G. Tetrahedron Lett. 1994,
35, 6981.

Pd-Catalyzed Cyclocarbonylation of o-Iodoanilines
J . Org. Chem., Vol. 65, No. 9, 2000 2777
10d ,33 10e-f 34) and Pd2(dba)3‚CHCl3 were prepared accord-
mixture was stirred in an oil bath at 100 °C for 24 h, cooled,
and filtered. The filtrate was concentrated and then purified
by silica gel column chromatography using a 1:1 mixture of
ethyl acetate/pentane as the eluant. Melting points, IR, NMR,
MS, and analytical data of selected examples of of 5 and 11
are as follows. (See the Supporting Information for all other
examples of 5 and 11.)
35
ing to literature procedures. Organic solvents were dried and
distilled prior to use.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloca r bon yla tion of o-Iod oa n ilin es (1) w ith Isocya n a tes
(2a -e). An autoclave, its glass liner, and a magnetic stirring
bar were dried in an oven and then cooled in a desiccator before
use. The liner was charged with the palladium catalyst (2 mol
%), 1 equiv of bidentate phosphine ligand, and 3 mL of dried
solvent. After the mixture was stirred under nitrogen for 15
min, o-iodoaniline (1, 1 mmol), isocyanate (2, 2 mmol), 1.5
mmol of base, and another 2 mL of solvent were added to the
mixture. The autoclave was then attached to a gauge block
assembly and was flushed three times with CO and pressur-
ized to 300 psi. After 12 h in an oil bath at 70-80 °C, the
autoclave was removed and allowed to cool to room tempera-
ture. The excess gas was discharged and the system disas-
sembled. The reaction mixture was then filtered, and the
filtrate was concentrated and purified by column chromatog-
raphy on silica gel using 1:1 mixture of ethyl acetate/pentane
as the eluant. Melting points, IR, NMR, MS, and analytical
data of selected 2,4-(1H,3H)-quinazolinediones 3 are as follows
(see the Supporting Information for all other examples of 3).
2-(p -Ch lor op h en yla m in o)-3-(p -Ch lor op h en yl)-4(3H )-
qu in a zolin on e (5a ) (R ) H, R′′ ) p-ClC6H4): mp 175-177
°C; IR 1684, 1607 cm-1 1H (CDCl3 200 MHz) δ 5.89 (s (br),
;
1H, NH), 7.22-7.66 (m, 11H), 8.15 (dd, 1H, J ) 7.90, and 1.50
Hz); 13C (CDCl3 75 MHz) δ 118.2, 122.2, 124.0, 125.6, 127.2,
128.9, 129.2, 130.5, 131.1, 132.7, 135.0, 136.2, 136.6, 145.7,
148.1, 162.2; MS (m/e) 380 [M - 2]+, 382 [M]+. Anal. Calcd for
C
20H13Cl2N3O: C, 62.84; H, 3.43; N, 10.99. Found: C, 63.00;
H, 3.45; N, 10.98.
6-Met h yl-2-(p h en yla m in o)-3-p h en yl-4(3H )-q u in a zoli-
n on e (5f) (R ) CH3, R′′ ) C6H5): mp 184-185 °C; IR 1686,
1606 cm-1; 1H (CDCl3 200 MHz) δ 5.98 (s (br), 1H, NH), 7.08-
7.67 (m, 12H), 8.10 (d, 1H, J ) 2.38 Hz); 13C (CDCl3 75 MHz)
δ 110.1, 121.0, 124.3, 126.4, 127.2, 128.9, 130.4, 130.9, 134.2,
135.0, 137.5, 146.5, 147.0, 161.4; MS (m/e) 346 [M - 1]+, 347
[M]+. Anal. Calcd for C20H14ClN3O; C, 69.07; H, 4.06; N, 12.08.
Found: C, 68.75; H, 4.11; N, 12.02.
3-(p-Ch lor oph en yl)-2,4-(1H,3H)-qu in azolin edion e (3a)11j
(R ) H, R′′ ) p-ClC6H4): mp 296-297 °C (lit.11j mp 295-296
2-(1-E t h oxyca r b on ylet h yl)-3-p h en yl-4(3H)-q u in a zoli-
n on e (11a ) (R ) H, R1) C6H5, R2 ) CH3, R3 ) COOEt): mp
1
°C); IR 1725, 1649 cm-1; H (CDCl3 + DMSO-d6, 200 MHz) δ
75-76 °C; IR 1735, 1686 cm-1 1H (CDCl3 200 MHz) δ 1.15
;
6.59-7.10 (m, 7H), 7.45 (d, 1H, J ) 7.94 Hz), 10.99 (s, 1H,
NH); 13C (CDCl3 + DMSO-d6, 75 MHz) δ 113.1, 114.5, 118.7,
121.6, 126.7, 127.4, 128.0, 129.2, 132.8, 134.0, 138.6, 149.3,
161.3; MS (m/e) 272 [M]+.
(m, 3H), 1.50 (m, 3H), 3.58 (m, 1H), 4.08 (m, 2H), 7.20-7.80
(m, 8H), 8.24 (m, 1H); 13C (CDCl3 75 MHz) δ 13.9, 15.7, 61.3,
120.9, 126.9, 126.9, 127.5, 128.2, 129.0, 129.4, 129.9, 134.4,
136.8, 147.3, 154.6, 162.3, 171.0; MS (m/e) 322 [M]+. Anal.
Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.58; H, 5.68; N, 8.65.
3-(p-Meth oxyph en yl)-2,4-(1H,3H)-qu in azolin edion e (3e)
(R ) H, R′′ ) p-CH3OC6H4): mp 293-295 °C (lit.11j mp 297-
299 °C); IR 1735, 1649 cm-1; 1H (CDCl3 + DMSO-d6, 200 MHz)
δ 3.20 (s, 3H), 6.29 (m, 2H), 6.57-6.75 (m, 2H), 7.03-7.12 (m,
3H), 9.30 (s (br), 1H, NH); 13C (CDCl3 + DMSO-d6, 75 MHz) δ
54.1, 112.6, 120.5, 123.4, 127.1, 129.8, 135.3, 148.8, 149.8,
154.3, 158.3; MS (m/e) 268 [M]+. Anal. Calcd for C15H12N2O3:
C, 67.16; H, 4.51; N, 10.44. Found: C, 67.02; H, 4.45; N, 10.45.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloca r b on yla t ion of o-Iod oa n ilin es (1) w it h Ca r b od i-
im id es (4a -f) or w ith Keten im in es (10a -f). The cyclocar-
bonylation reactions of o-iodoanilines with carbodiimides or
ketenimines were performed in the same manner as that for
isocyanates except for the use of 1 equiv of a carbodiimide or
ketenimine in THF. Two mol % of the Pd(OAc)2-ddpf catalyst
system and K2CO3 were used for all reactions. The reaction
2-(1-Eth oxyca r bon yleth yl)-3-n -bu tyl-4(3H)-qu in a zoli-
n on e (11g) (R ) H, R1 ) C4H9, R2 ) CH3, R3 ) COOEt): mp
54-55 °C; IR 1744, 1681 cm-1; 1H (CDCl3 200 MHz) δ 0.95 (t,
3H), 1.17 (t, 3H), 1.43 (m, 2H), 1.63 (m, 5H), 2.42 (s, 3H), 3.92-
4.21 (m, 5H), 7.50 (m, 2H), 8.00 (s, 1H); 13C (CDCl3 75 MHz)
δ 13.6, 14.0, 16.0, 20.1, 21.2, 31.1, 43.6, 44.1, 61.5, 120.3, 125.9,
127.1, 135.4, 136.7, 145.0, 153.8, 162.1, 170.9; MS (m/e) 316
[M]+. Anal. Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85.
Found: C, 68.47; H, 7.66; N, 8.97.
Ack n ow led gm en t. We are grateful to the NSERC
of Canada for support of this research. C.L. is the
recipient of a Chulabhorn Graduate Research Scholar-
ship.
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Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 3a -f,h -k , 5a -i, and 11a -k ; 1H and 13C NMR
spectra of compounds 3b,d , 5g,i, and 11f. This material is
available free of charge via the Internet at http:/pubs.acs.org.
J O991922R