Palladium-catalyzed one-step synthesis of isoindole-1,3-diones by carbonylative cyclization of o-halobenzoates and primary amines

Article abstract of DOI:10.1021/jo800936h

(Chemical Equation Presented) The palladium-catalyzed aminocarbonylation of o-halobenzoates produces 2-substituted isoindole-1,3-diones in good yields. This methodology provides a good one-step approach to this important class of heterocycles and tolerates a variety of functional groups, including methoxy, alcohol, ketone, and nitro groups.

Full text of DOI:10.1021/jo800936h

Palladium-Catalyzed One-Step Synthesis of Isoindole-1,3-diones by
Carbonylative Cyclization of o-Halobenzoates and Primary Amines
Shilpa A. Worlikar and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed April 30, 2008
The palladium-catalyzed aminocarbonylation of o-halobenzoates produces 2-substituted isoindole-1,3-
diones in good yields. This methodology provides a good one-step approach to this important class of
heterocycles and tolerates a variety of functional groups, including methoxy, alcohol, ketone, and nitro
groups.
Introduction
against the growth of human cancer cultured cells.10 Some
isoindole-1,3-dione derivatives are active in reducing the growth
of colon adenocarcinoma, osteosarcoma, and KB nasopharynx.11
Isoindole-1,3-diones are also known for their antiviral,12 anti-
inflammatory,13 Chk1 inhibitory,14 sedative,15 bactericidal, and
fungicidal16 properties. They also find important applications
as synthetic intermediates in the dye,17 pesticide,18 and poly-
mer19 industries.
Due to their biological, pharmaceutical, and industrial im-
portance, the synthesis of isoindole-1,3-diones has received
considerable attention in the literature. The most common
method reported in the literature for the synthesis of isoindole-
1,3-diones involves the reaction of a phthalic acid anhydride
Isoindole-1,3-diones, commonly known as phthalimides, are
key structural units of a variety of biologically important
compounds, many of which are pharmaceutically significant.
The drug thalidomide [2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-
dione], was originally developed as a sedative, an alternative
to barbiturates, but was withdrawn from the market in the 1960s,
because it displayed teratogenic properties.1 Recently, interest
in this compound has increased, because of its interesting anti-
inflammatory and antiangiogenic2 properties and its possible use
in the treatment of acquired immunodeficiency syndrome
(AIDS) caused by the human immunodeficiency virus (HIV),3,4
leprosy,5 and other diseases.6-8 The isoindole-1,3-dione N-
phthaloyl-L-glutamic acid is a selective glutamate receptor
agonist,9 while 1,8-naphthalimide is known for its cytotoxicity
(10) Hall, I. H.; Chapman, J. M.; Wong, O. T. Anti-Cancer Drugs 1994, 5,
75.
(11) Hall, I. H.; Wong, O. T.; Scovill, J. P. Biomed. Pharmacother. 1995,
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2001, 1528.
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Process Res. DeV. 1999, 3, 139.
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V.; Kaplan, G. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5974.
(4) Figg, W. D.; Raje, S.; Bauer, K. S.; Tompkins, A.; Venzon, D.; Bergan,
R.; Chen, A.; Hamilton, M.; Pluda, J.; Reed, E. J. Pharm. Sci. 1999, 88, 121.
(5) Atra, E.; Sato, E. I. Clin. Exp. Rheumatol. 1993, 11, 487.
(6) Ochonisky, S.; Verroust, J.; Bastuji-Garin, S.; Gherardi, R.; Revuz, J.
Arch. Dermatol. 1994, 130, 66.
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Kobayashi, Y.; Kato, F.; Kato, M.; Hashimoto, Y. J. Med. Chem. 1997, 40,
2858.
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G. M.; Snyder, D. S.; Stein, A. S.; Smith, E. P.; Molina, A.; Stepan, D. E.;
Kashyap, A.; Planas, I.; Spielberger, R.; Somlo, G.; Margolin, K.; Zwingenberger,
K.; Wilsman, K.; Negrin, R. S.; Long, G. D.; Niland, J. C.; Blume, K. G.; Forman,
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Chemother. 2003, 14, 139.
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Leonce, S.; Golsteyn, R. M.; Pfeiffer, B.; Prudhomme, M. Eur. J. Pharmacol.
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1990, 40, 1073.
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Andreeva, E. I.; Kukalenko, S. S. Kimijas Serija 1983, 6, 739.
(17) (a) Kemmochi, H.; Kanda, T.; Hotta, H.; Akamatsu, T. Dyeing fibers
with reactive dyes. Jpn. Tokkyo Koho JP 45029233 19700924, 1970. (b)
Steffanut, P.; Klein, C.; Graciet, J. C.; Luecke, L.; Winter, M. A. Uses of
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10.1021/jo800936h CCC: $40.75
Published on Web 08/20/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7175–7180 7175

Worlikar and Larock
and a primary amine.20 Syntheses of isoindole-1,3-diones have
also been reported with other approaches, including the am-
moxidation of o-xylenes by vanadium/titanium/oxygen catalysis
and subsequent oxidation of intermediate o-tolunitriles,21 mi-
crowave irradiation of N-hydroxymethylphthalimides with aryl
amines or phthalic anhydrides with urea, the microwave-induced
cleavage of solid-supported o-amidoesters,22 the palladium-
catalyzed carbonylation of o-haloamides, and a combination of
carbonylation and nitrogenation of o-halophenyl alkyl ketones.23
1,3-diones from o-bromobenzamides and CO,30 while Perry et
al. have prepared isoindole-1,3-diones from o-dihaloarenes in
the presence of CO, a primary amine, a catalytic amount of
palladium, and a base in dipolar aprotic solvents.31 However,
these routes either limit the groups that can be introduced on
the nitrogen of the isoindole-1,3-dione, because one first needs
to prepare the starting benzamides, or they require high pressures
of CO and specialized equipment, like pressure reactors. To
the best of our knowledge, the synthesis of N-substituted
isoindole-1,3-diones by the palladium-catalyzed aminocarbo-
nylation of simple o-halobenzoates has not been reported
previously. We report herein a number of examples of such a
one-step synthesis of this important class of heterocycles in good
yields using readily available starting materials.
The development of new methods for the simultaneous
formation of both carbon-carbon and carbon-heteroatom bonds
in a single step is quite advantageous to the organic chemist,
since it allows the assembly of complex molecules from simple
precursors. Transition metal-catalyzed reactions, especially
palladium-catalyzed processes, which involve the insertion of
unsaturated molecules, such as carbon monoxide, alkynes, and
alkenes, into a carbon-metal bond are an important step toward
this goal. In the past couple of years, we have developed in our
laboratories the palladium-catalyzed annulation of dienes and
internal alkynes by aromatic and vinylic halides bearing a
neighboring nucleophilic substituent as an efficient way to
synthesize a wide variety of carbocyclic and heterocyclic
compounds,24 including indoles, isoquinolines,25 benzofurans,
benzopyrans, isocoumarins,26 R-pyrones,26 indenones, naph-
thalenes, and phenanthrenes. CO insertion into the aryl-palladium
bond to form an acylpalladium complex is a ubiquitous process
in organic synthesis.27 The resulting acylpalladium complexes
react with various nucleophiles to give aryl carbonyl compounds.
When nitrogen acts as the nucleophile, the process is aminocar-
bonylation,28 which is an important method for the synthesis
of amides. While many examples of such processes have been
reported to form acyclic amides,29 relatively few have
been reported for the formation of cyclic amides. Ban et al.
have reported the palladium-catalyzed formation of isoindole-
Results and Discussion
The focus of our early studies was the palladium-catalyzed
aminocarbonylation of o-halobenzoates to give 2-substituted
isoindole-1,3-diones in good yields. Methyl 2-iodobenzoate (1a)
was used as a model system for optimization of the reaction
conditions with benzylamine (2a) as the amine. Early in this
work, the reaction was run with 0.5 mmol of 1a, 1.2 equiv of
benzylamine, 5 mol % of Pd(OAc)2, 10 mol % of PPh3, and 2
equiv of Cs2CO3 as a base in 6 mL of toluene at 95 °C under
1 atm of CO to obtain a 75% isolated yield of the desired
2-benzylisoindole-1,3-dione (3a) (eq 1).
The yield of the desired product 3a slightly increased to 76%
when the amount of palladium catalyst and the triphenylphos-
phine ligand was increased to 10 and 20 mol %, respectively
(Table 1, entry 1). No desired product was obtained when the
reaction was carried out in the absence of the ligand PPh3.
Noting the importance of the ligand in the reaction, various
ligands were screened with the aim of increasing the yield
of the imide. More sterically hindered triarylphosphines gave
significantly lower yields (entries 2 and 3). More basic
tricyclohexylphosphine gave a high yield (entry 4), but PEt3
gave a poor yield (entry 5). Heterocyclic tri(2-furyl)phosphine
afforded a modest yield of imide (entry 6). Diphenyl-2-
pyridylphosphine improved the yield dramatically to 84%
(entry 7), but other bulky monodentate ligands gave only
modest yields (entries 8-11).
Since the yields of imide are highly dependent on the ligands
employed, we decided to screen bidentate ligands under similar
reaction conditions. BINAP and dppf gave poor yields, while
Tol-BINAP and Xantphos gave 71% and 78% yields, respec-
tively, which were close to those obtained with the parent
triphenylphosphine (entries 12-15). The ligands dppm and dppe
reduced the yields drastically to 34% and 5%, respectively
(entries 16 and 17), while dppp improved the yield to 91% (entry
18). With further elongation of the carbon chain of the bidentate
ligand, the yields decreased. Thus, 1,4-bis(diphenylphosphi-
no)butane and 1,5-bis(diphenylphosphino)pentane gave 81% and
64% yields, respectively (entries 19 and 20).
(20) (a) Kang, H. B.; Quan, L. G.; Lee, J. K.; Kim, S. Process for preparation
of chiral glycidylphthalimide in highly optical purity. PCT Int. Appl. WO
2007132990, 2007. (b) Han, T.; Chen, C. F. J. Org. Chem. 2007, 72, 7287. (c)
Sani, M.; Fossati, G.; Huguenot, F.; Zanda, M. Angew. Chem., Int. Ed. 2007,
46, 3526. (d) Abdel-Aziz, A. A.-M. Eur. J. Med. Chem. 2007, 42, 614. (e)
Kobrakov, K. I.; Zubkova, N. S.; Stankevich, G. S.; Shestakova, Y. S.; Stroganov,
V. S.; Adrov, O. I. Fibre Chem. 2006, 38, 183. (f) Sahu, S. K.; Mishra, S. K.;
Mandal, S.; Choudhury, P.; Sutradhar, S.; Misro, P. K. J. Ind. Chem. Soc. 2006,
83, 832. (g) Barooah, N.; Sarma, R. J.; Baruah, J. B. Eur. J. Inorg. Chem. 2006,
15, 2942. (h) Lima, L. M.; Castro, P.; Machado, A. L.; Fraga, C. A. M.; Lugnier,
C.; de Moraes, V. L. G.; Barreiro, E. J. Bioorg. Med. Chem. 2002, 10, 3067. (i)
Hellwinkel, D.; Lenz, R.; Laemmerzahl, F. Tetrahedron 1983, 39, 2073. (j)
Sheehan, J. C.; Chapman, D. W.; Roth, R. W. J. Am. Chem. Soc. 1952, 74,
3822. (k) Sheehan, J. C.; Frank, V. S. J. Am. Chem. Soc. 1949, 71, 1856. (l)
Billman, J. H.; Parker, E. E. J. Am. Chem. Soc. 1943, 65, 761.
(21) (a) Centi, G.; Pinelli, D.; Trifiro, F. Gazz. Chim. Ital. 1989, 119, 133.
(b) Cavani, F.; Parrinello, F.; Trifiro, F. J. Mol. Catal. 1987, 43, 117.
(22) (a) Sena, V. L. M.; Srivastava, R. M.; Simone, C. A. d.; Goncalves,
S. M. d. C.; Silva, R. O.; Pereira, M. A. J. Braz. Chem. Soc. 2007, 18, 1224. (b)
Mogilaiah, K.; Reddy, G. R. Ind. J. Chem., Sect. B 2004, 43B, 882. (c) Martin,
B.; Sekljic, H.; Chassaing, C. Org. Lett. 2003, 5, 1851. (d) Vidal, T.; Petit, A.;
Loupy, A.; Gedye, R. N. Tetrahedron 2000, 56, 5473.
(23) (a) Uozumi, Y.; Kawasaki, N.; Mori, E.; Mori, M.; Shibasaki, M. J. Am.
Chem. Soc. 1989, 111, 3725. (b) Wu, X.; Mahalingam, A. K.; Wan, Y.; Alterman,
M. Tetrahedron Lett. 2004, 45, 4635.
(24) (a) Larock, R. C. J. Organomet. Chem. 1999, 576, 111. (b) Larock,
R. C. Pure Appl. Chem. 1999, 71, 1435.
(25) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
(26) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(27) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; John Wiley & Sons, Ltd.: Chichester, U.K., 1995. (b) Colquhoun,
H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis of
Carbonyl Compounds; Plenum Press: New York and London, 1991.
(28) Minatti, A.; Muniz, K. Chem. Soc. ReV. 2007, 36, 1142.
(29) (a) Takacs, E.; Varga, C.; Skoda-Foeldes, R.; Kollar, L. Tetrahedron
Lett. 2007, 48, 2453. (b) Karimi, F.; Langstroem, B. J. Chem. Soc., Perkin Trans.
1 2002, 2111. (c) Morera, E.; Ortar, G. Tetrahedron Lett. 1998, 39, 2835.
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7176 J. Org. Chem. Vol. 73, No. 18, 2008

One-Step Synthesis of Isoindole-1,3-dione
TABLE 1. Optimization of the Palladium-Catalyzed
Carbonylative Cyclization of Methyl 2-Iodobenzoate and
Benzylamine, Using Various Phosphine Ligands (eq 1)a
TABLE 2. Optimization of the Palladium-Catalyzed
Carbonylative Cyclization of Methyl 2-Iodobenzoate and
Benzylamine with dppp as the Ligand (eq 1)a
entry
ligand (20 mol %)
% isolated yield
Pd(OAc)2
entry (mol %) (mol %) (equiv)
dppp
Cs2CO3
time temp
(h)
%
solvent
(°C) yieldb
1
2
3
4
5
6
7
8
9
10
PPh3
P(o-tolyl)3
76
14
38
82
39
66
84
31
53
66
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
5
2
2
5
5
20
20
20
20
20
20
20
10
10
4
10
20
10
10
10
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
3.0
2.0
CH3CN
CH3OH
DMSO
DMF
24
24
24
24
75
60
95
95
95
60
80
95
95
95
95
95
95
95
95
0
0
tri(2-methoxyphenyl)phosphine
tricyclohexylphosphine
triethylphosphine
∼5c
∼5c
10
42
79
76
89
78
49
53
73
90
78
tri(2-furyl)phosphine
CH3NO2 24
diphenyl-2-pyridylphosphine
(2-biphenyl)di-tert-butylphosphine
tri-tert-butylphosphine
THF
24
24
24
24
24
24
24
24
24
12
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
2-dicyclohexylphosphino-2′,6′-
dimethoxybiphenyl (S-PHOS)
2-dicyclohexylphosphino-2′-
(N,N-dimethylamino)biphenyl (DavePhos)
(()-2,2′-bis(diphenylphosphino)-1,
1′-binaphthalene (BINAP)
2,2′-bis(di-p-tolylphosphino)-1,
1′-binaphthalene (Tol-BINAP)
4,5-bis(diphenylphosphino)-9,
9-dimethylxanthene (Xantphos)
1,1′-bis(diphenylphosphino)
ferrocene (dppf)
1,1-bis(diphenylphosphino)
methane (dppm)
1,2-bis(diphenylphosphino)
ethane (dppe)
1,3-bis(diphenylphosphino)
propane (dppp)
1,4-bis(diphenylphosphino)
butane
9
10
11
12
13
14
15
11
12
13
14
15
16
17
18
19
20
64
19
71
78
17
34
∼5
91
81
64
5
5
a Representative procedure: methyl 2-iodobenzoate (0.5 mmol),
benzylamine (1.2 equiv), Pd(OAc)2, dppp, Cs2CO3, and the solvent (6
mL) were placed in a 4 dram vial. The vial was sealed and flushed with
CO. The reaction was then stirred at 95 °C for the indicated time with a
CO balloon on top of the vial. b Isolated yields. c GC yields.
cyclization are 0.5 mmol of 1a, 1.2 equiv of 2a, 5 mol % of
Pd(OAc)2, 10 mol % of dppp, and 2 equiv of Cs2CO3 in 6 mL
of toluene at 95 °C under 1 atm of CO for 24 h.
After obtaining our best reaction conditions for aminocar-
bonylation, we examined the scope of this reaction on various
substrates. The o-halo esters 1a, 1b, 1d, and 1e were obtained
from commercial sources, while 1c was prepared according to
a literature procedure.32 The model system under our optimized
conditions with benzylamine gave an 89% isolated yield of the
desired product 3a (Table 3, entry 1). Compound 3a was
obtained in a slightly lower 85% yield, when the reaction was
carried out on a larger scale (entry 2). A reaction with methyl
2-bromobenzoate (1b) gave a reduced yield of 55% (entry 3).
This is probably due to the fact that the oxidative insertion of
Pd(0) into a C-Br bond is less facile than that into a C-I bond.
For similar reasons, when two electron-donating methoxy groups
were placed on the o-iodobenzoate, the yield was reduced to
46% (entry 4). Electron donation by methoxy substituents is
known to slow oxidative addition to aromatic halides. The
limited electron-withdrawing effect of a bromo-substituent para
to the iodo group in the benzoate ester 1d sharply lowered the
yield to 51% when compared with that of the parent system
(entry 5). The presence of a strong electron-withdrawing NO2
group para to the bromo group in the benzoate ester 1e increased
the yield from 55% to 71% (compare entries 3 and 6).
We have also examined the reactivity of an ester bearing a
vinylic halide. When methyl 2-bromocyclohept-1-enecarboxylate
was subjected to aminocarbonylation under our optimized
conditions with use of benzyl amine, the desired product was
obtained in only a poor yield (<15%).
We also studied the scope of the reaction using various
amines. The reaction of 1a with phenethylamine (2b) gave the
desired product 3e in an 81% yield (entry 7). The more hindered
aliphatic amine cyclohexyl amine gave an excellent 92% yield
of the desired product 3f (entry 8). The lower boiling alcohol-
containing amine 2d gave a poor yield of 25% (entry 9), but
the yield was increased to 41% when the reaction was carried
1,5-bis(diphenylphosphino)
pentane
a Representative procedure: methyl 2-iodobenzoate (0.5 mmol),
benzylamine (1.2 equiv), Pd(OAc)2 (10 mol %), ligand (20 mol %),
Cs2CO3 (2 equiv), and toluene (6 mL) were placed in a 4 dram vial.
The vial was sealed and flushed with CO. The reaction was then stirred
at 95 °C for 24 h with a CO balloon on top of the vial.
With dppp as the ligand of choice, the reaction was carried
out in various solvents. Reactions in the low boiling polar
solvents CH3CN and CH3OH had to be carried out at lower
temperatures and they did not give the desired product (Table
2, entries 1 and 2). The higher boiling polar solvents DMSO
and DMF gave extremely poor yields at 95 °C (entries 3 and
4). Nitromethane gave a 10% yield of the desired product at
95 °C (entry 5), while THF gave a 42% yield of the desired
product at the lower temperature of 60 °C (entry 6). Reaction
in toluene as the solvent at the lower temperature of 80 °C
reduced the yield to 79% (entry 7). A reduction in the amount
of phosphine ligand to 10 mol % reduced the yield to 76% (entry
8). When the reaction was carried out with 10 mol % of the
dppp ligand and 5 mol % of the palladium catalyst, the yield
increased to 89% (entry 9), indicating that the ratio 1:2 of
palladium catalyst to phosphine ligand works better than a ratio
of 1:1. Maintaining the ratio of the palladium catalyst and
phosphine at 1:2, but reducing the amount of palladium to 2
mol %, the yield dropped to 78% (entry 10). An excess of the
ligand reduced the yield further to 49% (entry 11). Excess ligand
with 5 mol % of palladium also gave a poor yield of 53% (entry
12). The base Cs2CO3 proved to be very important for the
reaction as the yield was reduced to 73% when using only 1.5
equiv of the base (compare entries 9 and 13). Increasing the
amount of the base afforded no significant increase in the yield
(entry 14). A reduced reaction time gave a lower yield of 78%
(entry 15). Thus, our optimized conditions for the carbonylative
(32) Carme Pampin, M.; Estevez, J. C.; Estevez, R. J.; Maestro, M.; Castedo,
L. Tetrahedron 2003, 59, 7231.
J. Org. Chem. Vol. 73, No. 18, 2008 7177

Worlikar and Larock
TABLE 3. Synthesis of Isoindole-1,3-diones by the Aminocarbonylative Cyclization of o-Halobenzoate Estersa
a Representative procedure: o-halobenzoate ester 1 (0.5 mmol), amine 2 (1.2 equiv), Pd(OAc)2 (5 mol %), dppp (10 mol %), Cs2CO3 (2 equiv), and
toluene (6 mL) were placed in a round-bottomed flask. The flask was sealed and flushed with CO. The reaction was stirred at 95 °C for 24 h with a CO
balloon on top of the flask. b The reaction was scaled up to 2 mmol of halo ester. c The reaction was carried out with 10 equiv of amine.
out with an excess of the amine (entry 10). The reaction with
benzyl amine bearing an electron-donating p-methoxy group
gave a 68% yield of the desired product 3h (entry 11). Oxygen-
and sulfur-containing heterocyclic amines worked well under
our optimized conditions (entries 12-14). The nitrogen-contain-
ing heterocyclic amines N-(3-aminopropyl)morpholine and N-(3-
aminopropyl)imidazole failed to give the desired products under
our reaction conditions for reasons not presently understood.
After screening the above-mentioned aliphatic amines, we
decided to study the scope of the reaction with aromatic amines.
Amines 2i and 2j with electron-donating methyl groups gave
79% and 77% yields of the desired products 3l and 3m,
respectively (entries 15 and 16). 4-Aminophenol failed to give
the desired product apparently due to solubility problems. An
electron-withdrawing fluoro group did not have much of an
effect on the yield (entry 17). But the presence of a bromo or
iodo substituent at the para position of the aniline gave
somewhat lower yields of 68% and 57%, respectively (entries
18 and 19). It is possible that the desired products are perhaps
undergoing further reaction with palladium. The presence of
an electron-withdrawing ketone group on the amine drastically
reduced the yield of the desired product 3q to 25% (entry 20).
7178 J. Org. Chem. Vol. 73, No. 18, 2008

One-Step Synthesis of Isoindole-1,3-dione
SCHEME 1
V, which results in formation of the final isoindole-1,3-dione
VI by loss of a methoxy group. The insertion of CO in the
Pd(II) intermediate I to form the acylpalladium complex II is
a reversible process. We believe that the desired o-amidocar-
boxylate III is obtained in the presence of a more nucleophilic
amine by trapping the acylpalladium intermediate II. Amines
with strong electron-withdrawing groups, due to their poor
nucleophilicity, fail to trap the acylpalladium complex II to form
the corresponding o-amidocarboxylate III, but apparently they
react with the Pd(II) intermediate I to form the corresponding
amino ester (refer to Table 3, entries 21 and 22). Amino ester
products 3t to 3x (refer to Table 3, entries 23 to 27) are
apparently formed by more rapid reaction of the intermediate
arylpalladium intermediate I directly with the more hindered
amine rather than the acylpalladium intermediate II.
An alternative mechanism might involve initial conversion
of the ester to an amide and subsequent carbonylation and
cyclization as suggested by Wu.23 However, we have never
observed such o-halobenzamides as side products in any
reactions, even those run only partially to completion, which
seems to disfavor such a mechanism.
The isoindole-1,3-diones obtained by this simple palladium-
catalyzed aminocarbonylation process appear to be promising
intermediates for the preparation of more highly substituted
isoindole-1,3-diones. To expand the scope of our chemistry, we
subjected isoindole-1,3-dione 3c to a palladium/copper-catalyzed
Sonogashira reaction to obtain an excellent 86% isolated yield
of the substituted isoindole-1,3-dione 4 (Scheme 2). The Suzuki
coupling of 3c with p-methoxyphenylboronic acid gave a 51%
yield of the desired product 5.
The presence of strong electron-withdrawing NO2 and CF3
groups on the amine failed to give the desired cyclic products.
Instead these substrates formed 3r and 3s in 62% and 61%
yields, respectively (entries 21 and 22). Amine 2q also failed
to form the desired cyclic product (entry 23). To establish if
the reason this substrate failed to carbonylate and cyclize was
its slightly electron-deficient nature or its steric bulk, we studied
the aminocarbonylation of 1-naphthylamine (2r). To our
surprise, this substrate also failed to carbonylate and cyclize.
Instead we obtained ester 3u in a 55% isolated yield (entry 24).
We have also examined the reaction of amine 2s to confirm
that sterically hindered aromatic amines fail to give the desired
cyclic isoindole-1,3-diones under our reaction conditions. Again
an amino ester was obtained (entry 25). Even the simple mono
ortho-substituted amines 2t and 2u failed to give the desired
cyclic products, but afforded decent yields of the corresponding
amino esters (entries 26 and 27).
We believe that the mechanism of these carbonylative
cyclizations involves a two-step process: (1) palladium-catalyzed
formation of the corresponding o-amidocarboxylates, followed
by (2) base-catalyzed cyclization of these o-amidocarboxylates
to the cyclic isoindole-1,3-diones (Scheme 1). Palladium
undergoes oxidative insertion into the carbon-halogen bond
to give Pd(II) intermediate I, which then inserts CO to form
the acylpalladium complex II. The acylpalladium complex then
reacts with the amine to give the o-amidocarboxylate III. This
species then participates in a base-catalyzed cyclization. The
base extracts the amide proton to give anionic nitrogen species
IV, which attacks the ester carbonyl to afford cyclic intermediate
Conclusions
A range of isoindole-1,3-diones have been obtained by the
one-step palladium-catalyzed aminocarbonylation of simple o-ha-
lobenzoate ester starting materials that are readily available or
easily synthesized. The reaction conditions are mild and the
products are easy to isolate in good yields. A halogen moiety
can also be introduced into the products, which provides a useful
handle for further functionalization of the resulting heterocycles.
The Sonogashira and Suzuki products 4 and 5 have been
obtained in good to excellent yields in this manner. Our
methodology tolerates a number of functional groups, including
alcohol, ketone, methoxy, and nitro groups, and works well for
both aliphatic and aromatic primary amines. The methodology
provides a very convenient one-step approach to this important
class of heterocycles.
Experimental Section
General Procedure for the Palladium-Catalyzed Carbonyla-
tive Cyclization of o-Halobenzoates and Primary Amines. To a
SCHEME 2
J. Org. Chem. Vol. 73, No. 18, 2008 7179

Worlikar and Larock
solution of 0.5 mmol of the o-halobenzoate in PhCH3 (6 mL) was
added the primary amine (1.2 equiv), Pd(OAc)2 (5 mol %), dppp
(10 mol %), and Cs2CO3 (2.0 equiv). The flask was then sealed
and flushed with CO. A balloon filled with CO was placed on the
top of the flask and the reaction was stirred at 95 °C for 24 h.
After the reaction was over, the resulting solution was diluted with
EtOAc (10 mL) and filtered through celite. The celite was
thoroughly washed with EtOAc (15 mL) to ensure complete
extraction of the crude product. The combined EtOAc fractions
were dried over anhydrous Na2SO4 and concentrated under vacuum
to yield the crude product, which was purified by flash chroma-
tography on silica gel with use of ethyl acetate/hexanes as the eluent.
Solid products were further recrystallized from ethanol.
128.9, 129.4, 129.7, 130.9, 132.0, 132.5, 136.3, 137.0, 167.5, 167.6;
IR (neat, cm-1) 2924, 1708, 1627, 1436, 1359, 1106, 955; HRMS
m/z 337.11077 (calcd C23H15NO2, 337.11028).
2-Benzyl-5-(4-methoxyphenyl)isoindoline-1,3-dione (5). This com-
pound was prepared by the following procedure. To 63 mg of
2-benzyl-5-bromoisoindoline-1,3-dione (3c) (0.2 mmol) was added
46 mg (1.5 equiv) of 4-methoxyphenylboronic acid, PdCl2 (5 mol
%), KHCO3 (1.5 equiv) and 4:1 DMF/H2O (5 mL). The reaction
mixture was stirred at 80 °C for 12 h. The resulting solution was
cooled to room temperature, diluted with H2O (5 mL), and extracted
with ethyl acetate (3 × 15 mL). The combined ethyl acetate
fractions were washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuum to yield the crude product, which
was further purified by flash chromatography on silica gel by using
hexanes/ethyl acetate as the eluent to obtain the desired compound
5 in a 51% yield as a white solid: mp 167-168 °C; 1H NMR (400
MHz, CDCl3) δ 3.86 (s, 3H), 4.86 (s, 2H), 7.01 (d, J ) 8.8 Hz,
2H), 7.24-7.34 (m, 3H), 7.44 (d, J ) 7.2 Hz, 2H), 7.57 (d, J )
8.6 Hz, 2H), 7.85 (d, J ) 0.8 Hz, 2H), 8.01 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 41.8, 55.6, 114.8, 121.5, 123.9, 127.9, 128.6,
128.7, 128.8, 129.9, 131.5, 132.0, 133.2, 136.6, 147.2, 160.5, 168.2,
168.3; IR (neat, cm-1) 2916, 1774, 1700, 1596, 1250, 1033; HRMS
m/z 343.12126 (calcd C22H17NO3, 343.12084).
2-Benzylisoindoline-1,3-dione (3a). This compound was obtained
as a white solid: mp 119-121 °C (lit.22d mp 118-120 °C); H
1
NMR (400 MHz, CDCl3) δ 4.84 (s, 2H), 7.25-7.33 (m, 3H), 7.43
(d, J ) 7.1 Hz, 2H), 7.67-7.70 (m, 2H), 7.82-7.84 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 41.7, 115.4, 123.4, 127.9, 128.7, 132.2,
134.1, 136.5, 168.1; IR (neat, cm-1) 2926, 2253, 1770, 1712, 1394,
909; HRMS m/z 237.07927 (calcd C15H11NO2, 237.07898).
2-Benzyl-5-(phenylethynyl)isoindoline-1,3-dione (4). This com-
pound was prepared by the following procedure. To a solution of
63 mg of 2-benzyl-5-bromoisoindoline-1,3-dione (3c) (0.2 mmol)
in Et3N (2 mL) was added PdCl2(PPh3)2 (2 mol %) and CuI (1.5
mol %), and the mixture was stirred for 10 min under Ar. A solution
of 0.3 mmol of phenylacetylene dissolved in 0.5 mL of Et3N was
then added dropwise and the reaction mixture was allowed to stir
at 60 °C for 24 h. The reaction was monitored by TLC. After the
reaction was over, the resulting solution was diluted with H2O (5
mL) and extracted with ethyl acetate (3 × 10 mL). The combined
ethyl acetate fractions were dried over anhydrous Na2SO4 and
concentrated under vacuum to yield the crude product, which was
purified by flash chromatography on silica gel by using hexanes/
ethyl acetate as the eluent to obtain the desired compound 4 in an
86% yield as a pale brown solid: mp 166-167 °C; 1H NMR (400
MHz, CDCl3) δ 4.84 (s, 2H), 7.25-7.44 (m, 8H), 7.54-7.56 (m,
2H), 7.81 (d, J ) 0.6 Hz, 2H), 7.95 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 41.9, 87.9, 94.0, 122.2, 123.5, 126.3, 128.0, 128.7, 128.8,
Acknowledgment. We thank the National Institute of General
Medical Sciences (GM070620 and GM079593) and the National
Institutes of Health Kansas University Center of Excellence for
Chemical Methodologies and Library Development (P50
GM069663) for support of this research, and Johnson Matthey,
Inc., and Kawaken Fine Chemicals Co., Ltd., for donations of
palladium catalysts.
Supporting Information Available: General experimental
procedures and spectral data for all previously unreported
starting materials and products. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800936H
7180 J. Org. Chem. Vol. 73, No. 18, 2008