substrates for the model reaction and for optimization of
the reaction conditions. The results are presented in Table
Scheme 1
1
. First, the nature of the neutralizing base plays an
Table 1. Optimization of the Palladium-Catalyzed Dicarbonylation
a
Reaction of 1,2-Dibromobenzene and Allylamine
Phthalimide derivatives have been used extensively in
synthetic chemistry, with a wide range of applications,
particularly in biological chemistry. Some phthalimides
time
(h)
entry
catalyst
Pd(OAc)2
base solvent
CO
A
B
5
display pharmacological activities as anticonvulsants, anti-
1
2
3
4
5
6
7
8
9
Cs CO IL 102 300 psi 24 42%
38%
ND
7%
13%
6%
15%
8%
2
3
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
Cs
2
CO
3
THF
300 psi 24 ND
inflammatories, analgesics, herbicidal and insecticidal
DBU
DBU
DBU
DBU
DBU
IL 102 300 psi 24 70%
IL 102 600 psi 24 54%
IL 102 300 psi 48 65%
IL 102 300 psi 24 27%
IL 102 300 psi 24 80%
IL 102 300 psi 24 Messy
agents. Typically, phthalimide derivatives are synthesized
via the condensation of amines with phthalic anhydride in
refluxing organic solvents. High boiling point solvents such
Pd
2
(dba)
3 2
(PPh )
3
PdCl
2
1
0
as acetic acid, DMF, and dioxane are commonly used.
PdCl (PPh ) TEA
2
3
2
PdCl
2
(PPh
3
)
2
DBU
DBU
DBU
IL 102 1 atm
IL 102 1 atm
THF
24 90%
24 83%
24 ND
trace
trace
ND
Synthesis in solvent-free conditions can be achieved by
refluxing a mixture of phthalic anhydride with the amine or
1
1
0
1
a
Pd(OAc)
Pd(OAc)
2
2
1 atm
1
1
by using a catalyst such as DABCO at room temperature.
There has also been work on using microwave irradiation
Reaction conditions: dibromobenzene (1 mmol), allylamine (1.2 mmol),
Pd catalyst (0.05 mmol), base (2 mmol), IL 102 (2.0 g), 110 °C. All yields
1
2
are isolated yields.
as a heating method. Few publications have appeared
concerning the synthesis of phthalimides by palladium-
catalyzed carbonylation reactions, and the method has
important role in this reaction. Use of the hindered amine
1
3
suffered from a limitation of solvents.
DBU gave the best result in comparison with using Cs
and TEA (Table 1, entries 1, 3, and 8). In PSIL 102,
without any ligand, both Pd(OAc) and PdCl (PPh were
useful in catalyzing the reaction and provided compound
A as the main product while Pd (dba) gave inferior
2 3
CO
Herein we report the first examples of synthesizing the
phthalimide derivatives by the palladium-catalyzed double
carbonylation reaction of o-dihaloarenes and allylamines in
PSILs, which can tolerate a wide array of functional groups
and afford products in good to excellent yields (Scheme 2).
2
2
3 2
)
2
3
selectivity and yields (Table 1, entries 3, 6, and 7). We
also found that higher CO pressure or longer reaction times
did not benefit the reaction. The double carbonylation
reaction of o-dibromobenzene in PSIL 102 proceeded even
more efficiently under 1 atm CO and afforded 83% yield
Scheme 2
of A with Pd(OAc)
2
as the catalyst without any added
as the catalyst, the yield of A
ligand. With PdCl (PPh )
2
3 2
was 90% (Table 1, entries 9 and 10). In this study, the
phosphonium salt ionic liquid also showed better efficiency
for the reaction when compared with THF. By using
To improve the reaction selectivity for compound A,
Pd(OAc) as the catalyst but no added ligand, there was
2
1
,2-dibromobenzene and allylamine were chosen as the
no reaction in THF (Table 1, entries 2 and 11).
A variety of PSILs were also screened for the carbonylation
reaction of 1,2-dibromobenzene and allylamine (Table 2). The
reactions were conducted under 1 atm of CO, 110 °C, with
(
(
5) Abdel-Hafez, A. A. Arch. Pharm. Res. 2004, 27, 495.
6) (a) Lima, L. M.; Castro, P.; Machado, A. L.; Fraga, C. A. M.;
Lugnier, C.; Gonc, V. L.; Barreiro, E. J. Bioorg. Med. Chem. 2002, 10,
067. (b) Collin, X.; Robert, J.; Wielgosz, G.; Le Baut, G.; Bobin-Dubigeon,
3
2 3 2
PdCl (PPh ) as the catalyst and DBU as the base. PSIL 102 is
C.; Grimaud, N.; Petit, J. Eur. J. Med. Chem. 2001, 36, 639. (c) Groutas,
W. C.; Chong, L. S.; Venkataraman, R.; Kuang, R.; Epp, J. B.; Houser-
Archield, N.; Huang, H.; Hoidal, J. R. Arch. Biochem. Biophys. 1996, 332,
the best PSIL for the reaction and furnished the target product
in 90% isolated yield, while other PSILs gave the double
carbonylated products in appreciably lower yields (21-64%).
3
35.
(
7) Antune, R.; Buttista, H.; Strivastuva, R. M. Bioorg. Med. Chem.
Lett. 1998, 8, 3071.
(
(
8) Kawagushi, S.; Ikeda, O. Jpn. Pat. Appl. JP2001328911, 2001.
(11) Heravi, M. M.; Shoar, R. H.; Pedram, L. J. Mol. Catal. A 2005,
231, 89.
9) Ebihara, K.; Oora, T.; Nakaya, M.; Shiraishi, S.; Yasui, N. Jpn. Pat.
Appl. JP08245585, 1996.
10) (a) Perry, C. J.; Parveen, Z. J. Chem. Soc., Perkin Trans. 2 2001,
12. (b) Lima, L. M.; Brito, F. C. F.; Souza, S. D.; Miranda, A. L. P.;
Rodrigues, C. R.; Fraga, C. A. M.; Barreiro, E. J. Bioorg. Med. Chem.
002, 12, 1533. (c) Zhang, C.; Ping, Q.; Zhang, H.; Shen, J. Eur. Polym.
(12) (a) Mogilaiah, K.; Reddy, G. R. Indian J. Chem., Sect. B 2004, 43,
882. (b) Martin, B.; Sekljic, H.; Chassaing, C. Org. Lett. 2003, 5, 1851. (c)
Li, H.; Zhang, J.; Zhau, Y.; Li, T. Synth. Commun. 2002, 32, 927. (d) Vidal,
T.; Petit, A.; Loupy, A.; Gedye, R. N. Tetrahedron 2000, 56, 5473. (e)
Borah, H. N.; Boruah, R. C.; Sandhu, J. S. J. Chem. Res. (S) 1998, S272.
(13) (a) Mori, M.; Chiba, K.; Ohta, N.; Ban, Y. Heterocycles 1979, 13,
329. (b) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573.
(
5
2
J. 2003, 39, 1629. (d) Sinkeldam, R. W.; Houtem, M. H. C. J.; Koeckel-
berghs, G.; Vekemans, J. A. J. M.; Meijer, E. W. Org. Lett. 2006, 8, 383.
Org. Lett., Vol. 12, No. 18, 2010
4127