Carbonylative cyclization of o-halobenzoic acids for synthesis of N-substituted phthalimides using polymer-supported palladium-N-heterocyclic carbene as an efficient, heterogeneous, and reusable catalyst

Article abstract of DOI:10.1055/s-0032-1316565

The carbonylative cyclization of o-iodobenzoic acid with a variety of primary amines and carbon monoxide (1 bar) using a polymer-supported palladium-N-heterocyclic carbene complex (PS-Pd-NHC) as the catalyst gives N-substituted 1H-isoindole-1,3(2H)-diones (phthalimides) in good to excellent yields with a short reaction time. The catalyst is efficient, heterogeneous, and phosphine-free, it exhibited remarkable activity and it is also recyclable (4 consecutive cycles). The use of methyl o-iodobenzoate as the substrate under these conditions also gave N-substituted 1H-isoindole-1,3(2H)-diones, but with lower yields. Cyclization of o-iodobenzyl alcohol with carbon monoxide under these conditions gave isobenzofuran-1(3H)-one (phthalide). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316565

PAPER
▌2623
pCapaerrbonylative Cyclization of o-Halobenzoic Acids for Synthesis of N-Substi-
tuted Phthalimides Using Polymer-Supported Palladium–N-Heterocyclic
Carbene as an Efficient, Heterogeneous, and Reusable Catalyst
Carbonylative Cyclization Reaction
Mayur V. Khedkar, Shoeb R. Khan, Kishor P. Dhake, Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai 400 019, India
Fax +91(22)33611020; E-mail: bm.bhanage@gmail.com; E-mail: bm.bhanage@ictmumbai.edu.in
Received: 13.03.2012; Accepted after revision: 01.06.2012
1
5
16
amides and the carbonylation of diols using a rutheni-
um-metal catalyst have been recently explored for
phthalimide synthesis. More recently, Chang and co-
Abstract: The carbonylative cyclization of o-iodobenzoic acid
with a variety of primary amines and carbon monoxide (1 bar) using
a polymer-supported palladium–N-heterocyclic carbene complex
(
PS-Pd-NHC) as the catalyst gives N-substituted 1H-isoindole- workers demonstrated the synthesis of N-substituted
1
,3(2H)-diones (phthalimides) in good to excellent yields with a phthalimides by intermolecular oxidative C–N bond for-
17
short reaction time. The catalyst is efficient, heterogeneous, and
phosphine-free, it exhibited remarkable activity and it is also recy-
clable (4 consecutive cycles). The use of methyl o-iodobenzoate as
the substrate under these conditions also gave N-substituted 1H-
mation.
The literature reveals that, diiodoaryls, dibromoaryls, o-
halobenzoates, and substituted benzamide have all been
isoindole-1,3(2H)-diones, but with lower yields. Cyclization of o- utilized as substrates for carbonylative phthalimide syn-
iodobenzyl alcohol with carbon monoxide under these conditions thesis, however the use of inexpensive o-halobenzoic acid
gave isobenzofuran-1(3H)-one (phthalide).
has not been well explored. On the other hand, these ear-
Key words: carbonylative cyclization, heterogeneous catalysis, N- lier reported protocols for phthalimide synthesis suffered
heterocyclic carbene, phosphine-free, phthalimides, isoindoles
from one or more drawbacks, such as the use of expen-
sive, air/moisture-sensitive phosphine ligands and diffi-
culties associated with catalyst–product separation,
1
H-Isoindole-1,3(2H)-diones (phthalimides) are a key thereby limiting their applications. Also, the catalysts
component of the structure of various natural products and used are homogeneous and are not recyclable. Further-
biologically important compounds. They also make a vital more, these protocols required longer reaction times and
contribution in medicinal chemistry due to their applica- higher carbon monoxide pressures, they had limited sub-
tion in the treatment of acquired immune deficiency syn- strate applicability and they were unreactivity towards
drome (AIDS) caused by the human immune deficiency heterocyclic amines, and they required higher catalyst
1
2
3
virus (HIV), leprosy, and other diseases. Moreover, loadings; this invites the development of new general
phthalimide derivatives are known for their pharmacolog- methodologies for phthalimide synthesis. To overcome
4
5
ical properties such as antiviral, anticonvulsant, anti- these issues, heterogeneous catalysts that permit the de-
6
7
inflammatory, and analgesic activity. Due to their wide- velopment of an efficient, economical, and facile protocol
spread applications, the synthesis of this privileged struc- with the additional advantage of catalyst recyclability are
ture has attracted considerable attention by organic an emerging alternative to earlier reported homogeneous
chemists. Typically, phthalimide derivatives are synthe- protocols.
sized via condensation of phthalic anhydride with primary
amines. In context, Mori et al. reported the palladium-
Recently, N-heterocyclic carbenes (NHC) have emerged
as an attractive alternative to phosphine ligands because
8
18
catalyzed formation of phthalimides from o-halobenz-
of their effective binding ability to transition metals irre-
spective of their oxidation state. Furthermore, NHC li-
gands have also shown excellent air/moisture stability and
have higher dissociation energies than those of other li-
gands, which have been quantified by theoretical calcula-
9
amides using carbon monoxide. This seminal work was
then followed by other groups, who used this reaction to
prepare this useful framework, including the synthesis of
1
0
phthalimide from o-haloaryls,
or 1,8-diiodonaph-
thalene11 using a homogeneous palladium catalyst. Cao
and Alper further extended this reaction using a similar
protocol that utilized a phosphonium salt ionic liquid.
19
tions for different metals. Therefore, the NHC–
transition-metal complex is much stronger, as well as be-
ing chemically and thermally more inert towards cleav-
age, than other metal complexes. Therefore researchers
are exploring NHC ligands for different organic transfor-
1
2
The carbonylative cyclization of o-halobenzoates in the
synthesis of phthalimides was explored by Worlikar et
13
14
al. and Buchwald et al. using a homogeneous palladi-
um catalyst. Both C–H bond activation of aromatic
20,21
mations.
Supported transition-metal-complex catalysts are an alter-
native catalyst system that potentially combine the advan-
tages of homogeneous and heterogeneous catalysts, such
as easy separation of the catalyst in large-scale synthesis.
The most reasonable technique to support transition-metal
SYNTHESIS 2012, 44, 2623–2629
Advanced online publication: 29.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316565; Art ID: SS-2012-N0264-OP
Georg Thieme Verlag Stuttgart · New York
©

2624
M. V. Khedkar et al.
PAPER
O
O
N
N
Me
AcO Pd OAc
Me
PS-Pd-NHC
Et3N, toluene
OH
X
+
CO + H NR
N R
2
100 °C
1
1
a X = I
b X = Br
2
O
3a–m
N
N
PS-Pd-NHC
Scheme 1 Carbonylative cyclization of o-halobenzoic acid
complexes involves the formation of a chemical bond be- Our continuing interest is in the development of new fac-
2
2
tween the solid support (polymer/resin) and a ligand ile phosphine-free protocols, herein we report a hetero-
group in the metal complex. In this way, transition-metal geneous, recyclable protocol for the carbonylative
complexes can be attached to the surface of the solid sup- cyclization of o-halobenzoic acids using PS-Pd-NHC as
port and this can then be used as heterogeneous catalysts. the catalyst under atmospheric carbon monoxide pressure
NHC ligands can bind to the polymer, and polymer- (Scheme 1). The methodology permits the synthesis of
supported N-heterocyclic carbenes (PS-NHC) to form various aromatic, aliphatic, and heterocyclic N-substitut-
complexes with transition-metal catalysts that have ad- ed phthalimides in good to excellent yields.
vantages, such as easy recovery, reuse of expensive tran-
A series of experiments were performed in order to opti-
sition metals and ligands, and the isolation of the product
mize the reaction conditions for the carbonylative cross-
without contamination by metal and ligand impurities.
coupling reaction using o-iodobenzoic acid (1a) with ani-
line (2a) as a model system in the presence of PS-Pd-NHC
PS-Pd-NHC has been previously used successfully for the
2
0
21a
Suzuki coupling, carbonylative Suzuki couplings, and
hydrogenation reactions.2 However, to the best of our
knowledge; no such polymer-supported, reusable, catalyt-
ic system has yet been explored for the carbonylative cy-
clization of o-halobenzoic acids in the synthesis of
phthalimides.
as the catalyst. Various reaction parameters such as the ef-
fect of the solvent, catalyst loading, base, temperature,
and time were studied (Table 1). The nature of solvent af-
fected the yield of reaction, toluene provided 3a in an ex-
cellent 96% yield, N,N-dimethylformamide and dimethyl
sulfoxide provided lower yields of 3a, whereas water gave
1b,c
Table 1 Optimization of Carbonylative Cyclization of o-Iodobenzoic Acida
b
Entry
PS-Pd-NHC (mol%)
Solvent
Base
Temp (°C)
Time (h)
Yield (%)
Effect of solvent
1
1
DMF
Et N
100
100
100
100
100
100
4
4
4
4
4
4
50
60
–
3
2
1
DMSO
Et N
3
3
1
H O
Et N
2
3
4
1
toluene
toluene
toluene
Et N
96
97
89
3
5
1.5
0.5
Et N
3
6
Et N
3
Effect of base
7
8
9
1
1
1
toluene
toluene
toluene
DBU
100
100
100
4
4
4
85
90
50
DABCO
K CO
2
3
Effect of temperature and time
1
1
0
1
1
1
toluene
toluene
Et N
80
4
2
80
90
3
Et N
100
3
a
Reaction conditions: o-iodobenzoic acid (1a, 1 mmol), aniline (2a, 1.5 mmol), base (2 mmol), PS-Pd-NHC, solvent (10 mL), CO (1 bar).
Yields based on GC analysis.
b
Synthesis 2012, 44, 2623–2629
© Georg Thieme Verlag Stuttgart · New York

PAPER
Carbonylative Cyclization Reaction
2625
no reaction (entries 1–4); hence toluene was used for fur- withdrawing groups were tested and in all cases good to
ther study. We also studied the catalyst loading from 0.5– excellent yield of the expected products 3b–h were ob-
1
.5 mol%; at 0.5 mol% the yield of 3a was 89%, increas- tained (entries 3–9). Aliphatic amines such as butylamine
ing the catalyst loading to 1 mol% increased the yield of and benzylamine furnished 3i,j respectively in excellent
a to 96%, while a further increase had no profound effect yields (entries 10, 11).
3
(
entries 4–6). The reaction was examined using various
To the best of our knowledge N-heterocycle-substituted
phthalimides have not previously been synthesized from
o-halobenzoic acids, using 2-aminothiazole (2k) and 5-
methylfurfurylamine (2l) under these reaction conditions
we obtained 3k,l, respectively, in good to excellent yields
organic and inorganic bases (entries 4 and 7–9) and trieth-
ylamine was found to be the best base in this reaction sys-
tem. In order to examine the effect of temperature, we
carried out the reaction at 80 °C and 100 °C; lower yields
resulted at 80 °C (entry 4 vs. entry 10). Performing the re-
action for two or four hours showed that a lower yield of
(
entries 12, 13). New phthalimide derivatives, 2-(2-bro-
mophenyl)- (3g) and 2-[3-(trifluoromethyl)phenyl]-1H-
isoindole-1,3(2H)-dione (3m) were successfully synthe-
sized using this protocol (entries 8 and 14).
3
a was obtained using the shorter reaction time (entry 11
vs. entry 4). Thus, the optimized reaction conditions were:
o-iodobenzoic acid (1a, 1 mmol), aniline (2a, 1.5 mmol of
2
toluene (10 mL) at 100 °C under carbon monoxide (1 bar)
for four hours.
Phthalimide synthesis using o-halobenzoates was report-
a), PS-Pd-NHC (1 mol%), and triethylamine (2 mmol) in
ed by Worlikar and Larock using palladium(II) acetate
1
3
with a reaction time of 24 hours. Hence to ensure the ap-
plicability of our protocol, we synthesized phthalimides
With the optimized conditions in hand, we examined the
scope of the reaction system with various aromatic, ali-
phatic, and heterocyclic primary amines for the synthesis
of diverse N-substituted phthalimides 3 (Table 2). The re-
action of o-iodobenzoic acid (1a) with aniline (2a) under
the optimized conditions gave 2-phenyl-1H-isoindole-
3a,d,i,j from methyl o-iodobenzoate (4) in a short reaction
time of six hours, using atmospheric carbon monoxide
pressure. In all cases moderate to good yield of the desired
products were obtained (Scheme 2, Table 3). Aniline (2a)
and p-toluidine (2d) furnished the corresponding products
3a,d in 70% and 75% yields, respectively, whereas ali-
1
,3(2H)-dione (N-phenylphthalimide, 3a) in 92% isolated
phatic butylamine (2i) and benzylamine (2j) provided the
corresponding products 3i,j in 79% and 80% yields, re-
spectively.
yield (entry 1). For the first time the use of the unactivated
o-bromobenzoic acid (1b) was explored in phthalimide
synthesis, it gave 3a in a moderate 55% yield after 24
hours (entry 2). Thereafter, various substituted aromatic
amines 2b–h containing electron-donating or electron-
To expand the scope of this protocol, we investigated the
synthesis isobenzofuran-1(3H)-one (phthalide, 6) via a
Table 2 Reaction of o-Halobenzoic Acid with Different Aromatic, Aliphatic, and Heterocyclic Amines (Scheme 1)a
b
Entry
o-Halobenzoic acid
Amine
2a
2a
2b
2c
R
Product
3a
Yield (%)
1
2c
3
4
5
6
7
8
9
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Ph
92
55
89
75
89
90
76
81
80
91
90
80
85
80
Ph
3a
2-naphthyl
1-naphthyl
4-MeC H
3b
3c
2d
2e
3d
3e
6
4
4-MeOC H
6
4
2f
2-MeC H
3f
6
4
2g
2h
2i
2-BrC H
3g
6
4
4-AcC H
3h
3i
6
4
1
1
1
1
0
1
2
3
4
Bu
Bn
2j
3j
2k
2l
1,3-thiazol-2-yl
5-methylfurfuryl
3-F CC H
3k
3l
1
2m
3m
3
6
4
a
Reaction conditions: o-halobenzoic acid 1 (1 mmol), amine 2 (1.5 mmol), PS-Pd-NHC (1 mol%), Et N (2 mmol), toluene (10 mL), CO (1 bar)
3
1
00 °C, 4 h.
Isolated yield.
Reaction time 24 h.
b
c
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2623–2629

2626
M. V. Khedkar et al.
PAPER
o-iodobenzoic acid (1a) with aniline (2a) in the presence
of triethylamine as a base in toluene at atmospheric car-
bon monoxide pressure. The catalyst exhibited remark-
able activity and recyclability for four consecutive cycles
without decreasing the activity of the catalyst (Figure 1).
O
O
OMe
PS-Pd-NHC
Et3N, toluene
+
CO + H2NR
N R
I
100 °C, 6 h
O
3a,d,i,j
4
2
Scheme 2 Carbonylative cyclization of methyl o-iodobenzoate
Table 3 Reaction of Methyl o-Iodobenzoate (4) with Different Aro-
matic and Aliphatic Amines (Scheme 2)a
b
Entry
Amine
2a
R
Product
Yield (%)
1
2
3
Ph
3a
3d
3i
70
75
79
80
2d
4-MeC H
6
4
2i
Bu
Bn
Figure 1 Catalyst recyclability study. Reaction conditions: o-iodo-
benzoic acid (1a, 1 mmol), aniline (2a, 1.5 mmol), PS-Pd-NHC (1
4
2j
3j
a
Reaction conditions: methyl o-iodobenzoate (4, 1 mmol), amine 2
mol%), Et N (2 mmol), toluene (10 mL), CO (1 bar), 100 °C, 4 h.
3
(
1.5 mmol), PS-Pd-NHC (1 mol%), Et N (2 mmol), toluene (10 mL),
Yield based on GC analysis.
3
CO (1 bar), 100 °C, 6 h.
b
Isolated yield.
A plausible reaction mechanism is presented in Scheme 4.
Palladium undergoes oxidative insertion into the carbon–
cyclization reaction of o-iodobenzyl alcohol with carbon halogen bond of I to give intermediate II, which then in-
monoxide under the optimized reaction conditions serts carbon monoxide to form the acylpalladium complex
(
Scheme 3). This gave isobenzofuran-1(3H)-one (6) in ex- III. The acylpalladium complex then reacts with the
cellent yield (up to 85% yield). This observation, and the amine to give intermediate IV, which in the presence of
obtained results, thus suggests that varying the ortho sub- base gives intermediate V, this is then cyclized to produce
stituent on the o-haloaryls would lead to the synthesis of intermediate VI, which can reductively eliminate to give
1
3
various heterocycles, thus highlighting the potentially the corresponding phthalimide product VII.
wide applicability of this protocol.
O
O
I
CO
O
OH
OH
I
PS-Pd-NHC
+
CO
O
PdI
Et3N
toluene
I
II
OH
5
6 85%
PS-Pd-NHC
Pd
O
Scheme 3 Carbonylative cyclization in the synthesis of isobenzofu-
ran-1(3H)-one
OH
PdI
To confirm that the catalysis was due to the PS-Pd-NHC
O
III
2
1a
complex, we performed a hot filtration test. The carbon-
ylative cyclization reaction of o-iodobenzoic acid with
aniline was carried under the optimized reaction condi-
tions. Then the PS-Pd-NHC complex was hot-filtered be-
fore completion of the reaction, and the filtrate was
allowed to react further. We found that, after this hot fil-
tration, no further reaction occurred. This experimental
result suggests that the palladium metal did not leach out
of polymer support during the reaction. Thereafter ICP-
AES analysis of the reaction mixture was also carried and
palladium in solution was estimated to be below the de-
tectable level (below 0.01 ppm).
O
NH -R
O
N
O
2
OH
R + H2O
NH-R
O
VII
IV
+ BH
O–
OH
B
N-R
O
O
O
VI
OH
–
N -R
In order to make the catalytic system more economical,
we focused on the reusability of the PS-Pd-NHC catalyst
V
using the model system of the carbonylative cyclization of Scheme 4 Plausible reaction mechanism
Synthesis 2012, 44, 2623–2629
© Georg Thieme Verlag Stuttgart · New York

PAPER
Carbonylative Cyclization Reaction
2627
In conclusion, we have explored the carbonylative cycli- 2-Naphthalen-2-yl-1H-isoindole-1,3(2H)-dione (3b)23a
White solid; yield: 242 mg (89%).
zation of o-halobenzoic acids using polymer-supported
palladium–N-heterocyclic carbene complex as a hetero-
geneous, phosphine-free, and recyclable catalyst for the
–
1
IR (KBr): 3030, 1720, 1600, 1479, 1379, 1075, 852, 722 cm .
1
H NMR (500 MHz, CDCl ): δ = 8.00–7.81 (m, 8 H), 7.56–7.53 (m,
3
synthesis of 2-substituted 1H-isoindole-1,3(2H)-diones 3 H).
(
N-substituted phthalimides). In this study, the reaction
1
-Naphthalen-2-yl-1H-isoindole-1,3(2H)-dione (3c)23a
White solid; yield: 204 mg (75%).
conditions were milder with the additional advantage of
easy product isolation. Moreover, the developed protocol
was applicable to the synthesis of various 2-substituted
–
1
IR (KBr): 3055, 1721, 1569, 1375, 1105, 856, 726 cm .
1
H NMR (500 MHz, CDCl ): δ = 8.02–7.83 (m, 6 H), 7.62–7.25 (m,
3
1
H-isoindole-1,3(2H)-diones from different aromatic, al-
5
H).
iphatic, and heterocyclic amines with appreciable yields.
Catalyst reusability and palladium leaching were also ex- 2-(4-Methylphenyl)-1H-isoindole-1,3(2H)-dione (3d)13
Colorless solid; yield: 211 mg (89%).
amined, and the catalyst was effectively recyclable for
four consecutive runs without any significant loss in cata- IR (KBr): 2929, 1706, 1616, 1520, 1380, 1222, 1118, 825, 725
–
1
cm .
1
lytic activity. Furthermore, isobenzofuran-1(3H)-one was
also synthesized using the optimized reaction conditions,
which is an additional advantage to this protocol.
H NMR (500 MHz, CDCl ): δ = 7.95 (dd, J = 5.1, 3 Hz, 2 H), 7.78
dd, J = 5.1, 3 Hz, 2 H), 7.54–7.26 (m, 4 H), 2.24 (s, 3 H).
3
(
+
GC-MS (EI, 70 eV): m/z (%) = 238 (M , 100), 193 (45), 104 (29),
7
6 (39).
All chemicals and reagents were purchased from firms of repute
with their highest purity available and were used without further pu-
rification. The progress of reaction was monitored by gas chroma-
tography (Perkin Elmer Clarus 400 GC) equipped with capillary
column (Elite-1, 30 m × 0.25 mm × 0.25 μm) and a flame ionization
detector (FID). Products were purified by column chromatography
on silica gel (100–200 mesh). The products are well known in the
-(4-Methoxyphenyl)-1H-isoindole-1,3(2H)-dione (3e)10
2
White solid; yield: 227 mg (90%).
IR (KBr): 3470, 2955, 1779, 1501, 1475, 1382, 1130, 790, 712
cm .
1H NMR (500 MHz, CDCl
(d, J = 8.5 Hz, 2 H), 7.02 (d, J = 8.5 Hz, 2 H), 3.85 (s, 3 H).
–
1
): δ = 7.94 (m, 2 H), 7.78 (m, 2 H), 7.33
3
1
literature and were confirmed by H NMR and GC-MS analysis.
1
13
Newly synthesized compounds were characterized by H NMR,
C
+
GC-MS (EI, 70 eV): m/z (%) = 253 (M , 100), 238 (65), 210 (18),
2
NMR, IR, GC-MS, and HRMS. Polymer-supported palladium–N-
09 (16), 130 (12), 106 (20), 76 (35).
heterocyclic carbene complex (PS-Pd-NHC) used was prepared ac-
19
2-(2-Methylphenyl)-1H-isoindole-1,3(2H)-dione (3f)22a
White solid; yield: 180 mg (76%).
cording to the reported procedure in the literature. Loading of pal-
ladium catalyst on chloromethyl polystyrene resin support was
evaluated by ICP-AES analysis and was found to about 0.29
IR (KBr): 3078, 1727, 1612, 1507, 1383, 1222, 1110, 874, 776, 715
cm .
–1
21
mmol·g of support.
–1
1
2
-Substituted 1H-Isoindole-1,3(2H)-diones 3; General Proce-
H NMR (300 MHz, CDCl ): δ = 7.97 (dd, J = 5.7, 3 Hz, 2 H), 7.80
3
dure
(dd, J = 5.4, 3 Hz, 2 H), 7.39–7.22 (m, 4 H), 2.22 (s, 3 H).
To a 100-mL stainless steel autoclave, o-halobenzoic acid 1 or
methyl o-iodobenzoate (4) (1 mmol), 2 amine (1.5 mmol), PS-Pd-
+
GC-MS m/z (%) = 238 (M , 100), 191 (25), 104 (26), 76 (45).
NHC (1 mol%), toluene (10 mL), and Et N (2 mmol) were added.
The autoclave was closed, purged with CO (4 ×), pressurized with
3
2
-(2-Bromophenyl)-1H-isoindole-1,3(2H)-dione (3g)
White solid; yield: 243 mg (81%).
1
atm of CO and then heated at 100 °C for 4 h. After completion of
–1
IR (KBr): 2924, 1721, 1478, 1381, 1223, 1110, 888, 719, 529 cm .
the reaction, the reactor was cooled to r.t. and the remaining CO gas
was carefully vented. The reactor was opened and the mixture was
filtered, and the vessel was thoroughly washed with EtOAc (2 × 5
mL) to remove any traces of product and catalyst if present. The fil-
trate obtained was evaporated under vacuum to give the crude prod-
uct which was purified by column chromatography (silica gel, 100–
1
H NMR (500 MHz, CDCl ): δ = 7.98 (dd, J = 5.5, 2.5 Hz, 2 H),
3
7.82 (dd, J = 5.5, 2.5 Hz, 2 H), 7.75 (d, J = 8 Hz, 1 H), 7.47 (t, J =
7.5 Hz, 1 H), 7.38–7.34 (m, 2 H).
13
C NMR (125 MHz, CDCl ): δ = 166.61, 135.14, 134.22, 133.86,
3
1
32.89, 130.25, 129.13, 127.75, 124.68, 123.33.
200 mesh, petroleum ether–EtOAc, 95:5) to afford the desired prod-
+
uct 3 with high purity.
GC-MS (EI, 70 eV): m/z (%) = 301 (2), 222 (M , 100), 164 (5), 166
(
8), 111 (7), 76 (25).
Recycling of PS-Pd-NHC Catalyst
The catalyst obtained after filtration was thoroughly washed with
+
HRMS (ESI): m/z [M + H] calcd for C H NO Br: 301.9817;
found: 301.9823.
1
4
9
2
distilled H O (3 × 5 mL) and then with MeOH (3 × 5 mL) to remove
2
any traces of organic material if present, and dried under reduced
pressure. The dried catalyst was then used for catalyst recyclability
experiment.
-(4-Acetylphenyl)-1H-isoindole-1,3(2H)-dione (3h)22a
2
Pale yellow solid; yield: 212 mg (80%).
–
1
IR (KBr): 2927, 1716, 1596, 1513, 1380, 1221, 829, 720 cm .
2
-Phenyl-1H-isoindole-1,3(2H)-dione (3a)22a
White solid; yield: 205 mg (92%).
1
H NMR (500 MHz, CDCl ): δ = 8.13 (d, J = 8.5 Hz, 2 H), 8.01 (dd,
3
J = 5.5, 3.5 Hz, 2 H), 7.85 (dd, J = 5.5, 3.5 Hz, 2 H), 7.65 (d, J = 8.5
Hz, 2 H), 2.67 (s, 3 H).
–
1
IR (KBr): 3079, 1700, 1590, 1489, 1390, 1119, 768, 717 cm .
1
+
H NMR (500 MHz, CDCl ): δ = 7.99 (dd, J = 5.5, 3.3 Hz, 2 H),
GC-MS (EI, 70 eV): m/z (%) = 265 (25), 250 (M , 100), 222 (29),
3
7.82 (dd, J = 5.4, 3.5 Hz, 2 H), 7.43–7.55 (m, 5 H).
166 (20), 104 (28), 76 (20).
+
GC-MS (EI, 70 eV): m/z (%) = 223 (M , 100), 179 (75), 104 (20),
-Butyl-1H-isoindole-1,3(2H)-dione (3i)22a
2
76 (48), 50 (10).
Colorless liquid; yield: 184 mg (91%).
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2623–2629

2628
M. V. Khedkar et al.
PAPER
1
IR (neat): 3323, 2922, 1765, 1691, 1430, 1335, 1327, 1190, 969,
H NMR (500 MHz, CDCl ): δ = 7.94 (d, J = 7.5 Hz, 1 H), 7.7 (t,
3
–1
719 cm .
J = 7 Hz, 1 H), 7.51–7.57 (m, 2 H), 5.35 (s, 2 H).
1
13
H NMR (300 MHz, CDCl ): δ = 7.84–7.83 (m, 2 H), 7.72–7.71 (m,
C NMR (125 MHz, CDCl ): δ = 171.49, 146.49, 133.89, 129.00,
3
3
2
H), 3.69 (t, J = 7.5 Hz, 2 H), 1.66 (qt, J = 7.5 Hz, 2 H), 1.36 (qt,
125.71, 122.07, 69.62.
J = 7.5 Hz, 2 H), 0.95 (t, J = 7.5 Hz, 3 H).
+
GC-MS (EI, 70 eV): m/z (%) = 134 (31), 105 (M , 100), 77 (55), 51
(20).
+
GC-MS (EI, 70 eV): m/z (%) = 203 (40), 161 (50), 160 (M , 100),
133 (20), 130 (22), 105 (14), 77 (29).
2
-Benzyl-1H-isoindole-1,3(2H)-dione (3j)22a
Acknowledgment
White solid; yield: 213 mg (90%).
The author (M.V.K) is greatly thankful to UGC (University Grant
Commission, India) for providing Junior Research Fellowship.
Also authors express their gratitude towards Prof I. N. N. Namboo-
thiri, Indian Institute of Technology (Bombay, India) for providing
HRMS analysis facility.
IR (KBr): 3555, 2965, 1753, 1716, 1660, 1389, 1189, 1081, 1018,
–
1
918, 716 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.86–7.87 (m, 2 H), 7.72–7.73 (m,
3
2
H), 7.45 (d, J = 7.5 Hz, 2 H), 7.32–7.34 (m, 3 H), 4.87 (s, 2 H).
+
GC-MS (EI, 70 eV): m/z (%) = 237 (M , 100), 219 (50), 208 (21),
1
04 (60), 91 (10), 77 (35).
Supporting Information for this article is available online at
-(1,3-Thiazol-2-yl)-1H-isoindole-1,3(2H)-dione (3k)22a
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
2
White solid; yield: 184 mg (80%).
IR (KBr): 3082, 1730, 1625, 1501, 1448, 1335, 1190, 751, 714
cm .
References
–
1
1
(1) (a) Makonkawkeyoon, S.; Limson-Pobre, R. N. R.; Moreira,
H NMR (500 MHz, CDCl ): δ = 8.03 (dd, J = 5.5, 2 Hz, 2 H), 7.85
dd, J = 5.5, 2 Hz, 2 H), 7.83 (d, J = 3.5 Hz, 1 H), 7.27 (d, J = 3.5
3
A. L.; Schauf, V.; Kaplan, G. Proc. Natl. Acad. Sci. U.S.A.
(
1
993, 90, 5974. (b) Figg, W. D.; Raje, S.; Bauer, K. S.;
Hz, 1 H).
Tompkins, A.; Venzon, D.; Bergan, R.; Chen, A.; Hamilton,
M.; Pluda, J.; Reed, E. J. Pharm. Sci. 1999, 88, 121.
+
GC-MS (EI, 70 eV): m/z (%) = 230 (M , 100), 76 (51), 50 (10).
(
2) Atra, E.; Sato, E. I. Clin. Exp. Rheumatol. 1993, 11, 487.
2
-(5-Methylfuran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione
2
2a
(3) (a) Ochonisky, S.; Verroust, J.; Bastuji-Garin, S.; Gherardi,
R.; Revuz, J. Arch. Dermatol. 1994, 130, 66. (b) Miyachi,
H.; Azuma, A.; Ogasawara, A.; Uchimura, E.; Watanabe, N.;
Kobayashi, Y.; Kato, F.; Kato, M.; Hashimoto, Y. J. Med.
Chem. 1997, 40, 2858. (c) Parker, P. M.; Chao, N.;
Nademanee, A.; O‘Donnell, M. R.; Schmidt, 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, S. J.
Blood 1995, 86, 3604.
(3l)
Pale yellow solid; yield: 204 mg (85%).
IR (KBr): 3086, 1772, 1616, 1566, 1396, 1334, 1187, 1052, 914,
–
1
719, 529 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.86–7.85 (m, 2 H), 7.71–7.70 (m,
3
2
H), 6.23 (d, J = 3 Hz, 1 H), 5.87 (d, J = 2.1 Hz, 1 H), 4.80 (s, 2 H),
2.24 (s, 3 H).
+
GC-MS m/z (%) = 241 (M , 100), 226 (18), 198 (70), 170 (26), 95
(39), 78 (56).
2
-[3-(Trifluoromethyl)phenyl]-1H-isoindole-1,3(2H)-dione
(4) Balzarini, J.; Clercq, E. D.; Kaminska, B.; Orzeszko, A.
Antiviral Chem. Chemother. 2003, 14, 139.
(
3m)
White solid; yield: 203 mg (80%).
(5) Abdel-Hafez, A. A. Arch. Pharmacal. Res. 2004, 27, 495.
IR (KBr): 2921, 1711, 1610, 1456, 1384, 1115, 1069, 877, 715
cm .
(6) (a) Meng, X. B.; Han, D.; Zhang, S. N.; Guo, W.; Cui, J. R.;
Li, Z. J. Carbohydr. Res. 2007, 342, 1169. (b) 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,
–
1
1
H NMR (500 MHz, CDCl ): δ = 7.98 (dd, J = 5.5, 3.5 Hz, 2 H),
3
7.83 (dd, J = 5.5, 3.5 Hz, 2 H), 7.78 (s, 1 H), 7.63–7.70 (m, 3 H).
3067. (c) Groutas, W. C.; Chong, L. S.; Venkataraman, R.;
13
C NMR (125 MHz, CDCl ): δ = 166.80, 135.36, 134.09, 132.36,
3
Kuang, R.; Epp, J. B.; Houserarchield, N.; Huang, H.;
Hoidal, J. R. Arch. Biochem. Biophys. 1996, 332, 335.
(7) Antune, R.; Buttista, H.; Strivastuva, R. M. Bioorg. Med.
Chem. Lett. 1998, 8, 3071.
131.51, 130.32, 129.00, 125.34, 124.68, 124.07, 123.32.
+
GC-MS (EI, 70 eV): m/z (%) = 291 (M , 100), 247 (92), 104 (32),
76 (72), 50 (20).
HRMS (ESI): m/z [M + H]+ calcd for C H NO F : 292.0585;
found: 292.0584.
(8) (a) Kang, H. B.; Quan, L. G.; Lee, J. K.; Kim, S. WO
1
5
9
2 3
2
007132990, 2007. (b) Han, T.; Chen, C. F. J. Org. Chem.
007, 72, 7287. (c) Sani, M.; Fossati, G.; Huguenot, F.;
2
Isobenzofuran-1(3H)-one (6)
Zanda, M. Angew. Chem. Int. Ed. 2007, 46, 3526.
(d) Kobrakov, K. I.; Zubkova, N. S.; Stankevich, G. S.;
Shestakova, Y. S.; Stroganov, V. S.; Adrov, O. I. Fibre
Chem. 2006, 38, 183. (e) Sheehan, J. C.; Chapman, D. W.;
Roth, R. W. J. Am. Chem. Soc. 1952, 74, 3822. (f) Sheehan,
J. C.; Frank, V. S. J. Am. Chem. Soc. 1949, 71, 1856.
(9) Mori, M.; Chiba, K.; Ohta, N.; Ban, Y. Heterocycles 1979,
To a 100-mL stainless steel autoclave, o-iodobenzyl alcohol (5, 1
mmol), PS-Pd-NHC (1 mol%), toluene (10 mL), and Et N (2 mmol)
3
were added. The autoclave was closed and pressurized with 1 atm
of CO and then heated at 100 °C for 4 h. After completion of the re-
action, the reactor was cooled to r.t. and the remaining CO gas was
carefully vented. The reactor was opened and the mixture was fil-
tered, and the vessel was thoroughly washed with EtOAc (2 × 5 mL)
to remove any traces of product and catalyst if present. Column
chromatography (silica gel, 100–200 mesh; petroleum ether–
1
3, 329.
(
(
(
10) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573.
11) Takacs, A.; Acs, P.; Kollar, L. Tetrahedron 2008, 64, 983.
12) Cao, H.; Alper, H. Org. Lett. 2010, 12, 4126.
2
3b
EtOAc, 95:5) gave 6 as a white solid; yield: 113 mg (85%).
IR (KBr): 3491, 1767, 1713, 1596, 1313, 1289, 1200, 1062, 743,
(13) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175.
–
1
661, 474 cm .
Synthesis 2012, 44, 2623–2629
© Georg Thieme Verlag Stuttgart · New York

PAPER
Carbonylative Cyclization Reaction
2629
(
14) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102.
15) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2009, 131, 6898.
(20) Byun, J.; Lee, Y. Tetrahedron Lett. 2004, 45, 1837.
(21) (a) Qureshi, Z. S.; Deshmukh, K. M.; Tambade, P. J.;
Bhanage, B. M. Synthesis 2011, 243. (b) Bagal, D. B.;
(
Qureshi, Z. S.; Dhake, K. P.; Khan, S. R.; Bhanage, B. M.
Green. Chem. 2011, 13, 1490. (c) Bagal, D. B.; Watile, R.
A.; Khedkar, M. V.; Dhake, K. P.; Bhanage, B. M. Catal.
Sci. Technol. 2012, 2, 354.
(
(
16) Senthilkumar, M.; Hong, S. H. Synlett 2011, 1481.
17) Kim, H. J.; Jiyu, K.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2
011, 133, 16382.
(
18) (a) Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, 1290.
(22) (a) Khedkar, M. V.; Khan, S. R.; Sawant, D. N.; Bagal, D.
B.; Bhanage, B. M. Adv. Synth. Catal. 2011, 353, 3415.
(b) Khedkar, M. V.; Tambade, P. J.; Qureshi, Z. S.;
Bhanage, B. M. Eur. J. Org. Chem. 2010, 6981.
(c) Tambade, P. J.; Patil, Y. P.; Panda, A. G.; Bhanage, B.
M. Eur. J. Org. Chem. 2009, 3022. (d) Tambade, P. J.; Patil,
Y. P.; Bhanushali, M. J.; Bhanage, B. M. Synthesis 2008,
2347.
(b) Ofele, K. J. Organomet. Chem. 1968, 12, 42.
(c) Wanzlick, H.; Schonherr, H. Angew. Chem., Int. Ed.
Engl. 1968, 7, 141. (d) Hauwert, P.; Boerleider, R.; Warsink,
S.; Weigand, J. J.; Elsevier, C. J. J. Am. Chem. Soc. 2010,
1
32, 16900.
(19) (a) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.;
Herrmann, W. A. Angew. Chem. Int. Ed. 1999, 38, 2416.
(
b) Schwarz, J.; Biihm, V. P. W.; Gardiner, M. G.; Grosche,
(23) (a) Hodgson, H. H.; Crook, J. H. J. Chem. Soc. 1936, 1844.
(b) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102,
4193.
M.; Herrmann, W. A.; Hieringer, W.; Raudaschl-Sieber, G.
Chem.–Eur. J. 2000, 6, 1773.
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2623–2629