Efficient Synthesis of a (Z)-3-Methyleneisoindolin-1-one Library Using Cu(OAc)2·H2O/DBU under Microwave Irradiation

Article abstract of DOI:10.3390/molecules18010654

Microwave-promoted efficient synthesis of a (Z)-3-methyleneisoindolin-1-one library from 2-bromobenzamides and terminal alkynes using Cu(OAc) ₂·H₂O/DBU is described. Various benzamide substituents, ring substitutions, including heter

Full text of DOI:10.3390/molecules18010654

Molecules 2013, 18, 654-665; doi:10.3390/molecules18010654
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Efficient Synthesis of a (Z)-3-Methyleneisoindolin-1-one Library
Using Cu(OAc)2•H2O/DBU under Microwave Irradiation
Li Zhang 1,*, Yongliang Zhang 2, Xin Wang 2 and Jingkang Shen 2
1
Instrumental Analysis Center, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institute for Biological Sciences, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, China
* Author to whom correspondence should be addressed; E-Mail: lizhang09@sjtu.edu.cn;
Tel.: +86-21-3420-6173; Fax: +86-21-3420-5722.
Received: 3 December 2012; in revised form: 21 December 2012 / Accepted: 27 December 2012 /
Published: 4 January 2013
Abstract: Microwave-promoted efficient synthesis of a (Z)-3-methyleneisoindolin-1-one
library from 2-bromobenzamides and terminal alkynes using Cu(OAc)2•H2O/DBU is
described. Various benzamide substituents, ring substitutions, including heteroaryl, aryl
acetylenes and aliphatic alkynes, could be applied to afford the desired products in good to
moderate yield with high stereoselectivity. It is noteworthy that DBU maybe play a dual
role as not only the base, but also as a ligand for copper. The reaction is catalyzed by the
complex of Cu(OAc)2•H2O and DBU without other additives.
Keywords: (Z)-3-methyleneisoindolin-1-one; Cu(OAc)2•H2O/DBU; domino reaction;
cross coupling; microwave irradiation
1. Introduction
3-Methyleneisoindolin-1-one is an important scaffold that is present in a number of natural
products and biologically active compounds (Figure 1). For example, the alkaloid fumaridine is a
secophthalide-isoquinoline ene-lactam [1]. DN-2574 is an isoindoloquinoline derivative used as a
cognition enhancing agent [2]. Additionally, a 3-methyleneisoindolin-1-one is a key intermediate in
the total synthesis of lennoxamine [3].

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Figure 1. Structures of some natural products and biologically active 3-methyleneisoindolin-
655
1-one compounds.
OMe
MeO
O
O
MeO
MeO
N
NH
O
O
O
O
N
O
O
NEt2
Me2N
fumaridine
DN-2574
lennoxamine
There are several methods available for the synthesis of 3-methyleneisoindolin-1-ones.
General methods rely on the Wittig reaction [4], nucleophilic additions of organometallic reagents
to phthalimides followed by dehydration [5], Horner-Wadsworth-Emmons condensation of
3-(diphenyl-phosphinoyl)isoindolin-1-ones with aldehydes [6,7], base promoted nucleophilic additions
to benzonitrile derivatives [8,9], dimethyl isoindolin-1-one-3-yl-phosphonates followed by a Horner
reaction [10] or photodecarboxylative addition of carboxylates to phthalimides [11]. In recent years,
efficient approaches based on palladium-mediated cyclization reactions have been reported [12–20].
Ma et al. [21] reported a CuI/L-proline-catalyzed domino reaction to form 3-methyleneisoindolin-1-ones.
The desired products were formed at 85–110 °C for 24–48 h, L-proline had to be used as a ligand and
K2CO3 was used as base. However, most of these methods are not suitable for parallel synthesis to
obtain large numbers of (Z)-3-methyleneisoindolin-1-ones analogues for drug discovery research. As
part of our ongoing drug discovery research, we required a facile route to prepare a library of
(Z)-3-methyleneisoindolin-1-ones.
Therefore, we investigated an efficient parallel synthesis of (Z)-3-methyleneisoindolin-1-ones from
2-bromobenzamides and terminal alkynes in a stereoselective manner through a Cu(OAc)2·H2O/DBU
catalyzed domino reaction under microwave irradiation. As microwave-assisted synthesis has become
a powerful tool with the potential to improve the yields and dramatically shorten reaction times [22,23],
there are several advantages to this method: (i) simple use of inexpensive complex of Cu(OAc)2•H2O
with DBU, without other additives, (ii) the reaction is not sensitive to water, (iii) environmentally-friendly
EtOH as the solvent, (iv) remarkably short reaction time, only 20 min being needed, (v) moderate to
high yields with high stereoselectivity, only Z-isomers were obtained as product, and (vi), a broader
substrate scope accommodating various benzamide substituents, aromatic rings including heteroaryl
substitutions, aryl acetylenes and aliphatic alkynes were used. Therefore, this method are suitable to
synthesize (Z)-3-methyleneisoindolin-1-one libraries efficiently and conveniently.
2. Results and Discussion
In order to develop an efficient methodology for the synthesis of a (Z)-3-methyleneisoindolin-1-one
library, N-benzyl-2-bromobenzamide 1{1} and phenylacetylene 2{1} were used as representative
reactants for optimization of the reaction conditions (Scheme 1). Various catalysts, bases, solvents,
temperatures and reaction times were investigated (Table 1). Firstly, we compared the system of CuI
and Cu(OAc)2•H2O as catalyst, the result showed that the Cu(OAc)2•H2O under microwave irradiation
was better than the CuI system (Table 1, entries 1–2). Next, Cu(OAc)2•H2O was used as catalyst, and
we compared different solvent effects under microwave irradiation, whereby CH3CN and EtOH

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showed similar results and better yields than DMSO, DMF or dioxane (Table 1, entries 3–7). Due to its
lower toxicity and price, EtOH was chosen as the solvent for subsequent optimization. Further
investigation showed that the nature of the base played an important role in the reaction process, with
DBU exhibiting the best results (Table 1, entry 7). Only traces of product were detected when Cs2CO3
was used as base (Table 1, entry 10) and no product was detected in the presence of other organic or
inorganic bases, such as DABCO, NEt3, NaOH and K3PO4 (Table 1, entries 8–9 and 11–12). DBU
maybe play the dual role as not only the base, but also the ligand for copper. We also found that
increasing the reaction temperature to 130 °C afforded improved yields (Table 1, entry 13). Finally, the
ratio of catalyst to base was optimized. The best result was obtained when the reaction was carried out
with 0.3 equiv. Cu(OAc)2•H2O and 4.0 equiv. DBU at 130 °C for 20 min under microwave irradiation
(Table 1, entry 14). When the reaction time was increased to 30 min, the yield was found to decrease
slightly (Table 1, entry 15).
Scheme 1. Synthesis of (Z)-2-benzyl-3-benzylideneisoindolin-1-one.
O
O
Catalyst
Base
Bn
+
N
N Bn
Ph
Ph
H
Solvent
MW
Br
3{1}
1{1}
2{1}
Table 1. Optimization for the synthesis of (Z)-2-benzyl-3-benzylideneisoindolin-1-one a.
Catalyst
Base
Temp
(°C)
100
100
120
120
120
120
120
120
120
120
120
120
130
130
130
Time
(min)
20
Yield of 3{1} b
Entry
Solvent
(equiv.)
(equiv.)
(%)
20 c
30
58
60
30
77
77
0
1
2
CuI (0.1)
K2CO3 (2.0)
DBU (2.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DABCO (3.0)
NEt3 (3.0)
Cs2CO3 (3.0)
NaOH (3.0)
K3PO4 (3.0)
DBU (3.0)
DBU (4.0)
DBU (4.0)
i-PrOH
DMSO
DMSO
DMF
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.1)
Cu(OAc)2•H2O (0.3)
Cu(OAc)2•H2O (0.3)
20
3
20
4
20
5
dioxane
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
20
6
20
7
20
8
20
9
20
0
10
11
12
13
14
20
trace
0
20
20
0
20
83
91
87
20
15
30
a
b
Reaction conditions: 1{1}(0.25 mmol), 2{1}(0.375 mmol), solvent (0.50 mL);
Isolated yield;
c
L-proline as ligand.
Utilizing the above optimized conditions, a library of (Z)-3-methyleneisoindolin-1-ones was
designed and synthesized. Firstly, electronic and steric effects of various N-substituents on
the 2-bromobenzamides were explored (Scheme 2). Both aromatic and aliphatic substituents were

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tolerated in the reaction (Table 2, entry 2–10). N-benzyl-substituted-2-bromobenzamides gave better
yields than N-aryl-substituted-2-bromobenzamides (Table 2, entries 2–8). For the primary amide
(R1 = H), the desired product was also obtained in moderate yield (Table 2, entry 1).
(Z)-N-ethylheteroaryl 3-benzylideneisoindolin-1-ones could also be obtained with good yields (Table 2,
entries 9–10).
Scheme 2. Synthesis of N-substituted-3-benzylideneisoindolin-1-one.
O
O
.
R1
Cu(OAc)2 H2O
N
N R1
Ph
Ph
H
+
DBU EtOH
130 oC 20 min
MW
Br
2{1}
1
3
Table 2. Synthesis of N-substituted-3-benzylideneisoindolin-1-one a.
Entry
R1
Product Yield (%) b
1
H
3{2}
62
F
2
3
4
5
3{3}
77
3{4}
3{5}
3{6}
76
81
82
Cl
OMe
O
O
6
7
8
9
3{7}
3{8}
46
40
53
77
F
Me
3{9}
3{10}
S
N
10
3{11}
80
a
Reaction conditions: 1 (0.50 mmol), 2{1} (0.75 mmol), Cu(OAc)2•H2O (0.15 mmol), DBU (2.00 mmol),
EtOH (1.00 mL), MW, 130 °C, 20 min; b Isolated yield.
Next, we explored the scope of substituents tolerated on the aromatic ring of the aryl bromides
(Scheme 3). Good yields could be obtained regardless of the nature of the substituent (Table 3,
entries 1–4). Heteroaryl bromide was also found to provide desired product in moderate yield (Table 3,
entry 5).

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Scheme 3. Synthesis of substituted (Z)-2-benzyl-3-benzylideneisoindolin-1-one.
658
O
O
.
Bn
+
Cu(OAc)2 H2O
N
N Bn
Ph
Ph
H
DBU EtOH
130 oC 20 min
Br
R2
R2
2{1}
1
3
MW
Table 3. Synthesis of substituted (Z)-2-benzyl-3-benzylideneisoindolin-1-one a.
Entry
Product
Yield (%) b
O
N Bn
1
3{12}
3{13}
3{14}
3{15}
3{16}
86
Me
O
N Bn
2
3
4
5
92
89
89
53
Cl
F
O
N Bn
O
MeO
N Bn
O
N Bn
N
a
Reaction conditions: 1 (0.50 mmol), 2 (0.75 mmol), Cu(OAc)2•H2O (0.15 mmol), DBU (2.00 mmol),
EtOH (1.00 mL), MW, 130 °C, 20 min; b Isolated yield.
In addition, different arylacetylenes and aliphatic alkynes were chosen to investigate the reaction
scope (Scheme 4). When the triple bond was substituted with an aromatic ring, the reaction afforded
better yields than that substituted with an aliphatic group. Specially, 3-methylphenyl substitution of the
acetylene provided excellent result (Table 4, entry 2). 4-Fluorophenylacetylene also provided the
desired product in good yield (Table 4, entry 1). Aliphatic alkynes with steric hindrance afforded the
desired product in lesser yield than arylacetylenes (Table 4, entries 4).

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Scheme 4. Synthesis of 3{17}-3{20}.
O
O
.
Bn
+
Cu(OAc)2 H2O
N
N Bn
R3
R3
H
DBU EtOH
130 oC 20 min
MW
Br
1{1}
3
2
Table 4. Substrate Scope of alkyne in the Reaction with N-benzyl-2-bromobenzamide a.
Entry
Alkyne
Product
Yield (%) b
F
1
3{17}
85
Me
2
3{18}
95
OMe
3
4
3{19}
3{20}
69
33
a
Reaction conditions: 1 (0.50 mmol), 2 (0.75 mmol), Cu(OAc)2•H2O (0.15 mmol), DBU (2.00 mmol),
EtOH (1.00 mL), MW, 130 °C, 20 min; b Isolated yield.
All products were isolated in high purity and the process was highly stereoselective. All compounds
were confirmed to be Z-isomers. The geometry of unpublished compounds was established via
NOESY studies.
The possible reaction mechanism was shown in Scheme 5. The first step is likely to be the
Sonogashira coupling reaction [24]. The second step involves copper coordination to the triple bond,
followed by intramolecular hydroamination of the triple bond, and protodemetalation to form the
desired substituted 3-methyleneisoindolin-1-one. DBU might act as ligand and base in the reaction.
Scheme 5. Possible Mechanism.
O
O
R1
N
H
R1
.
R2
Cu(OAc)2 H2O
N
H
R3
R2
III
Cu
Br
R3
Cu L
L
L
R3
L
L
Br
L
O
O
R1
R1
R3
N
N
R2
H
R2
R3
L
Cu
OAc
L
O
O
R2
N R1
R2
N R1
R3
R3
L Cu
L
OAc
L=DBU

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3. Experimental
3.1. General
Proton (1H-) and carbon (13C-) NMR spectra were recorded on a Varian AMX-300 spectrometer at
300 MHz and 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm).
Chloroform-d was used as an internal standard. Data are reported as follows: (s = singlet; d = doublet;
t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; br = broad). Mass spectra were carried
out in EI or ESI mode. High and low resolution mass spectra were recorded on a Finnigan MAT-95 and
Finnigan LCQ-Dea-XP spectrometers. Infrared (IR) spectra were obtained on a Nicolet Magan 750
FT-IR spectrometer. Analytical TLC was performed on pre-coated silica gel 60F-254 plates.
Microwave-assisted synthesis was carried out in an Initiator single-mode microwave synthesizer
(Biotage, Uppsala, Sweden), equipped with an internal probe that monitors reaction temperature and
pressure, and maintains the desired temperature by computer control. Reactions were conducted in
5 mL sealed vials.
3.2. General Procedure for the Preparation of (Z)-3-Methyleneisoindolin-1-ones
Compound 2{1} (0.75 mmol) was added to the mixture of Cu(OAc)2•H2O (30 mg, 0.15 mmol),
DBU (293 μL, 2.00 mmol) and compound 1{1} (0.50 mmol) in EtOH (1.00 mL). The reaction vessel
was sealed and the reaction mixture was stirred at 130 °C for 20 min under microwave irradiation.
After cooling, the mixture was diluted with EtOAc. The organic layer separated and washed with 1 N
HCl, brine, dried over anhydrous Na2SO4. After evaporation under vacuum, the residue was purified by
flash column chromatography (petroleum ether/ethyl acetate = 20/1–10/1) to afford the desired product.
1
(Z)-2-Benzyl-3-benzylideneisoindolin-1-one (3{1}) [21]. H-NMR (CDCl3): δ 7.93 (d, J = 7.5 Hz, 1H),
7.74 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.28–7.22 (m, 3H),
7.08–7.02 (m, 5H), 6.72 (s, 1H), 6.53 (d, J = 6.9 Hz, 2H), 4.94 (s, 2H); ESI-MS m/z 312 [M+H]+.
(Z)-3-Benzylideneisoindolin-1-one (3{2}) [21]. 1H-NMR (CDCl3): δ 8.17 (brs, 1H), 7.88 (d, J = 7.5 Hz,
1H), 7.80 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.45–7.44 (m, 4H),
7.34–7.31 (m, 1H), 6.56 (s, 1H); ESI-MS m/z 222 [M+H]+.
(Z)-2-(3-Fluorobenzyl)-3-benzylideneisoindolin-1-one (3{3}). 1H-NMR (CDCl3): δ 7.93 (d, J = 7.8 Hz,
1H), 7.75 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.29–7.22 (m, 3H),
7.06–6.97 (m, 3H), 6.81–6.77 (m, 1H), 6.74 (s, 1H), 6.33 (d, J = 7.5 Hz, 1H), 6.18 (d, J = 9.9 Hz, 1H),
4.91 (s, 2H); 13C-NMR (CDCl3) δ 168.8, 162.6 (d, J = 244.5 Hz), 139.4 (d, J = 7.1 Hz), 138.3, 134.4,
134.2, 132.3, 129.5, 129.4, 129.1, 127.9 (2C), 127.5, 123.6, 121.8, 119.5, 113.7, 113.5, 113.4, 113.1,
107.6, 44.4; IR (KBr) ν 3053, 1713, 1655, 1616, 1591, 1452, 1392, 1352, 1254, 1113, 955, 762, 702
cm−1; EI-MS m/z 329 (M+); HRMS (EI) Calcd for m/z C22H16NOF 329.1216, found 329.1210.
1
(Z)-2-(4-Chlorobenzyl)-3-benzylideneisoindolin-1-one (3{4}) [21]. H-NMR (CDCl3): δ 7.94 (d,
J = 7.8 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.29–7.27

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(m, 3H), 7.09–7.07 (m, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 6.45 (d, J = 8.1 Hz, 2H),
4.91 (s, 2H); ESI-MS m/z 346 [M+H]+.
(Z)-2-(4-methoxybenzyl)-3-benzylideneisoindolin-1-one (3{5}) [21]. 1H-NMR (CDCl3): δ 7.91
(d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H),
7.29–7.28 (m, 3H), 7.13–7.12 (m, 2H), 6.71 (s, 1H), 6.58 (d, J = 8.4 Hz, 2H), 6.44 (d, J = 8.1 Hz, 2H),
4.88 (s, 2H), 3.71 (s, 3H); ESI-MS m/z 342 [M+H]+.
1
(Z)-2-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-benzylideneisoindolin-1-one (3{6}). H-NMR (CDCl3): δ
7.91 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H),
7.31–7.29 (m, 3H), 7.15–7.13 (m, 2H), 6.73 (s, 1H), 6.48 (d, J = 7.8 Hz, 1H), 6.06 (s, 1H),
13
5.94 (d, J = 7.8 Hz, 1H), 5.84 (s, 2H), 4.85 (s, 2H); C NMR (CDCl3) δ 168.9, 147.3, 146.3, 138.5,
134.6, 134.2, 132.1, 130.7, 129.7 (2C), 129.0, 128.0, 127.9 (2C), 127.4, 123.4, 119.8, 119.4, 107.7,
107.4, 107.1, 100.7, 44.4; IR (KBr) ν 3034, 1686, 1643, 1610, 1491, 1448, 1335, 1248, 945, 771, 700
cm−1; EI-MS m/z 355 (M+); HRMS (EI) Calcd for m/z C23H17NO3 355.1208, found 355.1216 .
1
(Z)-3-Benzylidene-2-phenylisoindolin-1-one (3{7}) [21]. H-NMR (CDCl3): δ 7.95 (d, J = 7.8 Hz, 1H),
7.86 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.08 (m, 5H), 6.97–6.84
(m, 5H), 6.83 (s, 1H); ESI-MS m/z 298 [M+H]+.
(Z)-3-Benzylidene-2-(4-fluorophenyl)isoindolin-1-one (3{8}). 1H-NMR (CDCl3): δ 7.95 (d, J = 7.2 Hz,
1H), 7.86 (d, J = 7.8 Hz, 1H), 7.69 (td, J = 7.8, 1.2 Hz, 1H), 7.54 (td, J = 7.5, 0.9 Hz, 1H), 7.06–6.94
13
(m, 5H), 6.88–6.85 (m, 3H), 6.78–6.75 (m, 2H); C NMR (CDCl3) δ 168.0, 161.1 (d, J = 245.1 Hz),
138.4, 134.4, 133.4, 132.5, 131.8, 129.3, 129.1 (2C), 128.8, 128.7, 127.6, 127.3 (2C), 126.8, 123.9,
119.4, 115.1, 114.9, 107.6; IR (KBr) ν 3435, 3066, 1711, 1645, 1508, 1387, 1219, 1124, 760, 692 cm−1;
EI-MS m/z 315 (M+); HRMS (EI) Calcd for m/z C21H14NOF 315.1059, found 315.1054.
1
(Z)-3-Benzylidene-2-p-tolylisoindolin-1-one (3{9}) [25]. H-NMR (CDCl3): δ 7.94 (d, J = 7.2 Hz, 1H),
7.85 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 6.98–6.84 (m, 9H),
6.81 (s, 1H), 2.22 (s, 3H); ESI-MS m/z 312 [M+H]+.
(Z)-3-Benzylidene-2-(2-(thiophen-2-yl)ethyl)isoindolin-1-one (3{10}). 1H-NMR (CDCl3): δ 7.86
(d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (td, J = 7.5, 1.2 Hz, 1H), 7.51 (td, J = 7.2, 0.6 Hz, 1H),
7.44–7.38 (m, 5H), 7.00 (dd, J = 4.8, 1.2 Hz, 1H), 6.83 (s, 1H), 6.79–6.76 (m, 1H), 6.32 (d, J = 3.3 Hz,
13
1H), 3.94 (td, J = 8.1, 2.4 Hz, 2H), 2.74 (td, J = 8.1, 2.4 Hz, 2H); C-NMR (CDCl3) δ 168.5, 139.8,
138.3, 134.7, 134.5, 132.0, 129.5 (2C), 129.0, 128.4 (2C), 128.2, 127.8, 126.6, 125.2, 123.6, 123.3,
119.3, 106.6, 42.9, 28.3; IR (KBr) ν 3390, 2939, 1701, 1664, 1614, 1471, 1444, 1346, 1097, 997, 756,
694 cm−1; EI-MS m/z 331 (M+); HRMS (EI) Calcd for m/z C21H17NOS 331.1031, found 331.1035.
1
(Z)-2-(2-(1H-Pyrrol-1-yl)ethyl)-3-benzylideneisoindolin-1-one (3{11}) H-NMR (CDCl3): δ 7.86 (td,
J = 7.5, 0.9 Hz, 1H), 7.77 (d, J = 7.2, 0.6 Hz, 1H), 7.63 (td, J = 7.5, 1.2 Hz, 1H), 7.52 (td, J = 7.5,
0.9 Hz, 1H), 7.49–7.37 (m, 5H), 6.82 (s, 1H), 6.07 (t, J = 2.1 Hz, 2H), 5.97 (t, J = 2.1 Hz, 2H), 4.01 (td,
13
J = 7.5, 1.8 Hz, 2H), 3.68 (td, J = 7.8, 2.4 Hz, 2H); C-NMR (CDCl3) δ 168.4, 138.1, 134.5, 134.4,
132.2, 129.6 (2C), 129.2, 128.5 (2C), 128.0, 127.9, 123.3, 120.6 (2C), 119.3, 108.1 (2C), 106.4, 46.6,

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42.2; IR (KBr) ν 2941, 1701, 1666, 1616, 1443, 1344, 1300, 1088, 1016, 712 cm−1; EI-MS m/z 314
(M+); HRMS (EI) Calcd for m/z C21H18N2O 314.1419, found 314.1415.
(Z)-2-Benzyl-3-benzylidene-5-methylisoindolin-1-one (3{12}) 1H-NMR (CDCl3): δ 7.81 (d, J = 7.8 Hz,
1H), 7.54 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.28–7.21 (m, 3H), 7.08–7.00 (m, 5H), 6.68 (s, 1H), 6.51 (d,
13
J = 8.4 Hz, 2H), 4.91 (s, 2H), 2.51 (s, 3H); C-NMR (CDCl3) δ 169.1, 142.8, 138.8, 136.9, 134.7,
134.4, 130.1, 129.6 (2C), 127.9 (2C), 127.8 (2C), 127.3, 126.6, 126.3 (2C), 125.7, 123.3, 119.8, 107.1,
44.8, 22.1; IR (KBr) ν 3032, 1695, 1649, 1624, 1491, 1444, 1344, 1151, 968, 696 cm−1; EI-MS m/z
325 (M+); HRMS (EI) Calcd for m/z C23H19NO 325.1467, found 325.1458.
1
(Z)-2-Benzyl-3-benzylidene-5-chloroisoindolin-1-one (3{13}) [18]. H-NMR (CDCl3): δ 7.85 (d,
J = 8.4 Hz, 1H), 7.71 (d, J = 0.9 Hz, 1H), 7.49 (dd, J = 8.1, 1.8 Hz, 1H), 7.29–7.25 (m, 3H), 7.06–7.04
(m, 5H), 6.69 (s, 1H), 6.50 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H); ESI-MS m/z 346 [M+H]+.
1
(Z)-2-Benzyl-3-benzylidene-6-fluoroisoindolin-1-one (3{14}). H-NMR (CDCl3): δ 7.71 (dd, J = 8.4,
4.2 Hz, 1H), 7.59 (dd, J = 7.5, 2.4 Hz, 1H), 7.36–7.22 (m, 4H), 7.10–7.02 (m, 5H), 6.67 (s, 1H),
13
6.54–6.51 (m, 2H), 4.93 (s, 2H); C-NMR (CDCl3) δ 167.8, 163.4 (d, J = 247.8 Hz), 136.5, 134.3,
133.5, 130.0, 129.9, 129.6 (2C), 128.0 (2C), 127.5, 126.8, 126.3 (2C), 121.3 (d, J = 8.6 Hz), 120.0, 119.7,
110.1, 109.9, 107.8, 45.0; IR (KBr) ν 3045, 1705, 1660, 1483, 1427, 1265, 1117, 702 cm−1; EI-MS m/z
329 (M+); HRMS (EI) Calcd for m/z C22H16NOF 329.1216, found 329.1213.
1
(Z)-2-Benzyl-3-benzylidene-6-methoxyisoindolin-1-one (3{15}) [18]. H-NMR (CDCl3): δ 7.63 (d,
J = 8.1 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.34–7.23 (m, 3H), 7.18 (dd, J = 8.4, 2.7 Hz, 1H), 7.09–7.05
(m, 5H), 6.60 (s, 1H), 6.54–6.52 (m, 2H), 4.92 (s, 2H), 3.93 (s, 3H); ESI-MS m/z 342 [M+H]+.
(Z)-6-Benzyl-7-benzylidene-6,7-dihydropyrrolo[3,4-b]pyridin-5-one (3{16}). 1H-NMR (CDCl3): δ 8.80
(dd, J = 4.8, 1.8 Hz, 1H), 8.20 (dd, J = 7.5, 1.8 Hz, 1H), 7.45 (dd, J = 7.5, 4.5 Hz, 1H), 7.28–7.25 (m,
4H), 7.14–7.05 (m, 5H), 6.56 (dd, J = 7.8, 1.8 Hz, 2H), 4.99 (s, 2H); 13C-NMR (CDCl3) δ 166.7, 156.7,
153.4, 136.4, 134.1, 133.4, 131.5, 129.5 (2C), 128.1 (2C), 127.9 (2C), 127.7, 126.9, 126.4 (2C), 123.8,
121.6, 110.0, 44.7; IR (KBr) ν 3026, 1718, 1662, 1605, 1585, 1493, 1448, 1400, 1360, 1171, 976, 781,
700 cm−1; EI-MS m/z 312 (M+); HRMS (EI) Calcd for m/z C21H16N2O 312.1263, found 312.1259.
1
(Z)-3-(4-Fluorobenzylidene)-2-benzylisoindolin-1-one (3{17}) [26]. H-NMR (CDCl3): δ 7.93 (d,
J = 7.2 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.63 (td, J = 6.3, 1.2 Hz, 1H), 7.56 (td, J = 6.3, 0.9 Hz, 1H),
7.09–6.88 (m, 7H), 6.64 (s, 1H), 6.55 (dd, J = 6.9, 1.8 Hz, 2H), 4.90 (s, 2H); ESI-MS m/z 330 [M+H]+.
(Z)-3-(4-Methxybenzylidene)-2-benzylisoindolin-1-one (3{18}). 1H-NMR (CDCl3): δ 7.93 (d, J = 7.2 Hz,
1H), 7.76–7.73 (m, 1H), 7.62 (td, J = 7.2, 1.2 Hz, 1H), 7.53 (td, J = 7.8, 1.5 Hz, 1H), 7.17 (t, J = 7.5 Hz,
1H), 7.11–7.06 (m, 4H), 6.92 (d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.57 (m, 2H), 4.92 (s, 2H),
2.21 (s, 3H); 13C-NMR (CDCl3) δ 169.0, 138.5, 137.5, 136.9, 134.4, 134.2, 132.0, 130.3, 128.9, 128.1,
128.0, 127.9 (2C), 127.7, 126.6 (2C), 126.2 (2C), 123.4, 119.4, 107.7, 44.9, 21.2; IR (KBr) ν 2924,
1695, 1657, 1429, 1396, 1344, 980, 766, 698 cm−1; EI-MS m/z 325 (M+); HRMS (EI) Calcd for m/z
C23H19NO 325.1467, found 325.1471.

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1
(Z)-3-(4-methoxybenzylidene)-2-benzylisoindolin-1-one (3{19}) [27]. H-NMR (CDCl3): δ 7.92 (d,
J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.09–7.06
(m, 3H), 7.01 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 6.61–6.59 (m, 2H),
4.96 (s, 2H), 3.85 (s, 3H); EI-MS m/z 341 (M+).
(Z)-2-Benzyl-3-(cyclohexylmethylene)isoindolin-1-one (3{20}). 1H-NMR (CDCl3): δ 7.89 (d, J = 7.5 Hz,
1H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.32–7.19 (m, 3H),
7.12 (d, J = 7.2 Hz, 2H), 5.40 (d, J = 10.8 Hz, 1H), 5.23 (s, 2H), 2.54–2.50 (m, 1H), 1.71–1.02 (m,
13
10H); C-NMR (CDCl3) δ 168.3, 138.4, 137.6, 131.7, 131.5, 128.6 (2C), 128.2, 127.7, 127.0 (2C),
125.8 (2C), 123.3, 119.0, 115.5, 44.9, 35.7, 33.7, 32.0, 25.7, 25.6; IR (KBr) ν 2929, 2848, 1701, 1660,
1437, 1402, 1362, 1126, 968, 762, 739, 696 cm−1; EI-MS m/z 317 (M+); HRMS (EI) Calcd for m/z
C22H23NO 317.1780, found 317.1773.
4. Conclusions
In conclusion, we have developed a practical and convenient protocol for the preparation of
(Z)-3-methyleneisoindolin-1-one libraries. Especially, only Z-isomers were obtained. This domino
reaction is efficiently promoted by easily available Cu(OAc)2•H2O in the presence of DBU under
microwave irradiation. Environmentally friendly EtOH was used as solvent. Various benzamide
substituents, and ring substitutions including heteroaryl, aryl acetylenes and aliphatic alkynes could be
applied to afford thre desired products in good to moderate yield with high stereoselectivity and high
purity. Short reaction times and simple reaction conditions make this method suitable for the synthesis
of (Z)-3-methyleneisoindolin-1-one libraries for biological and medicinal chemistry.
Acknowledgments
This work was financially supported by Natural Science Foundation of China grant
(No. 81102395).
References
1. Rys, V.; Couture, A.; Deniau, E.; Grandclaudon, P. First total synthesis of fumaridine.
Tetrahedron 2003, 59, 6615–6619.
2. Ishihara, Y.; Kiyota, Y.; Goto, G. Synthesis of Isoindolo[2,1-a]quinoline Derivatives and Their
Effects on N2-Induced Hypoxia. Chem. Pharm. Bull. 1990, 38, 3024–3030.
3. Fuwa, H.; Sasaki, M. An efficient method for the synthesis of enol ethers and enecarbamates.
Total syntheses of isoindolobenzazepine alkaloids, lennoxamine and chilenine. Org. Biomol. Chem.
2007, 5, 1849–1853.
4. Flitsch, W.; Peters, H. Wittig-reaktionen an imiden. Tetrahedron Lett. 1969, 10, 1161–1162.
5. Bousquet, T.; Fleury, J.F.; Daich, A.; Netchitailo, P. Oxidized isoquinolinoisoindolinone and
benzazepinoisoindolinone alkaloids cores by convergent cyclisation processes: π-aromatic attack
of thionium and oxonium species. Tetrahedron 2006, 62, 706–715.
6. Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.
A
New Approach to
Isoindolobenzazepines. A Simple Synthesis of Lennoxamine. Tetrahedron 2000, 56, 1491–1499.

Molecules 2013, 18
664
7. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. A New Route to Aristocularine Alkaloids:
Total Synthesis of Aristoyagonine. J. Org. Chem. 2004, 69, 4527–4530.
8. Wu, M.J.; Chang, L.J.; Wei, L.M.; Lin, C.F. A direct anionic cyclization of 2-alkynylbenzonitrile
to 3-substituted-1(2H)-isoquinolones and 3-benzylideneisoindol-2-ones initiated by methoxide
addition. Tetrahedron 1999, 55, 13193–13200.
9. Lu, W.D.; Lin, C.F.; Wang, C.J.; Wang, S.J.; Wu, M.J. Substituent effect on anionic
cycloaromatization of 2-(2-substituted ethynyl)benzonitriles and related molecules. Tetrahedron
2002, 58, 7315–7319.
10. Reyes-Gonzalez, M.A.; Zamudio-Medina, A.; Ordonez, M. Practical and high stereoselective
synthesis of 3-(arylmethylene)isoindolin-1-ones from 2-formylbenzoic acid. Tetrahedron Lett.
2012, 53, 5756–5758.
11. Hatoum, F.; Engler, J.; Zelmer, C.; Wißen, J.; Motti, C.A.; Lex, J.; Oelgemoller, M.
Photodecarboxylative addition of carboxylates to phthalimides: A concise access to biologically
active 3-(alkyl and aryl)methylene-1H-isoindolin-1-ones. Tetrahedron Lett. 2012, 53, 5573–5577.
12. Cao, H.; McNamee, L.; Alper, H. Syntheses of Substituted 3-Methyleneisoindolin-1-ones By a
Palladium-Catalyzed Sonogashira Coupling−Carbonylation−Hydroamination Sequence in
Phosphonium Salt-Based Ionic liquids. Org. Lett. 2008, 10, 5281–5284.
13. Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Synthesis of 3-(arylmethylene)isoindolin-1-ones
from ynamides by Heck–Suzuki–Miyaura domino reactions. Application to the synthesis of
lennoxamine. Tetrahedron 2006, 62, 3882–3895.
14. Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Heck–Suzuki–Miyaura Domino Reactions Involving
Ynamides. An Efficient Access to 3-(Arylmethylene)isoindolinones. Org. Lett. 2004, 6, 2511–2514.
15. Sun, C.Y.; Xu, B.A. Tandem Elimination−Cyclization−Suzuki Approach: Efficient One-Pot
Synthesis of Functionalized (Z)-3-(Arylmethylene)isoindolin-1-ones. J. Org. Chem. 2008, 73,
7361–7364.
16. Kundu, N.G.; Khan, M.W. An expeditious synthesis of Z-3-alkylidene isoindolinones via combined
palladium catalysed and friedel-crafts reactions. Tetrahedron Lett. 1997, 38, 6937–6940.
17. Kundu, N.G.; Khan, M.W.; Mukhopadhyay, R. Heteroannulation through combined palladium
catalysed and Friedel-Crafts reactions strategy: Synthesis of 3-alkylidene isoindolin-1-ones.
Tetrahedron 1999, 55, 12361–12376.
18. Hellal, M; Cuny, G.D. Microwave assisted copper-free Sonogashira coupling/5-exo-
digcycloisomerization domino reaction: Access to 3-(phenylmethylene)isoindolin-1-ones and
related heterocycles. Tetrahedron Lett. 2011, 52, 5508–5511.
19. Gabriele, B.; Mancuso, R.; Ziccarelli, I.; Salerno, G. A new approach to isoindolinone derivatives
by sequential palladium iodide-catalyzed oxidative aminocarbonylation–heterocyclization of 2-
ethynylbenzamides. Tetrahedron Lett. 2012, 53, 6694–6696.
20. Lee, H.G.; Kim, K.H.; Kim, S.H.; Kim, J.N. Palladium-catalyzed oxidative arylation of
trisubstituted olefin: an efficient synthesis of 3-(disubstituted)alkylidene-oxindoles. Tetrahedron Lett.
2013, 54, 170–175.
21. Li, L.; Wang, M.; Zhang, X.J.; Jiang, Y.W.; Ma, D.W. Assembly of Substituted
3-Methyleneisoindolin-1-ones via a CuI/L-Proline-Catalyzed Domino Reaction Process of
2-Bromobenzamides and Terminal Alkynes. Org. Lett. 2009, 11, 1309–1312.

Molecules 2013, 18
665
22. Kappe, C.O.; Dallinger, D. Controlled microwave heating in modern organic synthesis:
Highlights from the 2004–2008 literature. Mol. Divers. 2009, 13, 71–193.
23. Jiang, B.; Xue, L.Y.; Wang, X.H.; Tu, M.S.; Liu, Y.P.; Tu, S.J. Microwave-assisted
multicomponent reaction of aryl amidines: Regiospecific synthesis of new polysubstituted
thiopyrano-, and pyrano[4,3-d]pyrimidines. Tetrahedron Lett. 2012, 53, 1261–1264.
24. Xie, Y.X.; Deng, C.L.; Pi, S.F.; Li, J.H.; Yin, D.L. Cu(OAc)2/Pyrimidines-Catalyzed Cross-
coupling Reactions of Aryl Iodides and Activated Aryl Bromides with Alkynes under Aerobic,
Solvent-free and Palladium-free Conditions. Chin. J. Chem. 2006, 24, 1290–1294.
25. Khan, M.W.; Kundu, N.G. A Highly Regio and Stereoselective Synthesis of (Z)-3-
Aryl(alkyl)idene Isoindolin-1-ones via Palladium Catalyzed Annulation of Terminal Alkynes.
Synlett 1997, 12, 1435–1437.
26. Cao, H.; McNamee, L.; Howard, A. Syntheses of Substituted 3-Methyleneisoindolin-1-ones By a
Palladium-Catalyzed Sonogashira Coupling–Carbonylation–Hydroamination Sequence in
Phosphonium Salt-Based Ionic liquids. Org. Lett. 2008, 10, 5281–5284.
27. Kundu, N.G.; Khan, M.W. Palladium-Catalysed Heteroannulation with Terminal Alkynes:
A Highly Regio- and Stereoselective Synthesis of (Z)-3-Aryl(alkyl)idene Isoindolin-1-ones.
Tetrahedron 2000, 56, 4777–4792.
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