One-pot synthesis of isoindolinones via three-component Mannich/lactamization cascade reaction

Article abstract of DOI:10.1080/00397911.2010.535948

An efficient synthesis of 3-substituted 2,3-dihydroisoindolin-1-ones was achieved with good yields (up to 88%). The process features broad substrate scope, high efficiency, and simplicity, using an one-pot, three-component Mannich/lactamization cascade reaction in the absence or presence of p-toluenesulfonic acid. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.535948

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One-Pot Synthesis of Isoindolinones
via Three-Component Mannich/
Lactamization Cascade Reaction
Haoyi Zhang a , Yixin Leng a , Wenjing Liu a & Wenhu Duan a b
a School of Pharmacy, East China University of Science and
Technology, Shanghai, China
b Department of Medicinal Chemistry, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai, China
Accepted author version posted online: 21 Oct 2011.Version of
record first published: 22 Dec 2011.
To cite this article: Haoyi Zhang, Yixin Leng, Wenjing Liu & Wenhu Duan (2012): One-Pot Synthesis
of Isoindolinones via Three-Component Mannich/Lactamization Cascade Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:8, 1115-1127
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Synthetic Communications1, 42: 1115–1127, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535948
ONE-POT SYNTHESIS OF ISOINDOLINONES VIA
THREE-COMPONENT MANNICH/LACTAMIZATION
CASCADE REACTION
Haoyi Zhang,1 Yixin Leng,1 Wenjing Liu,1 and Wenhu Duan1,2
1School of Pharmacy, East China University of Science and Technology,
Shanghai, China
2Department of Medicinal Chemistry, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai, China
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of 3-substituted 2,3-dihydroisoindolin-1-ones was achieved
with good yields (up to 88%). The process features broad substrate scope, high efficiency,
and simplicity, using an one-pot, three-component Mannich/lactamization cascade reaction
in the absence or presence of p-toluenesulfonic acid.
Keywords Cascade reaction; isoindolinone; lactamization; Mannich reaction; three-
component
INTRODUCTION
Molecules containing 3-substituted isoindolinone skeletons have drawn much
attention in recent years because of their broad distribution and biological activi-
ties.[1] Typical examples include clinically used anxiolytic drugs pagoclone (1) and
pazinaclone (2),[2] anticonvulsant agent zopiclone (3) (Fig. 1),[3] as well as other
Received August 22, 2010.
Address correspondence to Wenhu Duan, Department of Medicinal Chemistry, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. E-mail: whduan@
mail.shcnc.ac.cn
1115

1116
H. ZHANG ET AL.
Figure 1. Examples of three isoindolinone therapeutic agents.
Scheme 1. The synthetic route to 2,3-disubstituted isoindolinones via a Mannich=lactamization cascade
reaction.
therapeutic agents.[4] Despite their synthetic and medicinal importance, only a hand-
ful of synthetic methods relying on the use of a strong base[5] or metal-mediated
catalysis[6] are available. More efficient synthetic protocols therefore are still needed.
In this communication, we report an efficient three-component Mannich=lactamiza-
tion cascade process for the facile synthesis of 3-substituted isoindolinones under
mild reaction conditions.
The Mannich reaction is a cornerstone of synthetic organic chemistry that has
afforded a multitude of nitrogenous compounds. As a result, the reaction has
long-standing interest to organic chemists. An abundance of imaginative reagents,
catalysts, and protocols have been devised for the synthesis of structurally diversified
building blocks and pharmaceutical products.[7] We envision that through the de
novo design of proper substrates and careful manipulation of functional group reac-
tivity, a one-pot, three-component strategy with incorporation of an unprecedented
Mannich-initiated lactamization reaction sequence can be applied for the efficient
preparation of synthetically and biologically significant 3-substituted isoindolinones
(Scheme 1).
RESULTS AND DISCUSSION
In the proposed process, 2-formylbenzoate 5 is the essential reactant, which
serves as an acceptor for the Mannich reaction and also as a substrate for the
subsequent lactamization. Although the Mannich reaction between aryl aldehydes
and ketones has been intensively studied, to our knowledge, the version of 2-formyl-

SYNTHESIS OF ISOINDOLINONES
1117
benzoate 5 with ketones 6 and amines 7 has not been reported. A classic intermole-
cular three-component Mannich reaction, which consists of an amine and two differ-
ent carbonyl species, is plagued by undesired side reactions, such as deamination and
formation of methylene bisketones.[8] Moreover, because of the highly sensitive nat-
ure of both substrate structures and reaction conditions, the Mannich reaction with
2-formylbenzoate 5 requires optimal reaction conditions, which are also suitable for
the subsequent lactamization process.
In an initial exploration, we found that the reaction occurred smoothly
between methyl 2-formylbenzoate (5a), acetone (6a), and 4-methoxyaniline (7a,
R4¼4-MeO-Ph) (Table 1, entry 1). This result led to our focus on the Mannich=lac-
tamization cascade reaction in the absence of catalyst. To our knowledge, a
catalyst-free Mannich=lactamization cascade reaction is unprecedented, although
several catalyst-free Mannich reactions have been documented.[9]
We first examined the effect on reactivity of a range of substituted anilines and
aliphatic amines in acetone at ambient temperature using Mannich acceptor methyl
2-formylbenzoate and Mannich donor acetone. With respect to anilines, the sub-
stituent pattern on phenyl played a very important role in the Mannich=lactamiza-
tion process. The result revealed that anilines with electron-withdrawing and
electron-donating substituents at the para-position were very reactive and gave good
yields (78–84%) of the isoindolinones 4 (Table 1, entries 1–4). However, anilines with
electron-donating substituents at the ortho- and meta-position gave only a trace
amount of corresponding products (Table 1, entries 5 and 6). We speculated
that the lactamization was delicately affected by the electronic effects (meta-position)
and steric hindrance (ortho-position) of the ring substituents, indicating the
structural sensitivity of the Mannich process. On the other hand, no reaction
Table 1. Scope of amines in the three-component catalyst-free Mannich=lactamization processa
Entry
R1
Time (h)
Products
Yieldb (%)
1
2
3
4
5
6
7
8
9
4-MeO-Ph
Ph
1
4
4a
4b
4c
4d
4e
4f
82
78
4-Cl-Ph
4-Me-Ph
2-MeO-Ph
3-MeO-Ph
n-Bu
4
84
80
4
12
8
<5
Complex
No reaction
No reaction
No reaction
24
24
24
4g
4h
4i
PhCH2
Cyclohexyl
a5a (0.2 mmol), acetone (0.8 mL), and amine 7 (0.2 mmol) were used.
bIsolated yield.

1118
H. ZHANG ET AL.
Table 2. Effect of solvent on the three-component cascade reactiona
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
CH2Cl2
CHCl3
MeOH
i-PrOH
MeCN
DMF
1
1
88
85
68
73
52
50
<5
1
1
1
1
12
H2O
a5a (0.2 mmol), cyclohexanone (0.2 mmol), 4-methoxybenzenamine (0.2 mmol), and solvent (0.5 mL)
were used.
bIsolated yield.
occurred with aliphatic amines such as n-butylamine, benzylamine, and cyclohexyla-
mine (Table 1, entries 7–9) under the catalyst-free condition.
The reaction media had a signicicant impact on the cascade reaction (Table 2).
In halogenated solvents (entries 1 and 2), the process proceeded smoothly to give
3-disubstituted isoindolinone 4j in good yield; whereas in alcoholic media (entries
3 and 4) and polar aprotic solvents (entries 5 and 6), deamination was observed,
resulting in slighly lower reaction yields. In addition, water is not suitable for the
process (entry 7). Based on these experimental results, dichloromethane (DCM)
was selected as solvent for exploration of the generality of the process.
To examine the scope of the Mannich donor, three ketones and two dicarbonyl
compounds were tested. As shown in Table 3, under the optimal reaction conditions,
unsymmetric ketones smoothly participated in the process. As represented by buta-
none, the reaction afforded a mixture of regioisomeric products with a selectivity of
2.5=1 (less substituted product is major) (entry 2). Disappointingly, the process was
completely inert to Mannich donors such as acetophenone (entry 3). With respect to
the dicarbonyl compounds, acetylacetone and ethyl acetoacetate, the major deami-
nation products were predominantly isolated and only a small portion of expected
isoindolinones was observed (entries 4 and 5).
The effect of substitution on the phenyl of Mannich acceptor methyl 2-formyl-
benzoates 5 was probed next. However, the reaction of 5-substituted methyl 2-for-
mylbenzoates with 4-methoxyaniline (7a) in acetone failed to give the desired
products. We again speculated that the electronic effect of the substituents greatly
affects the subsequent lactamization.
To generate a diverse set of 3-substituted isoindolinones, all of the unsuccessful
examples under catalyst-free condition were reexamined in the presence of 20 mol%

SYNTHESIS OF ISOINDOLINONES
1119
Table 3. The scope of Mannich donorsa
Entry
R1, R2
Time (h)
Products
Yieldb (%)
1
(CH2)4
Et, H
Ph, H
1
10
24
10
10
4j
4k
–
88%
70%
2a
3
No reaction
<5%
<5%
4
CH3COCH2, H
EtOOCCH2, H
–
5
–
a5a (0.2 mmol), 6 (0.2 mmol), 4-methoxybenzenamine (0.2 mmol), and dichloromethane (0.5 mL) were
used.
bRegioselectivity ratio 2.5=1 (less substituted product dominantly).
p-toluenesulfonic acid. To our delight, this process proceeded smoothly to give
3-substituted isoindolinones (Table 4). The results showed that primary amines were
more suitable substrates than secondary amines, which could be explained by the
Table 4. Scope of the three-component Mannich=lactamization cascade in the presence of p-TsOHa
Entry
5
R2
Time (h)
Products
Yieldb (%)
1
2a
3
5a (R1, H)
n-Bu
Benzyl
1
10
10
20
10
10
6
4g
4h
4i
83
80
45
76
85
71
73
86
82
78
78
74
5a (R1, H)
5a (R1, H)
Cyclohexyl
i-Bu
4
5a (R1, H)
4l
5
5a (R1, H)
2-Ethoxyethyl
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4m
4n
4o
4p
4q
4r
6
5n (R1, 5-F)
5o (R1, 5-Cl)
5p (R1, 5-Br)
5q (R1, 5-OH)
5r (R1, 5-OMe)
5s (R1, 5-Ph)
5t (R1, 5-NO2)
7
8
6
9
6
10
11
12
6
6
4s
6
4t
a5 (0.2 mmol), acetone (0.8 mL), amine 7 (0.2 mmol), and the catalyst p-toluenesulfonic acid (0.04 mmol)
were used.
bIsolated yield.

1120
H. ZHANG ET AL.
formation of a substantial amount of deamination by-product in the secondary
amine case (entry 4).
CONCLUSIONS
In brief, we have developed a one-pot, three-component Mannich=lactamiza-
tion approach to the synthesis of 3-substituted isoindolinones under catalyst-free
conditions or in the presence of p-toluenesulfonic acid. This method features a broad
substrate scope, simple process (one pot), mild reaction conditions, and moderate to
good yields. Therefore, this method should serve as a useful tool for the construction
of biologically active molecules with the isoindolinone scaffold.
EXPERIMENTAL
Commercially available reagents were used as received, unless specified. 1H and
13C NMR spectra were recorded on Bruker Avance-400 spectrometers. Chemical
shifts are reported in parts per million (ppm) from tetramethylsilane (TMS) with
the solvent resonance as the internal standard. The following abbreviations were
used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; dd, doub-
let of doublets; m, multiplet; and br, broad. Mass spectrometry was performed on a
Micromass GCT CA055. Routine monitoring of reaction was performed by thin-
layer chromatography (TLC) with silica gel GF254 precoated on glass plates, and
spots were visualized with ultraviolet light. Flash column chromatography was per-
formed on silica gel. Infrared (IR) spectra were recorded on an IR200 spectrometer.
Melting points were measured with micro-melting-point apparatus.
General Procedure for Synthesis of 4
Method A (catalyst-free). Ketone (0.2 mmol, 1 eq) and amine (0.2 mmol,
1 eq) were added to a solution of 5a (0.2 mmol, 1 eq) in solvent (0.8 mL), the result-
ing solution was stirred at room temperature. The reaction was monitored by TLC.
When the reaction was completed, the reaction mixture was diluted with 20 mL
DCM, washed with diluted HCl (0.1 M) (10 mL ꢀ 3) and brine, dried over anhydrous
Na2SO4, and filtered. The solvent was removed under reduced pressure, and the resi-
due was purified with flash chromatography on silica gel to give compound 4.
Method B (catalyzed by p-toluenesulfonic acid). The amine (0.2 mmol, 1
eq), ketone (0.2 mmol, 1 eq), and the catalyst p-toluenesulfonic acid (8.0 mg,
0.04 mmol, 0.2 eq) were added to a stirred solution of 5a (0.2 mmol, 1 eq) in solvent
(0.8 mL). The resulting mixture was stirred at room temperature. The reaction was
monitored by TLC. When the reaction finished, the reaction mixture was diluted
with 20 mL DCM, washed with diluted HCl (0.1 M) (10 mL ꢀ 3) and brine, dried
over anhydrous Na2SO4, and filtered. The solvent was removed under reduced press-
ure, and the residue was purified with flash chromatography on silica gel to give
compound 4.
2-(4-Methoxyphenyl)-3-(2-oxopropyl)isoindolin-1-one (4a). The com-
pound 4a was prepared following general method A to give a white solid, 48 mg,

SYNTHESIS OF ISOINDOLINONES
1121
1
yield: 82%. Mp: 127–130 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.92 (d, 1H,
J ¼ 7.6 Hz, ArH), 7.42–7.59 (m, 5H, ArH), 6.98 (d, 2H, J ¼ 7.6 Hz, ArH), 5.63
(dd, 1H, J ¼ 9.0, 3.6 Hz, NCH), 3.84 (s, 3H, OMe), 3.00 (dd, 1H, J ¼ 17.8, 3.6 Hz,
COCH2), 2.63 (dd, 1H, J ¼ 17.8, 9.0 Hz, COCH2), 2.10 (s, 3H, COCH3); 13C
NMR (100 MHz, CDCl3) (d, ppm): 206.1, 166.8, 157.7, 145.0, 132.1, 132.9, 129.3,
128.6, 125.6, 124.0, 122.8, 114.6, 57.1, 55.5, 46.5, 30.7; MS (EI) m=z (%) 295.1
(Mþ, 18), 264.0 (17), 238.1 (100), 108.1 (12), 77.0 (9). IR (KBr): 2962, 2917, 1708,
1687, 1518, 1403, 1250 cmꢂ1; HRMS (EI) m=z calcd. for C18H17NO3 295.1208
(Mþ); found 295.1209.
2-Phenyl-3-(2-oxopropyl)isoindolin-1-one (4b). The compound 4b was
prepared following general method A to give a white solid, 41 mg, yield: 78%. Mp:
1
89–90 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.92 (d, 1H, J ¼ 7.2 Hz, ArH),
7.56–7.58 (m, 5H, ArH), 7.43–7.53 (m, 4H, ArH), 7.23–7.28 (m, 1H, ArH), 5.72
(dd, 1H, J ¼ 9.2, 3.2 Hz, NCH), 3.05 (dd, 1H, J ¼ 18, 3.2 Hz, COCH2), 2.64 (dd,
1H, J ¼ 18.0, 9.2 Hz, COCH2), 2.10 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3)
(d, ppm): 206.1, 166.8, 145.0, 136.5, 132.4, 131.8, 129.3, 128.7, 125.7, 124.1, 123.4,
122.8, 56.5, 46.5, 30.7; MS (EI) m=z (%) 265.1 (Mþ) (12), 236.1 (12), 222.1 (84),
208.1 (100), 77.0(18); HRMS (EI) m=z calcd. for C17H15NO2 265.1103 (Mþ); found
265.1105.
2-(4-Chlorophenyl)-3-(2-oxopropyl)isoindolin-1-one (4c). The compound
4c was prepared following general method A to give a white solid, 50 mg, yield: 84%.
1
Mp: 107–108 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.91 (d, 1H, J ¼ 7.2 Hz,
ArH), 7.46–7.61 (m, 5H, ArH), 7.40–7.43 (m, 2H, ArH), 5.69 (dd, J ¼ 9.2, 3.2 Hz,
NCH), 3.04 (dd, J ¼ 18.0, 3.2 Hz, COCH2), 2.65 (dd, 1H, J ¼ 18.0, 9.2 Hz), 2.13 (s,
3H, COCH3); 13C NMR (100 MHz, CDCl3) (d, ppm): 205.8, 166.8, 144.9, 135.2,
132.6, 131.4, 131.0, 129.4, 128.8, 124.3, 124.2, 122.8, 56.3, 46.3, 30.7; MS (EI) m=z
(%) 299.1 (Mþ) (22), 270.1 (11), 256.1 (43), 242.0 (100), 111.0 (10), 77.0 (4); HRMS
(EI) m=z calcd. for C17H14ClNO2: 299.0713 (Mþ); found 299.0717.
2-(4-Methylphenyl)-3-(2-oxopropyl)isoindolin-1-one (4d). The com-
pound 4d was prepared following general method A to give a white solid, 44 mg,
1
yield: 80%. Mp: 132–133 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.90 (d, 1H,
J ¼ 3.2 Hz, ArH), 7.42–7.58 (m, 5H, ArH), 7.24–7.28 (m, 2H, ArH), 5.67 (dd, 1H,
J ¼ 9.2, 3.2 Hz, ArH), 3.03 (dd, 1H, J ¼ 18.0, 3.2 Hz, COCH2), 2.62 (dd, 1H,
J ¼ 18.0, 9.2 Hz, COCH2), 2.37 (s, 3H, ArCH3), 2.09 (s, 3H, COCH3); 13C NMR
(100 MHz, CDCl3) (d, ppm): 206.1, 166.7, 145.0, 135.6, 133.9, 132.2, 131.9, 129.9,
128.6, 124.1, 123.6, 122.8, 56.7, 46.5, 30.7, 20.9; MS (EI) m=z (%) 279.1 (Mþ) (24),
236.1 (58), 222.1 (100), 91.1 (13); HRMS (EI) m=z calcd. for C18H17NO2 279.1259
(Mþ); found 279.1260.
2-Butyl-3-(2-oxopropyl)isoindolin-1-one (4g). The compound 4g was pre-
pared following general method B to give a light yellow oil, 41 mg, yield: 83%.
1H NMR (400 MHz, CDCl3) (d, ppm): 7.82 (d, 1H, J ¼ 7.2 Hz, ArH), 7.43–7.52
(m, 2H, ArH), 7.38 (d, 1H, J ¼ 7.2 Hz, ArH), 5.08 (dd, 1H, J ¼ 13.6, 5.2 Hz,
CHN), 3.95–4.03 (m, 1H), 2.99–3.06 (m, 2H), 2.70 (dd, 1H, J ¼ 17.6, 7.6 Hz), 2.23
(s 3H), 1.49–1.69 (m, 2H), 1.29–1.38 (m, 2H), 0.94 (t, 3H, J ¼ 7.6 Hz); 13C NMR
(100 MHz, CDCl3) (d, ppm): 205.8, 168.0, 145.4, 132.0, 131.5, 128.4, 123.6, 122.5,

1122
H. ZHANG ET AL.
54.8, 46.4, 39.8, 30.8, 30.2, 20.0, 13.7; IR (neat): 2958, 2931, 2871, 1716, 1679, 1469,
1413, 1365, 1160, 1091, 755, 694, 538 cmꢂ1; MS (EI) m=z (%) 245.1 (Mþ) (10), 202.1
(100), 188.1 (23), 146.1 (34), 131.1 (32), 77.0 (4), 43.0 (4); HRMS (EI) m=z calcd. for
C15H19NO2 245.1416 (Mþ); found 245.1416.
2-Benzyl-3-(2-oxopropyl)isoindolin-1-one (4h). The compound 4h was
prepared following general method B to give a light yellow solid, 45 mg, yield:
1
81%. Mp: 89–90 ꢁC. H and 13C NMR spectroscopic data are in agreement with
those reported. 1H NMR (400 MHz, CDCl3) (d, ppm): 7.89 (d, 1H, J ¼ 7.2 Hz,
ArH), 7.46–7.54 (m, 2H, ArH), 7.35 (d, 1H, J ¼ 7.2 Hz, ArH), 7.25–7.32 (m, 5H,
ArH), 5.02 (t, 1H, J ¼ 6.0 Hz), 4.90 (d, 1H, J ¼ 15.6 Hz), 4.60 (d, 1H, J ¼ 15.6 Hz),
2.89 (dd, J ¼ 17.8, 5.6 Hz), 2.69 (dd, J ¼ 17.8, 5.6 Hz), 1.91 (s, 3H); 13C NMR
(100 MHz, CDCl3) (d, ppm): 205.5, 168.5, 145.5, 137.2, 131.8, 131.7, 128.7, 128.4,
127.9, 127.5, 123.8, 122.4, 55.6, 46.7, 44.7, 30.3; IR (KBr): 3056, 2898, 2845, 1717,
1679, 1433, 1411, 1367, 1303, 1149, 989, 730 cmꢂ1; MS (EI) m=z (%) 279.1 (Mþ)
(4), 221.1 (28), 188.1 (100), 146.1 (86), 131.0 (23), 91.1 (81), 77.0 (4), 43.0 (4); HRMS
(EI) m=z calcd. for C18H17NO2 279.1259 (Mþ); found 279.1260.
2-Cyclohexyl-3-(2-oxopropyl)isoindolin-1-one (4i). The compound 4i was
prepared following the general method B to give a light yellow oil, 24 mg, yield: 45%.
1H NMR (400 MHz, CDCl3) (d, ppm): 7.76 (d, 1H, J ¼ 7.2 Hz), 7.39–7.47 (m, 2H),
7.31 (d, 1H, J ¼ 7.2 Hz), 5.08 (dd, 1H, J ¼ 9.2, 2.8 Hz), 3.19 (dd, 1H, J ¼ 17.6,
2.8 Hz), 2.68 (dd, 1H, J ¼ 17.6, 8.8, Hz), 2.19 (s, 3H), 1.99–2.03 (m, 1H), 1.76–1.87
(m, 5H), 1.66–1.69 (m, 1H), 1.29–1.41 (m, 2H), 1.15–1.24 (m, 1H); 13C NMR
(100 MHz, CDCl3) (d, ppm): 206.1, 168.3, 145.9, 134.3, 132.5, 131.5, 129.4, 128.3,
125.7, 123.4, 122.4, 55.6, 53.8, 47.9, 31.2, 31.0, 30.7, 26.1, 26.0, 25.4; HRMS (EI)
m=z calcd. for C17H21NO2 271.1572 (Mþ); found 271.1575.
2-(4-Methoxyphenyl)-3-(2-oxocyclohexyl)isoindolin-1-one (4j). The
compound 4j was prepared following general method A to give a white solid,
1
59 mg, yield: 88%. Mp: 145–147 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.91
(d, 1H, J ¼ 7.2 Hz, ArH), 7.54–7.58 (m, 3H, Ar), 7. 45–7.52 (m, 4H, ArH), 7.25–
7.28 (m, 1H, ArH), 6.02 (d, 1H, J ¼ 2.4 Hz, NCH), 3.85 (s, 3H, OMe), 2.83–2.88
(m, 1H, COCH), 2.49–2.53 (m, 1H, COCH2), 2.24–2.32 (m, 1H, COCH2), 1.96–
2.01 (m, 1H, CH2), 1.69–1.71 (m, 1H, CH2), 1.56–1.63 (m, 1H, CH2), 1.35–1.50
(m, 2H, CH2), 0.72–0.82 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3) (d, ppm):
211.1, 157.7, 142.9, 133.0, 131.9, 129.2, 128.4, 125.5, 124.4, 123.9, 114.7, 60.2,
55.5, 50.6, 42.0, 26.3, 25.2, 24.1; MS (EI) m=z (%) 335.2 (Mþ) (17), 238.1 (100),
167.1 (6). IR (KBr): 2941, 2927, 2848, 1685, 1606, 1510, 1467, 1382, 1251, 1128,
1031, 827, 755, 701, 528; HRMS (EI) m=z calcd. for C21H21NO3 335.1521 (Mþ);
found 335.1524.
2-(4-Methoxyphenyl)-3-(2-oxobutyl)isoindolin-1-one (4k). The com-
pound 4k was prepared following general procedure A to give an inseparable mix-
ture with a ratio of regioisomers 2=1, 30 mg, yield: 46%. 1H NMR (400 MHz,
CDCl3) (d, ppm): 7.92 (d, 1H, J ¼ 7.6 Hz, ArH), 7.51–7.56 (m, 2H, ArH), 7.41–
7.46 (m, 3H, ArH), 6.97–7.01 (m, 2H, ArH), 5.66 (dd, 1H, J ¼ 8.8, 3.6 Hz, NCH),
3.83 (s, 3H, OMe), 2.98 (dd, 1H, J ¼ 17.8, 3.6 Hz, COCH2), 2.60 (dd, 1H, J ¼ 17.8,
9.0 Hz, COCH2), 2.33 (q, 2H, J ¼ 7.2 Hz, COCH2Me), 1.01 (t, 3H, J ¼ 7.2 Hz,

SYNTHESIS OF ISOINDOLINONES
1123
COCH2CH3); 13C NMR (100 MHz, CDCl3) (d, ppm): 209.7, 208.9, 167.3, 166.8,
157.8, 157.7, 145.0, 141.9, 133.1, 132.1, 131.9, 131.8, 129.3, 129.2, 128.6, 125.6,
124.0, 123.8, 122.7, 114.7, 114.5, 61.2, 57.2, 55.5, 47.3, 45.3, 36.9, 28.7, 8.8, 7.5;
MS (EI) m=z (%) 279.1 (Mþ) (24), 236.1 (58), 222.1 (100), 91.1 (13); HRMS (EI)
m=z calcd. for C19H19NO3 309.1365 (Mþ); found 309.1364.
2-Isobutyl-3-(2-oxopropyl)isoindolin-1-one (4l). The compound 4l was
prepared following general method B to give a pale yellow oil, 38 mg, yield: 78%.
1H NMR (400 MHz, CDCl3) (d, ppm): 7.84 (d, 1H, J ¼ 7.6 Hz), 7.44–7.53 (m,
2H), 7.39 (d, 1H, J ¼ 7.6 Hz), 5.08 (dd, J ¼ 7.2, 5.2 Hz), 3.80 (dd, 1H, J ¼ 14.0,
10.0 Hz), 3.04 (dd, 1H, J ¼ 17.6, 4.8 Hz), 8.87 (dd, 1H, J ¼ 14.0, 5.2 Hz), 2.69 (dd,
1H, J ¼ 17.8, 8.0 Hz), 2.25 (s, 3H), 1.98–2.08 (m, 1H), 0.98 (d, 3H, J ¼ 6.8 Hz),
0.85 (d, 3H, J ¼ 6.8 Hz); 13C NMR (100 MHz, CDCl3) (d, ppm): 205.8, 168.3,
145.4, 131.9, 131.6, 128.4, 123.8, 122.5, 55.0, 47.3, 46.3, 30.9, 27.4, 20.4, 19.7; MS
(EI) m=z (%) 245.1 (Mþ) (9), 202.1 (100), 131.0 (35), 103.1 (5), 77.0 (4), 43.0 (4);
HRMS (EI) m=z calcd. for C15H19NO2 245.1416 (Mþ); found 245.1420.
2-(2-Ethoxylethyl)-3-(2-oxopropyl)isoindolin-1-one (4m). The compound
4m was prepared following general method B to give a pale yellow oil, 44 mg, yield:
1
85%. H NMR (400 MHz, CDCl3) (d, ppm): 7.81 (d, 1H, J ¼ 7.2 Hz, ArH), 7.50 (t,
1H, J ¼ 7.2 Hz, ArH), 7.43 (dd, 2H, J ¼ 7.6, 7.4 Hz, ArH), 5.18 (dd, 1H, J ¼ 7.6,
4.4 Hz, CHN), 4.01–4.07 (m, 1H), 3.68–3.73 (m, 1H), 3.53–3.58 (m, 1H), 3.37–3.48
(m, 3H), 3.30 (dd, 1H, J ¼ 17.8, 4.0 Hz); 13C NMR (100 MHz, CDCl3) (d, ppm):
206.1, 168.3, 145.9, 131.7, 131.6, 128.2, 123.5, 122.6, 69.1, 66.4, 56.6, 46.2, 40.8,
30.6, 15.1; HRMS (EI) m=z calcd. for C15H19NO3 261.1365 (Mþ); found 261.1378.
2-(4-Methoxyphenyl)-6-flouro-3-(2-oxopropyl)isoindolin-1-one (4n). The
compound 4n was prepared following the general method B to give a white solid,
1
44 mg, yield: 71%. Mp: 161–162 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.58
(dd, 1H, J ¼ 7.6, 2.4 Hz, ArH), 7.47 (dd, 1H, J ¼ 8.4, 4.4 Hz, ArH), 7.40–7.43 (m,
2H, ArH), 7.27 (ddd, 1H, J ¼ 8.4, 2.4 Hz, ArH), 6.98–7.01 (m, 2H, ArH), 5.59
(dd, 1H, J ¼ 9.6, 3.2 Hz, NCH), 3.85 (s, 3H, OCH3), 3.03 (dd, 1H, J ¼ 18.0,
3.2 Hz, COCH2), 2.59 (dd, 1H, J ¼ 18.0, 9.6 Hz, COCH2), 2.12 (s, 3H, COCH3);
13C NMR (100 MHz, CDCl3) (d, ppm): 206.0, 165.8, 165.7, 164.4, 161.9, 157.9,
140.5, 134.1, 134.0, 128.9, 125.5, 124.7, 124.6, 119.6, 119.4, 114.7, 110.8, 110.6,
56.8, 55.5, 46.5, 30.7; IR (KBr): 2919, 1708, 1686, 1518, 1490, 1401, 1255, 1174,
1137, 1027, 887, 833,782 cmꢂ1; MS (EI) m=z (%) 313.2 (Mþ) (49), 284.2 (8), 270.1
(22), 256.1 (100), 185.1 (8), 108.1 (10), 77.1 (2); HRMS (EI) m=z calcd. for
C18H16FNO3 313.1114 (Mþ); found 313.1115.
2-(4-Methoxyphenyl)-6-chloro-3-(2-oxopropyl)isoindolin-1-one (4o). The
compound 4o was prepared following the general method B to give a white solid,
1
48 mg, yield: 73%. Mp: 180–182 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 7.89
(d, 1H, J ¼ 2.0 Hz, ArH), 7.53 (dd, 1H, J ¼ 8.0, 2.0 Hz, ArH), 7.40–7.45 (m, 3H,
ArH), 6.99 (dd, 2H, J ¼ 8.0, 2.0 Hz, ArH), 5.60 (dd, 1H, J ¼ 9.2, 3.2 Hz, NCH),
3.85 (s, 3H, OCH3), 3.04 (dd, J ¼ 18.0, 3.2 Hz, COCH2), 2.59 (dd, J ¼ 18.0, 9.6 Hz,
COCH3), 2.12 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) (d, ppm): 205.9,
165.4, 157.9, 143.1, 135.0, 133.7, 132.2, 128.9, 125.5, 124.3, 124.1, 114.7, 56.9,
55.5, 46.4, 30.6; MS (EI) m=z (%) 329.1 (Mþ) (48), 286.1 (26), 272.1 (100), 108.1

1124
H. ZHANG ET AL.
(17), 77.1 (3); HRMS (EI) m=z calcd. for C18H16ClNO3 328.0819 (Mþ); found
328.0819.
2-(4-Methoxyphenyl)-6-bromo-3-(2-oxopropyl)isoindolin-1-one (4p). The
compound 4p was prepared following general method B to give a white solid, 64 mg,
1
yield: 86%. Mp: 198–201 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 8.04 (s, 1H,
ArH), 7.68 (dd, 1H, J ¼ 8.0, 1.6 Hz, ArH), 7.41 (d, 2H, J ¼ 8.8 Hz, ArH), 7.38 (d,
1H, J ¼ 8.0 Hz, ArH), 6.99 (d, 2H, J ¼ 8.8 Hz, ArH), 5.56 (dd, 1H, J ¼ 9.2, 3.2 Hz,
CHN), 3.84 (s, 3H, CH3), 3.03 (dd, 1H, J ¼ 18.0, 3.2 Hz, COCH2), 2.59 (dd, 1H,
J ¼ 18.0, 9.2 Hz, COCH2), 2.10 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) (d,
ppm): 205.9, 165.3, 157.9, 143.6, 135.0, 133.9, 128.8, 127.1, 125.6, 124.6, 122.8,
114.6, 56.9, 55.5, 46.3, 30.6; IR (KBr): 2964, 2911, 1706, 1686, 1517, 1399, 1175,
1022, 829, 781, 551 cmꢂ1; MS (EI) m=z (%) 373.2 (Mþ) (2), 328.2 (23), 314.2
(100), 243.2 (8), 108.1 (6), 77.1 (1); HRMS (EI) m=z calcd. for C18H16BrNO3
373.0314 (Mþ); found 373.0314.
2-(4-Methoxyphenyl)-6-hydroxy-3-(2-oxopropyl)isoindolin-1-one (4q).
The compound 4q was prepared following the general method B to give a white
1
solid, 51 mg, yield: 82%. Mp: 159–160 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm):
7.51 (d, 1H, J ¼ 2.4 Hz, ArH), 7.41 (d, 2H, J ¼ 9.2 Hz, ArH), 7.32 (d, 1H, J ¼ 8.4 Hz,
ArH), 7.13 (s, 1H, ArOH), 7.07 (dd, 1H, J ¼ 8.4, 2.4 Hz, ArH), 6.98 (d, 2H,
J ¼ 9.2 Hz, ArH), 5.55 (dd, 1H, J ¼ 9.2, 3.6 Hz, NCH), 3.84 (s, 3H, OCH3), 2.98
(dd, 1H, J ¼ 17.6, 3.6 Hz, COCH2), 2.60 (dd, 1H, J ¼ 17.6, 9.2 Hz, COCH2), 2.10
(s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) (d, ppm): 206.4, 167.4, 157.9,
157.3, 136.6, 132.8, 128.9, 125.9, 123.9, 120.5, 114.6, 110.2, 57.3, 55.5, 46.6, 30.8;
MS (EI) m=z (%) 311.2 (Mþ) (43), 282.2 (8), 268.2 (22), 254.1 (100), 183.1 (6),
108.1 (7), 77.1 (2); HRMS (EI) m=z calcd. for C18H17NO4 311.1158 (Mþ); found
311.1159.
2-(4-Methoxyphenyl)-6-methoxy-3-(2-oxopropyl)isoindolin-1-one
(4r). The compound 4r was prepared following the general method B to give a white
1
solid, 50 mg, yield: 77%. Mp: 138–139 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm):
7.43 (d, 2H, J ¼ 8.8 Hz, ArH), 7.40 (d, 1H, J ¼ 2.4 Hz, ArH), 7.37 (d, 1H, J ¼ 8.4 Hz,
ArH), 7.12 (dd, J ¼ 8.4, 2.4 Hz, ArH), 6.99 (d, 2H, J ¼ 8.8 Hz, ArH), 5.56 (dd, 1H,
J ¼ 9.2, 3.2 Hz, NCH), 3.89 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.00 (dd, 1H,
J ¼ 17.6, 3.2 Hz, COCH2), 2.58 (dd, 1H, J ¼ 17.6, J ¼ 9.2 Hz, COCH2), 2.10 (s,
3H, COCH3); 13C NMR (100 MHz, CDCl3) (d, ppm): 206.2, 166.8, 160.4, 157.7,
137.3, 133.3, 129.4, 125.6, 123.8, 120.4, 114.6, 106.6, 56.8, 55.7, 55.5, 46.7, 30.8;
MS (EI) m=z (%) 325.2 (Mþ) (42), 296.2 (8), 282.2 (20), 268.1 (100), 253.1 (10),
108.1 (5), 77.1 (2); HRMS (EI) m=z calcd. for C19H19NO4 325.1314 (Mþ); found
325.1314.
2-(4-Methoxyphenyl)-6-phenyl-3-(2-oxopropyl)isoindolin-1-one (4s). The
compound 4s was prepared following general method B to give a white solid,
1
58 mg, yield: 78%. Mp: 188–190 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 8.15
(d, 1H, J ¼ 1.2 Hz, ArH), 7.80 (dd, 1H, J ¼ 8.0, 1.6 Hz, ArH), 7.67 (s, 1H, ArH),
7.65 (s, 1H, ArH), 7.55 (d, 1H, J ¼ 8.0 Hz, ArH), 7.45–7.51 (m, 4H, ArH), 7.39–
7.42 (m, 1H, Ar), 7.00 (s, 1H, Ar), 7.02 (s, 1H, Ar), 5.68 (dd, 1H, J ¼ 9.2, 3.2 Hz,
NCH), 3.86 (s, 3H, OCH3), 3.06 (dd, 1H, J ¼ 18.0, 3.2 Hz, COCH2), 2.67 (dd, 1H,

SYNTHESIS OF ISOINDOLINONES
1125
J ¼ 18.0, 9.2 Hz, COCH2), 2.13 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) (d,
ppm): 206.1, 166.7, 157.7, 143.8, 142.1, 140.0, 132.6, 131.1, 129.3, 128.9, 127.8,
127.2, 125.6, 123.3, 122.4, 114,6, 57.0, 55.5, 46.6, 30.7; MS (EI) m=z (%) 373.0
(Mþ) (54), 330.0 (30), 316.0 (100), 303.0 (7), 288.0 (6), 166.1 (12), 108.1 (21), 77.0
(6); HRMS (EI) m=z calcd. for C24H21NO3 371.1521 (Mþ); found 371.1522.
2-(4-Methoxyphenyl)-6-nitro-3-(2-oxopropyl)isoindolin-1-one (4t). The
compound 4 t was prepared following the general method B to give a white solid,
1
50 mg, yield: 74%. Mp: 190–192 ꢁC. H NMR (400 MHz, CDCl3) (d, ppm): 8.75
(d, 1H, J ¼ 2.0 Hz, ArH), 8.44 (dd, 1H, J ¼ 8.4, 2.0 Hz, ArH), 7.71 (d, 1H, J ¼ 8.4 Hz,
ArH), 7.41 (d, 2H, J ¼ 6.8 Hz, ArH), 7.02 (d, 2H, J ¼ 6.8 Hz, ArH), 5.70 (dd, 1H,
J ¼ 9.6, 3.2 Hz, NCH), 3.86 (s, 3H, OCH3), 3.12 (dd, 1H, J ¼ 18.2, 3.2 Hz, COCH2),
2.66 (dd, 1H, J ¼ 18.2, 9.6 Hz, COCH2), 2.15 (s, 3H, COCH3); 13C NMR (100 MHz,
CDCl3) (d, ppm): 205.5, 164.5, 158.2, 150.6, 148.7, 133.7, 128.3, 126.9, 125.6, 124.4,
119.5, 114.8, 57.3, 55.5, 45.8, 30.5; MS (EI) m=z (%) 340.1 (Mþ) (100), 297.1 (47),
283.1 (90), 237.1 (50), 166.1 (11), 108.1 (21), 77.0 (3); HRMS (EI) m=z calcd. for
C18H16N2O5 340.1059 (Mþ); found 340.1050.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Science and Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Program’’
(Nos. 2009ZX09103-065 and 2009ZX09301-001), the Major Project of Chinese
National Programs for Fundamental Research and Development (No. 2009
CB918404), and the 111 Project of the Ministry of Education (No. B07023).
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