Room-temperature one-pot palladium-catalyzed synthesis of 3-hydroxyisoindolin-1-ones from phenylglyoxylic acids

Article abstract of DOI:10.3987/COM-15-13398

A room-temperature and efficient synthesis of 3-hydroxyisoindolin-1-ones by Pd-catalyzed C-H activation has been proposed. Wide ranges of benzamides and phenylglyoxylic acids indicated good functional group tolerance and wide potential application of this

Full text of DOI:10.3987/COM-15-13398

HETEROCYCLES, Vol. 92, No. 3, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 21st December, 2015, Accepted, 21st January, 2016, Published online,
DOI: 10.3987/COM-15-13398
.
ROOM-TEMPERATURE
SYNTHESIS OF
PHENYLGLYOXYLIC ACIDS
ONE-POT
PALLADIUM-CATALYZED
FROM
3-HYDROXYISOINDOLIN-1-ONES
Menglei Yuan, Yu Sun, Hui Yan, Jinxiong Wu, Gaofeng Ma, Feng Li, Siyu
Miao, Mengyao Hao, and Na Li*
*Department of Chemical Engineering & Process, North University of China,
Changning Road 65, Shuozhou, Shanxi, China, 036000; E-mail:
hellestar@163.com
Abstract
–
A
room-temperature
and
efficient
synthesis
of
3-hydroxyisoindolin-1-ones by Pd-catalyzed C-H activation has been proposed.
Wide ranges of benzamides and phenylglyoxylic acids indicated good functional
group tolerance and wide potential application of this approach. Moreover, good
yields of products further made it practical and attractive.
3-Hydroxyisoindolin-1-ones are common structures in various bioactive compounds, such as inhibitors of
the MDM2-p53 protein-protein interaction, HIV-1 integrase inhibitors, PTP1B inhibitors, antimicrobial
corollosporines, PARP-1 inhibitors, and potassium channel inhibitors.1-7 Additionally,
3-hydroxyisoindolin-1-ones are also important synthetic intermediates of potent C.N.S. agents, TRPM8
antagonists, MAPK pathway signaling inhibitors, and P2Y1 urea antagonists.8-11
Traditionally, 3-hydroxyisoindolin-1-ones are usually prepared from the reaction of phthalimide
derivatives and organometallic reagents.12,13 Hardcastle group reported a novel approach to
3-hydroxyisoindolin-1-ones with 2-benzoylbenzoic acids in two steps.2 Kundu and Terada groups
provided their synthesis of 3-alkylideneisoindolinones with similar intermediates of o-(substituted
ethynyl) benzamides.14,15 Meanwhile, lithiation-cyclization of N-acyl-2-bromobenzamides has been
reported as an alternative synthetic pathway to obtain 3-alkylideneisoindolinones.16 With phase transfer
catalysts, Liu group also synthesized 3-hydroxyisoindolin-1-ones via a metal-free transformation from
2-(phenylethynyl)benzoic acid and primary amines.17 These approaches above, however, are more or less
limited by rigorous reaction conditions, poor regioselectivity, availability of starting materials and
functional group tolerance, all reducing their potential application.

Recently, with the development of transition-metal-catalyzed reactions, it is recognized that
metal-catalyzed C-H activation could be desirable strategy for the synthesis of
a
3-hydroxyisoindolin-1-ones. It was first reported that Kim group directly synthesized
3-hydroxyisoindolin-1-ones via tandem Rh(III)-catalyzed oxidative acylation of secondary benzamides
with aldehydes and intramolecular cyclization.18 Then Huang group described their synthesis of
3-hydroxyisoindolin-1-ones by Pd-mediated C-H activation/annulation reactions with aldehydes or
alcohols.19,20 Yet, these reactions suffer from expensive Ag oxidant and high reaction temperature,
receptively. Herein, inspired by the activation of phenylglyoxylic acids with Pd, we report a
room-temperature and efficient synthesis of 3-hydroxyisoindolin-1-ones by Pd-catalyzed C-H activation
employing phenylglyoxylic acids as the simple coupling partners.21,22
Previous work
Terada group, 2009
Kundu group, 1997
Hardcastle group, 2006
Johnson group, 2014
Wang group, 2002
O
O
R2
N
O
Ph
H
N R1
P
COOH
R3
l
OC
1)S
2
h
O
-tBu
2
Z
P4
1NH2
n
t N
, E 3
2)R
o
r
P
Kim group, 2012
R1
h
L
i
O
O
O
[Rh]
oxidant
NH
R1
N
CHO
R2
R3
N
+
HO
[Pd]
oxidant
R1
[Pd]
oxidant
O
n-BuLi
O
NH
CHO
R1
+
O
O
OH
NH
R3
N
+
R2
Huang group, 2013
Br
Wolfe group, 1989
Huang group, 2013
O
O
N R4
Bu4N OAc
R4 NH2
OH
H2O
+
HO
Ph
Ph
Liu group, 2010
Scheme 1. Conventional approaches and catalyzed C-H activation reactions for the synthesis of
3-hydroxyisoindolin-1-one derivatives

This work
H
O
O
N
O
R1
OH
10 mol% Pd(OAc)2
R1
R2
N
H +
O
(NH4)2S2O8, THF
rt, 3 h
OH
R3
R2
R3
Scheme 2. Room-temperature one-pot palladium-catalyzed synthesis of 3-hydroxyisoindolin-1-ones with
phenylglyoxylic acids
Initially, we investigated the reactivity of benzamides with phenylglyoxylic acids by using
p-chlorobenzamide (1a) and p-chlorophenylglyoxylic acids (2a) as starting substrates. A screening of
catalysts showed that Pd(OAc)2 gave the best yield in the presence of (NH4)2S2O8 in diglyme. Meanwhile,
Pd(PPh3)2(OAc)2 and Pd(TFA)2 also could efficiently catalyze the reaction while PdCl2(dppf), FeCl2 and
CuI failed to facilitate the reaction (Table 1, entries 1–6). The effectiveness of the oxidant was also
examined. It was found that (NH4)2S2O8 was an effective oxidant while other oxidants, such as air, H2O2,
TBHP and m-CPBA, were relatively ineffective in the reaction (Table 1, entries 3 and 7-10).23 Common
organic solvents were screened. To our delight, THF was the optimal solvent prior to other solvents, such
as diglyme, DMF, dioxane, toluene and DME (Table 1, entries 3 and 11-15). It was also noted that
changing the oxidant amount or reaction time could reduce the yield of our desired product (Table 1,
entries 14 and 16-20). Finally, when benzamide was treated with 1.2 equivalents of phenylglyoxylic acid
in the presence of 10 mol% of Pd(OAc)2 and 8 equivalents of ammonium persulphate in THF at room
temperature for 3 h, our desired 3a was successfully isolated in a good 80% yield (Table 1, entry 14).
Table 1. Optimization of the reaction conditionsa
Entry
Catalyst
Oxidant
(equiv.)
Solvent Time Yield
(%)b
1
2
3
Pd(TFA)2
(NH4)2S2O8(8) diglyme 3 h
64
45
77
Pd(PPh3)2(OAc)2 (NH4)2S2O8(8) diglyme 3 h
Pd(OAc)2 (NH4)2S2O8(8) diglyme 3 h

4
PdCl2(dppf)
FeCl2
(NH4)2S2O8(8) diglyme 3 h trace
5
(NH4)2S2O8(8) diglyme 3 h
(NH4)2S2O8(8) diglyme 3 h
0
0
6
CuI
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
_
air
diglyme 3 h
24
8
H2O2(8)
diglyme 3 h trace
9
TBHP(8)
diglyme 3 h
diglyme 3 h
27
16
20
72
10
11
12
13
14
15
16
17
18
19
20
21
m-CPBA(8)
(NH4)2S2O8(8)
DMF
3 h
(NH4)2S2O8(8) dioxane 5 h
(NH4)2S2O8(8) toluene
3 h trace
(NH4)2S2O8(8)
(NH4)2S2O8(8)
(NH4)2S2O8(2)
(NH4)2S2O8(15)
(NH4)2S2O8(8)
(NH4)2S2O8(8)
(NH4)2S2O8(8)
(NH4)2S2O8(8)
THF
DME
THF
THF
THF
THF
THF
THF
3 h
3 h
80
42
37
42
70
50
20
0
3 h
3 h
7 h
1.5 h
0.5 h
3 h
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (10 mol%), oxidant (as indicated), solvent
(2 mL), sealed tube, rt. bIsolated yields.
Under the optimal condition, various substituted phenylglyoxylic acids were examined as shown in Table
2. In general, electron-deficient and electron-rich phenylglyoxylic acids all provided moderate to high
yields. It is worth noting that for phenylglyoxylic acid with chloro-substituent at para-position (3a)
afforded a higher yield than compared with other two positions (3b and 3f), probably due to steric
hindrance during the reaction. Similarly, meta-Me-phenylglyoxylic acid also provided an excellent yield
(3j, 87%), which is much higher than ortho-Me-phenylglyoxylic acid (3i, 53%). In addition, ortho-Cl-
and ortho-Me-phenylglyoxylic acids gave similar yields in the reaction (41% and 53%, respectively). It
was found that phenylglyoxylic acids with other halogen groups (F and Br) also had good to excellent
yields (65%-88%), providing an approach for further synthesis of bioactive compounds with
3-hydroxyisoindolin-1-one moiety.

Table 2. Scope of Phenylglyoxylic Acidsa,b
aReaction conditions: 1a (0.5 mmol), 2b-j (0.6 mmol), Pd(OAc)2 (10 mol%), (NH4)2S2O8 (4 mmol), THF
(2 mL), sealed tube, rt. bIsolated yields.
Encouraged by these results, we futher examined the scope of benzamides. Reactions with both
electron-withdrawing and electro-donating benzamides all went fluently and gave our desired products in
good to high yields. Interestingly, benzamides without any substituent afforded a higher yield (4b, 89%)
than substituted benzamides. Therefore, subestituents may more or less influence the process of reaction.
For substituent groups at meta-position, chloro-substituent gave a better yield (88%) than methyl and
methoxy-substituent (76% and 58%, respectively), while for substituent groups at ortho-position,
methoxy-substituent provided a better yield (88%) than methyl and chloro-substituent (77% and 53%,
respectively). However, the yields of the two single methyl-substituted benzamides were both less than
that of 3,5-dimethyl-substituted benzamides. Benzamides with methoxy-substituent and cyano-substituent
at para-position both displayed better reactivity and had similar good yields, 64% and 69% respectively.

Table 3. Scope of Benzamidesa,b
aReaction conditions: 1b-k (0.5 mmol), 2a (0.6 mmol), Pd(OAc)2 (10 mol%), (NH4)2S2O8 (4 mmol), THF
(2 mL), sealed tube, rt. bIsolated yields.
Based on the above experiments and results, a possible reaction mechanism was proposed in Scheme 3. In
the presence of Pd(OAc)2, intermediate A is formed with the assistance of amide nitrogen radical
generated by 1a. Then intermediate B is provided after the addition of acyl radical generated by 2a. The
C-H activation of intermediate B leads to the formation of intermediate C. Then after one step of
reductive elimination, intermediate D is formed. Intramolecular cyclization of intermediate D followed by
another reductive elimination provides our desired product 3a. Meanwhile, [Pd0] is oxidized into [PdII]
for the next reaction cycle.

Scheme 3. Proposed reaction mechanism
To test the reaction practicability and reliability, a gram-scale synthesis has also been examined. We
successfully isolated our desired product 3a in 68% yield under the optimal condition as shown in
Scheme 4.
Scheme 4. Gram-scale synthesis of 3a
In summary, we have demonstrated a highly efficient approach for the preparation of
3-hydroxyisoindolin-1-ones by Pd-catalyzed C-H activation at room temperature. This fast and
environmentally friendly approach has provided good to high yields under mild conditions. Meanwhile,
further synthesis of compounds targeting BET-BRD4 with antitumor activity in this approach is under
investigation.

EXPERIMENTAL
General
All the solvents and commercially available reagents were purchased from commercial sources and used
directly. All the reactions mentioned in this article were monitored by thin layer chromatography (TLC)
at 254 nm under a UV lamp with the following eluent system: petroleum ether/ethyl acetate. Column
chromatography separations were obtained on silica gel (200–300 mesh, purchased from Qing Dao Hai
Yang Chemical Industry) eluting with petroleum ether/ethyl acetate (5/1 to 3/1). %Purity of the procudts
1
(> 97%) were determined by HPLC analysis (UV detector, wavelength: 289 nm). H NMR and 13C NMR
spectra on a Bruker AV 300 MHz spectrometer were recorded in CDCl3 and DMSO-d6, respectively.
Chemical shifts were recorded in δ (ppm) units relative to TMS. High-resolution mass spectra (HRMS)
were recorded on a HewlettePackard 1100 LC/MSD spectrometer.
Starting Materials
1g and 1k were prepared following the procedure reported by Guimond et al.24 2a was prepared from
oxidation of the corresponding methyl ketone with SeO2 according to the reported procedure.25 Other
N-methoxybenzamides and α-oxocarboxylic acids were purchased from Sigma-Aldrich, TCI, Alfa Aesar
or Acros.
N-Methoxy-3,5-dimethylbenzamide (1g). 1H NMR (300 MHz, DMSO-d6): δ 11.63 (s, 1H), 7.35 (s, 2H),
7.17 (s, 1H), 3.68 (s, 3H), 2.30 (s, 6H).
1
4-Cyano-N-methoxybenzamide (1k). H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.97 (d, J = 8.4
Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 3.73 (s, 3H).
1
2-(4-Chlorophenyl)-2-oxoacetic acid (2a). H NMR (300 MHz, DMSO-d6): δ 7.96 (d, J = 8.8 Hz, 2H),
7.69 (d, J = 8.8 Hz, 2H).
Synthesis of 3-Hydroxyisoindolin-1-ones
A solution of benzamides (0.5 mmol), α-oxocarboxylic acids (0.6 mmol), Pd(OAc)2 (10 mol%) and
(NH4)2S2O8 (4 mmol) in THF (3 mL) was stirred in a sealed tube under air at room temperature for 3 h.
The reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was
washed with saturated aqueous Na2CO3 to remove the acid. The organic layer was dried over anhydrous
Na2SO4 and filtered, and the solvent was removed under vacuum or in vacuo to provide the crude product.
The purification was performed by flash column chromatography on silica gel (eluent: petroleum
ether/EtOAc = 4/1, v/v) to give 3-hydroxyisoindolin-1-ones.
5-Chloro-3-(4-chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (3a). Following the general
procedure, 3a was isolated as a white solid (140 mg, 80%): Mp 192-194 °C;1H NMR (300 MHz, CDCl3):
δ 7.73 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.1, 1.9 Hz, 1H), 7.44–7.39 (m, 2H), 7.38–7.33 (m, 2H), 7.25 (d,
13
J = 1.9 Hz, 1H), 3.89 (s, 3H), 3.87–3.79 (m, 1H); C NMR (75 MHz, DMSO-d6): δ 161.72, 148.05,

138.20, 137.42, 133.32, 130.18, 128.63, 128.18, 126.58, 124.97, 123.02, 89.66, 65.19; HRMS (ESI) m/z
calcd for C15H11Cl2NO3 [M+Na]+ 346.0116; found 346.0119.
5-Chloro-3-(3-chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (3b). Following the general
1
procedure, 3b was isolated as a white solid (122 mg, 70%): Mp 196-198 °C; H NMR (300 MHz,
CDCl3): δ 7.68 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.42 (dd, J = 8.1, 1.8 Hz, 1H), 7.33–7.27 (m, 1H),
13
7.25–7.18 (m, 3H), 3.85 (s, 3H), 3.82 (s, 1H); C NMR (75 MHz, DMSO-d6): δ 161.69, 147.79, 140.87,
138.20, 133.28, 130.56, 130.21, 128.59, 126.52, 126.07, 124.95, 124.84, 123.06, 89.48, 65.18; HRMS
(ESI) m/z calcd for C15H11Cl2NO3 [M+Na]+ 346.0116; found 346.0114.
5-Chloro-3-(3-fluorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (3c). Following the general
procedure, 3c was isolated as a white solid (146mg, 88%): Mp 158-160 °C; 1H NMR (300 MHz, CDCl3):
δ 7.74 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 13.9, 7.9 Hz, 1H), 7.28 (d, J = 9.0 Hz,
13
2H), 7.17 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.70 (br s, 1H); C NMR (75 MHz,
DMSO-d6): δ 163.82, 160.58, 147.88, 141.31, 138.12, 130.61 (d, J = 8.2 Hz), 130.13, 126.55, 124.90,
123.01, 122.05, 115.41 (d, J = 20.4 Hz), 113.34 (d, J = 23.4 Hz), 89.45, 65.10; HRMS (ESI) m/z calcd for
C15H11ClFNO3 [M+Na]+ 330.0411; found 330.0410.
5-Chloro-3-(4-fluorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (3d). Following the general
procedure, 3d was isolated as a white solid (132 mg, 80%): Mp 151-154 °C; 1H NMR (300 MHz, CDCl3):
δ 7.71 (d, J = 8.0 Hz, 1H), 7.51–7.40 (m, 3H), 7.27–7.26 (m, 1H), 7.07 (t, J = 8.6 Hz, 2H), 3.88 (s, 3H),
13
3.85 (s, 1H); C NMR (75 MHz, DMSO-d6): δ 163.71, 161.60, 160.46, 148.24, 138.09, 134.56 (d, J =
2.9 Hz), 130.04, 128.41 (d, J = 8.6 Hz), 126.56, 124.88, 122.96, 115.51, 115.23, 89.65, 65.08; HRMS
(ESI) m/z calcd for C15H11ClFNO3 [M+Na]+ 330.0411; found 330.0407.
5-Chloro-3-hydroxy-2-methoxy-3-(naphthalen-1-yl)isoindolin-1-one (3e). Following the general
procedure, 3e was isolated as a white solid (116 mg, 91%): Mp 162-163 °C; 1H NMR (300 MHz, CDCl3):
δ 7.92 (td, J = 8.0, 1.8 Hz, 1H), 7.77–7.71 (m, 1H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.44–7.35 (m, 1H),
13
7.30 (dd, J = 3.5, 1.3 Hz, 1H), 7.26–7.23 (m, 1H), 7.03–6.92 (m, 1H), 3.88 (s, 3H), 3.74 (br s, 1H); C
NMR (75 MHz, DMSO-d6) δ 161.97, 160.44, 157.15, 147.34, 137.85, 131.30, 131.18, 130.04, 129.58 (d,
J = 1.7 Hz), 127.40 (d, J = 2.1 Hz), 125.03, 124.90, 124.64, 124.57, 122.62, 116.01, 115.72, 87.15, 65.01;
HRMS (ESI) m/z calcd for C15H11ClFNO3 [M+Na]+ 330.0411; found 330.0410.
5-Chloro-3-(2-chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (3f). Following the general
procedure, 3f was isolated as a white solid (71 mg, 41%): Mp 205-207 °C; 1H NMR (300 MHz, CDCl3): δ
8.24 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.48–7.28 (m, 4H), 7.17 (s, 1H), 4.10 (s, 1H), 3.78 (s,
13
3H); C NMR (75 MHz, DMSO-d6): δ 162.04, 146.81, 137.72, 133.97, 130.96, 130.90, 130.84, 130.71,
130.03, 128.72, 127.44, 124.57, 122.47, 87.91, 64.57; HRMS (ESI) m/z calcd for C15H11Cl2NO3 [M+Na]+
346.0116; found 346.0113.

3-(4-Bromophenyl)-5-chloro-3-hydroxy-2-methoxyisoindolin-1-one (3g). Following the general
procedure, 3g was isolated as a white solid (128 mg, 65%): Mp 190-193 °C; 1H NMR (300 MHz, CDCl3):
δ 7.74 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.52–7.49 (m, 1H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H),
13
7.38–7.35 (m, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.25 (s, 1H), 3.90 (s, 3H), 3.68 (s, 1H); C NMR (75 MHz,
DMSO-d6): δ 161.66, 147.96, 138.15, 137.82, 131.50, 130.13, 128.45, 126.55, 124.91, 122.99, 121.90,
89.65, 65.13; HRMS (ESI) m/z calcd for C15H11BrClNO3 [M+Na]+ 389.9611; found 389.9614.
5-Chloro-3-hydroxy-2-methoxy-3-(3-(trifluoromethyl)phenyl)isoindolin-1-one (3h). Following the
general procedure, 3h was isolated as a white solid (117 mg, 61%): Mp 171-173 °C; 1H NMR (300 MHz,
CDCl3): δ 7.89 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.68–7.60 (m, 1H), 7.55–7.46 (m, 3H), 7.26 (s, 1H), 3.93
13
(s, 1H), 3.89 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 161.73, 147.66, 139.87, 138.28, 130.32, 129.91,
129.53, 129.47, 126.56, 125.54, 125.50, 125.01, 123.11, 122.63, 89.50, 65.22; HRMS (ESI) m/z calcd for
C16H11ClF3NO3 [M+Na]+ 380.0380; found 380.0384.
5-Chloro-3-hydroxy-2-methoxy-3-(o-tolyl)isoindolin-1-one (3i). Following the general procedure, 3i
was isolated as a white solid (86 mg, 53%): Mp 166-169 °C; 1H NMR (300 MHz, CDCl3): δ 7.49 (s, 1H),
7.38–7.32 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 6.6 Hz, 2H), 3.80 (s, 1H), 3.68 (s, 3H), 2.72 (s,
13
3H); C NMR (75 MHz, DMSO): δ 160.48, 147.83, 139.51, 138.11, 135.67, 134.83, 132.76, 132.31,
132.05, 129.06, 128.33, 127.78, 125.65, 123.60, 64.53, 21.34; HRMS (ESI) m/z calcd for C16H14ClNO3
[M+Na]+ 326.0662; found 326.0661.
5-Chloro-3-hydroxy-2-methoxy-3-(m-tolyl)isoindolin-1-one (3j). Following the general procedure, 3j
was isolated as a white solid (141 mg, 87%): Mp 154-156 °C; 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J =
8.1 Hz, 1H), 7.45 (dd, J = 8.1, 1.8 Hz, 1H), 7.26 (s, 4H), 7.19 (d, J = 6.1 Hz, 1H), 3.91 (s, 3H), 3.60 (s,
1H), 2.35 (s, 3H); 13C NMR (75 MHz, DMSO): δ 161.51, 148.43, 138.15, 137.79, 137.60, 129.72, 128.99,
128.31, 126.46, 126.34, 124.67, 123.09, 122.75, 89.91, 64.84, 20.99; HRMS (ESI) m/z calcd for
C16H14ClNO3 [M+Na]+ 326.0662; found 326.0665.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (4b). Following the general procedure, 4b
was isolated as a white solid (138 mg, 89%): Mp 180-182 °C; 1H NMR (300 MHz, CDCl3): δ 7.76 (d, J =
7.1 Hz, 1H), 7.50 (dt, J = 19.9, 7.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.24 (s,
1H), 3.87 (s, 3H), 3.73 (s, 1H); 13C NMR (75 MHz, DMSO-d6): δ 162.65, 146.26, 138.16, 133.45, 132.98,
129.75, 128.48, 128.06, 127.78, 122.83, 122.81, 89.92, 65.04; HRMS (ESI) m/z calcd for C15H12ClNO3
[M+Na]+ 312.0506; found 312.0511.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-7-methylisoindolin-1-one (4c). Following the general
procedure, 4c was isolated as a white solid (126 mg, 77%): Mp 174-177 °C; 1H NMR (300 MHz, CDCl3):
δ 7.42–7.39 (m, 1H), 7.39–7.33 (m, 2H), 7.32–7.26 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.5 Hz,
13
1H), 3.86 (s, 3H), 3.35 (s, 1H), 2.65 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 163.87, 146.90, 138.47,

136.50, 132.86, 131.38, 128.38, 128.12, 128.04, 124.52, 120.26, 89.14, 64.90, 16.88; HRMS (ESI) m/z
calcd for C16H14ClNO3 [M+Na]+ 326.0662; found 326.0659.
3-(4-Chlorophenyl)-3-hydroxy-2,7-dimethoxyisoindolin-1-one (4d). Following the general procedure,
1
4d was isolated as a white solid (152 mg, 88%): Mp 158-160 °C; H NMR (300 MHz, CDCl3): δ
7.51–7.45 (m, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.82 (d, J
= 7.5 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.08 (br s, 1H); 13C NMR (75 MHz, DMSO-d6): δ 162.21,
156.43, 148.63, 138.51, 135.26, 132.82, 128.38, 128.03, 114.58, 112.58, 88.91, 64.87, 55.85; HRMS
(ESI) m/z calcd for C16H14ClNO4 [M+Na]+ 342.0611; found 342.0611.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-6-methylisoindolin-1-one (4e). Following the general
procedure, 4e was isolated as a white solid (124 mg, 76%): Mp 165-169 °C; 1H NMR (300 MHz, CDCl3):
δ 7.59 (s, 1H), 7.44–7.38 (m, 2H), 7.38–7.30 (m, 3H), 7.15 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.57 (s, 1H),
13
2.41 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 162.83, 143.58, 139.58, 138.40, 134.01, 132.87, 128.39,
128.02, 127.89, 122.91, 122.60, 89.84, 64.98, 20.92; HRMS (ESI) m/z calcd for C16H14ClNO3 [M+Na]+
326.0662; found 326.0666.
7-Chloro-3-(4-chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (4f). Following the general
procedure, 4f was isolated as a white solid (92 mg, 53%): Mp 200-202 °C; 1H NMR (300 MHz, CDCl3): δ
7.50–7.32 (m, 6H), 7.17 (d, J = 6.3 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 1H); 13C NMR (75 MHz, DMSO-d6): δ
160.69, 148.80, 137.56, 134.84, 133.21, 131.02, 129.37, 128.55, 128.14, 123.74, 121.89, 88.72, 65.02;
HRMS (ESI) m/z calcd for C15H11Cl2NO3 [M+Na]+ 346.0116; found 346.0114.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-4,6-dimethylisoindolin-1-one (4g). Following the general
procedure, 4g was isolated as a white solid (146 mg, 85%): Mp 177-179 °C; 1H NMR (300 MHz, CDCl3):
δ 7.34 (s, 1H), 7.29 (s, 1H), 7.25–7.15 (m, 3H), 7.04 (s, 1H), 3.72 (s, 3H), 3.40 (s, 1H), 2.29 (s, 3H), 1.96
13
(s, 3H); C NMR (75 MHz, DMSO) δ 162.46, 140.30, 139.62, 137.27, 135.63, 133.23, 132.68, 128.56,
128.19, 120.40, 89.61, 64.90, 20.73, 16.59; HRMS (ESI) m/z calcd for C17H16ClNO3 [M+Na]+ 340.0819;
found 340.0820.
3-(4-Chlorophenyl)-3-hydroxy-2,6-dimethoxyisoindolin-1-one (4h). Following the general procedure,
4h was isolated as a white solid (100 mg, 58%): Mp 147-149 °C; 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J
= 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (dd, J =
8.4, 2.4 Hz, 1H), 3.90 (s, 3H), 3.84 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6): δ 162.62, 160.48,
138.49, 138.35, 132.84, 129.34, 128.39, 128.01, 124.11, 120.10, 106.67, 89.79, 64.97, 55.77; HRMS
(ESI) m/z calcd for C16H14ClNO4 [M+Na]+ 342.0611; found 342.0617.
6-Chloro-3-(4-chlorophenyl)-3-hydroxy-2-methoxyisoindolin-1-one (4i). Following the general
procedure, 4i was isolated as a white solid (154 mg, 88%): Mp 195-197 °C; 1H NMR (300 MHz, CDCl3):
δ 7.77 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz,

13
2H), 7.22 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.54 (s, 1H); C NMR (75 MHz, DMSO-d6): δ 161.25,
144.74, 137.51, 134.58, 133.40, 133.25, 129.89, 128.59, 128.13, 124.91, 122.74, 89.76, 65.15; HRMS
(ESI) m/z calcd for C15H11Cl2NO3 [M+Na]+ 346.0116; found 346.0115.
3-(4-Chlorophenyl)-3-hydroxy-2,5-dimethoxyisoindolin-1-one (4j). Following the general procedure,
4j was isolated as a white solid (110 mg, 64%): Mp 142-145 °C; 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J
= 8.3 Hz, 1H), 7.38–7.27 (m, 3H), 7.20 (s, 1H), 6.98–6.80 (m, 1H), 6.66 (d, J = 2.2 Hz, 1H), 3.82 (s, 3H),
13
3.73 (s, 3H), 3.56 (s, 1H); C NMR (75 MHz, DMSO-d6): δ 163.63, 163.07, 148.69, 138.32, 132.93,
128.43, 128.09, 124.72, 119.89, 115.98, 107.67, 89.72, 65.06, 55.88; HRMS (ESI) m/z calcd for
C16H14ClNO4 [M+Na]+ 342.0611; found 342.0611.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-1-oxoisoindoline-5-carbonitrile (4k). Following the
general procedure, 4k was isolated as a white solid (117 mg, 69%): Mp 172-175 °C; 1H NMR (300 MHz,
CDCl3): δ 7.92 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.47–7.33 (m, 4H), 4.10 (s, 1H),
13
3.90 (s, 3H); C NMR (75 MHz, DMSO): δ 160.70, 146.63, 136.86, 134.21, 133.43, 131.84, 128.60,
128.22, 126.87, 124.01, 117.85, 115.56, 89.75, 65.16; HRMS (ESI) m/z calcd for C16H11ClN2O3 [M+Na]+
337.0458; found 337.0455.
ACKNOWLEDGEMENTS
We gratefully acknowledge the Natural Science Foundation (No. BK 20141349) and the China National
Key Hi-Tech Innovation Project for the R&D of Novel Drugs (No. 2013ZX09301303-002) for their
financial support.
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