A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives under Pd(OAc)2/HCOOH system

Article abstract of DOI:10.1016/j.tetlet.2017.04.073

A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives from 2-formylbenzoic acid and amine under Pd(OAc)₂/HCOOH system has been described. The whole process is carried out in ligand-free conditions and furnished the desired products by reductive intramolecular cyclization. Furthermore, this procedure is applied successfully for the modification of natural products, such as vindoline and estrone.

Full text of DOI:10.1016/j.tetlet.2017.04.073

Accepted Manuscript
A facile and efficient method for the synthesis of N-substituted isoindolin-1-one
derivatives under Pd(OAc)2/HCOOH system
Yang Zhou, Ping Chen, Xue Lv, Junxing Niu, Yingying Wang, Min Lei, Lihong
Hu
PII:
S0040-4039(17)30525-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.073
TETL 48865
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 March 2017
21 April 2017
24 April 2017
Please cite this article as: Zhou, Y., Chen, P., Lv, X., Niu, J., Wang, Y., Lei, M., Hu, L., A facile and efficient method
for the synthesis of N-substituted isoindolin-1-one derivatives under Pd(OAc)2/HCOOH system, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.073
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Graphical Abstract
A facile and efficient method for the
Leave this area blank for abstract info.
synthesis of N-substituted isoindolin-1-one
derivatives under Pd(OAc)2/HCOOH system
Yang Zhou, Ping Chen, Xue Lv, Junxing Niu, Yingying Wang, Min Lei, Lihong Hu

1
Tetrahedron Letters
A facile and efficient method for the synthesis of N-substituted isoindolin-1-one
derivatives under Pd(OAc)2/HCOOH system
Yang Zhou a, Ping Chen a, Xue Lv b, Junxing Niu b, Yingying Wang b, Min Lei b, and Lihong Hu b,c,
aWuhan Polytechnic University, School of Biological and Pharmaceutical Engineering, Wuhan, PR China
bShanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
cJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources
Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing,
PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives
from 2-formylbenzoic acid and amine under Pd(OAc)2/HCOOH system has been described. The
whole process was carried out in ligand-free conditions and furnished the desired products by
reductive intramolecular cyclization. Furthermore, this procedure is applied successfully for the
modification of natural products, such as vindoline and estrone.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Formylbenzoic acid
Isoindolin-1-one
Pd(OAc)2
Hydrogenation
Cyclization
Isoindolin-1-ones are one of the most prevalent heterocyclic
compounds, which are present as the basic cores in many
alkaloids.1 For example, a lot of natural products, such as
narceineimide, fumaridine, fumaramine and aristoyagonine, are
contain isoindolin-1-one unit.1,2 In recent years, much attention
has been focused on isoindolin-1-ones due to their significant
biological activity.3 As shown in Figure 1, lenalidomide is a
clinically used drug for the treatment of multiple myeloma.4
Compound CC3052 is reported as a potent inhibitor of TNF-α
production.5 Indoprofen is a non-steroidal antiinflammatory drug
which can increase production of the survival of the motor
neuron protein.6 Thus, efficient synthesis of this heterocyclic
nucleus has been of great interest in recent years.
drawbacks such as unsatisfactory yields, high temperatures, and
long reaction time, and the use of expensive reagents. Therefore,
there is a need to develop efficient methods for the synthesis of
isoindolin-1-ones under mild and green conditions.
Due to the importance of the isoindolin-1-ones, many methods
for preparing these compounds have been developed: (i) 2-
bromobenzaldehyde and amine catalyzed by PdCl2(PhCN)2;7 (ii)
1-(bromomethyl)-2-iodobenzene and amine catalyzed by
Pd(OAc)2;8 (iii) isobenzofuran-1(3H)-one and amine under high
temperature;9 (iv) 2-formylbenzoic acid and amine under
hydrogenation conditions,10 (v) and other methods.3f,7,11
Although, a number of modified methods under improved
Figure 1. Examples of clinically used isoindolin-1-ones.
Our group has long been engaged in the research of the
synthesis of heterocyclic compounds.12 In the previous study, we
conditions have been reported, many of them suffer from
———
 Corresponding author.
E-mail address: mlei@simm.ac.cn (M. Lei)
 Corresponding author.
E-mail address: lhhu@simm.ac.cn (L. Hu)

2
Tetrahedron
have reported several efficient procedures for the synthesis of
producing the required product (99%). In addition, the amount of
Pd(OAc)2 was also optimized (Table 2). No desired product 3a
was formed when the reaction was carried out in absence of
Pd(OAc)2 (Table 2, entry 6).The yields of 3a was improved as
the amount of Pd(OAc)2 increased from 1 to 5 mol %. The use of
5 mol% Pd(OAc)2 in model reaction led to quantitatively the
target 3a (Table 2, entry 1). Hence, 5 mol% of Pd(OAc)2 was
considered to be the most suitable.
2,3-disubstituted isoindolin-1-one derivatives under mild
conditions.13 It was reported that organic groups, such as olefin,
nitro, could be reduction under [Pd]/HCOOH system.14 Therefore,
we wanted to know whether the reaction of 2-formylbenzoic acid
and amine could proceed to form isoindolin-1-ones in the
presence of [Pd]/HCOOH as reductant.
Table 1. Base screena
Table 2. Pd-Cat screena
Entry
Pd-Cat (mol%)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
PdSO4 (5)
Yield of 3a (%)b
1
99
82
24
27
41
0
2
Entry
Base (equiv)
/
Yield of 3a (%)b
3
1
60
4
PdCl2 (5)
2
Et3N (2.0)
93
5
Pd(PPh3)4 (5)
Pd(OAc)2 (0)
Pd(OAc)2 (1)
Pd(OAc)2 (2)
Pd(OAc)2 (3)
Pd(OAc)2 (4)
Pd(OAc)2 (6)
3
DIPEA (2.0)
Py (2.0)
94
6
4
NDc
99 (94)d
30
7
50
75
90
94
98
5
DABCO (2.0)
DMAP (2.0)
K2CO3 (2.0)
Na2CO3 (2.0)
DABCO (0.5)
DABCO (1.0)
DABCO (1.5)
8
6
9
7
94
10
11
8
93
9
79
aReaction conditions: 1a (300 mg, 2.0 mmol), 2a (224 mg, 2.4
mmol, 1.2 equiv), DABCO (448 mg, 2 equiv), HCOOH (0.5
mL), Pd-Cat, 1,4-dioxane (2 mL), 80 oC for 1 h.
10
11
88
91
aReaction conditions: 1a (300 mg, 2.0 mmol), 2a (224 mg, 2.4
mmol, 1.2 equiv), base, HCOOH (0.5 mL), Pd(OAc)2 (22.5 mg,
0.1 mmol, 5 mol%), 1,4-dioxane (2 mL), 80 oC for 1 h.
bYields were determined by LC-MS.
Having established the optimized reaction conditions, we then
successfully synthesized a variety of isoindolin-1-one derivatives
3 and the results were summarized in Table 3.
Table 3. Synthesis of isoindolin-1-ones a
bYields were determined by LC-MS.
cNo product were determined.
dIsolated yield.
Initially, we studied the reaction of 2-formylbenzoic acid (1a)
(2 mmol) and aniline (2a) (2.4 mmol) under Pd(OAc)2/HCOOH
o
in 1,4-dioxane (2 mL) at 80 C for 1 h to obtain the desired
Entry
R1
R2
Time
(h)
Produc
t 3
Yield
(%)b
product 3a in 60% yield. Further study revealed that base could
improve the yields significantly. Therefore, the model reactions
were carried out under different bases and the results are
summarized in Table 1. As shown in Table 1, various bases such
as Et3N, DIPEA, Py, DABCO, DMAP, K2CO3, and Na2CO3 were
applied to facilitate this model reaction. All the bases studied on
this reaction showed good effect in terms of the yields of 3a (93-
99%) but pyridine (3a was not determined) and DMAP (30%).
By screening of bases, DABCO was found to be the superior one
than others to afford 3a in 99% yield determined by LC-MS and
in 94% isolated yield. Therefore, DABCO was chosen as the base
for all further reactions. Furthermore, we found that the yields of
3a were improved as the amount of DABCO increased from 0.5
to 2.0 equiv (Table 1, entries 5, 9-11). In addition, to
investigation the solvent effect, various solvents such as EtOH,
THF, MeCN, 1,4-dioxane, DMF, DMSO, and EtOAc were
applied to promote this transformation. The results showed that
amongst these solvents, 1,4-dioxane was the solvent of choice in
terms of yield.
1
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
H 1a
C6H5 2a
1
1
1
5
1
1
5
1
1
5
5
1
1
3a
3b
3c
3d
3e
3f
94
2
4-CH3OC6H4 2b
3-CH3OC6H4 2c
2-CH3OC6H4 2d
4-CH3C6H4 2e
3-CH3C6H4 2f
2-CH3C6H4 2g
4-ClC6H4 2h
91
3
92
4
83
5
93
6
93
7
3g
3h
3i
82
8
70 (20)c
9
4-FC6H4 2i
92
10
11
12
13
4-NCC6H4 2j
4-HOOCC6H4 2k
4-EtOOCC6H4 2l
3j
93
3k
3l
94
91
3,4-(CH3O)2C6H3
3m
88
2m
Furthermore, to screen the Pd-Cat, various catalysts such as
Pd(OAc)2, Pd(TFA)2, PdSO4, PdCl2, and Pd(PPh3)4 were applied
to this model reaction (Table 2). Among the Pd-Cats screened,
Pd(OAc)2 showed excellent activity in terms of yield in
14
H 1a
3,4-(OCH2O)C6H3
2n
1
3n
85

3
15
16
17
18
19
20
H 1a
1-naphthyl 2o
C6H5CH2 2p
n-butyl 2q
5
1
1
1
1
1
3o
3p
3q
3r
3s
3t
73
91
90
93
90
92
As shown in Scheme 2, the propane-1,3-diamine (4) was
chose as substrate under the similar reaction conditions, and the
H 1a
corresponding product 5 was obtained in 85% yield.
H 1a
H 1a
cyclohexyl 2r
C6H5 2a
4-CN 1b
4-CN 1b
4-CH3OC6H4 2b
aReaction conditions: 1 (2.0 mmol), 2a (224 mg, 2.4 mmol,
1.2 equiv), DABCO (448 mg, 2 equiv), HCOOH (0.5 mL),
Pd(OAc)2 (22.5 mg, 0.1 mmol, 5 mol%), 1,4-dioxane (2 mL), 80
oC.
bIsolated yields.
cDechlorinated product 3a was determined.
As shown in Table 3, aromatic amines carrying substituents
(CH3- and CH3O-) at the meta or para position could react
efficiently to give the corresponding products without significant
differences (91-93%) (Table 3, entries 2, 3, 5 and 6). In contrast,
the use of ortho substituted amines led to medium yields (82-
83%) (Table 3, entries 4 and 7). It was noteworthy to mention
that dechlorinated product 3a (20%) was formed when using 4-
chloroaniline 2h as the substrate (Table 3, entry 8).
The results presented in Table 2 indicated that the electronic
effect from the aromatic amines had no significant impact on the
overall yields of the products 3. The aromatic amines with either
electron-donating (CH3- and CH3O-) or electron-withdrawing
groups (NC-, HOOC-, and CH3CH2OOC-) afforded the
corresponding products 3 in 91-94% yields (Table 3, entries 2, 5,
10-12). Furthermore, alkyl amines, such as benzylamine (2p), n-
butylamine (2q), and cyclohexylamine (2r), were also selected as
substrates for the synthesis of isoindolin-1-ones, and the
corresponding products were obtained in 91, 90, and 93% yields,
respectively. Furthermore, 4-cyano-2-formylbenzoic acid (1b)
was also used as starting material, and the reaction could proceed
smoothly to obtain the corresponding products in good yields
(Table 3, entries 19 and 20).
Scheme 3. The reaction of 2-formylbenzoic acid (1) and with natural
products 6 or 7.
Furthermore, this reaction was also applied in natural products
(Scheme 2). At first, vindoline and estrone were chosen as
starting materials, and 15-amino vindoline (6)15 and 2-amino
estrone (7)16 were synthesized according to the reported method.
Then, the reaction of 6 or 7 with 2-formylbenzoic acid (1) was
carried out under standard conditions for 5 h. The corresponding
products 8 and 9 were obtained in 75% and 65% yields,
respectively.
Scheme 1. The reaction of methyl 2-formylbenzoate (4) and aniline (2a).
As shown in Scheme 1, we also carried out the reaction using
methyl 2-formylbenzoate (4) instead of 2-formylbenzoic acid (1a)
under similar reaction conditions for 1 h, finding desired product
3a was formed in 95% yield.
Scheme 2. The reaction of 2-formylbenzoic acid (1) and propane-1,3-
diamine (2s).
Scheme 4. Plausible mechanism for the formation of N-substituted
isoindolin-1-ones.

4
Tetrahedron
(b) Kumar V, Sharma U, Singh B, KumarA N. Aust J Chem.
2012;65:1594;
(c) Ogiwara Y, Uchiyama T, Sakai N. Angew Chem Int Ed.
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Chem. 2012;14:3410;
A tentative mechanism to rationalize the products 3
formation is shown in scheme 4. Initially, 1 reacts with 2 to form
imine intermediate A, then, addition of A and formic acid on Pd-
Cat led to the formation of key intermediate palladium hydride
complex C. A new hydrido palladium complex D is formed from
C by releasing carbon dioxide. Upon reduction elimination,
complex D gave the intermediate E with regeneration of Pd-Cat.
(f) Mao F, Sui D, Qi Z, Fan H, Chen R, Huang J. RSC Adv.
2016;6:94068.
At last, desired product
dehydration from E.
3 is formed by intramolecular
11. (a) Ordóñez M, Tibhe GD, Zamudio-Medina A, Viveros-Ceballos
JL. Synthesis. 2012;44:569;
In conclusion, we have developed an efficient, green and
convenient method for the synthesis of N-substituted isoindolin-
1-ones via the reaction of 2-formylbenzoic acid and amine under
Pd(OAc)2/HCOOH system. This procedure is also suitable for the
modification of natural products. Moreover, the mild reaction
conditions, short reaction times, high yields of the products, ease
of work-up, compatibility with various functional groups, and the
ecologically clean procedure, will make the present method a
useful and important addition to the present methodologies for
the synthesis of N-substituted isoindolin-1-ones.
12. (a) Xiao C, Wang Z, Lei M, Hu L. Tetrahedron. 2017;73:204;
(b) Liu P, Lei M, Hu L. Tetrahedron. 2013;69:10405;
(c) Chen F, Lei M, Hu L. Tetrahedron. 2013;69:2954;
(d) Liu J, Lei M, Hu L. Green Chem. 2012;14:2534.
13. (a) Chen F, Lei M, Hu L. Green Chem. 2014;16:2472;
(b) You H, Chen F, Lei M, Hu L. Tetrahedron Lett. 2013;54:2972;
(c) Hu L-J, Zhan Z-J, Lei M, Hu L-H. ARKIVOC. 2013;(iii):189.
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2016;138:14864;
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Lett. 2016;57:4845;
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2007;7:1553.
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(b) Numazawa M, Kimura K. Steroids, 1983;41:675.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (grant: 81473110), Special Fund for
Strategic Pilot Technology Chinese Academy of Sciences
(XDA12040303), Shanghai Science & Technology Support
Program (13431900401).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
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5
Highlights
1. The isoindolin-1-ones are synthesized from 2-formylbenzoic acid and amine under Pd(OAc)2/HCOOH
system.
2. This procedure is green, efficient, and high yields.
3. This method is also suitable for the modification of natural products.