A practical synthesis of functionalized isoindolinones via [3?+?3] benzannulation of 1,3-bissulfonylpropenes and 4-arylmethylene-2,3-dioxopyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2018.11.074

A straightforward synthesis of isoindolinones has been developed via a [3 + 3] benzannulation of 4-arylmethylene-2,3-dioxopyrrolidines and 1,3-bissulfonylpropenes (or 4-sulfonylcrotonates). A series of functionalized isoindolinones were obtained in excellent yields. The reaction could be carried out under mild conditions without transition metal catalyst. The finding provides a practical approach for the preparation of isoindolinone derivatives with potential biological activities.

Full text of DOI:10.1016/j.tetlet.2018.11.074

Accepted Manuscript
A practical synthesis of functionalized isoindolinones via [3 + 3] benzannulation
of 1,3-bissulfonylpropenes and 4-arylmethylene-2,3-dioxopyrrolidines
Xiang-zheng Tang, Jing-xuan zhou, Hua-ju Liang, Xue-jing Zhang, Ming Yan,
Albert S.C. Chan
PII:
S0040-4039(18)31430-8
https://doi.org/10.1016/j.tetlet.2018.11.074
TETL 50459
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 October 2018
27 November 2018
30 November 2018
Please cite this article as: Tang, X-z., zhou, J-x., Liang, H-j., Zhang, X-j., Yan, M., Chan, A.S.C., A practical
synthesis of functionalized isoindolinones via [3 + 3] benzannulation of 1,3-bissulfonylpropenes and 4-
arylmethylene-2,3-dioxopyrrolidines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.074
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Graphical Abstract
A practical synthesis of functionalized
isoindolinones via [3 + 3]
Leave this area blank for abstract info.
benzannulation of 1,3-
bissulfonylpropenes and 4-
arylmethylene-2,3-dioxopyrrolidines
Xiang-zheng Tang, Jing-xuan zhou, Hua-ju Liang, Xue-jing Zhang, Ming Yan*, and Albert S. C. Chan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, China

1
Tetrahedron Letters
A practical synthesis of functionalized isoindolinones via [3 + 3] benzannulation
of 1,3-bissulfonylpropenes and 4-arylmethylene-2,3-dioxopyrrolidines
Xiang-zheng Tang , Jing-xuan zhou , Hua-ju Liang , Xue-jing Zhang , Ming Yan, and Albert S. C. Chan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A straightforward synthesis of isoindolinones has been developed via a [3+3] benzannulation of
4-arylmethylene-2,3-dioxopyrrolidines and 1,3-bissulfonylpropenes (or 4-sulfonylcrotonates). A
series of functionalized isoindolinones were obtained in excellent yields. The reaction could be
carried out under mild conditions without transition metal catalyst. The finding provides a
practical approach for the preparation of isoindolinone derivatives with potential biological
activities.
Available online
Keywords:
isoindolinone
2009 Elsevier Ltd. All rights reserved.
[3+3]benzannulation
1,3-bissulfonylpropene
4-arylmethylene-2,3-dioxopyrrolidine
4-sulfonylcrotonate
The isoindolinone derivatives are widely found in natural
products1 and synthetic drugs2 with significant biological
activities. For instance, indoprofen is a clinically used non-
steroidal anti-inflammatory drug (Scheme 1).3 Lenalidomide is
an antitumor agent used for the treatment of multiple myeloma.4
Isohericerin, a metabolite isolated from the H. erinaceum,
exhibited potent anti-proliferation activity.5 Moreover, The
isoindolinone derivatives are also versatile intermediates for the
total synthesis of complex alkaloids with attractive bioactivities.6
halo-N-alkylbenzamides.12 However, most of the methods require
the addition of stoichiometric oxidants, transition metal catalysts,
and toxic reagents. In addition, the synthetic strategies focus on
the construction of pyrrolidinone moiety.13 Alternatively, the
synthesis of isoindolinones via the construction of benzene
moiety had less been developed.14
Benzannulation is a powerful strategy for the synthesis of
aromatic compounds.15 In addition to the generally used [4 + 2]
benzannulation reactions, [3 + 3] benzannulation reactions are
also valuable.16 We have a special interest for the application of
1,3-bis(sulfonyl)propenes to [3 + 3] benzannulation reactions,
considering their good reactivity, the removal and diversified
transformation of the sulfonyl groups. In 2015, Menon group
reported the synthesis of 3-sulfonyl benzoic ester derivatives via
a [3 + 3] benzannulation reaction of 4-sulfonylcrotonates (or 1,3-
bissulfonylpropenes) with α,β-unsaturated aldehydes and
ketones.17 Recently, we developed the [3 + 3] benzannulation
reaction of 1,3-bis(sulfonyl)propenes and β,γ-unsaturated α-
ketoesters.18 A series of highly substituted diaryl sulfones were
prepared in good yields. As a continuous effort, herein we report
a practical synthesis of functionalized isoindolinones via [3 + 3]
benzannulation of 1,3-bissulfonylpropenes and 4-methylene-2,3-
dioxopyrrolidines.
Scheme 1. Representative isoindolinones with attractive bioactivities.
Over the past decades, a variety of synthetic methods of
isoindolinones have been developed.7 These approaches include
Initial studies were performed using 4-benzylidene-2,3-
dioxopyrrolidine 1a and 1,3-bis(p-toluenesulfonyl)propene 2a as
the model substrates in CHCl3 at room temperature. The results
are summarized in Table 1. This reaction was expected to take
place via cascade conjugate addition, intramolecular carbonyl
addition, and desulfonative aromatization.18 A screen of various
the
chemoselective
monoreduction
of
N-substituted
phthalimides,8 the reductive amination of 2-formylbenzoic acids,9
the Pd-catalyzed carbonylative cyclization of ortho-halogenated
benzamides,10 the intramolecular benzylic C−H amination of 2-
alkyl-benzamides,11 and intramolecular C−C coupling of ortho-
———
 Corresponding author. Fax/Tel: + 86-20-39943049; e-mail: yanming@mail.sysu.edu.cn

2
Tetrahedron
bases showed that DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) is
doesn't affect the reactivity of the substrate. The products 4f were
obtained with excellent yields (Table 3, entries 5-7). In these
cases, the elimination of sulfonyl group occurred exclusively.
most efficient. The desired product 3a was obtained in 73% yield
(Table 1, entry 1). Other bases such as DABCO (1,4-
diazabicyclo[2.2.2]octane), TMG (1,1,3,3-tetramethylguani-
dine), DMAP (4-dimethylamino-pyridine), NaHCO3 and K2CO3
are less effective (Table 1, entries 2-6). Among the tested
solvents, DMF, toluene, and MeCN delivered 3a with low yields
(Table 1, entries 7-9). Further investigation showed that an
improved yield could be obtained in THF (Table 1, entry 10).
The better yields were achieved at elevated reaction
temperatures. The optimum temperature was identified as 60 °C
(Table 1, entries 11-13). More details about the optimization of
the reaction conditions were provided in the supporting
information.
Table 2
Scope of 4-arylmethylene-2,3-dioxopyrrolidines.a
Entry
R
Product
Yieldb (%)
1
Ph
3a
3b
3c
3d
3e
3f
96
97
98
98
95
95
92
94
93
95
96
94
79
2
4-CH3C6H4
4-CH3OC6H4
4-F-C6H4
Table 1
3
Optimization of the reaction conditions.a
4
5
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
3-CH3-C6H4
3-Br-C6H4
2-Br-C6H4
2-naphthyl
2-thienyl
6
7
3g
3h
3i
Yieldb (%)
8
Entry
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
Base
T (C)
9
1
DBU
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
73
43
58
40
21
32
32
43
24
75
82
2
DABCO
TMG
10
11
12
13
3j
3
3k
3l
4
DMAP
NaHCO3
K2CO3
DBU
5
4-CH=CH-Ph
3m
6
aAll reactions were carried out with 1a-1m (0.21 mmol), 2a (0.20 mmol) and
DBU (0.24 mmol) in THF (4 mL) at 60 °C for 48 h.
7
bIsolated yields.
8
Toluene
CH3CN
THF
DBU
9
DBU
Table 3
10
11
DBU
Reaction of 1a with 1,3-bissulfonylpropenes 2b-2e and 4-sulfonylcrotonates
2f-2h.a
THF
DBU
12
13
THF
THF
DBU
DBU
60
80
96
92
aAll reactions were carried out with 1a (0.21 mmol), 2a (0.20 mmol) and base
(0.24 mmol) in solvent (4 mL) at indicated temperature for 48 h.
bIsolated yields.
Entry
R1
R2
Product
4b
Yieldb (%)
1
2
3
4
5
6
7
PhSO2
PhSO2
97
94
95
98
95
94
97
A variety of 4-methylene-2,3-dioxopyrrolidines 1a-1m was
examined and the results are summarized in Table 2. The
substitutions on the benzene ring with electron-donating group
(such as Me, OMe) or electron-withdrawing group (such as
halogen, CF3) are tolerated very well. Excellent yields were
generally obtained (Table 2, entries 2-10). The naphthyl and
thiophenyl derivatives 1k-1l also reacted smoothly to give the
products with excellent yields (Table 2, entries 11-12). The
styrylderivative 1m is also applicable. Good yield of 3m was
obtained (Table 2, entry 13).
4-FC6H4SO2
4-ClC6H4SO2
4-BrC6H4SO2
4-CH3C6H4SO2
PhSO2
4-FC6H4SO2
4-ClC6H4SO2
4-BrC6H4SO2
COOMe
COOMe
COOMe
4c
4d
4e
4f
4f
4-ClC6H4SO2
4f
aAll reactions were carried out with 1a (0.21 mmol), 2b-2h (0.20 mmol) and
DBU (0.24 mmol) in THF (4 mL) at 60 °C for 48 h.
Furthermore, the reaction of 1a with a number of 1,3-
bissulfonylpropenes 2b-2e and 4-sulfonylcrotonates 2f-2h were
examined and the results are summarized in Table 3. Excellent
yields were obtained for 1,3-bissulfonylpropenes 2b-2e bearing
para-halogen substitutions (Table 3, entries 2-4). The
replacement of one sulfonyl group with an ester group (2f-2h)
bIsolated yields.
To explore the synthetic potential of our methodology, a
scale-up reaction of 1a and 2a was examined (Scheme 2). The
product 3a was obtained in 93% yield, which is comparable to
that of small-scale reaction.

3
References and notes
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Scheme 2. Gram-scale synthesis of 3a.
The further transformations of the products were explored
(Scheme 3). The product 3a was reduced with LiAlH4 to furnish
isoindoline 5 in 83% yield. The debenzylation with 1-chloroethyl
chloroformate and the subsequent protection with (Boc)2O
provided product 6 in a good yield. The treatment of 3a with
Bu3SnH/AIBN afforded an organostannane intermediate, which
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Scheme 3. Synthetic applications of 3a.
In conclusion, we have developed a [3+3] benzannulation
strategy for the synthesis of functionalized isoindolinones from
4-arylmethylene-2,3-dioxopyrrolidines
and 1,3-bissulfonyl-
propenes (or 4-sulfonylcrotonates). Excellent yields were
generally obtained under mild reaction conditions. The sulfonyl
group acts as both the activating group at the initial stage and the
leaving group at the last stage. The further elaborations of the
products were also achieved via the reduction, the
desulfonylation and the Stille coupling. The new method is of
good practicability for the synthesis of isoindolinone derivatives.
18. Tang, X.-Z.; Tong, L.; Liang, H.-J.; Liang, J.; Zou, Y.; Zhang, X.-J.;
Yan, M.; Chan, A. S. C. Org. Biomol. Chem. 2018, 16, 3560.
Acknowledgments
We thank the National Natural Science Foundation of China (No.
21472248, 21772240), the Guangzhou Science Technology and
Innovation Commission (201707010210) for the financial support of
this study.
Supplementary Material
Supplementary data related to this article can be found at
https://doi.org/

4
Tetrahedron
Highlights


Novel and practical synthesis of functionalized
isoindolinones.
Excellent yields, simple procedure and mild reaction
conditions.


Gram-scale reaction without transition metal catalyst.
Diversified transformations of the products.