One-pot method to construct isoindolinones and its application to the synthesis of DWP205109 and intermediate of Lenalidomide

Article abstract of DOI:10.1016/j.tetlet.2021.153152

Herein a practical and efficient system for concise synthesis of isoindolinones is described by using substituted methyl 2-(halomethyl)benzoates and substituted amines. Structurally various methyl 2-(halomethyl)benzoates and amines were transformed into isoindolinones 80–99% yield and purity in catalyst-free and solvent-free conditions. The method has a wide substrate scope. The synthetic utility of the one-pot reaction was demonstrated by the concise syntheses of Lenalidomide intermediate and DWP205190.

Full text of DOI:10.1016/j.tetlet.2021.153152

Tetrahedron Letters 74 (2021) 153152
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot method to construct isoindolinones and its application to the
synthesis of DWP205109 and intermediate of Lenalidomide
a
Hongbo Wang a,1, Zhiqiang Xie b,1, Bowei Lu c,d,1, Kaikai Zhong a, Junrui Lu a, , Jinbiao Liu
⇑
a College of Chemistry and Chemical Engineering, Tianjin University of Technology, NO.391, Binshui West Road, Xiqing District, Tianjin 300384, PR China
b State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, PR China
c School of Chemical Engineering and Technology, Tianjin University, NO.135, Yaguan Road, Haihe Education Park, Jinnan District, Tianjin 300072, PR China
d Tianjin Ruiling Chemical Co., Ltd., NO.1, Gonghua Road, Huayuan Hi-tech Park, Tianjin 300384, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein a practical and efficient system for concise synthesis of isoindolinones is described by using sub-
stituted methyl 2-(halomethyl)benzoates and substituted amines. Structurally various methyl 2-(halo-
methyl)benzoates and amines were transformed into isoindolinones 80–99% yield and purity in
catalyst-free and solvent-free conditions. The method has a wide substrate scope. The synthetic utility
of the one-pot reaction was demonstrated by the concise syntheses of Lenalidomide intermediate and
DWP205190.
Received 9 March 2021
Revised 29 April 2021
Accepted 3 May 2021
Available online 6 May 2021
Keywords:
Ó 2021 Published by Elsevier Ltd.
Concise synthesis
One-pot method
Solvent-free
Catalyst-free
Green method
Isoindolinones
Introduction
immunomodulatory agent and blockbuster drug for multiple
myeloma and non-Hodgkin’s lymphoma with $9.68 billion in
Nitrogen-containing heterocycles are pivotal fragments in an
extensive scope of active organic compounds discovered in medici-
nes, pesticides and other specific materials frequently [1]. As an
important class of alkaloids, the unique five-membered lactam ring
structure of isoindolinones is widely present in natural products
and plays an irreplaceable role in medicines, which have multiple
biological activities, such as anti-thrombus [2a], anti-malaria [2b],
anti-anxiety [2c], anti-tumor [2d], anti-leukemia [2e], anti-fungus
[2f], etc. Because of its unique properties, many novel
isoindolinones and derivatives have been isolated and
synthesized to further investigate their physiological activities
and structure–activity relationships (Fig, 1) [3]. Narceine imide
[4a] has the effect of anti-leukemia and Stachybotrin C [4b] has a
strong potential in the treatment of neurodegenerative diseases.
Indobufen [4c] is an antiplatelet aggregation drug, which is
widely used in the field of human cardiovascular and
cerebrovascular diseases. Pictonamine [4d] is a kind of alkaloid
with potential biological activity, and DWP205190 [4e] is a
sales in 2018 as an isoindolinone derivative [4f,g].
Most of isoindolinone compounds are isolated and extracted
from plants, and their lactam skeleton often need structural mod-
ification and optimization to obtain molecules with biological
activity and drug applications [5]. Therefore, a variety of isoin-
dolinone skeleton units have attracted the attention as a key inter-
mediate in the synthesis of diverse useful organic molecules and
natural products. A lot of methods have been developed for the
preparation of isoindolinones via catalytic reduction of 2-formyl-
benzoics acid and amines [6], selective reduction of N-substituted
isoindoline-1,3-diones [7], catalytic reduction of phthalaldehydes
and amines [8], intramolecular cyclization of 2-alkyl-N-arylbenza-
mides [9], intramolecular cyclization of halogenated benzamides
[10], intermolecular carbonylation of N-alkylbenzylamines [11],
amination and lactamization N-substituted-1-phenylmethanimi-
nes [12], and so on [13]. However, these methods still need inno-
vating to reduce the use of organic solvents and catalysts or the
addition of other expensive reagents. In addition, the toxic metal
residues produced from the catalysts in the target isoindolinones
can hardly be completely removed, which is not an ideal approach
for the synthesis of active pharmaceutical ingredients (API) and
biological products [14] Therefore, the substitution of reaction con-
ditions should be considered carefully such as reactant
phosphodiesterase inhibitor. Lenalidomide is
a well-known
⇑
Corresponding author.
E-mail address: lujunrui@tjut.edu.cn (J. Lu).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2021.153152
0040-4039/Ó 2021 Published by Elsevier Ltd.

H. Wang, Z. Xie, B. Lu et al.
Tetrahedron Letters 74 (2021) 153152
Fig. 1. Examples of isoindolinone derivatives.
concentration, solvents, catalysts, temperature, pressure and other
factors affecting the reaction, even raw materials, to implement
atomic economy. Considering the atom economy of chemical pro-
cesses to simply and efficiently construct natural products and
drugs is still urgent and important, which has become a consensus
[15].
Herein, we develop a practical and efficient melting method
with nearly 100% yield and purity in preparation of various isoin-
dolinones from substituted methyl 2-(halomethyl)benzoates and
substituted amines in catalyst-free and solvent-free conditions.
This atom-economic reaction system eradicates toxic metal con-
taminations, reduces the use of organic solvents, simplifies the
post-treatment and has broad industrialization prospects.
melting point, the system synchronously needs to be heated up to
higher temperature to form better melting states and proceed
smoothly. The results were shown in Table 2. The experimental
results confirmed that various substituted amines and substituted
methyl 2-(halomethyl)benzoates still exhibited excellent yields in
the reactions of melting method. In the conditions without catalyst
or solvent, melting method still had a wide substrate scope, such as
different types of alkyl groups, various halogen-substituted phenyl
groups, bulky groups and ammonia.
Among the alkyl-based amines (Table 2, entries 3–7), different
kinds of amines were designed including straight-chain, cyclo-
hexyl, benzyl and 2-phenethyl groups, which increased the activity
of the reaction due to the effect of electron donating and the low
melting point of reactants and intermediates, making the process
smoother at mild temperature 40 °C and achieving high yields
within 5 min. The results also showed that aromatic amines carry-
ing halogen substituents (Table 2, entries 8–12) and bulky i-Pr and
t-Bu groups (Table 2, entries 14–15) as well as anilines with high
melting point (Table 2, entries 13,16) could be reacted efficiently
to give the satisfactory yields and purities within 2 h at higher tem-
perature 140 °C. Bromine substituted benzoate ring under opti-
mized reaction condition yielded the corresponding isoindolinone
product in 99% yield (Table 2, entries 22). Substituted anilines con-
taining sensitive functional groups such as hydroxyl groups
(Table 2, entries 17–18) exhibited the yields less than 90% because
of the excessive melting points and undesirable melting states of
substrates and intermediates. To optimize this problem, unreacted
portion should be separated easily from the system and recycled.
Conversely, nitro group substituted on compounds 1 (Table 2,
entries 19–21) showed excellent reactivity due to its electron-
withdrawing effect. The reactions could proceed smoothly at 40–
90 °C within 5 min mostly.
Results and discussion
The melting state, mixing uniformity and reaction rate of reac-
tants in the system were directly affected by reaction temperature.
Although the reactants had relatively low melting points, the inter-
mediates without cyclocondensation generated in the reaction
process were difficult to melt below 110 °C through experimental
result. Considering the smooth progress of the reaction and the
high yield of products, the reaction temperature was set at
110 °C to 150 °C (Table 1). Above 140 °C, the reaction yield was
quickly closed to 100% in 2 h mainly because of the appropriate
melting state, while the reaction rate below 140 °C was relatively
slow as there were still a portion of intermediates without cyclo-
condensation in the reaction system even after 4 h. This method
was also indicated to possess excellent chemoselectivity and good
atomic economy since the occurring impurities in products after
reaction completion were only trace intermediates without cyclo-
condensation and residual HBr, which can be easily separated,
recycled or absorbed.
With the optimum conditions were determined, a series of sub-
stituted amines and substituted methyl 2-(halomethyl)benzoates
were selected to expand the range of the condensation reaction.
Since the properties of different types of reactants vary greatly,
the reaction temperature for 3a, 3h~3r, 3u~3x was 140 °C, for
3c~3g, 3t was 40 °C and for 3b, 3s was 90 °C to reach the best
yields. It is worth mentioning that for raw materials with low melt-
ing point and high activity, the process can be realized at lower
temperature. When for the substrates and intermediates with high
Considering that 3-substituted isoindolinones exist in numer-
ous natural products and medicines [4a,d], highly efficient
synthesis of 3-position substituents isoindolinones is one of the
important challenges in synthesis. This method can achieve 3-
substituted isoindolinones smoothly with high yields (Table 2,
entries 23–24), which provides a good idea to synthesize natural
products and medicines of isoindolinones with 3-position
substituents.
The reaction of methyl 2-chloromethylbenzoate with amines
was designed (Table 2, entries 25–26), which also achieved excel-
2

H. Wang, Z. Xie, B. Lu et al.
Tetrahedron Letters 74 (2021) 153152
Table 1
Optimization of the reaction conditions.a
Entry
t/h
T/°C
Status
Yield(%)b
1
2
3
4
5
4
4
4
2
2
110
120
130
140
150
half molten
half molten
molten
molten
molten
71
77
92
98
98
a
Conditions: 1a (10 mmol), 2a (10 mmol), no catalyst, solvent-free.
Isolated yield.
b
Table 2
Reactions between substituted methyl 2-(halomethyl)benzoates and substituted amine.
Entry
R
R1
R2
t/h
Product
Yield (%)d
Purity (%)e
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
n-Bu
i-Pr
2 h
2 h
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
98a
97b
99c
99c
98c
97c
98c
96a
98a
98a
97a
96a
97a
98a
98a
96a
83a
80a
96b
99c
96c
98a
97a
98a
98a
98a
99
99
98
98
98
98
98
99
99
99
99
99
99
99
99
99
99
98
95
97
98
98
98
97
99
99
5 min
5 min
5 min
5 min
5 min
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
Cyclohexyl
Benzyl
2-Phenethyl
o-FC6H4
m-FC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-MeC6H4
4-(i-Pr)C6H4
4-(t-Bu)C6H4
p-MeOC6H4
p-NO2C6H4
m-OHC6H4
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
H
H
H
Ph
H
H
H
Methyl
Methyl
H
3-NO2
3-NO2
3-NO2
5-Br
H
H
H
H
3s
3t
n-Bu
Ph
Ph
i-Pr
5 min
5 min
2 h
2 h
2 h
3u
3v
3w
3x
3e
3a
Ph
Cyclohexyl
Ph
2 h
2 h
H
a
b
c
Conditions: 1(10 mmol), 2(10 mmol), no catalyst and solvent-free, 140 °C.
Conditions: 1 (10 mmol), 2 (10 mmol), no catalyst and solvent-free, 90 °C.
Conditions: 1 (10 mmol), 2 (10 mmol), no catalyst and solvent-free, 40 °C.
Isolated yield.
d
e
Determined by HPLC.
lent yields. From the above, this method has a wide substrate
scope.
Considering that higher temperatures may be required to com-
pletely convert the raw materials in large-scale production, several
DSC analyses were performed to further evaluate feasibility and
safety of the method (Fig, 2). For nitro-containing compounds,
decomposition under a high temperature condition cannot be
ignored, as it releases a lot of heat. However, the experimental
results showed that nitro-containing (upper two curves) and other
selected isoindolinones all have obvious stability in setting
3

H. Wang, Z. Xie, B. Lu et al.
Tetrahedron Letters 74 (2021) 153152
Fig. 2. DSC curves of several isoindolinones.
The developed method was utilized for the efficient synthesis of
DWP205190 and intermediate of Lenalidomide.
Lenalidomide, an antitumor drug with a chemical structure
similar to thalidomide and approved for marketing by U.S. Food
and Drug Administration (FDA) and European Medicines Agency
(MEA), is mainly used in multiple myeloma and non-Hodgkin’s
lymphoma, also has a pharmacological effect on myelodysplastic
syndrome, chronic lymphocytic leukemia and solid tumors [16].
Because of its important and irreplaceable features in medicines,
lenalidomide has attracted much attention of pharmacologists
and chemists to conduct more thorough biological activity studies
and more outstanding synthetic methods. Currently, there are sev-
eral main synthesis routes of Lenalidomide constructed including
ring forming with 3-aminpiperidine-2,6-dione, cyclization of L-glu-
Fig. 3. DSC curves of the reaction progress.
tamine and other methods [17]. However, there are some common
problems in these methods, such as long reaction time, low yield
and tedious post-processing. In addition, the preparation of the
key intermediate isoindolinone L1 is the most important step in
all methods. In view of the existing problems, the synthetic route
of Lenalidomide intermediate L1 is optimized in our method basi-
cally (Fig, 4).
Commercially available 1s was subject to our melting method
with catalyst-free and solvent-free conditions to produce Lenalido-
mide intermediate L1 in 95% yield and high purity closed to 100%.
DWP205190, a pharmacological molecule combining rolipram
and thalidomide, can inhibit the production of phosphodiesterase
(PDE)4 to block tumor necrosis factor-a (TNF-a). It is also a poten-
tially potent anti-inflammatory inhibitor which is safer and more
effective than thalidomide and rolipram [18]. At present, there
are two main methods for synthesizing DWP205190 including
reduction of substituted N-phenylphthalimides and intramolecular
coupling of 2-alkylbenzamides (Fig, 5). Here synthesis of
DWP205190 was achieved for the first time from methyl (2-bro-
momethyl) benzoate and 3-(cyclopentyloxy)-4-methoxyaniline in
one step, without any solvent or catalyst, which had an excellent
yield and high purity of product. To the best of our knowledge,
the synthesis of DWP205190 by our method to accomplish such
transformation is the highest yield at present, which fully follow
the principle of atom economy.
Fig. 4. Synthesis of Lenalidomide intermediate L1.
reaction temperatures below 270 °C. Therefore, this method was
demonstrated to be applied securely within a large temperature
range.
Taking methyl 2-bromomethyl benzoate and aniline as the
model reaction, the temperature profile of the reaction was ana-
lyzed by DSC (Fig, 3). The experimental result showed that no obvi-
ous exothermic phenomenon was observed, which further proved
the safety of the reaction progress.
4

H. Wang, Z. Xie, B. Lu et al.
Tetrahedron Letters 74 (2021) 153152
Fig. 5. Synthesis of DWP205190.
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In summary, we have successfully synthesized a variety of
isoindolinone derivatives by melting method with nearly 100%
yields and purities. The synthetic utility of the one-pot reaction
was proved by the concise syntheses of Lenalidomide intermediate
and DWP205190. This new method possesses avoids toxic metal
pollution from the source. Further research is under way in our
laboratory.
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6