A Catalyst-Free One-Pot Protocol for the Construction of Substituted Isoindolinones under Sustainable Conditions

Article abstract of DOI:10.1055/s-0035-1562614

An operationally simple, one-pot, catalyst-free method was developed for the synthesis of pharmaceutically important substituted isoindolinones by a three-component reaction of 2-formylbenzoic acid, a primary amine, and a 1,3-dione in ethanol under dielectric heating.

Full text of DOI:10.1055/s-0035-1562614

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–G
letter
A
K. V. Sashidhara et al.
Letter
Synlett
A Catalyst-Free One-Pot Protocol for the Construction of
Substituted Isoindolinones under Sustainable Conditions
Koneni V. Sashidhara*a
L. Ravithej Singha
Gopala Reddy Palnatia
Srinivasa Rao Avulaa
Ruchir Kantb
a Medicinal and Process Chemistry Division, CSIR - Central Drug
Research Institute, Lucknow, 226 031, India
b Molecular and Structural Biology Division, CSIR - Central Drug
Research Institute, Lucknow, 226 031, India
sashidhar123@gmail.com
kv_sashidhara@cdri.res.in
Received: 17.05.2016
O
Accepted after revision: 22.07.2016
Published online: 08.08.2016
MeO
N
O
DOI: 10.1055/s-0035-1562614; Art ID: st-2016-b0346-l
HO
OH
N
OH
Abstract An operationally simple, one-pot, catalyst-free method was
developed for the synthesis of pharmaceutically important substituted
isoindolinones by a three-component reaction of 2-formylbenzoic acid,
a primary amine, and a 1,3-dione in ethanol under dielectric heating.
OH
1 hericerin
2 clitocybin A
O
Key words isoindolinones, medicinal chemistry, multicomponent re-
action, formylbenzoic acid, amines, diones
O
N
N
N
N
Cl
The isoindolinone motif is present in many natural and
synthetic compounds with important biological properties.1
A representative natural product that contains this framework
is hericerin (1; Figure 1), isolated from the edible
mushroom Hericium erinaceus, used in traditional Chinese
medicine for the treatment of dyspepsia, gastric ulcers, and
enervation.2 Clitocybin A (2) is a novel isoindolinone with
free-radical-scavenging activity, isolated from the culture
broth of the mushroom Clitocybe aurantiaca.3 Nuevamine
(3) is an isoindolo[1,2-a]isoquinolinone alkaloid.4
OMe
MeO
O
N
O
3 nuevamine
O
4 pazinaclone
O
N
O
O
CH3
O
N
NH
COOH
NH2
5 lenalidomide
6 indoprofen
The isoindolinone motif is also present in many
pharmaceutically interesting compounds such as pazinaclone
(4; Figure 1), which is used as an anxiolytic,5 lenalidomide
(Revlimid, 5), used as an anticancer agent for the treatment
of multiple myeloma,6 and indoprofen (6), used as a
nonsteroidal antiinflammatory drug.7
Consequently, the development of new and efficient
methods for the synthesis of 3-substituted isoindolinones is
an area of current interest.8 General methods for the
synthesis of isoindolinones include nucleophilic addition of
organometallic reagents,9 palladium-catalyzed isocyanide
insertion,10 or rhodium/ruthenium-catalyzed annulation.11
Additionally, metal-free catalytic systems consisting of
tetrabutylammonium acetate or triflic acid have also been
developed for the preparation of isoindolinone-type
Figure 1 Examples of natural and synthetic pharmacologically active
isoindolinone-containing frameworks
compounds.12 Interestingly, 2-formylbenzoic acid has been
employed as a key starting material in a one-pot, three-
component reaction with amines and appropriate nucleophiles
such as benzimidazoles,13a dimethyl phosphate,13b or
β-dicarbonyl compounds13c for the synthesis of isoindolinones.
However, despite their significant contributions in the
development of efficient methodologies, these methods
suffer from one or more limitations, such as poor substrate
scopes, high temperatures, or long reaction times.
In addition, some of these procedures require specific
nucleophilic reagents (such as Grignard reagents), harsh
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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K. V. Sashidhara et al.
Letter
Synlett
reaction conditions (such as an anhydrous environment), or
expensive metal catalysts, which might prevent the elaboration
of some sensitive isoindolin-1-ones. Therefore, it was
imperative to develop mild and practical protocols involving
easily available materials to synthesize a library of bioactive
isoindolin-1-ones.
Microwave-assisted chemical synthesis is an emerging
technology in medicinal chemistry because microwaves
have specific effects that cannot be achieved by conventional
heating.14 Microwaves induce efficient internal heating by
the interaction of the electric-field component of high-
frequency electromagnetic radiation with dipoles in the
reaction mixture.15
Multicomponent reactions have emerged as powerful
tools in organic, combinatorial, and medicinal chemistry
because of their high bond-forming efficiency.16 In
multicomponent cascade or domino reactions, three or
more reactants proceed through multiple transformations
to give complex heterocyclic compounds from simple starting
materials with several new carbon–carbon or carbon–
heteroatom bonds being formed in a single operation.17 As
part of our continued interest in developing novel efficient
reactions for the synthesis of medicinally important
heterocyclic compounds,18 we report a successful one-pot
multicomponent reaction for the synthesis of isoindolinone
derivatives under sustainable reaction conditions. The
three-component condensation reaction can be carried out
efficiently to obtain 3-(2-hydroxy-4,4-dimethyl-6-oxocy-
clohex-1-enyl)-2-phenylisoindolin-1-one derivatives in
satisfactory yields from 2-formylbenzoic acid, an aromatic,
heteroaromatic, or aliphatic primary amine, and a cyclohexane-
1,3-dione derivative as the starting materials.
To achieve this goal, we performed preliminary experiments
with 2-formylbenzoic acid (7), p-toluidine (8a), and 5,5-di-
methylcyclohexane-1,3-dione (9a; dimedone) in refluxing
ethanol in the absence of a catalyst, which gave isoindolin-
1-one 10a in 34% yield (Table 1, entry 1). To optimize the
reaction conditions, we examined the use of the various
Lewis acids (entries 2–12). To our delight, CeCl3·7H2O
effectively catalyzed the cyclization to give the isoindolin-
Table 1 Optimization of the Reaction Conditionsa
O
N
OH
NH2
O
O
catalyst, EtOH
O
O
O
HO
time, reflux
H
7
8a
9a
10a
Entry
Catalyst (equiv)
Time (h)
Yieldb (%)
1
2
–
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
3.0
2.0
2.0
2.0
1.0
34
40
38
40
40
35
36
90
42
40
41
42
88
88
88
88
80
65
ZnCl2 (0.3)
3
FeCl3 (0.3)
4
AlCl3 (0.3)
5
SnCl2 (0.3)
6
CuCl2 (0.3)
7
BiCl3 (0.3)
8
CeCl3·7H2O (0.3)
InCl3 (0.3)
9
10
11
12
13
14
15
16
17
18
HgCl2 (0.3)
AgOTf (0.3)
AuCl3 (0.3)
CeCl3·7H2O (0.3)
CeCl3·7H2O (0.3)
CeCl3·7H2O (0.3)
CeCl3·7H2O (0.2)
CeCl3·7H2O (0.1)
CeCl3·7H2O (0.2)
a Reaction conditions: 2-formylbenzoic acid (7; 1 mmol), p-toluidine (8a; 1 mmol), dimedone (9a) (1 mmol), EtOH (1 mL), 80 °C.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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K. V. Sashidhara et al.
Letter
Synlett
1-one derivative 10a in 90% yield (entry 8);19 all the other
catalysts proved less effective. Next, we screened the
reaction time and catalyst loading with CeCl3·7H2O as the
catalyst (entries 13–18). The reaction occurred efficiently
with 20 mol% of CeCl3·7H2O in ethanol as solvent (entry 16).
However, the yield of 34% under metal-free conditions was
more interesting, and prompted us to develop a sustainable
procedure that does not require the use of a catalyst.
In the field of synthetic chemistry, interest in microwave
heating is increasing because it can induce fast, clean, high-
yielding, and efficient reactions. We therefore carried out
further optimizations under microwave conditions. We
performed a control experiment under the optimized
conventional reaction conditions, but with microwave
irradiation to evaluate the feasibility of the process. The
catalyst-containing mixture was stirred for one minute to
dissolve the reactants and to obtain a clear solution, and
then it was irradiated with microwaves for fifteen minutes
to give a good yield of the final product (Table 2, entry 4).
However, similar yields were obtained in shorter reaction
times in the absence of a catalyst (entries 1–3), clearly indi-
cating that a metal-free reaction is possible. Having identified
the catalyst-free reaction, we performed solvent screening
to find a suitable and relatively benign solvent, but the
yields were lower than that obtained in ethanol (entries 5–
13).
with the molecular formula C23H23NO3. The IR spectrum
showed absorption bands for hydroxy (3404 cm–1) and
conjugated carbonyl (1622 cm–1) functional groups. The
13C and DEPT-135 NMR spectra (in pyridine-d5) showed the
presence of only twenty-one carbon resonances, corresponding
to one carbonyl, one oxygenated aromatic quaternary, one
amide quaternary, six sp2 methine, four aromatic quaternary,
two aliphatic methylene, two aliphatic methyl, one aromatic
methyl, one aliphatic tertiary, and two aliphatic quaternary
carbons. The 1H NMR spectrum indicated the presence four
protons of two methylene groups at δ = 2.27 (d, J = 16.6 Hz,
1 H), 2.09 (d, J = 16.6 Hz, 1 H), 2.01 (d, J = 16.8 Hz, 1 H), and
1.84 (d, J = 16.9 Hz, 1 H), along with three methyl groups at
δ = 2.20 (s, 3 H), 0.89 (s, 3 H), and 0.49 (s, 3 H). In a COSY
experiment, we observed a correlation between four ortho-
coupled protons at δ = 7.28 (d, J = 7.8 Hz, 2 H) and 7.04 (d,
J = 7.9 Hz, 2 H), indicating the presence of a 1,4-disubstitut-
ed aromatic ring, which explains the absence of two carbon
signals in the 13C NMR. Further, the key HMBC correlations
of protons at δH = 6.43 (s, 1 H, H-3) with δC = 190.2 (C-18),
183.6 (C-22), 169.8 (C-1), 145.3 (C-9), 132.3 (C-8), 121.3 (C-4),
134.3 (C-10), and 108.5 (C-17) confirmed the formation of
an isoindalone skeleton. On the basis of this spectral evidence,
10a was confirmed to be 3-(2-hydroxy-4,4-dimethyl-6-
oxocyclohex-1-en-1-yl)-2-(4-tolyl)isoindolin-1-one.
The presence of a hydroxy group in 10a was further
confirmed by the formation of its acetyl derivative in
the presence of triethylamine and acetyl chloride in
dichloromethane (Scheme 1).
Table 2 Optimization of Microwave Reaction Conditionsa
Entry
Solvent
Time (min)
Yieldb (%)
O
O
1
2
EtOH
EtOH
EtOH
EtOH
MeCN
AcOH
THF
5
10
15
15
15
15
15
15
15
15
15
15
15
48
72
92
92
65
70
40
58
52
46
75
38
N
N
CH3
Et3N (3.0 equiv)
O
O
3
AcCl (2.0 equiv)
HO
O
4c
5
CH2Cl2, r.t., 2 h
O
10a
10ab
6
Scheme 1 Acetylation of compound 10a
7
8
DCE
9
PEG-400
acetone
DMF
Finally, the structure was confirmed by X-ray crystallog-
raphy.20 An ORTEP diagram of compound 10a is shown in
Figure 2.
10
11
12
13
H2O
d
neat
–
a Reaction conditions: 2-formylbenzoic acid (7; 1 mmol), p-toluidine (8a; 1
mmol), dimedone (9a; 1 mmol), solvent (1 mL), MW, 90 °C.
b Isolated yield.
c CeCl3·7H2O (20 mol %) was used.
d Reactants were recovered along with the imine intermediate.
Figure 2 ORTEP diagram for compound 10a
Isoindolin-1-one 10a was characterized by means of
spectral studies. The white solid showed a quasimolecular
ion peak at m/z = 362.1370 in the HRMS spectrum, consistent
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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K. V. Sashidhara et al.
Letter
Synlett
Next we screened a range of primary amines and
cyclohexane-1,3-dione derivatives to test the scope of our
new reaction. First, we studied the effect of substituents on
the aniline reactant (Scheme 2). Under the optimized
conditions, anilines containing either electron-donating or
electron-withdrawing groups underwent cyclization.
However, higher yields were observed in the case of anilines
containing electron-donating groups. Under the same
O
N
OH
O
O
N
N
X
X
O
MW, 15 min
90 °C, EtOH
H3N
O
O
HO
R2 R2
H
7
8
9a–b
R2
R2
10j–o
X = C, S, N
R2 = H, Me
O
O
N
N
O
N
N
conditions,
a trifluoromethyl aniline also underwent
N
Cl
N
cyclization smoothly in high yield.
S
O
O
O
Next, the applicability of the reaction conditions to
primary heteroaromatic amines was evaluated. Pyridin-2-
amine, pyrimidin-2-amine, and various aminothiazole
derivatives gave the corresponding cyclized products 10j–o
in good yields under the optimized reaction conditions
(Scheme 3). Pyrimidin-2-amine gave a lower yield of the
corresponding product than did pyridin-2-amine or the
aminothiazoles.
HO
HO
HO
10j 88%
10k 86%
10l 90%
O
O
O
OMe
N
N
N
S
N
N
N
S
O
N
O
O
HO
HO
HO
When propargyl, aliphatic, or benzylic amines were
employed under the optimized reaction conditions, all gave
good yields of the corresponding products (Scheme 4).
10m 89%
10n 88%
10o 78%
Scheme 3 Scope of heterocyclic amines under the optimized reaction
conditions
O
R1
OH
NH2
O
N
O
MW, 15 min
O
O
+
+
90 °C, EtOH
HO
O
R1
H
7
8
9b
10a–i
O
O
O
O
N
N
Cl
N
O
O
O
HO
HO
HO
10a 92%
10b 91%
10c 85%
O
O
O
O
O
N
N
OMe
N
OH
O
O
O
HO
HO
HO
10f 94%
O
10e 92%
O
10d 84%
NO2
O
CF3
N
N
N
O
O
O
HO
HO
HO
10g 85%
10h 82%
10i 90%
Scheme 2 Scope of aromatic amines under the optimized reaction conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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K. V. Sashidhara et al.
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Our postulated mechanism for the formation of
isoindolinones involves in situ formation of imine a from
2-formylbenzoic acid and p-toluidine (Scheme 6). This is
followed by nucleophilic attack by the diketone on the
imine to give the Michael addition product b. Further
intramolecular nucleophilic cyclization of the amine gives
the desired isoindolinone 10a.
O
OH
N
R2
O
O
MW, 15 min
90 °C, EtOH
O
H2N
R1
O
O
HO
H
7
8
9b–c
10p–v
O
O
O
O
NH2
COOH
N
N
N
N
COOH
N
O
O
O
O
CHO
– H2O
HO
HO
HO
HO
a
7
8a
O
O
O
OH
10p 94%
10q 96%
10r 91%
10s 90%
OMe
O
O
O
N
O
N
9b
N
N
COOH
H
O
O
O
N
HO
HO
O
HO
– H2O
HO
HO
O
10t 88%
10u 90%
10v 92%
10a
b
Scheme 4 Scope of amine diversification under optimized reaction
conditions
Scheme 6 Plausible mechanism for isoindolinone formation
It is noteworthy that five- or six-membered-ring
aliphatic 1,3-diones, as well as their aromatic congeners,
also worked well in this transformation (Scheme 5). After
the completion of the reaction, product settled as a white
solid in the reaction vial, and the pure product was
obtained by simple filtration, without additional workup or
column-purification steps. Homogeneous reaction mixtures
were, however, purified by column chromatography.
The proposed mechanistic rationalization was confirmed
by using 2-aminobenzenethiol or 2-aminobenzamide
(which both have amine and nucleophilic groups in the
same molecule) to synthesize fused isoindolinones 11 and
12 in good yields in the absence of a diketone (Scheme 7).21
The formation of these fused isoindolinones supports our
suggestion that nucleophilic attack by the diketone on the
imine system occurs to form a Michael addition product.
O
O
N
H2N
H2N
O
N
N
O
OH
H2N
O
N
O
HS
O
O
N
HO
HO
O
EtOH
EtOH
N
S
H
O
H
10w 85%
10x 90%
12 91%
7
11 84%
Scheme 7 Synthesis of fused isoindolinones
O
N
O
N
N
O
In conclusion, we have successfully developed a rapid
and efficient one-pot strategy for the synthesis of substituted
isoindolinones through sequential multicomponent reactions.
The scope of this reaction includes C–C, C–N, and C–S bond
formation, resulting in a variety of substituted isoindolinones
without the use of toxic heavy-metal catalysts. This cost-
effective and metal-free strategy is expected to be of
considerable interest to medicinal chemists for the synthesis
of libraries of diverse isoindolinones for the drug-discovery
O
HO
HO
O
10y 85%
10z 92%
Scheme 5 Scope of 1,3-diones under the optimized reaction conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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K. V. Sashidhara et al.
Letter
Synlett
process. The simple reaction setup and the variety of
commercially available starting materials are additional
merits of this method.
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Acknowledgment
The authors are grateful to the director of CSIR-CDRI for her constant
support and encouragement, to Dr. S. P. Singh for technical support,
and to SAIF for NMR, IR, and mass spectral data. The CSIR, New Delhi,
is thanked for the award of senior research fellowships to L.R.S., G.R.P.,
and A.S.R. We thank Dr. Tejender S. Thakur of the Molecular and
Structural Biology Division, CSIR-Central Drug Research Institute for
supervising the collection of X-ray data and the structure determination
for our compound reported in this paper. This is CDRI communication
number 9287.
Supporting Information
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S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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12789. (f) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.;
(19) 3-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-2-(4-
tolyl)isoindolin-1-one (10a); Typical Procedure
A mixture of 2-formylbenzoic acid (7; 1.0 mmol), p-toluidine
(8a; 1.0 mmol), and dimedone (9b; 1.0 mmol) in EtOH (1 mL)
was stirred for 1 min and then subjected to microwave irradia-
tion at 90 °C for 15 min. When the reaction was complete, the
mixture was filtered and the product was dried to give a white
solid; yield: 0.333 g (0.92 mmol, 92%); mp 264–266 °C; IR (KBr):
3404, 2922, 1622, 1206, 1095 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.72 (d, J = 7.4 Hz, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.4
Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.04 (d,
J = 7.9 Hz, 2 H), 6.43 (s, 1 H), 2.27 (d, J = 16.6 Hz, 1 H), 2.20 (s, 3
H), 2.09 (d, J = 16.6 Hz, 1 H), 2.01 (d, J = 16.8 Hz, 1 H), 1.84 (d, J =
16.9 Hz, 1 H), 0.89 (s, 3 H), 0.49 (s, 3 H). 13C NMR (75 MHz, pyri-
dine-d5): δ = 190.2, 183.6, 169.4, 148.0, 138.2, 135.4, 134.9,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

G
K. V. Sashidhara et al.
Letter
Synlett
133.1, 130.6, 129.0, 124.4, 123.8, 123.6, 111.1, 57.6, 49.2, 47.9,
When the reaction was complete (TLC), the excess EtOH was
evaporated under reduced pressure and the residue was puri-
fied by column chromatography [silica gel, MeOH–CH2Cl2
(2:98)] to give a white solid; yield: 0.200 g (0.84 mmol, 84%);
mp 173–175 °C. IR (KBr): 3404, 2922, 1622, 1206, 1095 cm–1; 1H
NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 7.3 Hz, 1 H), 7.68–7.63
(m, 2 H), 7.60–7.53 (m, 2 H), 7.22–7.16 (m, 2 H), 7.11–7.06 (m, 1
H), 6.99 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 168.5, 143.1,
136.6, 135.9, 133.2, 132.7, 129.9, 125.9, 125.9, 125.2, 123.6,
33.2, 29.7, 28.6, 22.0. HRMS (ESI): m/z [M + H]+ calcd for C23H24
-
NO3: 362.1751; found: 362.1730.
(20) CCDC 1460875 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(21) Isoindolo[1,2-b][1,3]benzothiazol-11(4bH)-one (11); Typical
Procedure
A mixture of 2-formylbenzoic acid (7, 1.0 mmol) and 2-amino-
benzenethiol (1.0 mmol) in EtOH (1 mL) was stirred for 1 min
then subjected to microwave irradiation at 90 °C for 15 min.
123.1, 118.5, 69.2. HRMS (ESI): m/z [M
14H10NOS: 240.0478; found: 240.0474.
+
H]+ calcd for
C
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G