Facile synthesis of diverse isoindolinone derivatives via Ugi-4CR followed by Cu-catalyzed deamidative C(sp2)-C(sp3) coupling

Article abstract of DOI:10.1016/j.tetlet.2012.12.091

The present work highlights a synthetic approach to the diverse isoindolinone derivatives using Ugi-4CR followed by a Cu-catalyzed deamidative C-C coupling reaction. This two-step sequence tolerates a broad range of amines, aldehydes, and isocyanides as starting materials for Ugi-4CR products to provide medicinally relevant isoindolinone derivatives in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2012.12.091

Tetrahedron Letters 54 (2013) 1279–1284
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of diverse isoindolinone derivatives via Ugi-4CR followed
by Cu-catalyzed deamidative C(sp2)–C(sp3) coupling
⇑
Vikas Tyagi, Shahnawaz Khan, Prem M. S. Chauhan
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present work highlights a synthetic approach to the diverse isoindolinone derivatives using Ugi-4CR
followed by a Cu-catalyzed deamidative C–C coupling reaction.
This two-step sequence tolerates a broad range of amines, aldehydes, and isocyanides as starting mate-
rials for Ugi-4CR products to provide medicinally relevant isoindolinone derivatives in moderate to good
yields.
Received 9 November 2012
Revised 18 December 2012
Accepted 22 December 2012
Available online 29 December 2012
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Copper catalysis
Isoindolenone
Ugi reaction
C–C coupling
Isoindolinone derivatives are valuable building blocks for the
synthesis of various drugs and natural products and are of signifi-
cant interest due to their broad range of biological activities such
as antihypertensive, antipsychotic, antiinflammatory, anesthetic,
and antiulcer activities.1 Additionally, the substituted isoindoli-
none scaffold is also found in a great variety of natural products
and biologically active compounds such as isoindolobenzazepine
alkaloid lennoxamine (1), antiproliferative agent (2), anxiolytic
synthesis of N-substituted isoindolinone using Pt nanowires as
catalyst.5
In the recent past, isocyanide-based multicomponent reactions
(IMCRs) followed by other synthetic transformations have
emerged as an approach to introduce a large degree of diversity
into final heterocyclic scaffolds in an atom economical fashion.6
For example, Andreana and co-workers reported the synthesis of
spiro-2,5-diketopiperazines via a cascade Ugi/6-exo-trig Aza-Mi-
chael reaction, Riva et al. described the synthesis of tricyclic N-het-
erocycles using an Ugi reaction with a tandem SN2-Heck double
cyclization reaction and Hulme’s group developed a strategy for
drug pagoclone (3), and
a potent dopamine D4 ligand (S)-
PD172938 (4) (Fig. 1).2
In fact, several common methods are available for the synthesis
of isoindolinone derivatives, but most of these traditional ap-
proaches suffer from low yields and/or poorly accessible precur-
sors and take place under harsh reaction conditions.3 In view of
their broad range of biological activities, isoindolinone derivatives
are an attractive synthetic target and a concise method involving
commercially available and cheap starting materials is still re-
quired for their practical synthesis.
Cl
O
OMe
O
MeO
N
N
HN
In this context, numerous transition metal catalyzed protocols
for the synthesis of substituted isoindolinone derivatives have re-
ceived considerable attention.4 Thus, Zhu et al. reported the syn-
thesis of isoindolinone via Rh catalyzed C–H olefination of N-
benzoylsulfonamides with internal alkenes, Massa and co-workers
reported the first organocatalytic asymmetric synthesis of 3-
substituted isoindolinone and Gu and co-workers reported the
N
O
2
1
O
O
O
NH
N
Me
N
N
Me
Me
N
Me
Cl
N
O
4
⇑
Corresponding author. Tel.: +91 522 2262411x4470; fax: +91 522 2623405.
E-mail addresses: premsc58@hotmail.com, prem_chauhan_2000@yahoo.com
3
(P.M.S. Chauhan).
Figure 1. Biologically active compounds containing the isoindolinone scaffold.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.091

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V. Tyagi et al. / Tetrahedron Letters 54 (2013) 1279–1284
O
X
R2
O
H
N
COOH
R2-CHO
N
R3
Ugi-4CR
Cu-catalyzed
deamidative
C-C coupling
7
N
R1
+
R1
O
X
R3-NC
5
R2
R1-NH2
8
9
10
6
X = I, Br
Scheme 1. General strategy for the synthesis of substituted isoindolinone.
O
O
R1
O
R1
O
X
R2
H
N
N
N
R2
N
R3
R2
X
R1
O
X
N
O
R3
NH
R3
X = I, Br
B
A
O
N
R1
R2
C
Scheme 2. Three possible structures in two-step sequence.
Table 1
the synthesis of 2,4,5-trisubstituted oxazoles using Ugi/Robinson–
Gabriel reactions.7 Recently, we have also reported the synthesis of
N-fused polycyclic heterocycles and isoquinolin-1(2H)-one scaf-
folds using IMCR-synthesized precursors.8
Investigation of the reaction conditions for Cu-catalyzed deamidative C–C couplinga
Cl
In our ongoing efforts to develop new strategies for the diver-
sity oriented synthesis of biologically important heterocycles,9
we report herein the synthesis of diverse isoindolinone derivatives
via Ugi-4CR followed by Cu-catalyzed deamidative C–C coupling.
To the best of our knowledge, it is the first report of the synthesis
of diverse isoindolinones using this approach.
The general strategy for the synthesis of substituted isoindoli-
none derivative 10 is shown in Scheme 1. 2-Halo benzoic acids 5
were reacted with various amines 6, aldehydes 7, and isocyanides
8 in the Ugi-4CR to prepare the corresponding products,10 which
were used as starting materials for a Cu-catalyzed deamidative
C–C coupling reaction.
O
O
H
N
N
Cu-cat., ligand
base, solvent
N
N
O
I
Cl
10a
9a
NH2
H2N
N
N
N
L3
L1
L2
As depicted in Scheme 2, there are three possible products A, B,
and C from reaction under Cu-catalyzed conditions. 1H NMR, 13C
NMR, and mass spectral data of compounds confirmed that the
products have the general structure C.
OMe
MeO
COOH
N
H
N
N
L5
L4
Table 2
Screening of solvent for coupling reaction
Entry
Catalyst
Ligand
Base
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
—
0c
Cl
CuTC
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L2
L1
L2
L2
L2
L3
L4
L5
L2
L2
L2
L2
19
41
34
54
79
60
32
11
23
48d
12
0e
O
O
H
N
N
Cu-cat., ligand
base, solvent
N
O
I
9
10
11
12
13
Cl
10a
9a
a
Entry
Solvent
Yield (%)
Reaction conditions: substrate 9a (1 mmol), catalyst (10 mol %), ligand
(10 mol %), base (4 mmol), solvent (2 mL) under nitrogen atmosphere, reaction
1
2
3
4
5
Benzene
Dioxane
DMF
NMP
Toluene
71
63
57
52
79
temperature (80 °C), reaction time (2 h).
b
Isolated yield.
No addition of catalyst and ligand.
Loading of catalyst (5 mol %).
No addition of base.
c
d
e

V. Tyagi et al. / Tetrahedron Letters 54 (2013) 1279–1284
1281
In the initial phase of the investigation, Ugi-MCR synthesized
product 9a was used as the model substrate for the optimization
of metal catalyzed deamidative C–C coupling reaction conditions
including different catalysts, bases, ligands, and solvents.
As shown in Table 1, the reaction failed when copper salt was
excluded (Table 1, entry 1). Among the three copper catalysts
(CuI, CuBr, CuTC) used, CuI was the best catalyst and provided
product 10a in 79% yield (Table 1, entry 6). Switching the Cu salt
Table 3
Scope of two-step procedurea
Entry
Starting material
IMCR products (9) yieldb (%)
Cl
Coupling products (10) yieldb (%)
CHO
COOH
O
N
I
O
I
H
N
NH2
Cl
1
N
CN
O
Cl
9a
9b
9c
9d
9e
9f
91%
85%
88%
79%
91%
89%
10a
10b
10c
10d
10e
10f
79%
72%
67%
69%
67%
CHO
OMe
COOH
O
N
I
O
I
H
N
NH2
OMe
CN
2
3
4
5
6
N
N
N
N
N
O
OMe
CHO
OMe
COOH
O
N
Cl
Cl
Cl
I
O
H
N
NH2
OMe
CN
O
I
Cl
OMe
Cl
CHO
Cl
COOH
O
N
I
O
H
N
NH2
Cl
O
CN
I
Cl
Cl
Cl
CHO
F
COOH
O
N
I
O
H
N
NH2
F
CN
O
I
Cl
F
Cl
CHO
F
COOH
O
N
I
O
I
H
N
NH2
F
CN
O
F
63%
(continued on next page)

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V. Tyagi et al. / Tetrahedron Letters 54 (2013) 1279–1284
Table 3 (continued)
Entry
Starting material
IMCR products (9) yieldb (%)
Coupling products (10) yieldb (%)
CHO
F
O
COOH
N
I
O
H
7
N
F
N
NH2
O
CN
I
F
9g
72%
10g
68%
Cl
CHO
COOH
O
Cl
N
I
O
I
Cl
H
N
NH2
Cl
8
N
O
Cl
CN
Cl
9h
79%
10h
72%
CHO
OMe
OMe
COOH
O
I
O
I
N
H
N
NH2
OMe
CN
MeO
N
9
O
OMe
OMe
9i
81%
10i
10f
78%
56%
F
F
O
I
O
I
H
N
H
N
10
N
N
N
N
O
O
9j
94%
CHO
Cl
COOH
I
O
I
H
N
NH2a
Cl
11
10a
72%
CN
O
9k
89%
CHO
Cl
COOH
Br
O
H
N
NH2
Cl
12
10a
68%
CN
O
Br
9l
90%
a
Reaction conditions: under nitrogen atmosphere, substrate 9 (1 mmol), CuI (10 mol %), L2 (10 mol %), KOtBu (4 mmol), toluene (2 mL), 80 °C, 2À4 h.
b
Isolated yield.
from CuI to CuBr or CuTC (copper(I) thiophene-2-carboxylate) did
(Table 1, entry 6). However, ligands L1 and L3 also provided the
product 10a but in lower yield, while ligands L4 and L5 were inef-
ficient ligands in the reaction (Table 1, entries 3 and 7–9). Next, to
test the effect of base, NaOtBu, KOtBu, K2CO3, and K3PO4 were
not improve the yield of product 10a (Table 1, entries 2 and 4). Fur-
ther, various ligands were also investigated; 1,10-phenanthroline
(L2) was found to be the most efficient ligand using CuI as catalyst

V. Tyagi et al. / Tetrahedron Letters 54 (2013) 1279–1284
1283
R2
acknowledge SAIF-CDRI for providing spectral and analytical data.
The CDRI communication number is 8366.
O
X
H
N
N
R3
R1
O
R1
N
Supplementary data
O
R2
9
base
Cu(I)
Supplementary data (copies of 1H and 13C NMR spectra of the
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.091.
O
R3
N
Cu
X
11
O
References and notes
N R1
R2
R1
N
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O
R2
O
10
R1
R2
O
R3
N
N
Cu
X
Cu
X
12
13
R3-NCO
or
R3-NH2 + CO2
Scheme 3. Proposed mechanism of the reaction.
screened; KOtBu was found to be the most effective base using CuI
as catalyst and 1,10-phenanthroline as ligand (Table 1, entry 6).
When the catalyst loading was decreased from 10 to 5 mol %, the
efficiency of the transformation was affected (Table 1, entry 11).
In addition, the reaction was unsuccessful when base was omitted
from the reaction mixture (Table 1, entry 13). The effect of solvent
was also investigated, and toluene was found to be the best solvent
at 80 °C using CuI as the catalyst and KOtBu as the base, while using
benzene, DMF, NMP, and dioxane under the same conditions pro-
duced 10a in lower yield (Table 2).
With this standard protocol in hand, we extended it to the syn-
thesis of various substituted isoindolenone derivatives (10a–i) via
different Ugi-MCR synthesized products (9a–l) in moderate to
good yields (Table 3). Very good yields were observed for the t-bu-
tyl isocyanide based IMCRs 9a–i,12 whereas moderate yield of
product was obtained in the case of cyclohexyl isocyanide based
IMCRs 9j (Table 3, entry 10). In addition, the reaction took longer
time to reach completion. Moreover, when 2-bromobenzoic acid
was used in Ugi-MCR, the cyclized product 10a was observed in
lower yield (Table 3, entry 12).
Although the exact mechanism of this reaction is not clear, a
probable mechanism for the synthesis of an isoindolinone of type
10 is depicted in Scheme 3.11 Initially, the Cu(I) catalyst oxidatively
adds to the Ugi-4CR synthesized precursor 9 to give metal complex
11. Intermediate 11 subsequently undergoes deamidation through
intermediate 12 leading to C–C bond formation in a new Cu-com-
plex 13, which undergoes reductive elimination to afford final
product 10.
In conclusion, we have reported an efficient methodology for
the synthesis of biologically important isoindolinone derivatives
via Ugi-MCR followed by a Cu-catalyzed deamidative C–C coupling
reaction. This strategy allows the synthesis of diverse isoindoli-
none derivatives for combinatorial chemistry and medicinal chem-
istry using a broad range of amines, aldehydes, and isocyanides as
starting materials for Ugi-MCR products.
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Acknowledgements
V.T. and S.K. are thankful to University Grant Commission, New
Delhi, for financial support in the form of SRF. The authors also

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V. Tyagi et al. / Tetrahedron Letters 54 (2013) 1279–1284
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12. Procedure for the synthesis of 10a: CuI (10 mol %), 1, 10-phenanthroline
(10 mol %), KOtBu (4 mmol), Ugi-4CR product 9a (1 mmol) and toluene
(2 mL) were added to a dry Schlenk tube under nitrogen. The reaction
mixture was stirred and heated at 80 °C for 2–4 h. After completion of the
reaction as indicated by TLC, the resulting mixture was cooled down to room
temperature, filtered through a pad of celite, and the celite was rinsed with
EtOAc. The solvent was evaporated under reduced pressure and the residue
was purified by flash column chromatography on silica gel (eluent: hexane/
EtOAc) affording the corresponding isoindolinone derivatives 10a in 79% yield.
Characterization data of 10a: Semi-solid, Yield 79%, FT-IR (neat)
m
(cmÀ1): 3441,
2926, 2108, 1683, 1490, 1285, 1016, 766, 706; 1H NMR (300 MHz, CDCl3): d
7.99–7.97 (m, 1H), 7.55–7.49 (m, 2H), 7.38–7.30 (m, 5H), 7.22–7.14 (m, 2H),
7.12–7.11 (m, 1H), 7.06 (d, J = 8.1 Hz, 2H), 5.46 (d, J = 14.7 Hz, 1H), 5.26 (s, 1H),
3.79 (d, J = 14.7 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3): d 168.4, 145.8, 136.8,
135.3, 134.6, 132.0, 131.2, 129.4, 129.1, 128.7, 128.5, 128.4, 127.7, 123.9, 123.0,
62.8, 43.8 ppm, HRMS (ESI) Calcd for C21H17ClNO [M+H]+ 334.0999 Found:
334.0983.