(±)-CSA catalyzed Friedel-Crafts alkylation of indoles with 3-ethoxycarbonyl-3-hydoxyisoindolin-1-one: An easy access of 3-ethoxycarbonyl-3-indolylisoindolin-1-ones bearing a quaternary α-amino acid moiety

Article abstract of DOI:10.1016/j.tetlet.2013.01.010

For the first time, a very simple, efficient, mild, catalytic, and one-step procedure for the synthesis of a series of new 3-ethoxycarbonyl-3- indolylsubstituted-isoindol-1-one derivatives has been achieved via a Friedel-Crafts alkylation of indoles with 3-hydroxy-3-ethoxycarbonylisoindolin- 1-one at room temperature using easily available inexpensive camphor-10-sulfonic acid as an organocatalyst. The current protocol provides good to excellent yields of the title compounds with high substrate scope. In addition, the desired product possesses a chiral quaternary carbon center at the 3-position on isoindolin-1-one ring which is flanked by indole moiety, amino and ester groups for further elaborations. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.010

Tetrahedron Letters 54 (2013) 1444–1448
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
( )-CSA catalyzed Friedel–Crafts alkylation of indoles with
3-ethoxycarbonyl-3-hydoxyisoindolin-1-one: an easy access of
3-ethoxycarbonyl-3-indolylisoindolin-1-ones bearing a quaternary
acid moiety
a-amino
⇑
Anvita Srivastava, Shivendra Singh, Sampak Samanta
Indian Institute of Technology Indore, Indore 452017, India
a r t i c l e i n f o
a b s t r a c t
Article history:
For the first time, a very simple, efficient, mild, catalytic, and one-step procedure for the synthesis of a
series of new 3-ethoxycarbonyl-3-indolylsubstituted-isoindol-1-one derivatives has been achieved via
a Friedel–Crafts alkylation of indoles with 3-hydroxy-3-ethoxycarbonylisoindolin-1-one at room temper-
ature using easily available inexpensive camphor-10-sulfonic acid as an organocatalyst. The current pro-
tocol provides good to excellent yields of the title compounds with high substrate scope. In addition, the
desired product possesses a chiral quaternary carbon center at the 3-position on isoindolin-1-one ring
which is flanked by indole moiety, amino and ester groups for further elaborations.
Received 13 October 2012
Revised 2 January 2013
Accepted 4 January 2013
Available online 11 January 2013
Keywords:
Brønsted acid catalyst
CSA
Ó 2013 Elsevier Ltd. All rights reserved.
Indole
3,3-Disubstituted-isoindolin-1-one
Friedel–Crafts alkylation
Quaternary carbon center
Cyclic a-amino acid moiety
The synthesis of 3-substituted isoindolin-1-one and its deriva-
tives has been the subject of growing interest in recent years be-
cause of its application as a valuable pharmacophore exhibiting a
wide range of therapeutic activities1 and also found in various nat-
ural products (Fig. 1). For example, AKS-186 (I) inhibits vasocon-
striction induced by thromboxane A2 analog,2 (R)-Pazinaclone
(II)3 exhibits anxiolytic activity and is of interest as sedative, hyp-
notic, and muscle relaxant, (S)-PD172938 (III) shows a dopamine
D4 receptor antagonist,4 and compound IV inhibits microsomal
alkylation of N-unprotected indoles with 3-alkyl-3-hydroxyisoin-
dolin-1-ones reported by Zhou and co-workers.9 There is no such
report on the organocatalytic F–C alkylation of both N-protected
and unprotected indoles with 3-ethoxycarbonyl-3-hydroxyisoin-
dolin-1-one as a nucleophilic acceptor. Nevertheless, this combina-
tion constitutes an important indole-substituted non-natural cyclic
a-amino acid moiety bearing a quaternary carbon center at the 3-
position on isoindolin-1-one ring. As we know the synthesis of
a-
amino acid derivative with a chiral quaternary carbon center is a
very challenging task for organic chemists and also has much bio-
logical significance.10 Therefore, it would be highly desirable to
synthesize the 3-ethoxycarbonyl-3-indolylsubstituted-isoindol-1-
ones in a more practical and efficient manner.
triglyceride transfer protein (MTP) and/or apolipoprotein
B
secretion.5 (+)-Lennoxamine (V) is
a
naturally occurring
isoindolobenzazepine alkaloid.6 In addition, 3-substituted isoin-
dol-1-ones are valuable segments in the synthesis of important
natural products.7 Owing to their great biological activities, several
methods have been documented for the syntheses of both racemic
and enantio-enriched 3-substituted isoindolin-1-one derivatives.8
Nonetheless, even with such progress, organocatalytic, direct syn-
theses of 3-indolyl substituted isoindol-1-one derivatives are rare.
As far as we are aware, there are only two isolated examples avail-
able in the literature, all were reported recently. Namely, chiral BI-
NOL-phosphoric acid catalyzed asymmetric Friedel–Crafts (F–C)
Recently F–C alkylation of indoles11 using a catalytic amount of
Brønsted acid has paid much attention due to the potential envi-
ronmental concerns of metal catalysis in general as well as the
application of indole framework present in various range of natural
products and medicinal chemistry.12 In this regard, easily available,
less toxic camphor-10-sulfonic acid (CSA) has emerged as a potent
Brønsted acid catalyst for various organic transformations in recent
years.13 As part of our continued interest toward the development
of organocatalyst mediated new synthetic transformations in an
environment friendly manner14 and synthesis of indole derivatives,
in 14 h we wish to report a clean, organocatalytic, highly efficient
⇑
Corresponding author. Tel.: +91 731 243 8742; fax: +91 731 236 4182.
E-mail address: sampaks@iiti.ac.in (S. Samanta).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.010

A. Srivastava et al. / Tetrahedron Letters 54 (2013) 1444–1448
1445
O
Cl
O
N
O
NH
N
Me
(R) N
N
H
Me
N
H
N
O
O
N
O
OH
III
(S)-PD172938
OMe
II
(R)-Pazinaclone
AKS-186 I
O
O
MeO
Me N
N
CO2Et
O
O
O
R1
N
H
O
R2
(+)-Lennoxamine V
O
IV
Figure 1. Some important biologically active 3-substituted-isoindolin-1-ones.
synthesis of 3-ethoxycarbonyl-3-(indol-3-yl)isoindol-1-one deriv-
atives through a F–C alkylation of N-protected and unprotected in-
doles with 3-ethoxycarbonyl-3-hydroxyisoindolin-1-one in the
presence of CSA as a Brønsted acid catalyst.
Table 1
F–C alkylation of indole with 3-ethoxycarbonyl-3-hydroxyisoindolin-1-one (3a)a
O
O
Catalyst (10 mol%)
Solvent, RT
NH
NH
We chose the model reaction between 3-ethoxycarbonyl-
3-hydroxyisoindolin-1-one (1a) and indole (2a) in the absence
of catalyst at room temperature for 24 h in DCM medium. Unfor-
tunately, the reaction did not proceed at all (Table 1, entry 1).
From this result, we envisioned that a Brønsted acid activation
is essential for initiation of this reaction to proceed. Therefore,
we employed a well known pTSA (10 mol %) as catalyst for this
reaction in CH2Cl2 medium at room temperature. Intriguingly,
after 24 h, the desired product 3a was obtained in 48% yield (Ta-
ble 1, entry 2). The structure of the product was assigned by IR, 1H
NMR, 13C NMR, and HRMS spectroscopy. Gratifyingly, these signif-
icant results motivated us to investigate the F–C alkylation reac-
tion of indole in detail. In order to find out the best catalyst for
this reaction, we screened readily available several Brønsted acids
such as TfOH, CSA, TCA (trichloroacetic acid), TFA (trifluoroacetic
acid), heterogeneous catalyst Amberlyst-15H, H2SO4, HCl etc in
CH2Cl2 medium at room temperature. The results are summarized
in Table 1. We were pleased to observe that in all these cases F–C
alkylation product 3a was isolated (Table 1, except entry 5). As
shown in Table 1, with a 10 mol % loading catalysts of TfOH and
TFA, both gave the desired product 3a with moderate yields in
42% and 58% ‘respectively’ under similar reaction conditions (en-
tries 3 and 7). It is noteworthy to mention that the reactions were
smooth initially in case of TfOH and pTSA, but slowed down
quickly afterward. Indole is not compatible with a strong Brønsted
acid such as TfOH and pTSA. A little amount of indole self-
trimerized product 4a was observed in both the cases,15 which
might be detrimental to the rate of the reaction. Indeed, our
control experiment verified this speculation. For the control
experiment (Scheme 1), when a mixture of compound 1a, indole
2a, pTSA (10 mol %), and self-trimerized product 4 (10 mol %) in
CH2Cl2 was stirred for 24 h at room temperature, very negligible
amount of product 3a was observed (2–3% conversion, Scheme 1).
The inferior results were also observed when mild acid TCA (entry
6) and mineral acids such as H2SO4 and HCl (entries 8–9) were
N
H
CO2Et
EtO2C
3a
HO
1a
NH
2a
Entry
Catalyst
Solvent
T (h)
Yieldb (%)
1d
2
3
None
pTSA
TfOH
CSA
Amberlyst-15H
TCA
TFA
H2SO4
HCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
24
24
24
24
36
36
24
NR
48
42
91
10
28
58
30
10
NR
4
5c
6
7
8
9
10d
L-Proline
11
12
13
14
15
16
17
18
19e
(S,S)-BINOL-phosphate
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CH2Cl2
Toluene
Hexane
THF
CHCl3
EtOH
MeOH
H2O
CH2Cl2
48
48
48
48
24
24
24
24
20
>5
28
32
27
82
>10
>10
>5
(À)-CSA
85
a
Unless otherwise mentioned, all reactions were carried out with compound 1a
(0.3 mmol), indole (0.45 mmol), and catalyst (0.03 mmol, 10 mol %) in specified
solvent (2.0 mL) at room temperature.
b
Yield of isolated product after column chromatography.
20.0 mg of Amberlyst-15H was used.
NR = no reaction.
c
d
e
1R-Camphor-10-sulfonic acid was used for this reaction, enantiomers were
separated by chiral OD-H column, enantiomeric excess (ee) was <5%.
CHCl3 was also a good solvent for this reaction (entry 15). The
reaction was witnessed to be much slower in case of protic sol-
vents like EtOH, MeOH, and H2O (Table 1, entries 16–18). The
reactivity studies with various solvents exhibited that CH2Cl2
was the best solvent in terms of reactivity for this F–C alkylation
reaction. Chiral BINOL-phosphoric acid was proven to be a supe-
rior Brønsted acid catalyst for the synthesis of 3-alkyl-3-indolylis-
oindolin-1-ones, where 3-alkylsubstituted-3-hydroxyisoindol-1-
ones were employed as nucleophilic acceptors.9 Strikingly, using
similar BINOL-phosphoric acid catalyst, almost no conversion
was observed when the substrate 1a was used as a nucleophilic
acceptor under the present reaction conditions (Table 1, entry
11). Hence improvised methodology was inevitable for these
conversions.
used. It was clear that organocatalyst like L-proline was unable
to catalyze this transformation (entry 10) at our present condi-
tions. Surprisingly, with a 10 mol % loading of CSA, the reaction
was completed within 24 h and F–C product was obtained in
91% yield (entry 4).16 For this catalyst, further screening of sol-
vents revealed that normal organic ones, such as toluene (entry
12), hexane (entry 13), and THF (entry 14), all led to inferior re-
sults (27–32% yield) as compared to CH2Cl2 (entry 4). However,

1446
A. Srivastava et al. / Tetrahedron Letters 54 (2013) 1444–1448
NH2
O
O
pTSA (10 mol%)
DCM, RT, 24h
NH
NH
CO2Et
+
N
H
EtO2C
3a
HO
1a
N
H
NH
2-3% conversion
N
H
2a
4
Scheme 1. Control experiment for F–C alkylation of indole.
Me
Me
Me
Me
O
O
O
S
O
O
O
O
O
O
HO3S
N
H
NH
NH
NH
-H2O
CO2Et
-CSA
CO2Et
H2O
CO2Et
HO
1a
EtO2C
1b
O
S
3a
N
H
O
O
N
H
O
Me
Me
Scheme 2. Reaction mechanism of the F–C alkylation of indole catalyzed by ( )-CSA.
In this direction, we investigated the asymmetric version of this
F–C alkylation reaction of indole 2a with 1a in CH2Cl2 medium
using enantio-enriched (1R)-CSA (10 mol %) at room temperature
(entry 19, Table 1). Unfortunately, almost no enantioselectivity
was observed for compound 3a.
We propose the following probable mechanism for the forma-
tion of product 3a (Scheme 2). The reaction is thought to proceed
via an iminium ion mechanism. First, cyclic ketimine 1b is gener-
ated through protonation of tertiary hydroxyl group of 1a by CSA
and followed by dehydration. In the second step, the nitrogen atom
of cyclic ketimine (1b) is protonated by CSA to form cyclic iminium
ion, which is subsequently attacked by indole (2a) resulting in
product 3a.
To study the scope and limitation of this F–C alkylation reac-
tion, we studied a wide range of structurally varied diverse steric
and stereoelectronic environments of indole derivatives with 3-
hydroxy-3-ethoxycarbonylisoindolin-1-one (1a) using 10 mol %
loading of CSA as catalyst at our standard conditions. The results
are compiled in Table 2. As is evident from Table 2, various ranges
of N-protecting groups of indole such as Me, OMe, allyl, propargyl,
benzyl, p-methoxybenzyl, p-trifluoromethylbenzyl, and tert-butyl
acetate were investigated (entries 2–9). In all these cases (except
entry 7), F–C alkylation methods were very smooth at room tem-
perature, leading to the formation of a series of new 3-indolylsub-
stituted-isoindol-1-ones with good to excellent yields (74–87%).
However, p-trifluoromethylbenzyl group provided a very poor
yield (>10%) at room temperature. Surprisingly, when the same
reaction was performed at 40 °C, excellent yield (94%) was
achieved (entry 7) within shorter time. Even sterically demanding
2-substituted indoles also reacted with compound 1a at our pres-
ent conditions. For example, 2-methylindole (entry 10), N-benzyl-
2-methylindole (entry 11), and N-benzyl-2-thiomethylindole (en-
try 12) all led to good yields of the desired products (82–86%
yields). Similarly, 7-methylindole (entry 18) was also a good sub-
strate for this F–C reaction, providing the desired product with
87% yield after 24 h. Indoles with weak electron withdrawing
substituents such as Br, Cl, and F at its 5-position afforded the tar-
geted products with slightly lower yields and longer reaction
times as compared to indole (entries 13–15) at room temperature.
The reason might be that electron withdrawing nature of halides
reduces the nucleophilicity of indoles which causes slower rate of
the reaction. The N-unprotected indoles having substituents at 5-
position like F, Me, OMe, and OBn did not react with 1a at room
temperature and starting materials were unchanged. Interestingly,
as anticipated, all these cases, F–C reactions proceeded well with-
in 10–12 h at 40 °C to furnish the desired products with excellent
yields of the corresponding products (88–93%, entries 15–17).
Next, we proceeded further with corresponding N-protected 5-
substituted indoles for verifying their reactivities. To our pleasure,
all these reactions ran efficiently at room temperature and pro-
duced the anticipated 3-(N-protected-5-substitutedindol-3-yl)-3-
ethoxycarbonylisoindol-1-ones in good to high yields (59–84%,
entries 19–22). Our present conditions are mild enough to tolerate
several sensitive functional groups like allyl, propargyl, CO2But,
OMe, OBn, SMe, N-OMe, Cl, Br etc. Therefore, it is an amiable
opportunity to achieve the suitable therapeutic targets by syn-
thetic modifications of these functional groups depending on the
requirement.
In order to envisage the application potential of the present
methodology, we extended the synthesized compounds 3w
(48% yield) and 3x (93%) into a novel access of spiro cyclic com-
pound 5 (Scheme 3). For example, the excellent yield (94%) was
obtained via a deprotection of Boc-group of compound 3x using
a TFA in DCM medium at room temperature and followed by
cyclization.
In this manuscript, we have developed a convenient and effi-
cient organocatalytic one-step method for the syntheses of biolog-
ically significant 3-ethoxycarbonyl-3-(indol-3-yl)isoindol-1-one
derivatives through a F–C alkylation of both N-protected and
unprotected indoles with 3-ethoxycarbonyl-3-hydroxyisoindole-
1-one at room temperature using commercial available less expen-
sive CSA (10 mol %) as catalyst. The mild reaction conditions (room

A. Srivastava et al. / Tetrahedron Letters 54 (2013) 1444–1448
1447
Table 2
( )-CSA catalyzed one-step synthesis of 3-ethoxycarbonyl-3-(indol-3-yl)isoindol-1-one derivatives (3a–v)a
O
NH
O
( )-CSA (10 mol%)
CH2Cl2, RT
R2
R1
NH
CO2Et
R2
N
R
EtO2C
HO
R1
3a-v
N
R
2a-v
1a
Entry
R
R1
R2
T (h)
Yieldb (%)
1
2
3
4
5
H
Me
CH2@CHCH2
CH„CCH2
PhCH2
4-(MeO)–C6H4CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
24
22
25
24
24
26
8
25
25
24
26
24
36
36
12
10
11
24
36
24
24
24
91
87
81
85
79
86
94
82
85
83
81
86
78
75
89
93
88
87
59
82
79
84
6
7c
4-(CF3)–C6H4CH2
8
9
CH2CO2But
MeO
H
PhCH2
PhCH2
H
H
H
H
H
H
Me
PhCH2
PhCH2
PhCH2
H
10
11
12
13
14
15c
16c
17c
18
19
20
21
22
Me
Me
SMe
H
H
H
H
H
H
H
5-Br
5-Cl
5-F
5-Me
5-OMe
7-Me
5-F
5-OMe
5-OBn
5-Me
H
H
H
a
Unless otherwise specified, all reactions were carried out with compound 1a (0.3 mmol), indole 2a–v (0.45 mmol), and catalyst (0.03 mmol,
10 mol %) in CH2Cl2 (2.0 mL) at room temperature.
b
Yield of isolated product after column chromatography.
Reaction was carried out at 40 °C.
c
O
NH
EtO2C
O
N
HN
N3
3w
O
O
Me
( )-CSA (10 mol%)
; 48%
NH
NH
N
Me
O
N
Me
X
CH2Cl2, 24h, RT
2w
( )
CO2Et
HO
5
NH
X = N3
X = NHBoc (
EtO2C
1a
2x
)
N
Me
BocHN
3x
; 93%
Scheme 3. Synthesis of spiro cyclic compound 5.
temperature), simple operation, inexpensive organocatalyst, low
catalyst loading, broad substrate scope, and high yields of adducts
make this procedure attractive. Moreover, this procedure offers a
Acknowledgments
The authors thank the CSIR research Grant (Project No.
02(0019)/11/EMR-II) for the generous financial support. A.S. and
S.S. are also thankful to UGC for their fellowship.
non-natural cyclic
nary carbon center at the 3-position on the isoindolin-1-one ring
which is flanked by an indole moiety and an -amino acid group
a-amino acid derivative bearing a chiral quater-
a
for further elaborations. Furthermore, this method demonstrates
the potential of camphor-10-sulfonic acid (CSA) as an organocata-
lyst. The enantioselective syntheses of these compounds and fur-
ther applications to biological systems are in progress.
Supplementary data
Supplementary data associated (copies of 1H NMR and 13C NMR
spectra of all listed in Table 2 and Scheme 3) . with this article can

1448
A. Srivastava et al. / Tetrahedron Letters 54 (2013) 1444–1448
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15. Indole self-trimerized product 4 was formed in the presence of a strong
Brønsted acid in CH2Cl2 medium at room temperature.
NH2
NH
N
H
4
16. Synthesis of 3-ethoxycarbonyl-3-(1H-indol-3-yl)isoindolin-1-one: To
a stirred
solution of 3-ethoxycarbonyl-3-hydroxyisoindolin-1-one (66.3 mg, 0.3 mmol)
and indole (52.6 mg, 0.45 mmol) in CH2Cl2 (2.0 mL) was added CSA (7.0 mg,
0.03 mmol) at room temperature for 24 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was
extracted with EtOAc (3 Â 10 mL), washed with water and brine respectively
and dried with Na2SO4. The organic phase was evaporated by rotary evaporator
under reduced pressure to give the crude product. The crude product was
purified by column chromatography over silica-gel to furnish the pure product
(87.3 mg, 91% yield). The product was characterized by corresponding
spectroscopic data (IR, NMR, HRMS).
3-Ethoxycarbonyl-3-(1H-indol-3-yl)isoindolin-1-one (Table 2 entry 1,): Yield 91%,
mp 190 °C; IR (KBr)
m ;
3061, 1736, 1697, 1615, 1468, 1352 cmÀ1 1H NMR
(400 MHz, CDCl3) d 8.26 (br s, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 7.0 Hz,
1H), 7.54–7.62 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.15–7.24 (m, 3H), 7.02–7.05
(m, 1H), 6.91 (br s, 1H), 4.24–4.34 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 169.9, 169.3, 145.1, 136.7, 132.5, 130.9, 129.4, 125.1, 124.7,
123.9, 122.9, 120.5, 119.2, 113.6, 111.6, 66.7, 62.7, 14.2; HRMS (ESI) m/z Calcd
For C19H16N2O3 [M+Na]+: 343.1053. Found 343.1099.
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