Asymmetric addition of indoles to isatins catalysed by bifunctional modified cinchona alkaloid catalysts

Article abstract of DOI:10.1002/chem.201000846

(Figure Presented) Simple and selective: An efficient organocatalytic enantioselective method for the synthesis of substituted-3-hydroxyoxindole derivatives with a quaternary chiral carbon has been developed. The cinchona alkaloid derived catalyst catalyses the Friedel Crafts-type addition of indole derivatives to the isatin derivatives under mild conditions to provide substituted 3-hydroxyoxindoles in good to excellent yields with high enantioselectivity (see scheme).

Full text of DOI:10.1002/chem.201000846

COMMUNICATION
DOI: 10.1002/chem.201000846
Asymmetric Addition of Indoles to Isatins Catalysed by Bifunctional
Modified Cinchona Alkaloid Catalysts
Pankaj Chauhan and Swapandeep Singh Chimni*[a]
The development of new and more efficient catalytic reac-
tions is of paramount importance, particularly for the syn-
thesis of complex molecules. Recently, organocatalytic asym-
metric reactions mediated by organocatalysts have emerged
as an active area of research in synthetic chemistry. Organo-
catalysts offer many advantages over traditional transition-
metal-mediated processes; for example, the reactions can
often be carried out under wet and aerobic conditions, the
catalysts are generally inexpensive and there are no associ-
ated toxicity problems.[1]
The use of organocatalysts for the formation of stereogen-
ic quaternary carbon centres by the addition of carbon nu-
cleophiles to ketones or ketimines has been less explored.[2]
The low reactivity of these substrates relative to aldehydes
and aldimines is often a limitation. This requires the activa-
tion of both the nucleophile as well as the substrate by a bi-
functional organocatalyst,[3] which has acidic and basic sites.
Cinchona alkaloids and their modified derivatives are very
efficient catalysts for a variety of enantioselective organic
transformations.[4] Thus, they are attractive catalytic targets
for further applications and developments. We reasoned
that, while the 9-hydroxy/or 6’-hydroxy (in the case of cu-
preine and cupreidine)[5] group of the cinchona alkaloid acti-
vates the carbonyl group of isatin through hydrogen bond-
ing, the quinuclidine N group binds and orients the indole
through the formation of a hydrogen bond. Therefore, we
planned to explore the applicability of cinchona and modi-
fied cinchona alkaloid catalysts for the Friedel–Crafts-type
addition of indole to isatin to procure enantiopure 3-hydro-
xyoxindole derivatives.
3-Hydroxyoxindole derivatives are important structural
motifs in a variety of natural products and biologically
active compounds, which have a quaternary chiral carbon.[6]
The enantioselective approaches for the synthesis of 3-hy-
droxyoxindoles involve nucleophilic addition to the carbonyl
carbon of the isatin; these are limited to the metal-catalysed
addition of arylboronic acids,[7] addition of organozinc re-
agents,[8] allylation, crotylation and reverse prenylation reac-
tions.[9] The organocatalytic approach for the synthesis of
chiral substituted 3-hydroxyoxindole is limited to aldol-type
addition reaction by enamine catalysis.[10] However, the
enantioselective organocatalytic Friedel–Crafts-type[11,12] ad-
dition to the isatin for the synthesis of 3-hydroxyoxindole
motifs are not known.[13] During the preparation of this
manuscript, a metal-complex-catalysed reaction of isatin
with indole was reported by Franz and co-workers.[14]
Herein, we report the first asymmetric organocatalytic reac-
tion of isatin derivatives with indole for procuring optically
active 3-(indolyl)hydroxyoxindole derivatives.
Initially, the catalytic ability of cinchona alkaloids CD,
CN, QN and QD (Scheme 1) was studied for the Friedel–
[a] P. Chauhan, Prof. S. S. Chimni
Department of Chemistry
U.G.C. Centre of Advance Studies in Chemistry
Guru Nanak Dev University, Amritsar 143005 (India)
Fax : (+91)183-2258820
E-mail: sschimni@yahoo.com
sschimni.chem@gndu.ac.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000846.
Scheme 1. Structures of the cinchona-derived organocatalysts.
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Crafts-type addition of indole to the isatin by using
10 mol% of the catalyst in THF. The product (7a) showed
moderate levels of enantioselectivity and yields (Table 1, en-
tries 1–4), interestingly the reactions catalysed by QN and
tivity (Table 1, entries 12 and 13). Interestingly, performing
the reaction in the presence of 4 ꢁ molecular sieves (MS)
results in the increased enantioselectivity of 7a (Table 1, en-
tries 14 and 15).
The screening of different organic solvents with catalyst
BnCPN shows that in the polar protic solvents the reaction
occurs with high yield but low enantioselectivity (Table 2,
entries 10 and 11). Solvents such as DMF (Table 2, entry 12)
Table 1. Catalyst screening for Friedel–Crafts-type reactions of indole
(6a) with isatin (5a).[a]
Table 2. Solvent screening for Friedel–Crafts-type reaction of indole 6a
with isatin 5a.[a]
Entry
Solvents
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
THF
diethyl ether
MTBE
1,4-dioxane
toluene
CH2Cl2
CHCl3
ClCH2CH2Cl
EtOAc
EtOH
92
38
33
83
41
99
96
94
50
94
95
15
93
96
80
71
82
39
80
60
49
18
49
33
46
À89
Entry
Catalysts ([mol%])
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
CD (10)
CN (10)
QN (10)
QD (10)
32
33
61
62
81
83
82
31
97
94
63
93
95
82
92
60 (À)
58 (+)
53 (À)
52 (+)
82 (+)
90 (+)
85 (À)
29 (+)
80 (+)
85 (+)
85 (+)
91 (+)
90 (+)
95 (+)
96 (+)
CPN (10)
BnCPN (10)
BnCPD (10)
CDT (10)
BnCPN (10)
BnCPN (10)
BnCPN (5)
BnCPN (15)
BnCPN (20)
BnCPN (10)
BnCPN (15)
9
10
11
12
13[d]
MeOH
DMF
THF
9[e]
10[f]
11
12
13
14[g]
15[g]
[a] Reaction conditions: isatin 5a (0.25 mmol), indole 6a (0.37 mmol),
4 ꢁ molecular sieves (100 mg) and 1 f (0.037 mmol) in dry THF. [b] Yield
refers to isolated yield after column chromatography. [c] Determined by
chiral HPLC. [d] Catalyst 2 f was used.
[a] Reaction conditions: 0.25 mmol isatin 5a, 0.37 mmol of indole 6a and
catalyst in dry THF. [b] Yield refers to isolated yield after column chro-
matography. [c] Enantiomeric excess (ee) determined by chiral HPLC.
[d] The sign in parentheses indicates the sign of the optical rotation.
[e] Reaction was performed at 508C. [f] Reaction was performed at
408C. [g] 4 ꢁ molecular sieves were added.
and EtOAc (Table 2, entry 9) proved to be inefficient. The
reaction proceeds at a faster rate in chlorinated solvents, but
results in low enantioselectivity (Table 2, entries 6–8).
Among different etheral solvents, THF emerges as the best
because it provides 7a in 92% yield and 96% ee (Table 2,
entry 1).
QD afforded higher yields of the product than those cata-
lysed by CD and CN. The same reaction with modified cin-
chona catalyst CPN provided the product with 82% enan-
tioselectivity and 81% yield, thus suggesting the role of the
6’-OH group of quinoline in increasing the reactivity and se-
lectivity (Table 1, entry 5). To determine this role, catalyst
BnCPN was prepared with 9-OH blocked with benzyl
group. The reaction with this catalyst provided enhanced
enantioselectivity (90% ee) and reactivity (yield 83%)
(Table 1, entry 6). The pseudoenantiomeric catalyst BnCPD
also provided similar levels of reactivity and selectivity and
could be used for obtaining the opposite enantiomer of 7a
(Table 1, entry 7). The same reaction catalysed by the 9-thio-
urea derivative of cinchonidine (CDT) afforded a lower
yield and enantioselectivity of the product (Table 1, entry 8).
The optimisation studies of the reaction conditions (sol-
vent, temperature, amount of catalyst) with catalyst BnCPN
are summarised in Tables 1 and 2. The reactions performed
above ambient temperatures increase the yield, but lower
the enantioselectivity (Table 1, entries 9 and 10). Lowering
the catalyst loading results in low yields and enantioselectiv-
ity (Table 1, entry 11), while increasing the catalyst loading
leads to high yield with a very small change in enantioselec-
Once armed with the optimised conditions, we investigat-
ed the substrate scope of this methodology by studying dif-
ferent derivatives of isatin and indole. The 5-chloro (5b)
and 5-bromo (5c) derivatives of isatin react well with
indole, yielding the corresponding 3-substituted-3-hydro-
xyindole in very good enantioselectivities (Table 3, entries 2
and 3). The reaction with the 5-nitroisatin (5d) results in a
high yield and moderate enantioselectivity (Table 3,
entry 4). The N-alkylated isatins (5e–5g) also react with
indole with similar reactivity and selectivity (Table 3, en-
tries 5–7).
The 5-substituted indoles also undergo enantioselective
adduct formation with isatin in high yields. The reactions of
5-methoxyindole (6b) with isatin derivatives provide an
access to quaternary carbon on oxindole with up to 99% ee
(Table 3, entries 8–10). However, 5-bromoindole (6c) with
isatin yields the product with a moderate ee value (80%)
(Table 3, entry 11). The ee value could be enriched to
>99% after a single recrystallisation (Table 3, entries 1 and
8).
To demonstrate the practical utility, the reaction of isatin
(5a) and indole (6a) was performed at the 10 mmol scale
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Asymmetric Addition of Indoles to Isatins
COMMUNICATION
Table 3. Substrate scope for the BnCPN-catalysed Friedel–Crafts-type
Table 3. (Continued)
Entry Product
reaction of indole derivatives (6) with isatin derivatives (5).[a]
Yield [%][b]
ee [%][c]
8
97
97 (>99)[d]
Entry
Product
Yield [%][b]
ee [%][c]
9
99
95
92
99
93
80
1
92
96 (>99)[d]
10
11
2
98
90
3
4
5
99
98
89
92
83
85
[a] Reaction conditions: isatin 5 (0.250 mmol), indole 6 (0.375 mmol), 1 f
(0.037 mmol) and 4 ꢁ molecular sieves (100 mg) in dry THF at RT.
[b] Yield refers to isolated yield after column chromatography. [c] Deter-
mined by chiral HPLC on a Chiralpak IB and AD-H column. [d] ee
value after a single recrystallisation.
(Scheme 2). The desired product was formed in 91% yield
and 95% ee. After a single recrystallisation 81% product
was isolated with >99% ee. The optically pure catalyst
could be recovered in 94% yield.[15]
6
7
88
99
88
88
Scheme 2. Gram-scale preparation of 3-substituted 3-hydroxyoxindole.
To demonstrate the bifunctional mode of catalysis by the
catalyst BnCPN (1 f), in which the quinuclidine moiety inter-
acts with indole NH and the C6’ hydroxyl group activates
the isatin carbonyl through hydrogen-bond interactions, cat-
alysis by BnCD (1c) and BnQN (1d), which has no free OH
group were studied. The reactions performed with these cat-
alysts did not yield adduct even after eight days. A similar
observation was made on running the reaction with catalyst
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S. S. Chimni and P. Chauhan
3, in which quinuclidine tertiary amine was converted to a
quaternary salt. This indicates that the simultaneous activa-
tion of both the reactants by the quinuclidine moiety and 6’-
hydroxyl group of the catalyst is required for the success of
the reaction. This point was further proved by the absence
of product formation in the reaction of N-methylindole with
isatin in which the NH hydrogen is not available for hydro-
gen-bonding interactions with the quinuclidine moiety. In
addition to activation, the bifunctional catalyst also provides
the favourable orientation for adduct formation in high
enantioselectivity. Based upon these observations, a transi-
tion state involving a ternary complex between the catalyst,
isatin and indole has been proposed (Scheme 3).
Acknowledgements
The research was supported by funds from CSIR, India (research grant
no. 01/2168/07/EMR-II) and UGC, India. The financial support of DST,
India under the FIST program is gratefully acknowledged.
Keywords: chirality · cinchona alkaloids · Friedel–Crafts
reactions · organocatalysis · oxindoles
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Scheme 3. Plausible transition state involving a ternary complex between
the catalyst, isatin and indole.
The absolute configuration of the stereogenic centre in
the adduct has been assigned as S in comparison to the di-
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In conclusion, we have developed the first highly enantio-
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indole to isatin. It is important to note that this new catalyt-
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indole derivatives under ambient conditions. The methodol-
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products in high yields and high enantioselectivity. Our cur-
rent investigations are focused on the elucidation of the
mechanism, as well as in the expansion of the general scope
and synthetic applications for obtaining bioactive molecules.
À
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General procedure for the organocatalytic enantioselective Friedel–
Crafts reaction of indole with isatin: Isatin (0.250 mmol) was added to a
stirred solution of indole 6a (0.375 mmol) and catalyst 1 f (0.05625 mmol)
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Asymmetric Addition of Indoles to Isatins
COMMUNICATION
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Received: April 5, 2010
Published online: June 8, 2010
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