Enantioselective Friedel-Crafts alkylation reaction of indoles with α,β-unsaturated acyl phosphonates catalyzed by chiral phosphoric acid

Article abstract of DOI:10.1039/c000862a

A variety of indoles underwent enantioselective Friedel-Crafts alkylation with α,β-unsaturated acyl phosphonates in the presence of 10 mol% chiral BINOL-based phosphoric acid and subsequent treatment with methanol and DBU to give methyl 3-(indol-3-yl)prop

Full text of DOI:10.1039/c000862a

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Enantioselective Friedel–Crafts alkylation reaction of indoles with
a,b-unsaturated acyl phosphonates catalyzed by chiral phosphoric acidw
Prabhakar Bachu and Takahiko Akiyama*
Received (in Cambridge, UK) 15th January 2010, Accepted 12th February 2010
First published as an Advance Article on the web 16th March 2010
DOI: 10.1039/c000862a
A variety of indoles underwent enantioselective Friedel–Crafts
alkylation with a,b-unsaturated acyl phosphonates in the presence
of 10 mol% chiral BINOL-based phosphoric acid and subsequent
treatment with methanol and DBU to give methyl 3-(indol-3-yl)-
propanoates in good yields and with high enantioselectivities.
In the past few years, (R)-BINOL-derived phosphoric acids
as chiral Brønsted acids have attracted considerable attention
in organocatalyzed asymmetric organic transformations.7,8
As part of our ongoing studies using chiral phosphoric acids
as organocatalysts,9 we investigated the chiral phosphoric acid
catalyzed Friedel–Crafts alkylation reaction of unprotected
indoles with a,b-unsaturated acyl phosphonate to afford
Friedel–Crafts adducts with excellent enantioselectivities.10
First, we investigated the reaction of indole 1 with
a,b-unsaturated acyl phosphonate 2 catalyzed by chiral
phosphoric acid as the model reaction (Table 1). The reaction
proceeded at room temperature in the presence of 10%
catalysts (R)-4a–h in toluene. Due to the instability of the
adduct, it was subsequently converted into methyl ester using
methanol and DBU, as shown in Table 1. From this survey,
we found that the use of sterically more hindered and bulkier
phosphoric acids as catalysts gave higher enantioselectivities
(Table 1, entries 6 and 7). The best result was obtained with
(R)-4f as a catalyst, which afforded methyl ester 3a in highest
yield (72%) and enantioselectivity (92%).
The enantioselective carbon–carbon bond forming reaction
has attracted much attention in both academia and industry
because of its numerous potential advantages.1 The formation
of new carbon–carbon bonds via the Friedel–Crafts reaction2
and the catalytic enantioselective variants has made a great
impact on stereoselective synthesis. Those variants involve
the addition of hetero-aromatic nucleophiles, such as indoles,
to electron-deficient olefins, resulting in 3-substituted indole
derivatives.3 It has potential application in the synthesis
of molecules with the indole framework or pharmacophore,
which are found in a range of natural products and medicinal
compounds of diverse therapeutic actions. The preparation of
polyfunctional indoles is therefore an important topic of
research.4 Several chiral metal catalysts5 as well as organo-
catalysts6 have been reported for the reactions with a,b-
unsaturated carbonyl compounds.
To further optimize the reaction conditions, we examined
the solvent, temperature, and catalyst loading (Table 2).
Toluene turned out to be the optimal solvent (Table 2, entry 5).
The stereoselective addition of
a nucleophile to an
a,b-unsaturated esters is not a trivial issue because of the
lower nature of the a,b-unsaturated ester as a Michael acceptor.
Thus, we envisaged that employing an a,b-unsaturated acyl
phosphonate to react with a nucleophile under organocatalytic
conditions would allow us to produce a chiral intermediate.
Under mild conditions, this intermediate can be converted to
the corresponding ester or amide without affecting the enantio-
merically enriched benzylic stereocenter (Scheme 1).
Table 1 Effect of the 3,30-substituents of chiral phosphoric acid 4a
So far only metal catalyzed reactions have been reported
in the conjugate addition of mainly protected indoles to
a,b-unsaturated acyl phosphonates with limited scope.5a,h
Entry
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
60
62
69
62
62
73
69
75
0
20
19
30
37
92
69
43
Scheme 1 Chiral phosphoric acid catalyzed Friedel–Crafts alkylation
reaction and subsequent transformation to ester or amide.
Department of Chemistry, Faculty of Science, Gakushuin University,
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
E-mail: takahiko.akiyama@gakushuin.ac.jp; Fax: +81 3 5992 1029;
Tel: +81 3 3986 0221
w Electronic supplementary information (ESI) available: General
experimental details and compound characterisations. See DOI:
10.1039/c000862a
4g
4h
a
All the reactions were performed using 1 (0.10 mmol), 2 (0.11 mmol)
b
and 4 (0.01 mmol) in solvent c = 0.1 M. Isolated yield. Enantiomeric
c
excess was determined by chiral HPLC.
ꢀc
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Table 3 Results of the Friedel–Crafts alkylation reactiona
Table 2 Effect of solvent and temperaturea
Entry
T/1C
Solvent
4f (mol%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
THF
10
10
10
10
10
5
50
46
54
50
73
61
50
31
64
82
89
88
92
86
92
90
CH2Cl2
Benzene
Mesitylene
Toluene
Toluene
Toluene
Toluene
ꢁ5
10
5
ꢁ5
a
All the reactions were performed using 1 (0.10 mmol) and 2
b
(0.11 mmol) in solvent c = 0.1 M. Isolated yield. Enantiomeric
c
excess was determined by chiral HPLC.
Lowering the reaction temperature (Table 2, entries 7 and 8)
and the catalyst loading (Table 2, entries 6 and 8) reduced the
yield and did not improve the enantioselectivity.
Experiments that probed the scope of the reaction of indoles
having different substitution patterns with a,b-unsaturated
acyl phosphonates catalyzed by chiral phosphoric acid 4f
revealed full conversion. The broad scope of the reaction is
summarized in Table 3. Chiral phosphoric acid 4f catalyst
tolerates aromatic, heteroaromatic, and aliphatic substituents
R1 on the a,b-unsaturated acyl phosphonates. The ee values
varied between 70% (entry 10) and 92% (entry 1); an exception is
3f. The electron-withdrawing or -donating substituent at C(5)
of the indoles is a competent substrate (entries 2–5 and 7). The
5-cyanoindole gave a corresponding adduct 3g with good
enantioselectivity (entry 7, 75% ee, 52% yield), although a
long reaction time was necessary to obtain good yields. In
terms of a product elaboration, amide 3h was efficiently
produced by treating the phosphonate adduct in situ with
morpholine, and the ee was excellent (entry 7, 88% ee, 73%
yield). On the other hand, 7-methylindole yielded 3f with low
ee (entry 9, 19% ee, 75% yield), presumably due to steric
inhibition of the attendant Brønsted acid catalyst. It is note-
worthy that the aromatic variation in the steric contribution of
the olefin substituent R1 can be accomplished with good
results in contrast to previous reports.5a,h
The absolute configurations of products 3 were correlated to
the absolute configuration of 3k, which was confirmed to be
S by comparison with the literature.10
a
All the reactions were performed using 5 (0.10 mmol), 6 (0.11 mmol)
b
and 4f (0.01 mmol), in solvent c = 0.1 M. Isolated yields were
To rationalize the reaction mechanism, N-benzyl substituted
indole was treated with a,b-unsaturated acyl phosphonate 2
under optimized conditions to afford the corresponding
adduct in 5% yield with 0% ee. Thus, the presence of the
N–H moiety of indole is essential to attain both high chemical
yield and enantioselectivity. We assume that the phosphoric
acid activates the carbonyl moiety and at the same time the
phosphoryl oxygen atom forms a hydrogen bond with the
hydrogen atom of the indole N–H moiety as previously
proposed (Fig. 1).9d,g
obtained for all the compounds and enantiomeric excess was determined
c
by chiral HPLC. The reaction was carried out at ꢁ10 1C.
In summary, chiral phosphoric acids are efficient catalysts
for the Michael type Friedel–Crafts addition reaction of
Fig. 1 Plausible transition state.
ꢀc
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electron-rich indoles with a,b-unsaturated acyl phosphonates to
generate adducts with excellent enantioselectivities and good
yields at room temperature. The reaction was shown to be a
general one for 5-substituted indoles and acyl phosphonates. Its
application to the construction of the potentially bio-active
natural products and their derivatives is under investigation.
We gratefully acknowledge the Japanese Society for
Promotion of Science, Japan for the support of this work
and for JSPS Postdoctoral fellowship to P. Bachu.
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ꢀc
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4114 | Chem. Commun., 2010, 46, 4112–4114