Asymmetric friedel-crafts reaction of 4,7-dihydroindoles with nitroolefins by chiral Bronsted acids under low catalyst loading

Article abstract of DOI:10.1002/chem.200900033

Asymmetric Friedel-Crafts reaction of 4,7-dihydroindoles with nitroolefins using Chiral Broonsted acids under low catalyst loading was reported. The study involved the reaction between 4,7-dihydroindose and nitroolefin catalyzed by different chiral phosop

Full text of DOI:10.1002/chem.200900033

COMMUNICATION
DOI: 10.1002/chem.200900033
Asymmetric Friedel–Crafts Reaction of 4,7-Dihydroindoles with Nitroolefins
by Chiral Brønsted Acids under Low Catalyst Loading
Yi-Fei Sheng,[a, b] Gong-Qiang Li,[a] Qiang Kang,[a] An-Jiang Zhang,[b] and Shu-Li You*[a]
Dedicated to Professor Li-Xin Dai on the occasion of his 85th birthday.
The enantioselective Friedel–Crafts reaction has attracted
considerable interest and witnessed significant progress re-
cently.[1] Indoles are the most widely distributed heterocyclic
compounds in nature and exist extensively as the structure
core of biologically active natural products and pharmaceut-
ical compounds.[2] The asymmetric Friedel–Crafts reaction
of indoles has stimulated intense activity and has become an
efficient tool for the synthesis of optically pure indole deriv-
atives.[3] In particular, the asymmetric Friedel–Crafts reac-
tion employing a nitroolefin as the electrophilic partner is
very attractive, since the nitro group of the products allows
subsequent versatile transformations.[4] Successful catalytic
systems for this asymmetric reaction include the SalenAlCl
complex,[5] bis-sulfonamides,[6] thioureas,[7] copper com-
plexes,[8] zinc complexes,[9] and recently chiral phosphoric
acids.[10] The latter were successfully introduced by Akiyama
and co-workers, and, for the first time, chiral phosphoric
acid was used to activate nitroolefins. Despite all the prog-
ress made in this area, most of the current catalytic systems
still require the use of a substoichiometric amount of cata-
lyst (5–20 mol%) and long reaction time (days) for the max-
imum yields and enantiomeric excesses.[11] A highly efficient
catalytic system that addresses both these issues would cer-
tainly improve the practicality of the asymmetric Friedel–
Crafts reaction of nitroolefins. In addition, to our knowl-
edge, to date, there is no report on the asymmetric synthesis
of products from the alkylation of nitroolefins at the 2-posi-
tion of indoles. As part of our continuing interest in explor-
ing the synthesis of 2-substituted indoles,[12] we recently
found that chiral phosphoric acids were efficient catalysts
for the asymmetric Friedel–Crafts reaction of nitroolefins
with 4,7-dihydroindoles, providing 2-substituted indole de-
rivatives after a subsequent oxidation (Scheme 1). More in-
Scheme 1. Route to 2-substituted indole by Friedel–Crafts alkylation.
terestingly, all the reactions proceeded to completion in 2 h
at room temperature with excellent yields and ee values
with only 0.5 mol% of the catalyst.[13] Herein, we report our
preliminary results.
We first examined the reaction between 4,7-dihydroindole
(2a) and nitroolefin 3a catalyzed by different chiral phos-
phoric acids.[14] After the screening of the chiral phosphoric
acids, we found that (S)-1 bearing 9-anthryl groups is the op-
timal catalyst. Notably, the acid bearing Ph3Si groups, the
best one in the Friedel–Crafts reaction between indoles and
nitroolefins,[10a] afforded 4aa with only moderate ee and re-
versed optical rotation. Different molecular sieves (MS)
were tested as the additive (Table 1). In the presence of
5 mol% of (S)-1 in dichloromethane/benzene (1/1) at room
temperature, 4 ꢀMS were found to be the best ones, leading
to the 2-substituted alkylation product 4aa in 95% yield
with 80% ee (entries 1–3, Table 1). Lowering the reaction
temperature to 08C and À208C did not show any effects on
the reaction outcomes, but the ee values decreased when the
reactions were carried out at lower temperatures (entries 4–
7, Table 1). To our delight, all the reactions proceeded to
completion within 1 h.
[a] Y.-F. Sheng, G.-Q. Li, Dr. Q. Kang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
54 Fenglin Lu, Shanghai 200032 (China)
Fax : (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
[b] Y.-F. Sheng, Prof. Dr. A.-J. Zhang
College of Chemistry and Material Engineering
Wenzhou University, Wenzhou 325027 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900033.
Chem. Eur. J. 2009, 15, 3351 – 3354
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3351

Table 1. Optimization of the reaction conditions for enantioselective
Friedel–Crafts reaction.
Table 3. Enantioselective Friedel–Crafts reaction of 4,7-dihydroindoles
with nitroolefins.
Entry[a]
2
3, R
4, Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
3a, C6H5
4aa, 96
4ab, 97
4ac, 97
4ad, 97
4ae, 94
4af, 97
4ag, 98
4ah, 96
4ai, 97
4aj, 96
4ak, 94
4ba, 94
4ca, 93
4da, 94
92
96
92
88
92
91
91
92
95
97
24
92
89
89
3b, 4-MeO-C6H4
3c, 4-Me-C6H4
3d, 3-Me-C6H4
3e, 4-CF3-C6H4
3 f, 4-Cl-C6H4
3g, 4-Br-C6H4
3h, 2-naphthyl
3i, 2-furyl
3j, 2-thienyl
3k, c-hexyl
3a, C6H5
3a, C6H5
3a, C6H5
Entry[a]
Additive
Temp [oC]
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
3 ꢀMS
4 ꢀMS
5 ꢀMS
4 ꢀMS
4 ꢀMS
4 ꢀMS
4 ꢀMS
rt
rt
rt
0
À20
À50
À78
1.0
1.0
1.0
1.0
1.0
1.0
1.0
95
95
95
94
94
93
93
49
80
57
80
80
54
13
9
10
11
12[d]
13
14[e]
[a] Reaction conditions: 1.5 equiv of 2a, 5 mol% of 1, 0.25 molLÀ1 of 3a
in CH2Cl2/benzene. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis (Chiralcel OD-H column).
pyrrole
[a] Reaction conditions: 1.5 equiv of 2, 0.5 mol% 1, rt, 0.25 molLÀ1 of 3
in CH2Cl2/benzene. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. [d] 1 mol% of the catalyst was used. [e] 10 mol%
of the catalyst was used.
A parallel reaction without the catalyst was set up and
disclosed a severe background reaction. We hypothesized
that a slow addition of the nitroolefin substrate would maxi-
mize the ratio between the catalyst and the nitroolefin in
the reaction mixture and therefore afford the product with
better ee and possibly allow the reduction of the catalyst
loading. As expected, by using a syringe pump to slowly add
the nitroolefin substrate over 1 h and 2 h, the ee of 4aa in-
creased to 90% and 91%, respectively (entries 1–3,
Table 2). To our great delight, the same level of yield and ee
with 4,7-dihydroindole 2a. In all cases, excellent yields and
enantioselectivities were obtained for the desired alkylation
products (97% yield, 88 to 96% ee, entries 2–4, Table 3).
The reaction also worked well with substituted nitroolefins
3e–g, which contained electron-withdrawing groups, and the
desired alkylation products were obtained in 94 to 98%
yield with 91 to 92% ee (entries 5–7, Table 3). When 2-naph-
thyl and heteroaryl-substituted nitroolefins 3h–j were used,
the reaction gave excellent results, 96 to 97% yield with 92
to 97% ee (entries 8–10, Table 3). Unfortunately, when ali-
phatic substituted nitroolefins such as 3k were used, a low
ee (24%) was obtained (entry 11, Table 3). 5-Methoxy-4,7-
dihydroindole (2b) and 5-fluoro-4,7-dihydroindole (2c)
were tested in the reaction with nitroolefin 3a, the alkyla-
tion products were obtained in excellent yield and ee (en-
tries 12 and 13, Table 3). When pyrrole was used, satisfying
results were obtained with 10 mol% of the catalyst (94%
yield, 89% ee, entry 14, Table 3).
Table 2. Screening the catalyst loading and the slow addition.
Entry[a] Syringe pump x [mol%] Time [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
no
5
5
5
1
0.5
0.1
1.0
1.0
2.0
2.0
2.0
2.0
96
95
96
96
96
96
80
90
91
92
92
81
yes
yes
yes
yes
yes
To demonstrate the suitability of the current methodology
for the synthesis of 2-substituted indole derivatives, the oxi-
dation of the 2-substituted 4,7-dihydroindole derivatives was
tested. After the reaction of the nitroolefin with 4,7-dihy-
droindole was complete, two equivalents of p-benzoquinone
were added to the reaction mixture (Scheme 2). The desired
2-indolyl compounds 5 were obtained smoothly in 85 to
91% yield with 88 to 95% ee, indicating the perfect reten-
tion of the stereochemistry during the oxidation process.
The absolute configuration of the product 5a was deter-
mined to be R as shown in Scheme 3. The nitro group in 5a
(93% ee) was reduced to amine followed by Ts protection,
leading to compound 7 in an overall 72% yield. It has the
same sign of optical rotation as that derived from enantio-
[a] Reaction conditions: 1.5 equiv of 2a, x mol% 1, rt, 0.25 molLÀ1 of 3a
in CH2Cl2/benzene. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis (Chiralcel OD-H column).
was obtained by using only 0.5 mol% of the catalyst (en-
tries 4 and 5, Table 2). Even with 0.1 mol% of the catalyst,
the reaction was also able to proceed to completion within
2 h with 81% ee (entry 6, Table 2).
The chiral phosphoric acid catalyzed Friedel–Crafts reac-
tion of 4,7-dihydroindoles with nitroolefins was found to be
general for nitroolefins bearing different substituents
(Table 3). Several substituted nitroolefins 3b–d, containing
electron-donating groups, have been tested in the reaction
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Chem. Eur. J. 2009, 15, 3351 – 3354

Enantioselective Friedel–Crafts Reaction of 4,7-Dihydroindoles with Nitroolefins
COMMUNICATION
In summary, we have developed an enantioselective Frie-
del–Crafts reaction of 4,7-dihydroindoles with nitroolefins
by utilizing chiral phosphoric acid 1 as an efficient catalyst.
With slow addition of the nitroolefin substrate by syringe
pump, the reaction allows the use of only 0.5 mol% of the
catalyst and proceeds to completion in 2 h. This metal-free
process together with the mild reaction conditions, high
yields, and excellent enantioselectivities, provides a practical
method to synthesize highly enantiopure 2-substituted-
indole and tetrahydro-g-carboline derivatives. Further appli-
cation of the current methodology and study of the reaction
mechanism are ongoing in our laboratory.
Scheme 2. Friedel–Crafts reaction of 2 with nitroolefin 3 and p-benzoqui-
none oxidation.
Experimental Section
General procedure for the catalytic asymmetric Friedel–Crafts reaction:
4,7-Dihydroindole (2, 0.45 mmol), chiral phosphoric acid (S)-1 (1 mg,
0.0015 mmol), 4 ꢀ molecular sieves (50 mg), and CH2Cl2/benzene
(0.6 mL, 1:1) were placed in a dry Schlenk tube under argon. The reac-
tion mixture was stirred at room temperature, and then a solution of ni-
troolefin 3 (0.3 mmol) in CH2Cl2/benzene (0.6 mL, 1:1) was added by sy-
ringe pump over two hours. The reaction was complete right after the ad-
dition for all cases. The reaction mixture was concentrated, and the resi-
due was purified by flash chromatography (dichloromethane/petroleum
ether=1/10–1/1) to afford the product.
Scheme 3. Determination of the absolute configuration of 5a.
pure aziridine (R)-6. As shown in Scheme 4, the Friedel–
Crafts product 5c was also transformed to tetrahydro-g-car-
boline derivative 8 without racemization. The two isomers
could be easily separated by silica gel column chromatogra-
phy, providing a facile synthesis of enantiopure tetrahydro-
g-carboline derivatives. The latter exist extensively as bio-
logically important compounds,[15] and their enantiopure
forms are not readily accessible by known methods.
Acknowledgements
We thank the National Natural Science Foundation of China, the Nation-
al Basic Research Program of China (973 Program 2009CB825300), the
Knowledge Innovation Program of the Chinese Academy of Sciences,
and the Science and Technology Commission of Shanghai Municipality
(07pj14106, 07 JC14063) for generous financial support.
Keywords: asymmetric catalysis · chiral Brønsted acids ·
conjugate addition
reaction
· enantioselectivity · Friedel–Crafts
Scheme 4. Derivatization of the Friedel–Crafts product 5c.
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Chem. Eur. J. 2009, 15, 3351 – 3354
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Received: January 7, 2009
Published online: February 19, 2009
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