Chiral phosphoric acid catalyzed enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes: Cooperative effect of 3 A molecular sieves

Article abstract of DOI:10.1002/anie.200800770

(Chemical Equation Presented) Crafty catalysts: Friedel-Crafts alkylation of indoles with nitroalkenes proceeded in the presence of phosphoric acid 1 and 3 A molecular sieves to give Friedel-Crafts adducts with excellent enantioselectivities (see scheme).

Full text of DOI:10.1002/anie.200800770

Communications
DOI: 10.1002/anie.200800770
Organocatalysis
Chiral Phosphoric Acid Catalyzed Enantioselective Friedel–Crafts
Alkylation of Indoles with Nitroalkenes: Cooperative Effect of 3 Š
Molecular Sieves**
Junji Itoh, Kohei Fuchibe, and Takahiko Akiyama*
The enantioselective Friedel–Crafts alkylation[1] of indoles
with nitroalkenes is one of the most important carbon–carbon
bond-forming reactions for the preparation of biologically
active compounds such as indole alkaloids.[2] Although
several chiral catalysts, including salen/AlCl complexes,[3a]
bis(sulfonamide) compounds,[3b] thiourea-contaning structur-
es,[3c,f] and ZnII or CuII–bisoxazoline complexes,[3d,e,g] have
been reported for the reaction, the enantioselectivities are not
always satisfactory. The development of more efficient
catalysts is required.
Scheme 1. Comparison of reactions from previous studies and this
Recently, novel Brønsted acid catalysts were developed
and used in a number of asymmetric reactions,[4] and the
chiral phosphoric acids derived from (R)-binol (binol = 2,2’-
dihydroxy-1,1’-binaphthyl) have been extensively studied as
versatile organocatalysts for enantioselective reactions.[5–7]
Most of the phosphoric acid catalyzed reactions reported
so far involve imine or iminium ion electrophiles, however,
there are scattered examples that include carbonyl com-
pounds[8a,b,9h,j] aziridines,[8c] or nitrones as electrophiles.[8d] The
application of chiral phosphoric acid catalysis to other
electrophiles is desirable, and the enantioselective addition
of a nucleophile to a nitroalkene by using a chiral phosphoric
acid has not previously been reported. We describe herein the
first chiral phosphoric acid catalyzed Friedel–Crafts alkyla-
tion of indoles[9] with nitroalkenes to afford Friedel–Crafts
adducts in excellent enantioselectivities (Scheme 1).
work.
yield was low (Table 1, entry 1).[10] To our delight, we found
that the addition of activated, powdered molecular sieves
(M.S.) significantly improved both the chemical yield and the
enantioselectivity. Among the molecular sieves examined, the
3 Š molecular sieves gave the best result (Table 1, entry 2).[11]
Since the addition of a small amount of water to the reaction
mixture deteriorates the chemical yield (Table 1, entry 5),[12,13]
we suppose that the molecular sieves absorb the small amount
of water present in the reaction medium.
We explored the scope and limitations of the reaction by
using various indoles and nitroalkenes under the optimized
reaction conditions, and the results are summarized in
Table 2. A wide range of nitroalkenes bearing electron-
donating (2b–c), electron-withdrawing (2d–e), and hetero-
Chiral phosphoric acid (R)-3 provided the best enantio-
selectivity in the Friedel–Crafts alkylation of indole 1a with
nitroalkene 2a (2equiv) in benzene/1,2-dichloroethane (1:1)
at À358C. Although the system resulted in the formation of
Friedel–Crafts adduct 4a with good enantioselectivity, the
Table 1: Effect of the 3Š molecular sieves. [a]
[*] Dr. J. Itoh, Dr. K. Fuchibe,[+] Prof. Dr. T. Akiyama
Department of Chemistry, Faculty of Science
Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax: (+81)3-5992-1029
E-mail: takahiko.akiyama@gakushuin.ac.jp
[+] Present address: Department of Chemistry
Graduate School of Pure and Applied Sciences
University of Tsukuba
Entry
M.S.
Yield [%][b]
ee [%][c]
1
2
5
Š
75
3
76
91
Tsukuba (Japan)
34 Š
4
5
69
5 Š
3
83
59
Š1
[**] This work was partially supported by a Grant-in Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformation of
Carbon Resources” from the Ministry of Education, Science, Sports,
Culture, and Technology (Japan). J.I. thanks the JSPS Research
Fellowships for Young Scientists.
88
60
[d]
[a] Reactions were carried out with 1a (0.2 mmol) and 2a (0.4 mmol;
2 equiv) in benzene (0.5 mL)/1,2-dichloroethane (0.5 mL). [b] Yield of
isolated product. [c] Enantiomeric excess was determined by HPLC
analysis. [d] Used 10 equiv of H2O.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2008, 47, 4016 –4018

Angewandte
Chemie
aromatic (2 f) groups underwent the Friedel–Crafts alkylation
reaction to afford Friedel–Crafts adducts 4 with excellent
enantioselectivities (Table 2, entries 1–6). Aliphatic nitroal-
kenes (2g–j) gave the corresponding adducts with high
Table 2: Chiral Brønsted acid catalyzed Friedel–Crafts alkylation of
indoles with nitroalkenes.[a]
Scheme 2. Derivatization of the Friedel–Crafts adduct. Conditions:
Entry
R1
R2
t [h] Yield [%][b]
ee [%][c]
a) NaBH4 (5 equiv), NiCl2·6H2O (1 equiv), MeOH, 30 min, 94%;
b) AcCl (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 16 h, 91%; c) PhCHO
(1.2 equiv), CF3CO2H (2 equiv), MgSO4, CH2Cl2, 68 h, 80%, anti:-
syn=91:9; d) TsCl (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 17 h, 97%.
Ts =p-toluenesulfonyl.
1
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
5-Cl (1b)
5-Br (1c)
Ph (2a)
48
116
119
115
72
76 (4a)
64 (4b)
74 (4c)
73( 4d)
84 (4e)
71 (4 f)
57 (4g)
91
90
91
91
91
90
88
90
90
91
90
90
94
91
2
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-ClC6H4 (2d)
4-CF3C6H4 (2e)
2-thienyl (2 f)
Ph(CH2)2 (2g)
CH3(CH2)2 (2h)
CH3(CH2)4 (2i)
CH3(CH2)8 (2j)
Ph (2a)
3[d,e]
4[e]
5
6[e]
92
95
7[e,f]
8[g]
previously proposed nine-mem-
bered transition state,[6a,b,g] wherein
the phosphoric acid worked as a
bifunctional catalyst.
23
4
47h0)(
9[g]
23
23
4
5
47i)7 (
46j)2 (
10[g]
11[e]
12[e]
13[e]
14[h]
119
119
8370 (
95
63( 4k)
72 (4l)
4m)
Ph (2a)
In summary, we have developed
a chiral phosphoric acid catalyzed
7-Me (1d) Ph (2a)
H (1a) Ph (2a)
>99 (4a)
Figure 1. Plausible tran-
Friedel–Crafts alkylation of indoles
sition state. The vinylic
with nitroalkenes to generate Frie-
hydrogen of the nitroal-
[a] Reactions were carried out with 1 (0.2 mmol) and of 2 (0.4 mmol;
2 equiv) in benzene (0.5 mL)/1,2-dichloroethane (0.5 mL). [b] Yield of
isolated product. [c] Enantiomeric excess was determined by HPLC
analysis. [d] The reaction was performed at À208C. [e] Employed 5 equiv
of 2. [f] Used 2 equiv of 1a and 20 mol% of (R)-3 at À208C. [g] Used
20 mol% of (R)-3. [h] The reaction was performed on a one-gram scale
(8.56 mmol) in the presence of 850 mg of 3Š molecular sieves and
5 equiv of 2a.
del–Crafts adducts with excellent
kene lies behind the
enantioselectivities. We found that
3 Š molecular sieves lead to an
efficient Friedel–Crafts alkylation
indole ring.
in the presence of a chiral phosphoric acid. This reaction is
the first example of nitroalkene activation catalyzed by a
chiral phosphoric acid, and additional investigations to clarify
the reaction mechanism and its application to other enantio-
selective reactions are underway.
enantioselectivities (Table 2, entries 7–10), but long reaction
times were necessary to obtain good yields. The reaction
tolerated a variety of different indoles (1b–d) and gave
excellent results (Table 2, entries 11–13).
Received: February 16, 2008
Published online: April 16, 2008
This reaction was carried out on a one-gram scale to
demonstrate the synthetic utility of the present system. When
1.00 g of indole 1a was treated with 5 equivalents of nitro-
alkene 2a, 2.28 g of corresponding adduct 4a was obtained in
high chemical yield without any loss in the enantioselectivity
(Table 2, entry 14).
Next, Friedel–Crafts adduct 4a was transformed into
triptamine 5,[2a] melatonin analogue 6,[2b] and 1,2,3,4-tetrahy-
dro-b-carboline derivative 7[2c] (Scheme 2). These products
were obtained in good yields without racemization.
To gain insight into the reaction mechanism we examined
N-Me indole as a substrate under the optimized conditions.
As expected, both the chemical yield and the enantioselec-
tivity deteriorated significantly (11% yield, 0% ee). The
Keywords: asymmetric synthesis · Brønsted acids ·
enantioselectivity · Friedel–Crafts alkylation · indoles
.
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[10] The absolute stereochemistry of 4a was determined by chiral
HPLC analysis by comparison to the retention time described in
the reference [3c].
[11] The powdered 3 Š molecuar sieves were activated by placing the
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10 minutes.
a heat gun for
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obtained in 3% yield.
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