Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid

Article abstract of DOI:10.1021/ja067417a

Highly enantioselective Friedel-Crafts reactions of indoles with imines catalyzed by a chiral phosphoric acid are developed, affording the 3-indolyl methanamine derivatives with up to >99% ee for a wide range of substrates. Copyright

Full text of DOI:10.1021/ja067417a

Published on Web 01/19/2007
Highly Enantioselective Friedel-Crafts Reaction of Indoles with Imines by a
Chiral Phosphoric Acid
Qiang Kang, Zhuo-An Zhao, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received October 17, 2006; E-mail: slyou@mail.sioc.ac.cn
The use of small organic molecules as catalysts, so-called
organocatalysts, to promote asymmetric reactions has emerged as
a new frontier in synthetic organic chemistry.1 Among numerous
chiral organocatalysts reported, chiral phosphoric acids 1, pioneered
by Akiyama et al. and Terada et al.,2 have recently received
considerable attention and have been applied in a wide range of
asymmetric organic transformations (Figure 1).3,4 Further extension
Figure 1. Chiral phosphoric acids.
of reaction types catalyzed by chiral phosphoric acid remains the
focus in this field. The asymmetric Friedel-Crafts reaction of
Table 1. Screening of the Phosphoric Acid Catalysts
indoles with imines is an important reaction to which chiral
phosphoric acid organocatalysts can be applied. The products of
this reaction provide easy access to the synthesis of enantiopure
3-indolyl methanamine derivatives.5 The latter exist in numerous
natural and unnatural products with significant biological activities.6
entrya
cat
time
yield (%)b
ee (%)c
An efficient, organocatalytic approach to 3-indolyl methanamine
is extremely desirable. Recently, Deng and co-workers applied
bifunctional organocatalysts to the asymmetric Friedel-Crafts
reaction of indoles with imines, affording the 3-indolyl methanamine
derivatives with up to 97% ee.7 In our recent studies on applications
of chiral phosphoric acids to asymmetric catalysis, we found that
chiral phosphoric acids are efficient organocatalysts for the Friedel-
Crafts reactions of indoles with imines. The reactions proceed to
completion within hours for most of the substrates, affording the
3-indolyl methanamine derivatives with up to >99% ee. In this
communication, we report our preliminary results.8
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
4 h
14 h
4 h
30 min
10 min
10 min
85
60
69
80
66
78
0
73
73
83
92
93
a Reaction conditions: 10 mol % of catalyst, 5 equiv of 2a, 0.25 mol/L
of 3a in toluene at room temperature. b Isolated yields. c Determined by
chiral HPLC analysis (Chiralcel OD-H).
Table 2. Investigation of the Reaction Temperature and Catalyst
Loadings
We first examined the reaction between indole 2a and imine 3a
catalyzed by phosphoric acid 1d. In the presence of 10 mol % of
1d in toluene at room temperature, reaction of 3a with equimolar
2a gave the desired product 4a in 59% yield with 67% ee (for
details, see Supporting Information), along with a bisindole addition
byproduct (5% yield). When we increased the amount of indole,
the reaction proceeded faster and led to the product with a slightly
higher enantioselectivity. When 5 equiv of indole was used, an
optimal result was obtained in terms of both the yield and
enantioselectivity of 4a (80% yield, 83% ee, entry 4, Table 1).
Under these reaction conditions, several phosphoric acids with
varying substituents at the 3- and 3′-positions of the binaphthyl
scaffold were tested, and the results are listed in Table 1. The
simplest catalyst 1a could catalyze the reaction smoothly (85%
yield) but afforded a racemic product (entry 1, Table 1). The product
was obtained with 73% ee when phosphoric acid 1b was used (entry
2, Table 1). Surprisingly, phosphoric acid 1c, with a very bulky
triphenylsilyl substituent, only afforded the product with moderate
enantioselectivity, 73% ee (entry 3, Table 1). We are very delighted
to find that high enantioselectivities of 92 and 93% ee could be
obtained using phosphoric acids 1e and 1f, respectively, as the
catalysts. It should be noted that the reaction was complete in 10
min in the presence of 10 mol % of 1e or 1f.
entrya
1f (mol %)
temp
time
yield (%)b
ee (%)c
1
2
3
4
5
6
7
10
10
10
10
10
5
rt
10 min
10 min
10 min
30 min
2 h
78
80
75
83
81
83
72
93
95
97
98
98
96
75
0 °C
-40 °C
-60 °C
-78 °C
-60 °C
-60 °C
1.5 h
10 h
2
a Reaction conditions: 5 equiv of 2a, 0.25 mol/L of 3a in toluene.
b Isolated yields. c Determined by chiral HPLC analysis (Chiralcel OD-
H).
We next investigated the effect of the reaction temperature and
catalyst loading using catalyst 1f. The results are summarized in
Table 2.
In general, lowering the temperature resulted in a decrease of
the reaction rate but an increase of the enantioselectivity. In the
presence of 10 mol % of 1f, 95 and 97% ee of 4a was obtained at
0 and -40 °C, respectively (entries 2 and 3, Table 2). Up to 98%
ee was attained when the reaction was run at -60 °C (entry 4,
9
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J. AM. CHEM. SOC. 2007, 129, 1484-1485
10.1021/ja067417a CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Enantioselective Friedel-Crafts Reaction of Indoles with
a 3-nitro group, 89% ee was given (entry 12, Table 3). Similarly,
good to excellent enantioselectivities were obtained with substrates
3e-g (which contain electron-withdrawing groups), where phos-
phoric acid 1d proved to be superior to 1f (entries 13-15, Table
3). Unfortunately, when an aliphatic aldehyde derived imine, such
as 3j, was tested, only moderate yield and enantioselectivity were
obtained (56% yield, 58% ee, entry 18, Table 3). To test the
practicality of the current catalytic system, reaction of 3b with 2
equiv of indole in the presence of 5 mol % of 1f was carried out
in a 10 mmol scale of 3b. The desired product was afforded in
94% yield with >99% ee (entry 19 versus entry 2, Table 3).
In summary, we have identified chiral phosphoric acids as
efficient organocatalysts for the Friedel-Crafts reactions of indoles
with imines, especially for the imines derived from aromatic
aldehydes. The reaction features a metal-free approach, high
efficiency of the catalyst, mild reaction conditions, high yields, and
excellent enantioselectivities, providing a practical method to
synthesize highly enantiopure 3-indolyl methanamine derivatives.
Further investigation of the reaction mechanism and extension of
the reaction scope are currently underway in our laboratory.
N-Sulfonyl Aldimines
entrya
2, R
3
time
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
2a, H
3a: R′ ) H, R′′ ) Ts
3b: R′ ) H, R′′ ) Bs
30 min
15 min
20 min
15 min
15 min
15 min
40 min
40 min
2 h
83
88
87
84
89
83
82
89
68
87
93
85
91
71
83
90
90
56
98
99
97
99
>99
99
98
>99
98
>99
>99
89
2b, 5-OMe 3a
3b
3a
3b
3a
3b
3a
3b
2c, 5-Me
2d, 5-Br
2e, 6-Cl
10
11
12
1.5 h
10 min
2a, H
2a, H
3c: R′ ) 4-Me, R′′ ) Ts
3d: R′ ) 3-NO2, R′′ ) Ts 15 min
13d 2a, H
14d,e 2a, H
15d,e 2a, H
3e: R′ ) 4-Cl, R′′ ) Ts
3f: R′ ) 4-Br, R′′ ) Ts
24 h
24 h
94
82(R)
85(R)
96
97
58
3g: R′ ) 4-CF3, R′′ ) Ts 14 h
3h: R′ ) 3-OMe, R′′ ) Ts 1 h
3i: R′ ) 3-OMe, R′′ ) Bs 1 h
16
17
18
2a, H
2a, H
2a, H
Acknowledgment. We gratefully acknowledge the Chinese
Academy of Sciences for generous financial support. We thank
Professor Yong Tang and Professor Li-Xin Dai for helpful
discussions.
3j:
5 h
19f 2a, H
3b
40 min
94
>99
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions: 5 equiv of indole, 10 mol % of 1f, -60 °C, 0.25
mol/L of 3 in toluene. b Isolated yields. c Determined by chiral HPLC
analysis. d 1d (10 mol %) was used instead of 1f. e Absolute configuration
was determined by comparison of the optical rotation with the known
compounds in the literature.5a,7 f Two equivalents of 2a and 5 mol % of 1f
were used in a 10 mmol scale of 3b.
References
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Table 2). Further decreasing the temperature to -78 °C also gave
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(8) After submission of this paper, Terada and Sorimachi reported a phosphoric
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A wide range of substituted indoles and imines have been tested
under the optimized reaction conditions (5 equiv of indole and 10
mol % of 1f in toluene at -60 °C), and the results are summarized
in Table 3.
When the protecting group in 3 was changed from N-Ts to N-Bs,
high enantioselectivities could also be realized (99% ee, entry 2,
Table 3). The phosphoric acid catalyzed Friedel-Crafts reaction
of indoles with N-sulfonyl aldimines was found to be general with
indoles bearing different substituents. Several substituted indoles
2b-e, containing either electron-donating groups or electron-
withdrawing groups, have been tested in the reaction with imines
3a and 3b, respectively. In all cases, high yields and excellent
enantioselectivities could be achieved (97-99% ee, entries 3-10,
Table 3), which contrast the results of a chiral Cu complex that
shows a strong electronic effect for substituted indoles.5a We then
examined the different substituents R′ on the imines 3. For the
substrates with electron-donating group such as 3c, 3h, and 3i, the
reactions went smoothly, affording the products with high yields
and excellent enantioselectivities (entries 11, 16, and 17, Table 3).
By introducing an electron-withdrawing group into the imine, we
observed a drop in the enantioselectivity. In the case of 3d having
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