Squaramide-catalyzed enantioselective Friedel-Crafts reaction of indoles with imines

Article abstract of DOI:10.1039/b922120d

Chiral squaramides are highly enantioselective catalysts for Friedel-Crafts reaction of indoles with N-tosyl imines, affording 3-indolyl methanamine products in 85-96% yields and 84-96% ees. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b922120d

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Squaramide-catalyzed enantioselective Friedel–Crafts reaction
of indoles with iminesw
Yong Qian,a Gaoyuan Ma,a Aifeng Lv,a Hai-Liang Zhu,a Jing Zhao*ab and
Viresh H. Rawal*c
Received (in College Park, MD, USA) 22nd October 2009, Accepted 25th February 2010
First published as an Advance Article on the web 23rd March 2010
DOI: 10.1039/b922120d
Chiral squaramides are highly enantioselective catalysts for
Friedel–Crafts reaction of indoles with N-tosyl imines, affording
3-indolyl methanamine products in 85–96% yields and
84–96% ees.
reaction of indoles with imines, two families of highly efficient
organocatalysts have been shown to be effective.6 In 2006,
Deng and coworkers showed that cinchona alkaloid-based
thiourea catalysts, at 10% loading, gave the aryl imine addition
products in 83–97% enantioselectivities.6a The following year,
You and coworkers reported chiral phosphoric acids to
be superb catalysts for analogous addition reactions, with
enantioselectivities of 499% having been observed in several
instances.6b,9 Other chiral phosphoric acids have also been
reported to promote such reactions, with excellent results.7,8
A small library of squaramide-based catalysts (Fig. 1)
was prepared and their capacity to promote Friedel–Crafts
Hydrogen bond catalysis is playing an increasingly important
role in the development of enantioselective reactions.1
Compared to many metal-based catalysts, hydrogen bond
catalysts are readily prepared, stable to moisture and oxygen,
and easily isolated and reused. The pioneering work of
Jacobsen2 and Takemoto3 on thiourea based chiral hydrogen
bond donors has inspired a myriad of related thiourea
catalysts as well as the development of numerous enantio-
selective transformations, many of which had eluded
traditional, metal-based catalysis. We have been interested
in uncovering new platforms for hydrogen bond catalysis,
particularly those capable of providing dual hydrogen
bond activation. In this regard, we recently reported on the
development of chiral squaramides as a new class of hydrogen
bond donor catalysts, with distinctly different structural
parameters than thioureas.4 In initial studies we showed that
a chiral squaramide nicely catalyzes the Michael addition
reactions of various 1,3-dicarbonyl compounds to a range of
nitroalkenes at very low catalyst loadings.4 More recently, we
have found a related chiral squaramide to be broadly effective
for the highly enantioselective conjugate addtion reaction of
diphenyl phosphite to assorted nitroalkenes.5 We now report
the first highly efficient squaramide-catalyzed enantioselective
Friedel–Crafts reaction of indoles with imines.
Fig. 1 Structures of squaramide-based H-bonding catalysts.
Table 1 Survey of reaction temperature and catalyst loading
The Friedel–Crafts reaction represents the main thorough-
fare by which C–C bonds are introduced on the indole frame-
work. As such, this process has been investigated extensively,
and many hydrogen-bonding promoted Friedel–Crafts
reactions of indoles have been reported over the past few
years.6–9 Specifically, for the enantioselective Friedel–Crafts
Entrya
Catalyst (mol%)
T/1C
Yield (%)b
ee (%)c
a State Key Laboratory of Pharmaceutical Biotechnology,
School of Life Sciences, Nanjing University, Nanjing, China.
E-mail: jingzhao@nju.edu.cn; Fax: +86 25 8359 2672;
Tel: +86 25 8359 2672
1
2
3
4
5
6
7
2.5
2.5
2.5
2.5
1
0
rt
32
52
80
76
31
81
90
94
93
92
85
88
91
91
50
75
50
50
50
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China
5
10
c Department of Chemistry, University of Chicago, 5735 South Ellis
Avenue, Chicago, IL 60637, USA. E-mail: vrawal@uchicago.edu;
Tel: +1 773 702 0805
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b922120d
a
Reaction conditions: 3 equiv. of imine, 1 M indole in CH2Cl2, 48 h.
c
Isolated yield. Determined by chiral HPLC analysis (Chiralcel
b
OD-H column).
ꢀc
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reactions of indoles was evaluated. The catalysts are easily
synthesized by sequential addition–elimination reactions of
two amines with commercially available dimethyl squarate
(3,4-dimethoxy-3-cyclobutene-1,2-dione).
(Table 1, entry 2). Interestingly, at 50 1C the product was
obtained in higher yield, with only a slight decrease in
enantioselectivity (92%, entry 3). Increasing the catalyst
loading offered no particular advantage (entries 6, 7). A brief
survey of solvents showed CH2Cl2 and tetrahydrofuran (THF)
to provide comparable results (Table 2). Since the best results
were obtained in THF—95% ee and 88% yield—it was
selected for further studies of this Friedel–Crafts reaction.
Early studies with imines of aliphatic aldehydes gave
promising results, but lower enantioselectivities (vide infra).
The optimized conditions were then used to assess the
effectiveness of several related chiral squaramides (Table 3).
Three catalysts having the core structure of 1a but differing in
the substituents on the aryl ring were examined, and all were
found to provide inferior results (entries 2–4). Three catalysts
The initial studies were carried out using the reaction of
indole (2) and N-tosylimine 3 as substrates and squaramide 1a
as the catalyst. When the reaction was carried out at room
temperature using 2.5 mol% of the catalyst, the addition
product (4) was formed in 93% ee, albeit in 52% yield
Table 2 Survey of the reaction solvent
Entry
Solvent
Yield (%)
ee (%)
1
2
3
4
5
Toluene
CH2Cl2
CHCl3
THF
75
85
83
88
70
92
94
94
95
93
having
a different chiral amine component were also
EtOAc
evaluated. Interestingly, catalyst 1e, which provided excellent
enantioselectivity in our recently reported Michael addition of
diphenyl phosphite to nitroalkenes, was a poor catalyst for the
present reaction, giving a nearly racemic product.5 Likewise,
the 1-amino-2-indanol containing squaramide (1f), while it
afforded the product in excellent yield, provided no enantio-
selectivity. On the other hand, the 1,2-diphenylethylenedi-
amine derived catalyst (1g) was quite effective and gave
the addition product in 81% yield and 92% ee. This
survey showed catalyst 1a to afford the best yield and
enantioselectivity.
Table 3 Survey of the squaramide catalysts
Entrya
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
80
48
49
50
24
90
81
94
84
85
86
4
0
92
1g
The scope of chiral squaramide catalyzed enantioselective
Friedel–Crafts reactions of a diverse range of indole and imine
substrates was evaluated next. The reactions were carried out
using catalyst 1a, under the optimized conditions noted above
a
Reaction conditions: 2.5 mol% catalyst, 3 equiv. of imine, 1 M
b
c
indole in CH2Cl2 at 50 1C, 24 h. Isolated yields. Determined by
chiral HPLC analysis (Chiralcel OD-H).
Table 4 Squaramide-catalyzed enantioselective Friedel–Crafts reaction of indoles with N-tosyl imines
Entrya
Product
R1
R2
R3
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-Cl
2-Cl
4-Br
2-Br
4-F
4-H
4-Me
4-OMe
4-isopropyl
4-H
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Cl
H
H
H
H
H
H
H
H
24
18
72
48
72
72
26
48
72
72
72
36
72
94
91
92
92
90
88
86
89
87
92
96
85
88
95.5
94
96
93
92
95
91
93
94
91
93
84
90
9
H
10
11
12
13
5j
5k
5l
5-Me
5-OMe
H
4-H
4-H
4-H
5m
2-Me
H
14
5n
H
92
75
81
a
b
c
Reaction conditions: 2.5 mol% catalyst, 4 equiv. of imine, 1 M indole in THF at 50 1C. Isolated yield. Determined by chiral HPLC analysis
(Chiralcel OD-H).
ꢀc
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(Table 4). All reactions proceeded in good to excellent yields
and, generally, excellent enantioselectivities. Importantly, the
Friedel–Crafts reaction of an aliphatic aldehyde derived imine
was also examined and afforded the expected product in good
yield and enantioselectivity (75% yield, 81% ee, 92 h, 5 mol%
catalyst loading, entry 14). Current efforts are focused on the
optimization of catalyst and conditions for aliphatic imine
substrates, and the results will be reported in due course.
The results above show that the chiral squaramide family of
hydrogen bond donors are highly effective catalysts for the
enantioselective Friedel–Crafts reaction of indoles with
imines. The ease of preparation combined with their modular
nature allows for convenient tuning of the chiral environment
and the pKa of the donor hydrogens of squaramides.
This work is supported by the National Basic Research
Program of China (2010CB923303), the National Science
Foundation of China (NSFC) (Grants no. 20902045). VHR
thanks the National Institutes of Health (R01GM069990) for
partial support.
3 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003,
125, 12672–12673.
4 The distance between the two donor hydrogens in squaramides is
estimated to be 33% larger than in thioureas. See: J. P. Malerich,
K. Hagihara and V. H. Rawal, J. Am. Chem. Soc., 2008, 130,
14416–14417.
5 Y. Zhu, J. P. Malerich and V. H. Rawal, Angew. Chem., Int. Ed.,
2010, 49, 153–156.
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E. B. Rowland, Y. Liang, J. A. Perman and J. C. Antilla,
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9 Q. Kang, X.-J. Zheng and S.-L. You, Chem.–Eur. J., 2008, 14,
3539–3542.
ꢀc
This journal is The Royal Society of Chemistry 2010
3006 | Chem. Commun., 2010, 46, 3004–3006