Asymmetric Friedel-Crafts addition of indoles to N-sulfonyl aldimines: A simple approach to optically active 3-indolyl-methanamine derivatives

Article abstract of DOI:10.1021/ol0602001

The enantioselective copper(II)-catalyzed Friedel-Crafts addition of indoles to N-sulfonyl aldimines was developed using chiral bisoxazoline as ligands, and high enantioselectivities (up to 96% ee) were achieved.

Full text of DOI:10.1021/ol0602001

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ORGANIC
LETTERS
2006
Vol. 8, No. 8
1621-1624
Asymmetric Friedel−Crafts Addition of
Indoles to N-Sulfonyl Aldimines: A
Simple Approach to Optically Active
3-Indolyl-methanamine Derivatives
Yi-Xia Jia, Jian-Hua Xie, Hai-Feng Duan, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity
Tianjin 300071, China
qlzhou@nankai.edu.cn
Received January 24, 2006 (Revised Manuscript Received March 4, 2006)
ABSTRACT
The enantioselective copper(II)-catalyzed Friedel−Crafts addition of indoles to N-sulfonyl aldimines was developed using chiral bisoxazoline
as ligands, and high enantioselectivities (up to 96% ee) were achieved.
The Lewis acid-catalyzed Friedel-Crafts (F-C) alkylation
reaction is a powerful carbon-carbon bond-forming process
in organic chemistry.1 The asymmetric version of this
reaction can provide a very useful approach to the enantio-
merically enriched alkylated arene products.2 However,
despite its importance, the catalytic asymmetric F-C reaction
has not been explored until 1990, when the first example of
the asymmetric addition of 1-naphthol to pyruvic esters using
a chiral zirconium complex was reported.3 Since this
pioneering work, the research of catalytic asymmetric F-C
reactions gained much attention, and the reactions of active
carbonyl compounds,4 expoxides,5 and electron-deficient
The asymmetric F-C reaction of imine substrates is a
completely atom-economical access to optically active func-
tionalized benzylic amines, which are potential starting
materials for many biologically active compounds. However,
the study of the chiral Lewis acid-catalyzed F-C reaction
of imines is only limited to the highly active N-protected
R-imino esters. Johannsen7 and Jørgensen8 reported, respec-
(4) (a) Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000,
65, 1597. (b) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517. (c) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009. (d) Lyle, M. P. A.; Draper,
N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901.
(5) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 84.
6
olefins as substrates have been extensively studied.
(6) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Zhou, J.; Tang, Y. J. Am. Chem.
Soc. 2002, 124, 9030. (c) Evans, D. A.; Scheidt, K. A.; Frandrick, K. R.;
Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780. (d) Palomo, C.;
Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc.
2005, 127, 4154. (e) Evans, D. A.; Fandrick, K. R.; Song, H. J. J. Am.
Chem. Soc. 2005, 127, 8942. (f) Jia, Y.-X.; Yang, Y.; Zhu, S.-F.; Zhou,
Q.-L. J. Org. Chem. 2006, 71, 75.
(1) Olah, G. A.; Khrisnamurti, R.; Prakash, G. K. S. In Comprehensive
Organic Synthesis, 1st ed.; Pergamon: New York, 1991; Vol. 3, pp 293-
339.
(2) For reviews, see: (a) Wang, Y.; Ding, K.-L.; Dai, L.-X. Chemtracts
2001, 14, 610. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 550.
(3) Erker, G.; Van der Zeijden, A. A. H. Angew. Chem., Int. Ed. Engl.
1990, 29, 512.
(7) Johannsen, M. Chem. Commun. 1999, 2233.
10.1021/ol0602001 CCC: $33.50
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Published on Web 03/16/2006

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tively, the F-C reactions of N-tosyl R-imino esters and
N-alkoxycarbonyl R-imino esters using chiral Tol-Binap/
Cu(I) catalysts in high enantioselectivities. In this reaction,
the substrate coordinated to copper by a 1,4-binding model
of the N atom of R-imine and the carbonyl O atom of ester.8b
In contrast, there was no report in the literature, to our best
knowledge, on the chiral Lewis acid-catalyzed asymmetric
F-C reaction of aryl aldimines,9 although the non-enantio-
selective version of this reaction has been well-explored by
several groups.10
In recent years, much interest has been attracted to the
synthesis of 3-substituted indoles due to their numerous
biologically significant activities.11 The 3-indolylarylmetha-
namine derivatives were the important intermediates of the
natural and natural-like products, such as hydro-γ-carboline
and pyrido[4,3-b]indole derivatives.12 The asymmetric F-C
addition of indole to aryl aldimines will provide a straight-
forward access to the optically active 3-indolylarylmethan-
amines. In this letter, we would like to present our primary
results in the reaction of indole with aryl aldimines catalyzed
by Cu(OTf)2/bisoxazoline complexes, providing chiral 3-in-
dolylarylmethanamines in excellent enantioselectivities.
The reaction of N-(4-nitrobenzylidene)-4-methylbenzene-
sulfonamide (1a) with indole catalyzed by Cu(OTf)2/(S)-Bn-
bisoxazoline (L1) complex was performed to optimize the
reaction conditions (Scheme 1). The catalyst was prepared
95% ee (Table 1, entry 1). The reaction also can be carried
Table 1. Asymmetric Friedel-Crafts Reaction of 1a with
Indolea
yield of 2ab
eec
entry L*
M
indole/imine
(%)
(%)
1
2
3
4
5
6
7
8
9
L1 Cu(OTf)2
L1 Zn(OTf)2
L1 Mg(OTf)2
L1 Fe(ClO4)2
L1 Ni(OTf)2
L1 (CuOTf)2C6H6
L1 Cu(OTf)2
L2 Cu(OTf)2
L3 Cu(OTf)2
L4 Cu(OTf)2
L5 Cu(OTf)2
L1 Cu(OTf)2
L1 Cu(OTf)2
L1 Cu(OTf)2
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
5/1
5/1
5/1
58
95
n.r.d
n.r.d
44
-3
0
78
n.r.d
72
50
33
39
25
86
94
95
32
-6
0
-17
95
95
10
11
12
13e
14e,f
92
92
a The reactions were performed with 10 mol % M, 15 mol % L*, and 5
mL CH2Cl2 under N2 at 20 °C for 3 days. b Isolated yield. c Determined by
chiral HPLC using a Chiralcel OD column (25 cm × 0.46 cm i.d.). d No
reaction. e 100 mg 4 Å molecular sieves were added. f 5 mol % catalyst, 6
days.
in CH2ClCH2Cl (58% yield and 92% ee), but not in THF
and dioxane. Screening of the metal in chiral Lewis acids
under the same reaction conditions showed that only copper-
(II) triflate had high enantioselectivity, and all other tested
catalysts gave either no reaction or racemic product (Table
1, entries 2-6). The comparison of ligands indicated that
the (S)-Bn-bisoxazoline (L1) was the best choice of ligand
in terms of enantioselectivity and yield (Table 1, entries
7-11).
Scheme 1
There are generally two main side-reactions affecting the
yield of the F-C reaction of aryl aldimines, namely, the
formation of double-alkylation product, like 3 and the
hydrolysis of aryl aldimine substrates.2b,8d It was delightful
to find that only a trace amount of achiral product 3 (<5%)
was detected in all cases of the reactions of aldimine 1a using
Cu(OTf)2/(S)-Bn-bisoxazoline catalyst. The hydrolysis of aryl
aldimines can be reduced by increasing the amount of indole.
For example, when the molar ratio of indole to aldimine 1a
was raised from 1:1 to 2:1 and 5:1, the yield of 2a was
remarkably improved from 58% to 72% and 86% (Table 1,
entries 7 and 12). The influence of additives to the reaction
was also examined. It was found that the addition of 4 Å
molecular sieve could further increase the yield of F-C
product to 94%, leaving the ee value unchanged (Table 1,
entry 13), while HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol)
lowered the enantioselectivity of the reaction to 88% ee.
Interestingly, when 1.2 equiv TMSCl was added, aldimine
1a was consumed completely within 0.5 h, and the achiral
double-alkylation product 3 was obtained quantitatively. The
catalyst loading could be reduced to 5 mol %, and the results
were comparable with that using 10 mol % catalyst, though
a longer reaction time was needed (Table 1, entry 14).
in situ by mixing Cu(OTf)2 with L1 in CH2Cl2 at room
temperature. After adding aldimine 1a and indole, the
mixture was stirred at room temperature for 3 days. The
addition product N-(indol-3-yl-4-nitrophenylmethyl)-4-me-
thylbenzenesulfonamide (2a) was isolated in 58% yield with
(8) (a) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 4114. (b) Saaby, S.; Bayon, P.; Aburel, P. S.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352.
(9) For the organocatalyzed asymmetric Friedel-Crafts reactions of
aldimines, see: (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804. (b) Terada, M.; Uraguchi, D. WO 2005070875.
(10) (a) Xie, W.-H.; Bloomfield, K. M.; Jin, Y.-F.; Dolney, N. Y.; Wang,
P. G. Synlett 1999, 498. (b) Mi, X.-L.; Luo, S.-Z.; He, J.-Q.; Cheng, J.-P.
Tetrahedron Lett. 2004, 45, 4567. (c) Luo, Y.; Li, C.-J. Chem. Commun.
2004, 1930. (d) Esquivias, J.; Arrayas, R. M.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2006, 45, 629.
(11) Sundberg, R. J. The Chemistry of Indoles; Academic: New York,
1996; pp 105-118.
(12) (a) Molina, P.; Alcantara, J.; Lopez-Leonardo, C. Tetrahedron 1996,
52, 5833. (b) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850.
1622
Org. Lett., Vol. 8, No. 8, 2006

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To extend the application of the reaction, variety of
N-tosylarylimines were subjected to the reaction with indole
under the optimal conditions. The data in Table 2 showed
1k, affording the corresponding indolyl-methanamine deriva-
tives 6 and 7 in 50% yield with 77% ee and 93% yield with
92% ee, respectively (Scheme 2).
Scheme 2
Table 2. Asymmetric Friedel-Crafts Reaction of N-Sulfonyl
Aldimines with Indolea
yieldb
(%)
ee
(%)
entry
Ar
R
In most examples of asymmetric F-C reactions reported
in the literature, the high enantioselectivity was only achieved
when the substrates can coordinate to Lewis acid catalyst to
form 1,4- or 1,5-chelating complexes.4,6 However, in the
reactions of N-tosyl and p-nitrobenzenesulfonyl aldimines,
the 1,3-binding mode of the nitrogen atom of imine and the
oxygen atom of the sulfonyl coordinated to Cu center is most
likely. As shown in Figure 1, indole added to the 4-bro-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-NO2C6H4 (1a)
3-NO2C6H4 (1b)
4-ClC6H4 (1c)
3-ClC6H4 (1d)
2-ClC6H4 (1e)
4-BrC6H4 (1f)
3-BrC6H4 (1g)
2-BrC6H4 (1h)
3,4-Cl2C6H3 (1i)
2,6-Cl2C6H3 (1j)
C6H5 (1k)
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ns
Ns
Ns
Ns
Ns
Ns
Ns
2a (94)
2b (94)
2c (75)
2d (79)
2e (72)
2f (89)
2g (87)
2h (78)
2i (63)
2j (47)
2k (86)
2l (68)
2m (84)
2n (91)
2o (63)
2p (47)
2q (85)
95
94
94
95
94
96 (S) c
94
94
95
93
94
92
94
95
89
4-FC6H4 (1l)
4-MeC6H4 (1m)
3-MeC6H4 (1n)
2-MeC6H4 (1o)
4-MeOC6H4 (1p)
1-Naph (1q)
88
81
a Reaction conditions: 10 mol % Cu(OTf)2, 15 mol % L1, 1.0 equiv
aldimines, 5.0 equiv indoles, 100 mg 4 Å molecular sieves, 3-5 days.
b Isolated yield. c Determined by single-crystal X-ray analysis.
that the reactions of N-tosyl aldimines 1 bearing an electron-
withdrawing group on the phenyl ring proceeded smoothly
to provide corresponding F-C adducts in good yields and
high ee values (93-96%) (Table 2, entries 1-10). However,
the reaction of N-tosylphenylimine gave only 35% yield of
the desired product in 88% ee. As for the substrates
containing an electron-donating group, no F-C product was
formed under the same reaction conditions, and most
aldimines were hydrolyzed to aldehydes. Apparently, the
electron-withdrawing substituent on the phenyl ring is critical
to the Friedel-Crafts reaction of N-tosylarylimines with
indole.
It was nice to find that, when the p-nitrobenzenesulfonyl
(Ns) group, instead of tosyl group, was used as protecting
group, the Friedel-Crafts addition of indole could be
extended to the aldimine substrates contained electron-
donating substituents. For instance, in the reaction of
N-benzylidene-4-nitrobenzenesulfonamide (1k), the yield and
the enantioselectivity reached to 86% and 94% ee (Table 2,
entry 11), which were much better than those of the reaction
of N-tosylphenylimine. Comparable results were obtained in
the reaction of the substrates with a methyl or methoxy group
(Table 2, entries 13-16). In addition to indole itself, 5-Br-
and 5-MeO-indoles (4 and 5) could also react with aldimine
Figure 1. Proposed coordination mode of N-sulfonyl aldimine and
X-ray crystallographic structure of (S)-2f.
mophenyl-N-tosylmethanimine (1f) from Re face to produce
N-[indol-3-yl-(4-bromophenyl)methyl]-4-methylbenzene-
sulfonamide (2f). The configuration of compound 2f was
determined to be S by X-ray crystallography, which sup-
ported the proposed coordination mode of N-sulfonyl aldi-
mine to Cu atom in Figure 1.13
To further prove this 1,3-coordination model, we carried
out the reaction of (E)-N-(4-nitrobenzylidene)-benzenamine
(8) with indole under the same conditions, and a completely
racemic product 9 was obtained in 65% yield (Scheme 3).
(13) See Supporting Information for the crystal data and structure
refinement of 2f.
Org. Lett., Vol. 8, No. 8, 2006
1623

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a copper center was the key point for enantiocontrol. This
new coordination template has a potential for wide applica-
tion of N-sulfonyl aldimines in the Lewis acid-catalyzed
asymmetric transformations, which is in progress in this
laboratory.
Scheme 3
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, the Major Basic Research
Development Program (grant G2000077506), the Ministry
of Education of China, and the Committee of Science and
Technology of Tianjin City for financial support.
The absence of enantioselectivity in the reaction of 8
conversely supported the presumption of the 1,3-coordination
model of substrates in the F-C reaction of N-sulfonyl
aldimines.
In conclusion, we have developed a copper-catalyzed
asymmetric Friedel-Crafts reaction of N-sulfonyl aldimines
with indoles to provide a simple approach to optically active
3-indolylmethanamine derivatives in high enantioselectivity.
The 1,3-binding model of N-sulfonyl aldimine substrates to
Supporting Information Available: Experimental de-
tails, spectroscopic data for new compounds, and the
determination of ee values of products (pdf). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0602001
1624
Org. Lett., Vol. 8, No. 8, 2006