Asymmetric Friedel-Crafts alkylations of indoles with nitroalkenes catalyzed by Zn(II)-bisoxazoline complexes

Article abstract of DOI:10.1021/jo0516537

A novel asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by Zn(II)-bisoxazoline complexes has been developed. The nitroalkylated indoles are synthesized in excellent yields and high enantioselectivities (up to 90% ee). The effec

Full text of DOI:10.1021/jo0516537

Asymmetric Friedel-Crafts Alkylations of Indoles with Nitroalkenes
Catalyzed by Zn(II)-Bisoxazoline Complexes
Yi-Xia Jia, Shuo-Fei Zhu, Yun Yang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Element Organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
qlzhou@nankai.edu.cn
ReceiVed August 6, 2005
A novel asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by Zn(II)-
bisoxazoline complexes has been developed. The nitroalkylated indoles are synthesized in excellent yields
and high enantioselectivities (up to 90% ee). The effects of ligand structure, metal salt, and solvent on
the reaction are discussed. The substrates of the reaction can be aromatic, heteroaromatic, and even
aliphatic nitroalkenes. The high reactivity and selectivity of the reaction are presumptively attributed to
the activation and asymmetric induction of chiral Lewis acids coordinated by nitroalkene substrates through
a 1,3-metal bonding model.
Introduction
acyl phosphonates,6 R-hydroxy enones,7 2-acyl imidazoles,8 and
other acylheterocycle compounds.9 These substrates are sup-
posed to form 1,4- or 1,5-chelating complexes with metal Lewis
acids in the reaction with arene compounds (Figure 1, A and
B). To explore new types of substrates and increase the pool of
available templates for catalytic asymmetric Friedel-Crafts
reactions, we herein report our efforts in the enantioselective
chiral Lewis acid catalyzed F-C reaction with nitroalkenes,
which are assumed to form a 1,3-metal bonding species with
metal of chiral Lewis acid (Figure 1, C).10
The Friedel-Crafts (F-C) alkylation reaction of arenes with
electron-deficient alkenes is one of the most important organic
transformations to employ Lewis acid catalysts, and it is a
particularly versatile carbon-carbon bond-forming reaction.1
While an asymmetric version of this reaction can provide access
to the important enantiomerically enriched alkylated arene
products, to date the successful examples of such processes are
limited because of the significant restrictions in the substrates.2
It is a well-known strategy to use a bidentate chelating substrate
to ensure high enantioselectivity in the Lewis acid catalyzed
F-C reaction.3 The suitable substrates, which gave good to
excellent enantioselectivities in the F-C alkylation reaction,
include â,γ-unsaturated R-ketoesters,4 alkylidene malonates,5
Nitroalkenes are very attractive Michael acceptors because
the nitro group is the strongest electron-withdrawing group
known11 and have been widely used in organic synthesis.12
(6) Evans, D. A.; Scheidt, K. A.; Frandrick, K. R.; Lam, H. W.; Wu, J.
J. Am. Chem. Soc. 2003, 125, 10780.
(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) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550. (b) Jørgensen, K. A. Synthesis 2003,
1117.
(7) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A.
J. Am. Chem. Soc. 2005, 127, 4154.
(8) Evans, D. A.; Fandrick, K. R.; Song, H. J. J. Am. Chem. Soc. 2005,
127, 8942.
(9) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. HelV.
Chim. Acta 2003, 86, 3753.
(3) For asymmetric F-C reaction using nonchelating substrates, see:
Bandini, M.; Fagioli, P.; Garavelli, M.; Melloni, A.; Trigari, V.; Umani-
Ronchi, A. J. Org. Chem. 2004, 69, 7511.
(4) Jensen, K. B.; Thorhauge, J.; Mazell, R.-G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160.
(5) (a) Zhuang, W.; Hausen, T.; Jørgensen, K. A. Chem. Commun. 2001,
347. (b) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (c) Zhou,
J.; Tang, Y. Chem. Commun. 2004, 432. (d) Zhou, J.; Ye, M.-C.; Huang,
Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309.
(10) For other example of four-membered chelating intermediates of
nitroalkenes with Lewis acid, see: Wada, E.; Yoshinaga, M. Tetrahedron
Lett. 2003, 44, 7953.
(11) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia
1979, 33, 1. (c) Calderari, G.; Seebach, D. HelV. Chim. Acta 1995, 68,
1592.
(12) See review: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877.
10.1021/jo0516537 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
J. Org. Chem. 2006, 71, 75-80
75

Jia et al.
presence of Cu(OTf)2, Ni(OTf)2, or Zn(OTf)2 indole reacted with
trans-â-nitrostyrene smoothly, giving the product 3-(2-nitro-1-
phenylethyl)-1H-indole (3aa) in good yields with high enanti-
oselectivities. In particular, the complex Zn(OTf)2/(S)-Ph-
bisoxazoline was found to be the best choice of catalyst which
gave fast reaction (within 11 h) and excellent yield (97%) (entry
9).
FIGURE 1. Binding models of substrate to catalyst in asymmetric
F-C reaction.
Ligand Effect. With Zn(OTf)2 as Lewis acid different chiral
bisoxazoline ligands were subsequently investigated in the
reaction. We focused our efforts on the oxazoline-containing
ligands displayed in Figure 2 because the typical phosphorus
ligands were normally inefficient in this reaction.19 The bisox-
azoline ligands L1, L2, L3, and L4, which contain different
substituted groups on the oxazoline ring, were first compared,
and (S)-Ph-bisoxazoline (L1) was found to be the best ligand
to provide the highest yield and enantioselectivity (Table 2,
entries 1-4). Apparently, the phenyl groups on the oxazoline
ring are critical for obtaining high enantioselectivity. We
accordingly prepared another two bisoxazoline ligands L5 and
L6 containing phenyl groups. However, both of them gave lower
enantioselectivity (27 and 50% ee, respectively) compared to
ligand L1. Ligand L7, which forms a seven-membered chelating
ring with zinc ion, also showed lower enantioselectivity (43%
ee). Using C1-symmetric quinoline-oxazoline ligand L820 led
a low reaction rate and low enantioselectivity (entry 8). Finally,
the tridentate pyridine-oxazoline ligand L9 was tested and
found to be completely inactive.
Solvent Effect. Solvent screening showed that toluene is a
good solvent to provide F-C alkylation product in excellent
yield with high enantiomeric excess. For example, in toluene,
the Zn(OTf)2/(S)-Ph-bisoxazoline catalyzed reaction of indole
(1a) with trans-â-nitrostyrene (2a) at room temperature pro-
duced 3-(2-nitro-1-phenylethyl)-1H-indole (3aa) in 93% yield
with 74% ee (Table 3, entry 1). The enantioselectivity was
improved to 84% ee when the reaction was performed at 0 °C
(entry 3). However, when the reaction temperature was further
lowered to -20 °C, the reaction became very slow and the
enantioselectivity was decreased to 62% ee (entry 5). The
additives often change the reactivity and enantioselectivity in
chiral Lewis acid catalyzed reactions.3,5d In this reaction, addition
of 10 mol % of NEt3 dramatically depressed the reaction rate
(13% yield was obtained after 60 h). In contrast, addition of 2
equiv of HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol) accelerated
the reaction, however, the enantioselectivity was decreased to
71% ee (entry 7). Besides toluene, ether is another solvent in
which the reaction proceeded smoothly, and the F-C alkylation
product was obtained in a comparable yield and ee (84% yield,
70% ee).
Recently, many examples regarding the application of nitroalk-
enes as Michael acceptors in asymmetric catalytic reactions were
reported, such as copper-catalyzed dialkylzinc addition to
nitroalkenes,13 rhodium-catalyzed addition of boronic acids to
nitroalkenes,14 the metal- and organo-catalyzed addition of 1,3-
dicarbonyl compounds to nitroalkenes,15 and conjugated reduc-
tion of nitroalkenes.16 Although the nonasymmetric Friedel-
Crafts alkylation reaction of arenes with nitroalkenes was
realized by using Lewis acid catalysts,17 the asymmetric version
of this reaction using a chiral Lewis acid catalyst has not been
documented.18 Assuming that nitroakenes form a 1,3-metal
binding template with catalysts, we expect that the F-C reaction
of nitroalkene catalyzed by a chiral metal Lewis acid can be
performed in high enantioselectivity.
Results and Discussion
Selection of Lewis Acids. Indole (1a), as an electron-rich
heteroaromatic substrate, was chosen to react with trans-â-
nitrostyrene (2a) for optimizing reaction conditions. A variety
of chiral Lewis acid catalysts generated in situ from metal salts
and the ligand 2,2-bis[2-[(S)-4-phenyl-4,5-dihydrooxazolyl]]-
propane ((S)-Ph-bisoxazoline) (L1) were evaluated as shown
in the illustrated reaction (Scheme 1), and the results are
summarized in Table 1. In the absence of catalyst (Table 1,
entry 1) or adding 10 mol % of Fe(ClO4)2‚xH2O and 12 mol %
of ligand L1 (entry 2), the reaction did not occur at 15 °C. When
CuOTf, Mg(OTf)2, AgOTf, or Pd(OAc)2 was employed as a
Lewis acid, the reaction took place slowly, and the enantiomeric
excess of the product was zero or negligible, while in the
(13) (a) Scha¨fer, H.; Seebach, D. Tetrahedron 1995, 51, 2305. (b)
Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579. (c) Duursma, A.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700. (d)
Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794. (e) Choi, H.; Hua, Z.;
Ojima, I. Org. Lett. 2004, 6, 2689. (f) Mampreian, D. M.; Hoveyda, A. H.
Org. Lett. 2004, 6, 2829.
(14) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000,
122, 10716.
(15) (a) Ji, J.-G.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger,
S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215. (b) Okino, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (c)
Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem.
Soc. 2004, 126, 11148. (d) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am.
Chem. Soc. 2004, 126, 9906.
The counterion of catalyst sometimes plays a significant role
in both activity and enantioselectivity of catalyst in asymmetric
catalysis.21 In the zinc-catalyzed F-C alkylation of indole with
nitroalkene, we found that in addition to Zn(OTf)2 other zinc
salts such as Zn(ClO4)2, Zn(BF4)2, Zn(SbF6)2, and Zn(PF6)2 can
also be used as Lewis acids to produce alkylated indole products
(16) (a) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42,
4793.
(17) (a) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Chem. Commun.
2005, 6, 789. (b) Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli,
L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941.
(c) Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003, 44,
5115. (d) Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A.
Synthesis 2002, 1110. (e) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.;
Sabitha, G. Synthesis 2001, 2165. (f) Komoto, I.; Kobayashi, S. J. Org.
Chem. 2004, 69, 680. (g) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
(18) During the revision of this manuscript Jørgensen and Ricci reported
respectively enantioselective Friedel-Crafts-type addition of indoles to
nitroalkenes using chiral oranocatalyst and achieved up to 64% and 89%
ee. See: (a) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Bio. Chem.
2005, 3, 2566. (b) Herrera, R. P.; Sgarzani, V.; Berbardi, L.; Ricci, A.
Angew. Chem., Int. Ed. 2005, 44, 6576.
(19) The monophosphoramidite ligand SIPHOS (see: Hu, A.-G.; Fu, Y.;
Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2002, 41, 2348), diphosphine ligand BINAP, and P-N ligand PHOX were
also investigated in the combination with Cu(OTf)2, and the F-C alkylation
product was obtained in very low enantioselectivity (<5% ee).
(20) Wu, X.-Y.; Li, X.-H.; and Zhou, Q.-L. Tetrahedron: Asymmetry
1998, 9, 4143.
(21) (a) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller,
S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798. (b) Johnson, J. S.; Evans,
D. A. Acc. Chem. Res. 2000, 33, 325.
76 J. Org. Chem., Vol. 71, No. 1, 2006

Asymmetric Friedel-Crafts Alkylations of Indoles
SCHEME 1. Asymmetric Catalytic Friedel-Crafts Alkylation of Indole with trans-â-Nitrostyrene
TABLE 1. Asymmetric Friedel-Crafts Alkylation of Indole with
trans-â-Nitrostyrene Catalyzed by Chiral MXn/(S)-Ph-bisoxazolinea
TABLE 3. Solvent Effect in the Friedel-Crafts Reaction of Indole
with trans-â-Nitrostyrenea
entry
MXn
time (h)
yieldb (%)
eec (%)
time
(h)
yield
(%)
ee
(%)
entry
solvent
T (°C)
1d
2d
3e
4e
5e
6e
7
60
60
60
60
60
60
60
20
11
Fe(ClO4)2‚xH2O
CuOTf
Mg(OTf)2
AgOTf
Pd(OAc)2
Cu(OTf)2
Ni(OTf)2
Zn(OTf)2
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
25
15
0
-10
-20
0
5
11
15
36
36
60
3
11
11
11
93
97
97
88
31
13
95
84
84
88
74
79
84
83
62
64
71
70
14
4
49
34
13
43
67
75
97
10
0
9
0
80
81
79
toluene + Et3N (10 mol %)
toluene + HFIP (2 equiv)
8
9
0
ether
CH2Cl2
THF
15
15
15
a The reaction was performed at 15 °C using 0.1 equiv of Lewis acid,
0.12 equiv of (S)-Ph-bisoxazoline, 1 equiv of indole, and 2 equiv of trans-
â-nitrostyrene in toluene under N2 atmosphere. b Isolated yield. c Determined
by chiral HPLC. The absolute configuration is S, ref 18a. d No reaction.
e The starting material was not completely converted.
10
a The reaction was performed under N2 atmosphere, Zn(OTf)2/L1/1a/
2a ) 0.1/0.12/1/2 (mmol) unless otherwise mentioned. For other reaction
conditions and analyses, see Table 1.
TABLE 4. Asymmetric Friedel-Crafts Alkylation Reaction of
Indole Derivatives with Nitroalkenes Using Zn(OTf)2/
(S)-Ph-bisoxazoline Catalysta
entry
R
R′
Ph (2a)
4-Me-Ph (2b)
4-MeO-Ph (2c) 3ac
3-MeO-Ph (2d) 3ad
2-MeO-Ph (2e) 3ae
4-F-Ph (2f)
4-Cl-Ph (2g)
2-Cl-Ph (2h)
4-Br-Ph (2i)
3-Br-Ph (2j)
4-NO2-Ph (2k)
2,4-Cl2-Ph (2l)
1-Np (2m)
2-thienyl (2n)
2-furyl (2o)
n-propyl (2p)
Ph (2a)
product yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
1-Me (1b)
2-Me (1c)
3aa
3ab
97
98
91
79
87
96
98
97
98
98
98
90
98
95
98
57
62
87
94
98
84 (S)
81
81
83
61
3af
83
FIGURE 2. Ligands used in the Friedel-Crafts alkylation reaction.
3ag
3ah
3ai
82
72
90
TABLE 2. Effect of Ligand in the Zn(OTf)2-Catalyzed
Friedel-Crafts Alkylation Reaction of Indole with
trans-â-Nitrostyrenea
3aj
86
3ak
3al
80
70
entry
ligand
time (h)
yield (%)
ee (%)
3am
3an
3ao
3ap
3ba
3ca
3da
3ea
78
82
78
70
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
11
13
13
13
15
13
13
20
20
97
75
53
92
97
84
92
90
79
15
15
2
3b
4
16
31 (S)d
21
5
6
7
-27
-50
-43
9
Ph (2a)
5-MeO (1d) Ph (2a)
5-Br (1e) Ph (2a)
79
80
8
9c
a Reaction was performed at 0 °C for 20 h using 1 equiv of indoles and
2 equiv of nitroalkenes in toluene under N2. b Isolated yield. c Determined
by HPLC. d Determined to be S by comparison of optical rotation with that
in ref 18b.
a For other reaction conditions, see Table 1. b The starting material was
not completely converted. c No reaction.
in high yields. However, the enantioselectivities of the reaction
were sharply reduced to 29-68% ee by using these zinc salts.
Scope of Substrate. Under the optimal reaction conditions,
a variety of nitroalkenes and indoles were investigated, and the
results are summarized in Table 4. Most nitroolefins reacted
well with indole and its derivatives to produce alkylated indoles
in excellent yields and high enantioselectivities. The reactions
of nitrostyrenes containing electron-donating groups in the
phenyl group had a slightly lower reaction rate than the reaction
of nitrostyrenes containing an electron-withdrawing group
(entries 2-5 vs entries 6-12). The ortho-substitution on the
phenyl in nitrostyrene, either with electron-donating groups or
electron-withdrawing groups, exclusively lowered the reaction
rate and the enantiomeric excesses of F-C alkylation products,
implying the existence of steric hindrance of ortho-substituents
to the reactivity and the enantioselectivity of reaction (entries
5, 8, and 12). In addition to nitrostyrene derivatives, the 1-((E)-
2-nitrovinyl)naphthalene (2m) and heteroaromatic nitroalkenes
2n and 2o can also serve as substrates in this reaction, giving
J. Org. Chem, Vol. 71, No. 1, 2006 77

Jia et al.
SCHEME 2. Proposed Catalytic Cycle for the Alkylation of
Indole with Nitroalkene
and (S)-Ph-bisoxazoline (20 mg, 0.06 mmol) under N2 atmosphere,
followed by addition of the toluene (5 mL). The solution was stirred
at room temperature for 2 h under N2 atmosphere, and the trans-
â-nitrostyrene (2a) (149 mg, 1.0 mmol) was added. The mixture
was cooled to 0 °C and stirred for 10 min before the indole (1a)
(57 mg, 0.5 mmol) was added. After the reaction was complete
(monitored by TLC), the solvent was removed under vacuum and
the residue was chromatographed on silica gel column with ethyl
acetate/petroleum ether (1:3, v/v) to afford the product (S)-3-(2-
nitro-1-phenylethyl)-1H-indole (3aa) (130 mg, 97% yield) as an
oil: [R]20 ) +25.3 (c 0.9, CH2Cl2), 84% ee [Daicel Chiralcel
D
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
tR ) 21.31 min (major) and 27.72 min]; 1H NMR (300 MHz,
CDCl3) δ 4.93 (dd, J ) 8.1, 12.9 Hz, 1H), 5.06 (dd, J ) 8.1, 12.9
Hz, 1H), 5.19 (t, J ) 8.1 Hz, 1H), 7.01 (d, J ) 2.1 Hz, 1H), 7.07
(t, J ) 7.5 Hz, 1H), 7.17-7.36 (m, 7H), 7.44 (d, J ) 8.1 Hz, 1H),
8.09 (s, 1H).
3-[1-(4-Methylphenyl)-2-nitroethyl]-1H-indole (3ab): oil; 98%
yield; [R]20 ) +16.4 (c 0.9, CH2Cl2), 81% ee [Daicel Chiralcel
D
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
tR ) 20.07 min (major) and 23.14 min]; 1H NMR (300 MHz,
CDCl3) δ 2.25 (s, 3H), 4.81 (dd, J ) 8.1, 11.7 Hz, 1H), 4.93 (dd,
J ) 8.1, 11.7 Hz, 1H), 5.08 (t, J ) 8.1 Hz, 1H), 6.82 (d, J ) 2.1
Hz, 1H), 7.0-7.22 (m, 7H), 7.40 (d, J ) 7.8 Hz, 1H), 7.93 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 21.1, 41.3, 79.7, 111.6, 114.5,
118.9, 119.9, 121.7, 122.6, 126.2, 127.7, 129.7, 136.3, 136.6, 137.3;
ESI MS m/z 279 (M- - 1). Anal. Calcd for C17H16N2O2: C, 72.84;
H, 5.75; N, 9.99. Found: C, 72.74; H, 5.63; N, 10.04.
the corresponding alkylated indoles in excellent yields and high
enantioselectivities (entries 13-15). It was delightful to find
that this reaction could be extended to aliphatic nitroalkene,
although a longer reaction time was needed. When 1-nitropen-
tene (2p) reacted with indole at 0 °C for 72 h, the F-C
alkylation product 3-(1-nitromethyl-butyl)-1H-indole (3ap) was
isolated in 57% yield with 70% ee.
The substituent effect on the indole ring was also studied.
When a 1-Me or 2-Me was introduced into indole ring the
enantioselectivity was dramatically lowered from 84% ee to 31%
ee or 21% ee (entries 17 and 18). On the other hand, neither
electron-donating group OCH3 nor electron-withdrawing group
Br at the 5-position of indole affected the enantionselectivity
of reaction, but the reaction rate was indeed influenced
unfavorablely in the case of 5-Br-indole (entries 19 and 20).
Moreover, other substrates, such as methyl 1H-indole-2-car-
boxylate, 1,3-dimethoxybenzene, 2-methylfuran, and benzofu-
ran, did not react with trans-â-nitrostyrene under the same
reaction conditions.
Proposed Reaction Mechanism. A mechanism of the Zn-
(II)(L1)-catalyzed Friedel-Crafts reaction between indoles and
nitroalkenes is proposed in Scheme 2. The nitroalkene was
activated by chelating to Zn(II) to form a four-membered
intermediate, which underwent a nucleophilic addition of indole
to provide the Friedel-Crafts alkylation adduct. Subsequently,
the H-transfer, followed by deassociation, affords the product
and regenerates the Zn(II)-bisoxazoline catalyst.
3-[1-(4-Methoxyphenyl)-2-nitroethyl]-1H-indole (3ac): white
powder; mp 149-150 °C; 91% yield; [R]20D ) +26.4 (c 1.1, CH2-
Cl2), 81% ee [Daicel Chiralcel OD-H column, n-hexane/i-PrOH )
70:30, 1.0 mL/min, 254 nm; tR ) 24.91 min (major) and 30.08
1
min]; H NMR (300 MHz, CDCl3) δ 3.73 (s, 3H), 4.85 (dd, J )
8.4, 12.3 Hz, 1H), 4.99 (dd, J ) 8.4, 12.3 Hz, 1H), 5.10 (t, J ) 8.4
Hz, 1H), 6.82 (d, J ) 8.1 Hz, 2H), 6.92 (d, J ) 2.1 Hz, 1H), 7.05
(t, J ) 7.8 Hz, 1H), 7.14-7.22 (m, 3H), 7.29 (d, J ) 8.4 Hz, 1H),
7.41 (d, J ) 7.5 Hz, 1H), 8.01 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 40.9, 55.3, 79.8, 111.4, 114.3, 114.7, 119.0, 119.9, 121.5, 122.7,
126.1, 128.8, 131.3, 136.6, 158.9; ESI MS m/z 297 (M+ + 1). Anal.
Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 69.13;
H, 5.68; N, 9.73.
3-[1-(3-Methoxyphenyl)-2-nitroethyl]-1H-indole (3ad): oil;
79% yield; [R]20 ) +18.3 (c 0.9, CH2Cl2), 83% ee [Daicel
D
Chiralcel OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min,
1
254 nm; tR ) 24.31 min (major) and 38.92 min]; H NMR (300
MHz, CDCl3) δ 3.66 (s, 3H), 4.82 (dd, J ) 8.1, 12.3 Hz, 1H), 4.93
(dd, J ) 8.1, 12.3 Hz, 1H), 5.09 (t, J ) 8.1 Hz, 1H), 6.74 (d, J )
8.1 Hz, 1H), 6.81-6.88 (m, 3H), 7.02 (t, J ) 7.5 Hz, 1H), 7.1-
7.25 (m, 3H), 7.42 (d, J ) 8.1 Hz, 1H), 8.0 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 41.6, 55.2, 79.5, 111.5, 112.5, 114.1, 114.1, 118.9,
119.9, 120.1, 121.7, 122.6, 126.1, 130.0, 136.5, 141.0, 160.0; ESI
MS m/z 295 (M- - 1). Anal. Calcd for C17H16N2O3: C, 68.91; H,
5.44; N, 9.45. Found: C, 68.70; H, 5.62; N, 9.70.
Conclusion
3-[1-(2-Methoxyphenyl)-2-nitroethyl]-1H-indole (3ae): oil;
87% yield; [R]20 ) +49.6 (c 0.75, CH2Cl2), 61% ee [Daicel
D
The catalytic asymmetric Friedel-Crafts alkylation reaction
of indole and its derivatives with nitroalkenes catalyzed by Zn-
(II)-bisoxazoline complexes was developed. The nitroalkylated
indoles were produced in excellent yields and high enantiose-
lectivities. The new template using nitroalkene for the asym-
metric Friedel-Crafts alkylation should have a wide application
in other Lewis acid catalyzed asymmetric transformations, and
studies are in progress in this laboratory.
Chiralcel OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min,
254 nm; tR ) 14.15 and 16.30 min (major)]; 1H NMR (300 MHz,
CDCl3) δ 3.83 (s, 3H), 4.87-5.02 (m, 2H), 5.57 (t, J ) 7.5 Hz,
1H), 6.78 (t, J ) 7.5 Hz, 1H), 6.86 (d, J ) 8.4 Hz, 1H), 6.95 (d,
J ) 2.1 Hz, 1H), 7.03 (t, J ) 7.5 Hz, 2H), 7.1-7.23 (m, 3H), 7.44
(d, J ) 8.4 Hz, 1H), 7.95 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
35.5, 55.6, 78.2, 110.9, 111.4, 113.8, 119.0, 119.7, 120.8, 122.1,
122.4, 126.5, 127.3, 128.7, 128.9, 136.4, 156.9; ESI MS m/z 295
(M- - 1). Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.68; H, 5.31; N, 9.70.
Experimental Section
3-[1-(4-Fluorophenyl)-2-nitroethyl]-1H-indole (3af): oil; 96%
yield; [R]20D ) +39.9 (c 0.85, CH2Cl2), 83% ee [Daicel Chiralcel
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
General Procedure for the Catalytic Asymmetric Friedel-
Crafts Reaction. (S)-3-(2-Nitro-1-phenylethyl)-1H-indole (3aa).17e
To a dried Schlenk tube were added Zn(OTf)2 (18.5 mg, 0.05 mmol)
1
tR ) 25.14 min (major) and 34.06 min]; H NMR (300 MHz,
78 J. Org. Chem., Vol. 71, No. 1, 2006

Asymmetric Friedel-Crafts Alkylations of Indoles
CDCl3) δ 4.93 (dd, J ) 8.4, 11.7 Hz, 1H), 5.08 (dd, J ) 8.4, 11.7
Hz, 1H), 5.25 (t, J ) 8.4 Hz, 1H), 6.96 (d, J ) 1.5 Hz, 1H), 7.06
(t, J ) 8.4 Hz, 2H), 7.21 (t, J ) 6.9 Hz, 1H), 7.27-7.39 (m, 4H),
7.52 (d, J ) 7.5 Hz, 1H), 8.15 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 40.9, 79.6, 111.7, 114.0, 115.7, 116.0, 118.9, 120.0, 121.7, 122.8,
126.0, 129.5, 135.1, 136.6; ESI MS m/z 283 (M- - 1). Anal. Calcd
for C16H13FN2O2: C, 67.60; H, 4.61; N, 9.85. Found: C, 67.47;
H, 4.82; N, 9.68.
CDCl3) δ 4.82-4.96 (m, 2H), 5.64 (t, J ) 8.4 Hz, 1H), 6.97 (d, J
) 2.1 Hz, 1H), 7.02-7.07 (m, 3H), 7.16 (t, J ) 8.1 Hz, 1H), 7.27
(d, J ) 7.8 Hz, 1H), 7.36 (d, J ) 7.2 Hz, 1H), 7.41 (s, 1H), 8.18
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 37.6, 77.5, 111.6, 112.7,
118.7, 120.1, 122.0, 122.9, 126.0, 127.6, 129.9, 129.9, 134.0, 134.5,
135.2, 136.5; ESI MS m/z 333 (M- - 1). Anal. Calcd for C16H12-
Cl2N2O2: C, 57.33; H, 3.61; N, 8.36. Found: C, 57.19; H, 3.87;
N, 8.09.
3-[1-(4-Chlorophenyl)-2-nitroethyl]-1H-indole (3ag): oil; 98%
3-(1-Naphthalen-1-yl-2-nitroethyl)-1H-indole (3am): oil; 98%
yield; [R]20D ) +22.3 (c 1.15, CH2Cl2); 78% ee [Daicel Chiralcel
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
yield; [R]20 ) +7.5 (c 1.2, CH2Cl2), 82% ee [Daicel Chiralcel
D
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
tR ) 26.95 min (major) and 35.88 min]; 1H NMR (300 MHz,
CDCl3) δ 4.91 (dd, J ) 8.7, 13.2 Hz, 1H), 5.06 (dd, J ) 8.7, 13.2
Hz, 1H), 5.2 (t, J ) 8.7 Hz, 1H), 6.97 (d, J ) 2.1 Hz, 1H), 7.15 (t,
J ) 7.8 Hz, 1H), 7.24-7.38(m, 6H), 7.47 (d, J ) 8.4 Hz, 1H),
8.11 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 41.0, 79.3, 111.6, 113.8,
118.8, 120.1, 121.6, 122.8, 125.9, 129.1, 129.2, 133.4, 136.5, 137.8;
ESI MS m/z 301 (M+ + 1). Anal. Calcd for C16H13ClN2O2: C,
63.90; H, 4.36; N, 9.31. Found: C, 63.75; H, 4.55; N, 9.52.
3-[1-(2-Chlorophenyl)-2-nitroethyl]-1H-indole (3ah): oil; 97%
yield; [R]20D ) +76.4 (c 0.95, CH2Cl2), 72% ee [Daicel Chiralcel
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
1
tR ) 26.52 and 31.17 min (major)]; H NMR (300 MHz, CDCl3)
δ 4.96-5.01 (m, 2H), 6.02 (t, J ) 7.5 Hz, 1H), 6.78 (s, 1H), 6.99
(t, J ) 7.5 Hz, 1H), 7.09-7.21 (m, 2H), 7.28 (d, J ) 5.4 Hz, 2H),
7.37-7.50 (m, 3H), 7.72 (t, J ) 4.5 Hz, 1H), 7.83 (d, J ) 6.0 Hz,
2H), 8.23 (d, J ) 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 37.0,
78.6, 111.5, 114.2, 118.8, 120.0, 122.7, 122.7, 124.7, 125.4, 126.0,
126.1, 126.9, 128.4, 129.2, 131.2, 134.2, 134.7, 136.6; ESI MS
m/z 315 (M- - 1). Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10;
N, 8.86. Found: C, 75.84; H, 5.07; N, 8.78.
3-(2-Nitro-1-thiophene-2-ylethyl)-1H-indole (3an): oil; 95%
yield; [R]20 ) +24.3 (c 1.0, CH2Cl2), 82% ee [Daicel Chiralcel
D
1
tR ) 16.95 and 29.34 min (major)]; H NMR (300 MHz, CDCl3)
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
1
δ 4.87-4.99 (m, 2H), 5.72 (t, J ) 7.8 Hz, 1H), 6.99-7.16 (m,
6H), 7.27 (d, J ) 8.4 Hz, 1H), 7.40 (t, J ) 7.5 Hz, 2H), 8.02 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 38.0, 77.7, 111.4, 113.2, 118.9,
120.0, 122.0, 122.8, 126.2, 127.3, 128.8, 129.0, 130.1, 133.8, 136.5;
ESI MS m/z 301 (M+ + 1). Anal. Calcd for C16H13ClN2O2: C,
63.90; H, 4.36; N, 9.31. Found: C, 64.03; H, 4.23; N, 9.42.
3-[1-(4-Bromophenyl)-2-nitroethyl]-1H-indole (3ai): oil; 98%
tR ) 24.47 and 27.23 min (major)]; H NMR (300 MHz, CDCl3)
δ 4.90-5.01 (m, 2H), 5.41 (t, J ) 8.7 Hz, 1H), 6.84-6.97 (m,
3H), 7.05-7.2 (m, 3H), 7.27 (d, J ) 8.4 Hz, 1H), 7.48(d, J ) 8.4
Hz, 1H), 8.03 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 37.0, 80.0,
111.6, 113.9, 118.8, 120.1, 122.1, 122.7, 124.9, 125.3, 125.7, 127.0,
136.4, 143.0; ESI MS m/z 271 (M- - 1). Anal. Calcd for
C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.49; H,
4.81; N, 10.18.
yield; [R]20 ) -1.7 (c 1.0, CH2Cl2), 90% ee [Daicel Chiralcel
D
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
tR ) 29.29 min (major) and 37.74 min]; 1H NMR (300 MHz,
CDCl3) δ 4.74 (dd, J ) 7.8, 12.3 Hz, 1H), 4.88 (dd, J ) 7.8, 12.3
Hz, 1H), 5.01 (t, J ) 7.8 Hz, 1H), 6.81 (d, J ) 2.1 Hz, 1H), 6.97
(t, J ) 7.5 Hz, 1H), 7.04-7.12 (m, 3H), 7.21 (d, J ) 8.4 Hz, 1H),
7.29 (t, J ) 8.4 Hz, 3H), 8.02 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 41.0, 79.2, 111.5, 113.7, 118.8, 120.1, 121.5, 121.6, 122.8, 125.9,
129.5, 132.0, 136.5, 138.3; ESI MS m/z 345 (M- + 1). Anal. Calcd
for C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12. Found: C, 55.95;
H, 3.98; N, 8.40.
3-(1-Furan-2-yl-2-nitroethyl)-1H-indole (3ao):17d oil; 98%
yield; [R]20 ) -78 (c 1.0, CH2Cl2); 78% ee [Daicel Chiralcel
D
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
1
tR ) 14.93 and 21.32 min (major)]; H NMR (300 MHz, CDCl3)
δ 4.75 (dd, J ) 7.5 Hz, 12.0 Hz, 1H), 4.91 (dd, J ) 7.5 Hz, 12.0
Hz, 1H), 5.11 (t, J ) 7.5 Hz, 1H), 6.01 (d, J ) 3.0 Hz, 1H), 6.17
(m, 1H), 6.87 (d, J ) 2.1 Hz, 1H), 6.98-7.11 (m, 2H), 7.17 (d, J
) 8.1 Hz, 1H), 7.24(s, 1H), 7.42 (d, J ) 8.1 Hz, 1H), 7.92 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 35.7, 77.9, 107.4, 110.5, 111.5, 111.6,
118.7, 120.1, 122.6, 123.8, 125.7, 136.3, 142.3, 152.3; ESI MS
m/z 257 (M+ + 1). Anal. Calcd for C14H12N2O3: C, 65.62; H, 4.72;
N, 10.93. Found: C, 65.44; H, 4.95; N, 11.13.
3-[1-(3-Bromophenyl)-2-nitroethyl]-1H-indole (3aj): oil; 98%
yield; [R]20 ) +14.7 (c 1.3, CH2Cl2), 86% ee [Daicel Chiralcel
D
3-(1-Nitromethylbutyl)-1H-indole (3ap): oil; 57% yield; [R]20
OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min, 254 nm;
tR ) 27.83 min (major) and 41.77 min]; 1H NMR (300 MHz,
CDCl3) δ 4.90 (dd, J ) 7.5, 12.0 Hz, 1H), 5.03 (dd, J ) 7.5, 12.0
Hz, 1H), 5.2 (t, J ) 7.5 Hz, 1H), 6.95 (s, 1H), 7.15-7.22 (m, 2H),
7.26-7.38 (m, 3H), 7.44 (d, J ) 7.5 Hz, 1H), 7.52 (t, J ) 7.5 Hz,
2H), 8.18 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 41.2, 79.2, 111.7,
113.4, 118.7, 120.1, 121.8, 122.8, 123.0, 125.9, 126.5, 130.5, 130.8,
130.9, 136.5, 141.8; ESI MS m/z 343 (M- - 1). Anal. Calcd for
C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12. Found: C, 55.49; H,
4.02; N, 8.27.
D
) -51.1 (c 0.45, EtOH), 70% ee [Daicel Chiralcel OD-H column,
n-hexane/i-PrOH ) 90:10, 1.0 mL/min, 254 nm; tR ) 31.54 and
1
34.76 min (major)]; H NMR (300 MHz, CDCl3) δ 0.81 (t, J )
7.2 Hz, 3H), 1.19-1.28 (m, 2H), 1.63-1.82 (m, 2H), 3.7-3.78
(m, 1H), 4.5-4.63 (m, 2H), 6.93 (d, J ) 2.1 Hz, 1H), 7.03-7.16
(m, 2H), 7.28 (d, J ) 8.1 Hz, 1H), 7.55 (d, J ) 7.8 Hz, 1H), 7.99
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 20.3, 34.6, 36.0, 80.5,
111.5, 114.1, 118.7, 119.7, 121.8, 122.4, 126.2, 136.5; ESI MS
m/z 233 (M+ + 1). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94;
N, 12.06. Found: C, 67.43; H, 7.10; N, 12.35.
3-[2-Nitro-1-(4-nitrophenyl)ethyl]-1H-indole (3ak): pale yel-
low powder; mp 171-172 °C; 98% yield; [R] 20D ) -13.3 (c 1.3,
CH2Cl2), 80% ee [Daicel Chiralcel OD-H column, n-hexane/i-PrOH
) 70:30, 1.0 mL/min, 254 nm; tR ) 59.25 min (major) and 80.29
(S)-1-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (3ba):17d oil;
62% yield; [R]20 ) +10.8 (c 0.6, CH2Cl2), 31% ee [Daicel
D
Chiralcel AS column, n-hexane/i-PrOH ) 98:2, 1.0 mL/min, 254
nm; tR ) 34.41 and 39.17 min (major)]; 1H NMR (300 MHz,
CDCl3) δ 3.74 (s, 3H), 4.93 (dd, J ) 8.1, 12.3 Hz, 1H), 5.05 (dd,
J ) 8.1, 12.3 Hz, 1H), 5.18 (t, J ) 8.1 Hz, 1H), 6.86 (s, 1H),
7.04-7.1 (m, 1H), 7.2-7.34 (m, 7H), 7.45 (d, J ) 7.8 Hz, 1H).
2-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (3ca):17d oil;
1
min]; H NMR (300 MHz, CDCl3) δ 4.99 (dd, J ) 9.0, 12.9 Hz,
1H), 5.11 (dd, J ) 9.0, 12.9 Hz, 1H), 5.31 (t, J ) 9 Hz, 1H), 7.0-
7.12 (m, 2H), 7.20-7.26 (m, 1H), 7.38 (t, J ) 7.8 Hz, 2H), 7.53
(d, J ) 8.7 Hz, 2H), 8.19 (d, J ) 8.7 Hz, 2H), 8.21 (s, 1H);13C
NMR (75 MHz, CDCl3) δ 41.2, 78.7, 111.6, 112.9, 118.5, 120.3,
121.6, 123.1, 124.1, 125.6, 128.7, 136.5, 146.7, 147.3; ESI MS
m/z 310 (M- - 1). Anal. Calcd for C16H13N3O4: C, 61.73; H, 4.21;
N, 13.50. Found: C, 61.49; H, 4.46; N, 13.80.
87% yield; [R]20 ) -13.9 (c 0.9, CH2Cl2), 21% ee [Daicel
D
Chiralcel AD-H column, n-hexane/i-PrOH ) 96:4, 1.0 mL/min,
1
254 nm; tR ) 74.83 min (major) and 79.58 min]; H NMR (300
MHz, CDCl3) δ 2.39 (s, 3H), 5.08-5.26 (m, 3H), 6.99-7.13 (m,
2H), 7.22-7.38 (m, 7H), 7.86 (s, 1H).
3-[1-(2,4-Dichlorophenyl)-2-nitroethyl]-1H-indole (3al): oil;
90% yield; [R]20 ) +59.5 (c 0.8, CH2Cl2), 70% ee [Daicel
D
Chiralcel OD-H column, n-hexane/i-PrOH ) 70:30, 1.0 mL/min,
5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (3da):17d oil;
254 nm; tR ) 19.83 and 34.43 min (major)]; 1H NMR (300 MHz,
94% yield; [R]20 ) -25.6 (c 1.1, CH2Cl2), 79% ee [Daicel
D
J. Org. Chem, Vol. 71, No. 1, 2006 79

Jia et al.
Chiralcel OD-H column, n-hexane/i-PrOH ) 85:15, 1.0 mL/min,
254 nm; tR ) 37.68 and 42.26 min (major)]; 1H NMR (300 MHz,
CDCl3) δ 3.77 (s, 3H), 4.93 (dd, J ) 8.1, 12 Hz, 1H), 5.05 (dd, J
) 8.1, 12 Hz, 1H), 5.14 (t, J ) 8.1 Hz, 1H), 6.84 (s, 1H), 6.86 (d,
J ) 8.4, 1H), 7.0 (d, J ) 2.4 Hz, 1H), 7.23-7.34 (m, 6H), 7.99 (s,
1H).
δ 4.88-5.16 (m, 3H), 7.08 (d, J ) 2.1 Hz, 1H), 7.21-7.34 (m,
7H), 7.55 (d, J ) 2.4 Hz, 1H), 8.16 (s, 1H).
Acknowledgment. We thank the National Natural Science
Foundation of China, the Major Basic Research Development
Program (Grant No. G2000077506), the Ministry of Education
of China, and the Committee of Science and Technology of
Tianjin City for financial support.
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (3ea):17d oil; 98%
yield; [R]20D ) -39.2 (c 1.15, CH2Cl2), 80% ee [Daicel Chiralcel
AD-H column, n-hexane/i-PrOH ) 90:10, 1.0 mL/min, 254 nm;
1
tR ) 20.97 and 22.96 min (major)]; H NMR (300 MHz, CDCl3)
JO0516537
80 J. Org. Chem., Vol. 71, No. 1, 2006