Enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by bifunctional tridentate bis(oxazoline)-Zn(II) complex

Article abstract of DOI:10.1021/ol060586f

A more practical and efficient catalytic asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes using bifunctional tridentate bis-(oxazoline)-Zn(OTf)₂ as catalyst has been developed. Various types of the nitroalkylated indoles were o

Full text of DOI:10.1021/ol060586f

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2115-2118
Enantioselective Friedel−Crafts
Alkylation of Indoles with Nitroalkenes
Catalyzed by Bifunctional Tridentate
Bis(oxazoline)−Zn(II) Complex
Shao-Feng Lu, Da-Ming Du,* and Jiaxi Xu
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering, College of Chemistry and
Molecular Engineering, Peking UniVersity, Beijing 100871, P. R. China
dudm@pku.edu.cn
Received March 10, 2006
ABSTRACT
A more practical and efficient catalytic asymmetric Friedel
(oxazoline) Zn(OTf)2 as catalyst has been developed. Various types of the nitroalkylated indoles were obtained in excellent yields (85
and high enantioselectivities (up to 98% ee).
−
Crafts alkylation of indoles with nitroalkenes using bifunctional tridentate bis-
−
−99%)
The Friedel-Crafts reaction is one of the most powerful
carbon-carbon bond-forming reactions in synthetic organic
chemistry.1 Recently, using nitroalkenes as substrates to
achieve asymmetric Friedel-Crafts alkylation of indoles has
been paid considerable attention.2 It is the result of chemists’
effort to develop new types of substrates for the enantiose-
lective version of the Friedel-Crafts reaction,3 which has
suffered from significant restrictions that R,â-unsaturated
carbonyl compounds were overwhelmingly investigated.4 In
addition, nitroalkenes are very active Michael acceptors,5 and
the easy transformation of the nitro group into a range of
different functionalities6 makes this methodology more
attractive. In fact, the products of alkylations of indoles with
nitroalkenes can be applied to the synthesis of many
biologically active compounds such as physostigmine,7 which
serves as a useful clinical anticholinergic drug.8
(3) For recent examples, see: (a) Jensen, K. B.; Thorhauge, J.; Mazell,
R.-G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160. (b) Zhuang,
W.; Gathergood, N.; Hazell, R. G. J. Org. Chem. 2001, 66, 1009. (c) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. (d) Zhou,
J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (e) Evans, D. A.; Scheidt,
K. A.; Frandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125,
10780. (f) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004,
69, 1309. (g) Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004,
69, 146. (h) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden,
A. J. Am. Chem. Soc. 2005, 127, 4154. (i) Evans, D. A.; Fandrick, K. R.;
Song, H. J. J. Am. Chem. Soc. 2005, 127, 8942. (j) Yamazaki, S.; Iwata, Y.
J. Org. Chem. 2006, 71, 739.
(4) For reviews, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550. (b) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199. (c) Wang Y.; Ding
K.-L. Chin. J. Org. Chem. 2001, 21, 763.
(5) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877.
(1) (a) Olah, G. A.; Khrisnamurti, R.; Prakash, G. K. S. In ComprehensiVe
Organic Synthesis, 1st ed.; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. III, p 293. (b) Roberts, R. M.; Khalaf, A. A. Friedel-
Crafts Alkylation Chemistry. A Centry of DiscoVery; Marcel Dekker: New
York, 1984.
(2) (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576. (b) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A.
Org. Biomol. Chem. 2005, 3, 2566. (c) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.;
Zhou, Q.-L. J. Org. Chem. 2006, 71, 75. (d) Bandini, M.; Garelli, A.;
Rovinetti, M.; Tommasi, M.; Umani-Ronchi, A. Chirality 2005, 17, 1.
10.1021/ol060586f CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/13/2006

However, the enantioselective Friedel-Crafts alkylation
of indoles with nitroalkenes needs to undergo continuous
development. In these pioneer reports, relatively high catalyst
loading was used2a,c,d and long reaction time was needed.2a,b
Surpringly, N-alkylated indole gave the product in dramati-
cally decreased enantioselectivity versus the free indole,2a,c
whereas in another case the result was the opposite.2b
Normally, alkyl substituents at the â-position of the nitroalk-
ene obtained lower enantioselectivity than aryl-substituted
analogues. Herein, we present our new results of using
bifunctional tridentate bis(oxazoline)-Zn(OTf)2 complex to
catalyze enantioselective Friedel-Crafts alkylation of indoles
with nitroalkenes.
Scheme 1. Alkylation of Indole 5 with Nitroalkene 6 To Give
Optically Active 3-Alkyl Indole Derivatives 7
catalyze the reaction in a bifunctional way. On one hand,
the chelated Lewis acid could activate nitroalkenes; on the
other hand, the NH group in ligands 1 and 2 could interact
with indoles and orient them in the intermediate. Then we
performed the alkylation of indole with trans-â-nitrostyrene
in toluene at room temperature using 10 mol % 1d-Zn-
(OTf)2 or 3-Zn(OTf)2 as the catalyst, respectively. Interest-
ingly, the catalyst 1d-Zn(OTf)2 furnished overwhelmingly
better result than the latter in enantioselectivity (66% vs 6%
ee), while both gave nearly quantitive yield.
We have recently reported the preparation of a series of
chiral C2-symmetric tridentate bis(oxazoline) 1 and bis-
(thiazoline) 2,9 in which a diphenylamine unit links the two
chiral oxazoline or thiazoline rings (Figure 1). The simply
To further investigate the reaction conditions, ligand 1c
was first chosen to explore Lewis acids under 10 mol %
catalyst loading, and the results are summarized in Table 1.
Table 1. Asymmetric Friedel-Crafts Alkylation of Indole 5a
with trans-â-Nitrostyrene 6a Catalyzed by Chiral 1c-Lewis
Acid Complexa
entry
Lewis acid
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9e
Zn(OTf)2
Yb(OTf)3
In(OTf)3
Sc(OTf)3
La(OTf)3
Cu(OAc)2
InBr3
13
42
48
48
25
122
122
116
8
99
51
60
59
73
53
64
87
99
85 (R)d
4
0
2
Figure 1. C2-Symmetric bis(oxazoline) and bis(thiazoline) ligands.
synthetic approach of bis(oxazoline) 1 is directly employing
2,2′-dicarboxyl diphenylamine, unlike a palladium-catalyzed
aryl amination coupling reported by Guiry.10 Meanwhile, our
laboratory has demonstrated that a dinuclear Lewis acid
complex of tridentate bis(oxazoline) 1 and bis(thiazoline) 2
can catalyze the asymmetric Henry reaction of nitromethane
with R-keto esters.11 C2-symmetric bis(oxazoline) ligand 3,
in which the NH group was replaced by a methylene group,
has also been synthesized to elucidate the crucial role of the
NH group in ligands 1 and 2.11 For the asymmetric Friedel-
Crafts alkylation of indoles 5 with nitroalkenes 6 (Scheme
1), we assumed that ligands 1 and 2 with Lewis acid could
0
1
0
53
NiCl2
Zn(OTf)2
83 (R)d
a Reaction conditions: indole 5a (0.50 mmol) with trans-â-nitrostyrene
6a (0.50 mmol) in 2 mL of toluene under 10 mol % 1c-Lewis acid complex.
b Isolated yield by column chromatography. c Determined by HPLC on
Daicel Chiracel OD-H column (hexane/2-propanol 70:30, 0.9 mL/min).d The
absolute configurations of the products were assigned by comparison with
literature values.2c e 5 mol % catalyst loading.
Except for Zn(OTf)2 and NiCl2, other Lewis acids gave
nearly no enantioselectivity. With Zn(OTf)2 as Lewis acid,
both high yield and enantioselectivity were achieved (Table
1, entry 1). When the catalyst loading was reduced from 10
to 5 mol %, the enantioselectivity decreased slightly (Table
1, entry 9).
A series of chiral bis(oxazoline) and bis(thiazoline) ligands
were subsequently investigated in the reaction under 5 mol
% catalyst loading with Zn(OTf)2 as the Lewis acid (Table
(6) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
(7) For review examples, see: (a) Robinson, B. Alkaloids 1971, 13, 213.
(b) Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225.
(8) For a review of pharmacology, see: Greig, N. H.; Pei, X. F.; Soncrant,
T. T.; Ingram, D. K.; Brossi, A. Med. Res. ReV. 1995, 15, 3.
(9) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry
2004, 15, 3433.
(10) McManus, H. A.; Guiry, P. J. J. Org. Chem. 2002, 67, 8566.
(11) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70,
3712.
2116
Org. Lett., Vol. 8, No. 10, 2006

was the best choice (entry 1). Using alkyl halides as the
solvent gave 7a in high yield with moderate enantioselectivity
(entries 2 and 3). Etheral solvents such as THF had a negative
influence on the catalytic activity of the catalyst (entry 4).
The use of a nonpolar solvent such as hexane produced 7a
in high yield with low enantioselectivity (entry 5). Then we
were pleased to find that cooling the reaction led to a slight
improvement in the enantioselectivity (entries 6 and 7). When
the reaction was performed at -20 °C, 7a was obtained in
94% ee (entry 7). Enhancement of the catalyst loading
improved the enantioselectivity only very slightly (entries 8
and 9), while satisfactory yield and enantioselectivity was
obtained even using only 2 or 1 mol % catalyst (entries 10
and 11). Finally, we determined that using 5 mol % 4-Zn-
(OTf)2 in toluene at -20 °C to catalyze the reaction was the
most practical.
Table 2. Effect of Ligands in the Zn(OTf)2-Catalyzed Friedel-
Crafts Alkylatin of Indole 5a with trans-â-Nitrostyrene 6aa
entry
ligand
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
4
94
85
99
99
95
93
95
99
99
87
99
30
71
83
66
68
11
46
78
59
2
10
11
90
a Reaction conditions: indole 5a (0.50 mmol) with trans-â-nitrostyrene
6a (0.50 mmol) in 2 mL of toluene under 5 mol % ligand-Zn(OTf)2
complex. b Isolated yield by column chromatography. c Determined by
HPLC on Daicel Chiracel OD-H column (hexane/2-propanol )70:30, 0.9
mL/min).
The scope of the enantioselective Friedel-Crafts alkylation
of indoles with nitroalkenes under the optimized reaction
conditions was explored, and the results are summarized in
Table 4. We first tested a few indoles 5a-d bearing different
2). The bis(oxazoline) ligands 1 (entries 1-5) gave better
enantioselectivities than their analogues bis(thiazoline) 2
(entries 6-10). The ligands 1c and 2c, which have phenyl
substituents on their hetereocycles, gave the best results
(entries 3 and 8). Apparently, the phenyl groups on the
hetereocycles are critical for obtaining high enantioselectivity.
Thus we further synthesized bis(oxazoline) ligand 4,12 which
has cis-phenyl groups at both the 4- and 5-positions of
oxazoline rings, and carried out the reaction with 4-Zn-
(OTf)2 complex as the catalyst. To our delight, the enantio-
meric excess of the product was dramatically enhanced to
90% (entry 11).
To get the most optimized reaction conditions, we further
screened different solvents, temperature, and catalyst loading.
Some typical results are presented in Table 3. First, a number
of solvents were successfully applied to the catalytic enan-
tioselective Friedel-Crafts reaction (entries 1-5). Toluene
Table 4. Friedel-Crafts Alkylation of Indoles 5 with
Nitroalkene 6 Catalyzed by 4-Zn(OTf)2 Complexa
en-
nitro-
yieldb
product (%)
eec
(%)
try indole R1 R2 alkene
R3
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5a
5a
5a
5a
5a
H
H
6a
6a
6a
Ph
Ph
Ph
Ph
2-MeO-Ph
2-Cl-Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
99 94 (R)d
96 98
88 81
93 90 (R)d
99 77
99 73
99 89
85 81
91 92
91 89
88 93
92 84
85 87
MeO H
Cl
H
H
H
H
H
H
H
H
H
H
H
Me 6a
H
H
H
H
H
H
H
H
H
6b
6c
6d
6e
6f
2-naphthyl
2-furyl
CH3(CH2)2
CH3(CH2)8
Ph(CH2)2
cyclohexyl
(CH3)3C
Table 3. Further Optimization of Reaction Conditions for the
Friedel-Crafts Alkylation of Indole 5a with
trans-â-Nitrostyrene 6aa
10 5a
11 5a
12 5a
13 5a
6g
6h
6i
7j
7k
7l
6je
7m
entry
solvent
T (°C) catalyst (mol %) yieldb (%) eec (%)
a Reaction conditions: indole 5 (0.50 mmol) with nitroalkene 6 (0.50
mmol) in 2 mL of toluene using 5 mol % 4-Zn(OTf)2 complex as the
catalyst at -20 °C for 15 h. b Isolated yield by column chromatography.
c Determined by HPLC. d Determined to be R by comparison of optical
rotation with that in ref 2c. e The reaction was carried out at 30 °C for 144
h.
1
2
3
4
5
6
7
8
9
toluene
10
10
10
10
10
5
5
5
5
5
5
5
20
10
2
99
91
90
67
94
99
99
99
99
95
94
90
67
69
16
30
93
94
95
94
92
90
CH2Cl2
ClCH2CH2Cl
THF
hexane
toluene
toluene
toluene
toluene
0
-20
-20
-20
-20
-20
substituents in the reaction with trans-â-nitrostyrene 6a
catalyzed by 5 mol % 4-Zn(OTf)2. The Friedel-Crafts
alkylation of indole 5a proceeded very smoothly at -20 °C
to furnish the product 7a in nearly quantitive yield with
excellent enantioselectivity (entry 1). When electron-rich
5-methoxyindole 5b was used, the enantiomeric excess of
10 toluene
11 toluene
1
a Reaction conditions: indole 5a (0.50 mmol) with trans-â-nitrostyrene
6a (0.50 mmol) in 2 mL of toluene using ligand-Zn(OTf)2 complex as the
catalyst. b Isolated yield by column chromatography. c Determined by HPLC
on Daicel Chiracel OD-H column (hexane/2-propanol 70:30, 0.9 mL/min).
(12) For the synthesis of ligand 4, see Supporting Information.
Org. Lett., Vol. 8, No. 10, 2006
2117

the product 7b was up to 98% (entry 2). An electron-
withdrawing substituent such as chlorine in the 5-position
of the indole ring in 5c caused moderate decrease in both
yield and enantioselectivity (entry 3). When we introduced
a methyl substituent to the indolic nitrogen atom, to our
delight, the reaction proceeded very well, giving the corre-
sponding derivatives 7d in high yield and enantioselectivity
(entry 4). The enantioselectivity was enhanced by 40%
compared with previous reports.2
The generality of the reaction was further demonstrated
by variation of the nitroalkene partner. Aromatic-, heteroaro-
matic-, and aliphatic-substituted nitroalkenes all reacted well
with indole to afford alkylated indoles in excellent yields
and high enantioselectivities (entries 5-12). The ortho-
substitution on the phenyl in nitrostyrene, either electro-
donating or electron-withdrawing groups, lowered the enan-
tiomeric excess of products, perhaps due to the steric effect
of ortho-substituents (entries 5 and 6). Naphthyl- and
heteroaryl-substituted nitroalkenes 6d and 6e could also react
smoothly, affording the corresponding products 7g and 7h
in good yields and enantioselectivities (entries 7 and 8).
Interestingly, the reaction could be easily extended to
aliphatic nitroalkenes while neither the reaction rate nor the
enantioselectivity suffered (entries 9-12). When unbranched
alkyl substituents were investigated, the number of the carbon
atoms of the chain had little effect on the reaction (entries 9
and 10). A terminal phenyl substituent on the alkyl chain
enhanced the enantioselectivity slightly in our experiment
(entry 11). The alkylation of indole 5a with the more
hindered cyclohexyl-substituted nitroalkene 6i could occur
smoothly in high enantioselectivity (entry 12). Even the very
bulky tert-butyl-substituted nitroalkene 6j could react with
indole in good yield and enantioselectivity, although the
reaction needed to be performed at 30 °C for 144 h (entry
13).
Figure 2. Possible bifunctional mode in transition state of the
catalyst 4-Zn(OTf)2.
two phenyl groups in the ligand could act as a donor for the
NH‚‚‚π (indole) interaction,13 which would direct the indole
to attack the nitroalkene preferably from si face as depicted
in Figure 2. Thus, we obtained the product with R config-
uration excessively, and even with N-protected indole the
enantioselectivity was kept at a high level.
In conclusion, we have developed a more practical
catalytic asymmetric Friedel-Crafts alkylation of indoles 5
with a variety of nitroalkenes 6 using tridentate bis(oxazoline)
4-Zn(OTf)2 complex as catalyst, which can activate ni-
troalkenes and orient indoles effectively at the same time.
Various types of the nitroalkylated indoles were obtained in
excellent yields and high enantioselectivities (up to 98% ee).
These chiral tridentate ligands 1, 2, and 4 contaning a
diphenylamine unit would have further applications in other
Lewis acid catalyzed asymmetric transformations. Studies
are in progress in our laboratory.
Acknowledgment. This project was supported by Na-
tional Natural Science Foundation of China (grant nos.
20372001, 20572003, and 20521202) and Peking University.
By comparison of ligands 3 and 1 in the Zn(OTf)2-
catalyzed alkylation of indole with trans-â-nitrostyrene, we
assumed that the NH group in ligands 1, 2, and 4 is crucial.11
When we mixed the ligand with Zn(OTf)2 in toluene, the
mixture became clear in 0.5 h. We supposed that the
tridentate ligand and Zn(OTf)2 formed a 1:1 complex. This
complex could activate the nitroalkene through the coordina-
tion of the nitro group to the Lewis acid center.2c We
envisioned that the 4-Zn(OTf)2 complex would act in a
bifunctional fashion (Figure 2). The NH group between the
Supporting Information Available: Experimental pro-
1
cedures and characterization, copies of H NMR and 13C
NMR of new compounds, and HPLC profiles. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL060586F
(13) For examples of NH‚‚‚π interactions, see: (a) Arata, S.; Torigoe,
H.; Iihoshi, T.; Matsumoto, N.; Dahan, F.; Tuchagues, J.-P. Inorg. Chem.
2005, 44, 9288. (b) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.;
Tanabe, K. J. Am. Chem. Soc. 2000, 122, 11450.
2118
Org. Lett., Vol. 8, No. 10, 2006