A new type of bis(sulfonamide)-diamine ligand for a Cu(OTf) 2-catalyzed asymmetric friedel-crafts alkylation reaction of indoles with nitroalkenes

Article abstract of DOI:10.1021/ol201914r

Chiral bis(sulfonamide)-diamine served as new type of ligand for a Cu(OTf)₂-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes. The desired products were obtained with up to 99% yield and 97% ee.

Full text of DOI:10.1021/ol201914r

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4834–4837
A New Type of Bis(sulfonamide)-Diamine
Ligand for a Cu(OTf)2-Catalyzed
Asymmetric FriedelÀCrafts Alkylation
Reaction of Indoles with Nitroalkenes
Jing Wu, Xincheng Li, Fan Wu, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
457 Zhongshan Road, Dalian 116023, China
bswan@dicp.ac.cn
Received July 14, 2011
ABSTRACT
Chiral bis(sulfonamide)-diamine served as new type of ligand for a Cu(OTf)2-catalyzed asymmetric FriedelÀCrafts alkylation reaction of indoles
with nitroalkenes. The desired products were obtained with up to 99% yield and 97% ee.
Indole derivatives are always considered to be attractive
synthetic targets due to their prevalence in numerous
natural products and pharmaceutical lead compounds.1
Meanwhile, the catalytic asymmetric FriedelÀCrafts alky-
lation reaction2 opens up access to construct a new CÀC
bond directly on indoles with a new stereogenic center. In
addition, nitroalkenes as active Michael acceptors have
drawn considerable attention due to their versatility in
further transformations. Over the past few years, significant
efforts have been made for this asymmetric reaction and
several successful catalytic systems have been developed
including hydrogen-bond-based organocatalysts3 and me-
tal catalysts.4À6 The organocatalysts were symbolized by
chiral thioureas3aÀe and chiral phosphoric acid,3f while the
metals used for metal catalysts were mainly focused on Al,4
Cu,5 and Zn.6 Efficient metal catalytic systems for this
transformation were very rare. Impressive studies were
reported by Du and Wang. Du6b,h developed bisoxazolines
and bisimidazolinesÀZn(OTf)2 systems, affording high
yields and enantioselectivities except in the case of
(3) For hydrogen-bond-based organocatalysts: (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) Fleming, E. M.; McCabe, T.; Connon, S. J.
Tetrahedron Lett. 2006, 47, 7037. (d) Ganesh, M.; Seidel, D. J. Am.
(1) (a) Moore, R. E.; Cheuk, C.; Yang, X. Q. G.; Patterson, G. M. L.;
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones,
N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52, 1036.
(b) Bosch, J.; Bennasar, M. L. Synlett 1995, 587. (c) Faulkner, D. J. Nat.
Prod. Rep. 2002, 19, 1. (d) Agarwal, S.; Cammerer, S.; Filali, S.; Frohner,
W.; Knoll, J.; Krahl, M. P.; Reddy, K. R.; Knolker, H. J. Curr. Org.
Chem. 2005, 9, 1601. (e) Chen, F. E.; Huang, J. Chem. Rev. 2005, 105,
4671. (f) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
(2) Selected reviews for asymmetric FredielÀCrafts reaction: (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) Poulsen, T. B.; Jørgensen, K. A.
Chem. Rev. 2008, 108, 2903. (d) Bandini, M.; Eichholzer, A. Angew.
Chem., Int. Ed. 2009, 48, 9608. (e) You, S. L.; Cai, Q.; Zeng, M. Chem.
Soc. Rev. 2009, 38, 2190.
ꢀ
ꢀ
Chem. Soc. 2008, 130, 16464. (e) Marques-Lopez, E.; Alcaine, A.;
Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2011, 3700. (f) Itoh, J.;
Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016. (g) Lin,
J. H.; Xiao, J. C. Eur. J. Org. Chem. 2011, DOI: 10.1002/ejoc.201100683
(4) Bandini, M.; Garelli, A.; Rovinetti, M.; Tommasi, S.; Umani-
Ronchi, A. Chirality 2005, 17, 522.
(5) For Cu(II) catalyst: (a) Singh, P. K.; Bisai, A.; Singh, V. K.
Tetrahedron Lett. 2007, 48, 1127. (b) Sui, Y.; Liu, L.; Zhao, J. L.; Wang,
D.; Chen, Y. J. Tetrahedron 2007, 63, 5173. (c) Arai, T.; Yokoyama, N.
Angew. Chem., Int. Ed. 2008, 47, 4989. (d) Arai, T.; Yokoyama, N.;
Yanagisawa, A. Chem.;Eur. J. 2008, 14, 2052. (e) Yokoyama, N.; Arai,
T. Chem. Commun. 2009, 3285. (f) Kim, H. Y.; Kim, S.; Oh, K. Angew.
Chem., Int. Ed. 2010, 49, 4476.
r
10.1021/ol201914r
Published on Web 08/23/2011
2011 American Chemical Society

nitroalkene substrates with ortho substituents on the phe-
nyl group. It is worthy to note that these systems were also
effective for aliphatic nitroalkenes and N-methyl indole.
Recently, Wang6g noted that a Schiff base and piperidine
performed as a combinational catalyst for aromatic ni-
troalkenes, including ortho-substituted substrates. Electron-
rich ortho-substituted aromatic nitroalkenes gave the
products in slightly better ee. However, we found that the
ligands employed therein were limited to the ligands con-
taining an oxazoline, an imidazoline, or a Schiff base.
Thus, it is still highly desirable to explore efficient alter-
native ligands for metal catalysts because of the great
utility of this reaction.
Table 1. Optimization of Reaction Conditions for the
Enantioselective FriedelÀCrafts Alkylation between 1a and 2aa
entry
ligand
solvent
t (°C)
yield (%)b
ee (%)c
1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
L6
L6
L6
L6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
68
91
77
58
76
94
45
99
99
86
99
99
98
99
99
78
21
2
5 (À)
18
3
4
18
5
11
6
91
7
22 (À)
86
8
9
85
10
11
12
13
14d
15e
16f
Benzene
PhCF3
88
92
PhCF3
94
PhCF3
À10
0
93
PhCF3
95
PhCF3
0
94
PhCF3
0
0
a Unless otherwise noted, all reactions were performed with indole 1a
(0.25 mmol) and trans-β-nitrostyrene 2a (0.375 mmol) with 5 mol %
catalyst (Cu(OTf)2:ligand = 1:1) in 1.5 mL of solvent under argon.
Figure 1. Bis(sulfonamide)-diamine ligands.
b Isolated yields. c Determined by HPLC with chiral AD-H columm. d
3
mL of solvent were used. e The reaction was performed in the open air.
f Without addition of Cu(OTf)2.
Very recently, we have developed a novel type of chiral
bis-sulfonamide diamine ligand (Figure 1) with several
chiral centers in the skeleton in favor of easily tuning the
stereo and electronic effect. This type of ligands proved to
be highly effective for a Cu-catalyzed enantioselective and
diastereoselective Henry reaction.7 Since Cu-catalyzed
FriedelÀCrafts alkylation of indole with nitroalkene has
been reported, we envisioned that this type of ligands may
be effective in this transformation. Herein, we describe that
bis-sulfonamide diamine served as a new type of ligand for
a Cu-catalyzed asymmetric FriedelÀCrafts alkylation of
indoles with nitroalkenes to provide the corresponding
products with up to 99% yield and 97% ee. As far as we
know, we obtained the best results of ortho-substituted
electron-withdrawing aromatic nitroalkenes.
conditions. A series of Lewis acid catalysts (CuII, CuI, ZnII,
FeIII, AgI complexes) were first investigated. Preliminary
studies revealed that only the complex generated in situ
from Cu(OTf)2 andligand L1promoted the reactionwith a
promising result giving the product with 68% yield and
21% ee (Table 1, entry 1). Sequential investigations on
modifying the structure of the bis-sulfonamide diamine
ligands showed that the ligand derived from (1R,2R)-1,2-
diphenylethylenediamine turned out to be better than the
one derived from (1S,2S)-1,2-diphenylethylenediamine
(Table 1, entries 1 and 2). Subsequently, the ligands
derived from two chiral 1,2-diamines with different
skeletons were compared. It was shown that the ligand
linked with (1R,2R)-1,2-diphenylethylenediamine was
superior to the one with (1R,2R)-cyclohexane-1,2-dia-
mine (Table 1, compare entries 1 and 3). Furthermore,
the substituent R2 of the ligands could also greatly affect
the reactivity and enantioselectivity of the reaction
(Table 1, entries 4À7). Gratifyingly, significant en-
hancement of enantioselectivity was observed when L6
with R2 as a phenyl group was employed affording the
corresponding adducts with 94% yield and 91% ee
(Table 1, entry 6).
Initially, the addition ofindole1atotrans-β-nitrostyrene
2a was selected as a model reaction for optimizing the
(6) For Zn(II) catalyst: (a) Jia, Y. X.; Zhu, S. F.; Yang, Y.; Zhou,
Q. L. J. Org. Chem. 2006, 71, 75. (b) Lu, S. F.; Du, D. M.; Xu, J. X. Org.
Lett. 2006, 8, 2115. (c) Liu, H.; Lu, S. F.; Xu, J.; Du, D. M. Chem.;
Asian J. 2008, 3, 1111. (d) Yuan, Z. L.; Lei, Z. Y.; Shi, M. Tetrahedron:
Asymmetry 2008, 19, 1339. (e) Lin, S.-Z.; You, T.-P. Tetrahedron 2009,
65, 1010. (f) McKeon, S. C.; Muller-Bunz, H.; Guiry, P. J. Eur. J. Org.
Chem. 2009, 4833. (g) Guo, F. F.; Lai, G. Y.; Xiong, S. S.; Wang, S. J.;
Wang, Z. Y. Chem.;Eur. J. 2010, 16, 6438. (h) Liu, H.; Du, D.-M. Adv.
Synth. Catal. 2010, 352, 1113. (i) Liu, H.; Du, D. M. Eur. J. Org. Chem.
2010, 2121. (j) Wu, M.; Wang, S. F.; Xia, C. G.; Sun, W. Chin. J. Chem.
2010, 28, 1424.
(7) (a) Jin, W.; Li, X. C.; Huang, Y. B.; Wu, F.; Wan, B. S. Chem.;
Eur. J. 2010, 16, 8259. (b) Jin, W.; Li, X. C.; Wan, B. S. J. Org. Chem.
2011, 76, 484.
Further optimization of the reaction conditions focusing
on the effect of the solvent (Table 1, entries 8À11) revealed
4835
Org. Lett., Vol. 13, No. 18, 2011

hindrance on ortho substitution of the phenyl group of
aromatic nitroalkenes. On the contrary, in this system, the
enantioselectivity increased rather than decreased when the
ortho substitution exists (Table 2, entries 4, 7, 8, and 11).
Furthermore, heteroaromatic nitroalkenes also served as
good substrates for this reaction giving good results
(Table 2, entries 13À15). However, to our disappointment,
when aliphatic nitroalkenes were subjected to this reaction
the results turned out to be not as good as the outcome of
aromatic nitroalkenes. 20 mol % catalyst was needed when
(E)-1-nitro-1-hexene 2p was involved as the substrate, and
only a moderate yield and ee were obtained (Table 2,
entry 16). Meanwhile, the substituent effect of indole
was also investigated (Table 2, entries 17À20). The
electronic properties of the substituent at the 5-position
of indole had little effect on enantioselectivities, but a
longer reaction time was needed when electron-drawing
groups were involved.
Table 2. Scope of the Asymmetric FriedelÀCrafts Alkylation of
Indoles with Various Nitroalkenesa
entry
R1
R2
Ph (2a)
yield (%)b
ee (%)c
1
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)
Me (1b)
OMe (1c)
F (1d)
Br (1e)
99 (3a)
96 (3b)
94 (3c)
99 (3d)
99 (3e)
99 (3f)
96 (3g)
97 (3h)
99 (3i)
96 (3j)
98 (3k)
99 (3l)
98 (3m)
95 (3n)
90 (3o)
65 (3p)
99 (3q)
99 (3r)
88 (3s)
99 (3t)
95 (R)d
92
94
97
93
88
93
96
93
92
96
94
88
95
93
70
94
95
94
94
2
4-ClC6H4 (2b)
3-ClC6H4 (2c)
2-ClC6H4 (2d)
4-MeC6H4 (2e)
4-MeOC6H4 (2f)
2-MeOC6H4 (2g)
2-BrC6H4 (2h)
3-BrC6H4 (2i)
4-BrC6H4 (2j)
2-FC6H4 (2k)
3-CF3C6H4 (2l)
2-furyl (2m)
1-naphthyl (2n)
2-naphthyl (2o)
n-Bu (2p)
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17
18
19
20
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
a Unless otherwise noted, all reactions were performed with indoles 1
(0.25 mmol) and nitroalkenes 2 (0.375 mmol) with 5 mol % catalyst
(Cu(OTf)2:L6 = 1:1) in 3 mL of PhCF3 under argon at 0 °C for 24À48 h.
b Isolated yields. c The ee value was determined by HPLC analysis.
d Determined to be R by comparison of optical rotation with that in
ref 3d. e The reaction was performed with 20 mol % catalyst at room
temperature.
Figure 2. Proposed transition state model of catalyst L6À
Cu(OTf)2.
To gain some insight into the mechanism of this reac-
tion, N-methyl indole was treated with nitroalkene under
the optimized conditions. The corresponding product was
obtained with only 51% yield and 17% ee. On the other
hand, the phenyl group as R2 was indispensable in the
ligand to gain an excellent yield and enantioselectivity.
Moreover, the poor results of aliphatic nitroalkenes were
obtained as mentioned above (Table 2, entry 16). Based on
these results, a plausible transition state was proposed as
showninFigure2. WeenvisionthatcatalystL6ÀCu(OTf)2
acts in a bifunctional way. The nitroalkenes are activated
by chelating to Cu(II), and a πÀπ stacking will exist
between the phenyl group R2 of the ligand and the phenyl
group of nitroalkenes. In addition, an indolic proton will
interact with the nitrogen atom which linked with the Ts
substituent through a weak hydrogen bond8 and the
bulky Ts on the back directs the indole to attack
nitroalkene on the Si face to afford the product with
the configuration of R.
that PhCF3 was the best solvent leading to the quantitive
conversion of the substrate in a shorter time and afforded
the product with 99% yield and 92% ee (Table 1, entry 11).
Decreasing the temperature to 0 °C slightly improved the
enantioselectivity without affecting the yield (Table 1,
entry 12). Further improvement of the enantioselectivity
was observed with a lower concentration of the substrate
(Table 1, entry 14). Importantly, the reaction was not
sensitive to air and moisture and could be conducted in
the open air without jeopardizing the yield and ee value
(entry 15). In addition, the control reaction showed that
the reaction could be catalyzed by the ligand L6 in the
absence of Cu(OTf)2 giving the racemic product in mod-
erate yield (entry 16).
Having found the optimized conditions, we set out to
investigate the scope of the reaction. As shown in Table 2,
regardless of steric hindrance or electronic properties of
various aryl substituents, aromatic nitroalkenes reacted
with indole 1a smoothly and afforded the corresponding
products in excellent yields and enantioselectivities (Table 2,
entries 1À12). It was noteworthy that several catalytic
systems suffered from lower enantioselectivities due to steric
(8) Indole analogues carrying substituents in positions 2 and 7 were
also tested. However, only racemic products were obtained with good
yields. We surmised that the substituents in positions 2 and 7 were near
the NÀH bond of indole and the hydrogen bond cannot be generated
because of the steric hindrance (see Supporting Information).
4836
Org. Lett., Vol. 13, No. 18, 2011

In conclusion, we have developed a highly enantioselec-
tive FriedelÀCraft alkylation of indoles with nitroalkenes
using a Cu(OTf)2/bis(sulfonamide)-diamine catalytic system.
The reaction performed well over a range of nitroalkenes,
especially sterically hindered aromatic nitroalkenes with
ortho substitution, giving the corresponding products with
up to 99% yield and 97% ee. Further exploration of the
mechanism and application of the ligands to other asym-
metric reactions is currently underway in our laboratory.
Acknowledgment. We are grateful for the financial
support from the National Basic Research Program of
China (2010CB833300).
Supporting Information Available. General experimen-
tal procedures, synthesis of the ligands L1À7, character-
ization data, 1H and 13C NMR spectra, and HPLC
analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
4837