Highly enantioselective Friedel-Crafts reaction of indoles with N-sulfonyl aldimines catalyzed by heteroarylidene malonate-type bis(oxazoline) copper(II) complexes

Article abstract of DOI:10.1016/j.tetasy.2011.10.017

The enantioselective Friedel-Crafts addition of indoles to N-sulfonyl aldimines was studied using a heteroarylidene malonate-type bis(oxazoline) as a chiral ligand. High to excellent enantioselectivities (up to >99% ee) were achieved using the complex of copper(II)-L1b with a benzyl group. The effects of ligand structure, solvent, temperature and substrate on the reaction were also investigated.

Full text of DOI:10.1016/j.tetasy.2011.10.017

Tetrahedron: Asymmetry 22 (2011) 1874–1878
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective Friedel–Crafts reaction of indoles with N-sulfonyl
aldimines catalyzed by heteroarylidene malonate-type bis(oxazoline)
copper(II) complexes
⇑
Lei Liu, Qiuying Zhao, Fengpei Du, Hongliang Chen, Zhaohai Qin, Bin Fu
Department of Applied Chemistry, China Agricultural University, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 September 2011
Accepted 24 October 2011
The enantioselective Friedel–Crafts addition of indoles to N-sulfonyl aldimines was studied using a het-
eroarylidene malonate-type bis(oxazoline) as a chiral ligand. High to excellent enantioselectivities (up to
>99% ee) were achieved using the complex of copper(II)–L1b with a benzyl group. The effects of ligand
structure, solvent, temperature and substrate on the reaction were also investigated.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
remains a great need to explore new asymmetric catalytic
methods for the Friedel–Crafts reaction of indoles with N-sulfonyl
aldimines.
The Friedel–Crafts reaction of arene is a powerful and versatile
carbon–carbon bond-forming process in organic chemistry.1 The
Over the past two decades, chiral bis(oxazoline) (BOX) ligands
have become a class of important and versatile ligands in catalytic
asymmetric synthesis.9 Although BOX ligands with diverse skele-
tons have been reported, new structure-types of BOX ligand are
still emerging.10 Recently, we reported that heteroarylidene
malonate-bis(oxazoline) ligand L with furan and thiophene units
on the double bond provided excellent asymmetric catalytic prop-
erties in the Cu(II) catalyzed Friedel–Crafts alkylation of indole
derivatives with arylidene malonates (up to 99% yield and >99%
ee).11 As a continuation of our ongoing research to explore the
application of chiral ligands in asymmetric transformation, we
herein report our primary results of using a heteroarylidene
malonate-type bis(oxazoline)–Cu(OTf)2 complex to catalyze the
enantioselective Friedel–Crafts reaction of indoles with N-sulfonyl
aldimines.
asymmetric Friedel–Crafts reaction of indoles can provide
a
straightforward access to optically active indole derivatives which
are potential intermediates for many biologically active com-
pounds and medicinal agents.2 Many substrates including
electron-deficient olefins, active carbonyl compounds and
epoxides, and so on, have been widely used in the Friedel–Crafts
reaction of indoles.3 Over the past decade, imine substrates for
the Friedel–Crafts reaction have received more and more attention.
In 1999, Johannsen et al. first reported the enantioselective addi-
tion of indole nucleophiles to electron-rich alkenes catalyzed using
BINAP–Cu(I) complexes.4 In 2006, Zhou et al. explored bis(oxazo-
line)–Cu(II) complexes to catalyze the same reaction, affording
high yield and enantioselectivity (up to 96% ee).5 In the meantime,
bifunctional organocatalysts were applied to the Friedel–Crafts
reaction of indoles with imines by Deng and co-workers, giving
3-indolyl methanamine derivatives with up to 97% ee.6 Subse-
quently, You et al. reported a chiral phosphoric acid-catalyzed
Friedel–Crafts reaction of indoles with similar N-tosyl imines, giv-
ing chiral methanamines in good yield with excellent enantioselec-
tivity.7 Very recently, Wang et al. showed that Trost’s dinuclear
zinc catalyst could efficiently catalyze this Friedel–Crafts reaction
with good enantioselectivities and high yields.8
2. Results and discussion
Initially the reaction of indole 1a with N-(4-nitrobenzylidene)-
4-methylbenzene sulfonamide 2a was used as a template to opti-
mize the reaction conditions (Scheme 1). The reaction occurred
smoothly under the catalysis of 10 mol % of Box–copper complexes
in dichloromethane at room temperature. Full conversion occurred
within 24 h to afford the desired adduct 3a in 70–85% yield for all
of the tested ligands. Meanwhile, a bisindole addition by-product 4
was also produced in approximately 10% yield. The screening
results indicated that the ligand’s structure had a significant influ-
ence on the enantioselectivity. The (S)-i-Pr-BOX L1a, L2a and (S)-
Ph-BOX L1c, L2c led to lower ee (Table 1, entries 1, 3, 4 and 6),
whereas the (S)-Bn-bis(oxazoline) L1b and L2b afforded much
Despite these impressive contributions, to date the number of
successful examples for this catalytic Friedel–Crafts reaction re-
mains limited. Owing to the importance of indole derivatives as
potential medicinal agents and agrochemical products, there
⇑
Corresponding author. Tel.: +86 10 62732873; fax: +86 10 62732948.
E-mail address: fubinchem@cau.edu.cn (B. Fu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.017

L. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 1874–1878
1875
NO2
O2N
Ts
N
NHTs
L
10 mol % Cu(OTf)2-
CHCl3
+
N
H
+
O2N
N
H
N
H
N
H
1a
2a
3a
4
H
L1. X = O
X
L2
. X = S
O
O
L =
a
b
c
. R = i-Pr
. R = Bn
. R = Ph
N
N
R
R
Scheme 1. Friedel–Crafts reaction of indole to N-sulfonyl aldimine.
Table 1
or chloroform, much better reactivity and enantioselectivity were
observed than in dichloromethane. The reaction proceeded well
in CHCl3 within 24 h, affording the desired product in 85% yield
and with 87% ee.
Optimization of the chiral ligands for the Friedel–Crafts reaction of indole with
N-sulfonyl aldiminesa
Entry
R1
T (°C)
Time (h)
Yieldb (%)
eec (%)
Under the optimized reaction conditions (5 equiv indole,
1 equiv aldimine and 10 mol % L1b in CHCl3 at 0 °C), a wide range
of aldimines and indoles were further investigated as outlined in
Table 3 (Scheme 2). In most cases, the reaction could be completed
within 24–48 h in good to high yield (70–90%) except for two cases
(entries 11 and 12). When R2 was a p-methoxy group on the phenyl
ring, the reaction was very sluggish even if the reaction time was
prolonged to 96 h. Apparently, the electron-withdrawing substitu-
ent on the phenyl ring of the aldimine is critical for high catalytic
efficiency, which is in agreement with Zhou’s report.5 In our opin-
ion, we believe that the electron-donating substituent on the phe-
nyl ring can increase the electron density of the carbon atom of the
C@N bond, reduce its electrophilicity, and thus lower the reactivity
of the Friedel–Crafts reaction. It is noteworthy that our catalyst
showed a much higher reactivity than former bis(oxazoline)–Cu(II)
complexes. For all of the aldimine substrates with electron-with-
drawing groups at the para-, meta-, and ortho-position of the phe-
nyl ring, the Friedel–Crafts reaction gave high to excellent
enantioselectivities in the range of 88–96% ee. Substituents at the
meta- or ortho-position had little to no effect on the yield or
enantioselectivity. Although the reaction of indole with N-benzyl-
idene-4-methylbenzene sulfonamide 2i was slower than those
with other N-sulfonyl imines with electron-withdrawing groups,
1
2
3
4
5
6
7
8
9d
L1a
L1b
L1c
L2a
L2b
L2c
L1b
L2b
L1b
rt
rt
rt
rt
rt
rt
0
24
24
24
24
24
24
48
48
96
80
80
75
75
80
80
85
85
80
15
73
4
13
69
2
80
78
80
0
0
a
Reaction conditions: 10 mol % of catalyst, 5 equiv indole, 1 equiv aldimine in
CH2Cl2, 100 mg Molecular sieves.
b
Isolated yields.
Determined by HPLC analysis.
5 mol % of catalyst.
c
d
higher ee (Table 1, entries 2 and 5). Through screening, L1b was
found to be the best ligand in terms of enantioselectivity and yield
(Table 1, entries 2). The reaction temperature was examined next.
When lowering the reaction temperature from ambient tempera-
ture to 0 °C, the yield and enantioselectivity were greatly enhanced
although the reaction becomes slightly slower (Table 1, entries 7
and 8). The bisindole addition by-product 4 was decreased to
<5% yield at 0 °C. In addition, the effect of the catalyst loading on
the reaction was also studied. Reducing the catalyst loading to
5 mol % gave rise to results comparable with those using
10 mol % catalyst, but a longer reaction time was needed (Table 1,
entry 9).
Table 3
L1b-Cu(OTf)2 catalyzed Friedel–Crafts reaction of Indoles with N-sulfonyl aldiminesa
We next investigated the solvent effect using L1b-Cu(OTf)2; the
results are summarized in Table 2. Reactions in several solvents
such as EtOH, THF, toluene, and diethyl ether led to either longer
reaction times or lower selectivities (Table 2, entries 1–4).
However in a halogenated solvent including 1,2-dichloroethane
Entry
R1
R2
Imine 2
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
H
H
H
H
H
H
H
H
H
H
H
p-F
p-Cl
p-Br
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
48
24
24
72
72
72
48
48
24
24
24
48
48
48
24
48
3b (80)
3c (82)
3d (90)
3e (85)
3f (85)
3g (81)
3h (90)
3i (85)
3j (84)
3k (80)
3l (70)
3m (0)
3n (85)
3o (80)
3p (82)
3q (86)
94
91
93
95
96
89
94
90
88
96
90
—
p-CN
p-F3C
m-NO2
m-CN
m-Br
m-CF3
o-CF3
H
p-MeO
p-CF3
p-CF3
p-CF3
p-CF3
Table 2
Optimization of the solvent for the Friedel–Crafts reaction of indole with N-sulfonyl
aldiminesa
Entry
Ligands
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
L1b
L1b
L1b
L1b
L1b
L1b
EtOH
THF
Toluene
Et2O
ClCH2CH2Cl
CHCl3
48
48
48
48
24
24
75
60
80
70
80
85
50
79
70
62
85
87
5-OMe
5-Me
5-Cl
6-Cl
91
95
97
>99
15
a
All reactions were conducted in CHCl3 under nitrogen using 10 mol % catalyst at
0 °C.
a
b
c
All reactions were performed under nitrogen at 0 °C.
Isolated yield.
Determined by HPLC.
b
Isolated yield.
Determined by chiral HPLC(Chiralcel OD-H and AD-H).
c

1876
L. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 1874–1878
R2
4. Experimental
Ts
N
NHTs
NMR spectra were recorded with a Bruker Avance DPX300 spec-
trometer with tetramethylsilane as the internal standard. Mass
spectra were obtained on Bruker APEX II FT-ICRMS mass spectrom-
eter. Optical rotations were measured on a Perkin–Elmer 341 LC
polarimeter. The enantiomeric excesses of the (R)- and (S)-enanti-
omers were determined by HPLC analysis over a chiral column
(Daicel Chiralcel OD-H and AD-H (25 cm ꢀ 0.46 cm ID); eluted
with hexane–isopropyl alcohol; UV detector, 254 nm). The abso-
lute configuration of the major enantiomer was assigned by com-
parison with the literature.5,7 Solvents were purified and dried by
standard procedures.
L1b
Cu(OTf)2-
CHCl3, 0oC
R1
+
R2
N
H
R1
N
H
2b-q
1
3b-q
Scheme 2.
H
X
O
O
4.1. General procedure I: asymmetric Friedel–Crafts reaction of
indoles with N-sulfonyl aldimines
N
N
R
R
Cu
S
Ar
O
N
4.1.1. (S)-N-[Indol-3-yl-(4-nitrophenyl)methyl]-4-
methylbenzenesulfonamide 3a
O
Under an N2 atmosphere, Cu(OTf)2 (10.83 mg, 0.03 mmol), and
(S)-Bn-bisoxazoline L1b (18.5 mg, 0.045 mmol) were dissolved in
CHCl3 (2 mL) The solution was stirred at room temperature for
2 h, then 4 Å molecular sieves (100 mg) were added and stirred
for another 10 min. Next, N-(4-nitrobenzylidene)-4-methylben-
zenesulfonamide 2a (91.2 mg, 0.30 mmol) and indole (176 mg,
1.5 mmol) were added, and the reaction mixture was stirred at
0 °C. After the reaction was complete, the solvent was removed un-
der vacuum and the residue was purified by flash column chroma-
tography on silica gel eluted with ethyl acetate/petroleum ether
(1:3, v/v)] to afford the product (S)-N-[indol-3-yl-(4-nitro-
phenyl)methyl]-4-methylbenzenesulfonamide 3a as white solid,
N
H
Re face (favored)
Figure 1. The proposed coordination mode.
the desired adduct was also obtained in 70% yield and with 90% ee
(Table 3, entry 11).
The generality of the reaction was further extended by variation
of indole. The reaction of N-(4-CF3-benzylidene)-4-methylbenzene
sulfonamide 2n–q with 5-methoxyindole, 5-methylindole, 5-chlor-
oindole, and 6-chloroindole gave rise to the adducts in high yields
and with excellent ee values (Table 3, entries 13–16). It was found
that indoles with electron-withdrawing groups gave higher enanti-
oselectivities than those with electron-donating groups, especially
in the case of 6-chloroindole (>99% ee was obtained).
Regarding the reaction mechanism, Zhou et al. have described a
transition-state model for this type of catalytic Friedel–Crafts ami-
doalkylation reaction, which presumably introduced the 1,3-bind-
ing mode of the nitrogen atom of the imine and the oxygen atom of
the sulfonyl coordinated to the Cu center.5 Considering the similar-
ities of the two classes of ligand structure, both catalytic processes
of the BOX–Cu(II) complex may have the same catalytic mecha-
nism as shown in Figure 1. However our catalyst provided a higher
catalytic efficiency and comparable enantioselectivity in compari-
son with Zhou’s report,5 thus demonstrating that the ligand’s
structure plays an important role in the catalytic process. For our
catalyst the higher catalytic efficiency could be attributed to the
electronic effect, which is the result of the heterocycle moiety (fur-
an or thiophene) attached to the double bond. As for the enantiose-
lectivity, the benzyl group on the oxazoline ring is a critical factor
for achieving the high enantioselectivity in the process of asym-
metric induction.
107 mg (85% yield, 87% ee). White powder; ½a D25
¼ ꢂ23:2 (c 0.32,
ꢁ
CH3CO2C2H5), 87% ee [Daicel Chiralcel OD-H column, n-hexane/i-
PrOH = 80:20, 1.0 mL/min, 254 nm; t (minor) = 33.05 min, t (ma-
jor) = 56.33 min]; 1H NMR (300 MHz, CDCl3): d 2.41 (s, 3H), 5.10
(d, J = 6.0 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H),
6.99–7.04 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.21 (m, 3H), 7.34 (d,
J = 11.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H),
8.07–8.09 (m, 2H), 8.10 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d
20.9, 54.0, 111.7, 114.4, 118.8, 118.9, 121.6, 123.2, 124.2, 125.4,
126.7, 128.5, 129.2, 136.5, 138.5, 142.4, 146.3, 149.5. HRMS (ESI):
m/z calcd for
C
22H19N3NaO4S (M+Na+): 444.09885; found:
444.09959.
4.1.2. N-[Indol-3-yl-(4-fluorophenyl)methyl]-4-
methylbenzenesulfonamide 3b
White powder; ½a D25
¼ ꢂ7:6 (c 0.25, CH3CO2C2H5), 94% ee [Dai-
ꢁ
cel Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 18.90 min, t (major) = 30.73 min]; 1H NMR
(300 MHz, CDCl3): d 2.39 (s, 3H), 4.99 (d, J = 6.5 Hz, 1H), 5.83 (d,
J = 6.5 Hz, 1H), 6.65–6.66 (m, 1H), 6.90 (t, J = 8.7 Hz, 2H), 7.00–
7.04 (m, 1H), 7.13–7.25 (m, 6H), 7.30–7.33 (m, 1H), 7.56–7.59
(m, 2H), 7.99 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 20.3, 53.3,
110.9, 113.8, 114.1, 115.0, 118.0, 118.3, 120.7, 123.2, 124.8,
124.9, 125.9, 128.3, 128.4, 128.5, 135.9, 137.3, 138.2, 141.4. HRMS
(ESI): m/z calcd for C22H19FN2NaO2S (M+Na+): 417.10435; found:
417.10393.
3. Conclusion
In conclusion, we have developed a highly enantioselective Fri-
edel–Crafts amidoalkylation of indoles with N-sulfonyl imines, cat-
alyzed by the Cu(OTf)2 complex of heteroarylidene malonate
bis(oxazoline) ligand L1b with a benzyl group. The reaction pro-
ceeded smoothly under mild conditions to afford the adducts in
high yields and enantioselectivities (up to >99% ee). Compared
with the previously published Box–Cu(OTf)2 complex, our catalyst
provided better reactivities and comparable enantioselectivities in
most cases. Further applications of this methodology to the synthe-
sis of functional chiral molecules are currently underway in our
laboratory.
4.1.3. N-[Indol-3-yl-(4-chlorophenyl)methyl]-4-
methylbenzenesulfonamide 3c
White powder; ½a D25
¼ ꢂ15:1 (c 0.25, CH2Cl2), 91% ee [Daicel
ꢁ
Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 19.01 min, t (major) = 30.66 min]; 1H NMR
(300 MHz, CDCl3): d 2.39 (s, 3H), 5.06 (d, J = 6.6 Hz, 1H), 5.81 (d,
J = 6.6 Hz, 1H), 6.63–6.64 (m, 1H), 7.00–7.21 (m, 8H), 7.29–7.32

L. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 1874–1878
1877
(m, 1H), 7.56 (dd, J = 1.7, 6.5 Hz, 2H), 8.00 (s, 1H); 13C NMR
(300 MHz, DMSO-d6): d 20.8, 53.8, 111.4, 115.1, 118.6, 118.8,
121.2, 123.7, 125.3, 126.4, 127.7, 128.9, 131.2, 136.3, 138.6,
254 nm; t (minor) = 13.10 min, t (major) = 16.95 min]; 1H NMR
(300 MHz, CDCl3): d 2.42 (s, 3H), 5.09 (d, J = 6.1 Hz, 1H), 5.86 (d,
J = 6.1 Hz, 1H), 6.59–6.61 (m, 1H), 7.00–7.05 (m, 1H), 7.15–7.23
(m, 4H), 7.32–7.39 (m, 2H), 7.47–7.51 (m, 2H), 7.57–7.62 (m,
3H), 8.09 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 20.6, 53.6,
110.6, 111.3, 114.6, 118.4, 118.5, 118.6, 121.2, 123.7, 125.0,
126.2, 128.8, 128.9, 130.1, 130.2, 131.8, 136.2, 138.1, 141.9,
140.5, 141.9. HRMS (ESI): m/z calcd for
C22H19ClN2NaO2S
(M+Na+): 433.07480; found: 433.07565.
4.1.4. (S)-N-[Indol-3-yl-(4-bromophenyl)methyl]-4-
methylbenzenesulfonamide 3d
142.5. HRMS (ESI): m/z calcd for C
23H19N3NaO2S (M+Na+):
White powder; ½a D25
ꢁ
¼ ꢂ15:5 (c 0.40, CH2Cl2), 93% ee [Daicel
424.10902; found: 424.10959.
Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 20.13 min, t (major) = 32.53 min]; 1H NMR
(300 MHz, CDCl3): d 2.40 (s, 3H), 5.04 (d, J = 6.5 Hz, 1H), 5.79 (d,
J = 6.5 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 7.00–7.04 (m, 1H), 7.11–
7.21 (m, 6H), 7.29–7.34 (m, 3H), 7.55 (d, J = 8.3 Hz, 2H), 8.00 (s,
1H); 13C NMR (75 MHz, DMSO-d6): d 20.4, 53.4, 111.0, 114.6,
118.1, 118.3, 119.3, 120.8, 123.3, 124.9, 125.9, 128.5, 128.8,
130.2, 135.9, 138.1, 140.5, 141.5. HRMS (ESI): m/z calcd for
4.1.9. N-[Indol-3-yl-(3-bromophenyl)methyl]-4-
methylbenzenesulfonamide 3i
White powder, ½a D25
¼ ꢂ18:2 (c 0.25, CH2Cl2), 90% ee [Daicel
ꢁ
Chiralcel AD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 13.21 min, t (major) = 15.29 min]; 1H NMR
(300 MHz, CDCl3): d 2.39 (s, 3H), 5.07 (d, J = 6.6 Hz, 1H), 5.81 (d,
J = 6.6 Hz, 1H), 6.63–6.64 (m, 1H), 7.03–7.08 (m, 2H), 7.10–7.19
(m, 6H), 7.23–7.33 (m, 4H), 7.54–7.57 (m, 2H), 8.05 (s, 1H); 13C
NMR (75 MHz, DMSO-d6): d 20.5, 53.5, 111.0, 114.6, 118.2, 118.3,
120.9, 123.3, 124.9, 125.8, 125.9, 128.4, 128.5, 129.0, 129.3,
129.5, 135.9, 138.0, 141.6, 143.7. HRMS (ESI): m/z calcd for
C
22H19BrN2NaO2S (M+Na+): 477.02428; found: 477.02388.
4.1.5. N-[Indol-3-yl-(4-cyanphenyl)methyl]-4-
methylbenzenesulfonamide 3e
White powder, ½a D25
ꢁ
¼ ꢂ28:5 (c 0.30, CH2Cl2), 95%ee [Daicel Chi-
C
22H19BrN2NaO2S (M+Na+): 477.002428; found: 477.02443.
ralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 33.99 min, t (major) = 51.88 min]; 1H NMR
(300 MHz, CDCl3): d 2.41 (s, 3H), 5.11 (d, J = 6.2 Hz, 1H), 5.86 (d,
J = 6.1 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 7.01 (t, J = 7.1 Hz, 1H), 7.11
(d, J = 7.8 Hz, 1H), 7.16–7.22 (m, 3H), 7.32 (d, J = 8.2 Hz, 1H), 7.44
(d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H),
8.07 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 21.0, 54.2, 109.5,
111.7, 114.7, 118.8, 118.9, 121.6, 124.0, 125.4, 126.6, 128.2,
129.2, 132.0, 136.5, 138.5, 142.3, 147.3. HRMS (ESI): m/z calcd for
4.1.10. N-[Indol-3-yl-(3-trifluoromethylphenyl)methyl]-4-
methylbenzenesulfonamide 3j
White powder, ½a D25
¼ ꢂ24:0 (c 0.38, CH2Cl2), 88% ee [Daicel
ꢁ
Chiralcel AD-H column), n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 8.29 min, t (major) = 27.50 min]; 1H NMR
(300 MHz, DMSO-d6): d 2.30 (s, 3H), 5.87 (d, J = 9.0 Hz, 1H), 6.73
(d, J = 2.3 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.04–7.11 (m, 3H), 7.32
(d, J = 8.1 Hz, 1H), 7.37–7.41 (m, 2H), 7.47 (d, J = 8.1 Hz, 3H), 7.56
(d, J = 5.6 Hz, 2H), 8.59 (d, J = 9.0 Hz, 1H), 10.92 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d 20.3, 53.5, 111.1, 114.6, 118.2, 118.3,
120.9, 123.0, 123.3, 124.9, 125.9, 128.5, 130.8, 135.9, 138.0,
C
23H19N3NaO2S (M+Na+): 424.10902; found: 424.10948.
4.1.6. N-[Indol-3-yl-(4-trifloromethylphenyl)methyl]-4-
methylbenzenesulfonamide 3f
141.5, 142.3. HRMS (ESI): m/z calcd for C23H19F3N2NaO2S
White powder, ½a D25
ꢁ
¼ ꢂ33:0 (c 0.42, CH2Cl2), 96% ee [Daicel
(M+Na+): 467.10115; found: 467.10052.
Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 18.04 min, t (major) = 29.05 min]; 1H NMR
(300 MHz, DMSO-d6): d 2.26 (s, 3H), 5.82 (d, J = 8.9 Hz, 1H), 6.78
(d, J = 2.3 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 7.04–7.11 (m, 3H),
7.31–7.38 (m, 2H), 7.45–7.50 (m, 6H), 8.58 (d, J = 8.9 Hz, 1H),
10.94 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 20.1, 53.5, 110.9,
114.1, 118.1, 120.8, 123.2, 124.0, 124.1, 124.7, 125.8, 127.3,
128.3, 135.8, 137.8, 141.4, 145.4. HRMS (ESI): m/z calcd for
4.1.11. N-[Indol-3-yl-(2-trifluoromethylphenyl)methyl]-4-
methylbenzenesulfonamide 3k
White powder; ½a D25
¼ ꢂ72:4 (c 0.30, CH2Cl2), 96% ee [Daicel
ꢁ
Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 8.58 min, t (major) = 11.01 min]; 1H NMR
(300 MHz, DMSO-d6): d 2.30 (s, 3H), 6.12 (d, J = 7.9 Hz, 1H), 6.32
(s, 1H), 6.33–6.98 (m, 1H), 6.98–7.16 (m, 3H), 7.28 (d, J = 8.0 Hz,
1H), 7.33 (d, J = 8.1 Hz, 1H), 7.38–7.52 (m, 4H), 7.57 (d, J = 6.9 Hz,
1H), 7.76 (d, J = 7.6 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 10.91 (s, 1H);
13C NMR (75 MHz, DMSO-d6): d 21.0, 49.8, 49.9, 111.7, 115.1,
118.5, 119.0, 121.6, 122.5, 124.7, 125.2, 125.3, 125.4, 125.5,
125.6, 125.9, 126.2, 127.3, 129.1, 129.5, 132.3, 136.5, 138.5,
C
23H19F3N2NaO2S (M+Na+): 467.10115; found: 467.10147.
4.1.7. N-[Indol-3-yl-(3-nitrophenyl)methyl]-4-
methylbenzenesulfonamide 3g
White powder, ½a D25
¼ ꢂ7:2 (c 0.28, CH3CO2C2H5), 89% ee [Dai-
ꢁ
cel Chiralcel AD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 15.29 min, t (major) = 18.97 min]; 1H NMR
(300 MHz, CDCl3): d 2.39 (s, 1H), 5.09 (d, J = 5.9 Hz, 1H), 5.94 (d,
J = 5.9 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 7.01–7.06 (m, 1H), 7.15–
7.24 (m, 4H), 7.34 (d, J = 8.2 Hz, 1H), 7.41–7.47 (m, 1H), 7.60 (d,
J = 8.3 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H), 8.05–8.07 (m, 2H), 8.08 (s,
1H); 13C NMR (75 MHz, DMSO-d6): d 20.4, 53.4, 111.2, 114.3,
118.4, 121.1, 121.2, 121.4, 123.7, 125.0, 126.1, 128.6, 129.0,
133.6, 136.1, 138.0, 141.7, 143.2, 147.2. HRMS (ESI): m/z calcd for
139.9, 142.2. HRMS (ESI): m/z calcd for C23H19F3N2NaO2S
(M+Na+): 467.10115; found: 467.10131.
4.1.12. N-(Indol-3-yl-phenylmethyl)-4-
methylbenzenesulfonamide 3l
White powder; ½a D25
¼ ꢂ10:8 (c 0.25, CH3CO2C2H5), 90% ee [Dai-
ꢁ
cel Chiralcel OD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min,
254 nm; t (minor) = 16.60 min, t (major) = 29.18 min]; 1H NMR
(300 MHz, DMSO-d6): d 2.27 (s, 3H), 5.74 (d, J = 8.6 Hz, 1H), 6.78
(d, J = 2.1 Hz, 1H), 6.85–6.90 (m, 1H), 7.00–7.06 (m, 1H), 7.10–7.20
(m, 5H), 7.24–7.31 (m, 4H), 7.49 (d, J = 8.2 Hz, 2H), 8.47 (d,
J = 8.8 Hz, 1H), 10.86 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 21.0,
54.6, 111.5, 115.8, 118.6, 119.0, 121.3, 123.8, 125.6, 126.5, 126.7,
127.2, 128.0, 129.0, 136.5, 139.0, 141.8, 141.9. HRMS (ESI): m/z
calcd for C22H20N2NaO2S (M+Na+): 399.11377; found: 399.11411.
C
22H19N3NaO4S (M+Na+): 444.09885; found: 444.09898.
4.1.8. N-[Indol-3-yl-(3-cyanphenyl)methyl]-4-
methylbenzenesulfonamide 3h
White powder, ½a D25
¼ ꢂ28:2 (c 0.30, CH2Cl2), 94% ee [Daicel
ꢁ
Chiralcel AD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,

1878
L. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 1874–1878
4.1.13. N-[5-Methoxy-indol-3-yl-(4-
(d, J = 1.9 Hz, 1H), 6.95 (dd, J = 1.8, 8.6 Hz, 1H), 7.07 (d, J = 8.0 Hz,
2H), 7.36–7.39 (m, 2H), 7.42–7.51 (m, 6H), 8.61 (d, J = 8.8 Hz,
1H), 11.07 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d 20.8, 54.0,
111.3, 115.2, 119.2, 120.3, 124.3, 124.9, 125.2, 126.3, 126.6,
128.0, 129.0, 136.9, 138.4, 142.1, 145.8. HRMS (ESI): m/z calcd for
trifluoromethylphenyl)methyl]-4-methylbenzenesulfonamide
3n
White powder; ½a D25
¼ ꢂ24:5 (c 0.30, CH3CO2C2H5), 91% ee [Dai-
ꢁ
cel Chiralcel OD-H column), n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 6.33 min, t (major) = 31.05 min]; 1H NMR
C
23H18ClF3N2NaO2S (M+Na+): 501.06218; found: 501.06350.
(300 MHz, DMSO-d6):
d 2.25 (s, 3H), 3.66 (s, 3H), 5.80 (d,
J = 8.7 Hz, 1H), 6.70–6.74 (m, 2H), 6.87 (d, J = 2.3 Hz, 1H), 7.09 (d,
J = 8.2 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.3 Hz, 6H),
8.57(d, J = 8.8 Hz, 1H), 10.80 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6): d 20.9, 54.3, 55.5, 101.1, 111.6, 112.3, 114.5, 124.7,
124.8, 124.9, 125.9, 126.6, 128.0, 129.1, 131.7, 138.6, 142.2,
Acknowledgments
We are grateful for financial support by the Ministry of Science
and Technology of China (No. 2009BAK61B04), the National Natu-
ral Science Foundation of China (No. 21172255) and the Chinese
Universities Scientific Fund Project (No. 2010JS030).
146.4, 153.3. HRMS (ESI): m/z calcd for
C24H21F3N2NaO3S
(M+Na+): 497.11172; found: 497.11104.
References
4.1.14. N-[5-Methyl-indol-3-yl-(4-
1. For reviews on the Friedel–Crafts reaction, see: (a) Poulsen, T. B.; Jøgensen, K. A.
Chem. Rev. 2008, 108, 2903; (b) Bandini, M.; Umani-Ronchi, A. Catalytic
Asymmetric Friedel–Crafts Alkylation; Wiley-VCH: Weinheim, Germany, 2009. p
1.
2. (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278–311; (b) Faulkner, D. J.
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Academic: New York, 1996. pp 105–118.
trifluoromethylphenyl)methyl]-4-methylbenzenesulfonamide
3o
White powder; ½a D25
¼ ꢂ25:0 (c 0.28, CH3CO2C2H5), 95% ee [Dai-
ꢁ
cel Chiralcel OD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 7.32 min, t (major) = 18.25 min]; 1H NMR
(300 MHz, DMSO-d6):
d 2.27 (s, 3H), 2.29 (s, 3H), 5.76 (d,
3. For recent reviews on the asymmetric Friedel–Crafts reaction of indoles, see:
(a) Husmann, R.; Sugiono, E.; Mersmann, S.; Raabe, G.; Rueping, M.; Bolm, C.
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Q.; Zhang, A.-J.; You, S.-L. Chem. Eur. J. 2009, 15, 3351–3354; (f) Cui, H. L.; Feng,
X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y. C. Angew. Chem. 2009, 121, 5847–5849.
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Chem. Soc. 2007, 129, 10029–10041.
J = 8.2 Hz, 1H), 6.66 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H),
6.98 (s, 1H), 7.14–7.21 (m, 3H), 7.47–7.53 (m, 6H), 8.52 (d,
J = 8.3 Hz, 1H), 10.81 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d
20.5, 20.9, 53.6, 110.9, 113.8, 117.8, 122.7, 123.8, 124.4, 124.5,
125.4, 126.2, 126.9, 127.5, 128.7, 134.4, 138.1, 141.8, 146.2.
HRMS (ESI): m/z calcd for
481.11680; found: 481.11710.
C
24H21F3N2NaO2S (M+Na+):
4.1.15. N-[5-Chloro-indol-3-yl-(4-
trifluoromethylphenyl)methyl]-4-methylbenzenesulfonamide
3p
4. Johannsen, M. Chem. Commun. 1999, 2233–2234.
White powder; ½a D25
¼ ꢂ28:2 (c 0.28, CH3CO2C2H5), 97% ee [Dai-
ꢁ
5. Jia, Y.; Xie, J.; Duan, H.; Wang, L.; Zhou, Q. Org. Lett. 2006, 8, 1621–1624.
6. Wang, Y.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156–
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7. Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484–1485.
8. Wang, B.-L.; Li, N.-K.; Zhang, J.-X.; Liu, G.-G.; Liu, T.; Shen, Q.; Wang, X.-W. Org.
Biomol. Chem. 2011, 9, 2614–2617.
cel Chiralcel OD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,
254 nm; t (minor) = 5.04 min, t (major) = 12.49 min]; 1H NMR
(300 MHz, DMSO-d6): d 2.27 (s, 3H), 5.81(d, J = 8.2 Hz, 1H), 6.82
(d, J = 2.2 Hz, 1H), 7.04–7.07 (m, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.26
(d, J = 1.9 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.44–7.55 (m, 6H), 8.59
(d, J = 8.3 Hz, 1H), 11.14 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d
20.9, 53.8, 113.2, 114.7, 118.1, 121.5, 123.6, 124.9, 125.0, 126.1,
126.6, 128.0, 129.2, 135.0, 138.4, 142.3, 146.1. HRMS (ESI): m/z
9. (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505–2550; (b) Desimoni,
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W.; Jensen, V.; Le Roux, R. E. J. Organomet. Chem. 2011, 696, 1691–1697; (b)
Lang, K.; Park, J. w.; Hong, S. J. Org. Chem. 2010, 75, 6424–6435; (c) Frain, D.;
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calcd for
501.06305.
C
23H18ClF3N2NaO2S (M+Na+): 501.06218; found:
4.1.16. N-[6-Chloro-Indol-3-yl-(4-
trifluoromethylphenyl)methyl]-4-methylbenzenesulfonamide
3q
White powder; ½a D25
¼ ꢂ50:0 (c = 0.15, CH2Cl2), >99%ee [Daicel
ꢁ
Chiralcel OD-H column, n-hexane/i-PrOH = 70:30, 1.0 mL/min,
11. Sun, Y.-J.; Li, N.; Zheng, Z. B.; Liu, L.; Yu, Y.-B.; Qin, Z.-H.; Fu, B. Adv. Synth. Catal.
2009, 351, 3113–3117.
254 nm;
(300 MHz, DMSO-d6): d 2.25 (s, 3H), 5.82 (d, J = 8.8 Hz, 1H), 6.82
t (minor) = 5.14 min, t
(major) = 8.57 min]; 1H NMR