Chiral bis(Oxazolinyl)thiophenes for enantioselective Cu(II)-catalyzed friedel-crafts alkylation of indole derivatives with nitroalkenes

Article abstract of DOI:10.1007/s10562-014-1228-2

A series of chiral bis(oxazoline)thiophenes were used as chiral ligands in the Cu(II)-catalyzed asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes, and the effects of reaction conditions on the yield and enantioselectivity were investigated. The ligand 1c was identified as the best ligand of this family in the same reaction. Springer Science+Business Media New York 2014.

Full text of DOI:10.1007/s10562-014-1228-2

Catal Lett (2014) 144:943–948
DOI 10.1007/s10562-014-1228-2
Chiral Bis(Oxazolinyl)thiophenes for Enantioselective
Cu(II)-Catalyzed Friedel–Crafts Alkylation of Indole
Derivatives with Nitroalkenes
Weijie Li
Received: 24 January 2014 / Accepted: 23 February 2014 / Published online: 12 March 2014
Ó Springer Science+Business Media New York 2014
Abstract A series of chiral bis(oxazoline)thiophenes were
used as chiral ligands in the Cu(II)-catalyzed asymmetric
Friedel–Crafts alkylation of indole derivatives with nitroal-
kenes, and the effects of reaction conditions on the yield and
enantioselectivity were investigated. The ligand 1c was
identified as the best ligand of this family in the same reaction.
indole derivatives in asymmetric Friedel–Crafts alkylations
and exhibit excellent enantioselectivities in most cases [30–
37]. Although chiral bis(oxazoline)thiophenes have been
synthesized and found to perform well in cyclopropanation
of 1,1-diphenylethene with EDA [38, 39], their development
and application are still lacking. As a rational extension of
my project, I would like to report my recent results on the
enantioselective Cu(OTf)2-catalyzed Friedel–Crafts alkyl-
ation of indole derivatives with nitroalkenes using bis(ox-
azoline)thiophenes as chiral ligands (Fig. 1).
Keywords Bis(oxazolinyl)thiophene Á Asymmetric
catalysis Á Friedel–Crafts alkylation Á Indole derivative Á
Nitroalkene
1 Introduction
2 Experimental
Indole ring is an important moiety that is present in many
natural alkaloids and bioactive molecules. Since its discov-
ery in 1869, indole and its derivatives have been widely
applied in pharmaceuticals, fragrances, agrochemicals,
pigments and material science [1, 2]. Owing to the impor-
tance of the indole framework-containing compounds, the
development of new strategies to synthesize indole deriva-
tives remain a subject of interest in the present days. During
the past several years, Friedel–Crafts alkylation using metal-
based chiral catalysts or chiral organocatalyts was the most
frequently employed tool for the synthesis of 3-substituted
indole derivatives [3–37]. In particular, chiral oxazoline-
containing ligands have been applied to prepare the alkylated
2.1 General Information
Thiophene-2,5-dicarboxylic acid and Cu(II) trifluoro-
methanesulfonate were purchased from Alfa Aesar Co.
Bis(oxazolinyl)thiophenes (1a–e) were prepared according to
the literature’s method [39]. Other reagents were of all ana-
lytical grade. Silica gel (200–300 mesh) was used for flash
chromatography purchased from Qingdao Haiyang Chemis-
1
try Company. H and 13C NMR were recorded on Bruker
DRX-500, DRX-400, DRX-300 or DRX-100 NMR spec-
trometers, using TMS as internal standard. ESI-MS were
measured on a MDS Sciex API 2000 LC/GC/MS instrument.
Optical rotation values were tested on a Polartronic HNQW 5
polarimeter. HPLC analysis was measured using a Daicel
Chiracel OD-H or Daicel Chiralpak AD-H column.
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-014-1228-2) contains supplementary
material, which is available to authorized users.
2.2 General Procedure for Enantioselective Friedel–
Crafts Alkylation Reactions
W. Li (&)
Department of Chemistry, Hanshan Normal University,
Chaozhou 521041, China
e-mail: weijieli1688@126.com
To a three-neck flask were added 0.01 mmol of the ligand
1, 3.6 mg (0.01 mmol) of Cu(OTf)2 and 5.0 ml ethyl ether
123

944
W. Li
Fig. 1 Structures of
bis(oxazoline)thiophene
ligands
3H), 6.97 (dd, J1 = 1.4 Hz, J2 = 8.4 Hz, 1H), 7.20–7.26
(m, 1H), 7.28–7.40 (m, 5H), 7.45–7.54 (m, 2H), 10.12 (s,
1H); 13C NMR (100 MHz, CD3COCD3): d = 21.6, 42.3,
80.2, 112.1, 114.3, 119.0, 123.0, 124.3, 127.6, 127.9,
128.8, 129.4, 136.1, 141.4; ESI-MS: m/z (%) = 281
([M?H]?, 100).
O
O
S
N
N
R
1
R
1a: R=Et
1b: R=i-Pr
1c: R=t-Bu
1d: R=Ph
1e: R=Bn
2.2.3 (S)-5-Methoxy-3-(2-Nitro-1-Phenylethyl)-1H-Indole
(4c)
under the protect of nitrogen atmosphere. The mixture was
refluxed for 30 min and cooled to ambient temperature,
then nitroalkene (0.25 mmol) was added. The mixture was
stirred for another 20 min at the same temperature and
cooled to -10 °C. Indole derivative (0.25 mmol) was
added at -10 °C. After completion of the addition, the
mixture was stirred at the same temperature until indole
derivative had disappeared. Ethyl ether was removed and
the residue was purified by flash chromatography on silica
gel, using petroleum ether–ethyl acetate 5:1–3:1 as eluent
to give the desired products. The configurations of the
products were determined by optical rotation and the
enantiomeric excesses were determined by HPLC analysis
using a Diacel Chiracel OD-H or Daicel Chiralpakl AD-H
column.
Yield: 94 %; colorless solid; mp 133–135 °C ; HPLC
analysis [Daicel Chiralcel OD-H, 15 % i-PrOH/hexane,
1.0 ml/min; tminor 27.8 min, tmajor 33.5 min, k = 254 nm
(UV)] gave the isomeric composition of the product: 98 %
ee; [a]2D0 = -33.3 (c 1.0, CH2Cl2) [Lit [17]. [a]2D0 = ?25.3
(c 0.4, CH2Cl2), 41 % ee, (R) configuration]; 1H NMR
(300 MHz, CDCl3): d = 3.73 (s, 3H), 4.90–5.02 (m, 2H),
5.59 (dd, J1 = 7.0 Hz, J2 = 8.5 Hz, 1H), 6.80 (t,
J = 7.2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.01–7.25 (m,
6H), 7.46 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H); 13C NMR
(500 MHz, CDCl3): d = 41.6, 56.0, 79.6, 100.9, 112.2,
112.9, 114.2, 122.4, 126.7, 127.7, 127.9, 129.1, 131.7,
139.5, 154.2; ESI-MS: m/z (%) = 297 ([M?H]?, 100).
2.2.4 (S)-5-Fluoro-3-(2-Nitro-1-Phenylethyl)-1H-Indole
(4d)
2.2.1 (S)-3-(2-Nitro-1-Phenylethyl)-1H-Indole (4a)
Yield: 93 %, yellow oil; HPLC analysis (Daicel Chiralpakl
AD-H, 10 % i-PrOH/hexane, 1.0 ml/min; tminor 19.4 min,
tmajor 23.0 min, k = 254 nm) gave the isomeric composi-
tion of the product: 94 % ee; [a]2D0 = ?20.5 (c 1.0, CH2-
Cl2); 1H NMR (400 MHz, CD3COCD3): d = 5.16–5.38
(m, 3H); 6.92 (m, 1H), 7.21–7.24 (m, 2H), 7.30–7.33 (m,
2H), 7.42 (dd, J1 = 4.5 Hz, J2 = 8.8 Hz, 1H), 7.46–7.55
(m, 3H), 10.38 (s, 1H); 13C NMR (100 MHz, CD3COCD3)
d = 42.1, 80.1, 104.3 (d, JC-F = 23.6 Hz), 110.8 (d, JC-
Yield: 99 %; white solid; mp 114–116 °C; HPLC analysis
[Daicel Chiralcel OD-H, 35 % i-PrOH/hexane, 1.0 ml/min;
tmajor 18.7 min, tminor 22.6 min, k = 254 nm (UV)] gave
the isomeric composition of the product: 97 % ee;
[a]D20 = ?32.5 (c 1.0, CH2Cl2) [Lit [34]. [a]2D0 = ?25.3
1
(c 0.9, CH2Cl2), 84 % ee]; H NMR (500 MHz, CDCl3):
d = 4.93 (dd, J1 = 8.5 Hz, J2 = 12.5 Hz, 1H), 5.06 (dd,
J1 = 7.6 Hz, J2 = 12.5 Hz, 1H), 5.18 (t, J = 8.0 Hz, 1H),
7.02 (d, J = 2.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H),
7.16–7.36 (m, 7H), 7.42 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H);
13C NMR (500 MHz, CDCl3): d = 41.6, 79.7, 111.5,
114.7, 119.1, 120.1, 121.7, 122.9, 126.3, 127.7, 127.9,
129.1, 136.7, 139.2; ESI-MS: m/z (%) = 267 ([M?H]?,
100).
= 26.5 Hz), 113.4 (d, JC-F = 9.6 Hz), 115.1 (d, JC-
F
= 4.6 Hz), 125.0, 127.7 (d, JC-F = 9.6 Hz), 128.1,
F
128.8, 129.5, 134.3, 141.2, 158.4 (d, JC-F = 232.5 Hz);
ESI-MS: m/z (%) = 285 ([M?H]?, 100).
2.2.5 (S)-5-Chloro-3-(2-Nitro-1-Phenylethyl)-1H-Indole
(4e)
2.2.2 (S)-5-Methyl-3-(2-Nitro-1-Phenylethyl)-1H-Indole
(4b)
Yield: 90 %; colorless solid; mp 133–134 °C; HPLC ana-
lysis [Daicel Chiralcel OD-H, 30 % i-PrOH/hexane,
1.0 ml/min; tminor 13.5 min, tmajor 15.1 min, k = 254 nm
(UV)] gave the isomeric composition of the product: 89 %
ee; [a]2D0 = -31.0 (c 1.0, CH2Cl2) [Lit [3]. [a]rDt = ?18
Yield: 95 %; colorless solid; mp 138–140 °C; HPLC ana-
lysis [Daicel Chiralcel OD-H, 20 % i-PrOH/hexane,
1.0 ml/min; tminor 31.7 min, tmajor 37.1 min, k = 254 nm
(UV)] gave the isomeric composition of the product: 98 %
ee; [a]2D0 = -13.3 (c 1.0, CH2Cl2) [Lit [12]. [a]2D0 = ?9.7
(c 0.9, CH2Cl2), 97 % ee, (R) configuration]; 1H NMR
(400 MHz, CD3COCD3): d = 2.38 (s, 3H), 5.12–5.36 (m,
1
(c 0.370, CHCl3), 71 % ee, (R) configuration]; H NMR
(400 MHz, CDCl3) d = 4.90 (dd, J1 = 8.0 Hz,
J2 = 12.5 Hz, 1H), 5.01 (dd, J1 = 8.0 Hz, J2 = 12.5 Hz,
1H), 5.11 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H),
123

Chiral Bis(Oxazolinyl)thiophenes for Enantioselective Cu(II)
945
7.16–7.35 (m, 7H), 7.53 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H);
13C NMR (100 MHz, CDCl3): d = 41.3, 79.4, 112.9,
113.5, 114.2, 121.6, 122.8, 125.7, 127.7, 127.8, 128.0,
129.2, 135.2, 138.8; ESI-MS: m/z (%) = 301 ([M?H]?,
100).
J2 = 12.6 Hz, 1H), 5.01 (dd, J1 = 7.5 Hz, J2 = 12.6 Hz,
1H), 5.13 (d, J = 8.0 Hz, 1H), 7.01 (dd, J1 = 0.6 Hz,
J2 = 2.5 Hz, 1H), 7.07 (m, 1H), 7.16–7.28 (m, 3H), 7.34
(d, J = 8.2 Hz, 1H), 7.38 (m, 1H), 7.41 (dd, J1 = 0.7 Hz,
J2 = 8.0 Hz, 1H), 7.44 (t, J = 1.8 Hz, 1H), 8.07 (s, 1H);
13C NMR (100 MHz, CDCl3): d = 41.2, 79.3, 111.7,
113.9, 118.9, 120.4, 121.7, 123.1, 123.3, 126.1, 126.6,
130.6, 131.0, 131.3, 136.7, 141.7; ESI-MS: m/z (%) = 346
([M?H]?, 100).
2.2.6 (S)-3-[1-(2-Methoxyphenyl)-2-Nitroethyl]-1H-Indole
(4f)
Yield: 96 %; colorless solid; mp 92–95 °C; HPLC analysis
[Daicel Chiralcel OD-H, 30 % i-PrOH/hexane, 1.0 ml/min;
2.2.9 (S)-3-[1-(3-Nitrophenyl)-2-Nitroethyl]-1H-Indole
t
minor 13.4 min, tmajor 15.3 min, k = 254 nm (UV)] gave the
(4i)
isomeric composition of the product: 88 % ee; [a]D20
=
-57.0 (c 1.0, CH2Cl2) [Lit [34]. [a]2D0 = ?49.6 (c 0.75,
CH2Cl2), 61 % ee, (R) configuration]; 1H NMR (400 MHz,
CD3COCD3): d = 3.94 (s, 3H), 5.19 (dd, J1 = 1.5 Hz,
J2 = 8.0 Hz, 2H), 5.64 (t, J = 8.0 Hz, 1H), 6.85 (t,
J = 7.5 Hz, 1H), 6.95–7.06 (m, 2H), 7.08–7.16 (m, 1H),
7.18–7.29 (m, 2H), 7.36–7.45 (m, 2H), 7.53 (d, J = 8.0 Hz,
1H), 10.27 (s, 1H); 13C NMR (100 MHz, CD3COCD3):
d = 35.9, 56.1, 78.9, 111.9, 112.4, 114.4, 119.5, 119.9,
121.4, 122.6, 123.5, 127.7, 129.0, 129.3, 129.6, 137.8, 158.0;
ESI-MS: m/z (%) = 297 ([M?H]?, 100).
Yield: 97 %; yellow oil; HPLC analysis [Daicel Chiralcel
OD-H, 30 % i-PrOH/hexane, 1.0 ml/min; tmajor 34.5 min,
tminor 48.4 min, k = 254 nm (UV)] gave the isomeric
composition of the product: 92 % ee; [a]2D0 = ?12.7 (c 1.0,
CH2Cl2) [Lit [12]. [a]2D0 = -17.9 (c 0.48, CH2Cl2), 95 %
ee, (R) configuration]; 1H NMR (300 MHz, CDCl3):
d = 5.02 (dd, J1 = 9.0 Hz, J2 = 12.6 Hz, 1H), 5.12 (dd,
J1 = 6.9 Hz, 1H), 5.33 (t, J = 7.8 Hz, 1H), 7.10–7.13 (m,
2H), 7.24 (t, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H),
7.53 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 8.16 (d,
J = 8.1 Hz, 1H), 8.23 (s, 1H), 8.25 (s, 1H); 13C NMR (100
MHz, CDCl3): d = 41.1, 78.7, 111.7, 112.8, 118.5, 120.1,
121.5, 122.5, 122.7, 123.1, 125.5, 129.8, 134.0, 136.5,
141.6, 148.6; ESI-MS: m/z (%) = 312 ([M?H]?, 100).
2.2.7 (S)-3-[1-(2-Chlorophenyl)-2-Nitroethyl]-1H-Indole
(4g)
Yield: 87 %; colorless oil; HPLC analysis [Daicel Chiral-
cel OD-H, 30 % i-PrOH/hexane, 1.0 ml/min; tminor
16.5 min, tmajor 25.8 min, k = 254 nm (UV)] gave the
isomeric composition of the product: 73 % ee;
[a]D20 = ?80.2 (c 1.0, CH2Cl2) [Lit [34]. [a]2D0 = ?79.4
2.2.10 (S)-3-[1-(4-Methoxyphenyl)-2-Nitroethyl]-1H-
Indole (4j)
Yield: 90 %; colorless solid; mp 142–144 °C; HPLC ana-
lysis [Daicel Chiralcel OD-H, 30 % i-PrOH/hexane,
1.0 ml/min; tmajor 19.1 min, tminor 24.7 min, k = 254 nm
(UV)] gave the isomeric composition of the product: 91 %
ee; [a]2D0 = ?30.5 (c 1.0, CH2Cl2) [Lit [17]. [a]2D0 = -11.8
1
(c 0.95, CH2Cl2), 72 % ee]; H NMR (400 MHz, CD3-
COCD3): d = 5.23 (dd, J1 = 7.8 Hz, J2 = 13.2 Hz, 1H),
5.32 (dd, J1 = 8.3 Hz, J2 = 13.2 Hz, 1H), 5.76 (t,
J = 8.0 Hz, 1H), 6.98–7.06 (m, 1H), 7.08–7.15 (m, 1H),
7.21–7.31 (m, 2H), 7.43 (m, 2H), 7.44–7.50 (m, 1H),
7.51–7.54 (m, 1H), 7.56 (d, J = 7.9 Hz, 1H), 10.33 (s, 1H);
13C NMR (100 MHz, CDCl3): d = 38.1, 77.8, 111.5,
113.3, 119.0, 120.1, 120.1, 122.1, 122.9, 126.3, 127.4,
129.0, 129.1, 130.2, 133.9, 136.6; ESI-MS: m/z (%) = 301
([M?H]?, 100).
1
(c 0.11, CH2Cl2), 44 % ee, (R) configuration]; H NMR
(500 MHz, CDCl3): d = 3.78 (s, 3H), 4.89 (dd,
J1 = 8.4 Hz, J2 = 12.3 Hz, 1H), 5.03 (dd, J1 = 7.5 Hz,
J2 = 12.3 Hz, 1H), 5.14 (t, J = 8.0 Hz, 1H), 6.81–6.87
(m, 2H), 7.00 (dd, J1 = 0.7 Hz, J2 = 2.5 Hz, 1H), 7.06 (t,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.21–7.25 (m,
2H), 7.35 (d, J = 8.1 Hz, 1H), 7.44 (dd, J1 = 0.7 Hz,
J2 = 8.0 Hz, 1H), 8.06 (s, 1H); 13C NMR (100 MHz,
CDCl3): d = 41.1, 55.4, 80.0, 111.5, 114.5, 115.0, 119.2,
120.2, 121.6, 122.9, 126.3, 129.0, 131.4, 136.8, 159.2; ESI-
MS: m/z (%) = 297 ([M?H]?, 100).
2.2.8 (S)-3-[1-(3-Bromophenyl)-2-Nitroethyl]-1H-Indole
(4h)
Yield: 95 %; colorless oil; HPLC analysis [Daicel Chiral-
cel OD-H, 30 % i-PrOH/hexane, 1.0 ml/min; tmajor
21.7 min, tminor 30.8 min, k = 254 nm (UV)] gave the
isomeric composition of the product: 94 % ee;
[a]D20 = ?13.5 (c 1.0, CH2Cl2) [Lit [12]. [a]2D0 = -15.8
2.2.11 (S)-3-[1-(4-Chlorophenyl)-2-Nitroethyl]-1H-Indole
(4k)
1
(c 0.64, CH2Cl2), 97 % ee, (R) configuration]; H NMR
Yield: 94 %; colorless solid; mp 133–134 °C; HPLC ana-
lysis (Daicel Chiralcel OD-H, 30 % i-PrOH/hexane,
(500 MHz, CDCl3): d = 4.88 (dd, J1 = 8.4 Hz,
123

946
W. Li
1.0 ml/min; tmajor 22.4 min, tminor 29.0 min, k = 254 nm)
gave the isomeric composition of the product: 95 % ee;
[a]2D0 = ?7.9 (c 1.0, CH2Cl2) [Lit [34]. [a]2D0 = ?7.5
(c 1.2, CH2Cl2), 82 % ee]; 1H NMR (400 MHz, CD3-
COCD3): d = 5.17–5.34 (m, 3H), 7.01–7.10 (m, 1H),
7.11–7.15 (m, 1H), 7.36–7.31 (m, 2H), 7.42 (m, 2H),
7.45–7.50 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 10.30 (s, 1H);
13C NMR (100 MHz, CD3COCD3): d = 41.6, 79.9, 112.5,
114.4, 119.4, 120.1, 122.8, 123.0, 127.2, 129.4, 130.6,
133.2, 137.8, 140.5; ESI-MS: m/z (%) = 301 ([M?H]?,
100).
1H NMR (400 MHz, CD3COCD3): d = 0.82 (t,
J = 6.5 Hz, 3H), 1.21–1.38 (m, 4H), 1.75–1.96 (m, 2H),
3.78–3.81 (m, 1H), 4.85 (d, J = 7.6 Hz, 1H), 7.04 (t,
J = 7.5 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.29 (s, 1H),
7.43 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 10.18
(s, 1H); 13C NMR (100 MHz, CD3COCD3) d = 14.2, 23.2,
30.1, 33.3, 37.0, 81.4, 112.5, 114.5, 119.4, 119.8, 122.4,
123.5, 127.5, 137.9; ESI-MS: m/z (%) = 247 ([M?H]?,
100).
3 Results and Discussion
2.2.12 (S)-3-[1-(4-Bromophenyl)-2-Nitroethyl]-1H-Indole
(4l)
The Friedel–Crafts alkylation reaction, one of the oldest
organic synthetic methods, is one of the most powerful car-
bon–carbon bond forming reaction. In the Cu(OTf)2-
Yield: 93 %; colorless solid; mp 148–149 °C; HPLC ana-
lysis [Daicel Chiralcel OD-H, 30 % i-PrOH/hexane,
1.0 ml/min; tmajor 26.5 min, tminor 36.6 min, k = 254 nm
(UV)] gave the isomeric composition of the product: 95 %
Table 1 Enantioselective Cu(II)-catalyzed Friedel–Crafts alkylation
of indole with b-nitrostyrene using the ligands 1a–e
ee; [a]2D0 = -2.7 (c 1.0, CH2Cl2); H NMR (400 MHz,
1
CD3COCD3): d = 5.18–5.35 (m, 3H), 7.02 (t, J = 7.5 Hz,
1H), 7.14 (t, J = 7.6 Hz, 1H), 7.41–7.44 (m, 4H),
7.45–7.56 (m, 3H), 10.30 (s, 1H); 13C NMR (100 MHz,
CD3COCD3): d = 41.7, 79.8, 112.5, 114.3, 119.4, 120.1,
121.4, 122.8, 123.0, 127.2, 130.9, 132.4, 137.8, 140.9; ESI-
MS: m/z (%) = 346 ([M?H]?, 100).
NO2
Ligand 1, Cu(OTf)2
NO2
+
N
N
H
H
3a
4a
2a
Entry Ligand Loading
(mol %)a
Solvent t (h)
T
Yield
ee
(%)c
2.2.13 (S)-3-(1-Furan-2-yl-2-Nitroethyl)-1H-Indole (4m)
(°C) (%)b
Yield: 86 %; yellow oil; HPLC analysis [Daicel Chiralcel
OD-H, 30 % i-PrOH/hexane, 1.0 ml/min; tminor 14.5 min,
tmajor 20.0 min, k = 254 nm (UV)] gave the isomeric
composition of the product: 82 % ee; [a]2D0 = -39.8 (c 1.0,
CH2Cl2) [Lit [13]. [a]2D0 = ?38.2 (c 1.02, CH2Cl2), 95 %
ee, (R) configuration];
1H NMR (400 MHz, CD3COCD3): d = 5.17 (dd,
J1 = 7.3 Hz, J2 = 12.3 Hz, 1H), 5.20–5.31 (m, 2H), 6.29
(d, J = 3.2 Hz, 1H), 6.36 (dd, J1 = 1.9 Hz, J2 = 3.2 Hz,
1H), 7.01–7.10 (m, 1H), 7.11–7.19 (m, 1H), 7.36 (d,
J = 2.5 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.48 (dd,
J1 = 0.7 Hz, J2 = 1.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H),
10.29 (s, 1H); 13C NMR (100 MHz, CD3COCD3):
d = 36.4, 78.7, 107.6, 111.2, 112.1, 112.6, 119.4, 120.1,
122.7, 124.2, 127.0, 137.7, 143.1, 154.3; ESI-MS: m/z
(%) = 257 ([M?H]?, 100).
1
1a
1b
1c
1d
1e
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
1.0
2.0
3.0
5.0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
20
20
20
20
20
10
12
36
-10 94
-10 98
-10 99
-10 96
-10 95
84
93
97
89
87
86
90
98
86
82
80
80
89
94
98
2
3
4
5
6
0
95
7
-5 93
-20 90
-10 95
-10 96
-10 92
-10 76
-10 87
-10 94
-10 99
8
9
CH2Cl2 20
THF 10
Toluene 20
10
11
12
13
14
15
Et2O
Et2O
Et2O
Et2O
20
20
20
20
The catalyst was prepared in situ by refluxing ligand 1 and Cu(OTf)2
in 5 ml of solvent
2.2.14 (S)-3-(1-Nitrohexan-2-yl)-1H-Indole (4n)
a
Loading: catalyst/indole (molar ratio)
b
Conditons: indole (0.25 mmol), b-nitrostyrene (0.25 mmol) and
solvent (5.0 ml). The reactions were performed under the protect of a
Yield: 92 %; yellow oil; HPLC analysis [Daicel Chiralcel
OD-H, 10 % i-PrOH/hexane, 1.0 ml/min; tminor 35.7 min,
tmajor 39.6 min, k = 254 nm (UV)] gave the isomeric
composition of the product: 93 % ee; [a]2D0 = -33.3 (c 1.0,
CH2Cl2) [Lit [6]. [a]D20 = -30.6 (c 1.0, CH2Cl2), 91 % ee];
nitrogen atmosphere
c
Enantiomeric excess was determined by HPLC using a Daicel
Chiracel OD-H column. All absolute configurations were determined
as S by optical roation measurements
123

Chiral Bis(Oxazolinyl)thiophenes for Enantioselective Cu(II)
947
Table 2 Enantioselective Cu(II)-catalyzed Friedel–Crafts alkylation of indole derivatives with nitroalkenes using the ligand 1c
R2
R1
NO2
R1
Ligand 1c, Cu(OTf)2
NO2
+
R2
N
H
N
H
4a-n
3a-j
2a-d
Entry
Product
R1
R2
Yield (%)a
ee (%)b
1
4a
4b
4c
H
Ph
99
95
94
93
90
96
87
95
97
90
94
93
86
92
97
98
98
94
89
88
73
94
92
91
95
95
82
93
2
Me
MeO
F
Ph
3
Ph
4
4d
4e
Ph
5
Cl
H
Ph
6
4f
2-MeOC6H4
2-ClC6H4
3-BrC6H4
3-NO2C6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-Furyl
CH3(CH2)3
7
4 g
4 h
4i
H
8
H
9
H
10
11
12
13
14
a
4j
H
4 k
4 l
4 m
4n
H
H
H
H
Conditions: catalyst/indole derivative = 4.0 mol %, indole derivative (0.25 mmol), nitroalkene (0.25 mmol), ethyl ether (5.0 ml), -10 °C,
20 h
b
Enantiomeric excesses were determined by HPLC using a Daicel Chiracel OD-H or Daicel Chiralpakl AD-H column. All absolute config-
urations were determined as S by optical rotation measurements
catalyzed asymmetric Friedel–Crafts alkylation of indole 2a
with b-nitrostyrene 3a, the catalytic activities of bis(oxazo-
line)thiophenes 1a–e in hand was first tested. The results are
summarized in Table 1. The enantioselectivity of Cu(II)–
bis(oxazoline)thiophene complexes is sensitive to the sub-
stituentson theoxazolinering. Good yields and enantiomeric
excesses can be obtained for ligands 1b and 1c with the
bulkier isopropyl and tert-butyl substituents (entries 2, 3 vs.
entries 1, 4, 5). Of them, the ligand 1c achieved the best
enantioselectivity. Next, the effect of temperature on the
catalytic reaction with bis(oxazoline)thiophene 1c as a chiral
ligand was investigated with Et2O as solvent. The reaction
proved to be temperature-dependent. When the reaction
temperature was decreased from 0 to -10 °C, the enantio-
meric excess value of the product 4a increased from 86 to
97 % (entries 3, 6 , 7). Although the catalytic reaction pro-
ceeded well at -20 °C, the reaction time was prolonged to
36 h and the ee value of 4a showed no significant improve-
ment (entry 8). As for solvent effect, the reaction exhibited a
preference for Et2O as solvent (entry 3). The use of aprotic
solvents such as dichloromethane, tetrahydrofuran and tol-
uene afforded 4a in good yield with middle enantioselec-
tivity (entries 9–11). Further, catalyst loadings were
investigated, and the results indicated that they were gener-
ally employed at 4.0 mol %, relative to indole 2a (entry 3 vs.
entries 12–14). The enantioselectivity can be slightly
improved to 98 % ee when the catalyst loading increased
from 4.0 to 5.0 mol % (entry 3 vs. entry 15).
After the reaction conditions were optimized, the gen-
erality of this reaction was further evaluated by examining
a variety of structurally different indole derivatives and
nitroalkenes (Table 2). High yields and excellent enanti-
oselectivities can be achieved for the indole derivatives
with both electron-donating and electron-deficient groups
in the five position (entries 1–5). The ortho-substitution on
the phenyl in nitrostyrenes, either electron-donating or
electron-withdrawing groups, decreased the enantiomeric
excess of products, perhaps due to the steric effect of ortho-
substitutes (entries 6 , 7). Meta or para-substitution on the
phenyl in nitrostyrenes and aliphatic-substituted nitroal-
kenes all reacted well with indole to give the alkylated
indoles in good yields and high enantioselectivities (entries
8–12 , 14). The nitroalkene containing furan gave 86 %
yield and 82 % ee (entry 13).
The Cu(II)-catalyzed asymmetric Friedel–Crafts alkyl-
ation of indole derivatives with nitroalkenes using the
123

948
W. Li
10. Rueping M, Nachtsheim BJ (2010) Beilstein J Org Chem 6:1
bis(oxazoline)thiophenes 1a–e can be achieved in the high
yields and excellent enantioselectivities in most cases, but
its catalytic mechanism is not clear at this stage. All
absolute configurations of the alkylated indole derivatives
4a–n were established as S by comparison of their optical
properties with those reported in the literatures [3, 6, 12,
17, 26, 34].
11. Kim HY, Kim S, Oh K (2010) Angew Chem Int Ed 49:1
12. Liu H, Du DM (2010) Adv Synth Catal 352:1113
13. Guo FF, Lia GY, Xiong SS, Wang SJ, Wang ZY (2010) Chem
Eur J 16:6433
14. Arai T, Awata A, Wasai M, Yokoyama N, Masu H (2011) J Org
Chem 76:5450
15. Lin S, Jacobsen EN (2012) Nat Chem 4:817
16. Chauhan P, Chimni SS (2012) R Soc Chem Adv 2:6117
17. Chen LY, Guillarme S, Saluzzo C (2013) Arkivoc 3:227
18. You SL, Cai Q, Zeng M (2009) Chem Soc Rev 38:2190
19. Lin SZ, You TP (2009) Tetrahedron 65:1010
20. Wu LY, Hao XQ, Xu YX, Jia MQ, Wang TN, Gong JF, Song MP
(2009) Organometallics 28:3369
4 Conclusion
With chiral bis(oxazoline)thiophenes 1a–e as templates,
the Cu(II)-catalyzed asymmetric Friedel–Crafts alkylation
of indole derivatives with nitroalkenes was investigated. In
most cases, the catalytic system with the ligand 1c and
Cu(II) trifluoromethanesulfonate gave the best yields (up to
99 %) and enantioselectivities (up to 98 % ee).
21. McKeon SC, Mu¨ller-Bunz H, Guiry PJ (2009) Eur J Org Chem
2009:4833
22. Yokoyama N, Arai T (2009) Chem Commun 22:3285
23. Kim HY, Kim S, Oh K (2010) Angew Chem Int Ed 49:4476
24. Terrasson V, De Figueiredo RM, Campagne JM (2010) Eur J Org
Chem 2010:2635
25. Zeng M, You SL (2010) Synlett 9:1289
26. Wu J, Li X, Wu F, Wan B (2011) Org Lett 13:4834
27. McKeon SC, Mu¨ller-Bunz H, Guiry PJ (2011) Eur J Org Chem
2011:7107
28. Hao XQ, Xu YX, Yang MJ, Wang L, Niu JL, Gong JF, Song MP
(2012) Organometallics 31:835
References
29. Chen LA, Tang X, Xi J, Xu W, Gong L, Meggers E (2013)
Angew Chem Int Ed 52:14021
1. Sundberg RJ (1970) In: The chemistry of indoles. Academic
Press, New York
2. Brown RK (1972) In: Houlihan WJ (ed) Indoles. Wiley-Inter-
science, New York
3. Herrea RP, Sgarzani V, Bernardi VL, Ricci A (2005) Angew
Chem Int Ed 44:6576
30. Liu H, Lu SF, Xu J, Du DM (2008) Chem Asian J 3:1111
31. Liu H, Du DM (2010) Eur J Org Chem 2010:2121
32. Peng J, Du DM (2012) Eur J Org Chem 2012:4042
33. Gao JR, Wu H, Xiang B, Yu WB, Han L, Jia YX (2013) J Am
Chem Soc 135:2983
34. Jia YX, Zhu SF, Yang Y, Zhou QL (2006) J Org Chem 71:75
35. Lu SF, Du DM, Xu J (2006) Org Lett 8:2115
36. Hargaden GC, Guiry PJ (2009) Chem Rev 109:2505
37. Desimoni G, Faita G, Jørgensen A (2011) Chem Rev 111:PR284
38. Gao MZ, Kong DY, Clearfied A, Zingaro RA (2004) Tetrahedron
Lett 45:5649
4. Gaunt MJ, Johansson CCC, McNally A, Vo NT (2007) Drug
Discovery Today 12:8
5. Poulsen TB, Jørgensen KA (2008) Chem Rev 108:2903
6. Ganesh M, Seidel D (2008) J Am Chem Soc 130:16464
7. Scettri A, Villano R, Acocella MR (2009) Molecules 14:3030
8. Terada M (2010) Synthesis 12:1929
39. Li WJ, Qiu SX (2010) J Heterocycl Chem 47:1340
9. Sakamoto T, Itoh J, Mori K, Akiyama T (2010) Org Biomol
Chem 8:5448
123