Novel chiral secondary amine-amide catalysts Friedel-Craft alkylation reaction

Article abstract of DOI:10.14233/ajchem.2017.20269

A highly efficient catalytic asymmetric Friedel-Crafts alkylation of indole with nitroalkenes using novel chiral secondary amine-amide as catalyst has been developed. Various types of nitroalkylated indoles were obtained in excellent yields (81-93 %) and high enantio-selectivities (up to 95 % ee).

Full text of DOI:10.14233/ajchem.2017.20269

Asian Journal of Chemistry; Vol. 29, No. 3 (2017), 595-600
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20269
Novel Chiral Secondary Amine-Amide Catalysts Friedel-Craft Alkylation Reaction
*
KEJUN HUANG, XUEHAI PEI, XIAOGANG YIN and ZHIMING CHEN
School of Chemistry and Materials Science, Guizhou Normal University Guiyang 550001, P.R. China
*Corresponding author: Tel: +86 13985009568; E-mail: czm000219@163.com
Received: 26 August 2016;
Accepted: 9 November 2016;
Published online: 30 December 2016;
AJC-18208
A highly efficient catalytic asymmetric Friedel-Crafts alkylation of indole with nitroalkenes using novel chiral secondary amine-amide as
catalyst has been developed. Various types of nitroalkylated indoles were obtained in excellent yields (81-93 %) and high enantio-selectivities
(up to 95 % ee).
Keywords: Nitroalkenes, Indole, Catalyst, Friedel-Craft alkylation.
Craft alkylation of nitrobenzenes [21-23] compounds and
indole and the study showed excellentresults in chemical yields
and enantioselectivity.
INTRODUCTION
Enantioselective Friedel-Crafts alkylation reaction repre-
sents one of the most significant approaches to the synthesis
of chiral aromatic compounds bearing benzylic stereogenic
centers [1-5]. Recently, using nitroalkenes as substrates to
achieve asymmetric Friedel-Crafts alkylation of indoles has
been paid considerable attention [6,7]. It is the result of chemists’
effort to develop new types of substrates for the enantioselective
version of the Friedel-Crafts reaction [8-11]. In present study,
indoles have attracted considerable attention as popular aromatic
substrates and many efficient reactions have been developed
to synthesize chiral indole derivatives [12,13]. However, the
enantioselective Friedel-Crafts alkylation of indoles with nitro-
alkenes needs to undergo continuous development. In these
pioneer reports, relatively high temperature or a long time was
used [14,15]. This paper studied hydrogenation reduction of
carboxyl group of L-proline.With the protection of amino group
of pyrrole by using BOC2O, it synthesizes BOC-L-proline after
a series of reactions as sulfonylation, azidation, hydrolysis,
etc. [16-20].Then we synthesized novel chiral secondary amine-
amide catalysts (Fig. 1) with reaction of benzoic acid derivatives
and naphthalene acid derivatives, which is applied into Friedel-
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded at 400 MHz
and 100 MHz, respectively, on a Bruker DRX (400 MHz)
spectrometer in CDCl3 or DMSO using tetramethylsilane
(TMS) as an internal standard, X-6 micro digital melting point
apparatus, high performance liquid chromatography, chiral
daicel (OD-H),Voyager-DE STR mass spectrometer,Vario EL-
Cube elemental analyzer, ThermoFisher infrared analyzer.
Synthesis of catalysts:According to previous work [16-20],
BOC-L-prolyl is synthesized in compliance with several steps
with the feedstock of L-proline.Weigh 0.72 g (3.5 mmol) DCC,
0.47 g (3.5 mmol) HOBt, 0.43 g (3.5 mmol) benzoate, then
add another 10 mL dichloromethane into 50 mL boiling flask.
Weigh 0.50 g (2.5 mmol) BOC-L-prolyl and put them into the
constant pressure funnel with another 2 mL dichloromethane.
Tracing the reaction with TLC. We can get intermediates a [2-
(benzamidomethyl)pyrrolidin-1-yl pivalate] after column
chromatography purification and then the catalyst was obtained
by acidification. Similarly, we can get intermediate 1b-1e.
N-(Pyrrolidin-2-ylmethyl)benzamide (1a): Yield
(63 %), 1H NMR (400 MHz, DMSO), δ: 1.69 (s, 2H), 1.91 (s,
1H), 2.04 (s, 1H), 2.51 (s, 1H), 3.70 (s, 3H), 7.46-7.53 (m,
O
C
O
C
O
C
H
N
H
N
H
N
N
H
N
H
Br
N
H
NO
2
1c
1a
1b
13
3H), 7.87 (d, J = 8 Hz 2H), 8.87 (s, 2H), 9.50 (s, 1H). C
OH
O
C
O
NMR (100 MHz, DMSO), δ: 23.17, 27.68, 40.65, 45.25, 59.83,
H
H
N
N
C
N
H
127.72, 128.81, 132.05, 134.16, 167.84. FTIR (KBr, νmax
,
N
H
cm-1): 1684.91 (C=O), 1541.43, 725.27 (N-H), 1490.79 (-CH2-
N-C=O), 1437.08 (-CH2-), 1313.37 (-CH-), 824.56, 801.56
OH
1e
1d
Fig. 1. Secondary amine-amide catalysts

596 Huang et al.
Asian J. Chem.
(C-N). MS calcd: 204.27, found: 205.1. Anal. calcd. for
C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.52; H,
7.86; N, 13.61.
1H NMR (400 MHz, CDCl3), δ: 4.97 (m, 1H), 5.10 (dd, J = 12
Hz 1H), 5.23 (t, J = 8 Hz 1H), 7.03-7.04 (m, 1H), 7.12 (t, J =
12 Hz 1H), 7.24 (t, J = 16 Hz 1H), 7.28-7.34 (m, 1H), 7.36 (t,
J = 12 Hz 5H), 7.49 (d, J = 8 Hz 1H), 8.11 (s, 1H). 13C NMR
(100 MHz, CDCl3), δ: 41.60, 79.59, 111.53, 114.27, 118.94,
119.96, 121.73, 122.69, 123.13, 127.63, 127.83, 128.98,
136.51, 139.27. FTIR (KBr, νmax, cm-1): 1636.30 (C=C),
1548.98 (C-NO2), 1384.39 (C-N), 688.44.
4-Bromo-N-(pyrrolidin-2-ylmethyl)benzamide (1b):
Yield (59 %), 1H NMR (400 MHz, CDCl3), δ: 2.06-2.16 (m,
3H), 3.25 (s, 1H), 3.65-3.87 (m, 2H), 7.28 (s, 2H), 7.55 (d, J
= 8 Hz 2H), 7.74 (d, J = 8 Hz 2H), 8.50 (s, 1H), 9.24 (s, 1H),
10.13 (s, 1H). 13C NMR (100 MHz, DMSO), δ: 23.12, 27.74,
40.62, 45.24, 59.74, 125.73, 129.92, 131.83, 133.47, 166.71.
FTIR (KBr, νmax, cm-1): 1677.12 (C=O), 1592.17, 757.2 (N-
H), 1430.55 (-CH2-N-C=O), 1493.40 (-CH2-), 1319.42 (-CH-),
824.56, 801.06 (C-N), 722.65(C-Br). MS:calcd: 283.16, found:
283.00. Anal. calcd. for C12H15N2OBr: C, 50.90; H, 5.34; N,
9.89. Found: C, 50.82; H, 5.24; N, 9.81.
4-Nitro-N-(pyrrolidin-2-ylmethyl)benzamide (1c):Yield
(62 %), 1H NMR (400 MHz, DMSO), δ: 1.23 (s, 1H), 1.69-
1.91 (m, 1H), 1.93-1.95 (m, 2H), 2.07 (d, J = 8 Hz 1H), 3.59
(s, 3H), 3.69-3.71 (m, 2H), 8.10 (d, J = 8 Hz 2H), 8.33 (d, J =
8 Hz 2H), 9.17 (s, 1H). 13C NMR (100 MHz, DMSO), δ: 23.10,
27.78, 40.56, 45.20, 59.55, 123.96, 129.32, 140.07, 149.63,
166.00. FTIR (KBr, νmax, cm-1): 1675.77(C=O), 1528.27,
1348.93 (NO2), 1601.77, 721.95 (N-H), 1430.28 (-CH2-N-
C=O), 1489.56 (-CH2-), 1301.88 (-CH-), 870.17, 836.83 (C-N).
MS:calcd: 249.27, found: 250.1. Anal. calcd. for C12H15N3O3:
C, 57.82; H, 6.07; N, 16.86. Found: C, 57.77; H, 6.04; N,
16.81.
6-Hydroxy-N-(pyrrolidin-2-ylmethyl)-2-naphthamide
(1d): Yield (64 %), 1H NMR (400 MHz, CDCl3), δ: 1.28 (s,
4H), 1.59 (s, 8H), 4.08 (s, 1H), 7.28 (s, 2H), 7.36 (dd, J = 8
Hz 1H), 8.71 (s, 1H), 10.71 (s, 1H). 13C NMR (100 MHz,
DMSO), δ: 23.30, 27.77, 40.74, 45.20, 59.81, 109.12, 120.01,
124.78, 126.40, 127.02, 128.14, 128.33, 131.00, 136.67,
157.60, 167.90. FTIR (KBr, νmax, cm-1): 1686.89 (C=O),
1541.53, 722.89 (N-H), 1636.91 (-CH2-N-C=O), 1437.87 (-
CH2-), 1203.13 (OH), 835.40 (C-N). MS: calcd: 270.33, found:
270.1.Anal. calcd. for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.00; H, 6.67; N, 10.32.
3-(2-Nitro-1-p-tolylethyl)-1H-indole (4b): White solid,
Yield (93 %), oil (Lit. [24]), 86 % ee [Daicel Chiralcel OD-H
column, n-hexane/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR =
9.52 min and 13.96 min (major)]; 1H NMR (400 MHz, CDCl3),
δ: 2.35 (s, 1H), 4.92-4.98 (m, 1H), 5.05-5.10 (m, 1H), 5.17-
5.21 (m, 1H), 7.03 (s, 1H), 7.10-7.14 (m, 3H), 7.15-7.17 (m,
3H), 7.23-7.25 (d, J = 8 Hz 1H), 7.27-7.28 (d, J = 4 Hz 1H),
13
8.12 (s, 1H). C NMR (100 MHz, CDCl3), δ: 21.23, 41.28,
79.72, 111.54, 114.46, 118.99, 119.93, 121.70, 122.66, 126.17,
127.71, 129.68, 136.27, 136.54, 137.29. FTIR (KBr, νmax, cm-1):
1617.38 (C=C), 1559.46 (C-NO2), 1384.44 (C-N), 619.84.
3-[1-(4-Chlorophenyl)-2-nitroethyl]-1H-indole (4c):
White solid, Yield (89 %), m.p.: 104-109 °C (Lit [24] 107-
108 °C), 85 % ee [Daicel Chiralcel OD-H column, n-hexane/
i-PrOH = 80:20, 1.0 mL/min, 254 nm; tR = 9.58 min and 14.03
min (major)]; 1H NMR (400 MHz, CDCl3), δ: 4.92-4.95 (m,
1H), 5.08-5.10 (m, 1H), 5.19-5.21 (m, 1H), 7.15 (s, 1H), 7.02-
7.08 (m, 1H), 7.23-7.27 (m, 4H), 7.37-7.39 (d, J = 8 Hz 1H),
7.62-7.64 (d, J = 4 Hz 2H), 8.16 (s, 1H). 13C NMR (100 MHz,
CDCl3), δ: 41.00, 79.34, 111.64, 113.79, 118.84, 120.11, 121.66,
122.88, 125.94, 129.15, 129.23, 133.41, 136.54, 137.84. FTIR
(KBr, νmax, cm-1): 1617.49 (C=C), 1550.93 (C-NO2), 1383.99
(C-N), 7445, 688.44.
3-[1-(4-Bromophenyl)-2-nitroethyl]-1H-indole (4d):
White solid, Yield (86 %), m.p.: 120.5-123 °C (Lit [24] 121-
122 °C), 85 % ee [Daicel Chiralcel OD-H column, n-hexane/
i-PrOH = 80:20, 1.0 mL/min, 254 nm; tR = 9.10 min and 13.88
min (major)]; 1H NMR (400 MHz, CDCl3), δ: 4.90-4.93 (m,
1H), 4.95-5.07 (m, 1H), 5.16-5.20 (m, 1H), 7.02 (s, 1H), 7.11-
7.13 (m, 1H), 7.22-7.24 (m, 3H), 7.27-7.28 (s, 1H), 7.37-7.48
(m, 3H), 8.16 (s, 1H). 13C NMR (100 MHz, CDCl3), δ: 41.05,
79.23, 111.59, 113.75, 118.82, 120.12, 121.55, 121.63, 122.89,
125.90, 129.56, 132.09, 136.52, 138.32. FTIR (KBr, νmax, cm-1):
1617.35 (C=C), 1578.47 (C-NO2), 1384.37 (C-N), 617.12.
3-[1-(4-Fluorophenyl)-2-nitroethyl]-1H-indole (4e):
White solid,Yield (81 %), m.p.: 129.6-134 °C; 91 % ee [Daicel
Chiralcel OD-H column, n-hexane/i-PrOH=80:20, 1.0 mL/
min, 254 nm; tR = 12.03 min and 21.31 min (major)]; 1H NMR
(400 MHz, CDCl3), δ: 4.93 (dd, J = 8 Hz 1H), 5.05-5.10 (m,
1H), 5.17-5.19 (m, 1H), 7.02 (d, J = 8 Hz 1H), 7.13 (t, J = 16 Hz
1H), 7.32 (dd, J = 12 Hz 4H), 7.37 (s, 1H), 7.44 (d, J = 8 Hz
2H), 8.16 (s, 1H). 13C NMR (100 MHz, CDCl3), δ: 40.89, 79.57,
111.53, 114.19, 115.75, 115.97, 118.87, 120.07, 121.51,
122.84, 125.96, 129.37, 129.45, 134.96, 136.53, 160.88. FTIR
(KBr, νmax, cm-1): 1618.18 (C=C), 1551.39 (C-NO2), 1383.98
(C-N), 744.64.
1-Hydroxy-N-(pyrrolidin-2-ylmethyl)-2-naphthamide
1
(1e): Yield (69 %), H NMR (400 MHz, CDCl3), δ: 1.78 (s,
3H), 1.97 (d, J = 8 Hz 1H), 2.13 (s, 1H), 3.24 (s, 1H), 3.74 (s,
1H), 3.93 (s, 1H), 7.23 (d, J = 8 Hz 1H), 7.28 (s, 2H) 7.50-
7.59 (m, 3H), 7.71 (d, J = 8 Hz 1H), 8.38 (d, J = 8 Hz 1H),
13
9.10 (s, 1H), 9.67 (s, 1H). C NMR (100 MHz, DMSO), δ:
23.82, 27.37, 40.52, 45.39, 60.54, 106.21, 118.44, 121.52,
123.66, 125.26, 125.80, 127.32, 129.09, 136.47, 160.55,
172.39. FTIR (KBr, νmax, cm-1): 1683.88 (C=O), 1597.28,
723.85 (N-H), 1545.19 (-CH2-N-C=O), 1395.76 (-CH2-),
1206.34 (OH), 801.38 (C-N). MS: calcd: 270.33, found: 270.1.
Anal. calcd. for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.01; H, 6.68; N, 10.31.
Catalyze the Michael addition reaction:Add indole 5.9
mg (0.05 mmol), dichloromethane 1 mL, catalysis 1e 1.4 mg
(0.005 mmol) into 25 mL round bottomed flask and stir it
under the condition of room temperature, tracing the reaction
with TCL. Then purify the product after stopping the reaction.
3-(2-Nitro-1-phenylethyl)-1H-indole (4a): White solid,
Yield (91 %), m.p.: 96-99 °C (Lit[24] 97 °C -99 °C), 95 % ee
[Daicel Chiralcel OD-H column, n-hexane/i-PrOH = 80:20,
1.0 mL/min, 254 nm; tR = 9.64 min and 14.16 min (major)];
3-[1-(2-Methoxyphenyl)-2-nitroethyl]-1H-indole (4f):
Oil (Lit [14]), Yield (92 %), 88 % ee [Daicel Chiralcel OD-H
column, n-hexane/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR =
1
13.20 min and 19.86 min (major)]; H NMR (400 MHz,
CDCl3), δ: 3.95 (s, 3H), 4.98-5.10 (m, 2H), 5.64-5.66 (d, J =

Vol. 29, No. 3 (2017)
Novel Chiral Secondary Amine-Amide Catalysts Friedel-Craft Alkylation Reaction 597
8 Hz 1H), 6.85-6.89 (m, 1H), 7.09-7.10 (m, 3H), 7.12-7.14
(m, 2H), 7.20-7.22 (d, J = 8 Hz 1H), 7.26-7.28 (d, J = 8 Hz
1H), 8.12 (s, 1H). 13C NMR (100 MHz, CDCl3), δ: 35.54, 55.59,
78.21, 110.87, 111.41, 113.80, 119.11, 119.75, 120.84, 122.11,
122.47, 126.55, 127.26, 128.72, 128.99, 136.44. FTIR (KBr,
7H), 7.48 (d, J = 8 Hz 1H). 13C NMR (100 MHz, CDCl3), δ:
32.86, 41.57, 79.59, 109.58, 112.80, 119.02, 119.49, 122.26,
126.42, 126.58, 127.55, 127.79, 128.95, 137.31, 139.44. FTIR
(KBr, νmax, cm-1): 1617.49 (C=C), 1558.72 (C-NO2), 1383.54
(C-N), 736.41, 701.28.
ν
max, cm-1): 1617.40 (C=C), 1559.78 (C-NO2), 1384.25 (C-N),
2-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (4l):
White solid,Yield (81 %), m.p.: 101-103 °C (Lit[24] 101-102
°C), 93 % ee [Daicel Chiralcel OD-H column, n-hexane/i-
PrOH = 90:10, 1.0 mL/min, 254 nm; tR = 28.32 min and 38.65
620.57.
3-[1-(2-Chlorophenyl)-2-nitroethyl]-1H-indole (4g):
Oil (Lit [14]), Yield (86 %), 91 % ee [Daicel Chiralcel OD-H
1
column, n-hexane/i-PrOH = 80:20, 1.0 mL/min, 254 nm; tR =
min (major)]; H NMR (400 MHz, CDCl3), δ: 2.43 (s, 3H),
1
13.64 min and 22.16 min (major)]; H NMR (400 MHz,
5.14-5.27 (m, 3H), 7.05 (t, J = 12 Hz 1H), 7.14 (t, J = 16 Hz
1H), 7.25-7.34 (m, 6H), 7.41 (d, J = 8 Hz 1H), 7.91 (s, 1H).
13C NMR (100 MHz, CDCl3), δ: 11.96, 40.52, 78.68, 08.74,
10.82, 118.62, 119.75, 121.33, 126.85, 127.13, 127.36, 128.83,
133.00, 135.44, 139.55. FTIR (KBr, νmax, cm-1): 1618.15
(C=C), 1552.03 (C-NO2), 1383.51 (C-N), 745.64, 697.76.
CDCl3), δ: 4.97-5.07 (m, 2H), 5.76-5.80 (m, 1H), 7.09-7.13
(m, 2H), 7.20-7.23 (m, 4H), 7.28-7.37 (m, 1H), 7.39-7.43 (d,
J = 16 Hz 2H), 8.19 (s, 1H). 13C NMR (100 MHz, CDCl3), δ:
FTIR (KBr, νmax, cm-1): 1636.76 (C=C), 1551.30 (C-NO2),
1383.98 (C-N), 744.67.
3-[2-Nitro-1-(3-nitrophenyl)ethyl]-1H-indole (4h): Oil
(Lit [24]), Yield (89 %), 92 % ee [Daicel Chiralcel OD-H
column, n-hexane/i-PrOH = 80:20, 1.0 mL/min, 254 nm; tR =
9.68 min and 14.11 min (major)]; 1H NMR (400 MHz, CDCl3),
δ: 5.00-5.05 (m, 1H), 5.12-5.17 (m, 1H), 5.31-5.35 (t, J = 16
Hz 1H), 7.10-7.14 (m, 2H), 7.23-7.28 (m, 2H), 7.41-7.23 (d,
J = 8 Hz 2H), 7.52-7.56 (t, J = 16 Hz 1H), 7.73-7.75 (d, J = 8
Hz 1H), 8.13-7.17 (d, J = 16 Hz 1H), 8.23-8.27 (m, 2H). 13C
NMR (100 MHz, CDCl3), δ: 41.11, 78.89, 111.85, 112.82,
118.51, 120.23, 121.86, 122.74, 122.78, 123.07, 125.73,
130.03, 134.31, 136.55, 141.75, 148.54. FTIR (KBr, νmax, cm-1):
1617.30 (C=C), 1558.98 (C-NO2), 1384.32 (C-N), 617.50.
1,2-Dimethyl-3-(2-nitro-1-phenyl)-1H-indole (4i): Oil,
Yield (83 %), 79 % ee [Daicel Chiralcel OD-H column, n-
hexane/i-PrOH = 94:6, 1.0 mL/min, 254 nm; tR = 20.32 min
and 27.63 min (major)]; 1H NMR (400 MHz, CDCl3), δ: 2.43
(s, 3H), 3.68 (s, 3H), 5.12-5.18 (m, 1H), 5.23-5.31 (m, 2H),
7.05 (dd, J = 8 Hz 1H), 7.18 (t, J = 12 Hz 1H), 7.22-7.35 (m,
6H), 7.40 (d, J = 8 Hz 1H). 13C NMR (100 MHz, CDCl3), δ:
10.52, 29.67, 40.75, 78.80, 108.16, 109.13, 118.66, 119.38,
120.90, 125.95, 127.07, 127.32, 128.78, 134.70, 138.98,
139.82. FTIR (KBr, νmax, cm-1): 1617.72 (C=C), 1547.16 (C-
NO2), 1383.99 (C-N), 743.68, 617.72.
RESULTS AND DISCUSSION
In order to optimize the reaction conditions, at first, the
catalytic effect was examined by carrying out the Friedel-Crafts
alkylation reaction. We compare five novel chiral secondary
amine-amide small organic molecules by using solvent CH2Cl2
and catalyst dosage (10 % mmol) at 35 °C. The study shows
that these five secondary amine-amide performed fairly catalytic
activity and higher yields. However, the catalyst 1a-1d have
no find superior enantioselective (entry1-4) and the catalyst
1e (1-hydroxy-N-(pyrrollidin-2-ylmethyl)-2-naphthamide)
obtains superior enantioselective (95 % ee, entry 5). Its possible
that the ortho hydroxyl group are enhance steric and electronic
effects, this can be used to maximize the use of multiple
hydrogen bonds in the molecular structure of the catalyst to
further activate the reaction system in the corresponding, to
enable it achieves better three-dimensional control and obtain
better catalytic activity in the asymmetric reaction.
TABLE-1
ASYMMETRIC FRIEDEL-CRAFTS ALKYLATION OF
INDOLE (2a) WITH NITROSTYRENE (3a)
CATALYZED BY CHIRAL (1a-1e)a
NO2
3-(2-Nitro-1-phenylethyl)-2-phenyl-1H-indole (4j):
Oil, Yield (89 %), 92 % ee [Daicel Chiralcel OD-H column,
n-hexane/i-PrOH = 80:20, 1.0 mL/min, 254 nm; tR = 19.95 min
and 22.95 min (major)]; 1H NMR (400 MHz, CDCl3), δ: 5.14-
5.25 (m, 2H), 5.33-5.37 (m, 1H), 7.14 (t, J = 16 Hz 1H), 7.25-
7.28 (m, 3H), 7.31-7.38 (m, 4H), 7.43 (d, J = 8 Hz 1H), 7.47-
7.50 (m, 4H), 7.55 (d, J = 8 Hz 1H), 8.21 (s, 1H). 13C NMR
(100 MHz, CDCl3), δ: 40.86, 79.13, 109.51, 111.53, 119.99,
120.32, 122.50, 127.04, 127.24, 127.52, 128.65, 128.82,
128.94, 128.98, 132.19, 136.11, 137.03, 139.92. FTIR (KBr,
NO2
HN
Cat (10%mmol)
CH2Cl2
N
H
35°C
3a
4a
ee (%)c
10
7
14
64
95
2a
Entry
Catalyst
Time
Yield (%)b
1
2
3
4
5
1a
1b
1c
1d
1e
24
20
26
18
12
84
83
89
83
91
aReaction conditions: indole 2a (0.50 mmol) with nitrostyrene 3a (0.50
ν
max, cm-1): 1617.57 (C=C), 1549.88 (C-NO2), 1384.00 (C-N),
609.78.
1-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (4k):
mmol) in 2 mL of CH2Cl2 under 10 mmol % secondary amineamide;
bIsolated yield after column chromatography; Determined by HPLC
c
analysis using Chiralpak OD-H column.
White solid,Yield (86 %), m.p.: 95-97 °C (Lit[24] 94-95 °C),
85 % ee [Daicel Chiralcel OD-H column, n-hexane/i-PrOH =
95:5, 1.0 mL/min, 254 nm; tR = 29.60 min and 57.47 min
(major)]; 1H NMR (400 MHz, CDCl3), δ: 3.78 (s, 3H), 4.97
(dd, J = 16 Hz 1H), 5.08 (dd, J = 16 Hz 1H), 5.21 (t, J = 16
Hz 1H), 6.89 (s, 1H), 7.10 (t, J = 16 Hz 1H), 7.23-7.38 (m,
We further examined different solvents. Some typical results
are presented in Table-2. A number of solvents were success-
fully applied to the catalytic enantioselective Friedel-Crafts
reaction (entries 1-10) with the presence of 10 mmol % 1e,
at 35 °C for 12 h (Table-2), used as system. The reaction was

598 Huang et al.
Asian J. Chem.
TABLE-3
influenced by the polarity of the solvent and in oxygen-
containing solvents, such as Et2O, THF, EtOAc, petroleum ether
and DMF (entries 1, 4, 5, 7 and 8), probably because the oxygen
atom coordinated to 1e, thus reducing its catalytic activity. On
the contrary, other solvents such as hexane, toluene, CH2Cl2
and CHCl3 were all effective in producing the desired product
4a in good yields. Using alkyl halides as the solvent gave 4a
in high yield with superior enantioselectivity (entries 3 and 6)
and dichloromethane was the best choice (entry 6).
FURTHER OPTIMIZATION OF REACTION CONDITIONS
FOR FRIEDEL-CRAFTS ALKYLATION OF INDOLE (2a)
WITH NITROSTYRENE (3a)a
NO2
NO2
HN
Cat 1e
N
H
CH2Cl2
3a
Cat 1e
(mmol %)
4a
2a
Temp.
(°C)
Time
(h)
Yield
(%)b
Entry
ee (%)c
TABLE-2
EFFECT OF SOLVENTS IN FRIEDEL-CRAFTS ALKYLATIN
OF INDOLE (2a) WITH NITROSTYRENE (3a)a
NO2
1
2
3
4
5
6
7
8
35
35
35
25
25
15
10
5
10
5
2.5
10
5
10
10
10
12
18
26
19
27
32
37
46
91
84
56
74
49
56
53
54
95
81
76
85
77
74
69
72
NO2
HN
Cat 1e (10%mmol)
35°C
N
H
2a
3a
Cat 1e
(mmol %)
4a
aReaction conditions: indole 5a (0.50 mmol) with nitrostyrene 6a (0.50
mmol) in 2 mL of CH2Cl2 using 1e secondary amine-amide as the
catalyst, bIsolated yield after column chromatography; cDetermined by
HPLC analysis using Chiralpak OD-H column.
Entry
Solvents
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
10
Et2O
CH3CH2OH
CHCl3
THF
EtOAc
CH2Cl2
PE
DMF
Toluene
Hexane
21
49
76
35
47
91
29
31
64
63
32
41
72
28
36
95
12
51
72
74
the steric effect of ortho-substituents. The catalytic hydrogen
bonds may activate receptor, in other words, the donor
hydrogen bonds and Friedel-Crafts alkylation receptor function
so that it reduces the electron areal density and activate that
effectively. Hence enhances the emergence of nucleophile in
the solvent and promoted the Friedel-Crafts alkylation. the
reaction could be easily extended to aliphatic nitroalkenes.
According to the literature [21-23], we have speculated
that NH and OH of secondary amine-amide catalyst similar to
the two NH of thiourea type organic catalyst, nitro olefins in
the nitro group by its role in hydrogen bonding, reducing the
density of their own and the receptor is activated and the affinity
of the receptor is increased, through the chiral framework to
control the direction of attack. Thus, we obtained the product
configuration excessively and even with N-protected indole the
enantioselectivity was kept at a high level.
10
aReaction conditions: indole 5a (0.50 mmol) with nitrostyrene 6a (0.50
mmol) in 2 mL of toluene under 10 mmol % 1e secondary amine-
c
amide. bIsolated yield after column chromatography; Determined by
HPLC analysis using Chiralpak OD-H column.
After identifying the optimal solvent, to get the most
optimized reaction conditions, we further studied different
temperature and catalyst loading. Some typical results are
presented in Table-3. The heating and increase catalyst loading
the reaction led to improvement in the enantioselectivity and
yield (entries 1 and 4). With the decrease of temperature and
the constant of catalyst loading led to the increase of reaction
time and the decrease of yield (entries 6, 7 and 8). When the
reaction was performed at 35 °C, 4a was obtained in 95 % ee
(entry 1). Enhancement of the catalyst loading decreased the
enantioselectivity ovious change (entries 2 and 3). Finally,
we determined that using 10 mmol % 1e in CH2Cl2 at 35 °C to
catalyze the reaction was the most practical.
The generality of the reaction was further demonstrated
by variation of the nitroalkene.Aromatic- and aliphatic-substi-
tuted nitroalkenes all reacted well with indole to afford alkylated
indoles in excellent yields and high enantioselectivities (entries
1-8). An electron withdrawing substituent such as chlorine in
the 1 and 2-position of the indole ring in 2b caused moderate
decrease in both yield and enantioselectivity (entry 9). When
we introduced a methyl substituent to the indolic nitrogen atom,
the reaction proceeded very well, giving the corresponding
derivatives 4k in high yield and enantioselectivity (entry 11).
The ortho substitution on the phenyl ring present in nitro-
styrene, either electrodonating or electron-withdrawing groups,
lowered the enantiomeric excess of products, perhaps due to
In conclusion, we have developed a more practical
catalytic asymmetric Friedel-Crafts alkylation of indoles (2)
with a variety of nitroalkenes (3) using secondary amine-amide
complex as catalyst, which can activate nitroalkenes and orient
indoles effectively.
H
O
NO2
N
N
H
O
N
HN
H
N
O
H
O
Ph
Fig. 2. Possible mechanism of catalyst 1e
Conclusion
In summary, we have found that new chiral secondary
amine-amide 1e can promote the Friedel-Craft alkylation
reaction of indole and nitroalkenes, which can activate indole
and nitroalkenes effectively. Various types of the nitroalkylated

Vol. 29, No. 3 (2017)
Novel Chiral Secondary Amine-Amide Catalysts Friedel-Craft Alkylation Reaction 599
TABLE-4
FRIEDEL-CRAFTS ALKYLATION OF INDOLES (2) WITH NITROALKENE (3) CATALYZED BY 1ea
R1
NO2
R2
NO2
N
R1
R3
Cat(10%mmol)
CH2Cl2 35
N
°
C
R2
2a-e
R3
3a-i
Nitroolefins
4a-l
Entry
1
Indoles
Product
Yield (%)b
ee (%)c
95
NO2
NO
3a
2
HN
HN
N
H
91
4a
4b
2a
NO2
NO
2
N
H
2
3
4
5
93
89
86
81
86
85
85
91
Me
3b
3c
2a
2a
2a
2a
Me
NO2
NO2
NO2
HN
HN
HN
4c
4d
N
H
Cl
Br
Cl
NO2
N
H
3d
3e
Br
NO2
NO
2
N
H
4e
F
F
NO2
NO
2
2
OCH3
HN
N
H
6
7
8
92
86
89
88
91
92
OCH
3
4f
2a
2a
3f
NO
Cl
2
NO
HN
N
H
Cl
4g
3h
NO
2
O N
2
NO
2
4h
HN
N
H
NO
2
3i
2a
N
CH3
NO2
NO
CH3
2
H3C
HN
4i
N
9
83
89
86
81
79
92
85
93
CH3
3a
2b
Ph
NO2
NO2
Ph
10
11
12
N
H
4j
2c
3a
3a
NO
2
NO2
NO2
H C
3
N
N
4k
CH3
2d
CH
3
NO
2
CH3
HN
4l
N
H
2e
3a
aReaction conditions: indole 5 (0.50 mmol) with nitroalkene 6 (0.50 mmol) in 2 mL of CH2Cl2 using 10 mmol % 1e secondary amine-amide as
catalyst at 35 °C for 12 h. bIsolated yield after column chromatography; cDetermined by HPLC analysis using Chiralpak OD-H column.

600 Huang et al.
Asian J. Chem.
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ACKNOWLEDGEMENTS
The authors thankThe National Natural Science Foundation
of China, No. 21362006, for financial support of this work.
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