Silica gel-mediated friedel-crafts reaction of indoles with functionalized nitroallylic acetates via an SN1 process

Article abstract of DOI:10.1002/jccs.201100643

An environmentally friendly Friedel-Crafts reaction was demonstrated between indoles and functionalized nitroallylic acetates in the presence of silica gel, providing the corresponding C-3-selective regioisomers in good to high overall chemical yields (70

Full text of DOI:10.1002/jccs.201100643

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Silica gel-Mediated Friedel-Crafts Reaction of Indoles with Functionalized Nitroallylic
Acetates via an SN1 Process
Ching-Yin Ho, Suparna Roy, Yan-Ming Chen and Kwunmin Chen*
Chemistry Department, National Taiwan Normal University, 88 Sec. 4, TingChow Rd., Taipei 116, Taiwan, R.O.C.
(Received: Nov. 5, 2011; Accepted: Mar. 21, 2012; Published Online: ??; DOI: 10.1002/jccs.201100643)
An environmentally friendly Friedel-Crafts reaction was demonstrated between indoles and function-
alized nitroallylic acetates in the presence of silica gel, providing the corresponding C-3-selective
regioisomers in good to high overall chemical yields (70-93%).
Keywords: Friedel-Crafts reaction; Indole; Nitroallylic acetate; Electrophile; SN1.
INTRODUCTION
The Friedel-Crafts reaction is an electrophilic aro-
Table 1. Standardization of silica gel-mediated Friedel-Crafts
reactiona
CO2Et
Ph
matic substitution reaction typically catalyzed by a Lewis
acid or Brønsted acid to derivatize the starting aromatic
compounds.1 In recent years, considerable attention has
been directed towards performing the Friedel-Crafts reac-
tion in an environmentally friendly manner by utilizing
various heterogeneous catalysts such as graphite,2 zeo-
lites,3 clays,4 and heteropoly acids.5 Ionic liquids have also
been effectively employed to minimize the corrosive
wastes.6
OAc
NO2
NO2
silica gel
EtO2C
NO2
+
Ph
+
EtO2C
Ph
1a
N
H
N
H
N
H
2a
3a (major)
4a (minor)
4a
(% yield)c
3a
(% yield)c
Entry 1a:2a 1a:silica gel b T (oC) t (h)
1
1.0:1.5
1.0:1.5
1.0:1.5
1.0:1.5
1.0:1.5
1.0:1.5
1.0:2.0
1.0:1.5
1.0:1.0
1.5:1.0
1:3
1:5
1:8
1:10
1:8
1:8
1:8
1:8
1:8
1:8
rt
rt
2.5
2.5
2
66
70
79
80
75
80
75
80
82
76
9
2
12
11
11
11
13
15
13
11
15
3
rt
4
rt
2
Indole derivatives constitute an important class of
structural frameworks that encompass various biologically
active natural products and pharmaceuticals.7 Indoles have
been found to be successful in Friedel-Crafts reactions as it
is a strong nucleophile. In general, the Friedel-Crafts al-
kylation of indole leads to the C-3-substituted product,8 but
there are reports of such reaction yielding the C-2-substi-
tuted product.9 Furthermore, N-alkylation becomes un-
avoidable in some instances.10 Recently, the allylic alkyla-
tion of indoles has met with some success in the presence of
metal complexes acting as catalysts.7a,c-e,h,j Herein, we re-
port functionalized nitroallylic acetates (1a-j) as effective
electrophilic components of the Friedel-Crafts reaction
with indoles. The silica gel-mediated reaction proceeded
smoothly to provide the corresponding C-3-alkylated prod-
ucts under neat conditions.
5
0
6
6
40
40
40
40
40
1
7
1
8
1
9
1
10
1
a All reactions were performed on a 0.13 mmol scale. b By
weight. c Isolated yields after flash column chromatography.
We have found that 1.0 equiv of nitroallylic acetate (1a)
and 1.5 equiv of indole afforded the desired 3a in 79% iso-
lated yield in the presence of silica gel at ambient tempera-
ture for 2 h (Table 1, entry 3). The minor product 4a was
isolated with 11% yield. We have also observed that reac-
o
tion rates accelerated in warmer conditions (40 C) and
took only 1 h to give comparable yields (Table 1, entry 6).
Later studies with different ratios of substrates revealed
that equal amounts of indole and nitroallylic acetate are
sufficient to obtain the best chemical yield (Table 1, entry
9).
RESULTS AND DISCUSSION
During optimization we chose ethyl 2-acetoxy-3-ni-
tro-4-phenylbut-3-enoate (1a)11 and indole (2a) as reaction
partners and scrutinized the silica gel-mediated reaction
between them under various reaction conditions (Table 1).
With suitable reaction conditions realized, we ex-
tended our methodology and various nitroallylic acetates
* Corresponding author. E-mail: kchen@ntnu.edu.tw
J. Chin. Chem. Soc. 2012, 59, 000-000
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Article
Ho et al.
Table 2. Silica gel-mediated Friedel-Crafts reaction of nitro-
allylic acetates with indolesa
CO2Et
have also been successfully brought into the scope of this
reaction (Table 2, entries 11-13). However, the reaction
with 5-chloro substituted indole (2d) took a longer time to
yield the corresponding products in good yields (Table 2,
entry 13).
Ar
EtO2C
OAc
NO2
NO2
R
silica gel, 40 oC
NO2
Ar
+
EtO2C
Ar
1a-j
R
R
+
N
H
N
H
N
H
2a-d
A scaled up reaction was performed to demonstrate
the utility of this synthetic protocol. Treatment of the in-
dole (0.8 g, 7.0 mmol) with nitroallylic acetate 1a (2.0 g,
7.0 mmol) at 40 oC for 1.5 h provided 3a and 4a with 77%
and 8% isolated yields, respectively.
3a-m
4a-m
Entry
1
Ar
R =
H
t (h) 3 (% yield)b 4 (% yield)b
1
3a (82)
3b (70)
4a (11)
4b (<5)
1a
2
3
H
H
1.5
1b
Br
In addition, various aromatic/heteroaromatic sub-
strates (benzene and benzene derivatives, pyridine, etc)
were tested under optimum conditions. Most failed the
electrophilic aromatic substitution, while the reaction of
1,3,5-trimoethoxybenzene with 1a proceeded smoothly to
give 6a with a 76% chemical yield (eq 1).
1.5
2
3c (75)
3d (76)
4c (10)
4d (14)
1c
1d
Br
4
H
Cl
5
6
7
H
H
H
2
2
3
3e (74)
3f (73)
3g (65)
4e (14)
4f (8)
CO2Et
OMe
1e
Cl
OAc
silica gel, 40 oC
NO2
NO2
EtO2C
Ph
eq 1
+
Ph
OMe
(76%)
MeO
OMe
1f
Me
MeO
4g (18)
OMe
1a
6a
5
1g
MeO
8
H
2.5
3h (75)
4h (12)
The reaction is believed to proceed through an SN1
process. The hydrogen bonding activation between the sil-
ica gel and the acetate group of the nitroallylic acetate led
to the formation carbocation intermediates (I and II). The
indole derivatives then reacted with the silica gel-induced
species. This is in agreement with previously reported
work that demonstrated the formation of carbocataion in-
termediate in the silica gel-mediated rearrangement of al-
lylic acetates under microwave irradiation.12 The formation
of the two regioisomers can be rationalized by the energy
difference of the two optimized intermediates I (minor) and
II (major, benzylic carbocation) (Scheme I). It is worth not-
ing that the Z-geometry (II) dominated when double bond
migration occurred.
1h
1i
OMe
O
9
H
H
2
3
3i (70)
3j (57)
4i (10)
4j (34)
1j
10
S
11
12
13
Me (2b)
Ome (2c)
Cl (2d)
1
1
8
3k (78)
3l (78)
4k (15)
4l (11)
1a
1a
1a
3m (70)
4m (16)
a All reactions were carried out on a 0.13 mmol scale of
nitroallylic acetates (1a-j) with 0.13 mmol indoles (2a-d) in the
presence of silica gel (304 mg) at 40 oC. b Isolated yields after
flash column chromatography.
(1a-j) with different substitution profiles and subject to the
Friedel-Crafts reaction with indoles (2a-d) (Table 2). The
corresponding products 3a-m and the minor regioisomers
4a-m were obtained in 57-82% and 34-<5% isolated yields,
respectively. These two products were readily separable by
flash column chromatography. We have also carried out re-
actions using furyl and thiophenyl derived nitroallylic ace-
tates as the electrophilic partners, and found that the latter
afforded the products with less selectivity (major:minor =
57:34) (Table 2, entry 10). Other substituted indoles (2b-d)
CONCLUSION
We have reported silica gel-mediated ‘green’Friedel-
Crafts reactions between functionalized nitroallylic ace-
tates and indoles to afford C-3 indole derivatives. Depend-
ing on the stability of the carbocation intermediate, two
functionalized regioisomers were isolated in high to excel-
lent overall chemical yields. The operationally simple,
metal-free, ecocompatible and neat conditions make this
process attractive.
2
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J. Chin. Chem. Soc. 2012, 59, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Silica gel-Mediated Friedel-Crafts Reaction
Proposed mechanism of the Friedel-Crafts
Scheme I
3b: Reaction Time: 1.5 h; yield 70%; Rf = 0.13 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.22 (s, 1H),
7.61 (d, J = 7.88 Hz, 1H), 7.52 (d, J = 7.92 Hz, 1H), 7.12-
7.37 (m, 6H), 6.78 (s, 1H), 6.23 (s, 1H), 5.67 (s, 1H), 4.19
(q, J = 7.16 Hz, 2H), 1.25 (t, J = 7.16 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 162.95, 159.70, 136.69, 133.70,
129.63, 129.55, 127.89, 126.01, 125.12, 124.52, 123.03,
120.45, 119.40, 119.40, 118.91, 111.97, 111.59, 62.01,
45.48, 13.75; IR (CH2Cl2) n 3416.97, 3055.35, 2988.92,
1727.18, 1664.51, 1539.17, 1465.43, 1369.58, 1266.35,
1196.31, 1096.77, 1023.04, 746.54 cm-1; HRMS [M+Na]+
calcd for C20H17BrN2O4 451.0269. Found 451.0278.
3c: Reaction Time: 1.5 h; yield 75%; Rf = 0.16 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.18 (s, 1H),
7.46-7.54 (m, 3H), 7.39 (d, J = 8.16 Hz, 1H), 7.25-7.28 (m,
3H), 7.16 (t, J = 7.68 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.69
(s, 2H), 4.19 (q, J = 7.16 Hz, 2H), 1.25 (t, J = 7.16 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 162.72, 160.22, 139.34,
136.67, 131.68, 131.35, 130.56, 127.19, 125.73, 124.51,
123.13, 120.57, 120.57, 118.91, 118.80, 112.76, 111.60,
61.99, 45.73, 13.73; IR (CH2Cl2) n 3424.35, 2981.54,
2922.50, 2856.08, 1727.18, 1660.82, 1542.85, 1461.75,
1369.58, 1262.67, 1196.31, 1096.77, 1026.72, 742.85
cm-1; HRMS [M+Na]+ calcd for C20H17BrN2O4 451.0269.
Found 451.0283.
reaction and the X-ray ORTEP drawing of
3a (30% probability)13
EXPERIMENTAL
Typical procedure
To a solution of nitroallylic acetate 1a (38 mg, 0.13
mmol) in CH2Cl2 (5 mL) was added silica gel (304 mg,
Merck silica gel 60, 230-400 mesh) in one portion. This
was added indole 2a (0.13 mmol) and the solvent was re-
moved in vacuo. The resulting mixture was stirred at 40 oC
for 1 h and purified by flash column chromatography
(eluted with hexanes:EtOAc = 6:1) to give the products 3a
(82%) and 4a (11%).
4c: yield 10%; Rf = 0.2 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.20 (s, 1H), 7.48-7.52 (m, 2H), 7.37-
7.40 (m, 2H), 7.12-7.28 (m, 6H), 7.06 (d, J = 2.48 Hz, 1H),
6.80 (s, 1H), 4.03-4.15 (m, 2H), 1.20 (t, J = 7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 163.64, 161.93, 141.01,
135.86, 131.07, 130.29, 129.96, 126.89, 126.79, 124.99,
124.99, 122.68, 122.61, 120.17, 118.69, 111.62, 111.30,
62.04, 39.96, 13.81; IR (CH2Cl2) n 3424.35, 2922.50,
2848.70, 1723.50, 1539.17, 1472.81, 1458.06, 1336.40,
1211.05, 742.85 cm-1; HRMS [M+Na]+ calcd for
C20H17BrN2O4 451.0269. Found 451.0291.
3a: yield 82%; Rf = 0.13 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.24 (s, 1H), 7.52 (d, J = 7.84 Hz, 1H),
7.29-7.32 (m, 6H), 7.18-7.22 (m, 1H), 7.12 (t, J = 7.92 Hz,
1H), 6.67 (d, J = 2.44 Hz, 1H), 5.67 (s, 2H), 4.15 (q, J =
7.16 Hz, 2H), 1.2 (t, J = 7.16 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 163.18, 161.41, 136.91, 136.73, 129.14, 128.70,
128.19, 125.88, 124.85, 122.91, 122.53, 120.00, 118.88,
113.06, 111.77, 62.05, 46.34, 13.82; IR (CH2Cl2) n 3424.35,
3070.11, 2996.30, 2922.50, 1727.18, 1539.17, 1458.06,
1369.58, 1266.35, 1200.00, 1096.77, 1026.72, 742.85,
o
694.93 cm-1; m.p. 97.7-100.3 C; HRMS [M+Na]+ calcd
3d: Reaction Time: 2 h; yield 76%; Rf = 0.17 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.23 (s, 1H),
7.51 (d, J = 7.84 Hz, 1H), 7.15-7.39 (m, 7H), 6.76 (s, 1H),
5.69 (s, 2H), 4.19 (q, J = 7.08 Hz, 2H), 1.25 (t, J = 7.08 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 162.77, 160.27,
139.07, 136.68, 134.99, 130.31, 128.78, 128.42, 126.78,
125.73, 124.53, 123.12, 120.56, 118.90, 118.79, 112.70,
111.63, 62.02, 45.78, 13.74; IR (CH2Cl2) n 3424.35,
2922.50, 1638.70, 1539.17, 1465.43, 1376.95, 1196.31,
1093.08, 1023.04, 742.85 cm-1; HRMS [M+Na]+ calcd for
C20H17ClN2O4 407.0775. Found 407.0783.
for C20H18N2O4 373.1164. Found 373.1173.
4a: yield 11%; Rf = 0.2 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.12 (s, 1H), 7.47 (d, J = 7.96, 1H),
7.10-7.36 (m, 9H), 6.94 (s, 1H), 6.74 (s, 1H), 3.93-4.02 (m,
2H), 1.11 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.66, 162.45, 138.40, 135.85, 128.40, 128.10, 127.07,
126.90, 125.00, 122.35, 122.22, 119.85, 118.73, 112.17,
111.24, 61.82, 40.62, 13.67; IR (CH2Cl2) n 3416.97,
1723.50, 1657.14, 1539.17, 1336.40, 1207.37, 742.85
cm-1; HRMS [M+Na]+ calcd for C20H18N2O4 373.1164.
Found 373.1180.
J. Chin. Chem. Soc. 2012, 59, 000-000
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3

Article
Ho et al.
4d: yield 14%; Rf = 0.2 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.14 (s, 1H), 7.48 (d, J = 8 Hz, 1H),
7.37 (d, J = 8 Hz, 1H), 7.04-7.25 (m, 8H), 6.70 (s, 1H),
3.94-4.09 (m, 2H), 2.32 (s, 3H), 1.15 (t, J = 7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 163.70, 162.76, 136.79,
135.94, 135.34, 129.17, 128.14, 127.03, 124.89, 122.45,
122.03, 119.96, 118.94, 112.79, 111.16, 61.80, 40.41,
21.02, 13.76; IR (CH2Cl2) n 3416.97, 3055.35, 2988.92,
2929.88, 2863.46, 1723.50, 1535.48, 1458.06, 1340.09,
1203.68, 1100.46, 1037.78, 857.14, 742.85 cm-1; HRMS
[M+Na]+ calcd for C21H20N2O4 387.1321. Found 387.1330.
3g: Reaction Time: 3 h; yield 65%; Rf = 0.13 (4:1
(400 MHz, CDCl3) d 8.20 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H),
7.36-7.40 (m, 2H), 7.12-7.24 (m, 7H), 7.06 (d, J = 2.40 Hz,
1H), 6.80 (s, 1H), 4.03-4.15 (m, 2H), 1.20 (t, J = 7.12 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 163.64, 162.00,
140.74, 135.87, 134.42, 129.66, 128.22, 127.36, 126.92,
126.31, 124.97, 122.69, 122.58, 120.17, 118.71, 111.68,
111.29, 62.03, 40.01, 13.81; IR (CH2Cl2) n 3416.97,
2988.92, 1719.81, 1657.14, 1535.48, 1340.09, 1207.37,
742.85 cm-1; HRMS [M+Na]+ calcd for C20H17ClN2O4
407.0775. Found 407.0783.
3e: Reaction Time: 2 h; yield 74%; Rf = 0.18 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.22 (s, 1H),
7.50 (d, J = 7.92 Hz, 1H), 7.15-7.38 (m, 7H), 6.74 (s, 1H),
5.68 (s, 2H), 4.18 (q, J = 7.00 Hz, 2H), 1.24 (t, J = 7.00 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 162.78, 160.53,
136.69, 135.53, 134.09, 129.97, 129.29, 125.73, 124.48,
123.11, 120.54, 118.85, 118.68, 112.98, 111.61, 61.99,
45.59, 13.74; IR (CH2Cl2) n 3409.59, 2988.92, 2937.26,
1723.50, 1664.51, 1539.17, 1369.58, 1196.31, 1093.08,
1015.66, 746.54 cm-1; m.p. 115.1-116.0 oC; HRMS
[M+Na]+ calcd for C20H17ClN2O4 407.0775. Found
407.0784.
4e: yield 14%; Rf = 0.2 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.17 (s, 1H), 7.45 (d, J = 8 Hz, 1H),
7.38 (d, J = 8 Hz, 1H), 7.22-7.32 (m, 5H), 7.10-7.13 (m,
2H), 7.03 (d, J = 2.40 Hz, 1H), 6.75 (s, 1H), 4.00-4.13 (m,
2H), 1.20 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.65, 162.24, 137.07, 135.92, 133.05, 129.62, 128.61,
126.83, 124.82, 122.67, 122.43, 120.14, 118.79, 112.09,
111.29, 62.00, 40.03, 13.80; IR (CH2Cl2) n 3424.35,
3062.73, 2922.50, 2848.70, 1727.18, 1535.48, 1336.40,
1203.68, 1089.40, 1011.98, 746.54 cm-1; HRMS [M+Na]+
calcd for C20H17ClN2O4 407.0775. Found 407.0780.
3f: Reaction Time: 2 h; yield 73%; Rf = 0.14 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.15 (s, 1H),
7.54 (d, J = 7.88 Hz, 1H), 7.35 (d, J = 8.12 Hz, 1H), 7.12-
7.24 (m, 6H), 6.74 (d, J = 2.32 Hz, 1H), 5.66 (s, 2H), 4.17
(q, J = 7.12 Hz, 2H), 2.34 (s, 3H), 1.23 (t, J = 7.12 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 162.93, 161.43, 137.79,
136.59, 133.75, 129.69, 128.46, 125.85, 124.49, 122.83,
120.29, 118.92, 117.87, 113.48, 111.45, 61.80, 45.86,
21.07, 13.70; IR (CH2Cl2) n 3416.97, 3062.73, 2981.54,
1730.87, 1542.85, 1373.27, 1270.04, 1203.68, 1093.08,
1023.04, 742.85 cm-1; m.p. 117.0-119.4 oC; HRMS [M+H]+
calcd for C21H20N2O4 365.1501. Found 365.1515.
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.18 (s, 1H),
7.53 (d, J = 7.88 Hz, 1H), 7.36 (d, J = 8.12 Hz, 1H),
7.13-7.25 (m, 4H), 6.87-6.90 (m, 2H), 6.76 (s, 1H), 5.65 (s,
2H), 4.17 (q, J = 7.12 Hz, 2H), 3.80 (s, 3H), 1.23 (t, J = 7.12
Hz, 3H); 13C NMR (100 MHz, CDCl3) d 162.93, 161.61,
159.27, 136.60, 129.69, 128.71, 125.79, 124.46, 122.80,
120.25, 118.90, 117.65, 114.37, 113.53, 111.47, 61.81,
55.25, 45.50, 13.69; IR (CH2Cl2) n 3409.59, 3055.35,
2988.92, 2848.70, 1727.18, 1664.51, 1535.48, 1513.36,
1458.06, 1369.58, 1251.61, 1192.62, 1030.41, 742.85
o
cm-1; m.p. 143.6-148.3 C; HRMS [M+H]+ calcd for
C21H20N2O5 381.1459. Found 381.1468.
4g: yield 18%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.14 (s, 1H), 7.03-7.47 (m, 8H), 6.84
(d, J = 8.68 Hz, 2H), 6.66 (s, 1H), 3.96-4.08 (m, 2H), 3.79
(s, 3H), 1.14 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 163.70, 162.76, 158.71, 135.96, 130.23, 129.52,
126.89, 124.76, 122.47, 121.91, 119.95, 118.96, 113.84,
113.01, 111.17, 61.81, 55.24, 40.15, 13.76; IR (CH2Cl2) n
3416.97, 3055.35, 2937.26, 2848.70, 1727.18, 1601.84,
1539.17, 1513.36, 1458.06, 1332.71, 1306.91, 1251.61,
1211.05, 1177.88, 1026.72, 857.14, 742.85 cm-1; HRMS
[M+Na]+ calcd for C21H20N2O5 403.1270. Found 403.1281.
3h: Reaction Time: 2.5 h; yield 75%; Rf = 0.12 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.19 (s, 1H),
7.54 (d, J = 7.92 Hz, 1H), 7.35 (d, J = 8.12 Hz, 1H), 7.14-
7.27 (m, 3H), 6.92 (d, J = 7.68 Hz, 1H), 6.84-6.87 (m,
2H),6.78 (s, 1H), 5.68 (s, 2H), 4.17 (q, J = 7.12 Hz, 2H),
3.77 (s, 3H), 1.23 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.90, 160.95, 159.96, 138.31, 136.53, 129.97,
125.77, 124.53, 122.80, 120.82, 120.26, 118.78, 118.23,
114.56, 113.20, 112.98, 111.48, 61.83, 55.20, 46.08, 13.67;
IR (CH2Cl2) n 3424.35, 3062.73, 2929.88, 2856.08,
1727.18, 1668.20, 1605.52, 1539.17, 1461.75, 1270.04,
1030.41, 882.94, 746.54 cm-1; m.p. 117.0-119.4 oC; HRMS
[M+H]+ calcd for C21H20N2O5 381.1450. Found 381.1459.
4f: yield 8%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
4
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Silica gel-Mediated Friedel-Crafts Reaction
4h: yield 12%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.16 (s, 1H), 7.50 (d, J = 8 Hz, 1H),
7.36 (d, J = 8 Hz, 1H), 7.18-7.25 (m, 2H), 7.09-7.13 (m,
2H), 7.04 (d, J = 2.12 Hz, 1H), 6.94-6.96 (m, 2H), 6.78-
6.81 (m, 1H), 6.73 (s, 1H), 3.94-4.09 (m, 2H), 3.75 (s, 3H),
1.15 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
163.69, 162.34, 159.72, 140.06, 135.88, 129.41, 127.05,
125.05, 122.48, 122.29, 120.54, 120.00, 118.84, 114.26,
112.30, 112.30, 111.19, 61.85, 55.19, 40.56, 13.76; IR
(CH2Cl2) n 3416.97, 3055.35, 2922.50, 2848.70, 1723.50,
1598.15, 1583.41, 1535.48, 1491.24, 1458.06, 1336.4,
1266.35, 1207.37, 1041.47, 742.85 cm-1; HRMS [M+Na]+
calcd for C21H20N2O5 403.1270. Found 403.1279.
709.67 cm-1; HRMS [M+H]+ calcd for C18H16N2O4S
357.0909. Found 357.0926.
4j: yield 34%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.18 (s, 1H), 7.55 (d, J = 7.96 Hz, 1H),
7.36 (d, J = 8.2 Hz, 1H), 7.04-7.29 (m, 7H), 6.96-6.97 (m,
1H), 4.20-4.24 (m, 2H), 1.27 (t, J = 7.12 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 163.70, 162.28, 142.03, 135.69,
126.76, 126.66, 126.36, 125.03, 124.81, 122.54, 121.67,
120.09, 118.57, 112.48, 111.29, 62.09, 35.89, 13.93; IR
(CH2Cl2) n 3409.59, 3099.63, 2922.50, 2848.70, 1749.30,
1638.70, 1535.48, 1314.28, 1211.05, 1056.22, 739.17
cm-1; HRMS [M+Na]+ calcd for C18H16N2O4S 379.0729.
Found 379.0738.
3i: Reaction Time: 2 h; yield 70%; Rf = 0.1 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H),
7.56 (d, J = 7.84 Hz, 1H), 7.43 (d, J = 1.36 Hz, 1H), 7.38 (d,
J = 8.08 Hz, 1H), 7.21-7.25 (m, 1H), 7.13-7.17 (m, 1H),
7.08 (d, J = 2 Hz, 1H), 6.33 (q, J = 1.96 Hz, 1H), 6.23 (d, J =
3.24 Hz, 1H), 5.77 (d, J = 9.84 Hz, 2H), 4.19 (q, J = 7.16
Hz, 2H), 1.24 (t, J = 7.16 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.69, 158.84, 149.94, 143.01, 136.38, 125.68,
124.05, 122.89, 120.41, 118.79, 117.76, 111.51, 110.66,
110.40, 109.33, 61.90, 39.90, 13.71; IR (CH2Cl2) n
3424.35, 2988.92, 1727.18, 1668.20, 1542.85, 1458.06,
1262.67, 1200.00, 1019.35, 742.85 cm-1; HRMS [M+H]+
calcd for C18H16N2O5 341.1137. Found 341.1144.
4i: yield 10%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.20 (s, 1H), 7.61 (d, J = 7.92 Hz, 1H),
7.14-7.39 (m, 5H), 7.08 (s, 1H), 6.94 (s, 1H), 6.34 (dd, J =
3.24, 1.92 Hz, 1H), 6.18 (d, J = 3.28 Hz, 1H), 4.23-4.29 (m,
2H), 1.31 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.77, 160.75, 151.98, 141.76, 135.66, 126.75, 124.95,
122.52, 121.96, 120.11, 118.72, 111.27, 110.61, 110.13,
107.79, 62.07, 31.92, 13.96; IR (CH2Cl2) n 3416.97,
3062.73, 2922.50, 2856.08, 1727.18, 1539.17, 1458.06,
1340.09, 1207.37, 1096.77, 1011.98, 742.85 cm-1; HRMS
[M+H]+ calcd for C18H16N2O5 341.1137. Found 341.1149.
3j: Reaction Time: 3 h; yield 57%; Rf = 0.13 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H),
7.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.12 Hz, 1H), 7.12-
7.27 (m, 3H), 6.97-7.03 (m, 3H), 5.99 (s, 1H), 5.80 (s, 1H),
3k: Reaction Time: 1 h; yield 78%; Rf = 0.13 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.05 (s, 1H),
7.24-7.36 (m, 7H), 7.05 (d, J = 8.32 Hz, 1H), 6.69 (d, J =
2.28 Hz, 1H), 5.67 (s, 2H), 4.18 (q, J = 7.12 Hz, 2H), 2.44
(s, 3H), 1.25 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.93, 161.18, 136.90, 134.89, 129.76, 128.98,
128.58, 128.00, 126.08, 124.63, 124.56, 118.38, 118.16,
112.83, 111.11, 61.81, 46.13, 21.49, 13.71; IR (CH2Cl2) n
3431.73, 2988.92, 2922.50, 2863.46, 1727.18, 1539.17,
1369.58, 1270.04, 1192.62, 1096.77, 1026.72, 798.15,
702.30 cm-1; HRMS [M+Na]+ calcd for C21H20N2O4
387.1321. Found 387.1332.
4k: yield 15%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.06 (s, 1H), 7.25-7.37 (m, 7H), 7.14
(s, 1H), 7.03 (d, J = 9.28 Hz, 1H), 7.00 (d, J = 2.52 Hz, 1H),
6.70 (s, 1H), 3.94-4.09 (m, 2H), 2.41 (s, 3H), 1.19 (t, J =
7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 163.71,
162.51, 138.56, 134.24, 129.28, 128.44, 128.16, 127.28,
127.08, 125.10, 124.15, 122.24, 118.41, 111.93, 110.87,
61.82, 40.65, 21.52, 13.77; IR (CH2Cl2) n 3416.97,
3062.73, 2922.50, 2856.08, 1727.18, 1657.14, 1539.17,
1447.00, 1373.27, 1340.09, 1266.35, 1207.37, 1096.77,
1034.10, 794.47, 739.17, 702.30 cm-1; HRMS [M+Na]+
calcd for C21H20N2O4 387.1321. Found 387.1329.
3l: Reaction Time: 1 h; yield 78%; Rf = 0.13 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.11 (s, 1H),
7.24-7.36 (m, 7H), 6.94 (d, J = 2.28 Hz, 1H ), 6.87-6.89 (m,
1H), 6.69 (d, J = 2.44 Hz, 1H), 5.69 (s, 1H), 5.65 (s, 1H),
4.18 (q, J = 7.12 Hz, 2H), 3.82 (s, 3H), 1.25 (t, J = 7.12 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 162.93, 160.85,
154.52, 136.82, 131.65, 128.99, 128.56, 128.02, 126.27,
125.19, 118.36, 113.07, 112.99, 112.28, 100.59, 61.84,
55.88, 46.18, 13.70; IR (CH2Cl2) n 3416.97, 2996.30,
2937.26, 1727.18, 1539.17, 1487.55, 1266.35, 1207.37,
4.19 (q, J = 7.16 Hz, 2H), 1.24 (t, J = 7.16 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) d 162.84, 160.68, 139.97, 136.49,
127.14, 127.11, 125.94, 125.57, 124.10, 122.93, 120.39,
118.78, 117.97, 112.93, 111.53, 61.94, 40.92, 13.70; IR
(CH2Cl2) n 3409.59, 2937.26, 2856.08, 1727.18, 1535.48,
1373.27, 1258.98, 1196.31, 1100.46, 1019.35, 746.54,
J. Chin. Chem. Soc. 2012, 59, 000-000
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Article
Ho et al.
1026.72, 798.15, 698.61 cm-1; HRMS (ESI) calcd for
C21H20N2O5 403.1270. Found 403.1277.
ACKNOWLEDGMENTS
The financial support of the National Science Council
of the Republic of China (NSC 99-2113-M-003-002-MY3
and NSC 99-2119-M-003-001-MY2) and National Taiwan
Normal University (100-D-06) are gratefully acknowl-
edged. Our gratitude goes to the Academic Paper Editing
Clinic at NTNU and the National Center for High-Perfor-
mance Computing for providing us with computer time and
facilities.
4l: yield 11%; Rf = 0.18 (4:1 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.08 (s, 1H), 7.25-7.37 (m, 6H), 7.14
(s, 1H), 7.04 (d, J = 2.52 Hz, 1H), 6.93 (d, J = 2.24 Hz, 1H),
6.85-6.88 (m, 1H), 6.72 (s, 1H), 3.97-4.09 (m, 2H), 3.78 (s,
3H), 1.17 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.76, 162.49, 154.32, 138.44, 130.98, 128.44, 128.06,
127.55, 127.08, 125.76, 122.17, 112.67, 111.98, 111.91,
100.85, 61.84, 55.80, 40.56, 13.79; IR (CH2Cl2) n 3424.35,
3062.73, 2922.50, 2848.70, 1723.50, 1539.17, 1487.55,
1340.09, 1211.05, 1026.72, 798.15, 698.61 cm-1; HRMS
[M+Na]+ calcd for C21H20N2O5 403.1270. Found 403.1281.
3m: Reaction Time: 8 h; yield 70%; Rf = 0.13 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H),
7.48 (d, J = 1.84 Hz, 1H), 7.26-7.38 (m, 6H), 7.19 (d, J =
1.92 Hz, 1H), 6.83 (d, J = 2.48 Hz, 1H), 5.63-5.65 (m, 2H),
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129.13, 128.56, 128.24, 126.95, 126.19, 125.75, 123.39,
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407.0782.
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(400 MHz, CDCl3) d 8.20 (s, 1H), 7.45 (d, J = 1.88, 1H),
7.26-7.32 (m, 6H), 7.11-7.18 (m, 3H), 6.70 (s, 1H), 4.00-
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128.14, 128.08, 127.29, 126.38, 125.87, 122.90, 122.44,
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3424.35, 3055.35, 2922.50, 2856.08, 1723.50, 1539.17,
1465.43, 1336.40, 1203.68, 1104.14, 1030.41, 894.00,
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407.0775. Found 407.0782.
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6a: Reaction Time: 8 h; yield 76%; Rf = 0.2 (4:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) d 7.24-7.36 (m,
5H), 6.11 (s, 2H), 5.97 (d, J = 1.84 Hz, 1H), 5.53 (d, J = 2
Hz, 1H), 4.17 (q, J = 7.12 Hz, 2H), 3.79 (s, 3H), 3.75 (s,
6H), 1.24 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 163.54, 163.32, 161.23, 159.04, 137.69, 129.27, 128.51,
127.31, 115.85, 106.06, 91.29, 61.40, 55.77, 55.25, 43.95,
13.76; IR (CH2Cl2) n 3446.49, 2944.64, 2841.32, 1727.18,
1605.52, 1542.85, 1458.06, 1200.00, 1118.89, 1026.72,
816.58, 702.30 cm-1; HRMS [M+Na]+ calcd for C21H23NO7
424.1372. Found 424.1380.
6
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Silica gel-Mediated Friedel-Crafts Reaction
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J. Chin. Chem. Soc. 2012, 59, 000-000
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
7