Chiral phosphoric acid catalyzed asymmetric friedel-crafts alkylation of indoles with nitroolefins

Article abstract of DOI:10.1080/10426507.2010.536189

Asymmetric Michael-type Friedel-Crafts (F-C) alkylations of indoles with nitroolefins catalyzed by a chiral H₈-BINOL-based phosphoric acid were investigated. The reactions took place very smoothly in the presence of only 5 mol-% of catalyst at

Full text of DOI:10.1080/10426507.2010.536189

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Phosphorus, Sulfur, and Silicon and the
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Chiral Phosphoric Acid Catalyzed
Asymmetric Friedel–Crafts Alkylation of
Indoles with Nitroolefins
Hong-Ying Tang a & Zhong-Biao Zhang a
a Tianjin Key Laboratory of Water Environment and Resources,
Tianjin Normal University, Tianjin, China
Published online: 14 Oct 2011.
To cite this article: Hong-Ying Tang & Zhong-Biao Zhang (2011) Chiral Phosphoric Acid Catalyzed
Asymmetric Friedel–Crafts Alkylation of Indoles with Nitroolefins, Phosphorus, Sulfur, and Silicon and
the Related Elements, 186:10, 2038-2046, DOI: 10.1080/10426507.2010.536189
To link to this article: http://dx.doi.org/10.1080/10426507.2010.536189
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Phosphorus, Sulfur, and Silicon, 186:2038–2046, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.536189
CHIRAL PHOSPHORIC ACID CATALYZED
ASYMMETRIC FRIEDEL–CRAFTS ALKYLATION
OF INDOLES WITH NITROOLEFINS
Hong-Ying Tang and Zhong-Biao Zhang
Tianjin Key Laboratory of Water Environment and Resources, Tianjin Normal
University, Tianjin, China
GRAPHICAL ABSTRACT
Abstract Asymmetric Michael-type Friedel–Crafts (F–C) alkylations of indoles with ni-
troolefins catalyzed by a chiral H8-BINOL-based phosphoric acid were investigated. The
reactions took place very smoothly in the presence of only 5 mol-% of catalyst at room tem-
perature to afford the desired F–C alkylation products in good yields and with moderate
enantioselectivities.
Keywords Asymmetric Friedel–Crafts alkylations; enantioselectivities; chiral phosphoric acid;
indoles; nitroolefins
INTRODUCTION
The indole framework represents a privileged structure motif in a large number of
natural products and therapeutic agents.1,2 We all know that indole is an electron-rich
Received 27 October 2010; accepted 27 November 2010.
This work is supported by Tianjin Natural Science Foundation (08JCYBJC26900), the Research Fund for
Young Scientist (No. 52LX29), Tianjin Normal University, and Tianjin High School Foundation for Development
of Science and Technology (2008ZD09).
Address correspondence to Zhong-Biao Zhang, Tianjin Key Laboratory of Water Environment and Re-
sources, Tianjin Normal University, Tianjin 300387, China. E-mail: ttxyx27@yahoo.com.cn
2038

FRIEDEL–CRAFTS ALKYLATION OF INDOLES
2039
heteroaromatic compound in which the pyrrole π-system is significantly activated toward
electrophilic substitution. Therefore, the asymmetric Friedel–Crafts (F–C) alkylation be-
comes a powerful strategy to the construction of indolic architectures3–6 and has drawn
much attention from organic chemists. Nitroolefins are very attractive Michael acceptors
and have been widely used in organic synthesis. The asymmetric F–C alkylated reactions
of indoles with nitroolefins are useful for the preparation of biologically active compounds
such as indole alkaloids7–10 and have been developed quickly since 2005. The asymmetric
F–C alkylation of indoles with nitroolefins is catalyzed mostly by metal complexes such
as Bandini’s salen/AlCl complexes,11 the ZnII or CuII–bisoxazoline complexes12–22 (e.g.,
Zhou11 reported the asymmetric reaction of indoles and nitroolefins with excellent ena-
tionselectivities catalyzed by chiral complexes of bisoxazoline and Zn(OTf)2), and Song’s
PtII or PdII complexes.23 However, fewer organocatalysts have been reported for the asym-
metric reactions. In 2005, Jϕrgenson first reported organocatalytic chiral bis(sulfonamide)
compounds for asymmetric F–C alkylated reactions of indoles with nitroolefins.24 In ad-
dition, a series of thiourea-containing organocatalysts were reported for the asymmetric
reaction.25–27 Recently, chiral phosphoric acids represent an attractive and widely applicable
class of enantioselective organocatalysts and have been proven to be versatile organocat-
alysts in many organic transformations.28–36 Most highly enantioselective transformations
using BINOL-derived monophosphoric acids as catalysts were demonstrated by Akiyama
and Terada.28,29,31,36 We reported here the application of chiral (R)-H8-BINOL phosphoric
acid that catalyzed the F–C reaction of indoles and nitroolefins.
RESULTS AND DISCUSSION
We first performed the F–C reaction between (E)-β-nitrostyrene and indole employ-
ing different BINOL phosphates 1a–j and H8-BINOL phosphates 2a–d as the catalysts. The
best enantiomeric excess value (37%, Table 1, Entry 13) was obtained when H8-BINOL
phosphate 2c was used. The introduction of an electron-withdrawing group in the catalyst,
such as trifluoromethyl at the 3,5-position of the benzene ring (1g, 2d), or at the 3, 3ꢁ-
position of the binol skeleton, has a detrimental effect on the reaction. The reaction became
sluggish, and the enantiomeric excess of the product was at a very low level (Table 1, Entry
14), or the racemic product (Table 1, Entry 7) was obtained.
In further experiments, catalyst loading, solvent, and reaction temperature were thor-
oughly examined using the model reaction between (E)-β-nitrostyrene and indole with 2c
as the catalyst. The results are listed in Table 2.
From Table 2, it was found that the enantioselectivity was enhanced with the in-
crease in catalyst loading. The maximum ee value was obtained when catalyst’s loading
reached to 5 mol-% (Entry 3) in methylene dichloride. Further increases in catalyst amount
(10 mol-%, Entry 4) led to a higher yield but lower enantioselectivity. In view of these

2040
H.-Y. TANG AND Z.-B. ZHANG
Table 1 Screening of catalysts for asymmetric F–C alkylation of (E)-β-nitrostyrenea
Entry
Cat.
R
Time (h)
Yield (%)b
ee (%)c
Configurationd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph2(PO)
Ph
24
24
24
24
24
24
48
24
24
48
24
24
24
24
32
56
73
74
80
68
45
73
72
56
77
74
68
46
7
S
S
S
S
S
S
–
S
S
S
R
R
R
R
18
23
27
2
28
0
31
32
14
16
28
37
15
4-ClC6H4
4-MeC6H4
4-CH3OC6H4
4-PhC6H4
35-(F3C)2C6H3
2-Naphthyl
4-tBuC6H4
9-Anthryl
Ph
1j
2a
2b
2c
2d
2-Naphthyl
4-ClC6H4
3,5-(F3C)2C6H3
aReactions were performed on a 0.25 mmol scale of (E)-β-nitrostyrene with a concentration of 0.33 mol L−1
.
bIsolated yield. cEnantiomeric excess was determined through HPLC analysis on an AD-H column, hexane/2-
propanol (85:15), flow rate 1.0 mL min−1, and Rt = 14.87 (major) and 16.10 min (minor). dAbsolute configuration
of the major isomer was assigned by comparison to the literature value of optical rotation in Ref. 12
Table 2 Optimization of the reaction conditionsa
Entry
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
CH3OH
Toluene
Ethyl acetate
THF
2c (mol-%)
Temp. (◦C)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1
2
5
10
5
5
5
5
5
5
20
20
20
20
20
20
20
20
20
20
0
66
68
70
75
70
72
62
60
Nrd
Nrd
64
83
7
18
23
27
2
28
0
31
32
14
16
28
10
11
12
CHCl3
CHCl3
5
5
40
aReactions were performed on a 0.25 mmol scale of (E)-β-nitrostyrene with a concentration of 0.33 mol L−1
.
bIsolated yield. cEnantiomeric excess was determined through HPLC analysis on an AD-H column, hexane/2-
propanol (85:15), flow rate 1.0 mL min-1, and Rt = 14.87 (minor) and 16.10 min (major). dNr: no reaction.

FRIEDEL–CRAFTS ALKYLATION OF INDOLES
2041
results, using 5 mol-% 2c, we screened the solvent effect on this reaction. It revealed that
chloroalkanes (CH2Cl2, CHCl3, and ClCH2CH2Cl) favored this transformation (Table 2,
Entries 3, 5, and 6), and chloroform was the best solvent to provide F–C alkylation product
with the best enantiomeric excess (Entry 5, 40% ee). The reactions in methanol and toluene
proceeded but resulted in racemic products (Entries 7, 8). No reaction occurred in tetrahy-
drofuran (THF) and ethyl acetate. Changes in reaction temperatures gave no improvement
on stereoselectivity, though the yields were affected to some extent (Entries 11, 12).
Further studies revealed a weak dependence of the initial substrate concentration on
the enantioselectivity of the product. When the concentration of (E)-β-nitrostyrene was
decreased from 0.33 to 0.17 M, the ee value increased from 40% to 42%, while further
diluting to 0.14 M led to a lower selectivity of 37% ee.
Under the optimal reaction conditions (5 mol-% of 2c as catalyst, 0.17 M nitroolefins,
◦
at 20 C in chloroform), a variety of nitroolefins and indoles were investigated, and the
results are summarized in Table 3.
Table 3 Asymmetric Friedel–Crafts alkylation of indole derivatives with different nitroolefins catalyzed by 2ca
Entry
R
R1
Yield (%)b
ee (%)c
Configuration
1(3a)
2(3b)
3(3c)
4(3d)
5(3e)
6(3f)
7(3g)
8(3h)
9(3i)
10(3j)
11(3k)
12(3l)
13(3m)
14(3n)
15(3o)
16(3p)
17(3q)
18(3r)
19(3s)
20(3t)
21(3u)
22(3v)
23(3w)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-Br
Ph
70
77
76
67
71
75
72
79
81
62
84
70
65
64
55
72
74
86
Nrf
68
Nr
75
81
41
42
35
33
40
42
41
S
ndd
nd
nd
nd
nd
nd
–
nd
nd
nd
nd
nd
nd
nd
nd
nd
Se
4-CH3OC6H4
4-ClC6H4
2-CH3OC6H4
3-CH3OC6H4
4-CH3C6H4
2,4-(CH3O)2C6H3
4-PhCH2OC6H4
4-FC6H4
2-CF3C6H4
1-Naphthyl
5-Methyl-2-furyl
2-thienyl
g
–
42
35
31
35
42
40
24
47
38
2
–
5
–
34
33
PhCH = CH-
n-Propyl
4-CH3OC6H4
4-CH3OC6H4
Ph
Ph
Ph
Ph
Ph
Ph
5-CH3O
1-CH3
1-Bn
2-CH3
2-CH3CO2
5-Br
–
nd
–
nd
nd
5-CH3O
aReactions were performed on a 0.25 mmol scale of nitroolefins with a concentration of 0.17 mol L−1. bIsolated
yield. cEnantiomeric excess was determined through HPLC analysis. dNd means not determined. eAbsolute
configuration of the major isomer was assigned by comparison to the literature value of optical rotation in Ref.
12. fNr means no reaction. gEnantiomeric excess could not be determined.

2042
H.-Y. TANG AND Z.-B. ZHANG
The reaction has broad applicability with respect to the nitroolefins. Most nitroolefins
containing either electron-donating or electron-withdrawing groups on the benzene ring
reacted well with indole and its derivatives, and the corresponding alkylated indoles were
obtained in good yields and moderate enantioselectivities (Table 3, Entries 2–10, 16, and
17). In addition to nitrostyrene derivatives, other aromatic nitroolefins, such as 1-naphthyl
and electron-rich 5-methyl-2-furyl and 2-thienyl substituted nitroolefins, can also serve as
substrates in this reaction, giving the corresponding alkylated indoles in good yields and
moderate enantioselectivities (Table 3, Entries 11–13). It is noted that this reaction could be
extended to aliphatic nitroolefins. For example, the reaction of 1-((1E, 3E)-4-nitrobuta-1,
3-dienyl) benzene or 1-nitropentene with indole ran smoothly to provide the corresponding
alkylation product in fair yields with 40% ee and 24% ee, respectively (Table 3, Entries 15,
16).
As for the substrate indoles, variation of the substituents on the indole nitrogen atom
revealed that the steric hindrance of the substituting group plays an important role in the
reaction. For example, in relation to the result of indole (Table 3, Entry 1, 42% ee), the
use of N-methyl indole led to a great decrease in ee value (Table 3, Entry 2, 2% ee),
whereas the employment of bulkier benzyl-substituted indole resulted in no adduct (Table
3, Entry 19). In general, substituents at the C(2)-indole position restrained the reaction.
Incorporation of methyl group at the C(2)-indole position had a detrimental effect on the
reaction, which gave the corresponding adduct in a marked loss of selectivity (Table 3,
Entry 20, 5% ee), while using 2-carboxylate substitued indole, no F–C alkylated product
was obtained (Table 3, Entry 21). On the contrary, either electron-donating group OCH3 or
electron-withdrawing group Br at the 5-position of indole accelerated the reaction slightly
(Table 3, Entries 16, 17, 22, 23). The use of 5-bromo-1H-indole with 1-methoxy-4-(E)-2-
nitrovinylbenzene afforded the corresponding adduct with the best enantioselectivity (Table
3, Entry 17, 47% ee).
CONCLUSION
We have studied the chiral (R)-H8-BINOL phosphoric acid catalyzed asymmetric
F–C alkylation of indoles and nitroolefins under very mild conditions with no addition. It is
worth noting that though moderate selectivity has been achieved, there are some advantages
of the reaction conditions over other organocatalytic asymmetric version of this reaction in
the limited literature reports, especially on the catalyst loading (only 5 mol-% versus 10–30
mol-%).
EXPERIMENTAL
General Information
1H and 31P NMR spectra were recorded in CDCl3 on a Bruker AMX-300 or Varian
400 MHz instrumental using tetramethylsilane (TMS) as an internal standard for 1H NMR
and 85% H3PO4 as an external standard for 31P NMR. Specific rotations were measured
on a Perkin-Elmer 341MC polarimeter. Enantiomeric excesses were determined on an
HP-1100 instrument (chiral column; mobile phase: hexane/i-PrOH). Elemental analyses
were conducted on a Yanaco CHN Corder MT-3 automatic analyzer. Melting points were
determined on a T-4 melting point apparatus. All temperatures were uncorrected.

FRIEDEL–CRAFTS ALKYLATION OF INDOLES
2043
Synthesis of Catalysts
Catalysts 1a–h, 2a–d were prepared through condensation of 3,3ꢁ-substituted BINOL
or H8-BINOL and phosphorus oxychloride in the presence of pyridine and then acidic
hydrolysis of the corresponding chlorophosphate according to the literature method.33
1a: White solid. Yield: 370 mg, 99%. Mp. 209–211 ◦C. [α]D20 −156.2 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.78 (br. s, 1 H, OH), 7.24–7.26 (m, 4 H), 7.41–7.84
(m, 26 H). 13C NMR (400 MHz, CDCl3): 123.5 (2C), 124.5 (2C), 125.1 (2C), 126.9 (2C),
127.6 (2C), 128.5 (2C), 129.5 (8C), 130.2 (2C), 132.4 (4C), 133.7 (8C), 134.3 (4C), 134.7
(2C), 137.7 (2C), 154.2 (2C). 31P NMR (161.7 MHz, CDCl3): δ = −0.47, 36.67, 37.39.
C44H31O6P3 (748.61): calcd. C 70.59, H 4.17; found C 70.41, H 4.04.
General Procedure for the 2c Catalyzed Asymmetric F–C Alkylation
of Indoles with Nitroolefins
Nitroolefins (0.25 mmol), indoles (0.3 mmol), and catalyst 2c (2.89 mg, 0.005 mmol)
were stirred in chloroform (1.5 mL) at room temperature. The reaction was monitored by
TLC analysis. After removal of solvent, the residue was purified by column chromatograph
on silica gel (200–300 meshes, gradient eluted with petroleum ether/ethyl acetate) to give
the desired product 3.
(S)-3-(2-nitro-1-phenylethyl)-1H-indole (3a): [12]: Yield: 70%. [α]2D0 +11.6 (c 1.3,
CH2Cl2). 41% ee. High-performance liquid chromatography (HPLC) conditions: AD-H
column, hexane/2-propanol (85:15), flow rate 1 mL min−1, and Rt = 14.24 (minor) and
15.43 min (major).
3-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-indole (3b) [12]: Yield: 77%. [α]D20
+13.6 (c 0.95, CH2Cl2). 42% ee. HPLC conditions: OD-H column, hexane/2-propanol
(70:30), flow rate 1 mL min−1, and Rt = 19.62 (minor) and 21.24 min (major).
3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indole (3c) [12]: Yield: 76%. [α]2D0 +3.2
(c 1.00, CH2Cl2). 35% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30),
flow rate 1 mL min−1, and Rt = 19.62 (minor) and 21.24 min (major).
3-(1-(2-methoxyphenyl)-2-nitroethyl)-1H-indole (3d) [12]: Yield: 67%. [α]D20
+23.2 (c 1.00, CH2Cl2). 33% ee. HPLC conditions: OD-H column, hexane/2-propanol
(70:30), flow rate 1 mL min−1, and Rt = 13.15 (minor) and 15.26 min (major).
3-(1-(3-methoxyphenyl)-2-nitroethyl)-1H-indole (3e) [12]: Yield: 71%. [α]2D0 +9.2
(c 1.00, CH2Cl2). 40% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30),
flow rate 1 mL min−1, and Rt = 23.08 (major) and 33.63 min (minor).
3-(1-(4-methylphenyl)-2-nitroethyl)-1H-indole (3f) [12]: Yield: 75%. [α]2D0 +9.6
(c 1.00, CH2Cl2). 42% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30),
flow rate 1 mL min−1, and Rt = 20.07 (major) and 23.14 min (minor).
3-(1-(2,4-dimethoxyphenyl)-2-nitroethyl)-1H-indole (3g): Pale yellow oil. Yield:
72%. [α]2D0 +23.2 (c 1.05, CH2Cl2). 41% ee. H NMR (CHCl3, 300 MHz): δ = 3.71 (s,
1
CH3), 3.73 (s, CH3), 4.91–5.03 (m, 2 H), 5.50 (dd, J = 8.8, 6.8 Hz, 1 H, CH), 6.80–7.16
(m, 4 H), 7.24–7.45 (m, 3 H), 7.55 (d, J = 8.8 Hz, 1 H), 8.03 (b, NH). HPLC conditions:
OD-H column, hexane/2-propanol (70:30), flow rate 1 mL min−1, and Rt = 14.26 (minor)
and 16.01 min (major). C18H18N2O4 (326.35): calcd. C 66.25, H 5.56, N 8.58; found C
66.27, H 5.49, N 8.35.
3-(1-(4-benzyloxyphenyl)-2-nitroethyl)-1H-indole (3h): Colorless oil. Yield: 79%.
[α]2D0 +33.2 (c 1.00, CH2Cl2). 1H NMR (CHCl3, 400 MHz): δ = 4.89 (dd, 1 H, one proton

2044
H.-Y. TANG AND Z.-B. ZHANG
of CH2), 5.04 (dd, J = 4.0, 12.4 Hz, 1 H, one proton of CH2), 5.02–5.07 (m, 3H), 5.15 (t,
J = 8.0 Hz, 1 H, CH), 6.93 (d, J = 8.4 Hz, 2 H), 7.01 (s, 1 H), 7.08 (t, J = 7.6 Hz, 1 H),
7.18–7.26 (m, 3 H), 7.30–7.50 (m, 7 H), 8.11 (bs, NH). C23H20N2O3 (372.42): calcd. C
74.18, H 5.41, N 7.52; found C 74.05, H 5.59, N 7.35.
3-(1-(4-fluorophenyl)-2-nitroethyl)-1H-indole (3i) [11]: Yield: 81%. [α]2D0 +20.2
(c 1.00, CH2Cl2). 42% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30),
flow rate 1 mL min−1, and Rt = 22.39 (major) and 28.67 min (minor).
3-(1-(4-trifluoromethylphenyl)-2-nitroethyl)-1H-indole (3j): Colorless oil. Yield:
62%. [α]2D0 +18.4 (c 0.95, CH2Cl2). 35% ee. 1H NMR (CHCl3, 400 MHz): δ = 4.84 (dd,
J = 7.6, 12.8 Hz, 1 H, one proton of CH2), 5.02 (dd, J = 7.6, 12.8 Hz, 1 H, one proton of
CH2), 5.70 (dd, J = 9.6, 6.0 Hz, 1 H, CH), 7.06 (t, J = 7.6 Hz 1 H), 7.16–7.24 (m, 2 H),
7.34–7.46 (m, 5 H), 7.76 (d, J = 8.4, 6.0 Hz, 1 H), 8.13 (bs, NH). HPLC conditions: AD-H
column, hexane/2-propanol (70:30), flow rate 1 mL min−1, and Rt = 7.96 (major) and 8.68
min (minor). C17H13F3N2O2 (334.29): calcd. C 61.08, H 3.92, F 17.05, N 8.38; found C
61.05, H 3.67, F 16.90, N 8.45.
3-(1-Naphthalen-1-yl-2-nitroethyl)-1H-indole (3k) [12]: Yield: 84%. [α]2D0 +7.5 (c
1.8, CH2Cl2). 31% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30), flow
rate 1 mL min−1, and Rt = 29.33 (minor) and 34.77 min (major).
3-(1-(5-methylfuran-2-yl)-2-nitroethyl)-1H-indole (3l): Pale yellow oil. Yield:
70%. [a]2D0 33.4 (c 1.01, CH2Cl2). 35% ee. H NMR (CHCl3, 400 MHz): δ = 2.27 (s,
1
CH3), 4.90 (dd, J = 7.6, 12.4 Hz, 1 H, one proton of CH2), 5.04 (dd, 1 H, J = 8.0, 12.4
Hz, one proton of CH2), 5.19 (t, J = 8.0 Hz, 1 H, CH), 5.87 (d, J = 2.0 Hz, 1 H), 6.02
(d, J = 2.8 Hz, 1 H), 7.11–7.16 (m, 2 H), 7.22 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0
Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 8.13 (1, NH). HPLC conditions: OD-H column,
hexane/2-propanol (70:30), flow rate 1 mL min−1, and Rt = 12.17 (minor) and 16.55 min
(major). C15H14N2O3 (270.28): calcd. C 66.66, H 5.22, N 10.36; found C 66.76, H 5.05,
N 10.55.
3-(2-Nitro-1-thiophene-2-ylethyl)-1H-indole (3m) [12]: Yield: 65%. [α]2D0 +13.4
(c 1.05, CH2Cl2). 42% ee. HPLC conditions: OD-H column, hexane/2-propanol (70:30),
flow rate 1 mL min−1, and Rt = 23.13 (minor) and 23.53 min (major).
3-(1-nitro-4-phenylbut-3-en-2-yl)-1H-indole (3n): Pale yellow oil. Yield: 64%.
[α]2D0 −10.4 (c 1.00, CH2Cl2). 40% ee. H NMR (CHCl3, 400 MHz): δ = 4.72 (dd,
1
J = 7.6, 14.8 Hz, 1 H, one proton of CH2), 4.80 (t, J = 11.6 Hz 1 H, CH), 4.87 (dd, J =
11.6, 7.6 Hz, 1 H, one proton of CH2), 6.43 (dd, J = 15.6, 7.6 Hz, 1 H, CH), 6.61 (d, J = 16
Hz, 1 H, CH), 7.07–7.44 (m, 9 H), 7.67 (d, J = 8.0, 1 H), 8.14 (bs, NH). HPLC conditions:
OD-H column, hexane/2-propanol (70:30), flow rate 1 mL min−1, and Rt = 23.66 (major)
and 27.77 min (minor). C18H16N2O2 (292.33): calcd. C 73.95, H 5.52, N 9.58; found C
73.79, H 5.45, N 9.40.
3-(1-nitromethylbutyl)-1H-indole (3o) [12]: Yield: 55%. [α]2D0 −18.9 (c 0.95,
EtOH). 24% ee. HPLC conditions: OD-H column, hexane/2-propanol (90:10), flow rate
1 mL min−1, and Rt = 37.67 (minor) and 40.55 min (major).
5-bromo-3-(1-(4-methoxyphenyl)-2- nitroethyl)-1H-indole (3p) [22]: 72%. [α]D20
−22.2 (c 1.22, CH2Cl2). 47% ee. HPLC conditions: OD-H column, hexane/2-propanol =
70:30, flow rate 1 mL/min, and Rt = 13.58 (minor) and 16.35 min (major).
5-methoxy-3-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-indole (3q) [22]: Yield:
74%. [α]2D0 −18.2 (c 1.20, CH2Cl2). 38% ee. HPLC conditions: OD-H column,
hexane/2-propanol (70:30), flow rate 1 mL min−1, and Rt = 15.17 (minor) and 17.27 min
(major).

FRIEDEL–CRAFTS ALKYLATION OF INDOLES
2045
1-methyl-3-(2-nitro-1-phenylethyl)-1H-indole (3r) [12]: Yield: 86%. [α]2D0 +0.75
(c 1.05, CH2Cl2). 2% ee. HPLC conditions: AD-H column, hexane/2-propanol (80:20),
flow rate 1 mL min−1, and Rt = 8.62 (major) and 7.42 min (minor).
2-methyl-3-(2-nitro-1-phenylethyl)-1H-indole (3t) [16]: Yield: 68%. [α]2D0 −1.0 (c
2.30, CH2Cl2). 5% ee. HPLC conditions: AD-H column, hexane/2-propanol (96:4), flow
rate 1 mL min−1, and Rt = 70.35 (minor) and 73.92 min (major).
5-bromo-3-(2-nitro-1-phenylethyl)-1H-indole (3v) [12]: Yield: 75%. [α]2D0 −13.2
(c 1.50, CH2Cl2). 34% ee. HPLC conditions: AD-H column, hexane/2-propanol (90:10),
flow rate 1 mL min−1, and Rt = 19.62 (minor) and 21.24 min (major).
5-methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (3w) [12]: Yield: 81%. [α]D20
−18.2 (c 1.45, CH2Cl2). 33% ee. HPLC conditions: OD-H column, hexane/2-propanol
(85:15), flow rate 1 mL min−1, and Rt = 19.62 (minor) and 21.24 min (major).
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