Enantioselective Friedel-Crafts alkylation of indoles with 2-enoylpyridine-N-oxides catalyzed by glucoBOX-Cu(ii) complex

Article abstract of DOI:10.1039/c2ob25315a

The glucosamine derived glucoBOX-Cu(ii) complex was found to be a unique catalytic system for enantioselective Friedel-Crafts alkylation of indoles with 2-enoylpyridine-1-oxides. A large number of 3-alkylated indole derivatives were prepared using 5 mol%

Full text of DOI:10.1039/c2ob25315a

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PAPER
Enantioselective Friedel–Crafts alkylation of indoles with 2-enoylpyridine-N-
oxides catalyzed by glucoBOX-Cu(II) complex†
Jimil George and B. V. Subba Reddy*
Received 13th February 2012, Accepted 17th April 2012
DOI: 10.1039/c2ob25315a
The glucosamine derived glucoBOX-Cu(II) complex was found to be a unique catalytic system for
enantioselective Friedel–Crafts alkylation of indoles with 2-enoylpyridine-1-oxides. A large number of
3-alkylated indole derivatives were prepared using 5 mol% glucoBOX-Cu(II) complex in excellent yields
with high enantioselectivity up to 99% ee.
The co-ordinating group, i.e. the pyridine-N-oxide moiety can
Introduction
easily be converted into the corresponding carboxylic acid.18
In recent years, tremendous interest has been devoted to the
preparation of substituted indoles due to their varied biological
activities including antioxidant, antibacterial, and insecticidal be-
havior.1 Some of the indole derivatives are found to exhibit
anticancer activity against various human cancers.2 Among
various derivatives of indoles, 3-substituted indoles are impor-
tant as they are widely distributed in nature and show a broad
range of biological activities.3 Therefore, there is a growing
interest in the development of improved methods for the syn-
thesis of 3-substituted indoles.4 As a result, several substrates
such as nitrostyrenes,5 α-ketoesters,6 2-acyl ketophosphonates,7
α-hydroxyenones,8 N-methylimidazoles,9 and arylidinemalo-
nates10 have been reported as excellent reaction partners for
Friedel–Crafts reactions in terms of yield and enantioselectivity.
Recently, organo-catalysts11 have also been shown to be efficient
catalysts for enantioselective Friedel–Crafts alkylation of
indoles.
While several electrophilic substrates are known to undergo
Cu(II)-catalyzed enantioselective Friedel–Crafts reactions, (ref.
5–10) 2-enoylpyrinine-N-oxides are less explored. Pedro et al.
have reported the 2-enoylpyridine-N-oxides as excellent sub-
strates for Cu(II)-catalyzed enantioselective Diels–Alder reac-
tions12 and hetero-Diels–Alder reactions.13 Recently, 2-
enoylpyridine-N-oxides have successfully been utilized for enan-
tioselective nitrone cycloaddition reactions.14 Later on, enantio-
selective Friedel–Crafts reactions of indoles have been reported
using Cu(II)-PyBOX complexes.15 Subsequently, the Friedel–
Crafts alkylation of pyrroles16 and Michael addition of dialkyl-
malonates17 have also been reported with chiral zinc complexes.
In most cases, L-amino acid derived bisoxazoline ligands are
known to provide the corresponding products with the same
absolute configuration (ref. 6 and 10). In the view of medicinal
chemistry, the syntheses of both enantiomers are equally impor-
tant. By applying an inversion protocol, some chiral compounds
(for example those with a hydroxyl group) can be converted into
the opposite enantiomer. However, in the case of Friedel–Crafts
reactions, the inversion of a chiral center has not been successful
yet. Therefore, the synthesis of both enantiomers requires the
expensive D-amino acid derived bisoxazoline ligands. Therefore,
D-sugar based bisoxazoline ligands have gained importance as
alternatives to D-amino acid derived bisoxazolines. Conse-
quently, Boysen et al. have introduced the sugar based bisoxazo-
line ligands for the first time for enantioselective
transformations19 (Fig. 1). Inspired by inherent catalytic features
of glucoBOX, we attempted the Friedel–Crafts alkylation of
indoles with 2-enoylpyridine-N-oxides using D-sugar derived
bisoxazolines.
Results and discussion
Following our interest in the Cu(II)-glucoBOX catalyzed enantio-
selective nitroaldol reaction,20 we herein report a highly efficient
Natural Product Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad, Andhra Pradesh, India. E-mail: basireddy@
iict.res.in; Fax: +91-040-27160512; Tel: +91-040-27193535
†Electronic supplementary information (ESI) available: Experimental
details, characterization of all ligands, NMR spectra, and HPLC chroma-
togram of Friedel–Crafts products. See DOI: 10.1039/c2ob25315a
Fig. 1 GlucoBOX ligands.
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Table 1 Screening of various glucoBOX-Cu(II) complexes for
enantioselective alkylation of indole with 2-enoylpyridine-N-oxide 2a
Though Friedel–Crafts alkylation proceeds well with 1e-Cu-
(OTf)2 complex, the enantioselectivity was negligible, 5% only
(entry 5). Similarly, a pivolyl derivative of glucoBOX, 1f-Cu-
(OTf)2 complex also gave the corresponding alkylated indole in
good yield with a moderate ee (70%) (Table 1, entry 6).
Further studies were focused on different Lewis acid catalysts
to improve the enantioselectivity. The efficiencies of various
copper salts and metal triflate catalysts were tested in the
Friedel–Crafts alkylation of indole with enone 2a (Table 2). The
reaction was extremely sluggish with copper halides (Table 2,
entries 2–5) compared to trifates (Table 2, entries 6–9). Of
various Lewis acids, metal triflates were found to be the most
effective catalysts. Of various copper salts, Cu(OTf)2 afforded
high enantioselectivity. Thus, the combination of Cu(OTf)2 and
ligand 1d was found to give the best yield and enantioselectivity
(Table 2).
After optimizing the ligand and catalyst, we next studied the
effect of temperature on enantioselectivity. By decreasing the
reaction temperature from 25 to −30 °C, the enantioselectivity
was considerably increased from 80 to 96%. At −30 °C, 4a was
obtained in 94% yield and with excellent enantiomeric excess
(96% ee) (Table 2, entry 10) whereas at −78 °C, the yield of 4a
was declined to 80% but the ee was decreased to 94% (Table 2,
entry 11). In order to optimize the solvent, we performed the
reaction of enone 2a with indole 3a in various solvents at
−30 °C. The desired product 4a was obtained with 90% ee
either in chloroform or THF (Table 2, entries 12 and 13).
However, the above reaction in diethyl ether gave the product 4a
with moderate enantiomeric excess (70% ee) (Table 2, entry 14).
Surprisingly, methanol gave very poor enantiomeric excess (5%
ee, Table 2, entry 15). However, toluene was equally as good as
dichloromethane for the enantioselective Friedel–Crafts reaction
(96% ee, Table 2, entry 16). Furthermore, acetonitrile and
dichoroethane were also found to be equally effective for this
reaction (94% ee) (Table 2, entries 17 and 18). The maximum of
97% ee was obtained with 5 mol% catalyst in dichloromethane
(Table 2, entry 19). No improvements in yield and enantioselec-
tivity were observed by further decreasing the amount of the cat-
alyst (Table 2, entry 20).
Entry
Liganda
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
1
1
36
1.5
2.5
1.5
96
94
35
97
85
90
77
58
25
80
05
70
a All the reactions were carried out in 0.5 mmol scale using 0.75 mmol
of indole in 2.0 mL of dichloromethane at room temperature. b Yield
refers to pure products after purification. c Enantiomeric excess was
determined by chiral HPLC analysis.
Scheme 1 Preparation of glucoBOX (1b).
catalytic enantioselective Friedel–Crafts alkylation of indoles
and pyrrole with 2-enoylpyridine-N-oxides. Accordingly, we first
attempted the Friedel–Crafts alkylation of indole with enoylpyri-
dine-1-oxide 2a using a 1 : 1 ratio of Cu(OTf)2 and the ligand
1a. The active catalyst i.e. glucoBOX-Cu(II) complex was gener-
ated in situ by mixing an equimolar ratio of the ligand 1a with
Cu(OTf)2 in CH2Cl2 at room temperature (Table 1).
The scope and limitations of the enantioselective Friedel–
Crafts reaction were studied using Cu(OTf)2-1d complex
(Table 3).
The use of a copper(II) complex of glucoBOX bearing acetate
groups 1a gave the Michael adduct 4a in 96% yield with a mod-
erate enantioselectivity (77% ee, Table 1, entry 1). Therefore, we
next prepared ligand 1b by simply replacing the geminal
dimethyl groups of ligand 1a with geminal diethyl groups
(Scheme 1). Though the product 4a was obtained in 94% yield
using ligand 1b-Cu(OTf)2 complex, the enantioselectivity was
quite low (58% ee, Table 1, entry 2). Surprisingly, a sterically
crowded ligand 1c also gave the product 3c in low ee (Table 1,
entry 3). The reason may be due to the presence of more bulki-
ness from the pivolyl group in ligand 1c. Therefore, we further
examined the efficiency of a modified glucoBOX 1d, wherein
two acetate groups in each pyranoside ring were replaced by a
benzal group. By using 1d-Cu(OTf)2 complex, the 3-alkylated
indole was obtained in 97% yield with 80% ee (Table 1, entry
4). Subsequently, acetate groups of ligand 1d were deprotected
to produce the ligand 1e bearing two free hydroxyl groups.
The alkylation proceeds smoothly with various indoles to
produce the corresponding 3-alkylated indoles in high yields
with excellent enantioselectivity (Table 3, entries 2–5 and 7–9).
For instance, 5-bromoindole gave the 3-substituted indole 4b in
88% yield with 90% ee (Table 3, entry 2). Similarly, 5-chloroin-
dole gave the Michael adduct 4c in 94% yield with 94% ee
(Table 3, entry 3). Like halogenated indoles, 4-methoxyindole
also afforded 4d in 94% yield with 85% ee (Table 3, entry 4). In
contrast, the alkylation of 2a with N-methylindole afforded 4e in
88% yield with fairly low ee (77%, Table 3, entry 5). On the
other hand, 2b reacts with indole efficiently to furnish the corre-
sponding 3-alkylated product 4f in 97% yield with 99% ee
(Table 3, entry 6). Similarly, 5-bromo- and 5-chloroindoles
reacts well with 2b to produce the corresponding products 4g
and 4h with high enantiomeric excess (Table 3, entries 7 and 8).
Furthermore, N-methyl indole also reacts well with 2b to afford
the product 4i in 84% yield with 70% ee (Table 3, entry 9).
4732 | Org. Biomol. Chem., 2012, 10, 4731–4738
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Table 2 Screening of various parameters for enantioselective Friedel–Crafts reaction of indole with 2-enoylpyridine-N-oxide 2a
Entry
Catalysta
Mol%
Solvent
Temp. (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Cu(OTf) 0.5Tol
CuCl2
CuCl
CuBr
CuI
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
25
25
25
25
25
25
25
25
12
12
12
24
24
0.5
0.5
2
2
2
5
2
6
6
6
4
2
2
3.5
10
85
83
70
75
5
50
17
40
60
d
Sc(OTf)3
In(OTf)3
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
86
89
92
95
94
80
95
88
76
85
90
92
94
94
76
2
3
20
89
96
94
90
90
70
5
96
94
94
97
93
9
0
10
11
12
13
14
15
16
17
18
19
20
−30
−78
−30
−30
−30
−30
−30
−30
−30
−30
−30
Et2O
CH3OH
Toluene
CH3CN
DCE
CH2Cl2
CH2Cl2
2
a All the reactions were performed with indole 3a (0.75 mmol) and pyridin-1-oxide 2a (0.5 mmol) with 10 mol% catalyst (Cu(OTf)2 : 1d, 1 : 1) in
2 mL solvent under nitrogen. b Yield after chromatography. c Enantiomeric excess was determined by HPLC with AD-H column. d Not determined.
Table 3 Enantioselective Friedel–Crafts reaction of various indoles with 2-enoylpyridine-N-oxides
Entry
R
R1
R2
Producta
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-Cl–Ph (2a)
4-Cl–Ph (2a)
4-Cl–Ph (2a)
4-Cl–Ph (2a)
4-Cl–Ph (2a)
Ph (2b)
Ph (2b)
Ph (2b)
Ph (2b)
4-NO2–Ph (2c)
4-CH3–Ph (2d)
4-F–Ph (2e)
4-Br–Ph (2f)
2-Cl–Ph (2g)
2-F–Ph (2h)
2-NO2–Ph (2i)
2-Br–Ph (2j)
3-NO2–Ph (2k)
2-Furyl (2l)
1-Naphthyl (2m)
tButyl (2n)
H
H
H
H
H
Me
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
1.0
2.0
2.0
2.0
7.0
1.0
2.0
2.0
2.0
1.0
4.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
4.0
24
94
88
94
94
88
97
91
94
84
98
87
94
91
92
98
96
94
94
91
88
65
trace
97
90
94
85
77
99
93
92
70
96
94
95
92
99
94
98
96
99
94
90
33
ndd
5-Br
5-Cl
4-OMe
H
H
5-Br
5-Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4t
4u
4v
Cyclohexyl (2o)
200
a All the reactions were carried out in 0.5 mmol scale using 0.75 mmol of indole derivatives at −30 °C in CH2Cl2. b Yield after chromatographic
purification. c Enantiomeric excess was determined by chiral HPLC analysis (see ESI for details†). d nd = not determined.
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Table 4 Enantioselective Friedel–Crafts reaction of pyrrole with 2-
enoylpyridine-1-oxides
Entry
R
Producta Time (h) Yieldb (%)
eec (%)
Fig. 2 A plausible transition state model for the enantioselective
Friedel–Crafts reaction of indole.
1
2
4-Cl–Ph (2a) 5a
Ph (2b) 5b
4
4
92
88
86
85
a All the reactions were carried out in 0.5 mmol scale using 1.0 mmol of
pyrrole at −30 °C in CH2Cl2. b Yield after chromatographic purification.
c Enantiomeric excess was determined by chiral HPLC analysis. (see
ESI for details†).
Finally, we correlated all our observations to devise a plausible
mechanism which reasonably explains the reactivity and stereo-
chemical outcome of the reaction. Mechanistically, we assume
that the reaction proceeds through a transition state which is
almost similar to Jørgensen’s transition state for Friedel–Crafts
reaction of indoles with α-ketoesters (see ref. 6b). A plausible
transition state model for the enantioselective Friedel–Crafts
reaction is presented in Fig. 2.The low enantioselectivity of N-
methylindole may be due to the unavailability of the N–H group
for hydrogen bonding with the acetate moiety in the transition
state. The low enantioselectivity of pyrrole in Friedel–Crafts
alkylation also supports the above transition state. Though the
hydrogen bond exists between pyrrole and catalyst, the π-orbital
of pyrrole, which is involved in Friedel–Crafts alkylation, is
different from that of indoles.
Next we studied the reactivity of p-substituted arylidinenoyl
pyridine-1-oxides for the Friedel–Craft reaction of indoles
(Table 3, entries 10–13). Both electron-rich and electron-
deficient enoylpyridine-1-oxides gave the corresponding pro-
ducts in high yields and enantioselectivities. The p-nitro-substi-
tuted pyridine-1-oxide 2c afforded 4j in 98% yield with 96% ee
(Table 3, entry 10). Similarly, arylidinenoyl pyridine-1-oxide 2d
also gave 4k in excellent yield with 94% ee (Table 3, entry 11).
The halogen substituted pyridine-1-oxides 2e and 2f gave the
expected products 4l and 4m in 95% and 92% ee respectively
(Table 3, entries 12 and 13).
Furthermore, we examined the efficiency of o-substituted ary-
lidinenoyl pyridine-1-oxides 2g, 2h, 2i and 2j. For example,
treatment of indole with 2g and 2h gave the 3-alkylated indoles
4n and 4o in 99% ee and 94% eerespectively (Table 3, entries
14 and 15). Other enoylpyridine-1-oxides 2i and 2j gave the 3-
alkylated indoles 4p and 4q with 98% ee and 96% ee respect-
ively (Table 3, entries 16 and 17). Furthermore, 3-nitrobenzyli-
din-2-enoylpyridine-1-oxide 2k also afforded the 3-alkylated
indole 4r in 94% yield and 99% ee (Table 3, entry 18).
Conclusions
In summary, we have demonstrated a highly efficient Friedel–
Crafts alkylation of indoles with 2-enoylpyridine-1-oxides to
afford the 3-substituted indole derivatives with excellent enan-
tioselectivities. This is the first report on the use of sugar based
chiral ligands for the enantioselective Friedel–Crafts reaction of
indoles. The end products could easily be converted into the cor-
responding carboxylic acid derivatives through the cleavage of
the pyridine-N-oxide moiety. The notable features are the high
enantioselectivity, excellent yields, ease of installation/removal
of co-ordinating group18 and short reaction times. Further appli-
cation of glucoBOX ligands for other enantioselective transform-
ations are in progress in our laboratory.
Next, we extended our investigation to arylidinenoyl pyridine-
1-oxides derived from heteroaromatic aldehydes. For instance, 2-
furyl substituted 2-enoylpyridine-1-oxide 2l gave the corre-
sponding Michael adduct 4s in 91% yield with 94% ee (Table 3,
entry 19). Notably, a sterically hindered 1-naphthyl-2-enoylpyri-
dine-1-oxide 2m furnished the corresponding Michael adduct 4t
in 88% yield with 90% ee (Table 3, entry 20).
Experimental
However, alkyl substituted 2-enoylpyridine-1-oxide 2n gave
the respective Michael adducts in low yield and enantioselectiv-
ity compared to its aromatic analogues (Table 3, entries 20 and
21). In addition, the reaction was too sluggish with alkylidine-
noyl pyridine-1-oxides. For instance, tert-butyl 2-enoylpyridine-
1-oxide 2n gave the corresponding 1,4-adduct 4u in moderate
yield (65%) with low ee (33%, Table 3, entry 21).
Inspired by the results obtained with indoles, we attempted the
Friedel–Crafts alkylation of pyrrole with 2-enoylpyridine-1-
oxide (Table 4).
Interestingly, high enantioselectivity was achieved with
pyrrole as well under the optimized reaction conditions. The
enoyl pyridine-1-oxide 2a gave the 2-alkylated pyrrole 5a in
92% yield with 86% ee (Table 4, entry 1). The substrate 2b also
reacts effectively with pyrrole to afford 5b in 88% yield with
85% ee (Table 4, entry 2).
General
The solvent dichloromethane was dried according to a standard
literature procedure. The reactions were performed in oven-dried
two necked round bottom flasks under an argon atmosphere.
Glass syringes were used to transfer the solvent. The products
were purified by column chromatography on silica gel of 60–120
or 100–200 mesh. Thin layer chromatography plates were visual-
ized by ultraviolet light and/or by exposure to iodine vapours
and/or by exposure to methanolic acidic solution of p-anisalde-
hyde followed by heating (<1 min) on a hot plate (∼250 °C).
Organic solutions were concentrated on rotary evaporator at
35–40 °C. IR spectra were recorded on a FT-IR spectrometer. 1H
and 13C NMR spectra were recorded in CDCl3 using 300, 400,
500 or 600 MHz NMR spectrometers. The chemical shifts (δ)
were reported in parts per million (ppm) with respect to TMS as
4734 | Org. Biomol. Chem., 2012, 10, 4731–4738
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an internal standard. The coupling constants (J) are quoted in
Hertz (Hz). Mass spectra were recorded on a mass spectrometer
by electrospray ionization (ESI) or atmospheric pressure chemi-
cal ionization (APCI).
and then cooled to −30 °C. To this mixture, a solution of indole
(0.75 mmol) in 0.5 mL dichloromethane was added and then
allowed to stir at −30 °C until completion of the reaction (as
judged by TLC analysis). The solvent was removed and the
resulting mixture was purified by column chromatography on
silica gel using 5% methanol in ethyl acetate to afford the pure
product (Note: All the products are moisture sensitive and
become brownish in colour. Therefore optical rotations were
measured after drying the products twice azeotropically with
THF to remove the brown colour). The absolute configuration of
the products was determined by comparing the optical rotation
with known values reported in literature.15,16 The absolute
configuration of new compounds were determined by analogy.
Preparation of ligands
Ligands 1a, 1c, 1d, 1e and 1f were prepared according to the
procedure reported previously in the literature.19b The ligand 1b
was also prepared by following a known procedure as reported
for ligand 1a.19a
Spectral data for ligand 1b. [α]2D5 = +58.5 (c = 1.0, in
CHCl3). 1H NMR (CDCl3, 300 MHz) δ: 0.84 (s, 6H), 1.92–2.20
(m, 4H), 2.04 (s, 12H), 2.12 (s, 6 H), 3.96 (ddd, J = 3.1, 9.8, 6.8
Hz, 2H), 4.12 (dd, J = 3.8, 12.8 Hz, 2H), 4.18–4.32 (m, 2 H),
4.24 (dd, J = 3.1, 12.8 Hz, 2H), 4.98 (d, J = 9.8 Hz, 2H), 5.38
(t, J = 2.3Hz, 2H), 5.98 (d, J = 7.6 Hz, 2H). 13C NMR (CDCl3,
75 MHz) δ: 8.2, 20.6, 20.7, 20.8, 26.5, 47.1, 62.5, 64.3, 67.5,
68.2, 70.0, 99.4, 168.9, 169.1, 169.4, 170.6. IR (KBr): νmax
(S)-2-(3-(4-Chlorophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide.15 (4a) (entry 1, Table 3). Yield 95% with 97% ee. [α]2D5
= −21 (c = 0.5, in THF). HPLC on Chiralpak AD-H column
(15 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 14.55 min (R) and 18.96 min (S); 1H NMR
(500 MHz; CDCl3) δ: 3.92 (dd, J = 7.9, 8.8 Hz, 1H), 4.20 (dd, J
= 6.9, 8.8 Hz, 1H), 4.88 (t, J = 6.9 Hz, 1H), 6.96 (t, J = 6.9 Hz),
7.08–7.20 (m, 4H), 7.20–7.30 (m, 4H), 7.32–7.38 (m, 2H),
3467, 2975, 1747, 1654, 1372, 1227, 1039, 935, 877 cm−1
.
HRMS (ESI): Exact mass calcd for C31H42N2O16Na 721.2432.
Found: 721.2438.
7.44–7.50 (m, 1H), 8.10 (brs, 1H), 8.14 (d, J = 6.0 Hz, 1H). 13
C
NMR (75 MHz; CDCl3) δ: 37.6, 48.8, 111.0, 118.0, 119.2,
119.3, 121.5, 122.1, 125.8, 126.3,126.6 127.7, 128.2, 129.2,
131.8, 136.4, 140.1, 142.4, 146.7, 196.4. HRMS (ESI): Exact
mass calcd for C22H17ClN2O2Na 399.0876. Found: 399.0870.
Preparation of 2-enoylpyridine-N-oxides.2 All the starting
materials were prepared according to the reported
procedure.12,15,16
Compound 2d. Yield 60%. m.p. 130–133 °C. 1H NMR
(CDCl3, 300 MHz) δ: 2.36 (s, 3H), 7.16 (d, J = 8.3 Hz, 2H),
7.34–7.42 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.62–7.74 (m, 2H),
7.76 (d, J = 15.9 Hz, 1H), 8.22 (d, J = 5.8 Hz). 13C NMR (CDCl3,
75 MHz) δ: 21.5, 123.2, 125.7, 127.1, 127.5, 128.8, 129.5, 131.7,
140.3, 141.4, 144.5, 147.2, 186.3. HRMS (APCI): Exact mass
calcd for C15H14NO2 [M + H]: 240.1025 Found: 240.1028.
Compound 2h. Yield 75%. m.p. 108–110 °C. 1H NMR
(CDCl3, 300 MHz) δ: 7.04–7.20 (m, 2H), 7.32–7.46 (m, 2H),
7.64 (dd, J = 2.4, 7.3 Hz, 2H), 7.74 (d, J = 16.0 Hz, 1H), 7.94
(d, J = 16.0 Hz, 1H), 8.24 (d, J = 5.8 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) δ: 116.0, 116.3, 124.4, 125.9, 126.3 (d, J = 6.5
Hz), 127.3, 127.8, 129.1, 132.3 (d, J = 8.7 Hz), 136.2, 140.4,
147.0, 163.4 (d, J = 254.6 Hz), 186.3 HRMS (APCI): Exact mass
calcd for C14H11N2O2F [M + H]: 244.0774 Found: 244.0768.
Compound 2j. Yield 55%. m.p. 114–116 °C. 1H NMR
(CDCl3, 300 MHz) δ: 7.20 (ddd, J = 1.51, 2.2, 6.8 Hz, 1H), 7.28
(dd, J = 6.8, 7.6 Hz, 1H), 7.38–7.46 (m, 2H), 7.58 (dd, J = 6.8,
1.5 Hz, 1H), 7.70 (dd ∼ q, J = 3.0, 3.8 Hz, 2H), 7.76 (dd, J =
1.5, 6.8 Hz, 1H), 8.14 (d, J = 15.9 Hz, 1H), 8.24 (dd, J = 2.2,
1.5 Hz, 1H). 13C NMR (CDCl3, 75 MHz) δ: 126.1, 126.5,
127.4, 127.6, 127.9, 128.2, 131.5, 132.5, 133.3, 134.4, 140.4,
142.0, 146.8, 185.8. HRMS (APCI): Exact mass calcd for
C14H11N2O2Br [M + H]: 303.9973 Found: 303.9980.
(S)-2-(3-(5-Bromo-1H-indol-3-yl)-3-(4-chlorophenyl)propa-
noyl)pyridine-1-oxide (4b) (entry 2, Table 3). Yield 88% and ee
90%. m.p. 181–184 °C. [α]2D5 = −71.7 (c = 0.5, in THF). HPLC
on Chiralpak AD-H column (25 cm × 0.46 cm), hexane/i-PrOH
= 80 : 20, flow rate 1.0 mL min−1, 254 nm; tR = 14.24 min (S)
1
and 22.10 min (R); H NMR (500 MHz; CDCl3 + DMSO-d6) δ:
3.76 (dd, J = 7.0, 8.0 Hz, 1H), 3.92 (dd, J = 7.0. 8.0 Hz, 1H),
4.76 (t, J = 8.0 Hz, 1H), 7.06 (dd, J = 7.0, 2.0 Hz, 1H), 7.14 (d,
J = 2.0 Hz, 1H), 7.18–7.30 (m, 7H), 7.36 (s, 1H), 7.40 (m, 1H),
8.18 (d, J = 6.0 Hz, 1H), 10.78 (brs, 1H). 13C NMR (75 MHz;
CDCl3 + DMSO-d6) δ: 36.2, 48.1, 118.6, 112.1, 115.5, 119.9,
122.5, 122.9, 124.7, 125.2, 127.0, 127.2, 128.1, 130.5, 141.6,
143.9, 145.3, 195.1. IR (KBr): ν 3414, 3113, 3074, 2922, 1715,
1674, 1601, 1562, 1487, 1458, 1425, 1319, 1287 cm−1. HRMS
(ESI): Exact mass calcd for C22H16BrClN2O2Na 476.9981.
Found: 476.9986.
(S)-2-(3-(5-Chloro-1H-indol-3-yl)-3-(4-chlorophenyl)propanoyl)-
pyridine-1-oxide (4c) (entry 3, Table 3). Yield 94% with 94%
ee. m.p. 209–212 °C [α]2D5 = −36.6 (c = 0.5, in THF). HPLC on
Chiralpak AD-H column (25 cm × 0.46 cm), hexane/i-PrOH =
80 : 20, flow rate 1.0 mL min−1, 254 nm; tR = 19.94 min (R) and
21.48 min (S); 1H NMR (500 MHz; CDCl3 + DMSO-d6) δ: 3.76
(dd, J = 6.9, 9.8 Hz, 1H), 3.92 (dd, J = 7.9, 8.0 Hz, 1H), 4.76 (t,
J = 7.9 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 7.13–7.28 (m, 8H),
7.36 (t, J = 6.9 Hz, 2H), 8.16 (d, J = 6.9 Hz, 1H), 10.70 (bs,
1H). 13C NMR (75 MHz; CDCl3 + DMSO-d6) δ: 35.3, 46.7,
111.2, 114.7, 116.1, 119.6, 121.9, 122.2, 124.1, 124.5, 125.6,
126.5, 127.7, 129.5, 133.4, 138.5, 141.2, 144.6, 152.7, 194.6. IR
(KBr): ν 3223, 2917, 1682, 1647, 1599, 1569, 1488, 1460,
1426, 1361, 1297, 1249, 1249 cm−1; HRMS (ESI): Exact mass
calcd for C22H16Cl2N2O2Na 433.0487. Found: 433.0476.
General procedure for the enantioselective Friedel–Crafts
reaction
A solution of a ligand 1d (17.0 mg, 0.025 mmol) and Cu(OTf)2
(9.0 mg, 0.025 mmol) in dry dichloromethane (2.0 mL) was
stirred at room temperature for 1 h under a nitrogen atmosphere.
To this solution, 2-enoylpyridine-1-oxide (0.5 mmol) was added.
The resulting mixture was stirred at room temperature for 10 min
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4731–4738 | 4735

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(S)-2-(3-(4-Chlorophenyl)-3-(4-methoxy-1H-indol-3-yl)propa-
noyl)pyridine-1-oxide (4d). (entry 4, Table 3). Yield 94% and ee
85%. m.p. 85–87 °C. [α]2D5 = +62.0 (c = 0.5, in THF). HPLC on
Daicel Chiralpak AD-H column (25 cm × 0.46 cm), hexane/
(S)-2-(3-(5-Chloro-1H-indol-3-yl)-3-phenylpropanoyl)pyridine-
1-oxide.15 (4h) (entry 8, Table 3). Yield 94% and 92% ee. [α]2D5
= −45.3 (c = 0.7, in THF). HPLC on Chiralpak AD-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 16.85 min (R) and 19.20 min (S); 1H NMR
(500 MHz; CDCl3 + DMSO-d6) δ: 3.74 (dd, J = 6.9, 7.9 Hz,
1H), 3.94 (dd, J = 7.9, 7.9 Hz, 1H), 4.74 (t, J = 6.9 Hz, 1H),
6.92 (d, J = 8.9 Hz, 1H), 7.08–7.30 (m, 10H), 7.32 (m, 1H),
8.14 (d, J = 5.9 Hz, 1H), 10.60 (brs, 1H). 13C NMR (75 MHz;
CDCl3 + DMSO-d6) δ: 36.9, 47.5, 11.5, 116.0, 116.8, 120.1,
122.4, 125.0, 125.1, 126.4, 126.5, 126.8, 127.1, 133.9, 138.9,
142.7, 145.0, 195.5. HRMS (ESI): Exact mass calcd for
C22H17ClN2O2 399.0876. Found: 399.0880.
i-PrOH = 80 : 20, flow rate 0.6 mL min−1, 254 nm; tR
=
1
61.1 min (R) and 63.79 min (S); H NMR (500 MHz; CDCl3 +
DMSO-d6) δ: 3.70 (s, 3H), 3.84 (d, J = 8.0 Hz, 1H), 5.18 (dd, J
= 8.0, 7.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.88–7.00 (m, 3H),
7.08 (ddd, J = 8.0, 11.1, 7.0 Hz, 3H), 7.22 (d, J = 8.0 Hz, 1H),
7.32 (t, J = 6.0 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 10.22 (s, 1H).
13C NMR (75 MHz; CDCl3) δ: 36.6, 47.7, 53.2, 97.5, 103.4,
114.9, 116.3,119.2, 120.8, 124.1, 124.6, 126.4, 126.5, 128.1,
129.3, 136.7, 138.6, 142.8, 145.3, 195.4. IR (KBr): ν 3396,
3113, 2928, 1699, 1589, 1499, 1428, 1361, 1428, 1361, 1254,
1167 cm−1
;
HRMS (ESI): Exact mass calcd for
(S)-2-(3-(1-Methyl-1H-indol-3-yl)-3-phenylpropanoyl)pyridine-
1-oxide.15 (4i) (entry 9, Table 3). Yield 84% and 70% ee. [α]2D5
=
C23H19ClN2O3Na 429.0982. Found: 429.0979.
+1.8 (c = 0.5, in THF). HPLC on Chiralpak OD-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
(S)-2-(3-(4-Chlorophenyl)-3-(1-methyl-1H-indol-3-yl)propanoyl)-
pyridine-1-oxide (4e) (entry 5, Table 3). Yield 88% and 77% ee.
Viscous liquid. [α]2D5 = +4.2 (c = 0.4, in THF). HPLC on Chiral-
pak OD-H column (25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20,
flow rate 1.0 mL min−1, 254 nm; tR = 19.7 min (S) and
24.57 min (R); 1H NMR (300 MHz; CDCl3) δ: 3.64 (s, 3H)
3.80–4.06 (m, 2H), 3.80–3.94 (m, 1H), 6.84–7.00 (m, 2H),
7.0–7.36 (m, 14H), 8.1 (bs, 1H). 13C NMR (75 MHz; CDCl3) δ:
32.7, 37.7, 48.9, 109.1, 116.7, 118.9, 119.3, 121.7, 125.9, 126.2,
126.7, 127.4, 128.2, 128.3, 129.2, 131.8, 137.1, 140.3, 142.5,
145.3, 196.3. IR (KBr): 3448, 3054, 2925, 1687, 1603, 1545, 1486,
1427, 1372, 1294, 1252, 1176, 1089 cm−1. HRMS (ESI): Exact
mass calcd for C23H19ClN2O2Na 413.1032. Found: 413.1028.
1
min−1, 254 nm; tR = 19.7 min (S) and 26.3 min (R). H NMR
(500 MHz; CDCl3) δ: 3.68 (s, 3H), 3.86 (dd, J = 8.0, 9.0 Hz,
1H), 3.96 (dd, J = 8.0, 9.0 Hz, 1H), 4.84 (t, J = 8.0 Hz, 1H),
6.92 (d, J = 2.0 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 7.04–7.12 (m,
3H), 7.12–7.22 (m, 3H), 7.26 (d, J = 7.0 Hz, 2H), 8.06 (d, J =
6.0 Hz, 1H). 13C NMR (75 MHz; CDCl3) δ: 32.5, 38.4, 48.9,
108.9, 117.1, 118.7, 119.3, 121.5, 126.2, 126.4, 126.9, 127.4,
127.7, 128.2, 137.0, 139.9, 143.8, 146.8, 196.9. HRMS (ESI):
Exact mass calcd for C23H20N2O2Na 379.1422. Found: 379.1418.
(S)-2-(3-(1H-Indol-3-yl)-3-(p-nitrophenyl)propanoyl)pyridine-
1-oxide.15 (4j) (entry 10, Table 3). Yield 98% and 96% ee. [α]2D5
= −21.4 (c = 0.5, in THF). HPLC on Chiralpak AD-H column
(15 cm × 0.46 cm), hexane/i-PrOH = 70 : 30, flow rate 1.0 mL
min−1, 254 nm; tR = 22.70 min (R) and 25.25 min (S); 1H NMR
(500 MHz; CDCl3 + DMSO-d6) δ: 3.90–4.08 (m, 2H), 4.94 (t, J
= 7.3 Hz, 1H), 6.94 (t, J = 7.1 Hz, 1H), 7.20–7.36 (m, 5H), 7.38
(m, 1H), 7.50 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 8.14
(d, J = 6.2 Hz, 1H), 10.58 (brs, 1H). 13C NMR (75 MHz;
CDCl3) δ: 36.7, 47.2, 110.4, 114.8, 117.3, 117.7, 120.4, 121.1,
122.2, 124.6, 125.0, 125.3, 127.1, 127.7, 135.6, 139.1, 145.0,
147.3, 151.3, 194.6. HRMS (ESI): Exact mass calcd for
C22H17N3O4Na 410. 1117. Found: 410.1124.
(S)-2-(3-(1H-Indol-3-yl)-3-phenylpropanoyl)pyridine-1-oxide.15
(4f) (entry 6, Table 3). Yield 97% and 99% ee. [α]2D5 = −17.1 (c
= 0.5, in THF). HPLC on Chiralpak AD-H column (25 cm ×
0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL min−1
,
254 nm; tR = 19.60 min (R) and 23.79 min (S); 1H NMR
(500 MHz; CDCl3) δ: 3.80 (m, 1H), 3.92 (m, 1H), 4.78 (m, 1H),
6.80 (t, J = 6.9 Hz, 2H), 6.98 (t, J = 7.9 Hz, 2H), 7.02 (t, J = 6.9
Hz, 2H), 7.10–7.20 (m, 4H), 7.20–7.28 (m, 2H), 7.30 (d, J = 7.9
Hz, 1H), 7.90 (bs, 1H), 8.40 (s, 1H). 13C NMR (75 MHz;
CDCl3) δ: 38.5, 48.9, 11.0, 118.4, 119.2, 119.3, 121.6, 121.9,
126.2, 126.6, 126.8, 127.4, 127.8, 128.2, 136.5, 140.2, 143.8,
147.3, 196.9. HRMS (ESI): Exact mass calcd for
C22H18N2O2Na 365.1266. Found: 365.1262.
(S)-2-(3-(1H-Indol-3-yl)-3-p-tolylpropanoyl)pyridine-1-oxide (4k)
(entry 11, Table 3). Yield 87% and 94% ee. m.p. 190–192 °C.
[α]2D5 = −4.2 (c = 0.5, in THF). HPLC on Chiralpak AD-H
column (15 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate
1.0 mL min−1, 254 nm; tR = 13.10 min (minor) and 16.56 min
(S)-2-(3-(5-Bromo-1H-indol-3-yl)-3-phenylpropanoyl)pyridine-
1-oxide.15 (4g) (entry 7, Table 3). Yield 91% and 93% ee. [α]2D5
= −51.2 (c = 0.4, in THF). HPLC on Chiralpak AD-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 16.92 min (R) and 19.68 min (S); 1H NMR
(500 MHz; CDCl3 + DMSO-d6) δ: 3.72 (dd, J = 7.8, 8.8 Hz,
1H), 3.94 (dd, J = 7.8, 8.8 Hz, 1H), 4.74 (t, J = 7.8 Hz, 1H),
7.04 (d, J = 8.8 Hz, 1H), 7.08–7.16 (m, 4H), 7.16 (m, 3H), 7.24
(d, J = 7.8 Hz, 2H), 7.34 (m, 2H) 8.14 (d, J = 5.8 Hz, 1H), 10.7
(brs, 1H). 13C NMR (75 MHz; CDCl3 + DMSO-d6) δ: 36.2,
46.9, 109.7, 111.7, 115.4, 119.3, 122.0, 122.1, 124.1, 124.4,
124.6, 125.9, 126.4, 126.5, 126.7, 133.6, 138.4, 142.4, 144.8,
194.9. HRMS (ESI): Exact mass calcd for C22H17BrN2O2
443.0371. Found: 443.0366.
1
(major); H NMR (500 MHz; CDCl3) δ: 2.22 (s, 3H), 3.80 (m,
1H), 3.94 (m, 1H), 4.78 (s, 1H), 6.82 (t, J = 6.9 Hz, 1H),
6.90–6.98 (m, 5H), 6.98 (m, 1H), 7.08 (d, J = 6.9 Hz, 4H), 7.16
(d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 8.0 (s, 1H), 8.36
(brs, 1H). 13C NMR (75 MHz; CDCl3) δ: 20.9, 38.1, 48.9,
110.9, 118.7, 119.2, 119.3, 121.4, 121.9, 125.8, 126.3, 126.5,
127.3, 127.6, 128.9, 135.6, 136.4, 139.9, 140.6, 146.9, 197.1. IR
(KBr): ν 3211, 3050, 2919, 2869, 1680, 1599, 1509, 1456, 1429,
1341, 1292, 1250, 1220, 1179, 1117 cm−1. HRMS (ESI): Exact
mass calcd for C23H20N2O2Na 379.1423 Found: 379.1416.
(S)-2-(3-(4-Fluorophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide.15 (4l) (entry 12, Table 3). Yield 94% and 95% ee. [α]2D5
4736 | Org. Biomol. Chem., 2012, 10, 4731–4738
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= −9.1 (c = 1, in THF). HPLC on Chiralpak AD-H column
(15 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 13.82 min (R) and 17.47 min (S); 1H NMR
(500 MHz; CDCl3) δ: 3.84 (dd, J = 8.0, 8.0 Hz, 1H), 3.94 (dd, J
= 7.0, 10.0 Hz, 1H), (4.80 (m, 1H), 6.82–6.88 (m, 3H),
7.02–7.10 (m, 3H), 7.16–7.28 (m, 5H), 8.04–8.22 (m, 2H). 13C
NMR (75 MHz; CDCl3) δ: 37.6, 49.0, 111.0, 114.8, 115.1,
118.4, 119.2, 119.3, 121.4, 122.0, 125.7, 126.4, 126.5, 127.6,
129.1, 136.4, 140.1, 146.8, 162.9, 196.6. HRMS (ESI): Exact
mass calcd for C22H17FN2O2Na 383.1172. Found: 383.1168.
(25 cm × 0.46 cm), hexane/i-PrOH = 70 : 30, flow rate 1.0 mL
min−1, 254 nm; tR = 16.82 min (S) and 25.70 min (R); 1H NMR
(500 MHz; CDCl3) δ: 3.80 (dd, J = 6.7, 10.5 Hz, 1H), 4.22 (dd,
J = 7.5, 9.8 Hz, 1H), 5.54 (t, J = 6.7 Hz, 1H), 6.90 (t, J = 7.5
Hz, 1H), 7.02 (t, J = 6.7 Hz, 1H), 7.18–7.64 (m, 10H), 7.74 (d, J
= 7.5 Hz, 1H), 8.14 (bs, 1H); 13C NMR (75 MHz; CDCl3) δ:
32.4, 48.5, 111.0, 116.9, 119.2, 119.5, 122.1, 122.4, 124.1,
125.9, 126.3, 126.8, 127.0, 127.8, 130.1, 132.6, 136.4, 138.4,
140.3, 146.2, 149.5, 195.0. HRMS (ESI): Exact mass calcd for
C22H17N3O4Na 410. 1117, Found: 410.1121.
(S)-2-(3-(4-Bromophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide (4m) (entry 13, Table 3). Yield 91% and 92% ee.
m.p. 201–203 °C. [α]2D5 = −16.9 (c = 0.5, in THF). HPLC on
Chiralpak AD-H column (15 cm × 0.46 cm), hexane/i-PrOH =
80 : 20, flow rate 1.0 mL min−1, 254 nm; tR = 15.60 min (R) and
20.19 min (S); 1H NMR (500 MHz; CDCl3) δ: 3.88 (dd, J = 7.9,
8.8 Hz, 1H), 3.96 (dd, J = 7.9, 8.8 Hz, 1H), 4.84 (t, J = 7.9 Hz,
1H), 6.90 (t, J = 6.9 Hz, 1H), 7.04–7.12 (m, 2H), 7.15 (d, J =
8.8 Hz, 2H), 7.20–7.28 (m, 3H), 7.28 (d, J = 8.8 Hz, 3H), 7.48
(s, 1H), 8.02 (bs, 1H), 8.08 (d, J = 5.9 Hz, 1H); 13C NMR
(75 MHz; CDCl3) δ: 38.2, 49.2, 115.5, 118.4, 119.6, 120.4,
122.0, 122.5, 126.1, 126.8, 127.0, 128.1, 130.0, 131.7, 136.9,
140.5, 143.4, 147.1, 196.7. IR (KBr): ν 3417, 3209, 2920, 2873,
1682, 1599, 1484, 1430, 1343, 1294, 1251, 1221, 1181,
(R)-2-(3-(2-Bromophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide (4q) (entry 17, Table 3). Yield 94% and 96% ee. m.
p. 97–99 °C. [α]2D5 = +56.1 (c = 0.5, in THF). HPLC on Chiral-
pak AD-H column (25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20,
flow rate 1.0 mL min−1, 254 nm; tR = 20.52 min (S) and
1
25.25 min (R); H NMR (500 MHz; CDCl3) δ: 3.60 (dd, J =
6.0, 11.0 Hz, 1H), 4.18 (dd, J = 9.0, 8.0 Hz, 1H), 5.34 (t, J = 7.0
Hz, 1H), 6.92 (t, J = 7.0Hz, 1H), 7.00 (m, 4H), 7.14–7.28 (m,
4H), 7.38 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 8.08 (d,
J = 8.0 Hz, 1H), 8.26 (bs, 1H). 13C NMR (75 MHz; CDCl3) δ:
37.2, 47.7, 111.0, 117.3, 119.2, 119.3, 121.9, 122.2, 124.2,
126.0, 126.4, 127.4, 127.5, 127.8, 129.2, 132.7, 136.4, 140.0,
142.5, 146.6, 196.1. IR (KBr): ν 3405, 3054, 2922, 2854, 1692,
1600, 1462, 1428, 1340, 1294, 1229, 1103 cm−1; HRMS (ESI):
Exact mass calcd for C22H17BrN2O2Na 443.0371. Found:
443.0365.
1122 cm−1
;
HRMS (ESI): Exact mass calcd for
C22H17BrN2O2Na 443.0371. Found: 443.0366.
(R)-2-(3-(2-Chlorophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide.15 (4n) (entry 14, Table 3). Yield 92% and 99% ee. [α]2D5
= +71.4 (c = 0.6, in THF). HPLC on Chiralpak AD-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 24.20 min (R) and 31.44 min (S); 1H NMR
(500 MHz; CDCl3) δ: 3.68 (dd, J = 7.0, 10.0 Hz, 1H), 4.16 (dd,
J = 8.0, 9.0 Hz, 1H), 5.38 (t, J = 7.0 Hz, 1H), 6.94 (t, J = 7.0
Hz, 1H), 7.02–7.12 (m, 4H), 7.18–7.38 (m, 6H), 7.42 (d, J = 8.0
Hz, 1H), 8.10 (d, J = 6.0 Hz, 1H), 8.16 (brs, 1H). 13C NMR
(75 MHz; CDCl3) δ: 34.4, 47.6, 111.0, 117.3, 119.2, 122.0,
122.1, 125.7, 126.0, 126.4, 126.8, 127.5, 128.1, 129.1, 129.4,
133.4, 136.4, 140.0, 140.9, 146.7, 196.1. HRMS (ESI): Exact
mass calcd for C22H17ClN2O2Na 399.0786. Found: 399.0779.
(S)-2-(3-(1H-Indol-3-yl)-3-(3-nitrophenyl)propanoyl)pyridine-
1-oxide.15 (4r) (entry 18, Table 3). Yield 94% and 99% ee. [α]2D5
= +3.3 (c = 1.0, in THF). HPLC on Chiralpak AD-H column
(15 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 40.28 min (R) and 42.20 min (S); 1H NMR
(500 MHz; CDCl3) δ: 4.02 (dd, J = 8.0, 9.0 Hz, 1H), 4.12 (dd, J
= 7.0, 10.0 Hz, 1H), 5.08 (t, J = 7.0 Hz, 1H), 6.96 (t, J = 7.0 Hz,
1H), 7.12–7.22 (m, 3H), 7.28–7.42 (m, 5H), 7.72 (d, J = 8.0 Hz,
1H), 7.98 (d, J = 8.0 Hz, 1H), 8.16–8.20 (m, 2H), 8.28 (bs, 1H);
13C NMR (75 MHz; CDCl3) δ: 37.7, 48.7, 111.2, 117.1, 118.8,
119.4, 121.4, 121.7, 122.2, 122.7, 125.8, 126.1, 126.7, 127.9,
128.1, 129.1, 134.3, 140.3, 146.3, 148.2, 195.5. HRMS (ESI):
Exact mass calcd for C22H17N3O4Na 410. 1117 Found:
410.1114.
(R)-2-(3-(2-Fluorophenyl)-3-(1H-indol-3-yl)propanoyl)pyridine-
1-oxide (4o) (entry 15, Table 3). Yield 98% and 94% ee.
Viscous, [α]2D5 = +15.6 (c = 0.4, in THF). HPLC on Chiralpak
AD-H column (25 cm × 0.46 cm), hexane/i-PrOH = 80 : 20,
flow rate 1.0 mL min−1, 254 nm; tR = 20.90 min (S) and
(R)-2-(3-(Furan-2-yl)-3-(1H-indol-3-yl)propanoyl)pyridine-1-
oxide.15 (4s) (entry 19, Table 3). Yield 91% and 94% ee. [α]2D5
=
+5.2 (c = 0.5, in THF). HPLC on Chiralpak OJ-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 70 : 30, flow rate 1.0 mL
min−1, 254 nm; tR = 42.22 min (R) and 76.45 min (S); 1H NMR
(500 MHz; CDCl3) δ: 3.88 (m, 2H), 4.94 (t, J = 8.0, 10.0 Hz,
1H), 5.96 (d, J = 2.0 Hz, 1H), 6.14 (s, 1H), 6.94–7.02 (m, 2H),
7.02 (q, J = 8.0 Hz, 2H), 7.14–7.26 (m, 4H), 7.48 (d, J = 8.0
Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 8.12 (bs, 1H); 13C NMR
(75 MHz; CDCl3) δ: 32.2, 46.9, 105.5, 110.0, 111.1, 115.6,
119.0, 119.2, 121.8, 122.1, 125.8, 126.1, 126.2, 127.5, 136.2,
139.8, 141.0, 146.5, 156.5, 196.4. HRMS (ESI): Exact mass
calcd for C20H16N2O3Na 355.1058. Found: 355.1050.
1
28.41 min (R); H NMR (300 MHz; CDCl3) δ: 4.044.14 (m,
2H), 5.12 (m, 1H), 6.84–7.38 (m, 12H), 7.38 (d, J = 7.5 Hz,
1H), 8.40 (bs, 1H). 13C NMR (75 MHz; CDCl3) δ: 31.0, 47.5,
111.1, 115.1, 115.4, 117.2, 119.0, 119.2, 121.8, 121.9, 124.0,
126.3, 126.4, 127.5, 127.7, 127.9, 129.3, 129.4, 130.5, 130.6,
136.3, 158.7, 161.9, 196.2. IR (KBr): ν 3404, 3109, 3054, 2922,
2854, 1692, 1602, 1487, 1455, 1428, 1338, 1293, 1224,
1172 cm−1; HRMS (ESI): Exact mass calcd for C22H17FN2O2Na
383.1172. Found: 383.1166.
(R)-2-(3-(1H-Indol-3-yl)-3-(2-nitrophenyl)propanoyl) pyridine-
1-oxide.15 (4p) (entry 16, Table 3). Yield 96% and 98% ee. [α]2D5
= +68.0 (c = 0.75, in THF). HPLC on Chiralpak AD-H column
(S)-2-(3-(1H-Indol-3-yl)-3-(naphthalen-1-yl)propanoyl)pyridine-
1-oxide.15 (4t) (entry 20, Table 3). Yield 88% and 90% ee. [α]2D5
= +30.2 (c = 1, in THF). HPLC on Chiralpak AD-H column
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4731–4738 | 4737

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(15 cm × 0.46 cm), hexane/i-PrOH = 80 : 20, flow rate 1.0 mL
min−1, 254 nm; tR = 13.31 min (S) and 17.75 min (R); 1H NMR
(500 MHz, CDCl3) δ: 3.98 (dd, J = 7.7, 10.0 Hz, 1H), 4. 24 (dd,
J = 7.8, 8.9 Hz, 1H), 5.82 (t, J = 7.7 Hz, 1H), 6.94–7.06 (m,
3H), 7.10–7.20 (m, 3H), 7.26 (q, J = 7.7, 8.8 Hz, 2H),
7.38–7.52 (m, 4H), 7.66 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 7.8
Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H), 8.14 (bs, 1H), 8.32 (d, J = 8.9
Hz, 1H). 13C NMR (75 MHz; CDCl3) δ: 33.5, 48.6, 111.0,
118.5, 119.2, 121.9, 122.4, 123.3, 124.7, 125.3, 125.4, 125.5,
126.0, 126.3, 126.6, 127.0, 127.3, 128.1, 128.7, 131.4, 133.9,
136.4, 139.4, 139.8, 146.9, 197.2. HRMS (ESI): Exact mass
calcd for C26H20N2O2Na 415.1423. Found: 415.1418.
Acknowledgements
J.G. thanks CSIR, New Delhi for the award of a Senior Research
Fellowship.
Notes and references
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(S)-2-(3-(1H-Indol-3-yl)-4,4-dimethylpentanoyl)pyridine-1-oxide
(4u) (entry 21, Table 3). Yield 65% yield with 33% ee. Paste.
[α]2D5 = +17.4 (c = 0.5, in THF). HPLC on Chiralpak AD-H
column (15 cm × 0.46 cm), hexane/i-PrOH = 90 : 20, flow rate
1.0 mL min−1, 254 nm; tR = 19.34 min (R) and 27.64 min (S);
1H NMR (500 MHz; CDCl3) δ: 0.83 (s, 6H), 3.34 (dd, J = 3.0,
10.9 Hz, 1H), 3.60 (dd, J = 3.9, 10.9 Hz, 1H), 4.14 (dd, J = 7.9,
6.9 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 6.74 (dd, J = 6.9, 7.9 Hz,
1H), 6.90–7.00 (m, 2H), 7.04–7.14 (m, 2H), 7.22 (d, J = 7.9 Hz,
1H), 7.34 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H), 8.10 (d, J = 6.9 Hz,
1H). 13C NMR (75 MHz; CDCl3) δ: 39.2, 48.4, 105.9, 108.0,
117.2, 126.2, 126.7, 127.9, 128.5, 129.1, 129.6, 132.3, 132.9,
140.2, 141.5, 195.9. IR (KBr): ν 3407, 3111, 3056, 2959, 2868,
1693, 1602, 1458, 1428, 1364, 1298, 1218; HRMS (ESI): Exact
mass calcd for C20H22N2O2Na 345.1579. Found: 345.1572.
(S)-2-(3-(4-Chlorophenyl)-3-(1H-pyrrol-2-yl)propanoyl)pyridine-
1-oxide.16 (5a) (entry 1, Table 4). Yield 92% with 86% ee. [α]2D5
= +2.4 (c = 0.5, in THF). HPLC on Chiralpak OJ-H column
(25 cm × 0.46 cm), hexane/i-PrOH = 90 : 20, flow rate 1.0 mL
9 D. A. Evans, K. R. Fandrick and H.-J. Song, J. Am. Chem. Soc., 2005,
127, 8942.
1
min−1, 254 nm; tR = 16.9 min (R) and 26.0 min (S); H NMR
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S. Ding and Y. C. Chen, Chem. Commun., 2007, 2228; (d) R. P. Herrera,
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Angew. Chem., Int. Ed., 2007, 46, 5565; (f) M. Terada and K. Sorimachi,
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13 S. Barroso, G. Blay, M. C. Muñoz and J. R. Pedro, Adv. Synth. Catal.,
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17 S. K. Ray, P. K. Singh and V. K. Singh, Org. Lett., 2011, 13, 5812.
18 A. R. Katritzky, Chemistry of the Heterocyclic N-Oxides, Academic
Press, London, 1971.
(500 MHz; CDCl3) δ: 3.62 (dd, J = 5.9, 10.9 Hz, 1H), 4.40 (dd,
J = 8.0, 9.0 Hz, 1H), 4.68 (t, J = 8.0 Hz, 1H), 6.04 (s, 1H), 6.62
(s, 1H), 7.06 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.22
(t, J = 8.0 Hz, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.38 (dd, J = 2.0,
5.9 Hz, 1H), 8.14 (d, J = 7.0 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H).
13C NMR (75 MHz; CDCl3) δ: 39.3, 48.4, 105.9, 108.1, 117.3,
126.3, 126.8, 127.9, 128.6, 129.2, 132.4, 140.3, 141.5, 196.0;
HRMS (ESI): Exact mass calcd for C18H15ClN2O2Na 349.0720.
Found: 349.0718.
(S)-2-(3-Phenyl-3-(1H-pyrrol-2-yl)propanoyl)pyridine-1-oxide.16
(5b) (entry 2, Table 4). Yield 88% with 85% ee. [α]2D5 = +4.4
(c = 0.5, in THF). HPLC on Chiralpak OD-H column (25 cm ×
0.46 cm), hexane/i-PrOH = 90 : 10, flow rate 1.0 mL min−1
,
1
254 nm; tR = 34.4 (R) and 39.3 min (S); H NMR (500 MHz;
CDCl3) δ: 3.66 (dd, J = 5.9, 11.0 Hz, 1H), 4.10 (dd, J = 9.0, 7.9
Hz, 1H), 4.70 (dd, J = 7.0, 7.9 Hz, 1H), 5.90 (s, 1H), 6.06 (q, J
= 3.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 7.18–7.28 (m, 8 H),
7.28–7.42 (m, 2H), 8.18 (d, J = 6.0 Hz, 1H), 8.46 (brs, 1H); 13
C
NMR (75 MHz; CDCl3) δ: 39.9, 48.4, 105.5, 107.7, 117.0,
126.4, 126.8, 127.1, 127.3, 127.6, 128.4, 140.1, 142.3, 146.6,
196.3. HRMS (ESI): Exact mass calcd for C18H16N2O2Na
315.1110. Found: 315.1104.
19 (a) M. Irmak, A. Groschner and M. M. K. Boysen, Chem. Commun.,
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20 B. V. S. Reddy and J. George, Tetrahedron: Asymmetry, 2011, 22, 1169.
4738 | Org. Biomol. Chem., 2012, 10, 4731–4738
This journal is © The Royal Society of Chemistry 2012