A chiral bicyclic skeleton-tethered bipyridine-Zn(OTf)2 complex as a Lewis acid: Enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes

Article abstract of DOI:10.1039/c9ob00545e

A conformationally rigid chiral bicyclic skeleton tethered bipyridine-Zn(OTf)₂ complex facilitated the enantioselective Friedel-Crafts alkylation of indoles with trans-β-nitroarylalkenes in an enantioselective manner at elevated temperature. Indoles reacted smoothly with β-nitroarylalkenes to generate the corresponding 3-(2-nitroalkyl)indoles in good to excellent yields (up to 94%) with moderate to excellent enantioselectivities (up to 91%). The stereochemical outcome of the product from indole and trans-β-nitrostyrene in the presence of the CRCB tethered bipyridine-Zn(OTf)₂ complex and the DFT calculation of the CRCB tethered bipyridine-Zn:trans-β-nitrostyrene complex support the si-face attack of indole on trans-β-nitrostyrene.

Full text of DOI:10.1039/c9ob00545e

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Chiral bicyclic skeleton-tethered bipyridine–Zn(OTf)2 complex as
Lewis acid: Enantioselective Friedel–Crafts alkylation of indoles
with nitroalkenes
Received 00th January 20xx,
Accepted 00th January 20xx
Kesa Venkatanna, Santhakumar Yeswanth Kumar, Muthupandi Karthick, Ramanathan
Padmanaban, Chinnasamy Ramaraj Ramanathan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A conformationally rigid chiral bicyclic skeleton tethered bipyridine–Zn(OTf)2 complex facilitated the enantioselective
Friedel-Crafts alkylation of indoles with trans--nitroarylalkenes in an enantioselective manner at elevated temperature.
Indoles reacted smoothly with -nitroarylalkenes to generate the corresponding 3-(2-nitro alkyl)indoles in good to
excellent yields (up to 94%) with moderate to excellent enantioselectivity (up to 91%). The stereochemical out come of
the product from indole and trans--nitrostyrene in presence of CRCB tethered bipyridine-Zn(OTf)2 complex and the DFT
calculation of CRCB tethered bipyridine-Zn:trans--nitrostyrene complex support the si-face attack of indole on trans--
nitrostyrene.
the ligand derived from chiral oxazolines, amines, imines,
Schiffs bases, pyridines or bipyridines
. Particularly, the
Introduction
Zn(OTf)2 in conjuncture with either bis(oxazolines) or the
combination of oxazoline with imidazole/thiazole or Schiffs
base with a hydroxyl group or pyridine with amine are
frequently utilized catalytic systems in an asymmetric Friedel-
Crafts reaction of indole with nitroalkenes (Fig. 1).12a,b,e,g,j,k
The Friedel-Crafts alkylation of arenes/heteroarenes with
electrophiles in presence of either Lewis acids or Brønsted
acids is one of the promising C-C bond forming protocol in
organic synthesis.1 Asymmetric Friedel-Crafts (AFC) alkylation
is one of the versatile methodologies to generate homochiral
entities. Since, the seminal contribution by Casiraghi,2 there
were sporadic reports appeared till 2000 using few chiral
metal complexes to realize Friedel-Crafts alkylated product
from electron rich arenes/heteroarenes and electrophiles such
as electron deficient carbonyl compounds or imines.3 From
2000, several groups participated actively in designing new
chiral catalyst to promote the asymmetric Friedel-Crafts
alkylation of arenes/heteroarenes with electrophiles such as
i. Previous work12a,b,e,g,j,k
ii. Present work
aldehydes,3 imines,4,5 unsaturatedeto esters,6 
unsaturated carbonyl etc.
-
compounds,7 oxiranes,8
Nitroalkenes are very recently added as a template of
electrophiles for the asymmetric Friedel-Crafts reaction with
arenes/heteroarenes. Both organocatalytic systems such as
thiourea9a-c and phosphoric acid9e as well as chiral metal
complexes10-12 are proved to be efficient in this
transformations. The chiral metal complexes are generally
derived from the salts of Al,10 Cu11 and Zn.12 The chiral
environment in these transformations are usually created by
Fig. 1 Chiral ligands utilized in the AFC alkylation of indoles with nitroalkenes
To the best of our knowledge, use of chiral bipyridine with
Zn(OTf)2 in asymmetric Friedel-Crafts alkylation reaction of
indole with nitroalkenes has not been reported. Further, the
utilization of chiral bipyridine in asymmetric Friedel-Crafts
alkylation of indole with nitroalkenes in the presence of either
coinage metal Cu or other metals are very scarcely reported.11
Chiral bipyridines, an N,N-bidentate ligands, having structural
Department of Chemistry, Pondicherry University,
Puducherry – 605 014, India.
Email: crrnath.che@pondiuni.edu.in
Fax: +91-413-2655987; Tel: +91-413-2654416
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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o
similarity with bis(oxazolines), whose ability in asymmetric temperature.15 Hence, the reactions were perforVmieewdAratictle5O5nlinCe
DOI: 10.1039/C9OB00545E
Friedel-Crafts alkylation has not been well explored. Wilson et in toluene to witness the product formation in presence of
al disclosed the first report on the enantioselective Friedel- Lewis acids (Table 1).
Crafts alkylation of indoles with methyl trifluoropyruvate using
a
Table 2 Optimization of reaction parameters in presence of L/Zn(OTf)2
a
chiral
non–racemic
C2-symmetric
2,2'-bipyridyl
copper(II)triflate complex.13 While developing chiral molecules
to be used in various catalytic asymmetric transformations,14
we became interested to examine the possibility of using
CRCB–tethered bipyridine system
L in conjuncture with
transition metals for asymmetric Friedel-Crafts alkylation of
indole with nitroalkene (Fig. 1).
Herein, we would like to disclose the efficiency of CRCB
tethered bipyridine-Zn(OTf)2 complex in catalysing the
asymmetric indole Friedel-Crafts alkylation reaction.
En
Temp.
(oC)
Solvent
Catalyst
(x mol%)
Time
(h)
Yield
(%)b
ee
Sign
of
try
(%)(c,d
)
op.rot
1
2
rt
40
55
70
90
110
40
40
40
40
40
40
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Fluoro-
benzene
CHCl3
5
5
24
48
24
24
20
16
48
48
48
48
48
48
-
-
96
98
88
85
95
83
85
88
92
88
81
78
74
65
53
31
75
78
78
80
60
67
(−)
(−)
(−)
(−)
(−)
(−)
(−)
(−)
(−)
(−)
(−)
3
5
Results and discussion
4
5
Recently, a chiral bipyridine N,N'-dioxide derived from a
conformationally rigid chiral bicyclic skeleton (CRCB) tethered
bipyridine molecule has been successfully utilized to effect the
desymmetrization of meso epoxides with SiCl4.14c Since, this
chiral bipyridine molecule possess required stereo-
differentiating features and such class of molecules has not
been explored, we decided to evaluate the CRCB-tethered
5
5
6
5
7
1
8
2
9
3
10
11
12
4
10
4
bipyridine
L in asymmetric Friedel-Crafts alkylation reaction.
To identify the suitable metal counterpart in this reaction, the
electron-rich heteroarene, indole 1a, was chosen to react with
trans-nitrostyrene 2a, in presence of various transition
metal salts and ligand L. All these metal salts failed to effect
this transformation at room temperature in toluene.
13
14
15
16
17
18
19
20
40
40
40
40
40
40
40
40
4
4
4
4
4
4
4
4
44
48
48
48
96
72
96
48
96
88
90
85
35
-
54
06
17
31
29
-
(−)
(+)
(−)
(+)
(−)
CH2Cl2
DCE
TCE
THF
CH3CN
Table 1 Effect of Lewis acids on asymmetric Friedel-Crafts alkylation of indole 1a with
transnitrostyrene 2aa
Ethanol
CF3CH2OH
45
60
21
21
(−)
(−)
21e
22f
23g
24h
25i
40
40
40
40
40
Toluene
Toluene
Toluene
Toluene
Toluene
4
4
4
4
4
96
48
48
24
24
37
85
-
63
74
-
(−)
(−)
-
-
-
-
a
Reaction conditions: Indole 1a (0.20 mmol) with trans--nitrostyrene 2a (0.20
Entry
Lewis acid
Sc(OTf)3
Time (h)
24
Yield (%)b
ee (%)c
mmol) in 3 mL of solvent using x mol% of L-Zn(OTf)2 complex as catalyst. b Isolated
1
2
86
82
-
0
c
yield by column chromatography. Determined by HPLC on Daicel Chiralcel OD-H
Yb(OTf)3
24
0
column (hexane/2-propanol 70:30, 0.9 mL/min). d The absolute configurations were
assigned by comparison of the reported sign of optical rotations and the retention
times on a chiral HPLC column. e 20 mg of 4 Å MS was used. f 2.0 equiv. of HFIP was
3
Cu(OTf)2
24
-
4
Zn(OTf)2
24
98
46
57
-
74 (R)
added. 10 mol% of pyrrolidine was used.h8 mol% of piperidine was used. i4 mol%
g
5
ZnCl2
72
0
0
-
6
Zn(OAc)2.2H2O
In(OTf)3
72
of TfOH was used.
7
72
8
NiCl2
72
-
-
The Lewis acids Sc(OTf)3 and Yb(OTf)3 along with ligand
L
9
Cu(OAc)2
CuCl
72
-
-
smoothly delivered the product 3a respectively in 86% and
82% yields in toluene at 55 C (Table 1, entries 1-2). But the
product 3a was obtained in racemic form. The indole 1a was
even failed to react with nitrostyrene in the presence of
o
10
11
72
-
-
TfOH (Bronsted acid)
24
-
-
a
Reaction conditions: Indole 1a (0.20 mmol) with trans--nitrostyrene 2a (0.20
mmol) in 3 mL of toluene with 5 mol% of L:Lewis acid complexes. b Isolated yield by
Cu(OTf)2, Cu(OAc)2, CuCl, In(OTf)3, NiCl2, along with
L (Table 1,
c
column chromatography. Determined by HPLC on Daicel Chiralcel OD-H column
(hexane/2-propanol 70:30, 0.9 mL/min).
assigned by comparison of the reported sign of optical rotations and the retention
times on a chiral HPLC column.
entries 3, 7-10). Quite interestingly, while employing the zinc
salts such as ZnCl2, Zn(OAc)2.2H2O as Lewis acid in the
presence of L, the product 3a was obtained in 46% and 57%
d
The absolute configurations were
yields respectively albeit in racemic form after 72 h (Table 1,
entries 5-6). The successful result was observed when indole
The reactivity and selectivity of some catalytic system in
asymmetric Friedel-Crafts reaction was realized at elevated
was treated with nitrostyrene in presence of Zn(OTf)2 and
L
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o
in toluene at 55 C. The expected indole alkylated product 3a from indole 1a andnitrostyrene 2a requires 4 mol% of
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DOI: 10.1039/C9OB00545E
o
was obtained in 98% yield with 74% ee (Table 1, entry 4).
L/Zn(OTf)2 in toluene at 40 C for 48 h (Table 2, entry 10).
This observation encouraged us to further optimize the
Under the optimized reaction conditions, a variety of
reaction conditions by varying the reaction temperature, nitroalkenes and indoles were investigated and the results are
catalyst loading and solvents in presence of ligand and summarized in Table 3. Strong electron donating and
L
Zn(OTf)2 (Table 2). By keeping the catalyst load at 5 mol%, the moderately electron donating substituent containing
reactions were performed at 40 oC, 55 oC, 70 oC, 90 oC and 110 nitroalkenes smoothly underwent asymmetric Friedel-Crafts
oC to identify the suitable temperature to get good yield and alkylation reaction with indole to deliver the corresponding
enantioselectivity in this reaction. Lowering the reaction alkylated products 3a-3o in 74%-94% yields with
o
o
temperature from 55 C to 40 C, a slight improvement in the enantioselectivities ranging from 70% to 91% (Table 3, 3a-3o).
enantioselectivity of the alkylated product 3a was observed
3 Asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes using
Table
Zn(OTf)2-bipyridine (L) complexa
with no appreciable change in the yield (Table 2, entries 2-3).
Increasing the reaction temperature, for example, from 55 C
o
to higher temperature resulted in poor enantioselectivity
(Table 2, entries 2-6). Hence, by retaining the reaction
o
temperature at 40 C in toluene, the catalyst load was varied
from 1 mol% to 10 mol%. Increase in enantioselectivity was
observed while increasing the catalyst load from 1 mol% to till
4 mol% (Table 2, entries 7-10). Further increase of catalyst
loading i.e, 5 mol% and 10 mol% showed a decrease in
enantioselectivity of the product 3a (Table 2, entries 2 and 11),
indicating that the 4 mol% of catalyst load is optimum for good
enantioselectivity. Then, we turned our attention to identify
the better solvent for this reaction. Accordingly, the reactions
were carried out in various coordinating, protic and non-
coordinating solvents. Invariably, all the solvents furnished the
product 3a with varied yields. But the reaction failed to occur
in acetonitrile (Table 2, entry 18). Toluene remains as a
suitable solvent for this transformation in the presence of
L
/Zn(OTf)2. To improve the enantioselectivity, the reaction
o
was carried out with 4 Å molecular sieves at 40 C in toluene.
Even after 96 h the product 3a was obtained only in 37% yield
with 63% ee (Table 2, entry 21). Further, this reaction was
performed with 2 equiv. of HFIP (1,1,1,3,3,3,-hexafluoro-2-
propanol) along with toluene solvent, though the reaction
proceeded smoothly, the enantioselectivity was found to be
only 74% ee (Table 2, entry 22). Secondary amines are known
to display beneficial effect along with the catalyst in this
reaction.[12g]
a Reaction conditions: Indole 1a-1d (1 equiv.) with trans--nitrostyrene 2a-2q (1
Hence, a reaction was carried out in the presence of 4
mol% of
L/Zn(OTf)2 along with 10 mol% of pyrrolidine,
equiv.) in 3 mL of toluene using 4 mol% of L/Zn(OTf)2 complex as the catalyst at
40 oC for 48 h. b Isolated yield by column chromatography. c Determined by HPLC
unfortunately, to witness a complete retardation of product
formation (Table 2, entry 23). Similarly, piperidine also failed
to show any beneficial effect in this catalytic system (Table 2,
entry 24). It was speculated that the liberation of TfOH from
the Lewis acid Zn(OTf)2 due to the presence of moisture in the
reaction might have enhanced the reactivity and selectivity in
this reaction. Therefore, to confirm this speculation, we have
carried out the experiment by adding additional TfOH (4 mol%)
d
on Daicel Chiralcel OD-H column (hexane/2-propanol 70:30, 1 mL/min).
The
absolute configurations were assigned by comparison of the reported sign of
optical rotations and the retention times on a chiral HPLC column.
Similarly, the heterocycle containing nitroalkenes reacted with
indole in presence of
L/Zn(OTf)2 (4 mol%) to deliver the
corresponding FC products 3p and 3q in excellent yield, (79%
and 89%) with moderate enantioselectivities, 63% ee and 61%
ee respectively (Table 3, entries 3p, 3q). To examine the effect
of substituents on indole, 5-methoxy indole and 5-bromo
indole were subjected to alkylation reaction with
nitrostyrene in presence of L/Zn(OTf)2 in toluene, these
along with 4 mol% of L/Zn(OTf)2 complex and the reaction
failed to generate the product 3a (Table 2 entry 25). This
observation indicates that there is no involvement of TfOH in
this reaction. Therefore, the optimized condition to get indole
alkylated product 3a in good yield and good enantioselectivity
nucleophiles also generated the corresponding alkylated
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products 3r and 3s in excellent yields (93% and 87%) with good was used for the metal atom under the solvent VeienwvAirrtoicnlemOnelinnet
DOI: 10.1039/C9OB00545E
enantioselectivities 76% ee and 78% ee respectively (Table 3, (toluene) using conductor-like polarizable continuum model
entries 3r
nitrostyrene in the presence of
,
3s).The reaction of N-methyl indole with (CPCM) at 313K.
/Zn(OTf)2 failed to generate
L
the corresponding alkylated product 3t, indicating that the
presence of free N-H group is indispensable for this
transformation (Table 3, entry 3t). To justify the synthetic
utilityof the present catalystic system, The Friedel-Crafts
alkylation reaction was carried out on a gram scale to justify
the synthetic utility of the present catalytic system.
Accordingly, the indole 1a (1.17 g, 10 mmol) was treated with
nitrostyrene 2e (2.28 g, 10 mmol) in the presence of 4 mol%
of L/Zn(OTf)2 under optimized reaction condition. The reaction
generated the corresponding alkylated product 3e in 79% yield
with 95% ee after a single recrystallization in a mixture of
solvents, dichloromethane and hexane (Scheme 1).
Fig. 3: Optimized geometry of the Complex I. Two regions labeled as I and II indicate
the re-face and si-face of trans--nitrostyrene, respectively.
a.
b.
Scheme 1 Gram scale enantioselective Friedel-Crafts alkylation reaction
Indole failed to react with -nitrostyrene in the presence of
catalytic amount of L/Zn(OTf)2 at room temperature. Whereas the
reaction is facilitated at elevated temperature, thus, the ligand L
and Zn(OTf)2 might have formed a strong tetrahedral complex at
room temperature. Probably, at elevated temperature, the ligand
exchange might have occurred between two triflates and nitro
group of -nitrostyrene to generate CRCB tethered bipyridine-Zn-
nitrostyrene complex I (Figure 2). This might have enhanced the
electrophilic nature of nitroalkene to accept the indole nucleophile.
LUMO = -443.000 kJ/mol
HOMO = -593.100 kJ/mol
d. Bond Parameters (Å)
c.
N1 - Zn
N2 - Zn
Zn - O1
Zn - O2
O1 - N3
O2 - N3
N3 - C1
C1 - C2
C2 - C3
C4 – C2
C5 - C2
C7- C2
2.084
2.083
2.016
2.020
1.355
1.347
1.334
1.383
1.439
3.929
3.854
4.494
4.378
Electrostatic Potential (ESP)
Fig. 2 CRCB tethered bipyridine-Zn:trans--nitrostyrene complex, I
C6- C2
Fig. 4 Frontier orbitals (HOMO and LUMO) and the electrostatic potential map diagram.
The re-face (red) and si-face (blue) regions are marked with double-arrow.
In order to evident the most favorable prochiral face of the
trans-

-nitrostyrene complexed with CRCB tethered bipyridine
) for the attack by nucleophile (indole), the
Zn(II) catalyst (
I
The frequency calculation ensures the stable conformation of the
complex I, and no imaginary mode was found. The optimized
geometry of the complex I is shown in Figure 3. The frontier orbital
diagrams with corresponding energies are depicted in Figure 4a-4b.
The bond parameters (Figure 4d) of the optimized structure, Figure
computations were done using Gaussian 09 suite for the
quantum chemistry program. The optimized geometry of the
complex (I) was obtained using B3LYP density functional
theory with Pople’s 6-31G(d,p) basis set for all atoms (except
zinc) and the Los Alamos pseudopotential (LANL2DZ) basis set
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3, reveal that the space between C4-C2 and C5-C2 (re-face) is and TLC analyses were facilitated using phosphomolybdic acid stain
View Article Online
DOI: 10.1039/C9OB00545E
comparatively less than that of C7-C2 and C6-C2 (si-face). in addition to UV light with Merck 60 GF254 pre-coated silica plates.
Moreover, the phenyl ring of nitrostyrene (2a) is tilted towards The CRCB tethered bipyridyl ligand L was prepared as reported.14c
region I (re-face), which further implies that the region II (si-face) is
relatively less crowded than the region I. Therefore, the si-face is a Typical procedure for the preparation of nitroolefins (2a-2q) 16a, b
Aldehyde (10.0 mmol), nitromethane (12.0 mmol) and
ammonium acetate (6.0 mmol) were added to 7 mL of glacial acetic
acid. The resulting solution was refluxed for 4 h. Then the reaction
mixture was poured into ice-water, and the yellow solid (mostly)
thus formed was collected by filtration to give crude product. The
solid residue was purified by column chromatography on silica-gel
using ethyl acetate and hexane (5:95) mixture as eluent. The
desired nitroolefins (2a-2q) were obtained in 67-77% yield.
favorable prochiral face of trans--nitrostyrene in complex I for the
nucleophile attack. The electrostatic potential map diagram, Figure
4c, shows again that the si-face attack is less crowded and more
feasible site for the nucleophile attack.
The stereochemical outcome of the product from indole and
trans--nitrostyrene in presence of CRCB tethered bipyridine-
Zn(OTf)2 complex and the DFT study supports the si-face attack of
indole on trans--nitrostyrene.
(E)-(2-nitrovinyl)benzene (2a) 16c,d
Conclusions
Compound 2a was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
In conclusion, the conformationally rigid chiral bicyclic skeleton
tethered bipyridine/Zn(OTf)2 complex proved to catalyze the
enantioselective Friedel-Crafts alkylation reaction of indoles with
nitroalkenes. The alkylated indole derivatives were obtained in
good yields with excellent enantioselectivities (up to 91% ee). This
is the first report on the use of chiral bipyridine ligand for the
enantioselective Friedel-Crafts alkylation of indoles with
nitroalkenes. Both experiment and DFT calculations support the si-
face attack of nucleophile on trans--nitrostyrene in presence of
(S,S)-CRCB tethered bipyridine ligand and Zn(OTf)2. Further
structural modification of CRCB tethered bipyridine ligand and their
application in enantioselective transformations is in progress in our
laboratory.
yield (1.04 g, 70%) as yellow solid, m.p. 60 C; 1H NMR (400 MHz,
o
CDCl3): δH 8.01 (d, J = 13.6 Hz, 1H), 7.58 (d, J = 13.6 Hz, 1H), 7.56-
7.54 (m, 2H), 7.50-7.48 (m, 1H), 7.47-7.43 (m, 2H).
(E)-1-Methoxy-2-(2-nitroethyl)benzene (2b)16d
Compound 2b was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
yield (1.28 g, 72%) as yellow solid, m.p. 46 C; 1H NMR (400 MHz,
o
CDCl3): δH 8.14 (d, J = 13.6 Hz, 1H), 7.88 (d, J = 13.6 Hz, 1H), 7.48-
7.44 (m, 2H), 7.23 (d, J = 7.6, 1.2 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H),
3.96 (s, 3H).
(E)-1-Methoxy-3-(2-nitrovinyl)benzene (2c)16d
Compound 2c was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
EXPERIMENTAL SECTION
o
yield (1.23 g, 69%) as yellow solid, m.p. 90 C; 1H NMR (400 MHz,
General Information
Instrumentation
CDCl3): δH 7.95 (d, J = 13.6 Hz, 1H), 7.55 (d, J = 13.6 Hz, 1H), 7.36 (t, J
= 7.6 Hz, 1H), 7.13 (d, J = 7.6, 1.2 Hz, 1H), 7.04-7.03 (m, 2H), 3.85 (s,
3H).
All reactions were performed in oven-dried round bottom
flasks. Stainless steel syringes were used to transfer air and
moisture sensitive liquids. Melting points reported in this paper are
uncorrected and were determined using Buchi Melting point
apparatus M-560. Infrared spectra were recorded on Thermo
Nicolet iS10 FT-IR Spectrophotometer and are reported in
frequency of absorption (cm-1). 1H and 13C NMR spectra were
recorded on Brucker AVANCE – II 400 MHz spectrometer. NMR
spectra for all the samples were measured in CDCl3 using TMS as an
internal standard. The chemical shifts are expressed in δ ppm down
field from the signal of internal TMS. Data are represented as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublet, ddd = doublet of
doublet of doublet, td = triplet of doublet, m = multiplet), coupling
constants in Hertz (Hz) and integration.
(E)-1-Methoxy-4-(2-nitrovinyl)benzene (2d)16c,d
Compound 2d was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
yield (1.32 g, 74%) as yellow solid, m.p. 89 C; 1H NMR (400 MHz,
CDCl3): δH 7.96 (d, J = 13.6 Hz, 1H), 7.53-7.49 (m, 3H), 6.95 (d, J = 9.2
Hz, 2H), 3.87 (s, 3H).
(E)-1-Bromo-2-(2-nitrovinyl)benzene (2e)16c
Compound 2e was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
yield (1.59 g, 70%) as solid, m.p. 85 C; 1H NMR (400 MHz, CDCl3):
δH 8.39 (d, J = 13.6 Hz, 1H), 7.70-7.68 (m, 1H), 7.57 (dd, J = 7.6, 2.0
Hz, 1H), 7.53 (d, J = 13.6 Hz, 1H), 7.40-7.32 (m, 2H).
Solvents used for the reactions were dried using standard
procedures. For the synthesis, chemicals such as aldehydes
supplied by Aldrich, USA were used. Remaining reagents from Avra,
RANKEM and Sd Fine Chemicals, India were used. Column
chromatography was performed on Merck silica gel 100-200 mesh,
(E)-1-Bromo-3-(2-nitrovinyl)benzene (2f)16d
Compound 2f was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
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yield (1.52 g, 67%) as solid, m.p. 62 C; 1H NMR (400 MHz, CDCl3):
o
View Article Online
DOI: 10.1039/C9OB00545E
δH 7.93 (d, J = 13.6 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.64-7.61 (m, (E)-1-(2-nitrovinyl)naphthalene (2n) 16b
1H), 7.56 (d, J = 13.6, 1.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.34 (d, J =
Compound 2n was purified through silica gel column
8.0 Hz, 1H).
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
yield (1.53 g, 77%) as brown solid, m.p. 82 C; 1H NMR (400 MHz,
(E)-1-Bromo-4-(2-nitrovinyl)benzene (2g)16b
CDCl3): δH 8.83 (d, J = 13.6 Hz, 1H), 8.14-8.10 (m, 1H), 8.02-7.99 (m,
Compound 2g was purified through silica gel column 1H), 7.94-7.91 (m, 1H), 7.70-7.64 (m, 2H), 7.55 (d, J = 5.6 Hz, 1H),
chromatography using hexane/ethyl acetate (95:05) as eluent to 7.64-7.61 (m, 1H), 7.60-7.57 (m, 1H).
yield (1.62 g, 71%) as yellow solid, m.p. 149 oC; 1H NMR (400 MHz,
CDCl3): δH 7.95(d, J = 13.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.41 (d, J = 8.4 (E)-2-(2-nitrovinyl)naphthalene (2o) 16c
Hz, 2H).
Compound 2o was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
(E)-1-Chloro-2-(2-nitrovinyl)benzene (2h)16d
yield (1.45 g, 73%) as brown solid, m.p. 119 C; 1H NMR (400 MHz,
Compound 2h was purified through silica gel column CDCl3): δH 8.16 (d, J = 13.6 Hz, 1H), 8.02 (s, 1H), 7.91-7.85 (m, 3H),
chromatography using hexane/ethyl acetate (95:05) as eluent to 7.69 (d, J = 13.6 Hz, 1H), 7.61-7.54 (m, 3H).
o
yield (1.25 g, 75%) as yellow solid, m.p. 49 C; 1H NMR (400 MHz,
CDCl3): δH 8.41 (d, J = 14.0 Hz, 1H), 7.70-7.57 (m, 2H), 7.49 (dd, J = (E)-2-(2-nitrovinyl)furan (2p) 16c
8.0, 1.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.36-7.31 (m, 1H).
Compound 2p was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
(E)-1-Chloro-3-(2-nitrovinyl)benzene (2i)16d
yield (0.99 g, 71%) as solid, m.p. 75 C; 1H NMR (400 MHz, CDCl3):
Compound 2i was purified through silica gel column δH 7.77 (d, J = 13.6 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 13.6
chromatography using hexane/ethyl acetate (95:05) as eluent to Hz, 1H), 6.88 (d, J = 3.6 Hz, 1H), 6.57 (dd, J = 3.6, 1.6 Hz, 1H).
o
yield (1.33 g, 73%) as yellow solid, m.p. 47 C; 1H NMR (400 MHz,
CDCl3): δH 7.92 (d, J = 13.6 Hz, 1H), 7.56 (d, J = 14.0 Hz, 1H), 7.52 (s, (E)-2-(2-nitrovinyl)thiophene (2q) 16c
1H), 7.47-39 (m, 1H).
Compound 2q was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
o
(E)-1-Chloro-4-(2-nitrovinyl)benzene (2j)16c,d
yield (1.03 g, 67 %) as solid, m.p. 60 C; 1H NMR (400 MHz, CDCl3):
Compound 2j was purified through silica gel column δH 8.15 (d, J = 13.6 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.50-7.45 (m,
chromatography using hexane/ethyl acetate (95:05) as eluent to 2H), 7.14 (dd, J = 4.8, 3.6 Hz, 1H).
yield (1.40 g, 77%) as yellow solid, m.p. 111 oC; 1H NMR (400 MHz,
CDCl3): δH 7.96 (d, J = 13.6. Hz, 1H), 7.55 (d, J = 13.6 Hz, 1H), 7.50- General procedure for the Catalytic Enantioselective Friedel-Crafts
7.48 (m, 2H), 7.45-7.42 (m, 2H).
reaction
In a dry two neck round bottom flask equipped with
condenser were added Zn(OTf)2 (2.92 mg, 0.008 mmol), and
(E)-1-Fluoro-4-(2-nitrovinyl)benzene (2k)16c
Compound 2k was purified through silica gel column bipyridine ligand L (5.70 mg, 0.008 mmol) under the nitrogen
chromatography using hexane/ethyl acetate (95:05) as eluent to atmosphere followed by the addition of toluene (1 mL). The
yield (1.15 g, 69%) as solid, m.p. 105 oC; 1H NMR (400 MHz, CDCl3): solution was stirred at room temperature for 30 min and 0.2 mmol
δH 7.98 (d, J = 13.6 Hz, 1H), 7.59-7.51 (m, 3H), 7.18-7.12 (m, 2H).
of nitroalkene (2a-2q) was added. The reaction mixture was stirred
for 10 min and then indole 1a (23.56 mg, 0.20 mmol) was added.
The contents were stirred for 48 h at 40 oC. The resulting
(E)-1-Nitro-3-(2-nitrovinyl)benzene (2l)16c
Compound 2l was purified through silica gel column suspension was cooled to room temperature and then quenched
chromatography using hexane/ethyl acetate (95:05) as eluent to with H2O (5 mL). The aqueous layer was extracted with ethyl
yield (1.39 g, 72%) as yellow solid, m.p. 117 oC; 1H NMR (400 MHz, acetate (2 x 10 mL). The combined organic layer was dried over
CDCl3): δH 8.42 (t, J = 2.0 Hz, 1H), 8.36-8.33 (m, 1H), 8.05 (d, J = 13.6 anhydrous Na2SO4 and filtered. The solvent was evaporated under
Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 6.67 (d, J = reduced pressure. The residue was purified through silica gel
13.6 Hz, 1H).
column chromatography using hexane/ethyl acetate (80:20) as
eluent to afford 3-(2-nitro-1-arylethyl)-1H-indoles 3a-3q and 3r-s.
(E)-1-Methyl-4-(2-nitrovinyl)benzene (2m)16c
Compound 2m was purified through silica gel column (R)-3-(2-Nitro-1-phenylethyl)-1H-indole (3a)12b,c,h
chromatography using hexane/ethyl acetate (95:05) as eluent to
Compound 3a was purified through silica gel column
o
yield (1.14 g, 70%) as yellow solid, m.p. 98 C; 1H NMR (400 MHz, chromatography using hexane/ethyl acetate (80:20) as eluent to
CDCl3): δH 7.98 (d, J = 13.6 Hz, 1H), 7.57 (d, J = 13.6 Hz, 1H), 7.44 (d, yield (49 mg, 92% yield) as oil. HPLC (Daicel Chiralcel OD-H,
J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H).
hexane/2-propanol = 70:30, flow rate 0.9 mL/min) tminor = 24.6 min,
tmajor = 28.0 min, 80% ee; IR (KBr, cm-1): 3426, 2922, 1550, 1456,
6 | J. Name., 2012, 00, 1-3
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1376; H NMR (400 MHz, CDCl3): δH 8.02 (brs 1H), 7.36 (d, J = 8.0 yield (65 mg, 94%) as oil. HPLC (Daicel Chiralcel ODV-iHew, AhreticxlaenOen/lin2e-
DOI: 10.1039/C9OB00545E
Hz, 1H), 7.28-7.22 (m, 5H), 7.19-7.17 (m, 1H), 7.12 (td, J = 7.2, 1.2 propanol = 70:30, flow rate 1.0 mL/min) tmajor = 17.3 min, tminor
=
Hz, 1H), 7.01-6.97 (m, 1H), 6.94 (d, J = 1.6 Hz, 1H), 5.11 (t, J = 8.0 Hz, 26.1 min, 91% ee; The gram scale reaction product 3e is a white
1H), 4.99 (dd, J = 12.4, 7.6 Hz, 1H), 4.86 (dd, J = 12.8, 8.4 Hz, 1H); solid; m.p 113-115 oC; HPLC (Daicel Chiralcel OD-H, hexane:2-
13C{1H} NMR (100 MHz, CDCl3): δC 139.30, 136.61, 129.06, 127.90, propanol 70:30, 1 mL/min, tmajor = 17.1 min, tminor = 28.0 min, 95%
1
127.70, 126.22, 122.83, 121.73, 120.09, 119.06, 114.55, 111.51, ee); IR (KBr, cm-1): 3425, 2923, 1551, 1427, 1374, 1101, 746; H
79.65, 41.67.
NMR (400 MHz, CDCl3): δH 8.22 (brs, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.43 (d, J = 7.6 Hz, 1H), 7.36-7.34 (m, 1H), 7.22-7.18 (m, 3H), 7.14-
7.06 (m, 3H), 5.73 (t, J = 8.0 Hz, 1H), 5.01-4.93 (m, 2H); 13C{1H} NMR
(R)-3-(1-(2-Methoxyphenyl)-2-nitroethyl)-1H-indole( 3b)12a,c,h
Compound 3b was purified through silica gel column (100 MHz, CDCl3): δC 138.20, 136.60, 133.59, 129.25, 128.03,
chromatography using hexane/ethyl acetate (80:20) as eluent to 126.31, 124.60, 122.89, 122.07, 120.12, 119.12, 113.44, 111.51,
yield (52 mg, 87%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- 77.90, 40.72.
propanol = 70:30, flow rate 0.9 mL/min) tmajor = 13.4 min, tminor
=
16.5 min, 81% ee; IR (KBr, cm-1): 3421, 2926, 1593, 1549, 1456, (R)-3-(1-(3-Bromophenyl)-2-nitroethyl)-1H-indole (3f)12a,c,h
1
1375, 1108, 750; H NMR (400 MHz, CDCl3): δH 8.01 (brs, 1H), 7.39
Compound 3f was purified through silica gel column
(d, J = 8.0, Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.17-7.13 (m, 1H), 7.12- chromatography using hexane/ethyl acetate (80:20) as eluent to
7.08 (m, 1H), 7.02-6.97 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.75 (t, J = yield (57 mg, 83%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
7.2 Hz, 1H), 5.54-5.50 (m, 1H), 4.98-4.86 (m, 2H), 3.83 (s, 3H); propanol = 70:30, flow rate 1.0 mL/min) tminor = 25.55 min, tmajor
=
13C{1H} NMR (100 MHz, CDCl3): δC 156.98, 136.51, 129.06, 128.77, 36.39 min, 86% ee; IR (KBr, cm-1): 3419, 3055, 2921, 1592, 1550,
1
127.30, 126.63, 122.57, 122.09, 120.90, 119.84, 119.21, 114.00, 1424, 1100, 745; H NMR (400 MHz, CDCl3): δH 8.06 (brs, 1H), 7.37
111.39, 110.91, 78.23, 55.65, 35.62.
(t, J = 1.6 Hz; 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.30-7.28 (m, 1H), 7.26 (d,
J = 8.0 Hz, 1H), 7.19 -7.15 (m, 1H), 7.14-7.07 (m, 2H), 7.02-7.00 (m,
1H), 6.91 (d, J = 2.0 Hz, 1H), 5.06 (t, J = 8.0 Hz, 1H), 4.94 (dd, J =
(R)-3-(1-(3-Methoxyphenyl)-2-nitroethyl)-1H-indole (3c)12a
Compound 3c was purified through silica gel column 12.8, 7.6 Hz, 1H), 4.81 (dd, J = 12.8, 8.4 Hz, 1H); 13C{1H}. NMR (100
chromatography using hexane/ethyl acetate (80:20) as eluent to MHz, CDCl3): δC 141.72, 136.57, 130.96, 130.91, 130.59, 126.57,
yield (51 mg, 86%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- 126.00, 123.10, 122.97, 121.70, 120.22, 118.83, 113.71, 111.62,
propanol = 70:30, flow rate 1.0 mL/min) tminor = 23.5 min, tmajor
31.7 min, 84% ee; IR (KBr, cm-1): 3419, 2926, 2847, 1597, 1552,
1456, 1375, 1100, 747; 1H NMR (400 MHz, CDCl3): δH 8.13 (brs, 1H), (R)-3-(1-(4-Bromophenyl)-2-nitroethyl)-1H-indole (3g)12a
7.47 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.26-7.24 (m, 1H), Compound 3g was purified through silica gel column
=
79.26, 41.23.
7.22-7.18 (m, 1H), 7.10-7.06 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H) 6.93 (d, chromatography using hexane/ethyl acetate (80:20) as eluent to
J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.81-6.78 (m, 1H), 5.16 (t, J = 8.0 Hz, yield (57 mg, 84%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
1H), 5.05 (dd, J = 12.8, 7.6 Hz, 1H), 4.93 (dd, J = 12.8, 8.4 Hz, 1H), propanol = 70:30, flow rate 1.0 mL/min) tminor = 28.0 min, tmajor
=
3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 160.02, 140.92, 34.6 min, 84% ee; IR (KBr, cm-1): 3432, 2923, 2856, 1549, 1459, 745;
136.57, 130.06, 126.21, 122.81, 121.72, 120.14, 120.07, 119.01, 1H NMR (400 MHz, CDCl3): δH 8.15 (brs, 1H), 7.44 (d, J = 8.4 Hz, 2H),
114.38, 114.13, 112.61, 111.51, 79.56, 55.33, 41.62.
7.41-7.36 (m, 2H), 7.23-7.19 (m, 3H), 7.08 (t, J = 8.0 Hz, 1H), 7.02 (d,
J = 2.4 Hz, 1H), 5.15 (t, J = 8.0 Hz, 1H), 5.06 (dd, J = 12.4, 7.6 Hz, 1H),
4.91 (dd, J = 12.4, 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δC
(R)-3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1H-indole (3d)12a,c,h
Compound 3d was purified through silica gel column 138.37, 136.62, 132.19, 129.78, 129.63, 125.99, 123.00, 121.66,
chromatography using hexane/ethyl acetate (80:20) as eluent to 120.23, 118.91, 113.96, 111.61, 79.31, 41.14.
o
yield (50 mg, 85%) as a white solid; m.p 148-150 C (Lit7. 149-150
oC). HPLC (Daicel Chiralcel OD-H, hexane/2-propanol = 70:30, flow (R)-3-(1-(2-Chlorophenyl)-2-nitroethyl)-1H-indole (3h)12a,c,g,h
rate 1.0 mL/min) tminor = 25.4 min, tmajor = 28.4 min, 70% ee; IR (KBr,
Compound 3h was purified through silica gel column
1
cm-1): 3422, 2923, 1549, 1509, 1376, 1250, 747; H NMR (400 MHz, chromatography using hexane/ethyl acetate (80:20) as eluent to
CDCl3): δH 8.10 (brs, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, yield (50 mg, 83%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
1H), 7.26-7.23 (m, 2H), 7.21-7.17 (m, 1H), 7.09-7.05 (m, 1H), 7.02 (d, propanol = 70:30, flow rate 1.0 mL/min) tmajor = 17.48 min, tminor
=
J = 2.4 Hz, 1H), 6.86-6.83 (m, 2H), 5.14-5.12 (m, 1H), 5.07-5.02 (m, 27.60 min, 90% ee; IR (KBr, cm-1): 3422, 2920, 1550, 1428, 1098,
1H), 4.90 (dd, J = 12.4, 8.4 Hz, 1H), 3.77 (s, 3H); 13C{1H} NMR (100 747; 1H NMR (400 MHz, CDCl3): δH 8.13(brs, 1H), 7.45-7.42 (m, 2H),
MHz, CDCl3): δC 159.00, 136.62, 131.29, 128.95, 126.21, 122.79, 7.37-7.34 (m, 1H), 7.23-7.14 (m, 4H), 7.11-7.08 (m, 2H), 5.75 (t, J =
121.58, 120.04, 119.11, 114.86, 114.39, 111.50, 79.87, 55.37, 40.97. 8.0 Hz, 1H), 5.04-4.94 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δC
136.57, 133.97, 130.27, 129.10, 128.98, 127.41, 126.29, 122.92,
(R)-3-(1-(2-Bromophenyl)-2-nitroethyl)-1H-indole (3e)12e
122.08, 120.15, 119.06, 113.37, 111.51, 77.82, 38.08.
Compound 3e was purified through silica gel column
chromatography using hexane/ethyl acetate (80:20) as eluent to
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130.08, 125.76, 123.20, 122.89, 122.80, 121.72, 120.41, 118.58,
View Article Online
(R)-3-(1-(3-Chlorophenyl)-2-nitroethyl)-1H-indole (3i)12g
113.11, 111.79, 78.97, 41.21.
DOI: 10.1039/C9OB00545E
Compound 3i was purified through silica gel column (R)-3-(2-Nitro-1-p-tolylethyl)-1H-indole (3m)12c,g,h
chromatography using hexane/ethyl acetate (80:20) as eluent to
Compound 3m was purified through silica gel column
yield (49 mg, 81%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- chromatography using hexane/ethyl acetate (80:20) as eluent to
propanol = 70:30, flow rate 1.0 mL/min) tminor = 24.1min, tmajor
=
yield (48 mg, 85%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
32.4 min, 81% ee; IR (KBr, cm-1): 3422, 2921, 1551, 1465, 1375, 747; propanol = 70:30, flow rate 1.0 mL/min), tminor = 18.72 min, tmajor
=
1H NMR (400 MHz, CDCl3): δH 8.16 (brs, 1H), 7.44 (dd, J = 8.0, 0.8 21.73 min, 75% ee; IR (KBr, cm-1): 3421, 2920, 1549, 1425, 1100,
Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.27-7.24 746; 1H NMR (400 MHz, CDCl3): δH 8.09 (brs, 1H), 7.46 (d, J = 8.0 Hz,
(m, 3H), 7.22 (dd, J = 8.0, 1.2 Hz, 1H), 7.13-7.09 (m, 1H), 7.05-7.04 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.24-7.18 (m, 3H), 7.13 (d, J = 8.0 Hz,
(m, 1H), 5.18 (t, J = 8.0 Hz, 1H), 5.06 (dd, J = 12.8, 7.6 Hz, 1H), 4.93 2H), 7.08 (td, J = 8.0, 0.8 Hz, 1H), 7.00 (m, 1H), 5.16 (t, J = 8.0 Hz,
(dd, J = 12.4, 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δC 141.45, 1H), 5.05 (dd, J = 12.4, 7.6 Hz, 1H), 4.93 (dd, J = 12.4, 8.4 Hz, 1H),
136.60, 134.91, 130.32, 128.09, 128.01, 126.12, 126.03, 123.02, 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 137.32, 136.59,
121.68, 120.26, 118.88, 113.82, 111.61, 79.28, 41.29.
136.25, 129.71, 127.73, 126.22, 122.75, 121.66, 120.02, 119.06,
114.69, 111.49, 79.75, 41.31, 21.17.
(R)-3-(1-(4-Chlorophenyl)-2-nitroethyl)-1H-indole (3j)12a,c,g,h
Compound 3j was purified through silica gel column (R)-3-(1-(Naphthalene-1-yl)-2-nitroethyl)-1H-indole (3n)12a
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (52 mg, 87%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- chromatography using hexane/ethyl acetate (80:20) as eluent yield
propanol = 70:30, flow rate 1.0 mL/min) tminor = 26.0 min, tmajor (49 mg, 78%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-propanol
31.2 min, 83% ee; IR (KBr, cm-1): 3423, 2923, 1550, 1423, 1096, 746; = 70:30, flow rate 1.0 mL/min) 1 mL/min, tmajor = 23.2 min, tminor
Compound 3n was purified through silica gel column
=
=
1
1H NMR (400 MHz, CDCl3): δH 8.07 (brs, 1H), 7.30 (dd, J = 14.4, 8.0 34.3 min, 75% ee; IR (KBr, cm-1): 3428, 2921, 1549, 1426, 743; H
Hz, 2H), 7.22-7.17 (m, 4H), 7.13-7.11 (m, 1H), 7.02-6.98 (m, 1H), NMR (400 MHz, CDCl3): δH 8.28 (d, J = 8.4 Hz, 1H), 8.10 (brs, 1H),
6.93 (d, J = 2.0 Hz, 1H), 5.08 (t, J = 8.0 Hz, 1H), 4.97 (dd, J = 12.4, 7.2 7.91-7.89 (m, 1H), 7.79 (t, J = 4.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (d,
Hz, 1H), 4.82 (dd, J = 12.4, 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, J = 8.0 Hz, 1H), 7.39-7.36 (m, 3H), 7.22-7.18 (m, 1H), 7.08-7.04 (m,
CDCl3): δC 137.86, 136.63, 133.56, 129.29, 129.26, 126.02, 123.01, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 1H), 5.16-5.08 (m,
121.66, 120.24, 118.94, 114.07, 111.62, 79.42, 41.09.
2H); 13C{1H} NMR (100 MHz, CDCl3): δC 136.71, 134.73, 134.30,
131.24, 129.31, 128.49, 127.01, 126.27, 126.08, 125.50, 124.79,
122.87, 122.82, 122.77, 120.14, 118.97, 114.47, 111.56, 78.64,
(R)-3-(1-(4-Fluorophenyl)-2-nitroethyl)-1H-indole (3k)12a,c
Compound 3k was purified through silica gel column 37.13.
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (49 mg, 86%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- (R)-3-(1-(Naphthalene-2-yl)-2-nitroethyl)-1H-indole (3o)9d,12b
propanol = 70:30, flow rate 1.0mL/min) tminor = 23.10 min, tmajor
=
Compound 3o was purified through silica gel column
29.70 min, 83% ee; IR (KBr, cm-1): 3402, 2921, 1603, 1550, 1424, chromatography using hexane/ethyl acetate (80:20) as eluent to
1101, 745; 1H NMR (400 MHz, CDCl3): δH 8.13(brs, 1H), 7.41 (dd, J = yield (51 mg, 81%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
8.0, 0.4 Hz, 2H), 7.37-7.28 (m, 2H), 7.22 (td, J = 7.2, 1.2 Hz, 1H), 7.10 propanol = 70:30, flow rate 0.9 mL/min) tminor = 37.04 min, tmajor
=
(td, J = 8.0, 0.8 Hz, 1H) ), 7.03-6.98 (m, 3H), 5.18 (t, J = 8.0 Hz, 1H), 58.93 min, 76% ee; IR (KBr, cm-1): 3429, 2924, 2857, 1643, 1551,
1
5.06 (dd, J = 12.4, 7.2 Hz, 1H), 4.91 (dd, J = 12.4, 8.4 Hz, 1H); 13C{1H} 1460, 728; H NMR (400 MHz, CDCl3): δH 8.12 (brs, 1H), 7.81-7.79
NMR (100 MHz, CDCl3): δC 163.41, 160.96, 136.62, 135.07, 135.04, (m, 4H), 7.49-7.42 (m, 4H), 7.35 (d, J = 8.0 Hz, 1H), 7.21-7.18 (m,
129.52, 129.44, 126.05, 122.93, 121.56, 120.15, 118.95, 116.04, 1H), 7.08-7.04 (m, 2H), 5.39-5.35 (t, J = 8.0 Hz, 1H), 5.15 (dd, J =
115.83, 114.34, 111.57, 79.65, 40.98.
12.4, 7.2 Hz, 1H), 5.06 (dd, J = 12.4, 8.4 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δC 136.77, 136.65, 133.57, 132.89, 128.93, 128.03,
127.81, 126.55, 126.49, 126.27, 126.24, 125.94, 122.87, 121.90,
(R)-3-(2-Nitro-1-(3-nitrophenyl)ethyl)-1H-indole (3l)12c,h
Compound 3l was purified through silica gel column 120.15, 119.07, 114.49, 111.54, 79.54, 41.79.
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (46 mg, 74%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2- (R)-3-(1-(Furan-2-yl)-2-nitroethyl)-1H-indole (3p)12a,c,h
propanol = 70:30, flow rate 1.0 mL/min) tminor = 54.46 min, tmajor
=
Compound 3p was purified through silica gel column
62.00 min, 83% ee; IR (KBr, cm-1): 3420, 2922, 1555, 1424, 1098, chromatography using hexane/ethyl acetate (80:20) as eluent to
742; 1H NMR (400 MHz, CDCl3): δH 8.29 (brs, 1H), 8.20 (t, J = 2.0 Hz, yield (41 mg, 79%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
1H), 8.12 (m, 1H), 7.71-7.69 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.40- propanol = 70:30, flow rate 1.0 mL/min) tmajor = 14.9 min, tminor
=
1
7.37 (m, 2H), 7.24-7.20 (m, 1H), 7.11-7.07 (m, 2H), 5.30 (t, J = 8.0 21.9 min, 63% ee; IR (KBr, cm-1): 3422, 2922, 1548, 1373, 740; H
Hz, 1H), 5.11 (dd, J = 12.8, 6.8 Hz, 1H), 5.00 (dd, J = 12.8, 8.8 Hz, 1H); NMR (400 MHz, CDCl3): δH 8.15 (brs, 1H), 7.56 (d, J = 8.0 Hz, 1H),
13C{1H} NMR (100 MHz, CDCl3): δC 148.72, 141.72, 136.62, 134.23, 7.39-7.37 (m, 2H), 7.24-7.20 (m, 1H), 7.15-7.12 (m, 2H), 6.31-6.30
(m, 1H), 6.17 (d, J = 3.2 Hz, 1H), 5.25 (t, J = 8.0 Hz, 1H), 5.06 (dd, J =
8 | J. Name., 2012, 00, 1-3
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12.4, 8.0 Hz, 1H), 4.93 (dd, J = 12.4, 7.2 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δC 152.31, 142.39, 136.44, 125.82, 122.84, 122.79,
120.21, 118.84, 111.76, 111.66, 110.60, 107.52, 78.00, 35.84.
Notes and references
View Article Online
DOI: 10.1039/C9OB00545E
1
G. A. Olah, R. Khrisnamurthi, G. K. S. Prakash, In
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(R)-3-(2-Nitro-1-(thiophen-2-yl)ethyl)-1H-indole (3q)12a,c,h
Compound 3q was purified through silica gel column
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (48 mg, 89%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
2
3
F. Bigi, G. Casiraghi, G. Casnati, G. Sartori, G -G. Fava, M. F.
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(a) B.-L. Wang, N.-K. Li, J.-X. Zhang, G.-G. Liu, T. Liu, Q. Shen,
propanol = 70:30, flow rate 1.0 mL/min) tmajor = 22.0 min, tminor
=
4
26.1 min, 61% ee; IR (KBr, cm-1) : 3423, 2922, 1550, 1425, 1375,
748; 1H NMR (400 MHz, CDCl3): δH 8.16 (brs, 1H), 7.52 (d, J = 7.6 Hz,
1H), 7.38 (d, J = 8.4 Hz, 1H), 7.24-7.19 (m, 2H), 7.13-7.10 (m, 2H),
6.99 (m, 1H), 6.95-6.93 (m, 1H), 5.47 (t, J = 8.0 Hz, 1H), 5.08-4.96
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δC 143.06, 136.52, 127.09,
125.83, 125.39, 125.04, 122.89, 122.09, 120.20, 118.94, 114.16,
111.65, 80.13, 37.05.
X.-W. Wang, Org. Biomol. Chem., 2011,
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Arai, J. Kakino, Angew. Chem. Int. Ed., 2016, 55, 15263.
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1996, 1047; (b) K. Manabe, N. Aoyama, S. Kobayashi, Adv.
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Giacomini, P. Melchiorre, S. Selva, A. Umani-Ronchi, J. Org.
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5
6
7
(R)-5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (3r)12a,c,g,h
Compound 3r was purified through silica gel column
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (56 mg, 93%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
propanol = 70:30, flow rate 1.0 mL/min) tmajor = 28.2 min, tminor
=
37.8 min, 76% ee; IR (KBr, cm-1): 3426, 2926, 1551, 1483, 1377,
1
1214, 1029, 700; H NMR (400 MHz, CDCl3): δH 8.04 (brs, 1H), 7.35-
8
9
(a) M. Kokubo, T. Naito, S. Kobayashi, Tetrahedron., 2010,
66, 1111; (b) B. Plancq, M. Lafantaisie, S. Companys, C.
Maroun, T. Ollevier, Org. Biomol. Chem., 2013, 11, 7463.
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V. Sgarzani, L. Bernardi, A. Ricci, Angew. Chem. Int. Ed., 2005,
44, 6576; (b) W. Zhuang, R. G. Hazell, K. A. Jørgensen, Org.
7.31 (m, 4H), 7.25-7.23 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 6.86-6.84
(m, 2H), 5.14 (t, J = 8.0 Hz, 1H), 5.05 (dd, J = 12.4, 7.6 Hz, 1H), 4.94
(dd, J = 12.4, 8.4 Hz, 1H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δC 154.30, 139.27, 131.71, 129.05, 127.89, 127.70, 126.69,
122.41, 114.20, 112.86, 112.23, 100.96, 79.61, 55.97, 41.65.
Biomol. Chem., 2005, 3, 2566; (c) E. M. Fleming, T. McCabe,
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(R)-5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (3s)12a,g
Compound 3s was purified through silica gel column
chromatography using hexane/ethyl acetate (80:20) as eluent to
yield (60 mg, 87%) as oil. HPLC (Daicel Chiralcel OD-H, hexane/2-
Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. Int. Ed., 2008, 47
,
4016.
10 M. Bandini, A. Garelli, M. Rovinetti, S. Tommasi, A. Umani-
Ronchi, Chirality 2005, 17, 522.
11 For Cu(II) based catalysts: (a) P. K. Singh, A. Bisai, V. K. Singh,
Tetrahedron Lett., 2007, 48, 1127; (b) Y. Sui, L. Liu, J. L. Zhao,
D. Wang, Y. J. Chen, Tetrahedron., 2007, 63, 5173; (c) T. Arai,
N. Yokoyama, Angew. Chem. Int. Ed., 2008, 47, 4989; (d) T.
propanol = 70:30, flow rate 0.7 mL/min) tmajor = 17.3 min, tminor
=
25.4 min, 78% ee; IR (KBr, cm-1): 3430, 2924, 1553, 1457, 1109, 750;
1H NMR (400 MHz, CDCl3): δH 8.14 (brs, 1H), 7.49 (d, J = 1.6 Hz, 1H),
7.30-7.21 (m, 5H), 7.20 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H),
7.00 (d, J = 2.4 Hz, 1H), 5.06 (t, J = 8.0 Hz, 1H), 4.96 (dd, J = 12.4, 8.0
Hz, 1H), 4.86 (dd, J = 12.4, 8.0 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δC.138.81, 135.21, 129.18, 127.97, 127.89, 127.78, 125.77,
122.87, 121.57, 114.12, 113.35, 112.99, 79.52, 41.41.
Arai, N. Yokoyama, A. Yanagisawa, Chem. Eur. J., 2008, 14
,
2052; (e) N. Yokoyama, T. Arai, Chem. Commun., 2009, 3285;
(f) H. Y. Kim, S. Kim, K. Oh, Angew. Chem. Int. Ed., 2010, 49
,
4476.
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, 1111; (d) Z. L. Yuan, Z. Y. Lei, M.
Conflicts of interest
There are no conflicts to declare
Shi, Tetrahedron: Asymmetry 2008, 19, 1339; (e) S.-Z. Lin, T.-
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Acknowledgements
We thank DST, New Delhi for financial support. KV thanks UGC,
New Delhi for SRF. We gratefully acknowledge CIF, Pondicherry
University for NMR/IR data. We gratefully acknowledge UGC-SAP,
Department of Chemistry, Pondicherry University for HPLC data.
13 M. P. A. Lyle, N. D. Draper, P. D. Wilson, Org. Lett., 2005, 7,
901.
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DOI: 10.1039/C9OB00545E
Someshwar, M. Karthick, C. R. Ramanathan, Synlett 2017, 28
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