Asymmetric Friedel-Crafts alkylation of indoles with 3-nitro-2H-chromenes catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II) complexes

Article abstract of DOI:10.1039/c2ob25360g

An efficient diastereo- and enantioselective Friedel-Crafts alkylation of indoles with 3-nitro-2H-chromenes catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II) complexes has been developed. This asymmetric Friedel-Crafts alkylation

Full text of DOI:10.1039/c2ob25360g

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4739
www.rsc.org/obc
PAPER
Asymmetric Friedel–Crafts alkylation of indoles with 3-nitro-2H-chromenes
catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II)
complexes†
Yang Jia, Wen Yang and Da-Ming Du*
Received 20th February 2012, Accepted 20th April 2012
DOI: 10.1039/c2ob25360g
An efficient diastereo- and enantioselective Friedel–Crafts alkylation of indoles with 3-nitro-2H-
chromenes catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II) complexes has
been developed. This asymmetric Friedel–Crafts alkylation led to medicinally privileged indolyl(nitro)
chromans in good yields with high enantioselectivities (up to 95% ee) and diastereoselectivities under
mild reaction conditions.
alkylation of different electron-rich heteroaromatics with
Introduction
nitroalkenes16d–f in the subsequent research. Inspired by the
As an important class of compounds, chroman derivatives are
widely found in naturally occurring compounds,1 many of which
exhibit useful biological activity.2 For example, they have been
identified as apoptosis-inducing agents,3 anti-HIV agents,4,5
modulators of the estrogen receptors,6 antibacterials,7 antioxi-
dants8 and anticonvulsants.9 Likewise, indole and many of its
derivatives are important units because of their pharmacological
and biological properties.10 So the synthesis of chiral fused
heterocyclic systems containing both chroman and indole moi-
eties should be significant work. There has been some evidence
demonstrating the biological activity of this kind of fused hetero-
cyclic system.11 3-Nitro-2H-chromenes, which can be easily pre-
pared from salicylaldehyde and nitroethylene,12 are valuable
intermediates for the synthesis of chroman derivatives. For
example, they present high reactivity for conjugate addition with
nucleophiles13 and 1,3-dipolar cycloaddition with azomethine,
azide, and diazo compounds.14 Yao’s group studied the Friedel–
Crafts alkylation of indole with 3-nitro-2H-chromene to achieve
fused heterocyclic systems,15 but no asymmetric reaction was
tried.
mechanism, we attempted to apply this kind of ligand to the
asymmetric Friedel–Crafts alkylation17,18 of 3-nitro-2H-chro-
menes and indoles. To our delight, good yields, enantioselectiv-
ities and diastereoselectivities were obtained as expected. In this
paper, we wish to report an efficient method to afford indolyl
(nitro)chromans in high yields with good enantioselectivities and
diastereoselectivities.
Results and discussion
We initially performed the Friedel–Crafts alkylation of indole 1a
with 3-nitro-2H-chromene 2a in toluene at room temperature
using L1–Zn(OTf)2 as the catalyst. The desired product 3a was
obtained in 73% yield with 65% ee and 98 : 2 dr. To identify a
more efficient ligand, we screened a series of diphenylamine-
linked bis(oxazoline) ligands L2–L6 and bis(thiazoline) ligands
L7 and L8 (Fig. 1). The results are summarized in Table 1.
When ligand L2 was used, excellent yield and an obvious
increase in the enantioselectivity (93% ee) were observed though
the diastereoselectivity slightly decreased. So we studied ligands
Our group has developed various diphenylamine-linked bis
(oxazoline) ligands and bis(thiazoline) ligands in recent years,16
which have been successfully applied in the asymmetric Henry
reaction of α-ketoesters,16a,b asymmetric Michael addition of
nitroethanes to nitroalkenes,16c and asymmetric Friedel–Crafts
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing 100081, People’s Republic of China. E-mail:
dudm@bit.edu.cn; Tel: +86 10 68914985
†Electronic supplementary information (ESI) available: 1H NMR
spectra, 13C NMR spectra and HPLC diagrams. CCDC reference
numbers 868579. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob25360g
Fig. 1 Diphenylamine-linked bis(oxazoline) and bis(thiazoline)
ligands.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4739–4746 | 4739

View Online
with only one substitution group on the hetereocycles (Table 1,
entries 3–4 and 7–8). Interestingly, the catalyst L2–Zn(OTf)2
furnished overwhelmingly better results than the other bis(oxazo-
line) or bis(thiazoline)–Zn(OTf)2 catalysts in enantioselectivity.
We wondered whether the electronic effect of the substitution
group on the diphenylamine skeleton would promote the result,
so ligand L5 and L6 were tested. However, no surpassing results
were achieved (Table 1, entries 5–6). Therefore, L2–Zn(OTf)2
was selected as the best catalyst for further optimization.
performed in all solvents tested, but variation of the solvents had
a pronounced effect on the selectivity. Our catalyst exhibited
high catalytic activity in toluene with 93% ee and 84 : 16 dr.
Xylene led to an obvious decrease in the enantioselectivity, in
spite of a slight improvement in the diastereoselectivity (Table 2,
entry 2). The use of chlorobenzene produced 3a in excellent
yield, but with moderate enantioselectivity and diastereoselectiv-
ity (Table 2, entry 3). Other solvents tested led to moderate to
low enantioselectivities (Table 2, entries 4–6). Then we con-
ducted a temperature effect study using toluene as the solvent. A
decrease in the yield was observed when the reaction temperature
dropped. But taking the enantioselectivities and diastereoselec-
tivities into account comprehensively, we chose 0 °C as the final
reaction temperature. As for zinc salts, the role of Zn(OTf)2
could not be carried out by ZnCl2, ZnBr2 or Zn(ClO4)2·6H2O
(Table 2, entries 9–11).
To get the optimal reaction conditions, we further evaluated
different solvents, temperatures, and zinc salts. As presented in
Table 2, the Friedel–Crafts alkylation could be efficiently
Table 1 Screening of ligands for the asymmetric Friedel–Crafts
alkylation of indole with 3-nitro-2H-chromenea
With the optimal reaction conditions established, we explored
the substrate scope of this asymmetric Friedel–Crafts alkylation.
The results are summarized in Table 3. We first surveyed a
variety of 3-nitro-2H-chromenes 2a–i bearing different substitu-
ents (Table 3, entries 1–9). They could react with indole in mod-
erate to good yields that varied from 61% to 94%, with good
diastereoselectivities. As for enantioselectivities, the substitution
on the phenyl of 3-nitro-2H-chromene, with either electron-
donating or electron-withdrawing groups, led to good enantio-
selectivities (83–89% ee, Table 3, entries 2–3 and 5–9), except
for the substrate 2d (Table 3, entry 4), with which the product
was obtained in moderate enantioselectivity (54% ee). The gen-
erality of the reaction was further demonstrated by variation of
indoles. When electron-rich 5-methylindole 1b and 5-methoxy-
indole 1c were used, the reaction proceeded very smoothly with
good yields, enantioselectivities and diastereoselectivities
(Table 3, entries 10–11). However, an electron-withdrawing sub-
stituent chlorine in the 5-position of the indole ring caused a
moderate decrease in both yield and selectivity, providing 3l in
68% yield, 62% ee and 82 : 18 dr (Table 3, entry 12). When we
Entry
Ligand
Yieldb (%)
Anti/sync
eec,d (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
73
96
81
71
91
60
96
90
98 : 2
65
93
81
83
81
71
86
73
84 : 16
88 : 12
77 : 23
77 : 23
86 : 14
83 : 17
86 : 14
a All the reactions were conducted in a 0.3 mmol scale in 3 mL of
toluene at room temperature for 48 h. b Isolated yields after column
chromatography purification. c Determined by chiral HPLC analysis.
d Enantiomeric excess of the anti-product.
Table 2 Optimization of reaction conditions for the asymmetric Friedel–Crafts alkylation of indole with 3-nitro-2H-chromenea
Entry
Solvent
T (°C)
Zn(II) Salt
Yieldb (%)
Anti/sync
eec,d (%)
1
2
3
4
5
6
7
8
Toluene
Xylene
Chlorobenzene
Chloroform
THF
rt
rt
rt
rt
rt
rt
0
−20
0
0
0
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
ZnCl2
96
92
97
74
73
62
80
78
82
80
80
84 : 16
90 : 10
72 : 28
76 : 24
89 : 11
81 : 19
89 : 11
91 : 9
93
86
77
78
48
23
94
91
0
Ethanol
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
79 : 21
72 : 28
75 : 25
ZnBr2
Zn(ClO4)2·6H2O
3
20
a All the reactions were conducted in a 0.3 mmol scale in 3 mL of solvent for 48 h. b Isolated yields after column chromatography purification.
c Determined by chiral HPLC analysis. d Enantiomeric excess of the anti-product.
4740 | Org. Biomol. Chem., 2012, 10, 4739–4746
This journal is © The Royal Society of Chemistry 2012

View Online
a,b
Table 3 Asymmetric Friedel–Crafts alkylation of indoles 1 with 3-nitro-2H-chromenes 2 catalyzed by L2–Zn(OTf)2
Entry
R1
R2
R3
Product
Time (h)
Yieldc (%)
Anti/synd
eed,e (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
46
48
48
60
60
60
60
60
60
60
60
60
60
80
80
94
80
84
92
61
90
90
88
92
68
94
89 : 11
88 : 12
84 : 16
90 : 10
89 : 11
92 : 8
95 : 5
90 : 10
92 : 8
94 : 6
91 : 9
82 : 18
92 : 8
94
83
86
54
89
88
88
83
87
92
93
62
95
6-Cl
6-Br
6-NO2
8-MeO
8-EtO
5,6-benzo
6,8-Cl2
6,8-Br2
H
9
H
10
11
12
13
Me
MeO
Cl
H
3j
3k
3l
H
H
H
3m
a All the reactions were conducted in a 0.3 mmol scale in 3 mL of toluene. b The absolute configuration of adduct 3c was assigned by single X-ray
crystallography, configurations of other adducts were assigned by analogy. c Isolated yields after column chromatography purification. d Determined by
chiral HPLC analysis. e Enantiomeric excess of the anti-product.
introduced a methyl substituent to the indolic nitrogen atom, to
our delight, the reaction proceeded very well, giving the corre-
sponding product 3m in high yield with good enantioselectivity
and diastereoselectivity (Table 3, entry 13).
To further extend the scope of this methodology, we also
examined other substituted chromenes, such as 3-nitro-2-phenyl-
2H-chromene 4, and other heterocycle pyrroles (Scheme 1).
Under the optimal reaction conditions we established, 3-nitro-2-
phenyl-2H-chromene 4 reacted with indole 1a giving the desired
alkylation product in 45% yield after 3 days. The major diaster-
eomer 5 was obtained with 58% ee and 86 : 14 dr. To the best of
our knowledge, the asymmetric Friedel–Crafts alkylation of
pyrrole with chromenes has not been developed though the
racemic form has been attempted.13d To our delight, the asym-
Scheme 1 Further investigation of substrate scope.
metric Friedel–Crafts alkylation of pyrrole 6 with 3-nitro-2H-
chromene 2a proceeded smoothly and the product 7 was
obtained with 88% yield, 77% ee and 65 : 35 dr.
To determine the absolute configuration of the major isomer
of products 3a–m, a single crystal suitable for X–ray crystallo-
graphic analysis was fortunately obtained from recrystallization
of anti-3c bearing a bromine atom. As shown in Fig. 2, the
absolute configuration of the major enantiomer of anti-3c is
(3R,4S).19 On the basis of the configuration of the product and
the XRD structure of the ligand we have published before,16a,20
we postulate the proposed transition state of the reaction as illus-
trated in Fig. 3. Our catalyst works in a bifunctional form, the
NH–π interaction directs the indole attack from the back
side,16e,20 and the Lewis acid activates the chromene molecule
through coordination of the zinc cation with the two oxygen
atoms in the nitro group. The hydrogen atom is directed to the
back side to eliminate the steric repulsion between the phenyl
group and incoming indole.
Fig. 2 X-ray crystal structure of enantiopure anti-3c.
Org. Biomol. Chem., 2012, 10, 4739–4746 | 4741
This journal is © The Royal Society of Chemistry 2012

View Online
General procedure for asymmetric Friedel–Crafts alkylation of
indoles with 3-nitro-2H-chromenes
To a flame-dried Schlenk tube Zn(OTf)2 (5.5 mg, 0.015 mmol)
and ligand L2 (8.3 mg, 0.018 mmol) were added under argon,
followed by addition of toluene (3 mL). After the mixture was
stirred at room temperature for 1.5 h, 3-nitro-2H-chromene 2 or
4 (0.3 mmol) was added and the mixture was cooled to 0 °C.
After 10 min, indole 1 (0.3 mmol) was added and the mixture
was stirred at 0 °C for the corresponding time. Then the mixture
was separated directly by silica gel column chromatography with
petroleum ether–ethyl acetate (10 : 1) as eluent to afford the
desired products 3a–m or 5.
Fig. 3 Proposed transition state of the asymmetric Friedel–Crafts alky-
lation catalyzed by L2–Zn(OTf)2 complex.
Conclusions
In conclusion, the diphenylamine-linked bis(oxazoline) L2–Zn
(OTf)2 complex showed excellent performance in asymmetric
Friedel–Crafts alkylation of indoles with 3-nitro-2H-chromenes.
Moderate to high levels of reactivity, enantioselectivity, and dia-
stereoselectivity are achieved with a wide variety of indolyl
(nitro)chromans, which have a wide range of potential appli-
cations in pharmaceutical chemistry. The transition state was pro-
posed on the basis of the absolute configuration of anti-3c. This
methodology was also effective in the reaction of pyrrole with 3-
nitro-2H-chromene. Further studies on asymmetric Friedel–
Crafts alkylation of other functional nitroalkenes are underway
in our laboratory, and will be reported in due course.
3-(3-Nitrochroman-4-yl)-1H-indole (3a). The title compound
3a (the mixture of the syn and anti diastereomer) was obtained
according to the general procedure as a white solid (70.4 mg,
80% yield). It was analyzed to determine the diastereoselectivity
and enantioselectivity of the reaction (89 : 11 dr, 94% ee for the
major anti distereomer) by HPLC (Daicel Chiralpak IB column,
n-hexane–2-propanol = 95 : 5 v/v, flow rate 1.0 mL min−1, detec-
tion at 254 nm): anti diastereomer: tR (major) = 52.6 min, tR
(minor) = 33.1 min; syn diastereomer: tR = 42.8 min, 56.6 min.
The anti diastereomer was obtained by recrystallization from pet-
roleum ether–ethyl acetate. [α]2D0 +138.2 (c 0.50, CH2Cl2); m.
p. 190–193 °C; IR (KBr, cm−1): ν 3406, 3116, 3055, 2925,
2889, 1585, 1547, 1488, 1462, 1426, 1385, 1357, 1222, 1209,
1093, 747, 618, 588; 1H NMR (400 MHz, CDCl3): δ (ppm)
8.11 (s, 1H, NH), 7.45–7.40 (m, 2H, ArH), 7.26–7.10 (m, 4H,
ArH), 6.97–6.89 (m, 2H, ArH), 6.80 (s, 1H, ArH), 5.22 (d, J =
2.8 Hz, 1H, CH), 5.08 (s, 1H, CH), 4.67 (dd, J = 11.4 Hz, 4.2
Hz, 1H, CH), 4.42 (d, J = 11.6 Hz, 1H, CH); 13C NMR
(100 MHz, DMSO-d6): δ (ppm) 152.8, 136.4, 130.2, 128.0,
125.3, 121.6, 121.4, 121.3, 118.9, 118.1, 116.2, 114.6, 111.8,
82.5, 63.3, 35.7; HRMS (ESI): m/z calcd for C17H15N2O3
[M + H]+: 295.10772, found: 295.10829.
Experimental
General methods
Commercially available compounds were used without further
purification. Toluene was purified according to standard pro-
cedures. Column chromatography was performed using silica gel
(200–300 mesh). Melting points were determined on
a
1
XT-4 melting point apparatus without correction. The H NMR
spectra were measured on a Varian Mercury-plus 400 MHz spec-
trometer. Chemical shifts were recorded in ppm (δ) relative to
tetramethylsilane (TMS) as the internal standard. 13C NMR
spectra were measured at 100 MHz. Chemical shifts were
reported in ppm with the solvent resonance as internal standard
(DMSO-d6, δ = 39.43; CDCl3, δ = 77.0; CD3COCD3, δ =
30.83). Infrared spectra were obtained with a Perkin Elmer Spec-
trum One spectrometer. ESI-HRMS spectra were measured with
a Bruker APEX IV Fourier-Transform mass spectrometer.
Optical rotations were measured with a WZZ-3 polarimeter after
the products were recrystallized. Enantiomeric excesses and dia-
stereomeric ratios were determined by chiral HPLC using an
Agilent 1200 LC instrument with a Daicel Chiralpak IB, IA or
AS–H column. The absolute configuration of compound anti-3c
was determined by single crystal X-ray analysis and others were
tentatively assigned by analogy.
3-(6-Chloro-3-nitrochroman-4-yl)-1H-indole (3b). The title
compound 3b (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a pale yellow
solid (78.9 mg, 80% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (88 : 12 dr,
83% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 95 : 5 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer:
tR (major) = 26.9 min, tR (minor) = 31.3 min; syn diastereomer:
tR = 36.2 min, 48.3 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
199–203 °C; [α]D20 +106.3 (c 0.54, CH2Cl2); IR (KBr, cm−1):
ν 3404, 3111, 3063, 2925, 1582, 1549, 1480, 1458, 1358, 1264,
1
1224, 1178, 1091, 825, 747, 614; H NMR (400 MHz, CDCl3):
δ (ppm) 8.16 (s, 1H, NH), 7.47 (d, J = 8.0 Hz, 1H, ArH) 7.42
(d, J = 8.0 Hz, 1H, ArH), 7.29–7.26 (m, 2H, ArH), 7.17 (d, J =
7.6 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 6.90 (d, J = 8.8 Hz, 1H,
ArH), 6.80 (s, 1H), 5.19 (s, 1H, CH), 5.04 (s, 1H, CH), 4.69 (d,
J = 11.6 Hz, 1H, CH), 4.39 (d, J = 11.6 Hz, 1H, CH); 13C NMR
(100 MHz, CD3COCD3): δ (ppm) 154.2, 138.9, 131.7, 130.0,
127.5, 127.3, 125.5, 123.9, 121.3, 120.1, 120.0, 116.9, 113.8,
84.2, 65.6, 37.8; HRMS (ESI): m/z calcd for C17H14ClN2O3
Preparation of 3-nitro-2H-chromenes 2a–i and 4
The 3-nitro-2H-chromenes were prepared following the reported
procedures.12,21
4742 | Org. Biomol. Chem., 2012, 10, 4739–4746
This journal is © The Royal Society of Chemistry 2012

View Online
[M
+
H]+: 329.06785, found: 329.06910; calcd for
1.0 mL min−1, detection at 254 nm)): anti diastereomer:
tR (major) = 41.1 min, tR (minor) = 30.8 min; syn diastereomer:
tR = 27.5 min, 33.9 min. The anti diastereomer was obtained
by recrystallization from petroleum ether–ethyl acetate. m.p.
72–75 °C; [α]2D0 +85.4 (c 0.52, CH2Cl2); IR (KBr, cm−1): ν
3368, 2935, 2838, 1589, 1549, 1484, 1457, 1358, 1337, 1266,
1120, 1035, 1011, 910, 767, 744, 730; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.17 (s, 1H, NH), 7.44 (d, J = 7.6 Hz, 1H,
ArH), 7.37 (d, J = 8.0 Hz, 1H, ArH), 7.24–7.21 (m, 1H, ArH),
7.14–7.10 (m, 1H, ArH), 6.86–6.81 (m, 2H, ArH), 6.75 (d, J =
2.4 Hz, 1H, ArH), 6.72–6.70 (m, 1H, ArH), 5.20 (d, J = 4.0 Hz,
1H, CH), 5.06–5.03 (m, 1H, CH), 4.76–4.72 (m, 1H, CH), 4.44
(dd, J = 11.6 Hz, 2.4 Hz, 1H, CH), 3.90 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): δ (ppm) 148.0, 142.8, 136.5, 125.0, 124.8,
122.7, 122.0, 121.3, 120.1, 118.2, 115.9, 111.7, 110.0, 82.5,
63.8, 55.9, 36.1; HRMS (ESI): m/z calcd for C18H17N2O4
C17H13ClN2NaO3 [M + Na]+: 351.05069, found: 351.05094.
3-(6-Bromo-3-nitrochroman-4-yl)-1H-indole (3c). The title
compound 3c (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a white solid
(105.2 mg, 94% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (84 : 16 dr,
86% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 95 : 5 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer:
tR (major) = 27.7 min, tR (minor) = 33.0 min; syn diastereomer:
tR = 38.5 min, 49.9 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.
p. 212–214 °C; [α]D20 +80.0 (c 0.27, CH2Cl2); IR (KBr, cm−1): ν
3404, 3109, 3062, 2922, 1729, 1578, 1547, 1478, 1458, 1357,
1
[M
+
H]+: 325.11828, found: 325.11882; calcd for
1265, 1224, 1177, 1094, 822, 747, 607; H NMR (400 MHz,
C18H16N2NaO4 [M + Na]+: 347.10023, found: 347.10068.
CDCl3): δ (ppm) 8.16 (s, 1H, NH), 7.48 (d, J = 7.6 Hz, 1H,
ArH), 7.42 (d, J = 8.4 Hz, 1H, ArH), 7.32–7.26 (m, 3H, ArH),
7.18–7.15 (m, 1H, ArH), 6.85 (d, J = 8.8 Hz, 1H, ArH), 6.79 (s,
1H, ArH), 5.19 (s, 1H, CH), 5.04 (s, 1H, CH), 4.68 (dd, J =
12.0 Hz, 3.2 Hz, 1H, CH), 4.38 (d, J = 12.0 Hz, 1H, CH); 13C
NMR (100 MHz, CDCl3): δ (ppm) 152.5, 136.6, 132.9, 131.5,
124.7, 123.1, 122.7, 120.5, 118.8, 118.1, 115.9, 114.0, 111.8,
82.2, 63.5, 35.9; HRMS (ESI): m/z calcd for C17H14BrN2O3
3-(8-Ethoxy-3-nitrochroman-4-yl)-1H-indole (3f). The title
compound 3f (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a pale yellow
solid (94.1 mg, 92% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (92 : 8 dr,
88% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 18.4 min, tR (minor) = 27.5 min; syn diastereomer: tR
= 21.4 min, 25.1 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
215–218 °C; [α]2D0 +137.6 (c 1.00, CH2Cl2); IR (KBr, cm−1): ν
3436, 3133, 3091, 2980, 2924, 2896, 1584, 1551, 1486, 1458,
[M
+
H]+: 373.01823, found: 373.01856; calcd for
C17H13BrN2NaO3 [M + Na]+: 395.00018, found: 395.00058.
3-(6-Nitro-3-nitrochroman-4-yl)-1H-indole (3d). The title
compound 3d (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a white solid
(81.9 mg, 80% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (90 : 10 dr,
54% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer:
tR (major) = 21.6 min, tR (minor) = 24.8 min; syn diastereomer:
tR = 33.6 min, 40.7 min. The anti diastereomer was obtained
by recrystallization from petroleum ether–ethyl acetate. m.p.
98–100 °C; [α]2D0 +60.0 (c 0.35, CH2Cl2); IR (KBr, cm−1): ν
3412, 3061, 2923, 1620, 1589, 1551, 1517, 1487, 1458, 1343,
1
1397, 1360, 1208, 1075, 875, 824, 806, 765, 725, 748, 726; H
NMR (400 MHz, CDCl3): δ (ppm) 8.17 (s, 1H, NH), 7.43 (d, J
= 7.6 Hz, 1H, ArH), 7.38 (d, J = 8.0 Hz, 1H, ArH), 7.23 (t, J =
7.8 Hz, 1H, ArH), 7.12 (t, J = 7.4 Hz,, 1H, ArH), 6.85–6.77 (m,
3H, ArH), 6.70 (dd, J = 7.2 Hz, 1.6 Hz, 1H, ArH), 5.18 (d, J =
4.0 Hz, 1H, CH), 5.08–5.05 (m, 1H, CH), 4.73 (dd, J = 11.8 Hz,
5.0 Hz, 1H, CH), 4.46 (dd, J = 11.6 Hz, 2.4 Hz, 1H, CH), 4.12
(q, J = 6.8 Hz, 2H, OCH2), 1.49 (t, J = 6.8 Hz, 3H, CH3); 13C
NMR (100 MHz, (CD3)2CO): δ (ppm) 149.6, 145.4, 138.9,
127.2, 123.8, 123.7, 122.7, 121.2, 120.1, 117.5, 113.7, 113.3,
84.7, 65.8, 65.4, 38.0, 16.2; HRMS (ESI): m/z calcd for
C19H19N2O4 [M + H]+: 339.13393, found: 339.13459; calcd for
C19H18N2NaO4 [M + Na]+: 361.11588, found: 361.11660.
1
1259, 1236, 1093, 908, 747, 606; H NMR (400 MHz, CDCl3):
δ (ppm) 8.30 (s, 1H, NH), 8.11–8.08 (m, 2H, ArH) 7.48 (d, J =
8.0 Hz, 1H, ArH), 7.42 (d, J = 8.4 Hz, 1H, ArH), 7.29–7.24 (m,
1H, ArH), 7.19–7.15 (m, 1H, ArH), 7.06–7.04 (m, 1H, ArH),
6.70 (d, J = 2.4 Hz, 1H, ArH), 5.25 (s, 1H, CH), 5.10–5.08 (m,
1H, CH), 4.82–4.78 (m, 1H, CH), 4.43 (dd, J = 12.2 Hz, 2.0 Hz,
1H, CH); 13C NMR (100 MHz, CDCl3): δ (ppm) 158.3, 142.2,
136.6, 126.8, 124.8, 124.6, 124.3, 123.3, 121.3, 120.6, 117.8,
115.2, 112.0, 81.4, 63.6, 35.9; HRMS (ESI): m/z calcd for
C17H14N3O5 [M + H]+: 340.09280, found: 340.09301; calcd for
C17H13N3NaO5 [M + Na]+: 362.07474, found: 362.07499.
3-[2,3-Dihydro-2-nitro-1H-naphtho[2,1-b]pyran-1-yl]-1H-
indole (3g). The title compound 3g (the mixture of the syn and
anti diastereomer) was obtained according to the general pro-
cedure as a pale yellow solid (62.8 mg, 61% yield). It was ana-
lyzed to determine the diastereoselectivity and enantioselectivity
of the reaction (95 : 5 dr, 88% ee for the major anti distereomer)
by HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol
90 : 10 v/v, flow rate 1.0 mL min−1, detection at 254 nm): anti
diastereomer: tR (major) = 15.5 min, tR (minor) = 21.2 min; syn
diastereomer: tR = 19.4 min, 23.1 min. The anti diastereomer
was obtained by recrystallization from petroleum ether–ethyl
acetate. m.p. 228–232 °C; [α]2D0 +295.2 (c 0.36, CH2Cl2); IR
(KBr, cm−1): ν 3413, 3112, 3058, 2923, 1625, 1600, 1546,
3-(8-Methoxy-3-nitrochroman-4-yl)-1H-indole (3e). The title
compound 3e (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a white solid
(82.1 mg, 84% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (89 : 11 dr,
89% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak AS-H column, n-hexane–2-propanol 85 : 15 v/v, flow rate
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4739–4746 | 4743

View Online
1515, 1470, 1458, 1353, 1241, 1222, 1098, 961, 906, 814, 747;
1H NMR (400 MHz, CDCl3): δ (ppm) 8.00 (s, 1H, NH), 7.85
(d, J = 7.2 Hz, 1H, ArH), 7.77–7.71 (m, 2H, ArH), 7.59 (d, J =
7.6 Hz, 1H, ArH), 7.42–7.40 (m, 1H, ArH), 7.33–7.25 (m, 4H,
ArH), 7.13 (d, J = 8.8 Hz, 1H, ArH) 6.52 (d, J = 2.4 Hz, 1H,
ArH), 5.74 (s, 1H, CH), 5.08 (d, J = 1.6 Hz, 1H, CH), 4.90–4.85
(m, 1H, CH), 4.42 (dd, J = 12.6 Hz, 1.8 Hz,, 1H, CH); 13C
NMR (100 MHz, CDCl3): δ (ppm) 151.0, 136.5, 132.3, 129.8,
129.4, 128.5, 126.7, 125.2, 124.9, 123.8, 123.04, 122.96, 120.5,
118.4, 117.9, 116.8, 111.8, 111.3, 81.2, 61.8, 32.2; HRMS
(ESI): m/z calcd for C21H17N2O3 [M + H]+: 345.12337, found:
345.12381; calcd for C21H16N2NaO3 [M + Na]+: 367.10531,
found: 367.10554.
CH), 4.41 (dd, J = 12.0 Hz, 1.6 Hz, 1H, CH); 13C NMR
(100 MHz, CDCl3): δ (ppm) 149.2, 136.4, 134.4, 132.1, 124.8,
124.7, 123.9, 123.1, 120.5, 117.8, 115.3, 113.7, 111.9, 111.7,
81.7, 64.0, 35.9; HRMS (ESI): m/z calcd for C17H13Br2N2O3
[M + H]+: 450.92874, found: 450.92904.
5-Methyl-3-(3-nitrochroman-4-yl)-1H-indole (3j). The title
compound 3j (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a bright yellow
solid (81.4 mg, 88% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (94 : 6 dr,
92% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 11.3 min, tR (minor) = 15.4 min; syn diastereomer: tR
= 14.6 min, 19.6 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
169–173 °C; [α]2D0 +107.7 (c 0.54, CH2Cl2); IR (KBr, cm−1): ν
3412, 3117, 3032, 2927, 2882, 1586, 1547, 1487, 1462, 1450,
1383, 1357, 1216, 1178, 1119, 1094, 1040, 859, 805, 758, 616,
3-(6,8-Dichloro-3-nitrochroman-4-yl)-1H-indole (3h). The title
compound 3h (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a yellow oil
(98.3 mg, 90% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (90 : 10 dr,
83% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak AS-H column, n-hexane–2-propanol 95 : 5 v/v, flow rate
1.3 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 32.6 min, tR (minor) = 42.5 min; syn diastereomer: tR
= 45.9 min, 49.1 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
75–78 °C; [α]2D0 +79.5 (c 0.42, CH2Cl2); IR (KBr, cm−1): ν
3419, 3060, 2923, 1619, 1551, 1468, 1420, 1356, 1243, 1180,
1101, 1038, 1012, 936, 909, 865, 852, 745. 706; 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.18 (s, 1H, NH), 7.46 (d, J = 8.0
Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.31 (d, J = 2.8
Hz, 1H, ArH), 7.26–7.24 (m, 1H, ArH), 7.18–7.14 (m, 1H,
ArH), 7.04–7.03 (m, 1H, ArH), 6.74 (d, J = 2.4 Hz, 1H, ArH),
5.18 (d, J = 3.2 Hz, 1H, CH), 5.05–5.02 (m, 1H, CH), 4.79 (dd,
J = 12.2 Hz, 4.2 Hz, 1H, CH), 4.42 (dd, J = 12.0 Hz, 1.6 Hz,
1H, CH); 13C NMR (100 MHz, CDCl3): δ (ppm) 147.9, 136.5,
128.9, 128.5, 126.3, 124.75, 124.71, 123.5, 123.2, 122.6, 120.5,
117.9, 115.2, 111.9, 81.7, 63.9, 36.0; HRMS (ESI): m/z calcd for
C17H13Cl2N2O3 [M + H]+: 363.02977, found: 363.02995; calcd
1
602; H NMR (400 MHz, CDCl3): δ (ppm) 8.01 (s, 1H, NH),
7.30–7.25 (m, 2H, ArH), 7.22–7.18 (m, 1H, ArH), 7.12–7.06
(m, 2H, ArH), 6.96–6.89 (m, 2H, ArH), 6.70 (d, J = 2.4 Hz, 1H,
ArH), 5.18 (d, J = 4.0 Hz, 1H, CH), 5.07–5.04 (m, 1H, CH),
4.70–4.65 (m, 1H, CH), 4.39 (dd, J = 12.0 Hz, 2.4 Hz, 1H, CH),
2.44 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ (ppm)
153.2, 134.8, 130.5, 129.6, 128.4, 125.3, 124.9, 124.4, 121.8,
120.5, 117.7, 116.8, 115.8, 111.4, 82.6, 63.3, 36.0, 21.5; HRMS
(ESI): m/z calcd for C18H17N2O3 [M + H]+: 309.12337, found:
309.12335; calcd for C18H16N2NaO3 [M + Na]+: 331.10531,
found: 331.10536.
5-Methoxy-3-(3-nitrochroman-4-yl)-1H-indole (3k). The title
compound 3k (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure as a pale yellow
solid (89.2 mg, 92% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (91 : 9 dr,
93% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IB column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 19.7 min, tR (minor) = 21.8 min; syn diastereomer: tR
= 30.2 min, 34.7 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
146–150 °C; [α]2D0 +102.6 (c 0.57, CH2Cl2); IR (KBr, cm−1): ν
3416, 2997, 2936, 2832, 1586, 1548, 1488, 1458, 1358, 1295,
1219, 1173, 1048, 1026, 909, 802, 757, 734; 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.06 (s, 1H, NH), 7.25–7.16 (m,
2H, ArH), 7.10 (d, J = 7.6 Hz, 1H, ArH), 6.95–6.86 (m, 3H,
ArH), 6.82 (s, 1H, ArH), 6.71 (d, J = 2.0, 1H, ArH), 5.14 (d, J =
4.4 Hz, 1H, CH), 5.02–4.99 (m, 1H, CH), 4.64 (dd, J = 11.8 Hz,
5.0 Hz, 1H, CH), 4.38 (dd, J = 11.8 Hz, 2.2 Hz, 1H, CH), 3.77
(s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 154.2,
153.2, 131.5, 130.4, 128.4, 125.5, 125.4, 121.8, 120.5, 116.7,
115.6, 112.7, 112.5, 100.1, 82.7, 63.4, 55.8, 36.2; HRMS (ESI):
m/z calcd for C18H17N2O4 [M + H]+: 325.11828, found:
325.11834; calcd for C18H16N2NaO4 [M + Na]+: 347.10023,
found: 347.10017.
for C17H12Cl2N2NaO3 [M
385.01152.
+
Na]+: 385.01172, found:
3-(6,8-Dibromo-3-nitro-chroman-4-yl)-1H-indole
(3i). The
title compound 3i (the mixture of the syn and anti diastereomer)
was obtained according to the general procedure as a yellow oil
(122.8 mg, 90% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (92 : 8 dr,
87% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IB column, n-hexane–2-propanol 80 : 20 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 14.5 min, tR (minor) = 9.8 min; syn diastereomer: tR =
12.8 min, 17.3 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
95–98 °C; [α]2D0 +68.1 (c 0.41, CH2Cl2); IR (KBr, cm−1): ν
3426, 3061, 2919, 1550, 1462, 1443, 1357, 1243, 1169, 1101,
1
911, 836, 746, 679; H NMR (400 MHz, CDCl3): δ (ppm) 8.18
(s, 1H, NH), 7.60 (d, J = 2.0 Hz, 1H, ArH), 7.47 (d, J = 8.0 Hz,
1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.29–7.15 (m, 3H,
ArH), 6.72 (d, J = 2.4 Hz, 1H, ArH), 5.18 (d, J = 2.8 Hz, 1H,
CH), 5.03–5.01 (m, 1H, CH), 4.79 (dd, J = 12.0 Hz, 4.0 Hz, 1H,
5-Chloro-3-(3-nitrochroman-4-yl)-1H-indole (3l). The title
compound 3l (the mixture of the syn and anti diastereomer) was
4744 | Org. Biomol. Chem., 2012, 10, 4739–4746
This journal is © The Royal Society of Chemistry 2012

View Online
obtained according to the general procedure as a pale yellow
solid (66.9 mg, 68% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (82 : 18 dr,
62% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IA column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer:
tR (major) = 12.1 min, tR (minor) = 14.3 min; syn diastereomer:
tR = 17.0 min, 20.7 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
120–122 °C; [α]D20 +49.5 (c 0.63, CH2Cl2); IR (KBr, cm−1): ν
3426, 3397, 3123 3032, 2922, 1586, 1547, 1489, 1460, 1357,
recrystallization from hexane–ethyl acetate. m.p. 245–248 °C;
[α]2D0 −5.7 (c 0.88, CH2Cl2); IR (KBr, cm−1): ν 3414, 3055,
1
2918, 1583, 1550, 1488, 1457, 1379, 1232, 1101, 745, 710; H
NMR (400 MHz, CDCl3): δ (ppm) 8.14 (s, 1H, NH), 7.65 (d, J
= 8.0 Hz, 1H, ArH), 7.46 (d, J = 8.4 Hz, 1H, ArH), 7.33–7.28
(m, 7H, ArH), 7.21 (d, J = 7.2 Hz, 2H, ArH), 7.13 (d, J = 8.4
Hz, 1H, ArH), 7.01 (t, J = 7.2 Hz, 1H, ArH), 6.73 (d, J = 2.8
Hz, 1H, ArH), 5.37 (d, J = 2.4 Hz, 1H, CH), 5.34 (t, J = 2.4 Hz,
1H, CH), 5.02 (s, 1H, CH); 13C NMR (100 MHz, CDCl3): δ
(ppm) 154.0, 136.6, 135.7, 130.5, 128.7, 128.6, 128.5, 125.7,
125.2, 123.1, 121.8, 120.5, 120.0, 118.1, 117.7, 117.0, 111.8,
87.4, 72.6, 37.1.
1
1281, 1222, 1099, 895, 805, 759; H NMR (400 MHz, CDCl3):
δ (ppm) 8.19 (s, 1H, NH), 7.35 (d, J = 2.0 Hz, 1H, ArH),
7.31–7.29 (m, 1H, ArH), 7.21–7.17 (m, 2H, ArH), 7.06 (d, J =
6.8 Hz, 1H, ArH), 6.98–6.90 (m, 2H, ArH), 6.84 (d, J = 2.4 Hz,
1H, ArH), 5.14 (d, J = 5.2 Hz, 1H, CH), 5.04–5.00 (m, 1H,
CH), 4.67–4.62 (m, 1H, CH), 4.42 (dd, J = 11.8 Hz, 2.6 Hz, 1H,
CH); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.1, 134.9,
130.2, 128.6, 126.2, 126.1, 125.8, 123.1, 121.9, 120.2, 117.7,
116.9, 115.5, 112.8, 82.7, 63.6, 36.3; HRMS (ESI): m/z calcd
for C17H14ClN2O3 [M + H]+: 329.06875, found: 329.06861;
calcd for C17H13ClN2NaO3 [M + Na]+: 351.05069, found:
351.05063.
2-(3-Nitrochroman-4-yl)-1H- pyrrole (7). The title compound
7 (the mixture of the syn and anti diastereomers) was obtained
according to the general procedure using 3-nitro-2H-chromene
2a (0.5 mmol) and pyrrole 6 (0.5 mmol) as a brown oil
(100 mg, 88% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (65 : 35 dr,
77% ee for the major distereomer) by HPLC (Daicel Chiralpak
IA column, n-hexane–2-propanol 80 : 20 v/v, flow rate 1.0 mL
min−1, detection at 254 nm): major diastereomer: tR (major) =
6.0 min, tR (minor) = 5.2 min; minor diastereomer: tR = 8.2 min,
8.4 min. The major diastereomer was obtained by silica gel
column chromatography (petroleum ether–ethyl acetate 10 : 1).
[α]2D0 +171.3 (c 0.48, CH2Cl2); IR (KBr, cm−1): ν 3426, 3099,
2923, 1586, 1550, 1489, 1461, 1384, 1359, 1225, 1099, 1029,
1-Methyl-3-(3-nitrochroman-4-yl)-1H-indole (3m). The title
compound 3m (the mixture of the syn and anti diastereomer)
was obtained according to the general procedure as a light pink
solid (86.8 mg, 94% yield). It was analyzed to determine the dia-
stereoselectivity and enantioselectivity of the reaction (92 : 8 dr,
95% ee for the major anti distereomer) by HPLC (Daicel Chiral-
pak IB column, n-hexane–2-propanol 90 : 10 v/v, flow rate
1.0 mL min−1, detection at 254 nm): anti diastereomer: tR
(major) = 11.4 min, tR (minor) = 15.8 min; syn diastereomer: tR
= 17.5 min, 24.2 min. The anti diastereomer was obtained by
recrystallization from petroleum ether–ethyl acetate. m.p.
111–115 °C; [α]2D0 +126.2 (c 0.23, CH2Cl2); IR (KBr, cm−1): ν
3045, 3025, 2934, 2891, 1583, 1547, 1487, 1452, 1359, 1231,
1
857, 806, 756, 728; H NMR (400 MHz, CDCl3): δ (ppm) 7.97
(s, 1H, NH), 7.07 (t, J = 7.2 Hz, 1H, ArH), 6.96 (d, J = 7.6 Hz,
1H, ArH), 6.82 (d, J = 7.2 Hz, 1H, ArH), 6.79 (d, J = 7.6 Hz,
1H, ArH), 6.52 (s, 1H, ArH), 6.01 (d, J = 2.8 Hz, 1H, ArH),
5.81 (s, 1H, ArH), 4.82 (d, J = 3.2 Hz, 1H, CH), 4.75–4.72 (m,
1H, CH), 4.50 (dd, J = 12.0 Hz, 4.4 Hz, 1H, CH), 4.17 (dd, J =
12.0 Hz, 2.4 Hz, 1H, CH); 13C NMR (100 MHz, CDCl3): δ
(ppm) 153.2, 130.3, 129.9, 128.8, 121.9, 119.1, 118.2, 117.0,
109.0, 108.1, 83.4, 63.6, 37.3; HRMS (ESI): m/z calcd for
C13H13N2O3 [M + H]+: 245.09207, found: 245.09222.
1
1059, 760, 752; H NMR (400 MHz, CDCl3): δ (ppm) 7.42 (d,
J = 8.0 Hz, 1H, ArH), 7.31 (d, J = 8.0 Hz, 1H, ArH), 7.27–7.15
(m, 2H, ArH), 7.10 (t, J = 6.8 Hz, 1H, ArH), 6.94–6.87 (m, 2H,
ArH), 6.59 (s, 1H, ArH), 5.17 (d, J = 3.6 Hz, 1H, CH),
5.03–5.00 (m, 1H, CH), 4.61 (dd, J = 11.8 Hz, 4.6 Hz, 1H, CH),
4.36 (dd, J = 12.0 Hz, 2.4 Hz, 1H, CH), 3.66 (s, 3H, CH3); 13C
NMR (100 MHz, CDCl3): δ (ppm) 153.2, 137.3, 130.4, 129.2,
128.3, 125.4, 122.3, 121.7, 120.7, 119.6, 118.3, 116.7, 114.5,
109.8, 82.8, 63.4, 36.1, 32.7; HRMS (ESI): m/z calcd for
C18H17N2O3 [M + H]+: 309.12337, found: 309.12350; calcd for
C18H16N2NaO3 [M + Na]+: 331.10531, found: 331.10548.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 20772006 and
21072020), the Science and Technology Innovation Program of
Beijing Institute of Technology (Grant Nos. 2011CX01008) and
the Development Program for Distinguished Young and Middle-
aged Teachers of Beijing Institute of Technology.
Notes and references
3-(3-Nitro-2-phenylchroman-4-yl)-1H-indole (5).15b The title
compound 5 (the mixture of diastereomers) was obtained accord-
ing to the general procedure as a colorless solid (50.3 mg, 45%
yield). It was analyzed to determine the diastereoselectivity and
enantioselectivity of the reaction (86 : 14 dr, 58% ee for the
major distereomer) by HPLC (Daicel Chiralpak IB column, n-
hexane–2-propanol 90 : 10 v/v, flow rate 1.0 mL min−1, detec-
tion at 254 nm): major diastereomer: tR (major) = 14.1 min, tR
(minor) = 13.0 min; minor diastereomer: tR = 19.4 min,
22.8 min. The major diastereomer was obtained by
1 G. P. Ellis, Chemistry of Heterocyclic Compounds, Wiley, New York,
1977, vol. 31.
2 (a) R. G. Schmidt, E. K. Bayburt, S. P. Latshaw, J. R. Koenig, J.
F. Daanen, H. A. McDonald, B. R. Bianchi, C. Zhong, S. Joshi,
P. Honore, K. C. Marsh, C. H. Lee, C. R. Faltynek and A. Gomtsyan,
Bioorg. Med. Chem. Lett., 2011, 21, 1338; (b) C. Conti, L. P. Monaco
and N. Desideri, Bioorg. Med. Chem., 2011, 19, 7357.
3 (a) W. Kemnitzer, S. Kasibhatla, S. Jiang, H. Zhang, J. Zhao, S. Jia,
L. Xu, C. Crogan-Grundy, R. Denis, N. Barriault, L. Vaillancourt,
S. Charron, J. Dodd, G. Attardo, D. Labrecque, S. Lamothe,
H. Gourdeau, B. Tseng, J. Drewe and S. X. Cai, Bioorg. Med. Chem.
Lett., 2005, 15, 4745; (b) A. Afantitis, G. Melagraki, H. Sarimveis,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4739–4746 | 4745

View Online
P. A. Koutentis, J. Markopoulos and O. Igglessi-Markopoulou, Bioorg.
Med. Chem., 2006, 14, 6686.
4 T. A. Engler, K. O. LaTessa, R. Iyengar, W. Y. Chai and K. Agrios,
Bioorg. Med. Chem., 1996, 4, 1755.
5 Y. Kashiwada, K. Yamazaki, Y. Ikeshiro, T. Yamagishi, T. Fujioka,
K. Mihashi, K. Mizuki, L. M. Cosentino, K. Fowke, S. L. Morris-
Natschke and K. H. Lee, Tetrahedron, 2001, 57, 1559.
6 (a) R. Kaltenbach, S. Robinson and G. Trainor, US patent 20050267183,
2005 (Chem. Abstr. 138: 204820); (b) X. Zhang and Z. Sui, US patent
20060020018, 2006 (Chem. Abstr. 144:170999).
7 (a) M. Kidwai, S. Saxena, M. K. R. Khan and S. S. Thukral, Bioorg.
Med. Chem. Lett., 2005, 15, 4295; (b) M. M. Khafagy, A. H. F. Abd El-
Wahab, F. A. Eid and A. M. El-Agrody, Farmaco, 2002, 57, 715.
8 J. H. Kwak, H. E. Kang, J. K. Jung, H. Kim, J. Cho and H. Lee, Arch.
Pharmacal Res., 2006, 29, 728.
14 (a) M. Nyerges, A. Viranyi, G. Marth, A. Dancso, G. Blasko and
L. Toeke, Synlett, 2004, 15, 2761; (b) A. Viranyi, G. Marth, A. Dancso,
G. Blasko, L. Toke and M. Nyerges, Tetrahedron, 2006, 62, 8720;
(c) R. Muruganantham, S. M. Mobin and I. N. N. Namboothiri, Org.
Lett., 2007, 9, 1125; (d) P. M. Habib, B. R. Raju, V. Kavala, C. W. Kuo
and C. F. Yao, Tetrahedron, 2009, 65, 5799; (e) V. Y. Korotaev, V.
Y. Sosnovskikh, M. A. Barabanov, E. S. Yasnova, M. A. Ezhikova, M.
I. Kodess and P. A. Slepukhin, Tetrahedron, 2010, 66, 1404.
15 (a) C. C. Lin, J. M. Hsu, M. N. V. Sastry, H. L. Fang, Z. J. Tu, J. T. Liu
and C. F. Yao, Tetrahedron, 2005, 61, 11751; (b) P. M. Habib, V. Kavala,
B. R. Raju, C. W. Kuo, W. C. Huang and C. F. Yao, Eur. J. Org. Chem.,
2009, 26, 4503.
16 (a) S. F. Lu, D. M. Du, S. W. Zhang and J. Xu, Tetrahedron: Asymmetry,
2004, 15, 3433; (b) D. M. Du, S. F. Lu, T. Fang and J. Xu, J. Org.
Chem., 2005, 70, 3712; (c) S. F. Lu, D. M. Du, J. Xu and S. W. Zhang, J.
Am. Chem. Soc., 2006, 128, 7418; (d) S. F. Lu, D. M. Du and J. Xu, Org.
Lett., 2006, 8, 2115; (e) H. Liu, J. Xu and D. M. Du, Org. Lett., 2007, 9,
4725; (f) H. Liu, S. F. Lu, J. Xu and D. M. Du, Chem. Asian J., 2008, 3,
1111; (g) H. Liu, W. Li and D. M. Du, Sci. China, Ser. B, 2009, 52,
1321.
17 For selected recent reviews, see: (a) T. B. Poulsen and K. A. Jørgensen,
Chem. Rev., 2008, 108, 2903; (b) M. Bandini and A. Eichholzer, Angew.
Chem., Int. Ed., 2009, 48, 9608; (c) S. L. You, Q. Cai and M. Zeng,
Chem. Soc. Rev., 2009, 38, 2190; (d) V. Terrasson, R. M. de Figueiredo
and J. M. Campagne, Eur. J. Org. Chem., 2010, 2635.
9 S. Emami, A. Kebriaeezadeh, M. J. Zamani and A. Shafiee, Bioorg. Med.
Chem. Lett., 2006, 16, 1803.
10 For examples, see (a) C. J. Swain, R. Baker, C. Kneen, J. Moseley,
J. Saunders, E. M. Seward, G. Stevenson, M. Beera, J. Staton and
K. Watling, J. Med. Chem., 1991, 34, 140; (b) T. Fukuyama and X. Chen,
J. Am. Chem. Soc., 1994, 116, 3125; (c) D. J. Rawson, K. N. Dack, R.
P. Dickinson and K. James, Bioorg. Med. Chem. Lett., 2002, 12, 125;
(d) A. C. Kinsman and M. A. Kerr, J. Am. Chem. Soc., 2003, 125,
14120; (e) J. Chang-Fang, J. B. Rangisetty, M. Dukat, V. Setola,
T. Raffay, B. Roth and R. A. Glennon, Bioorg. Med. Chem. Lett., 2004,
14, 1961.
18 For selected examples of asymmetric Friedel–Crafts reaction reported by
other groups, see: (a) R. P. Herrera, V. Sgarzani, L. Bernardi and
A. Ricci, Angew. Chem., Int. Ed., 2005, 44, 6576; (b) W. Zhuang, R.
G. Hazell and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 2566;
(c) Y. X. Jia, S. F. Zhu, Y. Ying and Q. L. Zhou, J. Org. Chem., 2006, 71,
75; (d) P. K. Singh, A. Bisai and V. K. Singh, Tetrahedron Lett., 2007,
48, 1127; (e) J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed.,
2008, 47, 4016; (f) T. Arai and N. Yokoyama, Angew. Chem., Int. Ed.,
2008, 47, 4989; (g) B. M. Trost and C. Müller, J. Am. Chem. Soc., 2008,
130, 2438; (h) S. C. McKeon, H. Müller-Bunz and P. J. Guiry,
Eur. J. Org. Chem., 2009, 4833; (i) Y. F. Sheng, G. Q. Li, Q. Kang, A.
J. Zhang and S. L. You, Chem.–Eur. J., 2009, 15, 3351; ( j) J. L. Zhou,
M. C. Ye, X. L. Sun and Y. Tang, Tetrahedron, 2009, 65, 6877; (k) L.
Y. Wu, X. Q. Hao, Y. X. Xu, M. Q. Jia, Y. N. Wang, J. F. Gong and M.
P. Song, Organometallics, 2009, 28, 3369; (l) N. Yokoyama and T. Arai,
Chem. Commun., 2009, 3285; (m) Y. Hui, W. Chen, W. Wang, J. Jiang,
Y. Cai, L. Lin, X. Liu and X. Feng, Adv. Synth. Catal., 2010, 352, 3174;
(n) F. Guo, G. Lai, S. Xiong, S. Wang and Z. Wang, Chem.–Eur. J., 2010,
16, 6438; (o) J. Wu, X. Li, F. Wu and B. Wan, Org. Lett., 2011, 13, 4834.
19 Crystallographic data for major enantiomer of anti-3c has been provided
as CIF file in ESI†.
11 (a) R. Gericke, J. Harting, I. Lues and C. Schittenhelm, J. Med. Chem.,
1991, 34, 3074; (b) G. Burrell, F. Cassidy, J. M. Evans, D. Lightowler
and G. Stemp, J. Med. Chem., 1990, 33, 3023; (c) V. A. Ashwood, R.
E. Buckingham, F. Cassidy, J. M. Evans, E. A. Faruk, T. C. Hamilton, D.
J. Nash, G. Stemp and K. Willcocks, J. Med. Chem., 1986, 29, 2194.
12 (a) D. Dauzonne and R. Royer, Synthesis, 1984, 4, 348; (b) A.
N. Mamdouh, K. Rafik and G. Gerald, Synth. Commun., 1990, 20, 783;
(c) R. Koussini and A. S. Al-Shihri, Jordan J. Chem., 2008, 3, 103.
13 (a) V. Y. Korotaev, V. Y. Sosnovskikh, I. B. Kutyashev and M. I. Kodess,
Lett. Org. Chem., 2005, 2, 616; (b) V. Y. Korotaev, V. Y. Sosnovskikh, I.
B. Kutyashev and M. I. Kodess, Russ. Chem. Bull., 2006, 55, 317; (c) V.
Y. Korotaev, V. Y. Sosnovskikh, I. B. Kutyashev and M. I. Kodess, Russ.
Chem. Bull., 2006, 55, 2020; (d) V. Y. Korotaev, V. Y. Sosnovskikh and I.
B. Kutyashev, Russ. Chem. Bull., 2007, 56, 2054; (e) V. Y. Korotaev, V.
Y. Sosnovskikh, I. B. Kutyashev, A. Y. Barkov and Y. V. Shklyaev, Tetra-
hedron Lett., 2008, 49, 5376; (f) Z. P. Hu, J. M. Zhang, C. L. Lou, J.
J. Wang, S. N. Nie and M. Yan, ARKIVOC, 2010, 10, 17; (g) P. Li, L.
L. Luo, X. S. Li and J. W. Xie, Tetrahedron, 2010, 66, 7590; (h) W.
Y. Chen, O. Y. Luo, R. Y. Chen and X. S. Li, Tetrahedron Lett., 2010, 51,
3972; (i) S. Nie, Z. Hu, Y. Xuan, J. Wang, X. Li and M. Yan, Tetra-
hedron: Asymmetry, 2010, 21, 2055; ( j) W. Y. Chen, P. Li, J. W. Xie and
X. S. Li, Catal. Commun., 2011, 12, 502.
20 H. Liu, N. D. Wang and D. M. Du, Lett. Org. Chem., 2010, 7, 114.
21 C. F. Yao, M. C. Yan and Y. J. Jang, Tetrahedron Lett., 2001, 42, 2717.
4746 | Org. Biomol. Chem., 2012, 10, 4739–4746
This journal is © The Royal Society of Chemistry 2012