Asymmetric Friedel-Crafts alkylation of indoles with nitrodienes and 2-propargyloxy-β-nitrostyrenes catalyzed by diphenylamine-linked bis(oxazoline)-Zn(OTf)2 complexes

Article abstract of DOI:10.1002/ejoc.201200382

The catalytic asymmetric Friedel-Crafts reaction of indoles with nitrodienes and 2-propargyloxy-β-nitrostyrenes was systematically investigated with diphenylamine-linked bis(oxazoline)-Zn(OTf)₂ complexes. Moderate to good enantioselectivities w

Full text of DOI:10.1002/ejoc.201200382

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DOI: 10.1002/ejoc.201200382
Asymmetric Friedel–Crafts Alkylation of Indoles with Nitrodienes and
2-Propargyloxy-β-nitrostyrenes Catalyzed by Diphenylamine-Linked
Bis(oxazoline)–Zn(OTf)2 Complexes
Jiahuan Peng[a] and Da-Ming Du*[a]
Keywords: Asymmetric catalysis / Alkenes / Alkylation / Nitrogen heterocycles / Synthetic methods
The catalytic asymmetric Friedel–Crafts reaction of indoles
with nitrodienes and 2-propargyloxy-β-nitrostyrenes was
systematically investigated with diphenylamine-linked bis-
(oxazoline)–Zn(OTf)2 complexes. Moderate to good enantio-
selectivities were obtained with both kinds of substrates (up
to 89% ee for nitrodienes and up to 93% ee for β-nitrostyrene
derivatives). Further transformation of the corresponding
Friedel–Crafts alkylation product of indole with 2-proparg-
yloxy-β-nitrostyrene was carried out to give the chiral isox-
azolobenzoxepane derivative, which is of medicinal chemis-
try interest, with retained enantiomeric purity.
β-Nitrostyrenes have been successfully utilized as an alk-
ylation reagent in the asymmetric Friedel–Crafts reaction
with indoles, pyrrole, and furans in our previous stud-
ies.[3e,3h,3o,3p,5a] However, with most of the ortho-substituted
β-nitrostyrenes, enantioselectivity decreased due to unfavor-
able steric interactions. We were thus interested in studying
the influence of ortho substitution on the enantioselectivity.
Moreover, a new kind of β-nitrostyrene, bearing a propar-
gyloxy group at the ortho position, was used as the Michael
acceptor in the Michael reaction with indole (also known
as Friedel–Crafts alkylation);[8] the corresponding products
were used for the synthesis of isoxazolobenzoxepane
through intramolecular nitrile oxide cycloaddition. To the
best of our knowledge, the asymmetric version of this reac-
tion has never been reported.
Compared with organocatalysts, such as chiral Brønsted
acids and secondary amines, metal complex catalytic sys-
tems for asymmetric Friedel–Crafts reaction have exhibited
some advantages such as low catalyst loading and short re-
action time.[2] Herein, we present our results on the use of
bis(oxazoline)–Zn(OTf)2 complexes for the asymmetric
Friedel–Crafts reaction of indoles with nitrodienes and β-
nitrostyrene derivatives bearing a propargyloxy group.
Introduction
As one of the most important carbon–carbon bond-
forming reactions in organic synthesis, the asymmetric cata-
lytic Friedel–Crafts reaction has attracted growing atten-
tion.[1,2] Electron-deficient olefins, such as nitroalkenes,
have been used as good substrates in the asymmetric Frie-
del–Crafts reaction with indoles,[3] electron-rich benzenes,[4]
and five-membered aromatic heterocycles[3h,3m,4a,5] in recent
years. Nitrodienes have been investigated as Michael ac-
ceptors in a series of reactions.[6] Differing from some other
functionalized nitro olefins,[7] such as β-nitroacrolein di-
methyl acetal or 3-nitroacrylate, in addition to cyclization,
the carbon–carbon double bond of a nitrodiene can be eas-
ily converted through metathesis into other groups. Progress
has been made in the development of nitrodienes in the
asymmetric catalytic conjugate addition and Rauhut–Cur-
rier reaction.[6] However, to the best of our knowledge, only
a few studies have been reported on the catalytic asymmet-
ric Friedel–Crafts reaction of indoles with nitrodienes. In
most of these investigations, the nitrodiene was only treated
as a single nitroalkene substrate and was not submitted to
a systematic investigation. Because of the ease with which
the carbon–carbon double bond or nitro group in nitro-
dienes can be converted into other useful functional groups,
and because of the importance of the bioactive indole het-
erocycle, we believed that it was important to investigate
the asymmetric Friedel–Crafts reaction of indoles with
nitrodienes.
Results and Discussion
Our initial exploratory efforts began with the optimiza-
tion of the model reaction between indole and nitrodiene.
The results are summarized in Tables 1 and 2. A series of
chiral bis(oxazoline) ligands (1a–e) and bis(imidazoline) li-
gands (2a–e), prepared according to our previous reports
(Figure 1),[3h,3o,9] were first investigated in the reaction at
10 mol-% catalyst loading with Zn(OTf)2 as the Lewis acid
(Table 1). The bis(oxazoline) ligands 1 (Table 1, Entries 1–
[a] School of Chemical Engineering and Environment, Beijing
Institute of Technology,
Beijing 100081, China
Fax: +86-10-68914985
E-mail: dudm@bit.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200382.
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J. Peng, D.-M. Du
FULL PAPER
5) gave better enantioselectivities than the bis(imidazoline) Table 2. Optimization of the reaction conditions for the asymmetric
Friedel–Crafts alkylation of indole with nitrodiene 4a.[a]
ligands 2 (Table 1, Entries 6–10). Compared with the bis-
(imidazoline) ligand 2e, the bis(oxazoline) ligand 1e, with
trans-diphenyl substitution on the oxazoline rings, gave the
best enantioselectivity; the product was obtained with
70% ee.
Table 1. Effect of ligands on the asymmetric Friedel–Crafts alkyl-
ation of indole with nitrodiene 4a.[a]
Entry Lewis acid Solvent
T [°C]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
AgOTf
toluene room temp.
59
60
84
78
36
50
25
91
70
79
49
85
26
58
85
76
81
0
0
0
0
0
3
0
70
77
87
63
69
17
4
61
48
15
Sc(OTf)3 toluene room temp.
La(OTf)3 toluene room temp.
Yb(OTf)3 toluene room temp.
In(OTf)3 toluene room temp.
CuOTf
toluene room temp.
Cu(OTf)2 toluene room temp.
Zn(OTf)2 toluene room temp.
Zn(OTf)2 toluene
Zn(OTf)2 toluene
Zn(OTf)2 toluene
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2 CH3CN room temp.
Zn(OTf)2 CH2Cl2 room temp.
Entry
Ligand
T [°C]
Yield [%][b]
ee [%][c]
8[d]
9[d]
10
11[e]
12
13
14
15
16
17
0
–20
–20
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
88
58
67
79
91
73
80
67
64
72
65
54
32
52
70
0
25
0
0
xylene room temp.
THF room temp.
Zn(OTf)2
Zn(OTf)2 hexane room temp.
DCE room temp.
10
58
[a] Reaction conditions: 3a (0.25 mmol), 4a (0.25 mmol), toluene
(3 mL), ligand–Zn(OTf)2 complex (10 mol-%), 48 h. [b] Isolated
yield after column chromatography. [c] Determined after HPLC
analysis with Daicel Chiralpak IB column (n-hexane/2-propanol,
70:30; 1.0 mL/min). [d] The reaction time was 24 h. [e] The reaction
was performed with 5 mol-% catalyst loading.
[a] Reaction conditions: 3a (0.25 mmol), 4a (0.25 mmol), toluene
(3 mL), ligand–Zn(OTf)2 complex (10 mol-%), 24 h. [b] Isolated
yield after column chromatography. [c] Determined by HPLC
analysis with Daicel Chirlpak IB column (n-hexane/2-propanol,
70:30; 1.0 mL/min).
To further investigate the reaction conditions, ligand 1e
was chosen to explore the effect of Lewis acids and solvents
with 10 mol-% catalyst loading; the results are summarized
in Table 2. After screening of the Lewis acid, the complex
Zn(OTf)2–1e was found to be the best choice of catalyst,
affording good yield and moderate enantioselectivity. With
CuI or CuII triflates, both the yield and the enantio-
selectivity were low (Table 2, Entries 6 and 7). Use of rare-
earth triflates gave nearly no enantioselectivity (Table 2, En-
tries 2–5). To improve the enantioselectivity of this asym-
metric Friedel–Crafts alkylation, we further screened a
range of solvents, temperature, and catalyst loading. Under
the catalysis of the 1e–Zn(OTf)2 complex, a significant sol-
vent effect was observed. Toluene was the best choice
(Table 2, Entry 8). Utilizing halogenated solvents gave the
product 5a in good yields and moderate enantioselectivities
(Table 2, Entries 15 and 16). It was then found that the
enantioselectivity of the product 5a was improved slightly
Figure 1. Diphenylamine-linked bis(oxazoline) and bis(imidazol-
ine) ligands.
by lowering the reaction temperature. When the reaction of substituents were evaluated in the asymmetric Friedel–
was performed at –20 °C, 5a was obtained in 87%ee Crafts reaction with nitrodiene 4a under the optimized re-
(Table 2, entry 10). When the catalyst loading was de- action conditions. The presence of an electron-withdrawing
creased to 5 mol-%, the enantioselectivity decreased substituent such as chlorine in the 5-position of the indole
slightly, and only 49% yield was obtained (Table 2, en- ring in 3b caused a moderate decrease in enantioselectivity,
try 11).
but the yield was maintained (Table 3, Entry 2). When elec-
After optimization of the reaction conditions, the sub- tron-rich 5-methoxyindole (3d) was used, the yield of the
strate scope of the enantioselective Friedel–Crafts alkyl- product 5d was enhanced to 91%, while the enantio-
ation of indoles with nitrodienes was explored; the results selectivity decreased slightly (Table 3, Entry 4). When N-
are summarized in Table 3. First, indoles bearing a range methylindole was used, the enantioselectivity decreased
2
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Asymmetric Friedel–Crafts Alkylation of Indoles
compared with the previously reported result (Table 3, En-
try 5).[3e] A series of nitrodienes were then evaluated in the
reaction with indole 3a. When the introduced substituent
was close to the reaction position, the reactivity decreased.
In the case of methyl-substituted nitrodiene 4b (Table 3, En-
try 6), both yield and enantioselectivity decreased, probably
for electronic and steric reasons. With bromo-substituted
substrate 4c, the yield of product 5g decreased to 23%, but
Scheme 1. Reduction and determination of the absolute configura-
the enantioselectivity was retained under the optimized re- tion.
action conditions (Table 3, Entry 7). When the reaction
temperature was increased to room temperature (25 °C),
product 5g was obtained with moderate yield and enantio-
To further extend the application of bis(oxazoline) and
bis(imidazoline) ligands in asymmetric Friedel–Crafts reac-
tions, β-nitrostyrene derivatives bearing a propargyloxy
group at the ortho position were used as substrates. Based
on the previous study, the reaction proceeded smoothly
with the ligand–Zn(OTf)2 complex. The bis(oxazoline) li-
gands 1a/1e and bis(imidazoline) ligands 2a/2e, which bear
phenyl groups on the oxazoline rings, were screened for the
asymmetric Friedel–Crafts reaction of indole with β-nitro-
styrene derivative 7a.
Initially, the reaction was carried out under the catalysis
of 10 mol-% of ligand–Zn(OTf)2 complex at room tempera-
ture in toluene. When ligand 1e was used, product 8a was
obtained with excellent yield and moderate enantio-
selectivity (Table 4, Entry 2). This result was better than
those achieved with other ligands in the reaction. To in-
crease the enantioselectivity of the reaction, the tempera-
ture was reduced to 0 °C. Excellent yield and a slight in-
crease in enantioselectivity was observed (Table 4, Entry 5).
When the reaction temperature was reduced to –20 °C, the
enantioselectivity increased slightly but the conversion de-
creased significantly due to problems with solubility
(Table 4, Entry 6). Finally, the reaction was found to pro-
ceed smoothly with 10 mol-% of 1e–Zn(OTf)2 at 0 °C in
selectivity (Table 3, Entry 8). Nitrodienes with an electron-
donating group such as methoxy at the para position of
the aromatic ring gave moderate enantioselectivity (Table 3,
Entry 10). Because of the solubility problem in the case of
p-nitro-substituted substrate 4f (Table 3, Entry 11), both the
yield and enantioselectivity were low. Due to electronic ef-
fects, 4-fluoro-substituted nitrodiene 4d gave the best result;
in this case, the corresponding product 5h was obtained in
75% yield and 89% ee (Table 3, Entry 9). It was found that
the unfavorable steric interaction between PhCH=CH and
the ligand caused a decrease in enantioselectivity compared
with 1-[(E)-4-nitrobut-3-enyl]benzene used in our previous
study.[3h]
Table 3. Asymmetric Friedel–Crafts alkylation of indoles and nitro-
dienes.[a]
Entry R1
R2
R3
R4 Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
H
H
H
H
H
Cl
Me
OMe
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
Me
Br
Br
H
5a
5b
5c
5d
5e
5f
5g
5g
5h
79
76
64
91
73
56
23
71
75
87
56
81
84
47
Table 4. Opitimization of reaction conditions for the asymmetric
Friedel–Crafts alkylation of indole with nitroalkene 7a.[a]
67
85
79[d]
89
4-FC6H4
4-Me-
OC6H4
4-O2NC6H4
2-O2NC6H4
10
H
H
H
5i
38
63
11
12
H
H
H
H
H
H
5j
5k
39
73
33
80
[a] Reaction conditions: 3 (0.25 mmol), 4 (0.25 mmol), toluene
(3 mL), 1e–Zn(OTf)2 complex (10 mol-%), –20 °C, 48 h. [b] Iso-
lated yield after column chromatography. [c] Determined by HPLC
analysis with Daicel Chiralpak IA or IB column. [d] The reaction
was performed at room temperature.
Entry
Ligand
T [°C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
1a
1e
2a
2e
1e
1e
room temp.
room temp.
room temp.
room temp.
0
95
98
97
77
98
27
63
75
4
67
81
83
The absolute configuration of the product was deter-
mined through chemical correlation (Scheme 1). After re-
duction, product 5a, which was obtained with 77% ee at
0 °C (Table 2, Entry 9), was transformed into the corre-
sponding product 6, which was reported in our previous
report.[3e] The configuration of 5a was thus tentatively as-
–20
[a] Reaction conditions: 3a (0.20 mmol), 7a (0.20 mmol), toluene
(3 mL), ligand–Zn(OTf)2 complex (10 mol-%), 24 h. [b] Isolated
yield after column chromatography. [c] Determined by HPLC
analysis with a Daicel Chiralpak IB column (n-hexane/2-propanol,
signed as (R) on the basis of the sign of its optical rotation. 70:30; 1.0 mL/min).
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J. Peng, D.-M. Du
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toluene to give 8a with moderate enantioselectivity and ex-
cellent yield.
The absolute configuration of product 8g was deter-
mined to be (S) by X-ray crystallographic analysis,[10] as
With the optimum reaction conditions in hand, we ex- shown in Figure 2. The configurations of other products
plored the substrate scope for this reaction. The reaction were assigned by analogy. To demonstrate the synthetic ap-
time was extended to 48 h, because the conversions were plication of this asymmetric reaction, the transformation of
low with some substrates at 0 °C; the results are summa- product 8a (one batch with 85% ee was used) was per-
rized in Table 5. All the substrates reacted smoothly to af- formed. After one step of intramolecular nitrile oxide cyclo-
ford products 8 with good to excellent yields. An electronic addition, according to the procedure reported by Per-
effect on the enantioselectivity was observed. When elec- umal,[8] chiral isoxazolobenzoxepane 9 was obtained in
tron-withdrawing chlorine was present at the 5-position of moderate yield with retained enantiomeric excess
indole, both the enantioselectivity and the yield decreased (Scheme 2).
(Table 5, Entry 2). Regardless of the steric restriction, the
presence of an electron-rich substituent such as a methoxy
or ethoxy group in the phenyl ring caused a moderate de-
crease of both the enantioselectivity and yield (Table 5, En-
tries 9 and 10). When a substrate bearing two sterically
bulky groups such as bromine and tert-butyl groups in the
phenyl ring was used, the enantioselectivity decreased com-
pared with that obtained with chlorine-substituted sub-
strates (Table 5, Entries 12 and 13 vs. Entry 11). Other aro-
matic groups, such as naphthalene, could be employed as
the 2-substituent of the nitroethene, and the corresponding
product was obtained with moderate enantioselectivity and
excellent yield (Table 5, Entry 14). According to these ex-
perimental results, unfavorable interactions between the or-
Figure 2. X-ray crystal structure of compound 8g.
tho-substituted group and the ligand was observed, which
resulted in a decrease in the enantioselectivities compared
with our previous studies.[3e,3h]
Table 5. Asymmetric Friedel–Crafts alkylation of indoles and nitro-
alkenes.[5]
Scheme 2. Intramolecular nitrile oxide cycloaddition.
Conclusions
We have developed a catalytic asymmetric Friedel–Crafts
alkylation of indoles with two kinds of nitroalkenes using
tridentate bis(oxazoline) 1e–Zn(OTf)2 complex as catalyst.
In the case of nitrodienes, moderate to good enantio-
selectivities (up to 89% ee) of the products were obtained
in moderate yields. In the case of 2-propargyloxy-β-nitro-
styrenes, moderate to good enantioselectivities (up to 93%
ee) and good to excellent yield of products were obtained.
To the best of our knowledge, this is the first example of a
systematic investigation of the asymmetric Friedel–Crafts
alkylation of indoles with nitrodienes and 2-propargyloxy-
β-nitrostyrenes. Further transformation of the correspond-
ing Friedel–Crafts alkylation products of indoles with 2-
[a] Reaction conditions: 3 (0.20 mmol), 7 (0.20 mmol), toluene
propargyloxy-β-nitrostyrenes could be carried out to access
(3 mL), ligand–Zn(OTf)2 complex (10 mol-%), 48 h. [b] Isolated
the chiral isoxazolobenzoxepane derivatives of medicinal
yield after column chromatography. [c] Determined by HPLC
chemistry interest, which demonstrated the synthetic utility
of this enantioselective reaction.
analysis with a Daicel Chiralpak IA or IB column.
4
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Asymmetric Friedel–Crafts Alkylation of Indoles
5-Methyl-3-[(2E)-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-
indole (5c): Compound 5c was obtained according to the general
procedure as a colorless oil (49.0 mg, 64% yield). The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IA col-
umn (n-hexane/2-propanol, 90:10 v/v; flow rate 1.0 mLmin–1; de-
tection at 254 nm): tR = 14.9 (minor enantiomer), 13.4 (major en-
antiomer) min; 81% ee. [α]2D5 = +53.5 (c = 2.17 g/100 mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.99 (s, 1 H, NH), 7.42 (s, 1 H,
ArH), 7.33–7.23 (m, 6 H, ArH), 7.06–7.01 (m, 2 H, ArH), 6.58 (d,
J = 15.6 Hz, 1 H, CH=), 6.43–6.36 (m, 1 H, CH=), 4.82–4.72 (m,
2 H, CH2), 4.66 (s, 1 H, CH), 2.45 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 136.5, 134.7, 132.5, 129.3, 128.5, 127.7,
126.9, 126.4, 126.0, 124.2, 121.8, 118.3, 112.4, 111.2, 79.3, 39.4,
Experimental Section
General Methods: Commercially available compounds were used
without further purification. Solvents were dried according to stan-
dard procedures. Column chromatography was performed with sil-
ica gel (200–300 mesh). Melting points were determined with an
XT-4 melting-point apparatus and are uncorrected. 1H NMR spec-
tra were measured with a Varian Mercury-plus 400 MHz spectrom-
eter. Chemical shifts are reported in δ (ppm) units relative to tet-
ramethylsilane (TMS) as the internal standard. 13C NMR spectra
were measured at 100 MHz; chemical shifts are reported in ppm
relative to TMS with the solvent resonance as internal standard.
Infrared spectra were obtained with a Perkin–Elmer Spectrum One
spectrometer. HR mass spectra (ESI) were measured with a Bruker
APEX IV Fourier-Transform mass spectrometer. Optical rotations
were measured with a WZZ-3 polarimeter. Enantiomeric excesses
were determined by chiral HPLC using an Agilent 1200 LC instru-
ment with a Daicel Chiralpak IA or IB column.
21.5 ppm. IR (KBr): ν = 3424, 3026, 2920, 2857, 1550, 1484, 1425,
˜
1378, 1100, 967, 797, 744, 694 cm–1. HRMS (ESI): calcd. for
C19H19N2O2 [M + H]+ 307.14410; found 307.14404; calcd. for
C19H18N2NaO2 [M + Na]+ 329.12605; found 329.12595; calcd. for
C19H18KN2O2 [M + K]+ 345.09999; found 345.09998.
5-Methoxy-3-[(2E)-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-
indole (5d): Compound 5d was obtained according to the general
procedure as a colorless oil (73.0 mg, 91% yield). The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IB col-
umn (n-hexane/2-propanol, 90:10 v/v; flow rate 1.0 mLmin–1; de-
tection at 254 nm): tR = 35.9 (minor enantiomer), 33.6 (major en-
General Procedure for the Catalytic Enantioselective Friedel–Crafts
Alkylation of Indoles with Nitrodienes: Into a dried Schlenk tube
were added Zn(OTf)2 (9.3 mg, 0.025 mmol) and ligand 1e (15.3 mg,
0.025 mmol) under argon, followed by addition of toluene (3 mL).
The solution was stirred at room temperature for 2 h, and then
nitrodiene 4 (0.25 mmol) was added. The mixture was stirred for antiomer) min; 84% ee. [α]2D5 = +77.6 (c = 3.55 g/100 mL, CH2Cl2).
10 min and cooled to –20 °C before indole 3 (0.25 mmol) was
added. After stirring at –20 °C for 48 h, the solvent was removed
under vacuum. Purification by column chromatography afforded
the desired product 5.
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H, NH), 7.32–7.20 (m,
6 H, ArH), 7.06 (s, 1 H, ArH), 6.99 (d, J = 2.4 Hz, 1 H, ArH),
6.87 (dd, J = 9, 2.2 Hz, 1 H, ArH), 6.58 (d, J = 16.0 Hz, 1 H,
CH=), 6.36 (dd, J = 15.8, 7.4 Hz, 1 H, CH=), 4.82–4.69 (m, 2 H,
CH2), 4.65–4.59 (m, 1 H, CH), 3.82 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.1, 136.4, 132.4, 131.5, 128.5, 127.8,
126.9, 126.4, 126.2, 122.4, 112.6, 112.4, 112.3, 100.7, 79.1, 55.9,
3-[(2E)-1-(Nitromethyl)-3-phenyl-2-propen-1-yl]-1H-indole
(5a):
Compound 5a was obtained according to the general procedure as
a white solid (57.4 mg, 79% yield); m.p. 152–154 °C. The enantio-
meric excess was determined by HPLC with a Daicel Chiralpak IB
column (n-hexane/2-propanol, 70:30 v/v; flow rate 1.0 mLmin–1;
detection at 254 nm): tR = 13.6 (minor enantiomer), 15.4 (major
enantiomer) min; 87% ee. [α]2D5 = +45.6 (c = 2.87 g/100 mL,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H, NH), 7.65
39.3 ppm. IR (KBr): ν = 3420, 3022, 2937, 2824, 1623, 1548, 1485,
˜
1456, 1378, 1217, 1173, 967, 800, 749, 694 cm–1. HRMS (ESI):
calcd. for C19H18N2NaO3 [M + Na]+ 345.12096; found 345.12106;
calcd. for C19H18KN2O3 [M + K]+ 361.09490; found 361.09518.
1-Methyl-3-[(2E)-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-
(d, J = 8.0 Hz, 1 H, ArH), 7.38–7.32 (m, 3 H, ArH), 7.30–7.26 (m, indole (5e): Compound 5e was obtained according to the general
2 H, ArH), 7.24–7.20 (m, 2 H, ArH), 7.16–7.12 (m, 1 H, ArH), procedure as a yellow oil (55.9 mg, 73% yield). The enantiomeric
7.06 (d, J = 2.4 Hz, 1 H, ArH), 6.59 (d, J = 15.6 Hz, 1 H, CH=),
6.40 (dd, J = 15.8, 7.4 Hz, 1 H, CH=), 4.86–4.81 (m, 1 H, CH2),
excess was determined by HPLC with a Daicel Chiralpak IA col-
umn (n-hexane/2-propanol, 90:10 v/v; flow rate 1.0 mLmin–1; de-
4.79–4.74 (m, 1 H, CH2), 4.71–4.65 (m, 1 H, CH) ppm. 13C NMR tection at 254 nm): tR = 10.2 (minor enantiomer), 9.5 (major en-
(100 MHz, CDCl3): δ = 136.4, 132.6, 128.5, 127.8, 126.8, 126.4, antiomer) min; 47% ee. [α]2D5 = +29.7 (c = 2.80 g/100 mL, CH2Cl2).
125.8, 122.7, 121.6, 120.0, 118.8, 113.0, 111.5, 79.2, 39.4 ppm.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 7.2 Hz, 1 H, ArH),
7.31–7.20 (m, 7 H, ArH), 7.14–7.11 (m, 1 H, ArH), 6.94 (s, 1 H,
ArH), 6.58 (d, J = 16.0 Hz, 1 H, CH=), 6.39 (dd, J = 15.8, 7.2 Hz,
1 H), 4.83–4.64 (m, 3 H, CH2 + CH), 3.71 (s, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.2, 136.4, 132.3, 128.5, 127.7,
127.0, 126.4, 126.3, 126.2, 122.1, 119.4, 118.8, 111.3, 109.6, 79.3,
5-Chloro-3-[(2E)-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-indole
(5b): Compound 5b was obtained according to the general pro-
cedure as a yellow oil (62.1 mg, 76% yield). The enantiomeric ex-
cess was determined by HPLC with a Daicel Chiralpak IA column
(n-hexane/2-propanol, 90:10 v/v; flow rate 1.0 mLmin–1; detection
at 254 nm): tR = 14.8 (minor enantiomer), 13.7 (major enantiomer)
min; 56% ee. [α]2D5 = +10.0 (c = 3.10 g/100 mL, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 8.19 (s, 1 H, NH), 7.61 (s, 1 H, ArH), 7.33–
7.25 (m, 6 H, ArH), 7.18 (d, J = 8.4 Hz, 1 H, ArH), 7.13 (s, 1 H,
ArH), 6.585 (d, J = 16.0 Hz, 1 H, CH=), 6.36 (dd, J = 15.8, 7.4 Hz,
1 H, CH=), 4.83–4.74 (m, 2 H, CH2), 4.68–4.62 (m, 1 H, CH) ppm.
39.3, 32.7 ppm. IR (KBr): ν = 3057, 3026, 2930, 1615, 1550, 1474,
˜
1448, 1427, 1376, 1330, 1254, 1157, 967, 741, 694 cm–1. HRMS
(ESI): calcd. for C19H19N2O2 [M + H]+ 307.14410; found
307.14398; calcd. for C19H18N2NaO2 [M + Na]+ 329.12605; found
329.12593; calcd. for C19H18KN2O2 [M + K]+ 345.09999; found
345.09983.
13C NMR (100 MHz, CDCl3): δ = 136.3, 134.8, 132.9, 128.6, 127.9, 3-[(2E)-2-Methyl-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-
126.9, 126.5, 126.4, 125.8, 123.1, 123.0, 118.3, 112.9, 112.6, 79.1,
39.2 ppm. IR (KBr): ν = 3423, 3026, 2925, 2852, 1548, 1496, 1463,
indole (5f): Compound 5f was obtained according to the general
procedure as a yellow oil (42.8 mg, 56% yield). The enantiomeric
˜
1378, 1104, 966, 799, 750, 694 cm–1. HRMS (ESI): calcd. for excess was determined by HPLC with a Daicel Chiralpak IB col-
C18H15ClN2NaO2 [M + Na]+ 349.07143; found 349.07141; calcd.
for C18H15ClKN2O2 [M + K]+ 365.04536; found 365.04596.
umn (n-hexane/2-propanol, 70:30 v/v; flow rate 1.0 mLmin–1; de-
tection at 254 nm): tR = 11.6 (minor enantiomer), 15.2 (major en-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
J. Peng, D.-M. Du
FULL PAPER
antiomer) min; 67% ee. [α]2D5 = +3.1 (c = 2.00 g/100 mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H, NH), 7.68 (d, J =
8.0 Hz, 1 H, ArH), 7.36–7.28 (m, 3 H, ArH), 7.24–7.18 (m, 4 H,
8.4 Hz, 2 H, ArH), 6.53 (d, J = 16.0 Hz, 1 H, CH=), 6.26 (dd, J =
15.8, 7.4 Hz, 1 H, CH=), 4.80–4.85 (m, 1 H, CH2), 4.72–4.77 (m,
1 H, CH2), 4.62–4.68 (m, 1 H, CH), 3.78 (s, 3 H, CH3) ppm. 13C
ArH), 7.14–7.10 (m, 1 H, ArH), 7.01 (d, J = 2.4 Hz, 1 H, ArH), NMR (100 MHz, CDCl3): δ = 159.3, 136.4, 131.9, 129.2, 127.6,
6.63 (s, 1 H, CH=), 4.97–4.85 (m, 2 H, CH2), 4.67–4.63 (m, 1 H, 125.8, 124.6, 122.5, 121.6, 119.9, 118.8, 113.9, 113.1, 111.5, 79.3,
CH), 1.80 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
55.2, 39.5 ppm. IR (KBr): ν = 3419, 3034, 2957, 2926, 2838, 1707,
˜
137.3, 136.4, 135.6, 128.9, 128.1, 127.7, 126.6, 126.4, 122.6, 121.5,
1607, 1547, 1511, 1458, 1421, 1379, 1248, 1176, 1031, 968, 820,
119.9, 119.0, 112.6, 111.4, 77.7, 45.2, 15.7 ppm. IR (KBr): ν = 3422,
744 cm–1. HRMS (ESI): calcd. for C19H18N2NaO3 [M + Na]+
˜
3056, 2918, 1640, 1619, 1551, 1490, 1457, 1378, 1102, 743, 345.12096; found 345.12099; calcd. for C19H18KN2O3 [M + K]+
699 cm–1. HRMS (ESI): calcd. for C19H18N2NaO2 [M + Na]+
329.12605; found 329.12615; calcd. for C19H18KN2O2 [M + K]+
345.09999; found 345.10015.
361.09490; found 361.09512.
3-[(2E)-1-(Nitromethyl)-3-(4-nitrophenyl)-2-propen-1-yl]-1H-indole
(5j): Compound 5j was obtained according to the general procedure
as a red oil (33.2 mg, 39% yield). The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak IA column (n-hexane/
2-propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 36.9 (minor enantiomer), 30.4 (major enantiomer) min; 33%
ee. [α]2D5 = +35.7 (c = 1.45 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.25 (s, 1 H, NH), 8.12 (d, J = 8.4 Hz, 2 H, ArH),
7.63 (d, J = 8.0 Hz, 1 H, ArH), 7.44–7.39 (m, 3 H, ArH), 7.25–
7.22 (m, 1 H, ArH), 7.18–7.14 (m, 1 H, ArH), 7.12 (d, J = 2.4 Hz,
1 H, ArH), 6.65 (d, J = 16.0 Hz, 1 H, CH=), 6.59 (d, J = 15.8,
6.2 Hz, 1 H, CH=), 4.90–4.80 (m, 2 H, CH2), 4.76–4.70 (m, 1 H,
CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.0, 142.8, 136.4,
131.9, 130.6, 127.0, 125.6, 123.9, 122.8, 121.8, 120.2, 118.6, 112.0,
3-[(2E)-2-Bromo-1-(nitromethyl)-3-phenyl-2-propen-1-yl]-1H-indole
(5g): Compound 5g was obtained according to the general pro-
cedure at room temperature as a gray oil (66.2 mg, 71% yield).
The enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IA column (n-hexane/2-propanol, 85:15 v/v; flow rate
1.0 mLmin–1; detection at 254 nm): tR = 12.6 (minor enantiomer),
10.1 (major enantiomer) min; 79% ee. [α]2D5 = +26.0 (c = 3.31 g/
1
100 mL, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H,
NH), 7.65 (d, J = 8.0 Hz, 1 H, ArH), 7.51 (d, J = 7.6 Hz, 2 H,
ArH), 7.38 (d, J = 8.4 Hz, 1 H, ArH), 7.34–7.27 (m, 3 H, ArH),
7.26–7.21 (m, 1 H, ArH), 7.18–7.14 (m, 2 H, ArH), 7.13 (s, 1 H,
CH=), 5.16 (dd, J = 12.0, 8.0 Hz, 1 H, CH2), 5.02 (t, J = 7.4 Hz,
1 H, CH), 4.90 (dd, J = 12.4, 6.8 Hz, 1 H, CH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 136.1, 135.0, 131.3, 129.0, 128.2, 128.1,
125.9, 124.6, 122.7, 122.0, 120.2, 118.6, 111.5, 111.0, 77.5,
111.7, 78.8, 39.5 ppm. IR (KBr): ν = 3422, 3055, 2922, 2846, 1641,
˜
1596, 1546, 1512, 1458, 1378, 1341, 1109, 970, 827, 744 cm–1
.
HRMS (ESI): calcd. for C18H15N3NaO4 [M + Na]+ 360.09548;
found 360.09573; calcd. for C18H15KN3O4 [M + K]+ 376.06941;
found 376.06961.
47.2 ppm. IR (KBr): ν = 3428, 3056, 2924, 2854, 1552, 1491, 1458,
˜
1421, 1376, 1339, 1102, 744, 695 cm–1. HRMS (ESI): calcd. for
C18H15BrN2NaO2 [M + Na]+ 393.02091; found 393.02127; calcd.
for C18H15BrKN2O2 [M + K]+ 408.99485; found 408.99473.
3-[(2E)-1-(Nitromethyl)-3-(2-nitrophenyl)-2-propen-1-yl]-1H-indole
(5k): Compound 5k was obtained according to the general pro-
cedure as a yellow oil (61.5 mg, 73% yield). The enantiomeric ex-
cess was determined by HPLC with a Daicel Chiralpak IB column
(n-hexane/2-propanol, 70:30 v/v; flow rate 1.0 mLmin–1; detection
at 254 nm): tR = 17.7 (minor enantiomer), 19.3 (major enantiomer)
3-[(2E)-3-(4-Fluorophenyl)-1-(nitromethyl)-2-propen-1-yl]-1H-indole
(5h): Compound 5h was obtained according to the general pro-
cedure as a yellow oil (58.2 mg, 75% yield). The enantiomeric ex-
cess was determined by HPLC with a Daicel Chiralpak IA column
(n-hexane/2-propanol, 90:10 v/v; flow rate 1.0 mLmin–1; detection
at 254 nm): tR = 20.7 (minor enantiomer), 19.2 (major enantiomer)
min; 89% ee. [α]2D5 = +39.5 (c = 2.75 g/100 mL, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 8.12 (s, 1 H, NH), 7.64 (d, J = 7.2 Hz, 1
H, ArH), 7.36 (d, J = 7.6 Hz, 1 H, ArH), 7.27–7.20 (m, 3 H, ArH),
7.16–7.12 (m, 1 H, ArH), 7.05 (s, 1 H, ArH), 6.95 (t, J = 8.8 Hz,
1 H, ArH), 6.54 (d, J = 16.0 Hz, 1 H, CH=), 6.30 (dd, J = 15.8,
1
min; 80% ee. [α]2D5 = +9.6 (c = 3.00 g/100 mL, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 8.22 (s, 1 H, ArH), 7.91 (d, J = 8.0 Hz, 1
H, ArH), 7.67 (d, J = 6.8 Hz, 1 H, ArH), 7.49 (s, 2 H, ArH), 7.38–
7.34 (m, 2 H, ArH), 7.24–7.07 (m, 4 H, ArH, CH=), 6.33 (dd, J =
15.6, 7.2 Hz, 1 H, CH=), 4.87–4.79 (m, 2 H, CH2), 4.74–4.70 (m,
1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.4, 136.4,
133.2, 132.5, 132.3, 129.1, 128.3, 128.2, 125.7, 124.5, 122.6, 121.9,
120.0, 118.6, 112.0, 111.6, 78.8, 39.2 ppm. IR (KBr): ν = 3419,
˜
7.4 Hz, 1 H, CH=), 4.83–4.72 (m, 2 H, CH2), 4.69–4.63 (m, 1 H,
3060, 2922, 2854, 1705, 1606, 1552, 1520, 1458, 1423, 1379, 1344,
101, 965, 786, 742 cm–1. HRMS (ESI): calcd. for C18H15N3NaO4
[M + Na]+ 360.09548; found 360.09519; calcd. for C18H15KN3O4
[M + K]+ 376.06941; found 376.06898.
1
CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.3 (d, JC,F
=
4
3
245.5 Hz), 136.40, 132.6 (d, JC,F = 3.1 Hz), 131.4, 128.0 (d, JC,F
= 7.9 Hz), 126.6 (d, JC,F = 2.0 Hz), 125.7, 122.7, 121.6, 120.0,
118.7, 115.4 (d, JC,F = 21.5 Hz), 112.8, 111.6, 79.2, 39.4 ppm. IR
2
3-[1-(Nitromethyl)-3-phenylpropyl]-1H-indole (6):[3e] To a solution
of 5a (45 mg, 0.15 mmol, 77%ee) in methanol (3 mL) was added
10% palladium on charcoal (163 mg, 0.015 mmol). The reaction
mixture was stirred under hydrogen for 1 h and then filtered. After
concentration under reduced pressure, the residue was purified by
(KBr): ν = 3420, 3038, 2912, 1640, 1619, 1547, 1508, 1457, 1378,
˜
1226, 1158, 967, 815, 744 cm–1. HRMS (ESI): calcd. for
C18H16FN2O2 [M + H]+ 311.11903; found 311.11884; calcd. for
C18H15FN2NaO2 [M + Na]+ 333.10098; found 333.10089.
3-[(2E)-3-(4-Methoxyphenyl)-1-(nitromethyl)-2-propen-1-yl]-1H- column chromatography to afford a yellow oil (37 mg, 84% yield).
indole (5i): Compound 5i was obtained according to the general
procedure as a yellow oil (30.5 mg, 38% yield). The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IB col-
umn (n-hexane/2-propanol, 70:30 v/v; flow rate 1.0 mLmin–1; de-
tection at 254 nm): tR = 23.3 (minor enantiomer), 24.7 (major en-
antiomer) min; 63% ee. [α]2D5 = +35.8 (c = 1.23 g/100 mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H, NH), 7.65 (d, J =
The enantiomeric excess was determined by HPLC with a Daicel
C h i r a l p a k I B c o l u m n ( n - h e x a n e / 2 - p ro p a n o l , 7 0 : 3 0
v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 10.9 (minor
enantiomer), 10.1 (major enantiomer) min; 78% ee. [α]2D5 = +24.0
(c = 1.88 g/100 mL). 1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1
H, NH), 7.60 (d, J = 7.6 Hz, 1 H, ArH), 7.37 (d, J = 8.0 Hz, 1 H,
ArH), 7.27–7.03 (m, 8 H, ArH), 4.69–4.60 (m, 2 H, CH2), 3.82–
7.2 Hz, 1 H, ArH), 7.36 (d, J = 7.6 Hz, 1 H), 7.20–7.27 (m, 3 H, 3.78 (m, 1 H, CH), 2.63–2.50 (m, 2 H, CH2), 2.25–2.08 (m, 2 H,
ArH), 7.12–7.16 (m, 1 H, ArH), 7.06 (s, 1 H, ArH), 6.82 (d, J = CH2) ppm.
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
Asymmetric Friedel–Crafts Alkylation of Indoles
General Procedure for the Catalytic Enantioselective Friedel–Crafts
Alkylation of Indoles with β-Nitrostyrene Derivatives: Into a dried
Schlenk tube were added Zn(OTf)2 (7.3 mg, 0.02 mmol) and ligand
1e (12.2 mg, 0.02 mmol) under argon, followed by addition of tolu-
ene (3 mL). The solution was stirred at room temperature for 2 h,
then nitroalkene 7 (0.20 mmol) was added. The mixture was stirred
for 10 min and cooled to 0 °C before indole 3 (0.20 mmol) was
added. After stirring at 0 °C for 48 h, the solvent was removed un-
der vacuum. Purification by column chromatography afforded the
desired product 8.
C
20H19N2O3 [M + H]+ 335.13902; found 335.13987; calcd. for
C20H18N2NaO3 [M + Na]+ 357.12096; found 357.12173.
5-Methoxy-3-{2-nitro-1-[2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-in-
dole (8d): Obtained according to the general procedure as a color-
less oil (66.8 mg, 95% yield). The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IA column (n-hexane/2-
propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 19.3 (minor enantiomer), 17.6 (major enantiomer) min; 84%
ee. [α]2D5 = –13.3 (c = 2.76 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.02 (s, 1 H, NH), 7.23–7.19 (m, 1 H, ArH), 7.17 (d,
J = 8.8 Hz, 1 H, ArH), 7.12 (dd, J = 1.6, 7.6 Hz, 1 H, ArH), 7.06
(d, J = 2.4 Hz, 1 H, ArH), 7.01 (dd, J = 0.8, 8.4 Hz, 1 H, ArH),
6.90–6.85 (m, 1 H, ArH), 6.81 (dd, J = 2.4, 8.8 Hz, 1 H, ArH),
5.53 (dd, J = 6.8, 8.8 Hz, 1 H, CH), 5.03 (dd, J = 12.8, 6.8, 1 H,
CH2), 4.95 (dd, J = 12.4, 9.2 Hz, 1 H, CH2), 4.77 (d, J = 2.4 Hz,
2 H, CH2), 3.76 (s, 3 H, CH3), 2.51 (t, J = 2.4 Hz, 1 H, CHϵ)
ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8, 153.9, 131.4, 129.1,
128.5, 127.8, 126.8, 122.5, 121.7, 113.3, 112.5, 112.4, 111.9, 100.9,
3-{2-Nitro-1-[2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-indole (8a): Ob-
tained according to the general procedure as a yellow oil (62.6 mg,
98 % yield). The enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IA column (n-hexane/2-propanol, 80:20
v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 10.4 (minor
enantiomer), 8.8 (major enantiomer) min; 81% ee. [α]2D5 = –50.4 (c
1
= 3.13 g/100 mL, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.04
(s, 1 H, NH), 7.47 (d, J = 8.0 Hz, 1 H, ArH), 7.30 (d, J = 8.4 Hz,
1 H, ArH), 7.24–7.10 (m, 4 H, ArH), 7.07–7.00 (m, 2 H, ArH),
6.87 (t, J = 7.6 Hz, 1 H, ArH), 5.58 (t, J = 8.0 Hz, 1 H, CH), 5.05
(dd, J = 12.4, 6.8 Hz, 1 H, CH2), 4.95 (dd, J = 12.6, 9.0 Hz, 1 H,
78.4, 78.0, 75.8, 56.0, 55.8, 35.4 ppm. IR (KBr): ν = 3426, 3289,
˜
2932, 1584, 1551, 1486, 1456, 1439, 1378, 1289, 1217, 1174, 1107,
1025, 922, 801, 755 cm–1. HRMS (ESI): calcd. for C20H19N2O4 [M
+ H]+ 351.13393; found 351.13345.
CH2), 4.78 (s, 2 H, CH2), 2.52 (t, J = 2.2 Hz, 1 H, CHϵ) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 154.8, 136.3, 129.2, 128.5, 127.8,
126.4, 122.4, 122.0, 121.7, 119.6, 119.0, 113.5, 112.4, 111.2, 78.4,
1-Methyl-3-{2-nitro-1-[2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-
indole (8e): Obtained according to the general procedure as a color-
less oil (65.5 mg, 98% yield). The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IA column (n-hexane/2-
propanol, 95:5 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 14.0 (minor enantiomer), 12.8 (major enantiomer) min; 74%
ee. [α]2D5 = –42.9 (c = 3.52 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.48 (d, J = 8.0 Hz, 1 H, ArH), 7.28 (d, J = 8.0 Hz, 1
H, ArH), 7.24–7.18 (m, 2 H, ArH), 7.15 (dd, J = 1.6, 7.6 Hz, 1 H,
ArH), 7.07–7.00 (m, 3 H, ArH), 6.88 (t, J = 7.4 Hz, 1 H, ArH),
5.57 (dd, J = 7.0, 9.0 Hz, 1 H, CH), 5.05 (dd, J = 12.4, 6.8 Hz, 1
H, CH2), 4.98 (dd, J = 12.4, 8.8 Hz, 1 H, CH2), 4.84–4.74 (m, 2
H, CH2), 3.74 (s, 3 H, CH3), 2.53 (t, J = 2.4 Hz, CHϵ) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.8, 137.1, 129.2, 128.4, 128.0,
126.9, 126.7, 121.9, 121.7, 119.2, 112.4, 111.9, 109.6, 109.3, 78.4,
78.0, 75.8, 56.0, 35.6 ppm. IR (KBr): ν = 3427, 3290, 3060, 2922,
˜
1600, 1551, 1489, 1457, 1421, 1378, 1219, 1106, 1023, 747 cm–1.
HRMS (ESI): calcd. for C19H16N2NaO3 [M + Na]+ 343.10531;
found 343.10578.
5-Chloro-3-{2-nitro-1-[2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-indole
(8b): Obtained according to the general procedure as a colorless oil
(63.2 mg, 89% yield). The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IA column (n-hexane/2-propanol,
90:10 v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 18.4
(minor enantiomer), 16.7 (major enantiomer) min; 65% ee. [α]2D5
=
1
–9.8 (c = 2.87 g/100 mL, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 8.14 (s, 1 H, NH), 7.43 (d, J = 1.2 Hz, 1 H, ArH), 7.26–7.17 (m,
3 H, ArH), 7.11–7.02 (m, 3 H, ArH), 6.89 (t, J = 7.4 Hz, 1 H,
ArH), 5.53 (dd, J = 6.4, 9.2 Hz, 1 H, CH), 5.02 (dd, J = 12.8,
6.4 Hz, 1 H, CH2), 4.95 (dd, J = 12.4, 9.6 Hz, 1 H, CH2), 4.86–
4.77 (m, 2 H, CH2), 2.55 (t, J = 2.4 Hz, 1 H, CHϵ) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.6, 134.6, 129.0, 128.7, 127.5,
127.4, 125.4, 123.2, 122.8, 121.8, 118.5, 113.4, 112.5, 112.3, 78.2,
78.1, 75.7, 56.0, 35.7, 32.8 ppm. IR (KBr): ν = 3291, 3060, 2924,
˜
2122, 1713, 1586, 1557, 1488, 1456, 1373, 1223, 1158, 1106, 1018,
927, 812, 743 cm–1.
3-{1-[5-Chloro-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H-indole
(8f): Obtained according to the general procedure as a yellow oil
(56 mg, 79% yield). The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IA column (n-hexane/2-propanol,
80:20 v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 10.8
77.9, 76.0, 56.0, 35.3 ppm. IR (KBr): ν = 3433, 3292, 2924, 1551,
˜
1489, 1458, 1377, 1219, 1105, 1021, 799, 754 cm–1. HRMS (ESI):
calcd. for C19H16ClN2O3 [M + H]+ 355.08440; found 355.08383.
5-Methyl-3-{2-nitro-1-[2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-
indole (8c): Obtained according to the general procedure as a color-
less oil (65.7 mg, 98% yield). The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IB column (n-hexane/2-
propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 11.9 (minor enantiomer), 10.7 (major enantiomer) min; 84%
ee. [α]2D5 = –30.1 (c = 2.92 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.92 (s, 1 H, NH), 7.27 (s, 1 H, ArH), 7.23–7.16 (m,
2 H, ArH), 7.13–7.11 (m, 1 H, ArH), 7.03–6.97 (m, 3 H, ArH),
6.87 (t, J = 7.6 Hz, 1 H, ArH), 5.55 (dd, J = 6.8, 8.8 Hz, 1 H, CH),
5.03 (dd, J = 12.8, 6.8, 1 H, CH2), 4.95 (dd, J = 12.6, 9.0 Hz, 1 H,
CH2), 4.78 (d, J = 2.4 Hz, 2 H, CH2), 2.51 (t, J = 2.4 Hz, 1 H,
CHϵ), 2.38 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
154.8, 134.6, 129.2, 128.9, 128.4, 127.9, 126.6, 124.0, 122.1, 121.7,
(minor enantiomer), 8.7 (major enantiomer) min; 90% ee. [α]2D5
=
1
–21.6 (c = 2.12 g/100 mL, CH2Cl2). H NMR (400 MHz, CDCl3):
δ = 8.09 (s, 1 H, NH), 7.46 (d, J = 8.0 Hz, 1 H, ArH), 7.32 (d, J
= 8.4 Hz, 1 H, ArH), 7.20–7.16 (m, 2 H, ArH), 7.11–7.05 (m, 3 H,
ArH), 6.95 (d, J = 8.8 Hz, 1 H, ArH), 5.56 (t, J = 7.8 Hz, 1 H,
CH), 4.98 (dd, J = 12.6, 6.6 Hz, 1 H, CH2), 4.93 (dd, J = 12.6,
9.0 Hz, 1 H, CH2), 4.82–4.73 (m, 2 H, CH2), 2.53 (t, J = 2.4 Hz, 1
H, CHϵ) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3, 136.2,
129.9, 129.1, 128.3, 126.7, 126.2, 122.6, 121.8, 119.8, 118.8, 113.8,
112.8, 111.3, 77.9, 77.7, 76.2, 56.3, 35.2 ppm. IR (KBr): ν = 3436,
˜
3292, 3059, 2922, 1551, 1484, 1458, 1421, 1378, 1223, 1126, 1021,
809, 746 cm–1. HRMS (ESI): calcd. for C19H15ClN2NaO3 [M +
Na]+ 377.06634; found 377.06702.
118.5, 112.9, 112.3, 110.9, 78.4, 78.0, 75.8, 56.0, 35.5, 21.4 ppm. IR 3-{1-[5-Bromo-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H-indole
(KBr): ν = 3431, 3291, 3032, 2919, 2863, 1551, 1489, 1456, 1423, (8g): Obtained according to the general procedure as a white solid
˜
1378, 1219, 1106, 1022, 798, 755 cm–1. HRMS (ESI): calcd. for (74.3 mg, 93% yield); m.p. 128–132 °C. The enantiomeric excess
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
J. Peng, D.-M. Du
FULL PAPER
was determined by HPLC with a Daicel Chiralpak IA column (n-
hexane/2-propanol, 80:20 v/v; flow rate 1.0 mLmin–1; detection at
254 nm): tR = 10.2 (minor enantiomer), 8.4 (major enantiomer)
at 254 nm): tR = 12.3 (minor enantiomer), 10.1 (major enantiomer)
min; 67% ee. [α]2D5 = –63.7 (c = 2.62 g/100 mL, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 8.07 (s, 1 H, NH), 7.55 (d, J = 8.0 Hz, 1
H, ArH), 7.29 (d, J = 8.4 Hz, 1 H, ArH), 7.15 (t, J = 7.4 Hz, 1 H,
min; 90% ee. [α]2D5 = –2.7 (c = 4.41 g/100 mL, CH2Cl2). H NMR
1
(400 MHz, CDCl3): δ = 8.11 (s, 1 H, NH), 7.46 (d, J = 7.6 Hz, 1 ArH), 7.08–7.02 (m, 2 H, ArH), 6.93 (t, J = 8.0 Hz, 1 H, ArH),
H, ArH), 7.34–7.31 (m, 2 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.12 6.80–6.73 (m, 2 H, ArH), 5.70 (dd, J = 7.2, 8.8 Hz, 1 H, CH), 5.06
(d, J = 2.4 Hz, 1 H, ArH), 7.09–7.05 (m, 1 H, ArH), 6.91 (d, J = (dd, J = 12.8, 6.8 Hz, 1 H, CH2), 5.01 (dd, J = 13.0, 9.4 Hz, 1
8.8 Hz, 1 H, ArH), 5.56 (t, J = 7.8 Hz, 1 H, CH), 4.98 (dd, J = H,CH2), 4.85 (dd, J = 15.6, 2.4 Hz, 1 H, CH2), 4.76 (dd, J = 15.6,
12.6, 7.0 Hz, 1 H, CH2), 4.94 (dd, J = 12.8, 8.8 Hz, 1 H, CH2), 2.4 Hz, 1 H, CH2), 4.04 (q, J = 6.8 Hz, 2 H, CH2), 2.47 (t, J =
4.82–4.73 (m, 2 H, CH2), 2.54 (t, J = 2.4 Hz, 1 H, CHϵ) ppm. 13
NMR (100 MHz, CDCl3): δ = 153.8, 136.2, 131.9, 131.3, 130.3,
C
2.4 Hz, 1 H, CHϵ), 1.44 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 151.8, 144.4, 136.3, 133.2, 126.4, 124.5,
126.2, 122.6, 121.8, 119.8, 118.8, 114.23, 114.16, 112.8, 111.3, 122.3, 121.7, 120.2, 119.6, 119.3, 114.0, 112.4, 111.2, 79.6, 78.3,
77.81, 77.75, 76.3, 56.3, 35.1 ppm. IR (KBr): ν = 3437, 3292, 3059, 75.5, 64.2, 59.9, 35.7, 14.8 ppm. IR (KBr): ν = 3422, 3290, 3058,
˜
˜
2923, 1551, 1483, 1458, 1421, 1377, 1222, 1120, 1021, 807, 2980, 2934, 1584, 1551, 1468, 1421, 1377, 1278, 1190, 1095, 1063,
745 cm–1. HRMS (ESI): calcd. for C19H16BrN2O3 [M + H]+
399.03388; found 399.03467; calcd. for C19H15BrN2NaO3 [M +
Na]+ 421.01583; found 421.01635.
996, 744 cm–1. HRMS (ESI): calcd. for C21H21N2O4 [M + H]+
365.14958; found 365.15038; calcd. for C21H20N2NaO4 [M + Na]+
387.13153; found 387.13235.
3-{1-[3,5-Dichloro-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H-
indole (8k): Obtained according to the general procedure as a yel-
low oil (71.0 mg, 91% yield). The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IA column (n-hexane/2-
propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 9.1 (minor enantiomer), 8.5 (major enantiomer) min; 89% ee.
[α]2D5 = –44.5 (c = 3.48 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.14 (s, 1 H, NH), 7.54 (d, J = 8.0 Hz, 1 H, ArH),
7.34 (d, J = 8.4 Hz, 1 H, ArH), 7.29 (d, J = 2.8 Hz, 1 H, ArH),
7.20 (t, J = 7.6 Hz, 1 H, ArH), 7.12–7.06 (m, 3 H, ArH), 5.73 (t,
J = 7.8 Hz, 1 H, CH), 5.01 (dd, J = 12.8, 7.2 Hz, 1 H, CH2), 4.97
(dd, J = 12.8, 8.8 Hz, 1 H, CH2), 4.81 (dABq, J = 15.6, 2.4 Hz, 2
H, CH2), 2.57 (t, J = 2.6 Hz, 1 H, CHϵ) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.6, 136.4, 136.3, 130.3, 129.6, 128.9,
127.2, 125.9, 122.8, 121.8, 120.0, 118.8, 112.6, 111.4, 78.1, 77.7,
3-{2-Nitro-1-[5-nitro-2-(2-propyn-1-yloxy)phenyl]ethyl}-1H-indole
(8h): Obtained according to the general procedure as a red oil
(72.9 mg, 99% yield). The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IA column (n-hexane/2-propanol,
80:20 v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 17.2
(minor enantiomer), 14.5 (major enantiomer) min; 93% ee. [α]2D5
=
1
–2.3 (c = 2.96 g/100 mL, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 8.23 (s, 1 H, NH), 8.15 (dd, J = 2.8, 9.2 Hz, 1 H, ArH), 8.04 (d,
J = 2.8 Hz, 1 H, ArH), 7.43 (d, J = 7.6 Hz, 1 H, ArH), 7.36 (d, J
= 8.0 Hz, 1 H, ArH), 7.22–7.18 (m, 2 H, ArH), 7.12 (d, J = 9.2 Hz,
1 H, ArH), 7.08 (t, J = 7.6 Hz, 1 H, ArH), 5.65 (t, J = 7.8 Hz, 1
H, CH), 5.01 (d, J = 8.0 Hz, 1 H, CH2), 4.92 (d, J = 2.0 Hz, 1 H,
CH2), 2.62 (t, J = 2.4 Hz, 1 H, CHϵ) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.5, 142.1, 136.3, 129.5, 126.0, 124.9, 124.8, 122.8,
121.9, 120.0, 118.5, 112.3, 112.2, 111.5, 77.5, 77.2, 76.8, 56.8,
77.0, 61.0, 35.7 ppm. IR (KBr): ν = 3438, 3294, 3074, 2925, 2125,
˜
34.9 ppm. IR (KBr): ν = 3421, 3291, 3060, 2925, 1589, 1553, 1516,
˜
1706, 1555, 1457, 1434, 1377, 1340, 1253, 1211, 1161, 1104, 987,
867, 841, 764, 746 cm–1. HRMS (ESI): calcd. for C19H15Cl2N2O3
[M + H]+ 389.04542; found 389.04439.
1487, 1457, 1423, 1378, 1341, 1263, 1231, 1100, 1011, 747 cm–1.
HRMS (ESI): calcd. for C19H16N3O5 [M + H]+ 366.10845; found
366.10937.
3-{1-[3,5-Dibromo-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H-
indole (8l): Obtained according to the general procedure as a purple
oil (81.1 mg, 85% yield). The enantiomeric excess was determined
by HPLC with a Daicel Chiralpak IA column (n-hexane/2-propa-
3-{1-[3-Methoxy-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H-
indole (8i): Obtained according to the general procedure as a color-
less oil (64.6 mg, 92% yield). The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IA column (n-hexane/2-
propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm):
tR = 15.6 (minor enantiomer), 13.5 (major enantiomer) min; 68%
ee. [α]2D5 = –65.9 (c = 2.50 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.06 (s, 1 H, NH), 7.55 (d, J = 8.0 Hz, 1 H, ArH),
7.28 (d, J = 8.0 Hz, 1 H, ArH), 7.15 (t, J = 7.6 Hz, 1 H, ArH),
7.06–7.02 (m, 2 H, ArH), 6.96 (t, J = 7.6 Hz, 1 H, ArH), 6.81–6.75
(m, 2 H, ArH), 5.71 (t, J = 7.8 Hz, 1 H, CH), 5.06 (dd, J = 12.6,
7.0 Hz, 1 H, CH2), 4.94 (dd, J = 12.8, 8.8 Hz, 1 H, CH2), 4.77
(dAB quartet, J = 15.6, 2.4 Hz, 2 H, CH2), 3.82 (s, 3 H, CH3), 2.47
(t, J = 2.4 Hz, 1 H, CHϵ) ppm. 13C NMR (100 MHz, CDCl3): δ
= 152.6, 144.3, 136.3, 133.3, 126.4, 124.6, 122.4, 121.7, 120.3, 119.6,
119.2, 114.0, 111.5, 111.2, 79.5, 78.3, 75.6, 60.0, 55.7, 35.6 ppm. IR
nol, 85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR
=
9.6 (minor enantiomer), 8.9 (major enantiomer) min; 64 % ee.
[α]2D5 = –25.5 (c = 3.48 g/100 mL, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.14 (s, 1 H, NH), 7.61 (d, J = 2.4 Hz, 1 H, ArH),
7.54 (d, J = 8.0 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH),
7.25 (d, J = 2.4 Hz, 1 H, ArH), 7.22–7.18 (m, 1 H, ArH), 7.12–
7.06 (m, 2 H, ArH), 5.74 (t, J = 8.0 Hz, 1 H, CH), 5.03–4.94 (m,
2 H, CH2), 4.82 (dd, J = 15.2, 2.4 Hz, 1 H, CH2), 4.76 (dd, J =
15.6, 2.4 Hz, 1 H, CH2), 2.58 (t, J = 2.4 Hz, 1 H, CHϵ) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.3, 136.9, 136.3, 135.2, 130.8,
125.9, 122.8, 121.9, 120.0, 118.9, 118.4, 118.2, 112.7, 111.4, 78.1,
77.7, 77.0, 61.2, 35.8 ppm. IR (KBr): ν = 3433, 3293, 3062, 2926,
˜
1552, 1457, 1426, 1376, 1339, 1214, 1144, 1103, 987, 864, 745 cm–1.
HRMS (ESI): calcd. for C19H15Br2N2O3 [M + H]+ 476.94439;
found 476.94329.
(KBr): ν = 3422, 3290, 3058, 2939, 2839, 1585, 1551, 1476, 1459,
˜
1438, 1377, 1278, 1200, 1177, 1089, 1069, 994, 745 cm–1. HRMS
(ESI): calcd. for C20H19N2O4 [M + H]+ 351.13393; found
351.13325.
3-{1-[3,5-Di-tert-butyl-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-
1H-indole (8m): Obtained according to the general procedure as
3-{1-[3-Ethoxy-2-(2-propyn-1-yloxy)phenyl]-2-nitroethyl}-1H- a colorless oil (69.7 mg, 81% yield). The enantiomeric excess was
indole (8j): Obtained according to the general procedure as a white
solid (66.4 mg, 91% yield); m.p. 145–149 °C. The enantiomeric ex-
cess was determined by HPLC with a Daicel Chiralpak IA column
(n-hexane/2-propanol, 85:15 v/v; flow rate 1.0 mLmin–1; detection
determined by HPLC with a Daicel Chiralpak IA column (n-hex-
ane/2-propanol, 95:5 v/v; flow rate 1.0 mL min–1; detection at
254 nm): tR = 12.0 (minor enantiomer), 10.6 (major enantiomer)
min; 36% ee. [α]2D5 = +31.2 (c = 5.86 g/100 mL, CH2Cl2). 1H NMR
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
Asymmetric Friedel–Crafts Alkylation of Indoles
(400 MHz, CDCl3): δ = 8.11 (s, 1 H, NH), 7.70 (d, J = 8.0 Hz, 1
H, ArH), 7.33 (d, J = 8.0 Hz, 1 H, ArH), 7.33 (d, J = 8.0 Hz, 1 H,
ArH), 7.29 (d, J = 2.4 Hz, 1 H, 1 H, ArH), 7.24–7.18 (m, 2 H,
ArH), 7.13 (t, J = 7.4 Hz, 1 H, ArH), 6.93 (d, J = 1.2 Hz, 1 H,
ArH), 5.65 (t, J = 8.0 Hz, 1 H, CH), 5.04 (dd, J = 12.6, 7.8 Hz, 1
H, CH2), 4.96 (dd, J = 12.4, 8.4 Hz, 1 H, CH2), 4.51 (dd, J = 15.0,
2.2 Hz, 1 H, CH2), 4.42 (dd, J = 15.2, 2.4 Hz, 1 H, CH2), 2.53 (t,
Acknowledgments
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 No. 2011CX01008) and the
Development Program for Distinguished Young and Middle-aged
Teachers of Beijing Institute of Technology.
J = 2.0 Hz, CHϵ), 1.42 (s, 9 H, CH3), 1.26 (s, 9 H, CH3) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 153.3, 146.6, 142.9, 136.5, 131.7,
126.1, 123.8, 123.1, 122.60, 122.57, 119.9, 118.9, 114.40, 111.38,
79.0, 75.6, 62.2, 35.4, 35.0, 34.6, 31.34, 31.28 ppm. IR (KBr): ν =
˜
[1]
[2]
G. A. Olah, R. Krishnamurti, G. K. S. Prakash, in Comprehen-
sive Organic Synthesis (Eds.: B. M. Trost, I. Fleming), 1st ed.,
Pergamon Press, Oxford, 1991, vol. 3, pp. 293–339.
3425, 3292, 3058, 2963, 2870, 1553, 1475, 1458, 1442, 1376, 1364,
1219, 1119, 998, 742 cm–1. HRMS (ESI): calcd. for C27H33N2O3
[M + H]+ 433.24857; found 433.24742.
For selected reviews on asymmetric Friedel–Crafts reaction,
see: a) K. A. Jøgensen, Synthesis 2003, 1117–1125; b) M. Band-
ini, A. Melloni, A. Umani-Ronchi, Angew. Chem. 2004, 116,
560; Angew. Chem. Int. Ed. 2004, 43, 550–556; c) M. Bandini,
A. Melloni, A. Umani-Ronchi, Synlett 2005, 1199–1222; d)
T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–
2915; e) M. Bandini, A. Eichholzer, Angew. Chem. 2009, 121,
9786; Angew. Chem. Int. Ed. 2009, 48, 9608–9644; f) S.-L. You,
Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201; g) M.
Zeng, S.-L. You, Synlett 2010, 1289–1301; h) V. Terrasson,
R. M. de Figueiredo, J. M. Campagne, Eur. J. Org. Chem. 2010,
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mol. Chem. 2005, 3, 2566–2571; c) Y.-X. Jia, S.-F. Zhu, Y. Yang,
Q.-L. Zhou, J. Org. Chem. 2006, 71, 75–80; d) M. Bandini, A.
Garelli, M. Rovinetti, M. Tommasi, A. Umani-Ronchi, Chiral-
ity 2005, 17, 522–529; e) S.-F. Lu, D.-M. Du, J. Xu, Org. Lett.
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non, Tetrahedron Lett. 2006, 47, 7037–7042; g) P. K. Singh, A.
Bisai, V. K. Singh, Tetrahedron Lett. 2007, 48, 1127–1129; h)
H. Liu, S.-F. Lu, J. X. Xu, D.-M. Du, Chem. Asian J. 2008, 3,
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3-{2-Nitro-1-[2-(2-propyn-1-yloxy)naphthalen-1-yl]ethyl}-1H-indole
(8n): Obtained according to the general procedure as a colorless oil
(73.3 mg, 99% yield). The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IA column (n-hexane/2-propanol,
85:15 v/v; flow rate 1.0 mLmin–1; detection at 254 nm): tR = 19.6
(minor enantiomer), 14.7 (major enantiomer) min; 82% ee. [α]2D5
=
1
–20.0 (c = 2.02 g/100 mL, CH2Cl2). H NMR (400 MHz, CDCl3):
δ = 8.32 (d, J = 8.8 Hz, 1 H, ArH), 7.98 (s, 1 H, NH), 7.78–7.76
(m, 2 H, ArH), 7.53–7.46 (m, 2 H, ArH), 7.36 (t, J = 7.4 Hz, 1 H,
ArH), 7.31–7.22 (m, 2 H, ArH), 7.131–7.09 (m, 2 H, ArH), –6.99
(t, J = 7.6 Hz, 1 H, ArH), 6.19 (t, J = 7.6 Hz, 1 H, CH), 5.43 (dd,
J = 12.6, 7.4 Hz, 1 H, CH2), 5.36 (dd, J = 12.8, 7.6 Hz, 1 H, CH2),
4.73 (dd, J = 15.6, 2.4 Hz, 1 H, CH2), 4.64 (dd, J = 15.8, 2.2 Hz,
1 H, CH2), 2.48 (t, J = 2.2 Hz, CHϵ) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.6, 135.9, 132.7, 130.0, 129.8, 128.9, 127.2, 126.4,
124.0, 122.9, 122.5, 122.1, 121.1, 119.7, 118.7, 114.7, 114.0, 111.2,
[3]
78.41, 78.36, 75.9, 56.8, 33.8 ppm. IR (KBr): ν = 3433, 3290, 3057,
˜
2923, 1622, 1596, 1547, 1512, 1458, 1421, 1377, 1261, 1218, 1088,
1012, 805, 744 cm–1. HRMS (ESI): calcd. for C23H19N2O3 [M +
H]+ 371.13902; found 371.13988; calcd. for C23H18N2NaO3 [M +
Na]+ 393.12096; found 393.12183.
Experimental Procedure for the Synthesis of Isoxazolobenzoxepane
9: Nitroalkane 8a (0.125 mmol) and DMAP (0.025 mmol) were dis-
solved in toluene (3 mL). Di-tert-butyl dicarbonate (0.312 mmol)
in toluene (3 mL) was added in portions at 90 °C to the nitroalkane
solution over a period of 0.5 h. The reaction was allowed to pro-
ceed for a further 2 h, then the mixture was concentrated, and the
product was purified by column chromatography to afford a yellow
oil (18.8 mg, 37% yield). The enantiomeric excess was determined
by HPLC with a Daicel Chiralpak IA column (n-hexane/2-prop-
anol, 90:10 v/v; flow rate 0.8 mLmin–1; detection at 254 nm): tR
=
13.3 (minor enantiomer), 8.1 (major enantiomer) min; 84 % ee.
[4]
a) T.-Y. Liu, H.-L. Cui, Q. Chai, J. Long, B.-J. Li, Y. Wu, L.-
S. Ding, Y.-C. Chen, Chem. Commun. 2007, 2228–2230; b) Y.
Sohtome, B. Shin, N. Horitsugi, R. Takagi, K. Noguchi, K.
Nagasawa, Angew. Chem. 2010, 122, 7457; Angew. Chem. Int.
Ed. 2010, 49, 7299–7303; c) H. Zhang, Y.-H. Liao, W.-C. Yuan,
X.-M. Zhang, Eur. J. Org. Chem. 2010, 3215–3218.
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B. M. Trost, C. Mueller, J. Am. Chem. Soc. 2008, 130, 2438–
2439; c) Y.-F. Sheng, Q. Gu, A.-J. Zhang, S.-L. You, J. Org.
Chem. 2009, 74, 6899–6901.
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Chem. 2009, 121, 5297; Angew. Chem. Int. Ed. 2009, 48, 5195–
5198; b) S. Belot, A. Quintard, N. Krause, A. Alexakis, Adv.
Synth. Catal. 2010, 352, 667–695; c) H. Ma, K. Liu, F.-G.
Zhang, C.-L. Zhu, J. Nie, J.-A. Ma, J. Org. Chem. 2010, 75,
1402–1409; d) P. Shanbhag, P. R. Nareddy, M. Dadwal, S. M.
Mobin, N. N. Namboothiri, Org. Biomol. Chem. 2010, 8, 4867–
4873; e) Z.-B. Li, S.-P. Luo, Y. Guo, A.-B. Xia, D.-Q. Xu, Org.
Biomol. Chem. 2010, 8, 2505–2508.
1
[α]2D5 = –78.9 (c = 1.88 g/100 mL). H NMR (400 MHz, CDCl3): δ
= 8.15 (s, 1 H, ArH), 8.05 (d, J = 7.2 Hz, 1 H, ArH), 7.64 (d, J =
8.0 Hz, 1 H, ArH), 7.39 (dd, J = 1.6, 7.4 Hz, 1 H, ArH), 7.36 (s, 1
H, ArH), 7.34–7.27 (m, 2 H, ArH), 7.20–7.12 (m, 3 H, ArH), 5.72
(s, 1 H, CH), 5.29 (d, J = 14.8 Hz, 1 H, CH2), 4.94 (d, J = 14.8 Hz,
1 H, CH2), 1.63 (s, 9 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 201.6, 160.4, 157.6, 153.1, 133.0, 130.1, 129.7, 129.4, 125.2,
124.6, 124.3, 123.2, 122.5, 119.8, 119.3, 116.1, 115.2, 109.9, 83.7,
[5]
[6]
65.1, 38.7, 28.1 ppm. IR (KBr): ν = 2977, 1732, 1601, 1488, 1452,
˜
1419, 1371, 1255, 1154, 1075, 1018, 860, 746 cm–1. HRMS (ESI):
calcd. for C24H23N2O4 [M + H]+ 403.16523; found 403.16513;
calcd. for C24H22N2NaO4 [M + Na]+ 425.14718; found 425.14734;
calcd. for C24H22KN2O4 [M + K]+ 441.12112; found 441.12130.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the HPLC chromatograms, 1H and 13C NMR spec-
tra of all new products.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
J. Peng, D.-M. Du
FULL PAPER
[7] a) S. L. Zhu, S. Y. Yu, D. Ma, Angew. Chem. Int. Ed. 2008, 47,
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Perumal, Tetrahedron Lett. 2010, 51, 3006–3009.
[9] a) S.-F. Lu, D.-M. Du, S.-W. Zhang, J. Xu, Tetrahedron: Asym-
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[10]
CCDC-871943 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: March 27, 2012
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20382
/KAP1
Date: 05-06-12 18:16:15
Pages: 11
Asymmetric Friedel–Crafts Alkylation of Indoles
Asymmetric Catalysis
J. Peng, D.-M. Du* ........................ 1–11
Asymmetric Friedel–Crafts Alkylation of
Indoles with Nitrodienes and 2-Proparg-
yloxy-β-nitrostyrenes Catalyzed by Di-
phenylamine-Linked
(OTf)2 Complexes
Bis(oxazoline)–Zn-
Keywords: Asymmetric catalysis / Alkenes /
Alkylation / Nitrogen heterocycles / Syn-
thetic methods
The catalytic asymmetric Friedel–Crafts
reaction of indoles with nitrodienes and 2-
propargyloxy-β-nitrostyrenes was investi-
gated with diphenylamine-linked bis(ox-
azoline)–Zn(OTf)2 complexes. Moderate to
good enantioselectivities were obtained
with both kinds of substrate (up to 89%
ee for nitrodienes and up to 93% ee for β-
nitrostyrene derivatives).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11