Enantioselective friedel-crafts alkylation of indoles with aromatic αβ-unsaturated aldehydes catalyzed by diphenylprolinol silyl Ether

Article abstract of DOI:10.1055/s-0029-1217038

A catalytic enantioselective Friedel-Crafts alkylation of indoles with aromatic α,β-unsaturated aldehydes has been developed. The process is promoted by (S)-diphenylprolinol trimethyl silyl ether to afford, after sodium borohydride mediated reduction, 3in

Full text of DOI:10.1055/s-0029-1217038

3994
PAPER
Enantioselective Friedel–Crafts Alkylation of Indoles with Aromatic
a,b-Unsaturated Aldehydes Catalyzed by Diphenylprolinol Silyl Ether
E
nantioselective
h
Friedel–Cr
i
afts
A
lk
-
ylation
J
of Indolesing Wang,a Jian-Guo Yang,b Jun Jin,a Xin Lv,a Weiliang Bao*a
a
Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, P. R. of China
Fax +86(571)88273814; E-mail: wlbao@css.zju.edu.cn
b
Office of Assets Administration, Taizhou University, Linhai 317000, P. R. of China
Received 15 June 2009; revised 30 July 2009
hydes is not well documented. There is, so far, only one
example of the Friedel–Crafts reaction of N-methyl indole
with cinnamaldehyde,5,6c and no reaction of 1H-indole
with cinnamaldehyde has been reported. The NH moiety
Abstract: A catalytic enantioselective Friedel–Crafts alkylation of
indoles with aromatic a,b-unsaturated aldehydes has been devel-
oped. The process is promoted by (S)-diphenylprolinol trimethyl si-
lyl ether to afford, after sodium borohydride mediated reduction, 3-
indolyl-3-phenylpropanols in high enantioselectivities and good on the indole has significant influence on its reactivity and
yields.
1H-indoles and N-alkyl indoles show different reactivities
in many cases. In some reactions, 1H-indoles were more
reactive than N-alkyl indoles,8b,10 while in others, N-alkyl
indoles were superior to 1H-indoles. In the enantioselec-
tive addition of indole to N-acyl imines reported by
Antilla and co-workers, 1H-indole provided lower yields
and enantioselectivities than N-alkyl indole.9c Due to the
difference between 1H-indoles and N-alkyl indoles, the
enantioselective Friedel–Crafts alkylation of 1H-indoles
with aromatic a,b-unsaturated aldehydes is of signifi-
cance.
Key words: organocatalysis, enantioselectivity, Friedel–Crafts
alkylation, indoles, aromatic a,b-unsaturated aldehydes
The Friedel–Crafts reaction of aromatic compounds is one
of the most important reactions for the formation of C–C
bonds and direct derivatization of aromatic compounds in
organic synthesis.1 Various aromatic compounds, includ-
ing benzenes with electron-donating substituents, furans,
pyrroles and indoles, have been successfully applied in a
number of Friedel–Crafts reactions with electrophiles.
The indole framework represents a privileged structural
motif of established value in biologically active natural
products and pharmaceutical compounds.2 In this regard,
the enantioselective Friedel–Crafts reaction of indoles is
one of the most extensive areas of research. Catalytic
enantioselective versions of this fundamental transforma-
tion have been reported, most of which use metal-based
chiral complex catalysts.3 Recently, asymmetric organo-
catalysis has attracted considerable attention in terms of
its unique properties,4 and there have been several reports
of asymmetric Friedel–Crafts reactions of indole deriva-
tives with organocatalysts. In 2002, MacMillan and co-
workers first reported the asymmetric Friedel–Crafts re-
action of indoles and N-alkyl indoles with alkyl a,b-unsat-
urated aldehydes using chiral imidazolidinones as
catalysts, and demonstrated the feasibility of organocata-
lytic strategies based on LUMO-lowering activation of
a,b-unsaturated aldehydes via the reversible formation of
an iminium ion.5 Since then, a variety of catalytic asym-
metric reactions of indoles with electrophiles including
alkyl a,b-unsaturated aldehydes,6 nitroalkenes,7 a,b-un-
saturated ketones,8 imines,9 trifluoropyruvate,10 and elec-
tron-rich alkenes11 have been reported.
The products from a,b-unsaturated aldehydes are more
versatile than those from nitroalkenes and a,b-unsaturated
ketones, and the 1H-indole derivatives could easily under-
go further derivatization on the nitrogen atom. Therefore,
the enantioselective Friedel–Crafts reactions of 1H-in-
doles and a,b-unsaturated aldehydes would afford poten-
tially useful 3-substituted indole derivatives.
Diarylprolinol silyl ethers, which were first utilized as ef-
ficient asymmetric catalysts by Jørgensen in 2005,12a have
now been shown to be excellent organocatalysts for a
wide variety of asymmetric reactions.12–16 However, to the
best of our knowledge, its application to catalytic enanti-
oselective Friedel–Crafts alkylation has not been report-
ed. Herein, we would like to report the catalytic
enantioselective Friedel–Crafts reaction of indoles with
aromatic a,b-unsaturated aldehyde derivatives catalyzed
by diphenylprolinol silyl ether (Scheme 1).
The proposed enantioselective Friedel–Crafts reaction
was first examined using indole (2a), cinnamaldehyde
(3a), and 15 mol% of (S)-1 at room temperature in tolu-
ene. The desired Friedel–Crafts reaction product 4a was
obtained, which was reduced by sodium borohydride in
situ to the corresponding g-alcohol 5a with moderate yield
and enantioselectivity (50%, 57% ee). Addition of benzo-
ic acid did not improve the result (Table 1, entry 2). Vari-
ous solvents were then screened and, as shown in Table 1,
it is noteworthy that not only the catalytic yield but also
the asymmetric induction were highly dependent on the
solvents employed. Among the solvents tested, polar pro-
tic methanol was found to be the best with respect to both
However, the catalytic enantioselective Friedel–Crafts
alkylation of indoles with aromatic a,b-unsaturated alde-
SYNTHESIS 2009, No. 23, pp 3994–4000
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217038; Art ID: F12009SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Friedel–Crafts Alkylation of Indoles
3995
Ph
Ph
OTMS
Ph
N
O
O
H
(S)-1
+
H
H
Ph
N
H
HN
3a
2a
4a
Scheme 1 Enantioselective Friedel–Crafts reaction of indole with cinnamaldehyde
the catalytic activity and the asymmetric induction entries 1–10). Cinnamaldehydes with electron-withdraw-
(Table 1, entry 5). As expected, enantiomeric excess in- ing groups (4-Br, 4-Cl, 4-F, 4-CF3, 3-CF3, 3-Cl, and 2-Cl)
creased with a decrease in reaction temperature, reaching reacted efficiently with indole 2a and gave good yields as
83% ee at –10 °C, and good yield was attained after 96 h well as excellent enantioselectivities (Table 2, entries 2–
(Table 1, entry 14). After screening of the loading of the 8). The electron-donating groups (4-Me, 4-MeO, and 2-
catalyst, 20 mol% was selected as the optimal amount. MeO) on the aromatic ring of cinnamaldehyde were toler-
Thus, 5a was formed in the presence of 20 mol% of the ated, but had a negative influence on the the yield
catalyst (S)-1, in methanol at –10 °C, with 87% yield and (Table 2, entries 9–10). The Friedel–Crafts alkylation of
86% ee, respectively (Table 1, entry 15).
electron-rich indoles (2b–e) afforded the corresponding
products 5k–n with good results (Table 2, entries 11–14).
Electron-deficient indoles (5-NO2) caused a decrease in
the yield (Table 2, entry 15). As a limitation of the ap-
proach, it is worth mentioning that substitution in the
a-position (a-methyl) of the cinnamaldehyde and the
Under the above optimized reaction conditions (Table 1,
entry 15), the generality of the reaction was investigated;
the results are summarized in Table 2. All substituted cin-
namaldehydes tested were converted with very high levels
of stereocontrol into the expected products 5a–j (Table 2
Table 1 Optimization of the Reaction Conditionsa
Ph
OH
O
1) (S)-1 (cat.), solvent
+
H
Ph
2) excess NaBH4, MeOH
0 °C, 20 min
N
H
N
H
2a
3a
5a
Entry
Solvent
toluene
toluene
CHCl3
CH2Cl2
MeOH
EtOH
Time (h)
36
Temp (°C)
Cat. (mol%)
Yield (%)b
ee (%)c
57
1
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
15
15
15
15
15
15
15
15
15
10
15
20
10
15
20
50
40
44
42
65
42
46
33
trace
67
70
76
72
75
87
36
50d
70
3
36
4
36
60
5
36
73
6
36
49
7
MeCN
THF
36
72
8
36
63
9
DMF
36
n.d.e
77
10
11
12
13
14
15
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
72
72
0
80
72
0
82
96
–10
–10
–10
81
96
83
96
86
a Reaction conditions: indole (1.0 mmol), cinnamaldehyde (0.5 mmol), catalyst (S)-1 (15 mol%) and solvent (1.0 mL).
b Isolated yield.
c Enantiomeric excess was determined by chiral HPLC analysis.
d Benzoic acid (15 mol%) was added as a co-catalyst.
e Not determined.
Synthesis 2009, No. 23, 3994–4000 © Thieme Stuttgart · New York

3996
Z. J. Wang et al.
PAPER
Table 2 Catalytic Asymmetric Friedel–Crafts Reaction of Substituted Indoles and Cinnamaldehydesa
R2
OH
1) (S)-1 (20 mol%), MeOH
O
–10 °C, 96 h
R1
R1
+
H
R2
2) excess NaBH4, MeOH
0 °C, 20 min
N
H
N
H
2a–f
3a–j
5a–o
Entry
1
R1
R2
Product
5a
Yield (%)b
ee (%)c
86
H (2a)
Ph (3a)
87
79
74
79
72
75
70
79
56
63
70
74
75
77
60
2
H (2a)
4-BrC6H4 (3b)
4-ClC6H4 (3c)
4-FC6H4 (3d)
4-F3CC6H4 (3e)
3-F3CC6H4 (3f)
3-ClC6H4 (3g)
2-ClC6H4 (3h)
4-MeC6H4 (3i)
4-MeOC6H4 (3j)
Ph (3a)
5b
5c
91
3
H (2a)
86
4
H (2a)
5d
5e
87
5
H (2a)
86
6
H (2a)
5f
93
7
H (2a)
5g
89
8
H (2a)
5h
5i
95
9
H (2a)
86
10
11
12
13
14
15
H (2a)
5j
87
5-MeO (2b)
6-MeO (2c)
5-Me (2d)
7-Me (2e)
5-O2N (2f)
5k
5l
88
Ph (3a)
87
Ph (3a)
5m
5n
5o
87
Ph (3a)
94
Ph (3a)
86
a Reaction conditions: 2 (1.0 mmol), 3 (0.5 mmol), (S)-1 (0.10 mmol), MeOH (1.0 mL).
b Isolated yield.
c Enantiomeric excess was determined by chiral HPLC analysis.
4-position (4-Me and 4-COOMe) of the indole ring had a For the determination of the absolute configuration of the
detrimental effect on reactivity. The NH-moiety on the in- catalytic product 5a, we designed a route as shown in
dole ring could not be blocked. For example, N-methyl in- Scheme 2. From the comparison of its optical rotation
dole did not react with cinnamaldehyde. This feature has with that of (S)-8a, which was synthesized by the reaction
already been observed in other organocatalytic Friedel– of cinnamaldehyde with 1-methylindole catalyzed by
Crafts reactions of indoles believed to proceed via a dual chiral imidazolidinones,5 the absolute configuration of 5a
activation mechanism.7a,10 Alkyl a,b-unsaturated alde- was determined to be 3S.
hydes such as crotonaldehyde seemed unreactive under
our catalytic conditions.
In summary, we have developed a highly enantioselective
Friedel–Crafts reaction of indoles with aromatic a,b-un-
saturated aldehydes using diphenylprolinol silyl ether as
the organocatalyst. It could be a good complementary ap-
proach to MacMillan’s protocol. The reaction is applica-
ble to a variety of aromatic a,b-unsaturated aldehydes and
indoles, and high enantioselectivities are attained. The ap-
proach avoids the use of any additional acid or base, and
the products are potentially useful. Further investigations
into synthetic applications of the method are underway.17
Ph
O
OMe
OMe
Ph
(MeO)3CH
H
p-TSA, MeOH
HN
HN
4a
6a
Me I
KOH, CH2Cl2
OMe
OMe
Ph
Ph
O
HCl, THF–H2O
H
Commercial reagents were used as received, unless otherwise stat-
ed. The organocatalyst (S)-1 was prepared following the procedure
described in the literature. Racemates of 1 were prepared using ra-
cemic diphenylprolinol TMS-ether as the catalyst. All 1H NMR and
13C NMR spectra were measured in CDCl3 on a Bruker Avance 400
N
N
8a
7a
Me
Me
Scheme 2 The absolute configuration of the product 5a was deter-
mined as S by correlation to 8a
Synthesis 2009, No. 23, 3994–4000 © Thieme Stuttgart · New York

PAPER
Enantioselective Friedel–Crafts Alkylation of Indoles
3997
MHz instrument with TMS as the internal standard. Chemical shifts
are expressed in ppm and J values are given in Hz. Data for 1H NMR
are reported as follows: chemical shift (ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet) and
integral. Data for 13C NMR are reported as ppm. MS was obtained
using EI ionization on an HP6989B mass spectrometer. HRMS was
obtained using ESI ionization on an Apex III (7.0 tesla) Fourier
transform ion cyclotron resonance (FTICR) mass spectrometer.
Melting points are uncorrected. Optical rotations were measured
using a 1 mL cell with a 1 dm path length on a Perkin–Elmer 341
digital polarimeter and are reported as follows: [a]D20 (c in g per 100
mL of solvent). HPLC analysis was performed using Daicel
Chiralpak AD-H and OD-H columns.
J = 7.6 Hz, 1 H), 7.00–7.05 (m, 2 H), 4.38 (t, J = 7.6 Hz, 1 H), 3.60–
3.71 (m, 2 H), 2.40–2.47 (m, 1 H), 2.17–2.26 (m, 1 H), 1.37 (br s,
1 H).
13C NMR (100 MHz, CDCl3): d = 38.5 (2 × C), 61.0, 111.1, 119.2,
119.3, 119.4, 121.0, 122.2, 126.7, 128.5, 129.2, 131.7, 136.6, 143.3.
EI-MS: m/z = 285 [M+; 35Cl], 287 [M+; 37Cl].
Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C,
71.36; H, 5.69; N, 4.82.
5d
20
Pale-yellow oil; [a]D –3.8 (c = 1.27, CHCl3); 87% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 24.8 min; tminor = 18.4 min).
Indole Addition to a,b-Unsaturated Aldehydes (Table 2, Entry
1); Typical Procedure
1H NMR (400 MHz, CDCl3): d = 8.05 (br s, 1 H), 7.38 (d, J = 8.0
Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.20–7.23 (m, 2 H), 7.13 (t,
J = 7.6 Hz, 1 H), 7.00 (t, J = 7.4 Hz, 1 H), 6.89–6.95 (m, 3 H), 4.34
(t, J = 7.6 Hz, 1 H), 3.56–3.66 (m, 2 H), 2.36–2.44 (m, 1 H), 2.13–
2.20 (m, 1 H), 1.68 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.3, 38.6, 61.0, 111.1, 115.0,
115.2, 119.3, 119.4, 121.0, 122.1, 126.7, 129.2 (d, J = 7.4 Hz),
136.5, 140.4 (d, J = 2.3 Hz), 161.3 (d, J = 242.2 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C17H16FNONa: 292.1108;
found: 292.1104.
EI-MS: m/z = 269 [M+].
To catalyst (S)-1 (32 mg, 0.10 mmol, 20 mol%) dissolved in MeOH
(1 mL) in a 12 mL vial at –10 °C, was added cinnamaldehyde (66
mg, 0.5 mmol). The mixture was stirred for 30 min, and indole (117
mg, 1.0 mmol) was added to the mixture. The vial was capped and
the mixture was stirred at –10 °C for 96 h. Excess NaBH4 (57 mg,
1.5 mmol) was added, followed by the addition of MeOH (1 mL).
The –10 °C cooling bath was replaced by an ice bath, and the mix-
ture was stirred for a further 20 min. The mixture was slowly added
to sat. NH4Cl (5 mL) at 0 °C and extracted with Et2O (10 × 3 mL).
The organic layer was collected, washed with H2O (5 mL) and brine
(5 mL), then dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc–hexane, 1:1) to afford 5a.
5e
20
Pale-yellow oil; [a]D +5.6 (c 0.8, CHCl3); 86% ee by HPLC
(Daicel Chiralpak OD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 36.5 min; tminor = 56.0 min).
(S)-3-(1H-indol-3-yl)-3-phenylpropan-1-ol (5a)
Yield: 109 mg (87%); colorless oil; [a]D20 +4.0 (c 0.8, CHCl3); 86%
ee by HPLC (Daicel Chiralpak OD-H column; n-hexane–i-PrOH,
90:10; flow rate: 1.0 mL/min; tmajor = 44.6 min; tminor = 57.8 min).
1H NMR (400 MHz, CDCl3): d = 8.15 (br s, 1 H), 7.53 (d, J = 8.0
Hz, 2 H), 7.43 (d, J = 8.4 Hz, 3 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.19
(t, J = 7.6 Hz, 1 H), 7.02–7.07 (m, 2 H), 4.49 (t, J = 7.6 Hz, 1 H),
3.61–3.72 (m, 2 H), 2.44–2.52 (m, 1 H), 2.22–2.31 (m, 1 H), 1.65
(br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.3, 38.8, 60.8, 111.2, 118.5,
119.2, 119.5, 121.2, 122.3, 125.3 (q, J = 4.0 Hz), 125.6 (t, J = 280.5
Hz), 128.1, 128.2, 136.5, 149.0.
HRMS (ESI): m/z [M + Na]+ calcd for C18H16F3NONa: 342.1076;
found: 342.1079.
EI-MS: m/z = 319 [M+].
1H NMR (400 MHz, CDCl3): d = 8.00 (br s, 1 H), 7.43 (d, J = 7.6
Hz, 1 H), 7.22–7.31 (m, 5 H), 7.14 (dd, J = 8.8, 7.6 Hz, 2 H), 6.98–
7.02 (m, 2 H), 4.37 (t, J = 7.8 Hz, 1 H), 3.60–3.67 (m, 2 H), 2.40–
2.49 (m, 1 H), 2.21–2.30 (m, 1 H), 1.44 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.6, 39.2, 61.3, 110.1, 119.3,
119.5, 119.6, 121.1, 122.0, 126.1, 126.8, 127.8, 128.4, 136.5, 144.7.
EI-MS: m/z = 251 [M+].
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.77. Found: C,
81.13; H, 6.86; N, 5.47.
5f
5b
20
Pale-red oil; [a]D20 –12.0 (c 1.0, CHCl3); 91% ee by HPLC (Daicel
Chiralpak OD-H column; n-hexane–i-PrOH, 90:10; flow rate: 1.0
mL/min; tmajor = 43.8 min; tminor = 66.0 min).
Pale-yellow oil; [a]D +7.2 (c 2.2, CHCl3); 93% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 11.3 min; tminor = 10.8 min).
1H NMR (400 MHz, CDCl3): d = 8.15 (br s, 1 H), 7.62 (s, 2 H), 7.50
(d, J = 7.6 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.33–7.38 (m, 2 H),
7.19 (t, J = 7.6 Hz, 1 H), 7.04–7.08 (m, 2 H), 4.91 (t, J = 7.8 Hz,
1 H), 3.60–3.71 (m, 2 H), 2.43–2.52 (m, 1 H), 2.22–2.32 (m, 1 H),
1.79 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.4, 38.8, 60.8, 111.2, 118.5,
119.1, 119.4, 121.2, 122.2, 123.0 (q, J = 3.8 Hz), 124.2 (q, J = 270.8
Hz), 124.4 (q, J = 3.8 Hz), 126.6, 128.3, 131.3 (2 × C), 136.5, 145.9.
HRMS (ESI): m/z [M + Na]+ calcd for C18H16F3NONa: 342.1076;
found: 342.1072.
1H NMR (400 MHz, CDCl3): d = 8.05 (br s, 1 H), 7.35–7.40 (m,
3 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.13–7.18 (m, 3 H), 6.99–7.03 (m,
2 H), 4.35 (t, J = 7.8 Hz, 1 H), 3.58–3.69 (m, 2 H), 2.38–2.47 (m,
1 H), 2.16–2.24 (m, 1 H), 1.44 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.4, 38.5, 61.0, 111.1, 119.0,
119.3, 121.1, 122.2, 126.7, 129.6, 131.4, 136.6, 143.8.
EI-MS: m/z = 329 [M+; 79Br], 331 [M+; 81Br].
Anal. Calcd for C17H16BrNO: C, 61.83; H, 4.88; N, 4.24. Found: C,
61.85; H, 4.94; N, 4.31.
EI-MS: m/z = 319 [M+].
5c
20
Pale-yellow oil; [a]D –9.8 (c 2.0, CHCl3); 86% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 27.2 min; tminor = 19.1 min).
1H NMR (400 MHz, CDCl3): d = 8.04 (br s, 1 H), 7.40 (d, J = 7.6
Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.21–7.25 (m, 4 H), 7.15 (t,
5g
Colorless oil; [a]D20 –4.6 (c 1.33, CHCl3); 89% ee by HPLC (Daicel
Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow rate: 1.0
mL/min; tmajor = 18.0 min; tminor = 16.0 min).
Synthesis 2009, No. 23, 3994–4000 © Thieme Stuttgart · New York

3998
Z. J. Wang et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 8.06 (br s, 1 H), 7.42 (d, J = 8.0
Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.27 (s, 1 H), 7.12–7.20 (m,
4 H), 7.00–7.03 (m, 2 H), 4.36 (t, J = 7.8 Hz, 1 H), 3.58–3.69 (m,
2 H), 2.37–2.45 (m, 1 H), 2.17–2.27 (m, 1 H), 1.76 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.4, 38.7, 60.9, 111.2, 118.8,
119.3, 119.4, 121.1, 122.2, 126.1, 126.4, 126.7, 127.9, 129.6, 134.2,
136.5, 147.0.
1H NMR (400 MHz, CDCl3): d = 7.99 (br s, 1 H), 7.22–7.30 (m,
4 H), 7.14–7.16 (m, 2 H), 6.95 (d, J = 1.6 Hz, 1 H), 6.84 (d, J = 2.4
Hz, 1 H), 6.78 (dd, J = 6.4, 2.4 Hz, 1 H), 4.30 (t, J = 7.6 Hz, 1 H),
3.71 (s, 1 H), 3.60–3.66 (m, 2 H), 2.36–2.44 (m, 1 H), 2.18–2.27
(m, 1 H), 1.70 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.5, 39.1, 55.8, 61.2, 101.5,
111.7, 111.9, 119.2, 121.9, 126.1, 127.2, 127.8, 128.4, 131.7, 144.7,
153.6.
EI-MS: m/z = 285 [M+; 35Cl], 287 [M+; 37Cl].
EI-MS: m/z = 281 [M+].
Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C,
71.55; H, 5.60; N, 4.88.
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.87; H, 6.85; N, 4.86.
5h
20
Colorless oil; [a]D +73.1 (c 2.33, CHCl3); 95% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 26.7 min; tminor = 17.9 min).
5l
20
Pale-yellow oil; [a]D +5.3 (c 1.13, CHCl3); 87% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 47.5 min; tminor = 41.6 min).
1H NMR (400 MHz, CDCl3): d = 8.10 (br s, 1 H), 7.44 (d, J = 8.0
Hz, 1 H), 7.34–7.36 (m, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 7.18–7.22
(m, 1 H), 6.99–7.15 (m, 5 H), 4.93 (t, J = 7.0 Hz, 1 H), 3.56–3.79
(m, 2 H), 2.41–2.45 (m, 1 H), 2.19–2.27 (m, 1 H), 1.98 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 34.9, 38.4, 61.2, 111.1, 118.5,
119.3, 119.4, 121.5, 122.1, 126.9, 127.1, 127.3, 129.1, 129.4, 133.5,
136.4, 142.2.
1H NMR (400 MHz, CDCl3): d = 7.94 (br s, 1 H), 7.22–7.29 (m,
5 H), 7.14 (t, J = 7.0 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 6.75 (d,
J = 2.0 Hz, 1 H), 6.66 (dd, J = 6.4, 2.2 Hz, 1 H), 4.29 (t, J = 8.0 Hz,
1 H), 3.75 (s, 1 H), 3.57–3.65 (m, 2 H), 2.36–2.44 (m, 1 H), 2.17–
2.27 (m, 1 H), 1.70 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.5, 39.2, 55.6, 61.2, 94.6, 109.1,
119.4, 119.9, 120.0, 121.3, 126.1, 127.8, 128.4, 137.2, 144.8, 156.3.
EI-MS: m/z = 285 [M+; 35Cl], 287 [M+; 37Cl].
EI-MS: m/z = 281 [M+].
Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C,
71.42; H, 5.57; N, 4.90.
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.80; H, 6.77; N, 4.95.
5i
Yellow oil; [a]D20 –9.0 (c 1.13, CHCl3); 86% ee by HPLC (Daicel
Chiralpak OD-H column; n-hexane–i-PrOH, 90:10; flow rate: 1.0
mL/min; tmajor = 38.0 min; tminor = 52.8 min).
5m
20
Colorless oil; [a]D –26.8 (c 0.93, CHCl3); 87% ee by HPLC
(Daicel Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 20.4 min; tminor = 17.0 min).
1H NMR (400 MHz, CDCl3): d = 7.91 (br s, 1 H), 7.22–7.30 (m,
5 H), 7.13–7.16 (m, 2 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.88 (s, 1 H),
4.31 (t, J = 7.8 Hz, 1 H), 3.56–3.65 (m, 2 H), 2.37–2.42 (m, 1 H),
2.36 (s, 3 H), 2.19–2.26 (m, 1 H), 1.70 (br s, 1 H).
1H NMR (400 MHz, CDCl3): d = 8.02 (br s, 1 H), 7.48 (d, J = 8.0
Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.16
(t, J = 7.6 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.02–7.05 (m, 2 H),
4.36 (t, J = 7.6 Hz, 1 H), 3.66–3.71 (m, 2 H), 2.42–2.50 (m, 1 H),
2.31 (s, 3 H), 2.23–2.28 (m, 1 H), 1.45 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.9, 38.7, 38.8, 61.4, 111.0,
119.2, 119.5, 119.8, 121.0, 122.0, 126.9, 127.6, 129.1, 135.6, 136.5,
141.7.
13C NMR (100 MHz, CDCl3): d = 21.5, 38.7, 39.1, 61.3, 110.8,
118.8, 118.9 (2 × C), 121.3, 123.6, 126.0, 127.0, 127.8, 128.4,
134.8, 144.8.
EI-MS: m/z = 265 [M+].
EI-MS: m/z = 265 [M+].
Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C,
81.47; H, 7.19; N, 5.27.
Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C,
81.47; H, 7.23; N, 5.30.
5j
5n
20
Pale-yellow oil; [a]D –8.8 (c 0.8, CHCl3); 87% ee by HPLC
(Daicel Chiralpak OD-H column; n-hexane–i-PrOH, 90:10; flow
rate: 1.0 mL/min; tmajor = 63.7 min; tminor = 82.1 min).
Colorless oil; [a]D20 +21.3 (c 1.2, CHCl3); 94% ee by HPLC (Daicel
Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow rate: 1.0
mL/min; tmajor = 15.9 min; tminor = 17.8 min).
1H NMR (400 MHz, CDCl3): d = 8.01 (br s, 1 H), 7.44 (d, J = 7.6
Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.14
(t, J = 7.6 Hz, 1 H), 6.99–7.02 (m, 2 H), 6.80 (d, J = 8.8 Hz, 2 H),
4.33 (t, J = 7.8 Hz, 1 H), 3.75 (s, 3 H), 3.66–3.77 (m, 2 H), 2.40–
2.48 (m, 1 H), 2.19–2.27 (m, 1 H), 1.36 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.4, 38.8, 55.2, 61.4, 111.0,
113.8, 119.3, 119.5, 120.0, 120.9, 122.0, 126.8, 128.7, 136.6, 136.8,
157.9.
1H NMR (400 MHz, CDCl3): d = 8.02 (br s, 1 H), 7.28–7.36 (m,
3 H), 7.19–7.22 (m, 2 H), 7.03 (d, J = 2.4 Hz, 1 H), 6.97–7.00 (m,
2 H), 4.40 (t, J = 7.6 Hz, 1 H), 3.66–3.71 (m, 2 H), 2.45–2.53 (m,
1 H), 2.46 (s, 3 H), 2.26–2.34 (m, 1 H), 1.68 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 38.6, 39.3, 61.3, 117.2,
119.4, 120.0, 120.2, 120.8, 122.5, 126.0, 126.3, 127.8, 128.3, 136.0,
144.8.
EI-MS: m/z = 265 [M+].
EI-MS: m/z = 281 [M+].
Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C,
81.35; H, 7.28; N, 5.21.
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.84; H, 6.76; N, 4.90.
5o
5k
Yellow solid; mp 157–159 °C; [a]D20 –169.9 (c 0.67, CHCl3); 86%
ee by HPLC (Daicel Chiralpak AD-H column; n-hexane–i-PrOH,
90:10; flow rate: 1.0 mL/min; tmajor = 23.2 min; tminor = 38.8 min).
Yellow oil; [a]D20 –42.5 (c 0.53, CHCl3); 88% ee by HPLC (Daicel
Chiralpak AD-H column; n-hexane–i-PrOH, 90:10; flow rate: 1.0
mL/min; tmajor = 28.9 min; tminor = 98.7 min).
Synthesis 2009, No. 23, 3994–4000 © Thieme Stuttgart · New York

PAPER
Enantioselective Friedel–Crafts Alkylation of Indoles
3999
1H NMR (400 MHz, CDCl3): d = 8.54 (br s, 1 H), 8.41 (s, 1 H), 8.05
(d, J = 9.2 Hz, 1 H), 7.19–7.36 (m, 7 H), 4.44 (t, J = 7.8 Hz, 1 H),
3.64–3.71 (m, 2 H), 2.42–2.48 (m, 1 H), 2.26–2.34 (m, 1 H), 1.64
(br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 38.5, 38.8, 60.8, 111.0, 116.8,
117.9, 122.6, 123.9, 126.3, 126.7, 127.7, 128.7, 139.5, 141.5, 143.6.
9, 1403. (c) Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.-
F.; He, L.-N.; Tang, C.-C. Eur. J. Org. Chem. 2008, 1406.
(9) (a) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 8156. (b) Kang, Q.; Zhao, Z.-A.;
You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484.
(c) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J.
A.; Antilla, J. C. Org. Lett. 2007, 9, 2609. (d) Wanner, M.
J.; Hauwert, P.; Schoemaker, H. E.; de Gelder, R.;
van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem.
2008, 180.
EI-MS: m/z = 296 [M+].
Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C,
68.82; H, 5.41; N, 9.46.
(10) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.;
Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem.
Int. Ed. 2005, 44, 3086.
Acknowledgment
(11) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(12) For the first reports on the use of diarylprolinol silyl ethers,
see: (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 794.
(b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard, A.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 3703.
(c) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem. Int. Ed. 2005, 44, 4212.
This work was financially supported by the Specialized Research
Fund for the Doctoral Program of Higher Education of China
(20060335036) and Zhejiang Provincial Natural Science Founda-
tion of China under Grant No. Y406049.
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Synthesis 2009, No. 23, 3994–4000 © Thieme Stuttgart · New York