Chiral phosphoric acid catalyzed asymmetric Friedel-Crafts alkylation of indoles with simple α,β-unsaturated aromatic ketones

Article abstract of DOI:10.1002/ejoc.200700980

Asymmetric Michael-type Friedel-Crafts (F-C) alkylations of indoles with nonchelating α,β-unsaturated aromatic ketones catalyzed by a chiral H₈-BINOL-based phosphoric acid were investigated. The reactions took place smoothly in the presence of

Full text of DOI:10.1002/ejoc.200700980

FULL PAPER
DOI: 10.1002/ejoc.200700980
Chiral Phosphoric Acid Catalyzed Asymmetric Friedel–Crafts Alkylation of
Indoles with Simple α,β-Unsaturated Aromatic Ketones
Hong-Ying Tang,[a] Ai-Dang Lu,[a] Zheng-Hong Zhou,*[a] Guo-Feng Zhao,[a]
Lian-Nian He,*[a] and Chu-Chi Tang[a]
Keywords: Indoles / α,β-Unsaturated aromatic ketones / Asymmetric Friedel–Crafts alkylation / Chiral phosphoric acids /
Organocatalysis
Asymmetric Michael-type Friedel–Crafts (F-C) alkylations of
indoles with nonchelating α,β-unsaturated aromatic ketones
catalyzed by a chiral H8-BINOL-based phosphoric acid were
investigated. The reactions took place smoothly in the pres-
ence of only 2 mol-% of catalyst at room temperature to af-
ford the desired F-C alkylation products in good yields and
with moderate enantioselectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
strated that the combination of trifluoromethanesulfonic
acid and the diamine derived from cinchonine (30 mol-%)
was also an efficient catalytic system for asymmetric F-C
reactions between indole and α,β-unsaturated aliphatic
ketones, in which ees of up to 89% were obtained.[7] Xu et
al. described -camphor-based sulfonic acid catalyzed
(10 mol-%) asymmetric F-C alkylations of indoles with α,β-
unsaturated aromatic ketones with the highest ee value of
58%.[8] This was the only example of a chiral Brønsted acid
catalyzed process.
Despite these recent advances, there are still some draw-
backs in the previously reported procedures, such as sub-
strate limitation, the need for high catalyst loadings (10–
30 mol-%), and unsatisfactory selectivities; therefore, the
development of alternative catalysts for enantioselective
Michael-type F-C reactions between indoles and simple
α,β-unsaturated aromatic ketones would be highly desirable.
Recently, chiral phosphoric acids have been shown to be
versatile organocatalysts in many organic transforma-
tions.[9,10] Here we report the application of chiral phospho-
ric acids as Brønsted acid catalysts for the promotion of
the Michael-type F-C reactions between indoles and α,β-
unsaturated aromatic ketones.
Introduction
The indole framework represents a privileged structure
motif in a large number of natural products and therapeutic
agents.[1] In this regard, the development of effective asym-
metric routes to indole architectures has attracted much at-
tention from organic chemists. Indole is an electron-rich
heteroaromatic compound, in which the pyrrole π-system
is significantly activated toward electrophilic substitution.
Therefore, asymmetric Friedel–Crafts (F-C) alkylation has
become a powerful strategy for the construction of indol
architectures.[2] Among the F-C reactions, Michael-type F-
C reactions of indoles with α,β-unsaturated carbonyl com-
pounds have been widely investigated. A number of highly
selective metal-catalyzed asymmetric F-C reactions in the
presence of bidentate chelating carbonyl compounds have
been developed.[3] However, the corresponding organocata-
lytic asymmetric process has been less widely explored. In
2002, McMillan et al. developed the first examples of asym-
metric Michael-type F-C reactions between indoles and
α,β-unsaturated aldehydes in the presence of benzylimid-
azolidinone salts derived from -phenylalanine as the cata-
lysts.[4] Nevertheless, such catalytic systems were inefficient
for α,β-unsaturated ketones, with which poor ees (25%)
were observed.[5] Melchiorre et al. reported highly enantio-
selective (up to 96% ee) F-C alkylations of indoles with
simple α,β-unsaturated aliphatic ketones in the presence of
20 mol-% of the -N-Boc-phenylglycine salt of 9-amino(9-
deoxy)epihydroquinine as the catalyst.[6] Chen et al. demon-
Results and Discussion
We first performed the F-C reaction between (E)-1,3-di-
phenylprop-2-en-1-one (chalcone) and indole in the pres-
ence of different BINOL phosphates 1a–h and H8-BINOL
phosphates 2a–c as the catalysts. Generally, chiral phospho-
ric acids derived from octahydrobinaphthol exhibit better
catalytic activities than the corresponding binol derivatives
in terms of enantioselectivity (Table 1, Entries 9–11 vs. En-
tries 7, 6, 3), and the best enantiomeric excess (50%,
[a] State Key Laboratory of Elemento-Organic Chemistry, Insitute
of Elemento-Organic Chemistry, Nankai University
Tianjin 300071, P. R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2008, 1406–1410

Chiral Friedel–Crafts Alkylation of Indoles with α,β-Unsaturated Ketones
Table 1. Screening of catalysts for the asymmetric Michael-type F-C alkylation of chalcone.[a]
Entry
Catalyst
R
Time [h]
Yield (%)[b]
ee (%)[c]
Config.[d]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
Ph2P(O)
Ph
4-ClC6H4
4-MeC6H4
4-PhC6H4
2-naphthyl
3,5-(F3C)2C6H3
2,4,6-tBu3C6H2
3,5-(F3C)2C6H3
2-naphthyl
4-ClC6H4
24
24
24
24
24
24
48
72
24
24
24
61
75
73
72
66
73
73
61
56
69
87
7
2
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
35
11
10
15
28
1
33
46
50
10
11
[a] Reactions were performed on a 0.5 mmol scale of chalcone with a concentration of 0.33 molL–1. [b] Isolated yield. [c] Enantiomeric
excess was determined by HPLC analysis on an AD-H column, hexane/propan-2-ol (80:20), flow rate 1.0 mLmin–1, Rt = 14.95 and
16.92 min. [d] Absolute configuration of the major isomer was assigned by comparison with the literature value of optical rotation in ref.[6]
Table 1, Entry 11) was obtained when H8-BINOL phos-
phate 2c was used. The introduction of a bulky group such
as 2,4,6-tri-tert-butylphenyl (1h) at the 3,3Ј-positions of the
binol skeleton had a detrimental effect on the reaction,
which became very sluggish and almost racemic product
was obtained (Table 1, Entry 8).
In further experiments, the solvent, reaction temperature,
and catalyst loading were thoroughly examined with 2c as (Table 2, Entries 1–3 and 5). Use of protic solvents such as
the catalyst and the reaction between chalcone and indole methanol resulted in dramatic decreases in stereoselectivity
as the model. The results are listed in Table 2.
and afforded the racemic F-C adduct. Neither lowering nor
As shown in Table 2, solvent evaluation revealed that increasing of the reaction temperature gave any improve-
chloroalkanes and toluene favored this transformation, and ment in the stereocontrol of the reaction (Table 2, En-
the best reaction conducts were found in dichloromethane tries 10, 11 vs. Entry 1). In addition, adjusting the catalyst
Table 2. Optimization of the reaction conditions.[a]
Entry
Solvent
2c [mol-%]
Temp [°C]
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
ClCH2CH2Cl
CH3OH
toluene
ethyl acetate
THF
CH2Cl2
2
2
2
2
2
2
2
1
3
2
2
25
25
25
25
25
25
25
25
25
0
87
63
76
68
78
72
51
85
90
62
85
50
44
47
0
44
22
19
49
49
45
38
CH2Cl2
CH2Cl2
CH2Cl2
10
11
40
[a] Reactions were performed on a 0.5 mmol scale of chalcone with a concentration of 0.33 molL–1. [b] Isolated yield. [c] Enantiomeric
excess was determined by HPLC analysis on an AD-H column, hexane/propan-2-ol (80:20), flow rate 1.0 mLmin–1, Rt = 14.95 (major)
and 16.92 (minor) min.
Eur. J. Org. Chem. 2008, 1406–1410
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Z.-H. Zhou, L.-N. He et al.
Table 3. Asymmetric Friedel–Crafts alkylation of indoles with different α,β-unsaturated aromatic ketones catalyzed by 2c.[a]
FULL PAPER
Entry
R
R1
Ar
Ar1
Yield (%)[b]
ee (%)[c]
Config.
1 (3a)
2 (3b)
3 (3c)
4 (3d)
5 (3e)
6 (3f)
7 (3g)
8 (3h)
9 (3i)
H
CH3
Bn
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
73
63
92
82
88
89
67
71
80
69
85
56
47
24
18
51
39
34
43
36
38
51
(R)[d]
nd[e]
nd
Ph
Ph
(S)[f]
nd
4-H3COC6H4
Ph
4-O2NC6H4
4-BrC6H4
2-ClC6H4
Ph
2-ClC6H4
2-ClC6H4
4-O2NC6H4
nd
nd
nd
nd
nd
nd
Ph
2-ClC6H4
4-H3COC6H4
2-H3COC6H4
2-H3COC6H4
10 (3j)
11 (3k)
H
H
[a] Reactions were performed on a 0.5 mmol scale of enones with a concentration of 0.17 molL–1. [b] Isolated yield. [c] Enantiomeric
excess was determined by HPLC analysis on an AD-H column. [d] Absolute configuration of the major isomer was assigned by compari-
son with the literature value for optical rotation in ref.[6] [e] nd = not determined. [f] Absolute configuration of the major isomer was
established by comparison with the reported optical rotation in ref.[11]
loading demonstrated no obvious effect on the ee values group also had a detrimental effect on the reaction, which
obtained from the reaction. For example, the use of larger gave the corresponding adduct with a sharp loss in enantio-
or smaller amounts of phosphoric acid 2c resulted only in selectivity (Table 2, Entry 4, 19% ee). As for the substrate
slight losses of enantioselectivity (Table 2, Entries 10, 11; α,β-unsaturated aromatic ketones, generally, either intro-
both are 49% ee).
duction of an electron-deficient aryl group at the 1-position
The influence of additives on the reaction was also evalu- or incorporation of an electron-rich aryl group at the 1-
ated, and it was found that the introduction of additives position favored the reaction. The corresponding conjugate
had a negative effect. For example, use of either acidic addi- addition products were obtained with moderate enantio-
tives such as phenol or acetic acid or of the basic additive selectivities (Table 3, Entries 5–11, 34–51% ees).
pyridine led to obvious decreases in ee values (33% ee,
In addition, the optimal conditions also applied for the
37% ee, and 34% ee, respectively). Although significant rate cyclic enones. However, both stereoselectivity and chemical
acceleration was observed with molecular iodine as the ad- yield were decreased for this type of substrate. For example,
ditive (the reaction was complete in less than 8 h), almost the F-C alkylation product 4 of indole with cyclohex-2-en-
racemic product (3% ee) was isolated, though in excellent one in the presence of 2 mol-% of 2c was obtained in 56%
yield.
yield with 29% ee.
Further studies revealed that the concentration of chal-
cone had an important effect on the enantioselectivity.
When the concentration of chalcone was decreased to
0.17 , the ee value was improved to 56%, while further
decreasing the concentration to 0.13  led to a lower selec-
tivity of 53% ee.
With the optimal reaction conditions (2 mol-% of 2c as
the catalyst, 0.17  enones, at 25 °C in dichloromethane) to
hand, we then examined the scope and limitations of these
stereoselective indole alkylations. The results are summa-
rized in Table 3.
Conclusions
We have developed an efficient chiral phosphoric acid
As shown in Table 3, variation of the substituents on the organocatalyst for the asymmetric Michael-type Friedel–
indole nitrogen atom revealed that the steric hindrance of Crafts alkylation of indoles and simple α,β-unsaturated aro-
the substituting group plays an important role on the reac- matic ketones. It is worth noting that moderate enantio-
tion. For example, in relation to the result for indole selectivity has been achieved in the presence of only 2 mol-
(Table 3, Entry 1, 56% ee), the use of N-methylindole led to % of catalyst. This is a great advantage over other organ-
a moderate decrease in ee value (Table 3, Entry 2, 47% ee), ocatalytic asymmetric version of this reaction in the limited
whereas the employment of a bulkier benzyl-substituted in- literature reports. Mechanistic studies and further applica-
dole resulted in a marked loss of selectivity (Table 3, En- tion of this type of readily available Brønsted acid catalysts
try 3, 24% ee). Moreover, incorporation of a 2-methyl in stereoselective reactions are ongoing in our laboratory.
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Eur. J. Org. Chem. 2008, 1406–1410

Chiral Friedel–Crafts Alkylation of Indoles with α,β-Unsaturated Ketones
7.53 (t, J = 7.6 Hz, 1ϫHarom), 7.91 (d, J = 7.6 Hz, 2ϫHarom) ppm.
Experimental Section
General Information: 1H and 31P NMR spectra were recorded in
CDCl3 with a Bruker AMX 300 or a Varian 400 MHz instrument
with TMS as an internal standard for H NMR and 85% H3PO4
as an external standard for 31P NMR spectroscopy. Specific rota-
tions were measured with a Perkin–Elmer 341MC polarimeter. En-
antiomeric excesses were determined with an HP-1100 instrument
(chiral column; mobile phase: hexane/iPrOH). Elemental analyses
were conducted with a Yanaco CHN Corder MT-3 automatic ana-
lyzer. Melting points were determined with a T-4 melting point
apparatus. All temperatures are uncorrected.
C30H25NO (415.51): calcd. C 86.71, H 6.06, N 3.37; found C 86.34,
H 5.82, N 3.11. HPLC conditions: AD-H column, hexane/propan-
2-ol (90:10), flow rate 1.0 mLmin–1, Rt = 14.36 (major) and 15.16
(minor) min.
1
(S)-3-(2-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3d): Vis-
cous oil. Yield 139 mg, 82%. [α]2D0 = +6.6 (c = 2.43, CHCl3), 18%
1
ee. H NMR (CHCl3, 300 MHz): δ = 2.36 (s, 3 H, CH3), 3.88 (dd,
J = 7.2, 15.9 Hz, 1 H, one proton of CH2), 3.95 (dd, J = 7.2,
15.9 Hz, 1 H, one proton of CH2), 5.09 (t, J = 7.2 Hz, 1 H, CH),
6.96–7.07 (m, 2ϫHarom), 7.11–7.24 (m, 4ϫHarom), 7.33–7.38 (m,
4ϫHarom), 7.45–7.50 (m, 2ϫHarom), 7.76 (br. s, 1 H, NH), 7.87 (d,
J = 7.2 Hz, 2ϫHarom) ppm. C24H21NO (339.42): calcd. C 84.92, H
6.24, N 4.13; found C 84.77, H 6.03, N 3.96. HPLC conditions:
AD-H column, hexane/propan-2-ol (80:20), flow rate 1.0 mLmin–1,
Rt = 20.55 (major) and 22.37 (minor) min.
Synthesis of Catalysts: Catalysts 1a–h and 2a–c were prepared by
condensation of 3,3Ј-substituted BINOL or H8-BINOL and phos-
phorus oxychloride in the presence of pyridine and subsequent
acidic hydrolysis of the corresponding chlorophosphate by a litera-
ture method.[10b]
3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-(4-nitrophenyl)propan-1-
one (3e): Yellow solid. Yield 176 mg, 88%, M.p. 140–141 °C. [α]2D0
1a: White solid. Yield 370 mg, 99%. M.p. 209–211 °C. [α]2D0 –156.2
(c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.78 (br. s, 1 H,
1
= –11.3 (c = 0.53, CHCl3), 51% ee. H NMR (CHCl3, 400 MHz):
OH), 7.24–7.26 (m, 4ϫHarom), 7.41–7.84 (m, 26ϫHarom) ppm. 31
P
δ = 3.73 (dd, J = 7.2, 16.4 Hz, 1 H, one proton of CH2), 3.75 (s, 3
H, OCH3), 3.82 (dd, J = 7.2, 16.4 Hz, 1 H, one proton of CH2),
4.98 (t, J = 7.2 Hz, 1 H, CH), 6.80 (d, 2 ϫ Harom), 6.98 (d,
1 ϫ Harom), 7.03 (t, 1 ϫ Harom), 7.16 (t, 1 ϫ Harom), 7.25 (d,
2ϫHarom), 7.33 (d, 1ϫHarom), 7.43 (d, J = 8.0 Hz, 1ϫHarom), 8.00
(d, J = 8.4 Hz, 2ϫHarom), 8.01 (br. s, 1 H, NH) ppm. C24H20N2O4
(400.41): calcd. C 71.99, H 5.03, N 7.00; found C 71.85, H 4.91, N
6.89. HPLC conditions: AD-H column, hexane/propan-2-ol
(70:30), flow rate 1.0 mL min–1, Rt = 27.29 (major) and 33.24
(minor) min.
NMR (161.7 MHz, CDCl3):
C44H31O6P3 (748.61): calcd. C 70.59, H 4.17; found C 70.41, H
4.04.
δ = –0.47, 36.67, 37.39 ppm.
General Procedure for the 2c-Catalyzed Asymmetric F-C Alkylation
of Indoles with α,β-Unsaturated Aromatic Ketones: The α,β-unsatu-
rated aromatic ketones (0.5 mmol), indoles (0.6 mmol), and catalyst
2c (5.77 mg, 0.001 mmol) were stirred in dichloromethane (3 mL)
at room temperature. The reaction was monitored by TLC analysis.
After removal of the solvent, the residue was purified by column
chromatograph on silica gel (200–300 mesh, gradient elution with
petroleum ether/ethyl acetate) to give the desired product 3.
1-(4-Bromophenyl)-3-(1H-indol-3-yl)-3-phenylpropan-1-one (3f):
Pale yellow solid. Yield 180 mg, 89%. M.p. 171–173 °C. [α]2D0
=
1
–15.9 (c = 0.91, CHCl3), 39% ee. H NMR (CHCl3, 400 MHz): δ
= 3.68 (dd, J = 7.2, 16.4 Hz, 1 H, one proton of CH2), 3.78 (dd, J
= 7.2, 16.4 Hz, 1 H, one proton of CH2), 5.04 (t, J = 7.2 Hz, 1 H,
CH), 6.98–7.04 (m, 3ϫHarom), 7.13–7.19 (m, 3ϫHarom), 7.32–7.35
(m, 3ϫHarom), 7.43 (d, J = 8.0 Hz, 1ϫHarom), 7.56 (d, J = 8.4 Hz,
2ϫHarom), 7.78 (d, J = 8.4 Hz, 2ϫHarom), 7.97 (br. s, 1 H, NH)
ppm. C23H18BrNO (404.29): calcd. C 68.33, H 4.49, N 3.46; found
C 68.12, H 4.29, N 3.20. HPLC conditions: AD-H column, hexane/
propan-2-ol (70:30), flow rate 1.0 mLmin–1, Rt = 12.43 (major) and
14.16 (minor) min.
(R)-3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (3a): White solid.
Yield 118 mg, 73%. M.p. 127–126 °C. [α]2D0 –17.0 (c = 1.11, CHCl3),
56% ee. 1H NMR (CHCl3, 400 MHz): δ = 3.73 (dd, J = 7.2,
16.4 Hz, 1 H, one proton of CH2), 3.83 (dd, J = 7.2, 16.4 Hz, 1 H,
one proton of CH2), 5.08 (t, J = 7.2 Hz, 1 H, CH), 7.00–7.04 (m,
2ϫHarom), 7.13–7.18 (m, 3ϫHarom), 7.24–7.37 (m, 4ϫHarom),
7.41–7.56 (m, 4ϫHarom), 7.94 (d, J = 8.0 Hz, 2ϫHarom), 7.98 (br.
s, 1 H, NH) ppm. C23H19NO (325.39): calcd. C 84.89, H 5.89, N
4.30; found C 84.76, H 6.01, N 4.08. HPLC conditions: AD-H
column, hexane/propan-2-ol (80:20), flow rate 1.0 mLmin–1, Rt =
14.95 (major) and 16.92 (minor) min.
1-(2-Chlorophenyl)-3-(1H-indol-3-yl)-3-phenylpropan-1-one (3g):
White solid. Yield 121 mg, 67%. M.p. 99–101 °C. [α]2D0 = –6.8 (c =
1
3-(1-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3b): White
solid. Yield 107 mg, 63%. M.p. 159–164 °C. [α]2D0 = –11.2 (c = 0.49,
CHCl3), 47% ee. 1H NMR (CHCl3, 400 MHz): δ = 3.72 (s, 3 H,
CH3), 3.74 (dd, J = 7.2, 16.8 Hz, 1 H, one proton of CH2), 3.81
(dd, J = 7.2, 16.8 Hz, 1 H, one proton of CH2), 5.06 (t, J = 7.2 Hz,
1 H, CH), 6.84 (s, 1ϫHarom) 7.01 (t, J = 7.2 Hz, 1ϫHarom), 7.14–
7.20 (m, 2ϫHarom), 7.24–7.28 (m, 2ϫHarom), 7.35–7.57 (m,
6ϫHarom), 7.94 (d, J = 7.2 Hz, 2ϫHarom) ppm. C24H21NO
(339.42): calcd. C 84.92, H 6.24, N 4.13; found C 84.69, H 5.94, N
4.02. HPLC conditions: AD-H column, hexane/propan-2-ol
(80:20), flow rate 1.0 mLmin–1, Rt = 9.22 (minor) and 11.74
(major) min.
0.56, CHCl3), 34% ee. H NMR (CHCl3, 400 MHz): δ = 3.71 (dd,
J = 7.2, 16.4 Hz, 1 H, one proton of CH2), 3.79 (dd, J = 7.2,
16.4 Hz, 1 H, one proton of CH2), 4.92 (t, J = 8.0 Hz, 1 H, CH),
6.98–7.02 (m, 2ϫHarom), 7.07–7.09 (m, 1ϫHarom), 7.12–7.19 (m,
3ϫHarom), 7.22–7.25 (m, 2ϫHarom), 7.30–7.35 (m, 4ϫHarom), 7.39
(t, J = 8.0 Hz, 1ϫHarom), 8.01 (br. s, 1 H, NH) ppm. C23H18ClNO
(359.83): calcd. C 76.77, H 5.04, N 3.89; found C 76.61, H 4.90, N
3.67. HPLC conditions: AD-H column, hexane/propan-2-ol
(70:30), flow rate 1.0 mLmin–1, Rt = 7.08 (major) and 8.32 (minor)
min.
3-(2-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3h):
Viscous oil. Yield 128 mg, 71%. [α]2D0 = –28.5 (c = 2.35, CHCl3),
43 % ee. 1H NMR (CHCl3, 400 MHz): δ = 3.68 (dd, J = 6.4,
16.8 Hz, 1 H, one proton of CH2), 3.80 (dd, J = 8.0, 16.8 Hz, 1 H,
one proton of CH2), 5.54 (dd, J = 6.4, 8.0 Hz, 1 H, CH), 6.99–7.03
(m, 2ϫHarom), 7.10–7.16 (m, 3ϫHarom), 7.21–7.24 (m, 1ϫHarom),
3-(1-Benzyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3c): White so-
lid. Yield 191 mg, 92%. M.p. 136–138 °C. [α]2D0 = –10.9 (c = 0.48,
1
CHCl3), 24% ee. H NMR (CHCl3, 400 MHz): δ = 3.73 (dd, J =
7.2, 16.4 Hz, 1 H, one proton of CH2), 3.81 (dd, J = 7.2, 16.4 Hz,
1 H, one proton of CH2), 5.09 (t, J = 7.2 Hz, 1 H, CH), 5.26 (s, 2 7.31 (d, J = 8.0 Hz, 1ϫHarom), 7.38–7.46 (m, 4ϫHarom), 7.53–7.57
H, CH2), 6.95 (s, 1ϫHarom), 6.99–7.06 (m, 3ϫHarom), 7.10–7.24
(m, 6ϫHarom), 7.28–7.30 (m, 1ϫHarom), 7.36–7.46 (m, 5ϫHarom),
(m, 1ϫHarom), 7.98 (d, J = 7.2 Hz, 2ϫHarom), 8.01 (br. s, 1 H,
NH) ppm. C23H18ClNO (359.83): calcd. C 76.77, H 5.04, N 3.89;
Eur. J. Org. Chem. 2008, 1406–1410
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Z.-H. Zhou, L.-N. He et al.
FULL PAPER
found C 76.53, H 4.86, N 3.72. HPLC conditions: AD-H column,
hexane/propan-2-ol (80:20), flow rate 1.0 mL min–1, Rt = 11.03
(major) and 14.97 (minor) min.
ppm. C14H15NO (213.27): calcd. C 78.84, H 7.09, N 6.57; found C
78.59, H 6.84, N 6.34. HPLC conditions: AD-H column, hexane/
propan-2-ol (85:15), flow rate 1.0 mLmin–1, Rt = 9.79 (major) and
11.86 (minor) min.
1-(2-Chlorophenyl)-3-(1H-indol-3-yl)-3-(4-methoxyphenyl)propan-1-
one (3i): White solid. Yield 156 mg, 80%. M.p. 134–136 °C. [α]2D0
=
1
+5.49 (c = 3.28, CHCl3), 36% ee. H NMR (CHCl3, 300 MHz): δ
= 3.69 (dd, J = 7.8, 16.5 Hz, 1 H, one proton of CH2), 3.76 (s, 3
H, OCH3), 3.77 (dd, J = 7.8, 16.5 Hz, 1 H, one proton of CH2),
4.87 (t, J = 7.8 Hz, 1 H, CH), 6.78 (d, J = 8.7 Hz, 2ϫHarom), 6.98–
7.08 (m, 3ϫHarom), 7.10–7.18 (m, 3ϫHarom), 7.21 (d, J = 8.7 Hz,
2 ϫ Harom), 7.29–7.36 (m, 2 ϫ Harom), 7.40 (d, J = 8.1 Hz,
1 ϫ Harom), 8.00 (br. s, 1 H, NH) ppm. C24H20ClNO2 (389.86):
calcd. C 73.93, H 5.17, N 3.59; found C 73.74, H 5.02, N 3.27.
HPLC conditions: AD-H column, hexane/propan-2-ol (80:20),
flow rate 0.5 mLmin–1, Rt = 33.04 (minor) and 35.10 (major) min.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (20472033, 20772058) and the Key Science and Technology
Project of the Ministry of Education of China for generous finan-
cial support of our programs.
[1]
[2]
a) D. J. Faulkner, Nat. Prod. Rep. 2002, 19, 1–49; b) A. Klee-
man, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Sub-
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For recent reviews on catalytic asymmetric Friedel–Crafts reac-
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gew. Chem. Int. Ed. 2004, 43, 550–556; b) K. A. Jorgensen, Syn-
thesis 2003, 1117–1125.
1-(2-Chlorophenyl)-3-(1H-indol-3-yl)-3-(2-methoxyphenyl)propan-1-
one (3j): Colorless oil. Yield 135 mg, 69%. [α]2D0 = –6.8 (c = 1.10,
1
CHCl3), 38% ee. H NMR (CHCl3, 400 MHz): δ = 3.68 (dd, J =
8.8, 16.4 Hz, 1 H, one proton of CH2), 3.78 (dd, J = 6.8, 16.4 Hz,
1 H, one proton of CH2), 3.83 (s, 3 H, OCH3), 5.28 (dd, J = 6.8,
8.8 Hz, 1 H, CH), 6.80 (t, J = 7.2 Hz, 1ϫHarom), 6.86 (d, J =
8.4 Hz, 1 ϫ Harom), 6.98–7.03 (m, 2 ϫ Harom), 7.09–7.19 (m,
5ϫHarom), 7.29–7.43 (m, 4ϫHarom), 8.07 (br. s, 1 H, NH) ppm.
C24H20ClNO2 (389.86): calcd. C 73.93, H 5.17, N 3.59; found C
73.69, H 4.98, N 3.35. HPLC conditions: AD-H column, hexane/
propan-2-ol (80:20), flow rate 1.0 mLmin–1, Rt = 9.92 (major) and
13.20 (minor) min.
[3]
For selected examples, see: a) D. A. Evans, K. A. Scheidt, K. R.
Fandrick, H. W. Lam, J. Wu, J. Am. Chem. Soc. 2003, 125,
10780–10781; b) C. Palomo, M. Oiarbide, B. G. Kardak, J. M.
Gareia, A. Linden, J. Am. Chem. Soc. 2005, 127, 4154–4155;
c) D. A. Evans, K. R. Fandrick, H.-J. Song, J. Am. Chem. Soc.
2005, 127, 8942–8943.
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J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
1172–1173.
D.-P. Li, Y.-C. Guo, Y. Guo, W.-J. Xiao, Chem. Commun. 2006,
799–801.
G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P.
Melchiorre, Org. Lett. 2007, 9, 1403–1405.
3-(1H-Indol-3-yl)-3-(2-methoxyphenyl)-1-(4-nitrophenyl)propan-1-
one (3k): Yellow solid. Yield 170 mg, 85%. M.p. 170–172 °C.
[α]2D0 = –27.6 (c = 0.34, CHCl3), 51% ee. 1H NMR (CHCl3,
300 MHz): δ = 3.68 (dd, J = 6.6, 15.3 Hz, 1 H, one proton of CH2),
3.76 (dd, J = 6.6, 15.3 Hz, 1 H, one proton of CH2), 3.87 (s, 3 H,
OCH3), 5.37 (t, J = 6.6 Hz, 1 H, CH), 6.78–6.90 (m, 2ϫHarom),
6.96–7.20 (m, 6ϫHarom), 7.34 (t, J = 8.7 Hz, 1ϫHarom), 8.02 (br.
s, 1 H, NH), 8.10 (d, J = 8.7 Hz, 2ϫHarom), 8.25 (d, J = 8.7 Hz,
2ϫHarom) ppm. C24H20N2O4 (400.41): calcd. C 71.99, H 5.03, N
7.00; found C 71.78, H 4.95, N 6.86. HPLC conditions: AD-H
column, hexane/propan-2-ol (70:30), flow rate 1.0 mLmin–1, Rt =
18.14 (minor) and 22.03 (major) min.
W. Chen, W. Du, L. Yue, R. Li, Y. Wu, L.-S. Ding, Y.-C. Chen,
Org. Biomol. Chem. 2007, 5, 816–821.
W. Zhou, L.-W. Xu, L. Li, L. Yang, C.-G. Xia, Eur. J. Org.
Chem. 2006, 5225–5227.
For selected reviews, see: a) T. Akiyama, Chem. Rev. 2007, 107,
5744–5758; b) S. J. Connon, Angew. Chem. Int. Ed. 2006, 45,
3909–3912; c) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int.
Ed. 2006, 45, 1520–1543; d) T. Akiyama, J. Itoh, K. Fuchibe,
Adv. Synth. Catal. 2006, 348, 999–1010.
3-(1H-Indol-3-yl)cyclohexanone (4): Colorless oil. Yield 60 mg,
56%. [α]2D0 = –4.1 (c = 0.21, CHCl3), 29% ee. 1H NMR (CHCl3,
400 MHz): δ = 1.81–1.89 (m, 1 H, one proton of CH2), 1.96–2.09
(m, 2 H, CH2), 2.24–2.29 (m, 1 H, one proton of CH2), 2.35–2.49
(m, 2 H, CH2), 2.60–2.66 (m, 1 H, one proton of CH2), 2.78–2.83
(m, 1 H, one proton of CH2), 3.42–3.49 (m, 1 H, CH, one proton
of CH2), 6.99 (d, J = 2.0 Hz, 1ϫHarom), 7.13 (t, J = 7.6 Hz,
1ϫHarom), 7.21 (t, J = 7.6 Hz, 1ϫHarom), 7.38 (d, J = 7.6 Hz,
1ϫHarom), 7.63 (d, J = 7.6 Hz, 1ϫHarom), 8.01 (br. s, 1 H, NH)
[10]
[11]
For pioneering studies on chiral phosphoric acid catalysis, see:
a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
Int. Ed. 2004, 43, 1566–1568; b) D. Uraguchi, M. Terada, J.
Am. Chem. Soc. 2004, 126, 5356–5357.
M. Bandini, M. Fagioli, M. Garavelli, A. Melloni, V. Trigari,
A. Umani-Ronchi, J. Org. Chem. 2004, 69, 7511–7518.
Received: October 17, 2007
Published Online: January 11, 2008
1410
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Eur. J. Org. Chem. 2008, 1406–1410