Synthesis of functionalized indoles with a trifluoromethyl-substituted stereogenic tertiary carbon atom through an enantioselective Friedel-Crafts alkylation with β-trifluoromethyl-α,β-enones

Article abstract of DOI:10.1002/chem.201000568

Chiral complexes of BINOL-based ligands with zirconium tert-butoxide catalyze the Friedel-Crafts alkylation reaction of indoles with β-trifluoromethyl-α,β-unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α-trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99%.

Full text of DOI:10.1002/chem.201000568

FULL PAPER
DOI: 10.1002/chem.201000568
Synthesis of Functionalized Indoles with a Trifluoromethyl-Substituted
Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–
Crafts Alkylation with b-Trifluoromethyl-a,b-enones
Gonzalo Blay,[a] Isabel Fernꢀndez,[a] M. Carmen MuÇoz,[b] Josꢁ R. Pedro,*[a] and
Carlos Vila[a]
Dedicated to Professor Pelayo Camps on occasion of his 65th birthday
Abstract: Chiral complexes of BINOL-based ligands with zirconium tert-butoxide
catalyze the Friedel–Crafts alkylation reaction of indoles with b-trifluoromethyl-
a,b-unsaturated ketones to give functionalized indoles with an asymmetric tertiary
carbon center attached to a trifluoromethyl group. The reaction can be applied to
a large number of substituted a-trifluoromethyl enones and substituted indoles.
The expected products were obtained with good yields and ees of up to 99%.
Keywords: alkylation
substitution · asymmetric catalysis ·
enones · fluorinated compounds
·
aromatic
Introduction
could be used (Scheme 1). The first route is the conjugated
nucleophilic trifluoromethylation of a,b-unsaturated carbon-
yl compounds. This strategy seems to be straightforward and
It is known that the introduction of a trifluoromethyl moiety
to an organic structure can greatly modify its physicochemi-
cal features and consequently its biological properties. Be-
cause of this, trifluoromethylated compounds have played a
unique and significant role in agricultural and medicinal
chemistry.[1] This fact explains the continuing interest in de-
veloping general methods for the synthesis of this kind of
compound and especially in the enantioselective construc-
tion of stereogenic centers bearing a CF3 group. Among
these compounds, molecules having an asymmetric tertiary
carbon center attached to a trifluoromethyl group without
any heteroatom substituent have been shown to be challeng-
ing synthetic targets.[2]
Scheme 1. Retrosynthetic analysis to chiral trifluoromethylated indoles.
uses the Ruppert–Prakash (Me3SiCF3) reagent. However, al-
though this reagent has found widespread application in the
trifluoromethylation of C=O and C=N bonds,[3] its enantio-
selective addition to electron-deficient alkenes (Michael re-
action) has remained virtually unexplored.[4] In fact, to the
best of our knowledge, no enantioselective conjugate tri-
fluoromethylation reaction of a,b-unsaturated ketones has
been reported so far. A second strategy may be the addition
of carbon nucleophiles to b-trifluoromethyl a,b-unsaturated
carbonyl compounds. However, this reaction still constitutes
a major challenge in synthetic chemistry. So far, the use of
b-trifluoromethyl a,b-unsaturated carbonyl compounds as
acceptors in conjugated addition reactions has been limited.
A few examples of non-enantioselective reactions have been
reported,[5] and the addition of arylboronic acids is the only
enantioselective example of such a addition reported so
far.[2]
In this context, two general strategies for the asymmetric
synthesis of this type of stereogenic tertiary carbon center
[a] Dr. G. Blay, Dr. I. Fernꢀndez, Prof. Dr. J. R. Pedro, C. Vila
Departament de Quꢁmica Orgꢂnica,
Facultat de Quꢁmica, Universitat de Valꢃncia
Dr. Moliner 59, 46100 Burjassot, Valꢃncia (Spain)
Fax : (+34)963544328
E-mail: jose.r.pedro@uv.es
[b] Prof. Dr. M. C. MuÇoz
Centro de Tecnologꢁas Fꢁsicas
Universidad Politꢄcnica de Valencia
Camꢁ de Vera S/N, 46022 Valencia (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000568.
Chem. Eur. J. 2010, 16, 9117 – 9122
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9117

Table 1. Ligand evaluation and optimization of the enantioselective Frie-
On the other hand, the indole nucleus is present in nu-
merous compounds of biological and/or pharmaceutical in-
terest, and new chemical methods for its synthesis have
been developed for more than a hundred years.[6] Recently,
the Lewis-acid-catalyzed Friedel–Crafts alkylation of indoles
has proved to be one of the most efficient methods to
obtain enantiomerically enriched alkylated indoles by using
prochiral unsaturated compounds as electrophiles in the
presence of chiral metal complexes.[7] To date, most of the
successful examples of such processes are limited to the use
of bidentate chelating carbonyl substrates[8] and nitroal-
kenes,[9] whereas the use of simple nonchelating a,b-unsatu-
rated carbonyl compounds as electrophiles remains rare.[10]
Very recently, during the preparation of this manuscript,
Shibata et al. reported the enantioselective Friedel–Crafts
reaction of b-trifluoromethylated acrylates with pyrroles and
indole.[11]
del–Crafts reaction of 1a with 2a.[a]
Solvent
Catalyst
L1–Zr(OtBu)4
L2–Zr(OtBu)4
L3–Zr(OtBu)4
L4–Zr(OtBu)4
L5–Zr(OtBu)4
L6–Zr(OtBu)4
L3–Ti(OiPr)4
L3–Hf(OtBu)4
L3–Zr(OtBu)4
L3–Zr(OtBu)4
L3–Zr(OtBu)4
L3–Zr(OtBu)4
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
N
5
6
62
52
87
22
32
18
78
91
23
–
12
8
AHCTUNGTRENNUNG
E
3.5
22
22
24
44
5
20
24
24
4.5
96
25
50
60
15
86
80
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
T
10
11[d]
12[e]
ACHTUNGTRENNUNG
CH2Cl2
CH2Cl2
R
64
80
86
99
AHCTUNGTRENNUNG
[a] Reaction carried out with 1a (0.15 mmol), 2a (0.125 mmol), (R)-L
(0.025 mmol), metal alkoxide (0.025 mmol) in solvent (2 mL) at RT.
[b] Isolated yield of 3aa. [c] Determined by chiral HPLC analysis.
[d] 10 mol% catalyst used in this run. [e] Reaction carried out at 08C.
Herein, we describe the enantioselective Friedel–Crafts
reactions of b-trifluoromethyl-a,b-unsaturated ketones 2
with indoles 1 catalyzed by a chiral BINOL-type zirconi-
tetrahydrogenated ring. Ligand L3, with two bromine atoms
at the 3,3’ positions, led to the best result and gave com-
pound 3aa with 87% yield and 96% ee (Table 1, entry 3).
This result seemed to indicate that substitution at the 3,3’-
positions of BINOL was essential to obtain high enantiose-
lectivities. However, use of the highly hindered 3,3’-diaryl-
BINOL ligand (L6) led to reaction product 3aa with low
yield (18%) and 60% ee (Table 1, entry 6). The use of other
group IV metal alcoxides was also tested. Performing the re-
ACHTUNGTRENNUNGum(IV) tert-butoxide complex as a new convenient method
to functionalize the C3 position of the indole nucleus with a
side chain bearing a stereogenic tertiary center attached to a
trifluoromethyl group.[12]
Results and Discussion
Our initial studies were performed by using b-trifluorometh-
yl-a,b-enone 2a, which is readily prepared according to a
modified literature procedure,[13] and indole (1a) as shown
in Scheme 2, Table 1. The first reactions were carried out in
CH2Cl2 at room temperature and were aimed at exploring
action with Ti
tion rate, and product 3aa was obtained with low ee
(Table 1, entry 7), whereas by using Hf(OtBu)4 (Table 1,
entry 8) the reaction product was obtained with good yield
(91%), albeit with a somewhat lower enantioselectivity
ACHTUNGTERNN(UNG OiPr)4 and ligand L3 resulted in a slow reac-
AHCTUNGTRENNUNG
the effectiveness of Zr
G
(86% ee) than with ZrACTHNGUTERNNU(G OtBu)4. The use of aromatic hydro-
other BINOL-type ligands (L2–L5), which contain electron-
withdrawing groups at the 3,3’ and 6,6’ positions as well as a
carbon solvents (toluene) or ethers (THF) resulted in lower
yields and enantioselectivities (Table 1, entries 9 and 10).
An attempt to decrease the catalyst loading to 10 mol% re-
sulted in a lower yield and enantioselectivity (Table 1,
entry 11). Finally, lowering the temperature to 08C im-
proved the enantioselectivity up to 99% ee, although the
yield of product 3aa was somewhat lower (84%; Table 1,
entry 12).
With these optimized reaction conditions (Table 1, en-
tries 3 and 12), we next investigated the Friedel–Crafts reac-
tion of various b-trifluoromethyl-a,b-enones 2 with indole
(1a). b-Trifluoromethyl enones 2 with a sterically demand-
ing aromatic group bound to the carbonyl group produced
trifluoroalkylated indoles 3aa–aj in excellent yields and high
enantioselectivities (up to 99% ee) in most cases (Table 2).
The reaction with b-trifluoromethyl-a,b-enones containing
weak electron-donating or electron-withdrawing groups on
the aromatic ring gave better enantioselectivities than those
containing strong electron-donating or electron-withdrawing
groups on the aromatic ring (Table 2, entries 2 and 5 vs. en-
tries 4 and 6). The ortho substitution on the aromatic ring of
the b-trifluoromethyl-a,b-enone lowered the reaction rate
and the yield of the trifluoroalkylation product dropped to
Scheme 2. Friedel–Crafts reaction of indole (1a) with b-trifluoromethyl-
a,b-enone 2a, and the structure of the BINOL-type ligands used in this
study.
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Chem. Eur. J. 2010, 16, 9117 – 9122

Enantioselective Friedel–Crafts Reaction
FULL PAPER
Table 2. Enantioselective Friedel–Crafts reaction of indole (1a) with b-trifluoromethyl-a,b-enones 2 catalyzed
analysis (Figure 1) to be R, and
for the rest of the products it
was assigned on the assumption
of a uniform mechanistic path-
way.[15]
by L3–ZrACHTUNGTRENNUNG
(OtBu)4.[a]
Compounds 3 could be trans-
formed into several CF3-con-
taining building blocks by
chemical transformation of the
carbonyl group (Scheme 3). For
example, we have carried out
an interesting reduction of the
carbonyl group of compounds
3aa, 3ab, 3ai, and 3ba to meth-
ylene to give compounds 4aa,
4ab, 4ai, and 4ba in almost
quantitative yield.
Enone
R1
R2
t [h]
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2 f
2g
2h
2i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
3.5 (4.5)
2 (5)
22
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
87 (80)
95 (98)
30
93 (99)
89 (85)
97 (88)
97 (82)
93 (90)
44
96 (99)
97 (95)
94
91 (97)
93 (81)
64 (66)
76 (92)
96 (98)
92
p-MeC6H4
o-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NO2C6H4
2-naphthyl
2-thienyl
Ph
7 (23)
1.5 (3)
1.2 (4)
6 (22)
5 (23)
48
CF3CF2
CF3CF2
10
2j
p-MeC6H4
31
3aj
46
93
Considering the usefulness of
[a] Reaction carried out with 1a (0.15 mmol), 2 (0.125 mmol), (R)-L3 (0.025 mmol), ZrACTHNUTRGENUGN(OtBu)4 (0.025 mmol)
in CH2Cl2 (2 mL) at RT. Data in parenthesis are for the same reaction carried out at 08C. [b] Isolated yield of pyrroles as pharmaceuticals, we
3. [c] Determined by chiral HPLC analysis. The (R)-configuration was assigned from X-ray crystallographic
analysis of 3ae and on the assumption of a uniform mechanistic pathway for the rest of products 3.
have also attempted to expand
the scope of the reaction to in-
30% (94% ee), which indicates the existence of a steric
Table 3. Enantioselective Friedel–Crafts reaction of indole (1a) with b-
trifluoromethyl-a,b-enones 2 catalyzed by L3–ZrACTHNUTRGNEUNG
(OtBu)4.[a]
effect of the ortho substituents on the reactivity (Table 2,
entry 3). In addition, the 2-naphthyl- and the heteroaromatic
b-trifluoromethyl-a,b-enones 2g and 2h can also serve as
substrates in this reaction, giving the corresponding
trifluoroACHTUNGTRENNUNGalkylated indoles in excellent yields and high enan-
tioselectivities (Table 2, entries 7 and 8). The influence of
the size of the fluoroalkyl group (CF3 or CF3CF2)[14] at the b
position was also investigated. In the case of CF3CF2, a di-
minished reactivity and lower yield were observed (Table 2,
entries 9–10), but the reactions proceeded with high enantio-
selectivities (92–93% ee). Finally, we studied the indole
scope of the reaction. Indoles bearing electron-donating
groups (CH3, CH3O) or electron-withdrawing groups (Br) at
the 5-position of the indole ring (1b–d) were treated with b-
trifluoromethyl-a,b-enone 2a to provide the corresponding
Indole R1 R2 R5
R6 R7
t
Prod- Yield[b] ee[c]
uct [%] [%]
[h]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me 22
H
H
3.5 (4.5) 3aa
5.5 (23) 3ba
4 (22)
27
87(80) 96 (99)
95 (69) 90 (94)
99 (76) 85 (82)
Me
MeO
Br
H
H
H
3ca
3da
3ea
3 fa
3ga
3ha
89
76
64
34
90
94
82
70
24
90
27
22
5
H
trifluoroACHTUNGTRENNUNGalkylated indoles 3aa–da in good to excellent yields
[a] Reaction carried out with 1 (0.15 mmol), 2 (0.125 mmol), (R)-L3
(0.025 mmol), Zr(OtBu)4 (0.025 mmol) in CH2Cl2 (2 mL) at RT. Data in
and enantioselectivities (Table 3, entries 2–4). With regard
to the substituent effect on the indole ring (Table 3), neither
the presence of electron-donating groups (CH3, CH3O) nor
electron-withdrawing groups (Br) at the 5-position of the
indole nucleus affected the enantioselectivity of the reac-
tion, but the reaction rate was indeed unfavorably influ-
enced in the case of 5-bromoindole (1d), which required a
reaction time of 27 h at room temperature (Table 3, en-
tries 1–4). Also, 2-methylindole (1e) and 7-methylindole
(1 f) reacted with 2a, although with decreased reactivity, to
give 3ea and 3 fa, respectively, with yields and enantioselec-
tivities somewhat lower (Table 3, entries 5–6). Finally, 1-
methylindole (1g), with a substituted nitrogen atom, gave
the corresponding alkylated product 3ga with low yield and
enantioselectivity (Table 3, entry 7).
AHCTUNGTRENNUNG
parenthesis are for the same reaction carried out at 08C. [b] Isolated
yield of 3. [c] Determined by chiral HPLC analysis. (R)-Configuration
was assigned on the assumption of a uniform mechanistic pathway for
products 3, cf. 3ae.
clude pyrrole (5) as a nucleophilic heteroarene (Scheme 4).
When the set of reaction conditions used in the Friedel–
Crafts reaction of indoles 1 with b-trifluoromethyl-a,b-
enones 2 was applied to the reaction with pyrrole (5;
10 equiv to avoid the formation of dialkylated products), the
reaction was complete in 1 h and gave the 2-trifluoroalkyl-
AHCTUNGTREGaNNNU ted-pyrrole 6a in excellent yield (99%) although with a
low ee (27%). Unfortunately, further attempts to optimize
the reaction with pyrrole led to modest results, the best
result was obtained with ligand L6, which afforded the tri-
The absolute configuration of the stereogenic center in
compound 3ae was determined by X-ray crystallographic
Chem. Eur. J. 2010, 16, 9117 – 9122
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. R. Pedro et al.
Experimental Section
General methods: Glassware was oven-dried overnight at 1208C. Reac-
tions were monitored by TLC analysis by using Merck silica gel 60 F-254
thin-layer plates. Flash column chromatography was performed on Merck
silica gel 60, 0.040–0.063 mm. NMR spectra were run by using a Bruker
Avance 300 spectrometer with residual nondeuterated solvent as the in-
ternal standard. Specific optical rotations were measured by using a
Perkin–Elmer polarimeter using sodium light (D line 589 nm). EI mass
spectra were recorded by using a Fisons Instruments VG Autospec
GC 8000 series at 70 eV. ESI mass spectra were recorded by using a
Waters Q-TOF premier mass spectrometer with an electrospray source
and a capillary voltage of 3.3 kV. Chiral HPLC analyses were performed
by using an Agilent 1100 series instrument equipped with a refraction
index detector or by using a Hitachi Elite Lachrom instrument equipped
with a Hitachi UV diode-array L-4500 detector and chiral stationary col-
umns from Daicel. CH2Cl2 and toluene were dried over CaH2 prior to
use. All BINOL-type ligands and all indoles 1 were commercially avail-
able and used as purchased without further purification.
Figure 1. X-ray structure for compound 3ae. Flack parameter 0.03 (10).
General procedure for the synthesis of b-trifluoromethyl-a,b-enones (2a–
h): Pyrrolidine (0.6 mL, 7 mmol), trifluoroacetaldehyde hemiacetal
(1.29 mL, 10 mmol) and the corresponding acetophenone (10 mmol)
were dissolved in toluene. The mixture was heated at reflux until the
starting material was completely reacted (monitored by TLC). Then, the
solvent was removed under reduced pressure and the resulting product
was chromatographed on silica gel by eluting with hexane/EtOAc (97:3
to 95:5) to afford the desired b-trifluoromethyl-a,b-enones 2a–h.
(E)-4,4,4-Trifluoro-1-phenylbut-2-en-1-one (2a):[16] Yellow liquid, 79%
yield. H NMR (300 MHz, CDCl3): d=7.98 (dd, J=7.2, 1.5 Hz, 2H), 7.65
(t, J=7.4 Hz, 1H), 7.58–7.49 (m, 3H), 6.82 ppm (dq, J=15.5, 6.7 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): d=188.0 (C), 136.1 (C), 134.1 (CH),
Scheme 3. Hydrogenation of compounds 3. a) H2, 10% Pd/C, EtOH/
THF.
1
131.0 (q, J
N
ACHTUNGERTN(NUNG C,F)=35.0 Hz; CH), 129.0
(CH), 128.8 (CH), 122.5 ppm (q, JAHCNUTGTRENNUNG
General procedure for the synthesis of b-pentafluoro enones (2i–j): Pyr-
rolidine (0.21 mL, 2.5 mmol), pentafluoropropionaldehyde monohydrate
(950 mg, 5 mmol), and acetic acid (0.21 mL, 2.5 mmol) were dissolved in
the corresponding acetophenone (2.5 mL). The mixture was heated at
reflux until starting material was completely reacted (monitored by
TLC). Then the solvent was removed under reduced pressure and the re-
sulting product was chromatographed on silica gel by eluting with
hexane/EtOAc (97:3 to 9:1) to afford the b-hydroxyketones. These b-hy-
droxyketones were dissolved in toluene (15 mL) and p-toluenesulfonic
acid (15 mol%) was added. The mixture was heated at reflux until the
starting material was completely reacted (monitored by TLC). Then, the
solvent was removed under reduced pressure and the product was chro-
matographed on silica gel by eluting with hexane/EtOAc (97:3) to afford-
ed the desired enone (2i–j).
Scheme 4. Enantioselective Friedel–Crafts reaction of pyrrole 5 with b-
trifluoromethyl-a,b-enone 2a. The reaction was carried out by using 5
(1.25 mmol), 2a (0.125 mmol), (R)-L6 (0.025 mmol), ZrACTHNUTRGNEUNG(OtBu)4
(0.025 mmol) in CH2Cl2 (2 mL) at RT.
fluoroalkylated pyrrole with 82% yield and 55% ee of the
opposite enantiomer.
(E)-4,4,5,5,5-Pentafluoro-1-phenylpent-2-en-1-one (2i):[16] Yellow liquid,
93% yield. 1H NMR (300 MHz, CDCl3): d=7.98 (dd, J=8.4, 1.2 Hz,
2H), 7.65 (tt, J=7.6, 1.8 Hz, 1H), 7.60 (dt, J=15.7, 2.1 Hz, 1H), 7.53 (t,
J=7.5 Hz, 1H), 6.85 ppm (tq, J=15.7, 11.9, 0.8 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=187.5 (C), 136.1 (C), 134.2 (CH), 133.0 (t, J-
Conclusion
In conclusion, we have shown that chiral BINOL-type/Zr-
ACHTUNGTRENNUNG(OtBu)4 complexes are very effective catalysts for the enan-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
tioselective Friedel–Crafts reaction of indole derivatives
with a number of b-trifluoromethyl-a,b-unsaturated ketones.
The reaction proceeds with good yields and excellent enan-
tioselectivities (up to 99%) and gives functionalized indoles
with an asymmetric tertiary carbon center attached to a tri-
fluoromethyl group. The conditions are of application to a
large number of substituted b-trifluoromethyl aryl enones
and indoles. The use of ligands that are commercially avail-
able in both enantiomeric forms (thus providing access to
both enantiomeric products) and a simple experimental pro-
cedure at room temperature constitute additional advantag-
es of this method.
AHCTUNGTRENNUNG
solution of ligand L3 (11.1 mg, 0.025 mmol) in dry CH2Cl2 (1 mL) under
N2 at RT. After 1 h, a solution of indole 1 (0.15 mmol) and enone 2
(0.125 mmol) in dry CH2Cl2 (1 mL) was added and the mixture stirred at
RT. After completion of the reaction (monitored by TLC), the mixture
was filtered through a short pad of silica gel (eluent: Et2O). The solvents
were removed under reduced pressure and products 3 were directly iso-
lated by flash chromatography on silica gel (hexane/EtOAc or hexane/
CH2Cl2 mixtures).
(R)-4,4,4-Trifluoro-3-(1H-indol-3-yl)-1-phenylbutan-1-one (3aa): The ee
(99%) was determined by HPLC analysis, Chiralcel OD-H, iPrOH/
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Chem. Eur. J. 2010, 16, 9117 – 9122

Enantioselective Friedel–Crafts Reaction
FULL PAPER
hexane (1:9), flow rate=1.0 mLminÀ1
,
major enantiomer (R) tr =
[5] a) O. Marrec, J. Borrini, B. Thierry, B. R. Langlois, Synlett 2009,
1241–1244; b) J. L. Garcꢁa-Ruano, T. de Haro, R. Singh, M. B. Cid,
J. Org. Chem. 2008, 73, 1150–1153; c) A. Powell, M. Al Nakeeb, B.
Wilkinson, J. Micklefield, Chem. Commun. 2007, 2683–2695;
d) V. Y. Sosnovskikh, M. A. Barabanov, B. I. Usachev, J. Org. Chem.
2004, 69, 8297–8304; e) N. Miyake, T. Kitazume, J. Fluorine Chem.
2003, 122, 243–246.
[6] a) I. Mancini, G. Guella, H. Zibrowius, F. Pietra, Tetrahedron 2003,
59, 8757–8762; b) T. Kam, Y. Choo, J. Nat. Prod. 2004, 67, 547–552;
c) A. C. Kinsman, M. A. Kerr, J. Am. Chem. Soc. 2003, 125, 14120–
14125; d) U. Huber, R. E. Moore, G. M. L. Patterson, J. Nat. Prod.
1998, 61, 1304–1306; e) D. J. Rawson, K. N. Dack, R. P. Dickinson,
K. James, Bioorg. Med. Chem. Lett. 2002, 12, 125–128; f) R. D. Dil-
lard, N. J. Bach, S. E. Draheim, D. R. Berry, D. G. Carlson, N. Y.
Chirgadze, D. K. Clawson, L. W. Hartley, L. M. Johnson, N. D.
Jones, E. R. McKinney, E. D. Mihelich, J. L. Olkowski, R. W. Sche-
vitz, A. C. Smith, D. W. Snyder, C. D. Sommers, J.-P. Wery, J. Med.
Chem. 1996, 39, 5119–5136; g) J. Chang-Fong, J. B. Rangisetty, M.
Dukat, V. Setola, T. Raffay, B. Roth, R. Glennon, Bioorg. Med.
Chem. Lett. 2004, 14, 1961–1964.
[7] a) For reviews on the Friedel–Crafts reaction, see: G. A. Olah, R.
Krishnamurti, G. K. S. Prakash in Comprehensive Organic Synthesis,
Vol. 3 (Eds.: B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991,
pp. 293–339. For reviews on enantioselective Friedel–Crafts reac-
tions, see: b) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew.
Chem. 2004, 116, 560–566; Angew. Chem. Int. Ed. 2004, 43, 550–
556; c) K. A. Jørgensen, Synthesis 2003, 1117–1125; d) M. Bandini,
A. Melloni, S. Tommasi, A. Umani-Ronchi, Synlett 2005, 1199–
1222; e) T. B. Poulsen, K. A. Jorgensen, Chem. Rev. 2008, 108, 2903–
2915; f) Catalytic Asymmetric Friedel–Crafts Alkylations (Eds.: M.
Bandini, A. Umani-Ronchi), Wiley-VCH, Weinheim, 2009.
[8] a) K. B. Jensen, J. Thorhauge, R.-G. Hazell, K. A. Jørgensen,
Angew. Chem. 2001, 113, 164–167; Angew. Chem. Int. Ed. 2001, 40,
160–163; b) D. A. Evans, K. A. Scheidt, K. R. Frandrick, H. W.
Lam, J. Wu, J. Am. Chem. Soc. 2003, 125, 10780–10781; c) W.
Zhuang, T. Hausen, K. A. Jørgensen, Chem. Commun. 2001, 347–
348; d) J. Zhou, Y. Tang, J. Am. Chem. Soc. 2002, 124, 9030–9031;
e) J. Zhou, Y. Tang, Chem. Commun. 2004, 432–433; f) J. Zhou, M.-
C. Ye, Z.-Z. Huang, Y. Tang, J. Org. Chem. 2004, 69, 1309–1320;
g) C. Palomo, M. Oiarbide, B. G. Kardak, J. M. Garcia, A. Linden, J.
Am. Chem. Soc. 2005, 127, 4154–4155; h) D. A. Evans, K. R. Fan-
drick, H. J. Song, J. Am. Chem. Soc. 2005, 127, 8942–8943; i) H.
Yang, Y.-T. Hong, S. Kim, Org. Lett. 2007, 9, 2281–2284; j) G. Desi-
moni, G. Faita, M. Toscanini, M. Boiochi, Chem. Eur. J. 2008, 14,
3630–3636; k) M. Rueping, B. J. Nachsteim, S. A. Moreth, M. Bolte,
Angew. Chem. 2008, 120, 603–606; Angew. Chem. Int. Ed. 2008, 47,
593–596; l) P. K. Singh, V. K. Singh, Org. Lett. 2008, 10, 4121–4124;
m) A. J. Boersma, B. L. Feringa, G. Roelfes, Angew. Chem. 2009,
121, 3396–3398; Angew. Chem. Int. Ed. 2009, 48, 3346–3348; n) Y.
Liu, D. Shang, X. Zhou, X. Liu, X. Feng, Chem. Eur. J. 2009, 15,
2055–2058.
14.9 min, minor enantiomer (S) tr =13.9 min; m.p. 117–1208C (CH2Cl2/
hexane); [a]2D5 +57.5 (c=0.74 in CHCl3, 99% ee); 1H NMR (300 MHz,
CDCl3): d=8.14 (brs, 1H), 7.92 (dd, J=7.2, 1.2 Hz, 2H), 7.76 (dd, J=
6.9, 1.2 Hz, 1H), 7.56 (tt, J=7.4, 1.5 Hz, 1H), 7.44 (t, J=7.4 Hz, 2H),
7.35 (dd, J=6.9, 2.4 Hz, 1H), 7.24–7.15 (m, 3H), 4.70–4.56 (m, 1H), 3.75
(dd, J=17.6, 8.3 Hz, 1H), 3.66 ppm (dd, J=17.4, 4.8 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=195.9 (C), 136.3 (C), 136.0 (C), 133.5 (CH), 128.7
(CH), 128.0 (CH), 127.4 (q, J
ACHTUNGTERN(NGNU C,F)=277.5 Hz, CF3), 126.5 (C), 123.4
(CH), 122.4 (CH), 120.1 (CH), 119.2 (CH), 111.4 (CH), 109.7 (q, J-
ACHTUNGTRENNUNG(C,F)=2.3 Hz; C), 38.3 (q, JAHCTUNRTEGNN(GUN C,F)=1.5 Hz; CH2), 36.7 ppm (q, JACTHNUGTREN(NUGN C,F)=
28.8 Hz, CH); 19F NMR (282 MHz, CDCl3): d=À70.59 ppm (s, CF3); EI
MS: m/z (%): 297 [M]+ (81), 297 (34), 212 (58), 198 (55), 105 (100), 77
(32); HRMS: m/z calcd for C18H14F3NO: 317.1027 [M]+; found: 317.1019.
General procedure for the reduction of the carbonyl group: Compound 3
was dissolved in a mixture of EtOH/THF (2:1) on a two-necked flask.
After that, 10% Pd/C (20 mg) was added, and the mixture was stirred
under H2 at atmospheric pressure. After completion of the reaction
(monitored by TLC), the mixture was filtered through a short pad of
silica gel (eluent: Et2O). The solvents were removed under reduced pres-
sure to give compound 4.
(R)-3-(1,1,1-Trifluoro-4-phenylbutan-2-yl)-1H-indole (4aa): The product
was isolated as an oil. The ee (98%) was determined by HPLC analysis,
Chiralpak AD-H, iPrOH/hexane (1:9), flow rate=1.0 mLminÀ1, major
enantiomer (R) tr =8.1 min, minor enantiomer (S) tr =13.5 min; [a]D25
À12.3 (c 1.23, CHCl3, 98% ee); 1H NMR (300 MHz, CDCl3): d=8.20
(brs, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.42 (dt, J=7.8, 0.9 Hz, 1H), 7.30–
7.15 (m, 6H), 7.09 (dd, J=8.1, 1.5 Hz, 2H), 3.75 (dqd, J=19.1, 9.5,
4.3 Hz, 1H), 2.68 (ddd, J=13.8, 9.0, 5.4 Hz, 1H), 2.58–2.25 ppm (m, 3H);
13C NMR (75.5 MHz, CDCl3): d=140.9 (C), 136.2 (C), 128.5 (CH), 128.4
(CH), 127.4 (q, J
(CH), 122.5 (CH), 120.0 (CH), 119.2 (CH), 111.3 (CH), 109.6 (q, J-
(C,F)=2.5 Hz; C), 40.8 (q, J(C,F)=27.9 Hz; CH), 32.8 (CH2), 30.3 ppm
ACHTUNGTRENNUNG(C,F)=277.8 Hz; CF3), 127.2 (C), 126.1 (CH), 123.4
A
ACHTUNGTRENNUNG
(q, JACHTUNGTRENNUNG
(s, CF3); ESI HRMS: m/z calcd for C19H17F3N: 304.1313 [M+H]+; found:
304.1310.
Acknowledgements
Financial support from the Ministerio de Ciencia e Innovaciꢆn and
FEDER (grants CTQ2006-14199 and CTQ2009-13083) and from Gener-
alitat Valenciana (ACOMP/2009/338) is acknowledged. C.V. thanks the
Generalitat Valenciana for a pre-doctoral grant.
[1] a) Organofluorine Compounds: Chemistry Applications (Ed.: T.
Hiyama), Springer, New York, 2000; b) P. Kirsch, Modern Fluoroor-
ganic Chemistry, Wiley-VCH, Weinheim, 2004; c) R. D. Chambers,
Fluorine in Organic Chemistry, Blackwell, Oxford, 2004; d) P. A.
Shah, D. Westwell, J. Enzyme Inhib. Med. Chem. 2007, 22, 527–540;
e) K. Mꢇller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886;
f) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305–321; g) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37,
320–330.
[9] a) W. Zhuang, R. G. Hazell, K. A. Jørgensen, Org. Biomol. Chem.
2005, 3, 2566–2571; b) R. P. Herrera, V. Sgarzani, L. Bernardi, A.
Ricci, Angew. Chem. 2005, 117, 6734–6737; Angew. Chem. Int. Ed.
2005, 44, 6576–6579; c) Y. X. Jia, S. F. Zhu, Y. Yang, Q. L. Zhou, J.
Org. Chem. 2006, 71, 75–80; d) J. Itoh, K. Fuchibe, T. Akiyama,
Angew. Chem. 2008, 120, 4080–4082; Angew. Chem. Int. Ed. 2008,
47, 4016–4018; e) M. Ganesh, D. Seidel, J. Am. Chem. Soc. 2008,
130, 16464; f) T. Arai, N. Yokoyama, Angew. Chem. 2008, 120,
5067–5070; Angew. Chem. Int. Ed. 2008, 47, 4989–4992.
[10] a) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
7894–7895; b) M. Bandini, M. Fagioli, M. Garavelli, A. Melloni, V.
Trigari, A. Umani-Ronchi, J. Org. Chem. 2004, 69, 7511–7518; c) M.
Terada, K. Sorimachi, J. Am. Chem. Soc. 2007, 129, 292–293; d) G.
Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P. Mel-
chiorre, Org. Lett. 2007, 9, 1403–1405; e) W. Chen, W. Du, L. Yue,
R. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, Org. Biomol. Chem. 2007, 5,
816–821; f) G. Blay, I. Fernꢀndez, J. R. Pedro, C. Vila, Org. Lett.
2007, 9, 2601–2604; g) G. Blay, I. Fernꢀndez, A. Monleꢆn, J. R.
[2] T. Konno, T. Tanaka, T. Miyabe, A. Morigaki, T. Ishihara, Tetrahe-
dron Lett. 2008, 49, 2106–2110.
[3] a) T. Billard, B. R. Langlois, Eur. J. Org. Chem. 2007, 891–897; b) N.
Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008, 19,
2633–2644; c) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1-
PR43; d) K. Uneyama, T. Katagiri, H. Amii, Acc. Chem. Res. 2008,
41, 817–829; e) S. Matsukawa, M. Saijo, Tetrahedron Lett. 2008, 49,
4655–4657.
[4] a) A. A. Zemtsov, V. V. Levin, A. D. Dilman, M. I. Struchkova, P. A.
Belyakov, V. A. Tartakovsky, Tetrahedron Lett. 2009, 50, 2998–3000;
b) A. D. Dilman, V. V. Levin, P. A. Belyakov, M. I. Struchkova,
V. A. Tartakovsky, Tetrahedron Lett. 2008, 49, 4352–4354.
Chem. Eur. J. 2010, 16, 9117 – 9122
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9121

J. R. Pedro et al.
Pedro, C. Vila, Adv. Synth. Catal. 2009, 351, 2433–2440; h) Y. Chi,
S. T. Scroggins, J. M. J. Frechet, J. Am. Chem. Soc. 2008, 130, 6322–
6323; i) L. Hong, L. Wang, C. Chen, B. Zhang, R. Wang, Adv. Synth.
Catal. 2009, 351, 772–778; j) P. Galzerano, F. Pasciaioli, A. Mazzan-
ti, G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121, 8032–8034;
Angew. Chem. Int. Ed. 2009, 48, 7892–7894; k) Q. Cai, Z.-A. Zhao,
S.-L. You, Angew. Chem. 2009, 121, 7564–7567; Angew. Chem. Int.
Ed. 2009, 48, 7428–7431; l) S. Adachi, F. Tanaka, K. Watanabe, T.
Harada, Org. Lett. 2009, 11, 5206–5209.
S. Sasaki, T. Yamauchi, K. Higashiyama, Tetrahedron Lett. 2010, 51,
2326–2328.
[13] K. Funabiki, K. Matsunaga, M. Nojiri, W. Hashimoto, H. Yamamo-
to, K. Shibata, M. Matsui, J. Org. Chem. 2003, 68, 2853–2860.
[14] K. Funabiki, H. Nagaya, M. Ishihara, M. Matsui, Tetrahedron 2006,
62, 5049–5053.
[15] CCDC-767788 (3ae) 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.
[16] G. Blond, T. Billard, B. R. Langlois, J. Org. Chem. 2001, 66, 4826–
4830.
[11] Y. Huang, E. Tokunaga, S. Suzuki, M. Shiro, N. Shibata, Org. Lett.
2010, 12, 1136–1138.
[12] For a very recent example of enantioselective Friedel–Crafts reac-
tion of indoles with a’-trifluoromethyl-a,b-unsaturated ketones, see:
Received: March 4, 2010
Published online: June 25, 2010
9122
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Chem. Eur. J. 2010, 16, 9117 – 9122