Enantioselective friedel-crafts alkylation of indoles with (e)-1-aryl-4-benzyloxybut-2-en-1-ones catalyzed by an (R)-3,3′-Br 2BINOLate-Hafnium(IV) complex

Article abstract of DOI:10.1002/ejoc.201201636

A highly enantioselective Friedel-Crafts reaction of unprotected indoles with (E)-1-aryl-4-benzyloxybut-2-en-1-ones catalyzed by a new chiral [Hf{(R)-3,3′-Br₂-BINOL}(OtBu)₂]₂ complex has been developed to functionalize the C-3 position of the indole nucleus with a side chain bearing a 1,4-difunctionalized moiety and a benzylic stereogenic center. The reaction proceeds in good to excellent yields and excellent enantioselectivities (up to 97 % ee). The usefulness of this approach was illustrated with the synthesis of a tryptophol derivative. Friedel-Crafts alkylation of unprotected indoles with (E)-1-aryl-4-benzyloxybut-2-en-1-ones is catalyzed by a chiral [Hf{(R)-3,3′-Br₂-BINOL}(OtBu) ₂]₂ complex to give C-3-functionalized indoles with good yields and enantiomeric excesses up to 98 %. The broad applicability of the reactions is shown with 18 examples, and its usefulness was illustrated with the synthesis of a tryptophol derivative.

Full text of DOI:10.1002/ejoc.201201636

FULL PAPER
DOI: 10.1002/ejoc.201201636
Enantioselective Friedel–Crafts Alkylation of Indoles with (E)-1-Aryl-4-
benzyloxybut-2-en-1-ones Catalyzed by an (R)-3,3Ј-Br2BINOLate–
Hafnium(IV) Complex
Gonzalo Blay,[a] Isabel Fernández,[a] M. Carmen Muñoz,[b] José R. Pedro,*[a] and
Carlos Vila[a]
Dedicated to the memory of Juan Fernández Torreblanca
Keywords: Alkylation / Asymmetric catalysis / C–C coupling / Hafnium / Regioselectivity
A highly enantioselective Friedel–Crafts reaction of unpro-
tected indoles with (E)-1-aryl-4-benzyloxybut-2-en-1-ones
catalyzed by a new chiral [Hf{(R)-3,3Ј-Br2-BINOL}(OtBu)2]2
complex has been developed to functionalize the C-3 posi-
tion of the indole nucleus with a side chain bearing a 1,4-
difunctionalized moiety and a benzylic stereogenic center.
The reaction proceeds in good to excellent yields and excel-
lent enantioselectivities (up to 97% ee). The usefulness of
this approach was illustrated with the synthesis of a trypto-
phol derivative.
In this paper we report the enantioselective Friedel–
Crafts reaction of indoles 1 with (E)-1-aryl-4-benzyloxybut-
2-en-1-ones 2[19] catalyzed by a new chiral (R)-3,3Ј-Br2-
BINOLate–hafnium(IV) tert-butoxide complex as a new
convenient procedure to functionalize the C-3 position of
the indole nucleus with a side chain bearing a 1,4-di-
functionalized moiety and a benzylic stereogenic center
(Scheme 1).
Introduction
The indole nucleus is present in many compounds of bio-
logical and pharmaceutical interest.[1] Consequently, there
has been continuing interest in the development of new
methods for the synthesis of indole derivatives. In the last
years, several catalytic systems based on chiral metal com-
plexes or organocatalysts have been developed and success-
fully applied to the enantioselective Friedel–Crafts alkyl-
ation of indoles with prochiral unsaturated electrophiles,
leading to enantiomerically enriched alkylated indoles.[2]
Most of the successful examples of such processes have
been limited to the use of bidentate chelating substrates[3–15]
and nitroalkenes,[16] whereas the use of nonchelating elec-
trophile substrates is usually limited to structurally simple
monofunctional α,β-unsaturated aldehydes[17] and en-
ones.[18] The study of new electrophilic partners for the
enantioselective Friedel–Crafts reaction that can provide
access to a broader range of functionalized enantiomer-
ically enriched indoles is of great interest for the develop-
ment of new synthetic strategies toward drugs and bioactive
compounds.
Scheme 1. Enantioselective Friedel–Crafts reaction between indoles
1 and (E)-1-aryl-4-benzyloxybut-2-en-1-ones 2 and BINOL-derived
ligands used in this study (M = group IV metal alkoxide).
[a] Departament de Química Orgánica, Facultat de Química,
Universitat de València,
C/Dr. Moliner 50, 46100 Burjassot (València), Spain
Fax: +34-963544328
E-mail: jose.r.pedro@uv.es
Homepage: www.uv.es
[b] Departament de Física Aplicada, Universitat Politècnica de
València,
Results and Discussion
Camino de Vera s/n, 46022 València, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201636.
Previously, we reported the enantioselective Friedel–
Crafts reaction of indoles with simple α,β-unsaturated
1902
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1902–1907

Enantioselective Friedel–Crafts Alkylation of Indoles
ketones and β-trifluoromethyl-α,β-unsaturated ketones the efficiency of [Zr(OtBu)4] with other BINOL-derived li-
catalyzed by a [Zr2{(R)-3,3Ј-Br2-BINOL}2(OtBu)4] com- gands, (L1, L2 and L4–L6). However, none of these ligands
plex.[20] These reactions were carried out with 20 mol-% cat- improved the results obtained with L3 (the results are not
alyst in dichloromethane at room temperature, giving the included in the Table 1). The use of other group IV metal
corresponding alkylated indoles with good yields and high alkoxides with L3 was then tested. Performing the reaction
enantioselectivities after 3.5 h. However, when these condi- with [Ti(OiPr)4] resulted in a slow reaction rate, and the
tions were applied to the Friedel–Crafts alkylations of the product 3aa was obtained in low yield (24%) and enantio-
indole (1a) with the new electrophile (E)-4-benzyloxy-1- selectivity (6% ee; Table 1, Entry 2). Interestingly, when
phenylbut-2-en-1-one (2a), we observed a slower reaction, [Hf(OtBu)4] was used, the reaction product was obtained
compared with our previous works, and the resulting prod- with good yield (90%) and excellent enantioselectivity
uct 3aa was obtained with good enantioselectivity (89% ee), (94% ee; Table 1, Entry 3). Ligands L1, L2 and L4–L6 were
albeit with low yield (49%; Table 1, Entry 1). A modifica- also tested with [Hf(OtBu)4], but they gave rise to lower
tion of the reaction conditions was first explored to improve enantioselectivities (Entries 4–8) than those obtained with
L3 (Entry 3). Next, a range of solvents were tested with
[(R)-L3-Hf(OtBu)4]. The results indicated that the solvent
Table 1. Screening of ligands, metal alkoxides and solvents for the
Friedel–Crafts reaction of 1a and enone 2a.[a]
plays an important role in governing the rate and enantio-
selectivity of the reaction. Coordinating and polar solvents
such as dioxane and diethyl ether (Entries 9 and 10) had a
negative influence on the catalytic activity of the [(R)-L3-
Hf(OtBu)4] complex. Other chlorinated solvents such as
chloroform and 1,2-dichloroethane (Entries 11 and 12) were
also investigated, but no superior results were obtained.
When the reaction was carried out in toluene (Entry 13)
good results were obtained, although they were somewhat
lower than those obtained with dichloromethane as solvent.
Reduction of the catalyst load to 10 mol-% had a deleteri-
ous effect on the reaction. Therefore, the optimal reaction
conditions were established as follows: indole (1a;
0.15 mmol), enone 2 (0.125 mmol) and [(R)-L3-Hf(OtBu)4]
(20 mol-%, 1:1), in CH2Cl2 (1.8 mL) at room temperature.
Under the optimized reaction conditions (Table 1, En-
try 3), several (E)-1-aryl-4-benzyloxybut-2-en-1-ones 2a–h
and indole (1a) were screened, giving the desired alkylated
indoles with high to excellent enantioselectivities (up to
97% ee). It is noteworthy that the electronic nature as well
as the position of the substituent on the phenyl ring of the
enone had little influence on the enantioselectivity or yield
of the reaction (Table 2, Entries 2–6). However, (E)-4-
benzyloxy-1-(p-methoxyphenyl)but-2-en-1-one (2e) reacted
Entry
Solvent
t
[h]
M(OR)4
L
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
Et2O
7
20
2
1.5
21
3
20
22
–
21
3
Zr(OtBu)4
Ti(OiPr)4
L3
L3
L3
L1
L2
L4
L5
L6
L3
L3
L3
L3
L3
49
24
90
98
55
94
12
19
–
58
60
48
87
89
6
94
33
4
33
52
67
–
67
54
72
92
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
CHCl3
(CH2Cl)2
toluene
24
4.5
[a] Reaction conditions: 1a (0.15 mmol, 1.2 equiv.), enone 2a
(0.125 mmol, 1 equiv.), (R)-BINOL ligand (20 mol-%), metal alk-
oxide (20 mol-%), solvent (1.8 mL), room temp., N2. [b] Isolated
yield of 3aa after flash chromatography. [c] Determined by HPLC
analysis on a Chiralcel OD-H column.
Table 2. Catalytic enantioselective Friedel–Crafts alkylation of indole (1a) with (E)-1-aryl-4-benzyloxybut-2-en-1-ones 2a–h catalyzed by
[(R)-L3-Hf (OtBu)4].[a]
Entry
2
R1
t [h]
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
2
3
2
2
24
2
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
90
86
98
81
45
78
90
93
94
92
97
84
87
86
92
84
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
p-BrC6H4
2-thienyl
2g
2h
1
2
2-furyl
[a] Reaction conditions: indole 1a (0.15 mmol, 1.2 equiv.), enones 2a–h (0.125 mmol, 1.0 equiv.), (R)-L3-Hf(OtBu)4 complex (0.025 mmol,
20 mol-%; 1:1), CH2Cl2 (1.8 mL) room temp., N2. [b] Isolated yield after flash chromatography. [c] Determined by chiral HPLC analysis.
Eur. J. Org. Chem. 2013, 1902–1907
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Blay, I. Fernández, M. C. Munoz, J. R. Pedro, C. Vila
FULL PAPER
slower, giving product 3ae with only 45% yield. In addition,
the heteroaromatic substrates 2g and 2h could also serve as
substrates for this reaction, giving the corresponding alkyl-
ated indoles with excellent yields and enantioselectivities
(Entries 7 and 8).
With regard to the substituent effect on the indole nu-
cleus, the reactions of a range of indoles 1a–i with enones
2a, 2b and 2f were examined (Table 3). Neither electron-
donating groups (CH3, CH3O) nor electron-withdrawing
groups (Br) at the 5-position of indole affected the enantio-
selectivity of the reaction, although the reaction rate and
yield were indeed unfavorably influenced in the case of 5-
bromoindole (1e), which required a reaction time of 22 h at
room temperature (Entry 7). Similarly, 2-methylindole (1g)
reacted slowly with 2a to give 3ga with good yield and
enantioselectivity (92% ee). However, the presence of a
methyl group at C-7 brought about a decrease in the reac-
Figure 1. X-ray structure of compound 3bf. Hydrogen atoms (ex-
cept N–H) have been omitted for clarity.
tion rate, yield, and enantioselectivity, with compound 3ha bly bridged [HfIV{μ-(R)-3,3Ј-Br2BINOL}]2 motif, in which
being obtained with only 48% yield and 51% ee (Entry 10). each BINOL ligand acts as bridge between the metal cen-
Finally, 1-methylindole (1i) gave the corresponding alkyl- ters, and all the tert-butoxide groups are terminal (Figure 2;
1
ated product 3ia in a 65% yield and 5% ee (Entry 11).
for H and 13C NMR spectra of the complex see the Sup-
The absolute configuration of the stereogenic center in porting Information).[23]
compound 3bf was determined to be (R) on the basis of X-
Activation of the benzyloxyenone 2 by HfIV coordination
ray crystallographic analysis (Figure 1); the configurations forms a substrate–catalyst complex B, which undergoes H-
of the rest of the products were assigned on the assumption bond-assisted (C) nucleophilic addition of the indole to the
of a uniform mechanistic pathway.[21]
double bond of the enone to provide the Friedel–Crafts ad-
A plausible catalytic cycle for the [(R)-L3-Hf(OtBu)4]- duct D. Subsequent H-transfer and decoordination of the
catalyzed Friedel–Crafts reaction between indoles and chiral enolate E afford the Friedel–Crafts product and re-
benzyloxyenones is outlined in Scheme 2. Based on our re- generate the catalyst A (Scheme 2). In this case, the use of
cent experimental and theoretical studies on the structure additional alcohol to facilitate the catalyst turnover[24] is
of complexes derived from (R)-3,3Ј-Br2-BINOL ligand and not necessary, because the 2 equiv. of tBuOH released after
group IV metal alkoxides,[22] the catalytic species generated generation of the complex seems to be enough to carry out
from stoichiometric quantities of (R)-3,3Ј-Br2-BINOL and catalyst regeneration.
tert-butoxide of Hf (without elimination of the tBuOH re-
Our working model to account for the stereoselectivity
leased) is a dimer at room temperature consisting of a dou- of the reaction is shown in Figure 3. The benzyloxyenone
Table 3. Catalytic enantioselective Friedel–Crafts alkylation of indoles 1a–i with (E)-1-aryl-4-benzyloxybut-2-en-1-ones 2a, 2b and 2f
catalyzed by [(R)-L3-Hf (OtBu)4].[a]
Entry
1
R1
R2
R3
R4
R5
2
Ar
t [h]
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1d
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
Me
Me
MeO
F
F
Br
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
2a
2a
2f
Ph
2
3
2
3
5
3aa
3ba
3bf
3ca
3da
3db
3eb
3fa
3ga
3ha
3ia
90
94
54
80
93
94
97
83
94
Ph
p-BrC6H4
Ph
2a
2a
2b
2b
2a
2a
2a
2a
Ph
92
p-MeC6H4
p-MeC6H4
Ph
3
85
93
22
24
30
30
2
52 (24)[d]
70
67 (98)[d]
68
92
51
5
1g
1h
1i
H
H
H
H
H
H
Ph
Ph
Ph
74
48
65
10
11
Me
H
H
[a] Reaction conditions: indoles 1a–i (0.15 mmol, 1.2 equiv.), (E)-1-aryl-4-benzyloxybut-2-en-1-ones 2a, 2b and 2f (0.125 mmol, 1.0 equiv.),
[(R)-L3-Hf(ButO)4] complex (0.025 mmol, 20 mol-%; 1:1), CH2Cl2 (1.8 mL), room temp., N2. [b] Isolated yield of 3. [c] Determined by
chiral HPLC analysis. [d] Yield and enantiomeric excess after crystallization are given in parentheses.
1904
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Eur. J. Org. Chem. 2013, 1902–1907

Enantioselective Friedel–Crafts Alkylation of Indoles
Figure 3. Proposed working stereomodel for the bifunctional mode
of action of the catalyst.
The alkylated indoles 3 prepared by this methodology
can be used to synthesize tryptophol derivatives by re-
duction of their carbonyl group and deprotection of the
benzyl ether. Thus, the hydrogenation of 3aa with Pd/C as
catalyst gave 2-(2-phenylethyl)-2-(3-indolyl)ethanol, [2-(2-
phenylethyl)tryptophol] (4) quantitatively, without any ap-
preciable loss of the enantiomeric excess of the starting ma-
terial (Scheme 3). Tryptophols are a class of indoles bearing
a 3-(hydroxyethyl) side chain substituted or not in the α-
and/or β-positions. Tryptophol and a number of its deriva-
tives have been isolated from a variety of natural sources,
and some are known to possess biological activity; thus, for
example, esters of 5-methoxytryptophol possess anticholin-
ergic activity.[26] Compared with previous established meth-
ods for the synthesis of tryptophols,[27] our methodology is
simple to conduct and delivers tryptophol derivatives with
high yields in enantiomerically pure form.
Scheme 2. Proposed catalytic cycle for the Friedel–Crafts alkylation
of indole with 4-benzyloxy-α,β-unsaturated ketones catalyzed by
[Hf{(R)-3,3Ј-Br2BINOL}(OtBu)2]2.
Figure 2. Dimeric structure of the hafnium complex [Hf{(R)-3,3Ј-
Br2BINOL}(OtBu)2]2.
Scheme 3. Synthesis of [2-(2-phenylethyl)tryptophol] (4).
coordinates to the hafnium atom in an approximately octa-
hedral geometry in complex B. The attack of indole on (E)-
1-aryl-4-benzyloxybut-2-en-1-one (2) takes place preferably
Conclusions
We have shown that the [Hf2{(R)-3,3Ј-Br2-BINOL}2-
from the Re face, leading to formation of the predominant (OtBu)4] complex is a very effective catalyst for the enantio-
(R)-configured adduct. The model shows also that the H selective Friedel–Crafts alkylation of unprotected indole de-
atom of the N–H group of the indole must form a hydrogen rivatives with a number of nonchelating (E)-1-aryl-4-benz-
bond with the basic oxygen atom of one 3,3Ј-Br2-BINOLate yloxybut-2-en-1-ones to give chiral indoles with a side chain
ligand, which plays an important role in stabilizing the tran- bearing a 1,4-difunctionalized moiety and a benzylic
sition state of the process. Accordingly, the absence of the stereogenic center. The reaction proceeds with yields and
hydrogen-bond interaction in the case of N-methylindole enantioselectivities ranging from good to excellent. The use
(1i) might explain why a lower enantiomeric excess was ob- of ligands that are commercially available in both enantio-
tained for product 3ia (65% yield, 5% ee). A bifunctional meric forms and a simple experimental procedure at room
mode of action of catalyst [Hf{(R)-(3,3Ј-Br2-BINOL)}- temperature constitutes additional advantages of this
(OtBu)2]2 is therefore proposed with simultaneous acti- method. Furthermore, the use of N-protecting groups can
vation of the benzyloxyenone by one hafnium atom and of be avoided in this indole alkylation, which enhances the effi-
the indole through BINOLate oxygen coordination with the ciency by which substituted indoles can be synthesized. Fi-
N–H group.[25]
nally, the alkylated indoles prepared by this methodology
Eur. J. Org. Chem. 2013, 1902–1907
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Blay, I. Fernández, M. C. Munoz, J. R. Pedro, C. Vila
FULL PAPER
hydrous CH2Cl2 (0.8 mL) at room temperature under nitrogen was
added [Hf(OtBu)4] (10 μL, 0.025 mmol). The mixture was stirred
for 1 h, then a solution of indole 1 (0.15 mmol) and (E)-1-aryl-4-
benzyloxy-2-buten-1-one 2 (0.125 mmol) in anhydrous CH2Cl2
(0.8 mL) were added by using a syringe. After completion of the
reaction (TLC), the mixture was filtered through a short pad of
silica gel eluting with diethyl ether. The solvents were removed un-
der reduced pressure, and the Friedel–Crafts products 3 were iso-
lated directly by flash chromatography on silica gel (hexane/
EtOAc).
can be efficiently transformed into tryptophol derivatives
by reduction of their carbonyl group and deprotection of
the benzyl ether without any appreciable loss of stereo-
chemical integrity.
Experimental Section
General Methods: All catalytic reactions were carried out in glass-
ware dried at 120 °C overnight. All air- and moisture-sensitive ma-
nipulations were performed under nitrogen by using standard tech-
niques. Reactions were monitored by using TLC (Merck Silica gel
60 F254). Flash column chromatography was performed on silica
gel 60, 0.040–0.063 mm. Melting points were measured with a
Büchi M-560 instrument and are uncorrected. NMR spectra for
the characterization of the Friedel–Crafts products were recorded
at 300 MHz for 1H and at 75 MHz for 13C nuclei with a Bruker
Avance 300 spectrometer. NMR studies of the catalytic species were
Experimental Procedure for the Synthesis of (R)-2-(2-Phenyleth-
yl)tryptophol (4): Alkylated indole 3aa (50 mg, 0.136 mmol) was
dissolved in a mixture of EtOH/THF (2:1, 3 mL) in a two-necked
flask; 10% Pd/C (10 mg) was added, and the reaction mixture was
stirred under hydrogen at atmospheric pressure. After completion
of the reaction (TLC), the mixture was filtered through a short pad
of silica gel eluting with diethyl ether. The solvents were removed
under reduced pressure to give (R)-2-(2-phenylethyl)tryptophol (4;
35.9 mg, 99%) as an oil. [α]2D5 = –5.9 (c = 1.25, CHCl3) (94% ee).
1H NMR (300 MHz, CDCl3): δ = 8.18 (br. s, 1 H), 7.66 (d, J =
7.9 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.30–7.12 (m, 7 H), 7.09
(d, J = 2.3 Hz, 1 H), 3.92–3.81 (m, 2 H), 3.22–3.13 (m, 1 H), 2.72–
2.56 (m, 2 H), 2.15 (t, J = 7.8 Hz, 2 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 142.3 (C), 136.7 (C), 128.4 (CH), 128.3 (CH), 126.9
(C), 125.7 (CH), 122.2 (CH), 122.1 (CH), 119.4 (CH), 119.3 (CH),
115.9 (C), 111.3 (CH), 66.5 (CH2), 39.5 (CH), 33.7 (CH2), 33.3
(CH2) ppm. HRMS (ESI): calcd. for C18H20NO [M + H+]
266.1545; found 266.1544. The enantiomeric excess (94%) was de-
termined by chiral HPLC analysis (Chiralpack AD-H; 2-propanol/
hexane, 20%; 1.0 mL/min): tR = 13.7 [(R), major], 11.2 [(S), minor]
min.
1
conducted at 400 MHz for H and 100 MHz for 13C nuclei with a
Bruker Avance 400 spectrometer. Residual non-deuterated solvent
was used as internal standard in all cases (δ = 7.26 ppm for 1H and
1
77.0 ppm for 13C in the case of CDCl3, δ = 5.35 ppm for H and
53.5 ppm for 13C NMR in the case of CD2Cl2). The carbon multi-
plicity was determined by DEPT experiments. Specific optical rota-
tions were measured by using sodium light (D line, 589 nm) and a
1 dm cell; concentrations (c) are given in g/100 mL. Chiral HPLC
analyses were performed with an Agilent 1100 series instrument
equipped with a refraction index detector or in a Hitachi Elite
Lachrom instrument equipped with a Hitachi UV diode-array L-
4500 detector by using chiral stationary columns from Daicel. Mass
spectra (EI) were recorded at 70 eV, and mass spectra (FAB) were
carried out at 30 kV in an MNBA matrix with a Fisons Instru-
ments VG Autospec GC 8000 series. ESI mass spectra were re-
corded with a Q-TOF premier mass spectrometer with an electro-
spray source. Nitrogen was used as the drying as well as the nebuliz-
ing gas. CH2Cl2 was distilled from P2O5 and stored over molecular
sieves (4 Å). THF was freshly distilled from Na/benzophenone un-
der nitrogen. All BINOL-type ligands, all indoles, LDA, NEt3,
methanesulfonyl chloride, aryl methyl ketones and 2-benzyloxyace-
taldehyde were commercially available and used as purchased with-
out further purification; [Zr(OtBu)4] and [Hf(OtBu)4] were pur-
chased from Fluka or Strem Chemicals and [Ti(OiPr)4] from Ald-
rich. (E)-1-Aryl-4-benzyloxy-2-buten-1-ones 2 were synthesized by
aldol reaction followed by dehydration (see the Supporting Infor-
mation).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, synthesis and characterization of en-
ones 2, characterization data for compounds 3 and 4; copies of
1H and 13C NMR spectra for compounds 3 and 4; chiral HPLC
chromatograms for compounds 3 and 4; 1H and 13C NMR spectra
of (R)-3,3Ј-Br2BINOL (L3) and the complex [Hf(OtBu)4-(R)-L3].
Acknowledgments
Financial support from the Ministerio de Ciencia e Innovación,
Gobierno de España and FEDER, European Union (Grant CTQ
2009-13083) and the Generalitat Valenciana (Grants ACOMP/
2012/212 and ISIC 2012/001) is acknowledged. C. V. thanks the
Generalitat Valenciana for a predoctoral grant.
Preparation and Characterization of the Chiral Metal Complex
[Hf2{(R)-3,3Ј-Br2-BINOL}2(OtBu)4]:
[Hf(OtBu)4]
(11 μL,
0.025 mmol) was added by using a syringe to a solution of ligand
[1] For examples of relevant natural products and potential medic-
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1
room temp. H NMR (400 MHz, CD2Cl2): δ = 8.27 (s, 1 H, 4-H),
8.06 (s, 1 H, 4Ј-H), 7.91 (dd, J = 8.1, 0.5 Hz, 1 H, 5Ј-H), 7.88 (d,
J = 8.2 Hz, 1 H, 5-H), 7.42 (ddd, J = 8.1, 6.7, 1.3 Hz, 1 H, 6-H),
7.33 (ddd, J = 8.0, 6.8, 1.1 Hz, 1 H, 6Ј-H), 7.25 (ddd, J = 8.1, 6.7,
1.3 Hz, 1 H, 7-H), 7.18 (d, J = 8.1 Hz, 1 H, 8-H), 7.08 (ddd, J =
8.3, 6.8, 1.3 Hz, 1 H, 7Ј-H), 6.86 (dd, J = 8.5, 0.4 Hz, 1 H, 8Ј-H),
0.95 (s, 9 H, tBu), 0.94 (s, 9 H, tBu) ppm. 13C NMR (100.1 MHz,
CD2Cl2): δ = 154.0 (C), 151.9 (C), 132.5 (C), 132.6 (CH), 132.5
(C), 130.8 (C), 130.7 (CH), 130.1 (C),127.5 (CH), 127.4 (CH), 127.1
(CH), 126.8 (CH), 126.4 (CH), 125.3 (CH), 125.1 (CH), 123.5
(CH), 122.6 (C), 119.3 (C), 117.5 (C), 117.2 (C), 78.4 (C), 78.0 (C),
32.3 (CH3), 31.8 (CH3) ppm.
General Procedure for the Catalytic Enantioselective Friedel–Crafts
Reaction: To a solution of ligand L3 (11.1 mg, 0.025 mmol) in an-
1906
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Eur. J. Org. Chem. 2013, 1902–1907

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Received: December 4, 2012
Published Online: February 11, 2013
Eur. J. Org. Chem. 2013, 1902–1907
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1907