Catalytic Enantioselective Addition of Aryl Grignard Reagents to Ketones

Article abstract of DOI:10.1002/ejoc.201402935

We report a catalytic system for the challenging enantioselective addition of aryl Grignard reagents to ketones. Using a simple, one-pot procedure under mild conditions, a wide range of aromatic ketones are converted into diaryl alcohols in good yields and with good enantioselectivities. The catalytic enantioselective addition of aryl Grignard reagents to ketones is now possible. Using a readily available Ar-BINMOL ligand and titanium(IV) isopropoxide in a simple, one-pot procedure under mild conditions, a wide range of aromatic ketones are converted into diaryl alcohols in good yields and with good enantioselectivities.

Full text of DOI:10.1002/ejoc.201402935

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FULL PAPER
DOI: 10.1002/ejoc.201402935
Catalytic Enantioselective Addition of Aryl Grignard Reagents to Ketones
Emilio Fernández-Mateos,[a] Beatriz Maciá,*[b] and Miguel Yus*[a]
Dedicated to Professor Santos Fustero on occasion of his 65th birthday
Keywords: Synthetic methods / Homogeneous catalysis / Grignard reaction / Enantioselectivity / Ketones / Titanium
We report a catalytic system for the challenging enantio-
selective addition of aryl Grignard reagents to ketones. Using
a simple, one-pot procedure under mild conditions, a wide
range of aromatic ketones are converted into diaryl alcohols
in good yields and with good enantioselectivities.
knowledge, no catalytic approach allows the enantioselec-
tive addition of an aryl Grignard reagent to a ketone.
We have recently developed a catalytic system for the ad-
dition of Grignard,[15] organoaluminum,[16] and organo-
lithium[17] reagents to aldehydes, based on the readily avail-
able chiral ligand L1[18] and an excess of titanium(IV) iso-
propoxide (Scheme 1). In addition, the challenging alkyl-
ation of aliphatic aldehydes with Grignard reagents was
successfully achieved using L2[19] as ligand (Scheme 1). We
envisioned that fine-tuning the ligand structure would fur-
ther upgrade our catalytic system and make it suitable for
less reactive substrates, such as ketones.
Introduction
The synthesis of chiral tertiary alcohols represents a
major challenge in asymmetric catalysis.[1] The enantioselec-
tive addition of organometallic reagents to ketones is the
most straightforward method for the preparation of this
type of valuable motif.[2] For the addition of alkyl groups,
this strategy has led to several studies where organozinc,[3]
organotitanium,[3] and organoaluminum[4] reagents were ef-
fectively used as nucleophiles in catalytic processes. The
higher reactivity of readily available and inexpensive Grig-
nard reagents, however, has limited their application in
catalytic asymmetric processes. With the exception of a very
recent catalytic approach based on the use of a copper-di-
phosphine ligand,[5] the alkylation of ketones with Grignard
reagents requires stoichiometric amounts of chiral ligand.[6]
Catalytic asymmetric propargylation with organo-
boron[7] or organolithium[8] reagents and allylation of
ketones with organosilane[9] reagents have also been suc-
cessful. For the addition of aryl groups to ketones,[10] some
notable enantioselective catalytic methods have been devel-
oped in the past decade with organoaluminum,[11] or-
ganoboron,[12] organotitanium,[13] and organozinc[3a,14] rea-
gents as the aryl nucleophiles. However, to the best of our
[a] Departamento de Química Orgánica and Instituto de Síntesis
Orgánica, University of Alicante,
Scheme 1. Previous work on the enantioselective addition of orga-
nometallic reagents to aldehydes.
Aptdo. 99, 03080 Alicante, Spain
E-mail: yus@ua.es
http://iso.ua.es/personal/investigadores/miguel-yus-astiz.html
[b] Division of Chemistry & Environmental Science Manchester
Metropolitan University,
Oxford Road, M1 5GD, Manchester, UK
E-mail: b.macia-ruiz@mmu.ac.uk
Results and Discussion
http://www.sste.mmu.ac.uk/staff/staffbiog/default.asp?StaffID
=853
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402935.
In this work, we describe the first catalytic approach for
the enantioselective arylation of aromatic ketones with
Grignard reagents to give valuable diarylmethanols.[20] The
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E. Fernández-Mateos, B. Maciá, M. Yus
FULL PAPER
challenging formation of the new quaternary stereocenter using the bulky 1-naphthyl-BINMOL ligand L6. Interest-
takes place with good levels of enantioselectivity, despite ingly, when 2-naphthyl-BINMOL ligand L7 was used, the
the fact that the substrate and the nucleophile both have conversion and the ee both dropped, to 27 and 40%, respec-
similar steric and electronic properties. The fact that this tively (Table 1, entry 9).
method uses readily accessible and inexpensive aryl Grig-
nard reagents as nucleophiles gives it a big advantage over
alternative approaches that rely on more expensive di-
arylzinc or organoboron reagents.
The starting point for our investigation was the modest
27% conversion and 24% ee that was obtained for the ad-
dition of PhMgBr to 1-(naphthalen-2-yl)ethanone (1a) un-
der the previously reported conditions for the addition of
Grignard reagents to aldehydes using L2[19] (Table 1, en-
Figure 1. Chiral ligands used in this study.
try 1). To improve the conversion of the reaction, we in-
creased the temperature from –20 to 0 °C, and observed not
From our previous work on the catalytic enantioselective
alkylation of aldehydes with Grignard reagents,[15,19] we
know that the relative stoichiometry of Ti(OiPr)4 and
RMgBr plays a very important role in the enantioselectivity
of the reaction; therefore, we carried out a careful optimiza-
tion of this parameter (Table 1, entries 10–12 and
Tables S1–2 in the Supporting Information). In general, we
observed that the use of less than 2.5 equiv. of PhMgBr led
to poor conversions (Table S2 in the Supporting Infor-
mation). For this reason, we set the amount of the nucleo-
phile to this value, and screened different amounts of the
titanium source (Table 1, entries 10–11 and Table S2 in the
Supporting Information). Unfortunately, the use of less
than 10 equiv. of Ti(OiPr)4 led to a detrimental drop in the
enantioselectivity (Table 1, entry 10), while the use of a
large excess of Ti(OiPr)4 (12 equiv.) impaired the conversion
of the reaction (Table 1, entry 11). Increasing the amounts
of both the nucleophile and the Ti(OiPr)4 while keeping
fixed optimal ratio of 1:4 resulted in a slightly improved
conversion, but caused an small decrease in the enantio-
selectivity of the reaction (Table 1, entry 12 vs. 8).
only a higher conversion (68%), but also a higher ee (46%;
Table 1, entry 2). A thorough screening of solvents (includ-
ing CH2Cl2, toluene, and tBuOMe) at different tempera-
tures, was carried out (see the Supporting Information for
further details),[21] and the use of diethyl ether at 0 °C gave
the highest enantioselectivity. Next, the influence of the li-
gand was studied using a selection of Ar-BINMOL ligands
(Figure 1) with different electronic and steric properties
(Table 1, entries 3–9).[22] The use of Ph-BINMOL (L1) and
the partially hydrogenated version H8-L1 gave low conver-
sions and enantiomeric excesses (Table 1, entries 3 and 4).
Methoxy-substituted Ar-BINMOLs L3–L5 were also evalu-
ated (Table 1, entries 5–7), but they proved to be inferior
ligands to L2 under the conditions tested. Finally, the aryl-
ation reaction of our model substrate 1a could be improved
to give 50% conversion and 74% ee (Table 1, entry 8) by
Table 1. Method optimization.[a]
Next, using the optimized reaction conditions, we carried
out the addition of PhMgBr to different ketones (Table 2).
The arylation reaction was achieved with moderate yields
and good enantioselectivities (68–80% ee) for a wide variety
of aryl methyl ketones, with both electron-poor and elec-
tron-rich substituents at the meta and para positions
(Table 2, entries 1–7). The arylation of o-methylacetophen-
one was an exception; it gave a very low yield (12%;
Table 2, entry 4) that did not improve with longer reaction
times (24 h). This is probably due to steric hindrance close
to the reactive site.
The reaction also worked with heteroaryl and α,β-unsat-
urated ketones, which gave very good yields in addition re-
actions with PhMgBr (Table 2, entries 8 and 9), although
the enantioselectivities of these reactions were moderate.[23]
Other alkyl aryl ketones were also examined. Increasing the
size of one of the ketone substituents (an aryl ethyl ketone
was used as substrate instead of an aryl methyl ketone) gave
a better enantioselectivity but a lower yield (Table 2, en-
try 10).
Entry
L
T [°C] Ti(OiPr)4 PhMgBr Conversion
ee
[equiv.]
[equiv.]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
L2
–20
0
0
0
0
0
0
0
0
10
10
10
10
10
10
10
10
10
7.5
12
15
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
3.8
27
68
32
28
30
32
41
50
27
21
22
66
24
46
36
10
46
26
20
74
40
28
70
70
L2
L1
H8-L1[d]
L3
L4
L5
L6
9
L7
10
11
12
L6
0
0
0
L6
L6
[a] Conditions: 1 (0.05 m; 0.1 mmol), PhMgBr (3 m in Et2O;
2.5 equiv.), (Sa,R)-L6 (20 mol-%), Ti(OiPr)4 (10 equiv.), Et2O, 0 °C,
12 h. [b] Determined by GC–MS. [c] Determined by chiral HPLC
(see the Supporting Information for details). [d] (Sa,R)-2Ј-
[hydroxy(phenyl)methyl]-5,5Ј,6,6Ј,7,7Ј,8,8Ј-octahydro-1,1Ј-binaphth-
alen-2-ol.
Cyclic ketones, such as 5-methylindanone and 1-tet-
ralone, were also tested under the optimized conditions.
2
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Catalytic Enantioselective Addition of Grignard Reagents
Table 2. Addition of PhMgBr to different ketones.[a]
[a] Conditions: 1 (0.06 m; 0.5 mmol), PhMgBr (3 m in Et2O; 2.5 equiv.), (Sa,R)-L6 (20 mol-%), Ti(OiPr)4 (10 equiv.), Et2O, 0 °C, 12 h.
[b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral HPLC. Configuration based on literature data (see the
Supporting Information for details). [d] Conversion determined by GC–MS.
The addition of PhMgBr to the more rigid indanone deriva- rivatives allowed the synthesis of alcohols 2b and 2m–2p
tive (Table 2, entry 11) proceeded with good enantio- (Table 3, entries 1–5) with enantioselectivities at the same
selectivity (76% ee) and in very high yield (92%). When levels as when PhMgBr was used as the nucleophile. It is
the larger six-membered-ring tetralone was used, the best worth noting that the addition of p-tolylmagnesium
enantioselectivity of the series was obtained (92% ee, bromide to acetophenone gave 2b with the opposite
Table 2, entry 12) but with a decrease in the yield of the stereochemistry to when it was formed by the addition of
reaction (to 60%).
phenylmagnesium bromide to p-methylacetophenone
Different aryl Grignard reagents were also evaluated as (Table 3, entry 1 vs. Table 2, entry 2), using the same chiral
nucleophiles in the reaction. The synthesis of chiral diaryl ligand [i.e., (Sa,R)-L6]. The p-methoxy-substituted Grig-
tertiary alcohols using Grignard reagents as the aryl source nard reagent gave very good yields, the highest of all the
is a very attractive and interesting strategy due to the ready experiments carried out in this study (Table 3, entries 3 and
availability, facile synthesis, and inexpensive character of 4). The addition of (p-fluorophenyl)magnesium bromide to
these organometallic species.
5-methylindanone gave the corresponding alcohol (i.e., 2q)
The addition of p-tolyl-, p-methoxy-, and (p-fluoro- in good yield and with good enantioselectivity (Table 3, en-
phenyl)magnesium bromides to different acetophenone de- try 6).
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E. Fernández-Mateos, B. Maciá, M. Yus
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Table 3. Addition of various Grignard reagents to ketones.[a]
Experimental Section
General Information: Low-resolution mass spectra were recorded
with a GC–MS spectrometer (Agilent Technologies® 6890N Net-
work GC System) equipped with a HP-5MS column (Agilent Tech-
nologies®, 30 mϫ0.25 mm), connected to an Agilent Technol-
ogies® 5973 Network mass-selective detector; or with a mass spec-
trometer (Agilent Technologies® 5973 Network) with a direct inser-
tion probe (73DIP-1), equipped with a transmission quadrupole
analyzer; the samples were ionized with an electron-impact source
(70 eV). High-resolution mass spectra were obtained with a
Waters® LCT Premier XE apparatus equipped with a time-of-flight
(TOF) analyzer; the samples were ionized by ESI techniques, and
introduced through an ultra-high pressure liquid chromatography
1
(UPLC) Waters® Acquity H Class model. H and 13C NMR spec-
tra were recorded with a Bruker® AC-300 instrument (300 and
75 MHz, respectively) using CDCl3 as solvent. Chemical-shift val-
ues are reported in ppm relative to tetramethylsilane, and residual
solvent signals were used as an internal standard (CDCl3: δ = 7.26
for 1H NMR, δ = 77.0 for 13C NMR). Data are reported as follows:
chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet, br = broad), coupling constants [Hz],
and integration. Optical rotations were measured with a Jasco® P-
1030 Polarimeter with a 5 cm cell (c given in g/100 mL). IR spectra
were recorded with a Jasco® FTIR – 4100 Fourier transform infra-
red spectrometer. Melting points were measured with a Reichtert®
Thermovar hot-plate apparatus. Enantioselectivities were deter-
mined by HPLC analysis with an Agilent Technologies® 1100
Series HPLC instrument equipped with a G1315B diode array de-
tector and a Quat Pump G1311A. The following chiral HPLC col-
umns were used to determine the enantioselectivities of all of the
chiral tertirary alcohols: Chiralcel OD-H, Chiralcel OJ, Chiralpak
AD-H, Chiralpak AS-H, and Chiralpak IA.
All reactions were carried out under an argon atmosphere unless
noted, using flame-dried glassware. Ti(OiPr)4 and anhydrous Et2O
[Ն99.7%, with 1 ppm of BHT (butylated hydroxytoluene) as inhibi-
tor] were purchased from Sigma–Aldrich®, and stored under an
argon atmosphere once opened. Panreac® Silica gel 60 (40–63 μm)
was used in the purification process of all products. Machery-Na-
gel® TLC silica gel 60, 0.20 mm, was used, and components were
visualized using UV light and phosphomolybdic acid (1 g/24 mL
EtOH) staining. Phenylmagnesium bromide (3.0 m in Et2O), p-tol-
ylmagnesium bromide (1.9 m in Et2O), (4-fluorophenyl)magnesium
bromide (2.0 m in Et2O), and (4-methoxyphenyl)magnesium brom-
ide (1.9 m in Et2O) were prepared from the corresponding aryl
bromide and magnesium turnings in anhydrous Et2O following
standard procedures, and were stored under an argon atmosphere.
Grignard reagents were titrated using 2-butanol and catalytic
amounts of 1,10-phenanthroline in anhydrous THF. Ketones were
used without any purification, except for 2-acetylfuran and 1-tet-
ralone, which were distilled in a Kugelrohr apparatus (Büchi® Glass
Oven B-585) immediately before use. Ligands L1–L7 and H8-L1
were prepared according to known procedures,[15–17,19] but further
details can be also found in the Supporting Information of this
manuscript. Racemic tertiary alcohols were synthesized by the reac-
tion of the corresponding ketone (1.0 mmol) and ArMgBr
(1.5 mmol) in anhydrous THF at 0 °C.
[a] Conditions: 1 (0.06 m; 0.5 mmol), ArMgBr (2 m in Et2O;
2.5 equiv.), (Sa,R)-L6 (20 mol-%), Ti(OiPr)4 (10 equiv.), Et2O, 0 °C,
12 h. [b] Isolated yield after flash silica gel chromatography. [c] De-
termined by chiral HPLC. Configuration of known compounds
based on literature data (see the Supporting Information for de-
tails).
Conclusions
In conclusion, we have developed an efficient enantiose-
lective catalytic system for the addition of aryl Grignard
reagents to ketones. This method allows the preparation of
challenging optically active diaryl tertiary alcohols in a sim-
ple one-pot procedure using cheap and readily available or-
ganometallic reagents. A bulky 1-naphthyl-BINMOL li-
gand L6 and an excess of titanium tetraisopropoxide were
crucial to achieving good enantioselectivities. This work, to-
gether with previously developed methods for the addition
of different organometallic reagents to aldehydes,[15–17,19]
shows the versatility of Ar-BINMOLs for asymmetric ad-
ditions to carbonyl compounds. We are working towards
the expansion of the substrate scope (to include aliphatic
ketones), and studying the mechanistic pathway of the reac-
tion.
Synthesis of Chiral Tertirary Alcohols: (Sa,R)-L6 (42.7 mg,
0.1 mmol) was dissolved in anhydrous Et2O (6.0 mL) in a flame-
dried Schlenk tube under an argon atmosphere. The solution was
cooled down to 0 °C, and Ti(OiPr)4 (1.53 mL, 5.0 mmol, 10 equiv.)
was added. After 5 min, ArMgBr (1.25 mmol, 2.5 equiv.) was
added. The mixture was stirred for an additional 15 min, then the
4
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Catalytic Enantioselective Addition of Grignard Reagents
corresponding ketone (0.5 mmol) was added. The reaction mixture
was stirred at 0 °C for 12 h. The reaction was quenched at 0 °C by
the addition of water (5 mL) and HCl (1 m aq.; 3 mL). The mixture
was extracted with EtOAc (3ϫ 10 mL). The combined organic ex-
tracts were neutralized with saturated aqueous NaHCO3 (2ϫ
10 mL), dried with MgSO4, and concentrated under vacuum. The
crude product was purified by chromatography on flash silica gel
to give the desired products (i.e., 2a–2q).
165 (33), 152 (23), 151 (10), 135 (12), 105 (16), 77 (10). ee determi-
nation by chiral HPLC analysis (Chiralcel OJ column, hexane/
iPrOH, 80:20, flow rate: 1.0 mL/min, λ = 210 nm): tR(R) =
17.0 min, tR(S) = 20.7 min (major enantiomer).
(S)-1-Phenyl-1-[3-(trifluoromethyl)phenyl]ethanol (2f):[11a] Com-
pound 2f was obtained after purification by flash silica gel
chromatography (hexane/EtOAc, 100:0 to 94:6) as a yellow viscous
oil (50% yield, 80% ee). [α]2D4 = +18.5 (c = 1.0, CH2Cl2) {ref. [α]2D5
= +24.8 (c = 4.5, CH2Cl2) for 93% ee}. 1H NMR (300 MHz,
CDCl3): δ = 7.76 (s, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.50 (d, J =
7.8 Hz, 1 H), 7.44–7.21 (m, 6 H), 2.26 (br. s, 1 H), 1.96 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 149.0, 147.0, 130.4 (q, JC,F
(S)-1-(Naphthalen-2-yl)-1-phenylethanol (2a):[11a] Compound 2a
was obtained after purification by flash silica gel chromatography
(hexane/EtOAc, 100:0 to 96:4) as a colorless viscous oil (50% yield,
76% ee). [α]2D5 = –9.7 (c = 1.0, CH2Cl2) {ref. [α]2D5 = –16.1 (c = 1.0,
1
CH2Cl2) for 92% ee}. H NMR (300 MHz, CDCl3): δ = 7.96 (s, 1
= 32.1 Hz), 129.4, 128.6, 128.4, 127.4, 125.8, 124.3 (q, JC,F
=
H), 7.87–7.77 (m, 2 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.49–7.37 (m, 5
H), 7.36–7.18 (m, 3 H), 2.32 (br. s, 1 H), 2.04 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 147.7, 145.2, 133.0, 132.4, 129.6,
128.23, 128.20, 127.9, 127.5, 127.0, 126.1, 125.9, 124.9, 123.7,
115.3, 76.4, 30.7 ppm. LRMS (EI-DIP): m/z (%) = 249 (10) [M +
1]+, 248 (52) [M]+, 234 (18), 233 (100), 205 (11), 155 (15), 128 (11),
127 (23), 105 (74), 77 (20), 43 (19). ee determination by chiral
HPLC analysis (Chiralcel OJ column, hexane/iPrOH, 80:20, flow
rate: 1.0 mL/min, λ = 220 nm): tR(S) = 14.7 min (major enantio-
mer), tR(R) = 18.5 min.
272.0 Hz), 123.7 (q, JC,F = 3.6 Hz), 122.4 (q, JC,F = 3.5 Hz), 76.0,
30.8 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.5 ppm. LRMS
(EI): m/z (%) = 266 (3) [M]+, 252 (16), 251 (100), 173 (49), 145
(17), 105 (9), 77 (9). ee determination by chiral HPLC analysis
(Chiralcel OD-H column, hexane/iPrOH, 96:4, flow rate: 1.0 mL/
min, λ = 220 nm): tR(R) = 9.6 min, tR(S) = 11.2 min (major
enantiomer).
(S)-1-(4-Chlorophenyl)-1-phenylethanol (2g):[11a] Compound 2g was
obtained after purification by flash silica gel chromatography (hex-
ane/EtOAc, 100:0 to 97:3) as a colorless oil (42% yield, 68% ee).
[α]2D8 = +6.3 (c = 1.0, CH2Cl2) {ref. [α]2D5 = +8.8 (c = 3.2, CH2Cl2)
(S)-1-Phenyl-1-(p-tolyl)ethanol (2b):[14b] Compound 2b was ob-
tained after purification by flash silica gel chromatography (hexane/
EtOAc, 100:0 to 95:5) as a pale yellow oil (45% yield, 76% ee).
[α]2D5 = –7.5 (c = 1.0, CH2Cl2) {ref. [α]2D5 = +16.0 (c = 1.2, CH2Cl2)
for 96 % ee}. 1H NMR (300 MHz, CDCl3): δ = 7.45–7.36 (m, 2 H),
7.34–7.19 [m, (including at 7.29 ppm, d, J = 8.0 Hz), 5 H], 7.11 (d,
J = 8.0 Hz, 2 H), 2.32 (s, 3 H), 2.21 (br. s, 1 H), 1.92 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 148.2, 145.1, 136.6, 128.8, 128.1,
126.8, 125.8, 76.1, 30.8, 21.0 ppm. LRMS (EI): m/z (%) = 212 (7)
[M]+, 198 (16), 197 (100), 194 (11), 179 (14), 178 (11), 119 (22), 105
(35), 91 (14), 77 (13). ee determination by chiral HPLC analysis
(Chiralpak AD-H column, hexane/iPrOH, 99:1, flow rate: 0.5 mL/
min, λ = 210 nm): tR(R) = 46.1 min, tR(S) = 48.7 min (major
enantiomer).
1
for 92 % ee}. H NMR (300 MHz, CDCl3): δ = 7.42–7.30 [m (in-
cluding at 7.33 ppm, d, J = 8.9 Hz), 5 H], 7.30–7.19 [m (including
at 7.26 ppm, d, J = 8.9 Hz, 4 H], 2.24 (br. s, 1 H), 1.92 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 147.4, 146.5, 132.7, 128.3,
128.2, 127.3, 127.2, 125.7, 75.9, 30.8 ppm. LRMS (EI): m/z (%) =
232 (7) [M]+, 219 (33), 218 (15), 217 (100), 141 (12), 139 (38), 111
(10), 105 (19), 77 (13). ee determination by chiral HPLC analysis
(Chiralpak AD-H column, hexane/iPrOH, 99:1, flow rate: 1.0 mL/
min, λ = 230 nm): tR(R) = 16.5 min, tR(S) = 17.8 min (major
enantiomer).
(S)-1-(Furan-2-yl)-1-phenylethanol (2h):[2b] Compound 2h was ob-
tained after purification by flash silica gel chromatography (hexane/
EtOAc, 100:0 to 95:5) as a yellow oil (78% yield, 46% ee). [α]2D9
=
(S)-1-Phenyl-1-(m-tolyl)ethanol (2c):[14b] Compound 2c was ob-
tained after purification by flash silica gel chromatography (hexane/
EtOAc, 100:0 to 97:3) as a pale yellow oil (40% yield, 76% ee).
[α]2D7 = –4.6 (c = 1.0, CH2Cl2) {ref. [α]2D5 = –14.3 (c = 1.2, CH2Cl2)
for 86 % ee}. 1H NMR (300 MHz, CDCl3): δ = 7.45–7.38 (m, 2 H),
7.35–7.26 (m, 2 H), 7.27–7.22 (m, 2 H), 7.18 (m, 2 H), 7.09–7.02
(m, 1 H), 2.32 (s, 3 H), 2.19 (br. s, 1 H), 1.93 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 148.1, 147.9, 137.7, 128.1, 128.0,
127.7, 126.9, 126.5, 125.8, 122.9, 76.2, 30.9, 21.6 ppm. LRMS (EI):
m/z (%) = 212 (7) [M]+, 198 (16), 197 (100), 194 (10), 179 (14), 178
(11), 119 (16), 105 (42), 91 (14), 77 (13). ee determination by chiral
HPLC analysis (Chiralpak IA column, hexane/iPrOH, 99:1, flow
rate: 0.5 mL/min, λ = 210 nm): tR(S) = 38.8 min (major enantio-
mer), tR(R) = 45.6 min.
–16.5 (c = 1.0, CH2Cl2) {ref. [α]2D2 = –34.1 (c = 5.4, CH2Cl2) for
96% ee}. 1H NMR (300 MHz, CDCl3): δ = 7.43–7.22 (m, 6 H),
6.33 (dd, J = 3.2, 1.8 Hz, 1 H), 6.24 (dd, J = 3.2, 0.8 Hz, 1 H), 2.54
(br. s, 1 H), 1.87 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
158.9, 145.8, 142.1, 128.1, 127.3, 125.2, 110.0, 106.2, 73.0,
29.2 ppm. LRMS (EI): m/z (%) = 188 (32) [M]+, 174 (12), 173
(100), 171 (12), 170 (36), 169 (12), 141 (28), 115 (23), 111 (15), 105
(16), 95 (65), 77 (17). ee determination by chiral HPLC analysis
(Chiralcel OD-H column, hexane/iPrOH, 99:1, flow rate: 0.5 mL/
min, λ = 220 nm): tR(R) = 30.1 min, tR(S) = 33.4 min (major
enantiomer).
(R,E)-2,4-Diphenylbut-3-en-2-ol (2i):[24] Compound 2i was obtained
after purification by flash silica gel chromatography (hexane/
EtOAc, 100:0 to 95:5) as a pale yellow oil (88% yield, 59% ee).
[α]2D6 = –9.7 (c = 1.0, CHCl3) {ref. [α]2D2 = –12.7 (c = 2.5, CHCl3)
for 81 % ee}. 1H NMR (300 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz,
2 H), 7.41–7.17 (m, 8 H), 6.64 (d, J = 16.1 Hz, 1 H), 6.50 (d, J =
(S)-1-(4-Methoxyphenyl)-1-phenylethanol (2e):[11a] Compound 2e
was obtained after purification by flash silica gel chromatography
(hexane/EtOAc, 100:0 to 94:6) as a pale yellow oil (43% yield, 72%
ee). [α]2D8 = –12.3 (c = 1.0, CH2Cl2) {ref. [α]2D5 = –14.6 (c = 0.7,
CH2Cl2) for 90% ee}. 1H NMR (300 MHz, CDCl3): δ = 7.44–7.36 16.1 Hz, 1 H), 2.06 (br. s, 1 H), 1.75 (s, 3 H) ppm. 13C NMR
(m, 2 H), 7.35–7.27 [m (including at 7.32 ppm, d, J = 8.9 Hz), 4
H], 7.27–7.18 (m, 1 H), 6.83 (d, J = 8.9 Hz, 2 H), 3.78 (s, 3 H),
2.18 (br. s, 1 H), 1.92 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.5, 148.3, 140.3, 128.1, 127.1, 126.8, 125.7, 113.4, 75.9, 55.2,
31.0 ppm. LRMS (EI): m/z (%) = 228 (7) [M]+, 213 (46), 211 (17),
210 (100), 209 (12), 195 (52), 179 (12), 178 (11), 167 (15), 166 (11),
(75 MHz, CDCl3): δ = 146.6, 136.7, 136.3, 128.5, 128.3, 127.7,
127.6, 127.1, 126.5, 125.2, 74.7, 29.8 ppm. LRMS (EI): m/z (%) =
224 (14) [M]+, 209 (12), 206 (48), 205 (24), 203 (12), 202 (10), 191
(21), 182 (17), 181 (100), 178 (10), 166 (12), 165 (15), 131 (15), 129
(12), 128 (18), 105 (20), 103 (22), 91 (29), 77 (21). ee determination
by chiral HPLC analysis (Chiralpak AS-H column, hexane/iPrOH,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 9
E. Fernández-Mateos, B. Maciá, M. Yus
FULL PAPER
99:1, flow rate: 0.5 mL/min, λ = 230 nm): tR(S) = 20.0 min, tR(R)
= 21.9 min (major enantiomer).
column, hexane/iPrOH, 90:10, flow rate: 1.0 mL/min, λ = 210 nm):
tR(S) = 22.1 min (major enantiomer), tR(R) = 27.3 min.
(S)-1-(4-Bromophenyl)-1-phenylpropan-1-ol (2j):[14b] Compound 2j
was obtained after purification by flash silica gel chromatography
(hexane/EtOAc, 100:0 to 98:2) as a pale yellow oil (35% yield, 84%
ee). [α]2D9 = +8.7 (c = 1.0, CH2Cl2) {ref. [α]2D5 = +9.9 (c = 1.7,
CH2Cl2) for 80% ee}. 1H NMR (300 MHz, CDCl3): δ = 7.41 (d, J
= 8.8 Hz, 2 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.35–7.17 (m, 5 H), 2.28
(q, J = 7.3 Hz, 2 H), 2.05 (s, 1 H), 0.87 (t, J = 7.3 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 146.4, 145.9, 131.1, 128.3, 128.0,
127.0, 126.0, 120.7, 78.2, 34.3, 8.0 ppm. LRMS (EI): m/z (%) = 291
(Ͻ1) [M]+, 264 (14), 263 (97), 262 (15), 261 (100), 185 (32), 183
(33), 105 (30), 77 (16). ee determination by chiral HPLC analysis
(Chiralpak IA column, hexane/iPrOH, 99:1, flow rate: 0.5 mL/min,
λ = 230 nm): tR(R) = 48.6 min, tR(S) = 53.7 min (major enantio-
mer).
(+)-1-(4-Methoxyphenyl)-1-[3-(trifluoromethyl)phenyl]ethanol (2n):
Compound 2n was obtained after purification by flash silica gel
chromatography (hexane/EtOAc, 100:0 to 91:9) as a yellow viscous
oil (96% yield, 82% ee). [α]2D9 = +32.5 (c = 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.53 (d, J = 7.7 Hz, 1 H),
7.49 (d, J = 7.7 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.31 (d, J =
8.9 Hz, 2 H), 6.85 (d, J = 8.9 Hz, 2 H), 3.79 (s, 3 H), 2.22 (br. s, 1
H), 1.94 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.8,
149.4, 139.3, 130.4 (q, JC,F = 32.1 Hz), 129.3, 128.5, 127.2, 124.2
(q, JC,F = 272.3 Hz), 123.6 (q, JC,F = 3.8 Hz), 122.3 (q, JC,F
=
3.8 Hz), 113.7, 75.7, 55.3, 31.0 ppm. 19F NMR (282 MHz, CDCl3):
δ = –62.4 ppm. IR (ATR): ν = 3456, 2962, 1611, 1510, 1327, 1254,
˜
1162, 1119 cm–1. LRMS (EI): m/z (%) = 296 (19) [M]+, 282 (17),
281 (100), 278 (15), 173 (56), 151 (19), 145 (18), 135 (10). HRMS
(ESI): calcd. for C16H14F3O [M – OH]+ 279.0997; found 279.0995.
ee determination by chiral HPLC analysis (Chiralcel OD-H col-
umn, hexane/iPrOH, 99:1, flow rate: 1.0 mL/min, λ = 220 nm):
tR(R) = 18.9 min, tR(S) = 19.9 min (major enantiomer).
(+)-5-Methyl-1-phenyl-2,3-dihydro-1H-inden-1-ol (2k): Compound
2k was obtained after purification by flash silica gel chromatog-
raphy (hexane/EtOAc, 100:0 to 95:5) as a yellow viscous oil (92%
yield, 76% ee). [α]2D9 = +13.6 (c = 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.43–7.19 (m, 5 H), 7.13 (s, 1 H), 7.02 (d,
J = 7.7 Hz, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 3.21–3.04 (dt, J = 16.0,
7.3 Hz, 1 H), 2.98–2.81 (dt, J = 16.0, 6.4 Hz, 1 H), 2.51–2.41 (m,
2 H), 2.36 (s, 3 H), 2.11 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 146.5, 145.2, 144.3, 138.3, 128.0, 127.9, 126.8, 125.7, 125.5,
(+)-1-(4-Bromophenyl)-1-(4-methoxyphenyl)ethanol (2o): Com-
pound 2o was obtained after purification by flash silica gel
chromatography (hexane/EtOAc, 100:0 to 90:10) as a yellow vis-
cous oil (Ͼ99% yield, 66% ee). [α]2D9 = +15.8 (c = 1.0, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 7.41 (d, J = 8.8 Hz, 2 H), 7.28 (d,
J = 7.2 Hz, 2 H), 7.25 (d, J = 7.2 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2
H), 3.77 (s, 3 H), 2.26 (br. s, 1 H), 1.88 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.6, 147.4, 139.6, 131.1, 127.6, 127.1,
123.7, 85.2, 45.0, 29.8, 21.4 ppm. IR (ATR): ν = 3381, 2938, 1612,
˜
1492, 1446, 1047 cm–1. LRMS (EI): m/z (%) = 224 (Ͻ1) [M]+, 222
(15), 194 (44), 193 (30), 180 (20), 179 (100), 178 (55), 165 (8), 89
(11). HRMS (ESI): calcd. for C16H15 [M – OH]+ 207.1174; found
207.1183. ee determination by chiral HPLC analysis (Chiralcel
OD-H column, hexane/iPrOH, 96:4, flow rate: 1.0 mL/min, λ =
220 nm): tR(R) = 7.8 min, tR(S) = 10.3 min (major enantiomer).
120.7, 113.5, 75.6, 55.2, 30.8 ppm. IR (ATR): ν = 3449, 2974, 1608,
˜
1509, 1509, 1248, 1176 cm–1. LRMS (EI): m/z (%) = 308 (17) [M
+ 1]+, 307 (3) [M]+, 306 (17), 294 (14), 293 (92), 292 (16), 291 (100),
290 (34), 288 (34), 185 (32), 183 (33), 166 (17), 165 (25), 151 (18),
135 (26). HRMS (ESI): calcd. for C15H14BrO [M – OH]+ 289.0228;
found 289.0227. ee determination by chiral HPLC analysis (Chi-
ralcel OJ column, hexane/iPrOH, 97:3, flow rate: 1.0 mL/min, λ =
230 nm): tR(S) = 58.0 min (major enantiomer), tR(R) = 63.0 min.
(S)-1-Phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (2l):[25] Compound
2l was obtained after purification by flash silica gel chromatog-
raphy (hexane/EtOAc, 100:0 to 97:3) as a yellow viscous oil (60%
yield, 92% ee). [α]2D7 = –29.5 (c = 1.0, CHCl3) {ref. [α]2D2 = –32.0 (c
= 4.2, CHCl3) for Ͼ99% ee}. 1H NMR (300 MHz, CDCl3): δ =
7.40–6.99 (m, 9 H), 2.94–2.84 (m, 2 H), 2.19 (br. s, 1 H), 2.16–2.09
(m, 2 H), 2.05–1.91 (m, 1 H), 1.86–1.70 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.9, 142.0, 137.6, 128.9, 128.8, 127.7,
127.5, 126.6, 126.44, 126.38, 75.3, 41.4, 29.9, 19.6 ppm. LRMS
(EI): m/z (%) = 224 (22) [M]+, 207 (14), 206 (75), 205 (11), 196
(22), 195 (100), 191 (16), 178 (14), 165 (12), 147 (59), 146 (15), 129
(11), 128 (11), 105 (10), 91 (26), 77 (15). ee determination by chiral
HPLC analysis (Chiralcel OD-H column, hexane/iPrOH, 99:1, flow
rate: 1.0 mL/min, λ = 220 nm): tR(R) = 9.7 min, tR(S) = 13.2 min
(major enantiomer).
(–)-1-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)ethanol (2p): Com-
pound 2p was obtained after purification by flash silica gel
chromatography (hexane/EtOAc, 100:0 to 75:25) as a yellow vis-
cous oil (38% yield, 64% ee). [α]2D9 = –4.8 (c = 1.0, CH2Cl2). 1H
3
NMR (300 MHz, CDCl3): δ = 7.36 (dd, J = 9.0, JH,F = 5.4 Hz, 2
H), 6.98 (t, 3J ≈ JH,F = 9.0 Hz, 2 H), 6.94 (d, J = 2.1 Hz, 1 H),
6.89 (dd, J = 8.4, 2.1 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 3.86 (s,
3 H), 3.81 (s, 3 H), 2.28 (br. s, 1 H), 1.91 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.6 (d, JC,F = 245.4 Hz), 148.6, 148.0,
143.9 (d, JC,F = 2.9 Hz), 140.5, 127.5 (d, JC,F = 8.0 Hz), 117.9,
114.7 (d, JC,F = 21.2 Hz), 110.4, 109.5, 75.7, 55.8, 31.2 ppm. 19F
NMR (282 MHz, CDCl ): δ = –116.2 ppm. IR (ATR): ν = 3505,
˜
3
2933, 1735, 1601, 1505, 1255, 1222, 1143 cm–1. LRMS (EI): m/z
(%) = 276 (38) [M]+, 261 (50), 259 (19), 258 (100), 243 (13), 183
(19), 171 (13), 170 (11), 123 (75), 121 (14). HRMS (ESI): calcd. for
C16H16FO2 [M – OH]+ 259.1134; found 259.1126. ee determination
by chiral HPLC analysis (Chiralcel OJ column, hexane/iPrOH,
85:15, flow rate: 1.0 mL/min, λ = 210 nm): tR(R) = 21.6 min, tR(S)
= 37.5 min (major enantiomer).
(+)-1-(3-Methoxyphenyl)-1-(p-tolyl)ethanol (2m): Compound 2m
was obtained after purification by flash silica gel chromatography
(hexane/EtOAc, 100:0 to 96:4) as a yellow oil (40% yield, 77% ee).
1
[α]2D9 = +15.8 (c = 1.0, CH2Cl2). H NMR (300 MHz, CDCl3): δ =
7.29 (d, J = 8.2 Hz, 2 H), 7.21 (dd, J = 8.2, 7.8 Hz, 1 H), 7.11 (d,
J = 8.2 Hz, 2 H), 7.01 (dd, J = 2.6, 1.7 Hz, 1 H), 6.94 (ddd, J =
7.8, 1.7, 0.9 Hz, 1 H), 6.76 (ddd, J = 8.2, 2.6, 0.9 Hz, 1 H), 3.77 (s,
3 H), 2.31 (s, 3 H), 2.21 (br. s, 1 H), 1.91 (s, 3 H) ppm. 13C NMR
(+)-1-(4-Fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-ol
(2q):
(75 MHz, CDCl3): δ = 159.4, 149.9, 144.9, 136.6, 129.1, 128.8, Compound 2q was obtained after purification by flash silica gel
125.7, 118.3, 111.9, 76.0, 55.2, 30.8, 21.0 ppm. IR (ATR): ν = 3452,
chromatography (hexane/EtOAc, 100:0 to 96:4) as a yellow viscous
oil (82% yield, 80% ee). [α]2D9 = +17.5 (c = 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.35 (dd, 3J = 9.0, JH,F = 5.4 Hz, 2 H),
7.14 (s, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 6.98 (t, J ≈ JH,F = 9.0 Hz,
2 H), 6.95 (d, J = 7.7 Hz, 1 H), 3.12 (dt, J = 16.0, 7.2 Hz, 1 H),
˜
2925, 1600, 1485, 1432, 1253 cm–1. LRMS (EI): m/z (%) = 242 (37)
[M]+, 228 (17), 227 (100), 224 (12), 135 (31), 119 (57), 91 (15).
HRMS (ESI): calcd. for C16H17O [M – OH]+ 225.1279; found
225.1290. ee determination by chiral HPLC analysis (Chiralcel OJ
3
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Catalytic Enantioselective Addition of Grignard Reagents
ketones, see: b) D. B. Biradar, H.-M. Gau, Org. Lett. 2009, 11,
499–502.
2.88 (dt, J = 16.0, 6.4 Hz, 1 H), 2.43 (dd, J = 7.2, 6.4 Hz, 2 H),
2.37 (s, 3 H), 2.06 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
[5]
[6]
a) F. Caprioli, A. V. R. Madduri, A. J. Minnaard, S. R. Haru-
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δ = 161.8 (d, JC,F = 245.0 Hz), 145.0, 144.3, 142.2 (d, JC,F
3.0 Hz), 138.6, 128.0, 127.4 (d, JC,F = 8.0 Hz), 125.6, 123.6, 114.7
(d, JC,F
21.2 Hz), 84.9, 45.1, 29.7, 21.4 ppm. 19F NMR
=
=
(282 MHz, CDCl ): δ = –116.6 ppm. IR (ATR): ν = 3384, 2940,
˜
3
1602, 1506, 1221, 1157 cm–1. LRMS (EI-DIP): m/z (%) = 243 (17)
[M + 1]+, 242 (100) [M]+, 241 (50), 228 (11), 227 (68), 226 (30),
225 (50), 224 (21), 212 (12), 210 (11), 209 (16), 207 (10), 183 (14),
148 (11), 147 (99), 133 (11), 123 (15), 105 (11), 95 (17), 91 (11).
HRMS (ESI): calcd. for C16H14F [M – OH]+ 225.1080; found
225.1078. ee determination by chiral HPLC analysis (Chiralcel
OD-H column, hexane/iPrOH, 96:4, flow rate: 1.0 mL/min, λ =
220 nm): tR(R) = 7.1 min, tR(S) = 9.5 min (major enantiomer).
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of ligands L1–L7 and H8-L1, additional data (opti-
mization), and spectroscopic and chromatographic data for com-
pounds 2.
[7]
[8]
Acknowledgments
[9]
For a review of allylation reactions, see: M. Yus, J. C.
González-Gómez, F. Foubelo, Chem. Rev. 2011, 111, 7774–
7854.
The authors acknowledge financial support from the Spanish
Ministerio de Ciencia y Tecnología (MCYT) (project numbers
CTQ2007-65218/BQU and CTQ2011-24151), Consolider Ingenio
2010 (grant number CSD2007-00006), and Generalitat Valenciana
(G. V. PROMETEO/2009/039 and FEDER). B. M. thanks the
European Commision for a Marie Curie Career Integration Grant.
E. F.-M. thanks the Ministerio de Educación y Ciencia (MEC) for
a FPU predoctoral fellowship (AP-2010-2926). Medalchemy and
Chemetall are thanked for gifts of chemicals. G. P. Howell is
thanked for helpful comments on the manuscript.
[10]
Some examples of the arylation of aldehydes, with organosilane
reagents, see: a) D. Tomita, R. Wada, M. Kanai, M. Shibasaki,
J. Am. Chem. Soc. 2005, 127, 4138–4139; with organoboron
reagents: b) D. Tomita, M. Kanai, M. Shibasaki, Chem. Asian
J. 2006, 1, 161–166; c) C. Bolm, J. Rudolph, J. Am. Chem. Soc.
2002, 124, 14850–14851; d) J.-X. Ji, J. Wu, T. T.-L. Au-Yeung,
C.-W. Yip, R. K. Haynes, A. S. C. Chan, J. Org. Chem. 2005,
70, 1093–1095; e) A. L. Braga, D. S. Lüdtke, F. Vargas, M. W.
Paixão, Chem. Commun. 2005, 2512–2514; f) S. Özçubukçu, F.
Schmidt, C. Bolm, Org. Lett. 2005, 7, 1407–1409; g) S. Dah-
men, M. Lormann, Org. Lett. 2005, 7, 4597–4600; with Grig-
nard reagents: h) X.-Y. Fan, Y.-X. Yang, F.-F. Zhuo, S.-L. Yu,
X. Li, Q.-P. Guo, Z.-X. Du, C.-S. Da, Chem. Eur. J. 2010, 16,
7988–7991; i) C.-S. Da, J.-R. Wang, X.-G. Yin, X.-Y. Fan, Y.
Liu, S.-L. Yu, Org. Lett. 2009, 11, 5578–5581; Y. Muramatsu,
T. Harada, Chem. Eur. J. 2008, 14, 10560–10563; j) D. Itakura,
T. Harada, Synlett 2011, 2875–2879; with organozinc reagents:
k) L. Salvi, J. G. Kim, P. J. Walsh, J. Am. Chem. Soc. 2009,
131, 12483–12493; l) J. G. Kim, P. J. Walsh, Angew. Chem. Int.
Ed. 2006, 45, 4175–4178; Angew. Chem. 2006, 118, 4281–4284;
with organoaluminium reagents: m) K.-H. Wu, H.-M. Gau, J.
Am. Chem. Soc. 2006, 128, 14808–14809; with organotitanium
reagents (see also ref.[6c): n) B. Weber, D. Seebach, Tetrahedron
1994, 50, 7473Ϫ7484; o) K.-H. Wu, S. Zhou, C.-A. Chen, M.-
C. Yang, R.-T. Chiang, C.-R. Chen, H.-M. Gau, Chem. Com-
mun. 2011, 47, 11668Ϫ11670; with organolithium: p) Y. Naka-
gawa, Y. Muramatsu, T. Harada, Eur. J. Org. Chem. 2010,
6535Ϫ6538; q) L. Zhang, L. Sun, Y.-Y. Li, Y. Liu, Y.-X. Yang,
R. Yuan, P. Wang, C.-S. Da, ChemCatChem 2013, 5,
3516Ϫ3519; r) A. Uenishi, Y. Nakagawa, H. Osumi, Chem.
Eur. J. 2013, 19, 4896Ϫ4905.
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Job/Unit: O42935
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Date: 01-09-14 17:07:38
Pages: 9
E. Fernández-Mateos, B. Maciá, M. Yus
FULL PAPER
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Received: July 16, 2014
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42935
/KAP1
Date: 01-09-14 17:07:38
Pages: 9
Catalytic Enantioselective Addition of Grignard Reagents
Asymmetric Catalysis
The catalytic enantioselective addition of
aryl Grignard reagents to ketones is now
possible. Using a readily available Ar-
BINMOL ligand and titanium(IV) iso-
propoxide in a simple, one-pot procedure
under mild conditions, a wide range of aro-
matic ketones are converted into diaryl
alcohols in good yields and with good
enantioselectivities.
E. Fernández-Mateos, B. Maciá,*
M. Yus* ............................................ 1–9
Catalytic Enantioselective Addition of Aryl
Grignard Reagents to Ketones
Keywords: Synthetic methods
/ Homo-
geneous catalysis / Grignard reaction / En-
antioselectivity / Ketones / Titanium
Eur. J. Org. Chem. 0000, 0–0
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