Catalytic enantioselective addition of MeMgBr and other Grignard reagents to aldehydes

Article abstract of DOI:10.1002/ejoc.201101283

Herein, we report an efficient catalyst for the challenging enantioselective addition of MeMgBr to aldehydes. Unprecedented yields and enantioselectivities are achieved in the reaction with a broad range of aldehydes. Moreover, a variety of Grignard reagents can be also added to aromatic and aliphatic aldehydes in good yields and enantioselectivities in a simple one-pot procedure under mild conditions.

Full text of DOI:10.1002/ejoc.201101283

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101283
Catalytic Enantioselective Addition of MeMgBr and Other Grignard Reagents
to Aldehydes
Emilio Fernández-Mateos,[a] Beatriz Maciá,*[a] Diego J. Ramón,[a] and Miguel Yus*[a]
Dedicated to Professor Dr. Carmen Nájera on the occasion of her 60th birthday
Keywords: Asymmetric catalysis / Grignard reaction / Aldehydes / Alcohols / Titanium
Herein, we report an efficient catalyst for the challenging
enantioselective addition of MeMgBr to aldehydes. Unprece-
of Grignard reagents can be also added to aromatic and ali-
phatic aldehydes in good yields and enantioselectivities in a
dented yields and enantioselectivities are achieved in the re- simple one-pot procedure under mild conditions.
action with a broad range of aldehydes. Moreover, a variety
the use of a high catalyst loading (40 mol-%).[11] Here, we
report a facile one-pot methodology for the addition of
Introduction
The chiral methyl carbinol moiety is present in a large
number of natural products and biologically active com-
pounds,[1] and its synthesis is of great importance to both
academia and industry. One of the most efficient ap-
proaches to this structural fragment is the catalytic asym-
metric addition of a methyl group to an aldehyde, which
involves the formation of both a new C–C bond and the
corresponding stereogenic center.[2] Enantioselective cata-
lyzed versions of this key transformation have been studied
extensively with dimethylzinc[3,4] and trimethylaluminum.[5]
However, for the highly reactive methyllithium and methyl
Grignard reagents, the progress has been limited[6] and
more than stoichiometric amounts of a chiral modifier are
usually required to obtain good enantioselectivity.[7] As an
alternative, methyl Grignard reagents can be transmetalated
into dimethylzinc[8] or methyltitanium triisopropoxide[9]
and, after tedious removal of the generated magnesium
salts, used in asymmetric additions to aldehydes. Recently,
two notable examples of the highly enantioselective cata-
lytic addition of Grignard reagents to aldehydes have been
reported by Harada[10] and later by Da.[11] Both approaches
comprise the use of an excess amount of titanium(IV) isop-
ropoxide and no salt exclusion is needed to achieve high
enantioselectivities. Nevertheless, none of these systems
seems to be effective for the addition of methyl Grignard
reagents, and very low enantioselectivities are obtained with
MeMgBr to different aldehydes by using an excess amount
of titanium tetraisopropoxide in the presence of a catalytic
amount of the readily available chiral ligand (Sa,R)-L1 (Fig-
ure 1).[12] This methodology provides the highest enantio-
selectivities and yields reported so far for this process.
Moreover, enantioselective alkylation of a wide variety of
aldehydes by using other longer-chain Grignard reagents
proved to be also effective with this catalytic system.
Figure 1. Chiral ligands used in this study.
Results and Discussion
The recently published straightforward synthesis of 1,1Ј-
binaphthalene-2-α-arylmethan-2Ј-ols (Ar-BINMOLs) by
Lai and Xu[12] encouraged us to analyze these kinds of bi-
naphthyl-based chiral diols as ligands in the enantioselec-
tive addition of Grignard reagents to carbonyl compounds.
As a model reaction for this study, we chose the addition
of MeMgBr to o-methylbenzaldehyde (1a) or benzaldehyde
(1b). The first promising results were achieved with 10 mol-
% of ligand (Sa,R)-L1, which provided 20 and 35%ee and
full conversion in the addition of MeMgBr to 1a at 0 °C
with the use of toluene or diethyl ether, respectively, as sol-
vent (Table 1, Entries 1 & 2). Other solvents like DCM,
THF, and tBuOMe were evaluated, but the enantio-
[a] Organic Chemistry Department, Alicante University, Aptdo. 99
03080 Alicante, Spain
Fax: +34-965-903-549
E-mail: beatriz.macia@ua.es
yus@ua.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101283.
Eur. J. Org. Chem. 2011, 6851–6855
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6851

E. Fernández-Mateos, B. Maciá, D. J. Ramón, M. Yus
SHORT COMMUNICATION
selectivities were lower in all cases (Table 1, Entries 3–5). with benzaldehyde (Table 2, Entry 2). Methoxy-substituted
The effect of the temperature was then analyzed. Lowering Ar-BINMOLs [(Sa,S)-L2, (Sa,R)-L3, and (Sa,R)-L4] gave
the temperature to –20 °C produced a drastic decrease in lower enantioselectivities (Table 2, Entries 3–5) than simpler
both conversion and enantioselectivity when the reaction phenyl-BINMOL (Sa,R)-L1 (Table 2, Entry 1). Moreover,
was carried out in diethyl ether (Table 1, Entry 6), probably lower conversion was observed in the case of meta-meth-
due to solubility problems.[13] Fortunately, the use of tolu- oxy-substituted (Sa,R)-L3. para-Fluoro-substituted ligand
ene at –40 °C provided an increase in the enantioselectivity (Sa,R)-L5 proved equally effective as (Sa,R)-L1 (Table 2,
up to 51% (Table 1, Entry 7), preserving the full conversion Entry 6), although it was less stable at ambient condi-
of 1a into 2a. Lower temperatures (–60 °C) led to a signifi- tions.[14]
cant decrease in the rate of the reaction (60% conversion;
Table 1, Entry 8), although the enantioselectivity was found
to be higher (54%).
Table 2. Asymmetric addition of MeMgBr to benzaldehyde: screen-
ing of ligands.[a]
Table 1. Addition of MeMgBr to o-methylbenzaldehyde.[a]
Entry
Ar in L
L
Conv. [%][b]
ee [%][b]
1
2
3
4
5
6
Ph
Ph
(Sa,R)-L1
(Sa,S)-L1
(Sa,S)-L2
(Sa,R)-L3
(Sa,R)-L4
(Sa,R)-L5
90
71
86
25
89
89
80
0
48
74
70
83
Entry
T
[°C]
Solvent
Ti(iPrO)4
[equiv.]
Conv.
[%][b]
ee
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
p-FC6H4
[%][c]
1
2
3
4
5
6
7
8
0
0
0
0
0
–20
–40
–60
–40
–40
–40
–40
–40
toluene
Et2O
DCM
THF
tBuOMe
Et2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10
10
10
10
10
10
10
10
0
2.5
5
7.5
12.5
99
98
99
70
99
20
99
60
90
99
89
90
90
20
35
16
8
0
5
51
54
0
[a] Conditions: 1b (1 equiv., 0.07 m), MeMgBr (3 m in Et2O,
2.5 equiv.), L (10 mol-%), Ti(iPrO)4 (10 equiv.), toluene, –40 °C,
4 h. [b] Determined by chiral GC (see the Supporting Information
for details).
9
Different additives such as dioxane, crown ethers, bis[2-
(N,N-dimethylamino)ethyl] ether (BDMAEE),[11] molecular
sieves, and so on were tested without any improvement in
the enantioselectivity. A wide variety of titanium sources
10
11
12
13
0
30
44
40
[a] Conditions: 1a (1 equiv., 0.07 m), MeMgBr (3 m in Et2O, [e.g., Ti(OMe)4, Ti(OEt)4, Ti(nPrO)4, Ti(tBuO)4] were also
2.5 equiv.), (Sa,R)-L1 (10 mol-%), Ti(iPrO)4 (x equiv.), 4 h. [b] De-
termined by GC. [c] Determined by chiral HPLC (see the Support-
obtained in all cases (see the Supporting Information for
ing Information for details).
used, but very low conversions and enantioselectivities were
further details).
In a last effort to improve our methodology, we exam-
The amount of titanium tetraisopropoxide was crucial to ined the influence of the catalyst loading and amount of
the process and low loadings led to a drastic decrease in the MeMgBr in the reaction with benzaldehyde (1b, Table 3).
enantioselectivity (Table 1, Entries 7, 9–13). We believe that Higher ligand loadings improved both the conversion and
a large excess of the Lewis acid Ti(iPrO)4 is needed to pre- enantioselectivity of the reaction (Table 3, Entries 1–3) up
vent the complexation of the magnesium salts (produced to 79% conversion and 85%ee when using 20 mol-% of
during the transmetalation process and responsible for the (Sa,R)-L1 (Table 3, Entry 3). To reach full conversion, the
uncatalyzed reaction)[10] to the carbonyl moiety. In view of number of equivalents of MeMgBr was increased to 3.75.
these results, we concluded that 4 equiv. of Ti(iPrO)4 with Under these last adjustments, the enantioselectivity slightly
respect to MeMgBr (Table 1, Entry 7) was the optimal increased up to 88% (Table 3, Entry 4).
amount to achieve the highest enantioselectivity.
With the optimized conditions in hand (Table 3, En-
With these preliminary conditions, we decided to screen try 4), we studied the addition of MeMgBr to different alde-
a small library of Ar-BINMOLs (Figure 1 and Table 2) as hydes (Table 4). The highly desirable addition of poorly re-
ligands for the addition of MeMgBr to benzaldehyde (1b). active MeMgBr was achieved in high yields with high
The corresponding diastereomer of (Sa,R)-L1, with same enantioselectivities (80–90%ee) for a wide variety of aro-
axial chirality but opposite configuration at the sp3 center, matic aldehydes with electron-poor and electron-rich sub-
was synthesized by treatment of (Sa,R)-L1 with 6 m HCl in stituents in the meta and para positions (Table 4, Entries 1,
THF at room temperature (20% yield, see the Supporting 3–9). The alkylation of o-methylbenzaldehyde proceeded
Information for details). However, new ligand (Sa,S)-L1 with lower enantioselectivity (53%ee; Table 4, Entry 2),
provided no enantioselectivity in the alkylation reaction probably due to the steric hindrance close to the reactive
6852
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Eur. J. Org. Chem. 2011, 6851–6855

Catalytic Enantioselective Addition of Grignard Reagents to Aldehydes
Table 3. Asymmetric addition of MeMgBr to benzaldehyde: effect
of catalyst loading.[a]
Table 4. Asymmetric addition of MeMgBr to aldehydes: scope of
the reaction.[a]
Entry
R1
Yield [%][b]
ee [%][c,d]
Entry (Sa,R)-L1 MeMgBr Ti(iPrO)4
Conv.
[%][b]
ee
[mol-%]
[equiv.]
[equiv.]
[%][b]
1
2
3
4
5
6
7
8
Ph
92
85
99
98
95
88
98
89
88 (S)
53 (S)
88 (S)
87 (S)
80 (S)
88 (S)
84 (S)
85 (S)
90 (S)
68 (S)
70 (S)
68 (S)
58 (S)
o-MeC6H4
m-MeC6H4
p-Me-C6H4
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
p-CNC6H4
2-naphthyl
Bn
1
2
3
4
5
1.25
1.25
1.25
3.75
5
5
5
60
73
79
98
78
83
85
88
10
20
20
15
[a] Conditions: 1b (1 equiv., 0.07 m), MeMgBr (3 m in Et2O,
x equiv.), (Sa,R)-L1 (5–20 mol-%), Ti(iPrO)4 (4x equiv.), toluene,
–40 °C, 4 h. [b] Determined by chiral GC (see the Supporting Infor-
mation for details).
9
92
43
70
10
11[e]
12
13
Bn
PhCH=CH
2-thienyl
90
53[f] (98)[g]
[a] Conditions:
1 (1 equiv., 0.12 m), MeMgBr (3 m in Et2O,
site. The reaction with phenylacetaldehyde proceeded with
moderated enantioselectivity (68%ee) and poor yield (43%)
at –40 °C (Table 4, Entry 10); gratifyingly, the yield could be
improved to 70% by increasing the temperature to –20 °C
3.8 equiv.), (Sa,R)-L1 (20 mol-%), Ti(iPrO)4 (15 equiv.), toluene,
–40 °C, 4 h. [b] Isolated yield after flash chromatography. [c] Deter-
mined by chiral GC or HPLC (see the Supporting Information for
details). [d] Absolute configuration determined by correlation with
without observing any loss in enantioselectivity (Table 4, known compounds (see the Supporting Information). [e] Per-
formed at –20 °C. [f] Volatile product. [g] Yield based on GC data.
Entry 11). The use of cinnamaldehyde or 2-thiophenecarb-
oxaldehyde prompted a decrease in the enantioselectivity
values (Table 4, Entries 12 & 13). It should be mentioned
that full conversion was achieved in almost all the cases and
no byproducts were formed under the optimized conditions.
Only phenylacetaldehyde did not react completely (proba-
bly due to the high acidity of the benzylic hydrogen atoms)
and it could be recovered at the end of the reaction (Table 4,
Entries 10 & 11). Moreover, ligand (Sa,R)-L1 could also be
recovered and recycled without observing any loss in cata-
lytic activity (see the Supporting Information for further
details).
which provided a very low conversion to the corresponding
racemic alcohol in the reaction with benzaldehyde (Table 5,
Entry 11). The addition of the sp2-hybridized Grignard rea-
Table 5. Asymmetric addition of R2MgBr to aldehydes: scope of
the reaction.[a]
Encouraged by the excellent results in the addition of the
challenging MeMgBr reagent, we turned our attention to
the use of other Grignard reagents (Table 5). The addition Entry
R1
R2
Yield [%][b]
ee [%][c],[d]
of linear Grignard reagents like EtMgBr and nBuMgBr
proceeded in good yields and with good enantioselectivities
(up to 96%ee) for a wide range of aromatic aldehydes with
electron-donating or electron-withdrawing groups (Table 5,
Entries 1–4, 6, and 7). Moreover, nBuMgBr could be added
at –20 °C to an aliphatic aldehyde with moderated enantio-
selectivity (50%ee; Table 5, Entry 8) and good yield.[15] The
use of nBuMgCl provided the same enantioselectivity as
that of its bromide-derived counterpart; however, the con-
version only reached a moderated level and 19% of benzyl
alcohol was formed during the reaction (Table 5, Entry 5).
Bulky iBuMgBr gave an excellent enantioselectivity but
poor yield in the reaction with benzaldehyde (96%ee, 41%
yield; Table 5, Entry 9) and the formation of 5% of benzyl
alcohol was detected. An improvement in the yield could
be achieved at higher temperatures (–20 °C), but at the ex-
pense of the enantioselectivity (Table 5, Entry 10). A limita-
1
2
3
4
Ph
p-MeC6H4
p-ClC6H4
Ph
Et
Et
Et
95
80
85
90
41
89
81
98
41
86 (S)
78 (S)
72 (S)
96 (S)
96 (S)
93 (S)
92 (S)
50 (S)
96 (S)
86 (S)
0
nBu
nBu
nBu
nBu
nBu
iBu
iBu
iPr
5[e,f]
6
Ph
p-ClC6H4
p-MeOC6H4
cyclohexyl
Ph
Ph
Ph
2-naphthyl
7
8[g]
9[h]
10[g,h]
11
12
91
nd (10)[i]
98 (99)[i]
Ph
15 (R)
[a] Conditions: 1 (1 equiv., 0.12 m), R2MgBr (3.8 equiv.), (Sa,R)-L1
(20 mol-%), Ti(iPrO)4 (15 equiv.), toluene, –40 °C, 4 h. [b] Isolated
yield after flash chromatography. [c] Determined by chiral GC or
HPLC (see the Supporting Information for details). [d] Absolute
configuration determined by correlation with known compounds
(see the Supporting Information). [e] nBuMgCl was used instead.
[f] 40% of unreacted 1a and 19% of benzyl alcohol were isolated.
[g] Performed at –20 °C. [h] 5% of benzyl alcohol was isolated.
tion of this methodology is the use of secondary iPrMgBr, [i] Yield based on GC data.
Eur. J. Org. Chem. 2011, 6851–6855
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E. Fernández-Mateos, B. Maciá, D. J. Ramón, M. Yus
SHORT COMMUNICATION
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Conclusions
In conclusion, we have developed an efficient enantiose-
lective catalytic system for the addition of MeMgBr to alde-
hydes. This methodology allows the preparation of the very
versatile optically active methyl carbinol motif in a simple
one-pot procedure by using an economical and commer-
cially available source of the methyl group. A readily avail-
able binaphthyl derivative is used as a chiral ligand and an
excess amount of titanium tetraisopropoxide was found to
be crucial to achieve high enantioselectivities. Moreover, the
addition of longer-chain Grignard reagents to aromatic and
aliphatic aldehydes could be also achieved in high yields
and with high enantioselectivities with the here-presented
catalytic system. Currently, efforts are directed towards the
elucidation of the reaction mechanism.
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Experimental Section
General Procedure for the Synthesis of Chiral Alcohols: In a flame-
dried Schlenk tube (Sa,R)-L1 (22.6 mg, 0.06 mmol) was dissolved
in toluene (2.5 mL) and Ti(iPrO)4 (1.33 mL, 15 equiv., 1.5 mmol)
was added to the solution at –40 °C. After 5 min, RMgX
(3.8 equiv., 0.38 mmol) was added, and the mixture was stirred for
10 min before adding the corresponding aldehyde (0.3 mmol). The
reaction mixture was stirred at –40 °C for 4 h and then quenched
with H2O (5 mL) and 2 m HCl (5 mL). The crude was extracted
with EtOAc (3ϫ10 mL), and the combined organic layers were
neutralized with aq. sat. NaHCO3, dried with MgSO4, and concen-
trated in vacuo. The crude product was purified by chromatography
on silica gel to give desired alcohols 2.
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[7]
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, screening of the titanium sources, copies
1
of the H and 13C NMR spectra, and traces of the GC and HPLC
chromatograms.
Acknowledgments
This work was financially supported by the Spanish Ministerio de
Ciencia
y
Tecnología (Projects CTQ2007-65218/BQU and
CTQ2011-24151), Consolider Ingenio 2010 (CSD2007-00006), and
Generalitat Valenciana (G.V. PROMETEO/2009/039 and
FEDER). Medalchemy is thanked for a gift of chemicals.
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Eur. J. Org. Chem. 2011, 6851–6855

Catalytic Enantioselective Addition of Grignard Reagents to Aldehydes
[12] a) G. Gao, F.-L. Gu, J.-X. Jiang, K. Jiang, C.-Q. Sheng, G.-Q.
Lai, L.-W. Xu, Chem. Eur. J. 2011, 17, 2698–2703; for other
applications of Ar-BINMOLs in asymmetric catalysis, see: b)
G. Gao, X.-F. Bai, H.-M. Yang, J.-X. Jiang, G.-Q. Lai, L.-W.
Xu, Eur. J. Org. Chem. 2011, 5039–5046.
[13] The reaction was also carried out in Et2O/toluene mixtures but
no improvement was observed.
[14]
We observed partial decomposition of ligand (Sa,R)-L5 after
3 weeks stored at room temperature.
[15] When the reaction was carried out at –40 °C, no conversion
was observed.
Received: September 1, 2011
Published Online: October 20, 2011
Eur. J. Org. Chem. 2011, 6851–6855
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6855