Catalytic asymmetric addition of alkyllithium reagents to aromatic aldehydes

Article abstract of DOI:10.1002/ejoc.201200464

Herein, we report the first efficient catalytic system for the asymmetric alkylation of aldehydes with organolithium reagents in the presence of titanium(IV) isopropoxide. A variety of alkyllithium reagents can be added to aromatic aldehydes in good yields with high enantioselectivities in a simple one-pot procedure under mild conditions. Herein, we report the first efficient catalytic system for the asymmetric alkylation ofaldehydes with organolithium reagents in the presence of titanium(IV) isopropoxide. A variety of alkyllithium reagents can be added to aromatic aldehydes in good yields with high enantioselectivities in a simple one-pot procedure under mild conditions. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200464

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200464
Catalytic Asymmetric Addition of Alkyllithium Reagents to Aromatic
Aldehydes
Emilio Fernández-Mateos,[a] Beatriz Maciá,*[a] and Miguel Yus*[a]
Dedicated to the memory of Dr. Michael M. Pollard
Keywords: Asymmetric catalysis / Lithium / Aldehydes / Chirality / Titanium
Herein, we report the first efficient catalytic system for the
asymmetric alkylation of aldehydes with organolithium rea-
gents in the presence of titanium(IV) isopropoxide. A variety
of alkyllithium reagents can be added to aromatic aldehydes
in good yields with high enantioselectivities in a simple one-
pot procedure under mild conditions.
aldehyde was reported by Harrison-Marchand and Madda-
luno.[14]
Introduction
Organolithium compounds are common bench reagents
that can be found in any organic synthetic laboratory and
are widely used in industry to produce numerous materials
from pharmaceutical to polymers.[1] For catalytic applica-
tions, the low price and good availability of organolithium
reagents make them desirable, but their high reactivity often
precludes their use in more complex systems such as asym-
metric C–C bond formation; (super) stoichiometric
amounts of a chiral modifier and extremely low tempera-
tures are usually required to obtain high enantio-
selectivity.[2] Only a few examples of asymmetric deproton-
ations,[3] addition to imines,[4] allylic alkylation reactions,[5]
and addition of alkynes[6] have been described in the litera-
ture as catalytic processes for organolithium reagents.
The enantioselective addition of organometallic reagents
to aldehydes is one of the most versatile methods for the
synthesis of highly valuable chiral secondary alcohols.[7]
Catalytic versions of this key transformation[8] have been
studied extensively with organozinc reagents[9] and, only re-
cently, with organomagnesium compounds.[10] However, for
organolithium reagents, the progress is limited to their cor-
responding transmetalation into less reactive intermediates
such as RTi(iPrO)3[11] (alkyllithiums) and zinc[12] or magne-
sium derivatives[13] (aryllithiums), involving the problematic
use of chelating additives and the tedious removal of the
generated lithium salts. Only last year, a substoichiometric
enantioselective addition of methyllithium to o-tolylbenz-
Recently, we described a highly enantioselective catalytic
system, based on the readily available chiral ligand L1 (Fig-
ure 1)[15] and an excess amount of titanium(IV) isopropox-
ide, for the addition of Grignard reagents to aldehydes.[10c]
This result prompted us to examine this system in reactions
with more challenging organolithium reagents. Herein, we
report a simple one-pot methodology for the alkylation of
aldehydes by using alkyllithium reagents and an excess
amount of Ti(iPrO)4 in the presence of catalytic amounts
of ligand L1 where no salt exclusion or additives are needed
to achieve high enantioselectivities.
Figure 1. Ar-BINMOLs ligands developed by Kiyooka, Lai, and
Xu used in this study.
Results and Discussion
As a starting point, MeLi was chosen as a nucleophile
based on the importance of methyl carbinol units in the
synthesis of natural products and biologically active com-
pounds.[16] Our first tests for the addition of MeLi to our
model substrate benzaldehyde (1a) provided very promising
results (Table 1). Desired alcohol 2a was obtained with 90%
enantioselectivity and 40% conversion when 1a was added
immediately after the addition of 1.5 equiv. of MeLi into a
toluene solution containing 10 mol-% of L1 and 4.5 equiv.
of Ti(iPrO)4 at –40 °C (Table 1, Entry 1). Both conversion
[a] Organic Chemistry Department and Institute of Organic
Synthesis, 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.201200464.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. Fernández-Mateos, B. Maciá, M. Yus
SHORT COMMUNICATION
and enantioselectivity could be improved by increasing the Table 2. Li/Ti ratio optimization.[a]
catalyst loading up to 20 mol-% (63% conv., 93%ee;
Table 1, Entry 2). However, changing the reaction tempera-
ture did not produce any better results; higher temperatures
(–20 °C) led to lower ee values (Table 1, Entry 3), whilst
lower temperatures (–60 °C) gave lower conversions
(Table 1, Entry 4). It should be noted that the addition pro-
Entry
MeLi
Ti(iPrO)4
Ti/Li
Conv.
[%][b]
ee
tocol had a significant influence on the outcome of the pro-
cess. When MeLi was added last to the reaction mixture,
the enantioselectivity dropped to 74% (Table 1, Entry 5).
More interestingly, when substrate 1a was added 15 min af-
ter the addition of MeLi to the reaction mixture containing
the ligand and titanium tetraisopropoxide, the conversion
drastically diminished to 19% (Table 1, Entry 6),[17] which
indicates that the active species formed upon addition of
MeLi to the L1-Ti(iPrO)4 complex has a short life time at
–40 °C.[18]
[equiv.]
[equiv.]
[%][b]
1
2
3
4
1.5
1.5
1.5
3.2
1.5
1.5
3.2
4.5
3.0
1.5
6.0
–
0.2
6.0
3:1
2:1
1:1
1.9:1
–
0.13:1
1.9:1
63
59
23
85
Ͼ99
Ͼ99
93
96
89
94
0
0
94
5
6
7[c]
86
[a] Conditions: 1a (0.1 mmol, 0.07 m), MeLi (1.6 m in Et2O),
(Sa,R)-L1 (20 mol-%), Ti(iPrO)4, toluene, –40 °C, 1 h. [b] Deter-
mined by chiral GC (see the Supporting Information for details).
[c] Reaction was carried out in hexane.
Table 1. Influence of catalyst loading, temperature, and addition
protocol.[a]
Different solvents were also evaluated in the reaction (see
the Supporting Information for further details), and al-
though hexane proved to be equally effective as toluene
(Table 2, Entry 7) its use was discarded to avoid possible
solubility problems with other substrates.
Under these optimized conditions, we screened a small
library of Ar-BINMOLs (Figure 1 and Table 3) as ligands
for the addition of MeLi to benzaldehyde (1a). The results
suggest that the stereochemical configuration of the ligand
is of crucial importance (Table 3, Entry 1 vs. 2 and footnote
c). Variation of the aromatic substituents (i.e., L1–L6) did
not have a significant effect on either the conversion or the
enantioselectivity (Table 3, Entry 1 vs. Entries 3–7), with
the exception of ortho-methoxy-substituted (Sa,S)-L3,
which provided lower conversion (Table 3, Entry 3).
Entry
L1 [mol-%]
T [°C]
Conv. [%][b]
ee [%][b]
1
2
3
10
20
20
20
20
20
–40
–40
–20
–60
–40
–40
40
63
50
20
63
19
90
93
66
84
74
86
4
5[c]
6[d]
[a] Conditions: 1a (1 equiv., 0.07 m, added last), MeLi (1.6 m in
Et2O, 1.5 equiv.), (Sa,R)-L1, Ti(iPrO)4 (4.5 equiv.), toluene, –40 °C,
1 h. [b] Determined by chiral GC (see the Supporting Information
for details). [c] MeLi was added last. [d] Compound 1a was added
15 min after the addition of MeLi.
Table 3. Ligand screening.[a]
In the second stage of the optimization process, we ad-
justed the amounts of MeLi and Ti(iPrO)4. As shown in
Table 2, lowering the ratio of Ti/Li to 2:1 had a beneficial
effect on the enantioselectivity of the reaction, although the
conversion obtained was slightly lower (Table 2, Entry 1 vs.
2). Equimolar Ti/Li amounts provided lower enantio-
selectivity and very poor conversion (Table 2, Entry 3). To
improve the conversion, we decided to increase the equiva-
lents of both MeLi and Ti(iPrO)4, keeping the Ti/Li ratio
close to the optimal 2:1. This strategy allowed the reaction
to reach very good levels of conversion (85%) and enantio-
selectivity (94%; Table 2, Entry 4). Interestingly, when the
reaction was performed in the absence or with catalytic
amounts of Ti(iPrO)4 (Table 2, Entry 5 and 6, respectively)
full conversion but no enantioselectivity was observed. This
seems to indicate that the active nucleophiles in the reaction
are the organotitanium species generated in situ by trans-
Entry
Ar in L
L
Conv. [%][b]
ee [%][b]
1
2
3
4
5
6
7
Ph
Ph
(Sa,R)-L1
(Sa,S)-L1[c]
(Sa,R)-L2
(Sa,S)-L3
85
60
79
15
81
84
87
94
0
94
93
90
86
94
o-MeC6H4
o-MeOC6H4
m-MeOC6H4 (Sa,R)-L4
p-MeOC6H4
p-FC6H4
(Sa,R)-L5
(Sa,R)-L6
[a] Conditions: 1a (0.1 mmol, 0.07 m), MeLi (1.6 m in Et2O,
3.2 equiv.), L (20 mol-%), Ti(iPrO)4 (6 equiv.), toluene, –40 °C,
45 min. [b] Determined by chiral GC (see the Supporting Infor-
mation for details). [c] Same axial chirality as (Sa,R)-L1 but oppo-
site configuration at the sp3 center.
The progress of the model reaction under optimal condi-
metalation of the organolithium reagent with the excess tions was monitored by GC (Figure 2, profile a) and com-
amount of Ti(iPrO)4. pared with the reaction progress in the absence of the ligand
2
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Catalytic Asymmetric Addition of Alkyllithiums to Aromatic Aldehydes
(Figure 2, profile b) or in the presence of 20 mol-% of (S)- electron-rich substituents at the meta and para positions
BINOL as ligand (Figure 2, profile c).[19] A pronounced (Table 4, Entries 1, 3–8). The lower yield and selectivity of
acceleration of the reaction rate was observed when the o-methylbenzaldehyde (Table 4, Entry 2) might be ascribed
Ti(iPrO)4-L1 complex was used and 92% of conversion was to higher steric hindrance around the reactive site.
reached in only 45 min, in contrast with the 80% conver-
The tolerance of this methodology towards function-
sion that the blank reaction achieved in 90 min or the 79% alized substrates should be emphasized: chloro and cyano
conversion that the Ti(iPrO)4-BINOL complex provided af- functionalities showed resistance to the very reactive lith-
ter 10 h of reaction.[20]
ium reagents when used under these reaction conditions
(Table 4, Entries 7 and 8). The reactions with 2-naphth-
aldehyde and the heteroaromatic substrates 2-thiophene-
carboxaldehyde and 2-furaldehyde gave 90, 88, and 72%ee,
respectively, along with very good yields (Table 4, En-
tries 9–11), whereas cinnamic aldehyde provided a moderate
enantioselectivity (Table 4, Entry 12). Remarkably, all reac-
tions were finished in less than 1 h without any byproduct
formation. Moreover, the unreacted starting material and
ligand could be easily recovered, and the latter, could be
recycled and reused without any loss of activity.[20] Regard-
ing aliphatic substrates, phenylacetaldehyde (Table 4, En-
try 13) gave low conversion and moderate enantioselectivity,
whereas the addition of MeLi to pivaldehyde (Table 4, En-
try 14) proceeded in less than 2% conversion.
Finally, we turned our attention to other alkyllithium
reagents (Table 5). Gratifyingly, the addition of other linear
reagents like EtLi and nBuLi proceeded in good yield (62
to 90%) and enantioselectivity (90 to 96%) for a wide range
of aromatic aldehydes bearing electron-donating or -with-
drawing groups (Table 5, Entries 1–8). It was also noted
that (i) an increase in the size of the nucleophile meant an
improvement in the enantioselectivity (Table 5, Entries 1–3
vs. 4–8); (ii) no evidence of common lithium–halogen ex-
change was found when halogenated aldehydes were used
as substrates (Table 5, Entries 5 and 6); (iii) labile function-
alities like carbonates were tolerated, as demonstrated by
Figure 2. Progress of the model reaction in toluene at –40 °C:
(a) 1a, MeLi (3.2 equiv.), (Sa,R)-L1 (20 mol-%), Ti(iPrO)4
(6 equiv.); (b) 1a, MeLi (3.2 equiv.), Ti(iPrO)4 (6 equiv.); (c) 1a,
MeLi (3.2 equiv.), (S)-BINOL (20 mol-%), Ti(iPrO)4 (6 equiv.).
Conversion determined by GC.
The scope of the addition of MeLi was then examined
with different aldehydes (Table 4). The new catalytic system
described above proved to be remarkably efficient; a versa-
tile range of methyl carbinol units was prepared in good
yield (74 to 91%) and enantioselectivity (72 to 90%)[21]
from a wide range of substrates bearing electron-poor or
Table 4. Asymmetric addition of MeLi to aldehydes: scope of the
reaction.[a]
Table 5. Asymmetric addition of alkyllithium to aldehydes: scope
of the reaction.[a]
Entry
R1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
87
78
87
81
91
82
74
84
85
90 (S)
62 (S)
82 (S)
88 (S)
89 (S)
88 (S)
84 (S)
82 (S)
90 (S)
88 (S)
72 (S)
68 (S)
62 (S)
nd[e]
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
p-CNC6H4
2-naphthyl
2-thienyl
2-furyl
Entry
R1
R2
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
Ph
p-MeC6H4
p-ClC6H4
Ph
Et
Et
Et
nBu
nBu
nBu
nBu
nBu
Ph
78
66
62
90
89
85
89
90
96
92
92 (S)
90 (S)
92 (S)
96 (S)
94 (S)
92 (S)
94 (S)
96 (S)
17 (S)
39 (R)
9
10
11
12
13
14
57 (90)[d]
56 (86)[d]
84
p-BrC6H4
p-ClC6H4
p-MeOC6H4
p-MeOCO2C6H4
2-naphthyl
cyclohexyl
PhCH=CH
PhCH2
23
Ͻ2
tBu
Ph
[a] Conditions: 1 (0.3 mmol, 1 equiv., 0.12 m), MeLi (1.6 m in Et2O,
3.2 equiv.), (Sa,R)-L1 (20 mol-%), Ti(iPrO)4 (6 equiv.), toluene,
–40 °C, 1 h. [b] Isolated yield after flash chromatography. [c] Deter-
mined by chiral GC or HPLC. Absolute configuration determined
by correlation with known compounds (see the Supporting Infor-
mation for details). [d] Volatile products, conversions based on GC
data in brackets. [e] Not determined.
[a] Conditions: 1 (0.3 mmol, 1 equiv., 0.12 m), R2Li (3.2 equiv.),
(Sa,R)-L1 (20 mol-%), Ti(iPrO)4 (6 equiv.), toluene, –40 °C, 1 h.
[b] Isolated yield after flash chromatography. [c] Determined by
chiral GC or HPLC. Absolute configuration determined by corre-
lation with known compounds (see the Supporting Information for
details).
Eur. J. Org. Chem. 0000, 0–0
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SHORT COMMUNICATION
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and moderate enantioselectivities in the addition to
2-naphthaldehyde and cyclohexanecarbaldehyde, respec-
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[3]
[4]
Conclusions
[5]
In conclusion, we have developed the first efficient enan-
tioselective catalytic system for the addition of alkyllithium
reagents to aromatic aldehydes by using an excess amount
of titanium tetraisopropoxide. This methodology allows the
preparation of highly valuable optically active alcohols
from economical and commercially available lithium rea-
gents. Reactions are performed in a simple and fast one-pot
procedure and no salt exclusion is needed. Moreover, the
potential problems associated with the high reactivity of
organolithium compounds are overcome under these reac-
tion conditions, as this methodology proves to be compati-
ble with functionalized substrates. Currently, efforts are di-
rected 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 (550 μL, 6 equiv., 1.8 mmol) was
added to the solution at –40 °C. After 5 min, RLi (3.2 equiv.,
0.96 mmol) was added followed by rapid addition of the aldehyde
(0.3 mmol). The reaction mixture was stirred at –40 °C for 1 h and
then quenched with H2O (2 mL) and 2 m HCl (2 mL). The crude
product was extracted with EtOAc (3ϫ5 mL), and the combined
organic layer was neutralized with aq. sat. NaHCO3, dried with
MgSO4, and concentrated in vacuo. The crude product was puri-
fied by chromatography on silica gel to give desired alcohol 2.
[10]
Supporting Information (see footnote on the first page of this arti-
cle): General procedures, characterization data, H NMR and 13C
1
NMR spectra, GC and HPLC chromatograms.
Acknowledgments
[11]
[12]
[13]
See, for example: B. Weber, D. Seebach, Tetrahedron 1994, 50,
The authors acknowledge financial support from the Spanish Min-
istry of Science and Technology (Projects CTQ2007-65218/BQU
and CTQ2011-24151), Consolider Ingenio 2010 (CSD2007-00006),
and Generalitat Valenciana (G.V. PROMETEO/2009/039 and
FEDER). Medalchemy and Chemetall are thanked for a gift of
chemicals. E. Fernández-Mateos thanks the Spanish Ministry of
Education for a predoctoral fellowship. G.P. Howell is thanked for
helpful comments on the manuscript.
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4
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/KAP1
Date: 05-06-12 15:33:46
Pages: 6
Catalytic Asymmetric Addition of Alkyllithiums to Aromatic Aldehydes
[16] Chiral methyl carbinol moiety is present in a large number of
natural products and biologically active compounds. See, for
example: a) F. Cohen, L. E. Overman, J. Am. Chem. Soc. 2006,
128, 2604–2608; b) G. Sabitha, C. S. Reddy, J. S. Yadav, Tetra-
hedron Lett. 2006, 47, 4513–4516; c) M. S. Scott, C. A. Luck-
hurst, D. J. Dixon, Org. Lett. 2005, 7, 5813–5816; d) G. Pat-
tenden, D. J. Critcher, M. Remunian, Can. J. Chem. 2004, 82,
353–365; e) G. B. Jones, M. Guzel, B. J. Chapman, Tetrahe-
dron: Asymmetry 1998, 9, 901–905; f) S. Hanessian, Total Syn-
thesis of Natural Products: The Chiron Approach, Pergamon,
Oxford, 1983.
[18] If 1a is added to the reaction mixture 30 min after the addition
of MeLi, the conversion is Ͻ5%.
[19] Compound 2a was obtained with 7%ee when BINOL was used
as the ligand.
[20] See the Supporting Information for details and extra data.
[21] Scaling up from 0.1 to 0.3 mmol of substrate did not have any
significant effect on the outcome of the reaction. Only for the
addition of MeLi to benzaldehyde did the conversion increase
from 85 to 92% and the enantioselectivity diminish from 94 to
90% (Table 2, Entry 4 vs. Table 4, Entry 1).
Received: April 11, 2012
[17] 81% of the starting material could be detected by CG.
Published Online: ᭿
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Job/Unit: O20464
/KAP1
Date: 05-06-12 15:33:46
Pages: 6
E. Fernández-Mateos, B. Maciá, M. Yus
SHORT COMMUNICATION
Asymmetric Catalysis
Herein, we report the first efficient catalytic
system for the asymmetric alkylation of
aldehydes with organolithium reagents in
the presence of titanium(IV) isopropoxide.
A variety of alkyllithium reagents can be
added to aromatic aldehydes in good yields
with high enantioselectivities in a simple
one-pot procedure under mild conditions.
E. Fernández-Mateos, B. Maciá,*
M. Yus* ............................................ 1–6
Catalytic Asymmetric Addition of Alkyl-
lithium Reagents to Aromatic Aldehydes
Keywords: Asymmetric catalysis / Lithium /
Aldehydes / Chirality / Titanium
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0