Discrete versus in situ-generated aluminum-salen catalysts in enantioselective cyanosilylation of ketones: Role of achiral ligands

Article abstract of DOI:10.1002/adsc.200700565

The monometallic species {Salen}AlX (X=Me, 2a,b; X=Cl, 4a,b; O-i-Pr, 5a,b) and open bimetallic species {Salen}[AlMe₂]₂ (3a,b) that result from binary combinations between an aluminum precursor [trimethylaluminum, dimethylaluminum chl

Full text of DOI:10.1002/adsc.200700565

FULL PAPERS
DOI: 10.1002/adsc.200700565
Discrete versus In Situ-Generated Aluminum-Salen Catalysts in
Enantioselective Cyanosilylation of Ketones: Role of Achiral
Ligands
a
a
a
Ali Alaaeddine, Thierry Roisnel, Christophe M. Thomas,
a,
and Jean-FranÅois Carpentier *
Catalysis and Organometallics, UMR 6226 Sciences Chimiques de Rennes, CNRS-University of Rennes 1, 35042 Rennes
Cedex, France
a
Fax : (+33)-223-236-939; e-mail: jean-francois.carpentier@univ-rennes1.fr
Received: December 3, 2007; Revised: January 30, 2008; Published online: March 12, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The monometallic species {Salen}AlX (X= these discrete catalysts display dramatically different
Me, 2a,b; X=Cl, 4a,b; O-i-Pr, 5a,b) and open bimet- performances than the catalyst systems in situ-gener-
allic species {Salen}
binary combinations between an aluminum precursor the achiral ligand X on both the enantioselectivity
trimethylaluminum, dimethylaluminum chloride, and activity of the cyanosilylation reaction has been
aluminum tris(isopropoxide)] and diprotio investigated, resulting in the definition of a highly
Salen}H2 pro-ligand 1a,b (a=1R,2R-cyclohexyl- active and productive hexafluoro-2-propoxide-based
salen; b=1R,2R-diphenylethylene-salen) have been catalyst for a variety of aryl alkyl ketones (TON up
A
H
E
N
[
a
{
ꢀ
1
isolated. The crystal structures of 3b, 4b and of m-oxo to 470, TOF up to 140 h at ꢀ208C for acetophe-
species [{diphenylethylene-salen}Al] O (6b) are re- none).
2
ported. The discrete species 2–5a,b have been indi-
vidually evaluated in the asymmetric cyanosilylation Keywords: aluminum; asymmetric catalysis; cyanosi-
of acetophenone. It is shown that, in several cases, lylation; homogeneous catalysis; Salen ligands
[
3g–j]
Introduction
additives.
Effective in situ combinations of an alu-
minum precursor AlX (or AlX X’) with a readily
3
2
Enantioselective cyanosilylation of ketones is a available {Salen}H pro-ligand and N,N-dimethylani-
2
common route for the preparation of cyanohydrins line N-oxide (DMAO) were thus recently identified
[
1]
[3j]
with a quaternary stereocenter, a much valuable (Scheme 1). This practical approach gives substan-
[
2]
class of intermediates in organic synthesis. Those re- tially higher ee values than the related bifunctional
actions are catalyzed, e.g., by a metal-based Lewis catalysts for a range of ketones (up to 94% ee for ace-
acid, which activates the ketone substrate. An im- tophenone). The reaction times were, however, slight-
portant development of such reactions, with wider im- ly extended due to modest catalyst activity. Also, the
plications across the field of asymmetric catalysis, exact nature of the actual active species or catalyst
[3]
[
3d–k,4]
consists in “double-activation catalysis”.
In this precursors in these in situ systems was not thoroughly
process, an extra Lewis base further activates the cya- investigated, hampering the establishment of clear
nosilylation agent [Me SiCN] and facilitates cyanide structure-activity-selectivity relationships.
3
delivery to the activated substrate (Scheme 1). This
In this work we have studied the organometallic
principle of double-activation catalysis was initially outcome of the catalyst systems in situ-generated
demonstrated with quite sophisticated bifunctional from an aluminum precursor AlX (or AlX X’) and a
3
2
[
3d–f,4]
Lewis-basic/chiral ligands.
Looking for simpler diprotio {Salen}H pro-ligand. The different species
2
catalyst systems, Feng and co-workers investigated that result from these binary combinations have been
the cyanosilylation of ketones in the presence of isolated, characterized and individually evaluated in
Lewis acid complexes based on commercially avail- the asymmetric cyanosilylation of acetophenone. It is
able ligands in combination with achiral Lewis base shown that, in some cases, these discrete catalysts dis-
Adv. Synth. Catal. 2008, 350, 731 – 740
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
731

Ali Alaaeddine et al.
FULL PAPERS
ed that open bimetallic complexes of the type {Salen}-
A
H
R
U
G
two equiv. of trialkylaluminum per {Salen}H pro-
2
[
5,6]
ligand.
In fact, we observed that the 1:1 reactions
of AlMe3 and {Salen}H2 pro-ligands derived from
trans-1R,2R-cyclohexyldiamine (1a) and trans-1R,2R-
diphenylethylenediamine (1b), under the conditions
used for the in situ generation of “{Salen}AlR’’-type
A
H
R
U
G
catalysts, that is, at room temperature in toluene solu-
tion, led in both cases to mixtures of 2a,b and 3a,b, as
revealed by NMR spectroscopy. Unexpectedly
enough, the open bimetallic complexes 3a,b were
often the major products observed in these reactions.
The influence of the parameters that may vary in
such a protocol, that is, the introduction order and
concentration of reagents, the reaction temperature
and reaction time, was systematically investigated.
Some representative results are summarized in
Table 1. No significant influence of the addition rate
Scheme 1.
play dramatically different performances than the of the second reagent on the overall reaction time
binary systems which are assumed to generate them. was noticed on the 2/3 relative proportions. Not sur-
The influence of the achiral ligand on both the enan- prisingly, addition of pro-ligands 1a,b onto AlMe af-
3
tioselectivity and activity of the reaction has been in- forded the open bimetallic complexes 3a,b in high
vestigated, resulting in the definition of a highly yield or as the exclusive product (entries 1 and 6). Re-
active hexafluoro-2-propoxide-based catalyst.
versal of the addition order, however, did not signifi-
cantly affect the outcome. Improved selectivity for
the desired five-coordinated monometallic complexes
2a,b was obtained upon increasing the reagent con-
centrations (compare entries 3 and 4) and even more
upon increasing the reaction temperature. Only at
high temperature (i.e., much higher than that used for
the in situ generation) could 2a,b be obtained in high
Results and Discussion
Reaction of {Salen}H Pro-ligands with Aluminum
2
Precursors
The reaction of {Salen}H pro-ligands with one equiv. yields, but were still contaminated by 3a,b.
2
of
Scheme 2). This reaction is anticipated to provide ed in good yields from these mixtures by recrystalliza-
the corresponding {Salen}AlR complex (2) as the tion at low temperature. As no crystal structure of
a
trialkylaluminum was first investigated
Complexes 2a,b and 3a,b were separated and isolat-
(
[
5]
major (exclusive) product via methane elimination.
Salen complexes derived from the 1,2-diphenylethy-
However, Atwood and co-workers previously report- lene backbone has been reported so far, X-ray diffrac-
Scheme 2.
732
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Adv. Synth. Catal. 2008, 350, 731 – 740

Discrete versus In Situ-Generated Aluminum-Salen Catalysts
FULL PAPERS
[a]
Table 1. Reaction of {Salen}H pro-ligands 1a,b with AlMe .
2
3
Entry
Temp [8C]
Time [h]
14
A
T
E
N
[reagent] [mol/L]
Addition order of reagents
2:3
1
22
3
20
0.10
1. AlMe , 2 .1a
12:88
27:73
55:45
68:32
91:9
0:100
13:87
47:53
3
0
14
0.10
1.
1a, 2. AlMe3
1. 1a, 2. AlMe3
1. 1a, 2. AlMe3
1. 1a, 2. AlMe3
2 !110
2 !110
110
20
20
0
0
4
4
4
14
14
4
0.04
0.14
0.14
0.03
0.03
0.14
4
[
b]
5
6
7
8
1. AlMe , 2 .1b
3
1. 1b, 2. AlMe3
1. 1b, 2. AlMe3
2 !110
0
[
[
a]
Reactions conducted in toluene solutions; complete conversion of the reagents was observed in all cases.
Solutions of both reagents were pre-heated before addition.
b]
tion studies were conducted in this series. The molec-
ular structure of open bimetallic complex 3b is shown
in Figure 1. Crystallographic details are available in
the Supporting Information (Table S1). The Al cen-
ters in 3b are in a slightly distorted tetrahedral envi-
ronment and the main geometric characteristics are
essentially similar to those reported for the related
[
6b]
{
cyclohexyl-salen} complex 3a.
Following similar alcohol or alkane elimination pro-
tocols, pro-ligands 1a,b react with Al(O-i-Pr) or
AlMe Cl in toluene to give the corresponding
AHCTREUNG
3
2
A
C
H
T
R
E
U
N
G
{Salen}AlX (X=Cl, 4a,b; O-i-Pr, 5a,b) complexes
(
Scheme 3). In these cases, no other species than
those expected were detected in the crude reaction
mixtures by NMR spectroscopy. Thus, all complexes
were isolated in pure form in high yields by simply
concentrating the reaction mixture under vacuum and
washing the final solid residue with hexanes. {Cyclo-
[
7]
[8]
hexyl-salen} complexes 4a and 5a were described
previously, while complexes 4b and 5b that have a
Figure 1. Molecular structure of 3b (60% ellipsoids; all H
atoms removed). Main bond distances (Š) and angles (deg):
Al(1)ꢀO(12), 1.7748(10), Al(1)ꢀC(2), 1.9552(16); Al(1)ꢀ
C(1), 1.9602(15), Al(1)ꢀN(3), 1.9795(11); O(12)ꢀAl(1)ꢀ
C(2), 111.25(6); O(12)ꢀAl(1)ꢀC(1), 106.27(6); C(2)ꢀAl(1)ꢀ
C(1), 120.04(7); O(12)ꢀAl(1)ꢀN(3), 93.63(5); C(2)ꢀAl(1)ꢀ
1
,2-diphenylethylene backbone are new. The latter
complexes were fully characterized by NMR, elemen-
tal analyses and an X-ray diffraction study for 4b. The
solid state structure of 4b (Figure 2and Supporting
Information, Table S1) contains two independent mol-
ecules per unit cell, whose geometric data (bond dis-
N(3), 110.94(6); C(1) Al(1) N(3), 111.41(6); N(3) C(4)
ꢀ
ꢀ
ꢀ
ꢀ
tances and angles) are slightly different (see Legend C(5), 108.98(10); dihedral angle C(5)ꢀC(4)ꢀC(4’)ꢀC(5’),
of Figure 2), but the general features are essentially 54.5(1).
similar. Overall, these two molecules compare very
Scheme 3.
Adv. Synth. Catal. 2008, 350, 731 – 740
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asc.wiley-vch.de
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Ali Alaaeddine et al.
FULL PAPERS
Figure 2. Moleculat structure of 4b (50% ellipsoids; all H
atoms removed; only one of the two independent molecules
is shown). Main bond distances (Š) and angles (deg) [data
in square brackets refer to the second independent mole-
cule, not shown]: Al(1)ꢀO(51), 1.7758(12) [1.7814(12)];
Scheme 4.
Al(1)ꢀO(1),
.9970(15)
1.7991(12)
[1.7870(12)];
Al(1)ꢀN(17),
1
[
[1.9927(14)];
Al(1)ꢀN(67),
2.0080(14)
1.9989(14)]; Al(1)ꢀCl(1), 2.1723(6) [2.1701(6)]; O(51)ꢀ
Al(1)ꢀO(1), 90.79(5) [90.42(5)]; O(51)ꢀAl(1)ꢀN(17),
48.59(6) [141.21(6)]; 89.05(6)
O(1)ꢀAl(1)ꢀN(17),
89.22(5)]; O(51)ꢀAl(1)ꢀN(67), 88.77(5) [88.62(5)]; O(1)ꢀ
Al(1)ꢀN(67), 155.81(6) [161.61(6)]; N(17)ꢀAl(1)ꢀN(67),
9.01(6) [80.15(5)]; 109.97(5)
O(51)ꢀAl(1)ꢀCl(1),
1
[
7
[
112.82(4)]; O(1)ꢀAl(1)ꢀCl(1), 102.83(4) [101.78(4)];
N(17)ꢀAl(1)ꢀCl(1), 100.66(4) [105.19(4)]; N(67)ꢀAl(1)ꢀ
Cl(1), 100.03(4) [95.50(4)]; N(17)ꢀC(18)ꢀC(19), 116.63(13)
[
116.80(13)]; dihedral angle C(19)ꢀC(18)ꢀC
A
H
R
U
G
A
T
E
N
(19’),
59.3(2) [58.4(2)].
well with other five-coordinated {Salen}AlCl com-
[
5,7,9]
plexes previously described.
The chemistry of chloro- and isopropoxy-Al-{Salen}
complexes (4 and 5) confirms to be simpler than that
of methyl-Al-{Salen} complexes (2 and 3). However,
all three complexes may also adventitiously generate Figure 3. Molecular structure of 6b (50% ellipsoids; all H
atoms and t-Bu groups on phenyl rings removed for clarity).
Main bond distances (Š) and angles (deg): Al(1)ꢀO(6),
a fourth type of species, that is hydrolysis products. In
fact, we observed that products 2–5 are all quite sensi-
tive to moisture, which might be present either in re-
action or recrystallization solvents, or might have
partly altered aged aluminum precursors as well.
1
.699(3); Al(1)ꢀO(12), 1.802(3); Al(1)ꢀO(8), 1.833(3);
Al(1)ꢀN(11), 2.014(4); Al(1)ꢀN(9), 2.035(3); Al(2)ꢀO(6),
1
.699(3); Al(2)ꢀO(5), 1.794(3); Al(2)ꢀO(11), 1.824(3);
Al(2)ꢀN(16), 2.026(4); Al(2)ꢀN(17), 2.029(4); Al(2)ꢀO(6)ꢀ
Al(1), 168.6(2); O(6)ꢀAl(2)ꢀO(5), 116.64(17); O(6)ꢀAl(2)ꢀ
Thus, in a couple of reactions starting from Al
A
H
R
U
G
Pr) or in some recrystallizations of 2–5b, the forma-
ꢀ
ꢀ
ꢀ
3
O(11), 107.00(15); O(5) Al(2) O(11), 89.33(14); O(6)
tion of a small amount of crystals differently shaped Al(2)ꢀN(16), 95.71(15); O(5)ꢀAl(2)ꢀN(16), 87.66(15).
than the main product was noticed (Scheme 4). Al-
though the quality of these crystals was always poor,
which was reflected in the X-ray diffraction data [thus ably also account for the nearly perpendicular ar-
not reported in detail; R=0.097, wR2=0.2584], the rangement of the two salen moieties in 6b, while the
latter technique allowed us to establish this product salen moieties are more eclipsed in [{ethylene-sa-
t-Bu
H
to be the m-oxo species [{diphenylethylene-salen}-
l] O (6b) (Figure 3). The overall structure of 6b is
A
H
R
U
G
ACHTREUNG
2
t-Bu
[10]
reminiscent to those of [{ethylene-salen }Al] O
2
H
[11]
and [{ethylene-salen }Al] O.
The most noticeable Discrete versus in situ-Generated Catalysts in
differences lie in the significantly more obtuse AlꢀOꢀ Cyanosilylation of Acetophenone
2
Al angle [168.6(2)8 in 6b vs. 159.5(5) and 152.0(3)8,
respectively], which is attributable to the presence of The catalytic performances of the different discrete
the bulky 1,2-phenyl groups; these bulky groups prob- complexes isolated in the previous section were evalu-
734
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Adv. Synth. Catal. 2008, 350, 731 – 740

Discrete versus In Situ-Generated Aluminum-Salen Catalysts
FULL PAPERS
ated and compared to those of the corresponding in and 3a from AlMe /1a combinations (Table 1). The
3
[
3j]
situ combinations. The cyanosilylation of acetophe- lower enantioselectivity of the in situ system suggests
none with 2equiv. of TMSCN at ꢀ208C was chosen that less or non stereoselective species other than 2a
as the model reaction; N,N-dimethylaniline N-oxide and 3a, for example, unreacted AlMe , contribute
3
(
(
DMAO, 1.0 mol%) was selected as the Lewis base also to a significant extent to the cyanosilylation pro-
Scheme 1). Representative results are summarized in cess. The same activity trend was observed for in situ
Table 2.
catalysts based on 1b and the corresponding discrete
We first investigated alkyl-Al systems. The in situ- species 2b and 3b (entries 7–10); i.e., the monometal-
[
3j]
generated systems derived from either AlEt3
or lic complex is a much more active catalyst (or precur-
AlMe with 1a were found to afford similar catalytic sor) than its bimetallic congener. With this ligand
3
activity (as judged from the final conversion of aceto- system, all in situ-generated and discrete catalyst sys-
[
12]
phenone) and enantioselectivity (Table 2; entries 1 tems afford similar enantioselectivity, and the inter-
and 2). On the other hand, quite different performan- vention of active species other than 2b and 3b can be
ces were observed for the corresponding discrete spe- discarded a priori.
cies produced from these mixtures. As compared to
Feng and co-workers reported very poor catalytic
the in situ system, monometallic complex 2a leads to performances for in situ-generated isopropoxide-Al
[
3j]
significantly enhanced activity and enantioselectivity systems based on 1b (entry 15). We did also observe
entry 3), whatever the solvent used (entries 4 and 5), very poor yield and enantioselectivity for the analo-
while the bimetallic complex 3a is much less active gous Al(O-i-Pr) /1a combination (entry 11). In con-
and less enantioselective (entry 6). The observation of trast, discrete complexes 5a and 5b, and even the m-
(
AHCTREUNG
3
[
13]
an “averaged” activity for the in situ system is consis- oxo complex 6b,
proved to be quite effective for
tent with the abovementioned formation of both 2a the cyanosilylation of acetophenone, leading to high
[a]
Table 2. Cyanosilylation of acetophenone with in situ-generated and discrete catalyst systems.
[b]
[c]
[d]
Entry
Catalyst system
Time [h]
Conversion [%]
ee [%]
[
e]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
{cyclohexyl-salen}H (1a)+AlEt
78
48
48
48
48
48
78
48
48
48
48
48
48
48
78
48
48
48
48
78
48
45
41
59
62
51
6
45
5280
81
8
51
54
76
75
70
66
83
2
3
{cyclohexyl-salen}H
(1a)+AlMe3
2
{cyclohexyl-salen}AlMe (2a)
{cyclohexyl-salen}AlMe (2a)
{cyclohexyl-salen}AlMe (2a)
[
[
f]
g]
{cyclohexyl-salen}
A
H
R
U
G
[
e]
{diphenylethylene-salen}H (1b)+AlEt
2
3
{diphenylethylene-salen}H (1b)+AlMe
2
3
{diphenylethylene-salen}AlMe (2b)
84
81
23
86
80
84
14
81
80
41
83
(87)
75
0
1
{diphenylethylene-salen}
A
H
R
U
G
{cyclohexyl-salen}H (1a)+Al
(O-i-Pr)
7
2
3
2{cyclohexyl-salen}AlO-
i-Pr (5a)
{cyclohexyl-salen}AlO-i-Pr (5a)
{cyclohexyl-salen}AlO-i-Pr (5a)
89
>99
46
17
71
98
4
51
traces
41
[
[
[
h]
i]
3
4
5
6
7
8
9
0
1
e]
{diphenylethylene-salen}H (1b)+Al
A
H
R
U
G
2
3
{diphenylethylene-salen}AlOiPr (5b)
[{diphenylethylene-salen}Al]2(m-O) (6b)
A
H
E
G
{cyclohexyl-salen}H (1a)+AlMe Cl
2
2
{cyclohexyl-salen}AlCl (4a)
[
e]
{diphenylethylene-salen}H (1b)+AlEt Cl
2
2
{diphenylethylene-salen}AlCl (4b)
[
a]
Reactions carried out at ꢀ208C with acetophenone (0.81 mmol, at 0.8m in THF), TMSCN (1.62mmol, 2equiv.), Al ( 2. 0
mol%), DMAO (1.0 mol%), unless otherwise stated.
b]
[
[
[
Reaction time was not necessarily optimized.
c]
1
Conversion of acetophenone to the cyanohydrin silyl ether, as determined by H NMR and GLC.
d]
The ee was determined by GLC with a CHIRASIL DEX.CB column; the major enantiomer has always a S configuration,
as determined from the specific optical rotation.
Results from ref.
Reaction run in dichloromethane.
Reaction run in toluene.
Reaction run at 08C.
Reaction run at ꢀ408C.
[
[
[
[
[
e]
[3j]
f]
g]
h]
i]
Adv. Synth. Catal. 2008, 350, 731 – 740
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
735

Ali Alaaeddine et al.
FULL PAPERS
yields and ees up to 86% (entries 12–14, 16 and 17). show that the 2a/i-PrOH combination affords identi-
In the same line, in situ-generated chloro-Al systems cal results (within experimental uncertainty) to those
based on 1a and 1b are poorly active (entries 18 and obtained with discrete 5a (Table 2, entry 12). One
[3j]
2
0), while discrete complexes 4a and 4b afford the may thus reasonably assume that this alcoholysis pro-
cyanosilylation product in 41–51% yields (entries 19 tocol effectively generates the desired {cyclohexyl-
and 21). salen}Al(OR) complexes, at least for secondary alco-
These results clearly evidence that in situ combina- hols.
tions of aluminum precursors with {salen}H pro-li- The influence of steric and electronic factors was
[
15]
2
gands do not necessarily afford equivalent catalyst next investigated with a variety of alcohols (Table 3).
systems to discrete complexes. This is especially the All the alcohols tested afforded systems more active
[
3j]
case for Al
systems require relatively harsh conditions to afford ception was for tributoxysilanol, which led to a com-
the desired {salen}Al(O-i-Pr) complexes (vide supra). pletely inactive system (entry 16). Primary and simple
A
C
H
T
R
E
U
N
G
(O-i-Pr) /1a,b combinations, since these than the initial methyl-Al precursor 2a. The only ex-
3
AHCTREUNG
Thus, the “in situ approach”, although enabling fast secondary alcohols afforded high yields (80–100%) of
screening of potentially diverse systems, can lead to the cyanosilylation product. l- and d-menthol and
erroneous conclusions and/or choices for further cata- tert-butyl alcohol afforded somewhat less active cata-
lyst development.
lysts (65–69% yields), which likely reflects the detri-
Another well-established feature in asymmetric cat- mental influence of excess steric bulkiness of the
alysis that is further confirmed from the performances alkoxy ligand on this process. Major enhancements on
of discrete catalysts 2, 4, 5a,b is that the achiral X catalytic activity were obtained by the introduction of
ligand (X=Me, Cl, O-i-Pr) can affect significantly not electron-withdrawing substituents. Only a slight in-
[14]
only the activity but also the enantioselectivity of crease in the final yield was observed moving from
the catalyst. Indirectly, these results demonstrate that ethanol (pKa=16) to trifluoroethanol (pKa=12) (en-
the X ligand remains in the coordination sphere of tries 2and 11). The influence was much more pro-
the active metal center throughout the cyanosilylation nounced by replacing 2-propanol (pKa=17) with hexa-
reaction. Due to the larger availability, diversity and fluoro-2-propanol (pKa=9) (entries 12–15). With this
lower cost of such X ligands as compared to chiral system, thus far unprecedented turnover frequencies
ꢀ
1
ꢀ1
{
salen}H pro-ligands, the nature of the X ligand is ob- up to 140 (mol acetophenone)
A
H
R
U
G
(at
2
ꢀ
1
tuning. In light of the valuable catalytic performances (mol acetophenone)(molAl)
A
H
R
U
G
were achieved at
of discrete isopropoxide complexes 5a and 5b ꢀ208C (Table 3, Figure 4). Enhanced Lewis acidity of
(
Table 2; entries 12–14 and 16), unrevealed in the ini-
the metal center induced by the electron-withdrawing
[3j]
tial study
for the aforementioned reason, we CF groups most likely accounts for the observed
3
became interested in varying the alkoxide ligand in higher catalytic activity and productivity.
those series of complexes. The cyclohexyl (a) ligand
framework was selected for this study.
The maximal enantioselectivity was observed for
the 2-propoxide catalyst system. Less bulky alkoxides
For this purpose, we decided to pursue another (ethoxide, benzyloxide) or bulkier alkoxides (tert-but-
route to the preparation of {cyclohexyl-salen}Al(OR) oxide, menthoxide, sec-butoxide) led to decreased
[
12]
complexes, that is the alcoholysis of methyl complex enantioselectivities. Interestingly, the presence of a
a with one equiv. of appropriate dry alcohols in chiral center in the alkoxide (menthoxide, sec-butox-
2
THF. The validity of this in situ protocol was evaluat- ide) ligand was found to be of marginal importance,
ed directly in the cyanosilylation of acetophenone as judged by the similar catalytic performances ob-
(
Scheme 5). The results reported in Table 3 (entry 4) served from both enantiomers in each case; in fact,
Scheme 5.
736
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Discrete versus In Situ-Generated Aluminum-Salen Catalysts
FULL PAPERS
[a]
Table 3. Cyanosilylation of acetophenone with alkoxide catalyst systems in situ-generated from complex 2a and ROH.
[b]
[c]
[d]
Entry
1
ROH
-
pKa
Time [h]
Conversion [%]
ee [%]
-
48
81
48
48
48
48
48
48
48
48
48
59
68
89
85
68
65
69
86
84
99
88
76
2
3
4
5
6
7
8
9
1
1
ethanol
16
48
14
17
18
15
15
17
17
14
12
benzyl alcohol
isopropyl alcohol
tert-butyl alcohol
l-menthol
d-menthol
(R)-sec-butanol
(S)-sec-butanol
71
83
77
74
75
78
82
67
66
0
1
(R)-2-phenylethanol
2,2,2-trifluoroethanol
1
- p2 rh oe px a nf l ou lo ro-2
9
48
100
73
[
[
[
e]
f]
13
14
15
16
hexafluoro-2-propanol
hexafluoro-2-propanol
hexafluoro-2-propanol
tributoxysilanol
9
9
9
6
3
90
83
94
0
73
76
75
-
14
48
48
g]
[
a]
Reactions carried out at ꢀ208C with acetophenone (0.81 mmol, at 0.8M in THF), TMSCN (1.62mmol, 2equiv.), Al ( 2. 0
mol%), ROH (2.0 mol%), DMAO (1.0 mol%), unless otherwise stated.
Reaction time was not necessarily optimized.
Conversion of acetophenone to cyanohydrin silyl ether as determined by H NMR and GLC.
The ee was determined by GLC with a CHIRASIL DEX.CB column; the major enantiomer has always a S configuration,
[
[
[
b]
c]
1
d]
as determined from the specific optical rotation.
[
[
[
e]
f]
1
0
0
.0 mol% Al; 1.0 mol% ROH; 0.5 mol% DMAO.
.5 mol% Al; 0.5 mol% ROH; 0.25 mol% DMAO.
.2mol% Al; 0.2mol% ROH; 0.1 mol% DMAO.
g]
effects (in addition to steric effects) cannot be dis-
[
16]
carded.
The efficiency of such hexafluoro-2-propoxide sys-
tems was further demonstrated by generating the cor-
responding catalyst from the chiral cyclohexyl-bridged
complex 2b and using a variety of aryl alkyl ketones
(
Scheme 6). Representative results are summarized in
Table 4. The reaction of acetophenone in the presence
of the 2b/(CF ) CHOH (1:1) system proceeds as fast
as with the analogous catalyst system derived from
a, with a conversion up to 81% after 1 h and a simi-
lar enantioselectivity (Table 4, entries 1 and 2). While
-naphthyl methyl ketone reacts with similar perform-
AHCTREUNG
3
2
2
2
ances as those observed for acetophenone (entry 3),
the introduction of ortho-substituents (R=2-Me,
Figure 4. Kinetics of the cyanosilylation of acetophenone
catalyzed by 2a/i-PrOH (~) and 2a/
(CF ) CHOH ( ) combi-
nations. Reactions carried out at ꢀ208C with acetophenone
0.81 mmol, at 0.8M in THF), TMSCN (1.62mmol,
equiv.), 2a (1.0 mol% vs. acetophenone), ROH (1.0
A
H
R
U
G
&
3
2
(
2
mol%), DMAO (0.5 mol%).
no obvious “matched-mismatched” effect could be
observed. A relatively lower enantioselectivity was
also observed with the hexafluoro-2-propoxide
system, though in that case the influence of electronic Scheme 6.
Adv. Synth. Catal. 2008, 350, 731 – 740
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asc.wiley-vch.de
737

Ali Alaaeddine et al.
FULL PAPERS
Table 4. Cyanosilylation of aryl alkyl ketones RCORꢁ with hexafluoro-2-propoxide catalyst systems in situ-generated from
[a]
complexes 2a,b and (CF ) CHOH.
3
2
[
b]
[c]
[d]
Entry
R
R’
Catalyst precursor
Time [h]
48[
Conversion [%]
100
100
98
100
100
100
100
100
96
ee [%]
1
2
3
4
5
6
7
8
9
C H5
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2b
2a
2a
2a
2a
2b
2a
2a
2b
2a
2b
73 (S)
76 (S)
75 (ꢀ)
72( ꢀ)
70 (ꢀ)
65 (ꢀ)
71 (ꢀ)
67 (S)
81 (S)
80 (S)
84 (ꢀ)
81 (ꢀ)
6
e]
[e]
C H5
14
6
2-naphthyl
2-MeC H
2-MeOC H
2-ClC H
2-ClC H
14
14
14
24
14
14
14
14
14
14
6
4
6
4
6
4
6
4
4-MeC H
6
4
C H5
6
1
1
1
0
1
2C
C H5
Et
i-Pr
i-Pr
98
89
96
6
C H5
6
6H5
[
a]
Reactions carried out at ꢀ208C with the given aryl alkyl ketone (0.81 mmol, at 0.8M in THF), TMSCN (1.62mmol,
2
equiv.), Al ( 2. 0 mol%), (CF ) CHOH (2.0 mol%), DMAO (1.0 mol%).
3
2
[
[
[
[
b]
c]
d]
e]
Reaction time was not necessarily optimized.
1
Conversion of the ketone to the cyanohydrin silyl ether as determined by H NMR and GLC.
Ee as determined by GLC with a CHIRASIL DEX.CB column.
8
1% conversion after 1 h.
Experimental Section
OMe, Cl), and a para-substituent (R=4-Me) as well,
on acetophenone resulted in a slight erosion of the
enantioselectivity (entries 4–8). On the other hand,
improvement of enantioselectivity [more significant
for the 2a than for the 2b system] was observed for
aryl alkyl ketones bearing larger alkyl groups (R’=
Et, i-Pr) (entries 9–12). As anticipated for these bulky
ketones, a slight decrease in activity was observed, al-
though the hexafluoro-2-propoxide systems still allow
high conversions within short reaction times.
Complementary details on instruments and measurements
used, spectroscopic and analytical data for new complexes
and cyanosilylation products, crystal structure determination
of 3b, 4b and 6b, and summary of crystal and refinement
data for complexes 3b and 4b, are available as Supporting
Information.
General Conditions
All manipulations requiring a dry atmosphere were per-
formed under a purified argon atmosphere using standard
Schlenk techniques or in a glovebox. Solvents (toluene, pen-
tane, hexanes, diethylether, THF) were freshly distilled from
Na/K alloy under nitrogen and degassed thoroughly by
freeze-thaw-vacuum cycles prior to use. CH Cl was dried
Conclusions
In summary, we have shown that dramatically differ-
ent catalytic performances can be obtained in the
asymmetric cyanosilylation of acetophenone upon
using either in situ combinations of an aluminum pre-
2
2
over CaH , distilled twice and degassed by freeze-thaw-
2
vacuum cycles prior to use. Deuterated solvents, except
CDCl , were freshly distilled from Na/K amalgam under
3
cursor AlX (or AlX X’) with a {Salen}H pro-ligand
3
2
2
argon and degassed prior to use.
[
17]
or discrete {Salen}AlX complexes. Despite the antici-
N,N-Dimethylaniline N-oxide,
pro-ligands {salen}H2
[19]
[18]
pated high reactivity of alkyl- and alkoxide-aluminum 1a,b (1R,2R)-{cyclohexyl-salen}AlMe (2a), (1R,2R)-{cy-
[
6b]
precursors versus a quite acidic bis
A
H
R
U
(phenol) pro- clohexyl-salen}
A
H
R
U
G
(3a),
(1R,2R)-{cyclohexyl-
(O-i-Pr)
5a) were synthesized following literature procedures.
2
2
[7]
ligand, slow kinetics and above all undesired path-
ways may result in mixtures of complexes that feature
significantly different catalytic activity and enantiose-
lectivity than the {Salen}AlX species putatively gener-
ated. {Salen}Al alkoxide complexes have been found
to be a valuable class of catalysts (or catalyst precur-
sors) for the asymmetric cyanosilylation of acetophe-
none. Electronic tuning of the alkoxide ligand affords
unprecedented high activity for cyanosilylation of aryl
alkyl ketones with Al-based catalysts.
A
H
R
U
G
ACHTREUNG
[8]
(
AlMe (2.0M solution in heptane), AlMe Cl (1.0M solution
3
2
in hexane), and Al(O-i-Pr) were purchased from Aldrich,
A
H
R
U
G
3
Acros and Strem, and used as received. Ketones (Aldrich or
Acros) and TMSCN (Aldrich) were dried over CaH or acti-
2
vated molecular sieves (other ketones than acetophenone),
distilled under argon and freshly degassed prior to use.
A
H
R
U
G
A solution of AlMe (77 mL of a 2.0M solution in heptane,
3
0
.155 mmol) was added dropwise at room temperature onto
738
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Adv. Synth. Catal. 2008, 350, 731 – 740

Discrete versus In Situ-Generated Aluminum-Salen Catalysts
FULL PAPERS
a solution of pro-ligand 1b (100 mg, 0.155 mmol) in toluene Crystal Structures
(
1 mL). The reaction mixture was refluxed for 4 h. Volatiles
Crystallographic data (excluding structure factors) for the
structures of 3b, 4b and 6b have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. 669373, 669374 and 675685, respectively.
Copies of the data can be obtained, free of charge from The
Cambridge Crystalographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif or from CCDC, 12Union Road,
Cambridge CB21EZ, UK, [fax: +44-(0)1223–336033].
were removed under vacuum to leave a yellow solid which
was recrystallized at ꢀ358C from toluene/hexane (2:1) to
give 2b as a yellow crystalline powder; yield 20 mg (39%).
A
C
H
T
R
E
U
N
G
(1R,2R)-{Diphenylethylene-salen}(AlMe ) (3b)
A
H
R
U
G
2 2
A solution of pro-ligand 1b (50 mg, 0.077 mmol) in toluene
(
2mL) was added dropwise onto a solution of AlMe 3
(
77.6 mL of a 2.0M solution in heptane, 0.155 mmol) in tolu-
ene (3 mL). The reaction mixture was stirred for 12h at
room temperature. Volatiles were removed in vacuum and
the yellow powder was washed several times with cold hex-
anes to give 3b; yield: 98 mg (82%).
Acknowledgements
AA thanks the Lebanese CIOEES for a PhD grant. JFC
gratefully thanks the CNRS for an ATIPE grant (2002–2005)
and the Institut Universitaire de France for a Junior IUF fel-
lowship (2005–2009).
A
C
H
T
R
E
U
N
G
(1R,2R)-{Diphenylethylene-salen}AlCl (4b)
This complex was prepared as described above for 4a, by
the addition of a solution of pro-ligand 1b (100 mg,
0.155 mmol) in toluene (5 mL) onto a solution of ClAlMe2
(
108 mg, 0.155 mmol) in toluene (2mL). Reaction at room
References
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yellow powder; yield: 90 mg (82%). Single crystals were ob-
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T
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E
U
N
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(1R,2R)-{Diphenylethylene-salen}Al(OiPr) (5b)
A
H
R
U
G
2
[
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0
(
ACHTREUNG
3
Typical Procedure for Acetophenone Cyanosilylation
with Discrete Aluminum Catalysts
1
23, 9908; d) Y. Hamashima, M. Kanai, M. Shibasaki, J.
A 10-mL double wall Schlenk flask was charged with the Al
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none), THF (1 mL), and acetophenone (94 mL, 0.81 mmol).
The reaction mixture was cooled to ꢀ208C. A solution N,N-
dimethylaniline N-oxide (DMAO, 1.1 mg, 0.008 mmol) in
THF (0.2mL), previously treated for 1 h at room tempera-
ture with TMSCN (216 mL, 1.62mmol), was then added
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8 h. Volatiles were removed under vacuum and the residue
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011; j) F.-X. Chen, H. Zhou, X.-H. Liu, B. Qin, X.-M.
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2
as a pale yellow oil.
[
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0.81 mmol) was next introduced, the mixture was cooled to
ꢀ
208C and the reaction was further carried out as described
above.
Adv. Synth. Catal. 2008, 350, 731 – 740
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
739

Ali Alaaeddine et al.
FULL PAPERS
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1
[
[
2
found to give a mixture of (SalBinap)AlOMe (70%)
2
and (m-h -SalBinap) Al
A
T
E
N
(m-OMe) (30%); a) N. Spassky,
2
2
2
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within experimental uncertainty, that is, ꢁ2%) during
the reaction course for all the catalyst systems studied.
13] Dimeric m-oxo complexes of the form [(salen)Ti(m-
O)] , in situ generated by hydrolysis of chiral (sa-
[
ACHTREUNG
2
A
C
H
T
R
E
U
N
G
len)TiCl complexes with water, have been shown to be
2
the real (pre)catalysts for the asymmetric cyanosilyla-
tion of aldehydes with TMSCN; see: Y. N. Belokon, S.
Caveda-Cepas, B. Green, N. S. Ikonnikov, V. N. Khrus-
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performances to those displayed by discrete complex
6
b (Table 2, entry 17).
[14] For the influence of the anionic X ligand on the activity
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[19] W. H. Leung, E. Y. Chan, E. K. Chow, I. D. Williams,
+
ꢀ
A
C
H
T
R
E
U
N
G
{Salen}] X catalysts, see: Y. K. Belekon, V. I. Maleev,
S. M. Peng, J. Chem. Soc. Dalton Trans. 1996, 1229.
740
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 731 – 740