Hydrosilylation of ketones catalyzed by C2-symmetric proline-derived complexes

Article abstract of DOI:10.1139/V06-116

Extracoordinate chiral hydrosilanes were generated in situ from triethoxysilane and a C₂-symmetric ligand derived from bisproline 7. In the presence of a catalytic amount of ligand 7, prochiral ketones were reduced in moderate yield with modera

Full text of DOI:10.1139/V06-116

1416
Hydrosilylation of ketones catalyzed by C2-
symmetric proline-derived complexes1
Li Gan and Michael A. Brook
Abstract: Extracoordinate chiral hydrosilanes were generated in situ from triethoxysilane and a C2-symmetric ligand
derived from bisproline 7. In the presence of a catalytic amount of ligand 7, prochiral ketones were reduced in moder-
ate yield with moderate enantioselectivity (up to 64% ee). Alternatively, TiF4 complexes of 7 were used to provide
higher enantioselectivity and with improved yields. The copper complex of ligand 7 and 29Si NMR data provide some
guidance as to the key factors responsible for the observed reactivity at the silicon and at the ligand centre.
Key words: extracoordinate chiral silane, C2-symmetry, enantioselectivity, Lewis acid titanium catalysis.
Résumé : On a effectué une génération in situ d’hydrosilanes chiraux extracoordinés à partir du triéthoxysilane et d’un
ligand de symétrie C2 dérivé de la bisproline 7. En présence d’une quantité catalytique du ligand 7, les cétones prochi-
rales sont réduites avec des rendements moyens et un énantiosélectivité modérée, allant jusqu’à 64 % d’excès énantio-
mère. D’une façon alternative, on a utilisé des complexes du tétrafluorure de titane du ligand 7 qui ont fourni une
énantiosélectivité supérieure et de meilleurs rendements. Le complexe de cuivre du ligand 7 et les données de la RMN
du 29Si donnent des indications sur les facteurs clés responsables au niveau de l’atome de silicium et du centre du li-
gand pour la réactivité observée.
Mots clés : silane chiral extracoordiné, symétrie C2, énantiosélectivité, catalyseur de titane agissant comme acide de
Lewis.
[Traduit par la Rédaction] Gan and Brook 1425
Scheme 1. Histidine-catalyzed ketone reduction.
Introduction
The enantioselective reduction of carbonyl groups remains
one of the fundamental operations in organic synthesis (1).
Typical catalytic systems utilize a chiral ligand complexed
with a transition metal (2). With the exception of boron,
such as the well-developed chiral boron catalyst (CBS) (3),
the use of chiral catalytic motifs based on main group ele-
ments is uncommon (4). However, in a process related to
that reported by Shiffers and Kagan (5) and Hosomi and co-
workers (6), we previously demonstrated that the complex
derived from hydrosilanes and a catalytic amount of amino
acids can reduce ketones enantioselectively (Scheme 1) (7).
These reactions with hydrosilanes occur via extraco-
ordinate silicon in the presence of anionic catalysts. Sakurai
and co-workers (8a, 8b) has demonstrated that diastereo-
selective allylation of carbonyl groups in the presence of
pentacoordinate silicon hydrides, for example, can best be
explained by invoking six-membered ring transition states
(Scheme 2). Coordination of the nucleophile, the carbonyl
group, to the extracoordinate silicon is followed by allyl
group transfer. As a departure point, we proposed that a re-
lated assembly of ketone and carboxylate on an extra-
coordinate silicon 1 could be used to explain the observed
stereoselectivity in the hydrosilane reduction of acetophen-
one, although related bidentate structures could also be en-
visaged. While the mechanisms of these reactions have not
yet been clearly established, the presence of extracoordinate
Received 6 March 2006. Accepted 17 May 2006. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on
11 October 2006.
It is a great pleasure to dedicate this paper to the superb career of Alfred Bader. I learned about his passion for chemistry and
chemists when we met several times when I was a graduate student and postdoctoral fellow. It meant a great deal to me then, and
now, that “Please Bother Us” meant anyone interested in chemistry, not just the professors. I thank him for sharing his vision and
enthusiasm for chemistry with me then and many times since. The example he set has profoundly affected the way my career has
evolved.
L. Gan and M.A. Brook.2 Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada.
1This article is part of a Special Issue dedicated to Dr. Alfred Bader.
2Corresponding author (e-mail: mabrook@mcmaster.ca).
Can. J. Chem. 84: 1416–1425 (2006)
doi:10.1139/V06-116
© 2006 NRC Canada

Gan and Brook
1417
Scheme 2.
_
_
SiF3
R2
R1
H
R1
O
O
F
HO
OH
F
PhCHO
O
O
Si
CH2Cl2
Si
F
Ph
R2
R1
R2
O
NEt3
F
Et3NH+
Et3NH+
OR
Si
H
O
OR
OR
_
H
OH
Ph
O
R1
F
H2O
O
NH2
Ph
Si
O
CH3
Ph
R1
O
R2
R2
F
O
N
Et3NH+
1
N
Li
Scheme 3.
Ph
N
Ph
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
N
H
2
3
4
N
H
N
H
H
H
H
H
O
O
N
N
N
N
N
N
N
N
H
N
H
N
N
N
N
N
NH
HN
5
6
7
Ph
Ph
Ph
Ph
silicon, particularly the pentacoordinate species, is evident
from Si NMR.
the C2-symmetric compound 7 (Scheme 3), the formation of
pentacoordinate silicon complexes on reaction of 7 with
HSi(OEt)3, as shown by 29Si NMR, the ability of this com-
plex to reduce ketones, and the characterization of its copper
complex 13 by an X-ray structure. In addition, the behaviour
of the Lewis acidic derivative formed from the reaction of 7
with TiF4 is described in the same carbonyl reduction pro-
cess.3
In an attempt to better understand the processes involved
in the reduction, recent research has turned to the utilization
of multidentate ligands that, on binding, would have fewer
degrees of freedom and, additionally, would be more amena-
ble to structural characterization. The use of C2-symmetry,
in particular, provides a more highly structured environment
for enantioselective reactions (9), a strategy we recently uti-
lized with silane-medicated reductions (2–6, Scheme 3) (10).
Unfortunately, only moderate ee were observed in these re-
actions.
Results and discussion
Preparation and characterization of the ligands
In this study, we developed a C2-symmetric multidentate
ligand that utilizes proline, perhaps the most widely utilized
amino acid chiral template (11). We report the synthesis of
A series of molecular modeling experiments were under-
taken with C2-symmetric diamino acid derivatives. Prelimi-
nary studies compared the geometries of bidentate
3 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5079. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 601366 and 601367 contain the crystal-
lographic data for this manuscript. These data can be obtained, free of charge, via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(Or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or de-
posit@ccdc.cam.ac.uk).
© 2006 NRC Canada

1418
Can. J. Chem. Vol. 84, 2006
Fig. 1. Molecular models of dimethylsilyl derivatives of 7.
Scheme 4. Preparation of bisproline 7.
O
OH
2
boc
N
EDCI, HOBt
O
O
TFA, CH2Cl2
87%
O
O
N
H
N
H
N
H
N
H
+
rt, 24 h
95%
NH2
NH2
N
N
NH
HN
boc
boc
Scheme 5. Formation of extracoordinate silicon with α-hydroxy
dimethylsilicon complexes based on various amino acid
complexes of 1,2-diaminobenzene. Among the amino acids
examined (phenylalanine, histidine, alanine, and proline),
the latter had a more tightly constrained structure, irrespec-
tive of whether the linkages occurred through the proline ni-
trogen 8, amide oxygen 9, or amide nitrogen 10 (Fig. 1). All
of the derivatives had more rigid and compact chiral envi-
ronments than structures based on the structural motifs
found in 4 or 5 (Scheme 3). Therefore, the bisproline ligand
7 was prepared by coupling 1,2-diaminobenzene with com-
mercially available N-protected L-proline (Scheme 4). The
optically pure ligand was obtained, after deprotection by
trifluoroacetic acid, by recrystallization from methanol in an
overall yield of 83% and structurally characterized by NMR
(1H, 13C), HRMS, and IR.
acids.
O
O
OMe
HO
O
2
OMe
-
O
OH
MeO
R
R
O
Si
Si
O
NMe2
11
NMe
+
O
2
H
–58.68 ppm, consistent with reported data for triethoxysilane
(15). Thus, the amine groups are insufficiently basic to en-
gender extracoordination at silicon. By contrast, when the
bisproline tetraanion of 7 was mixed with triethoxysilane in
a ratio of 1:2 (sensitivity of the NMR precluded lower con-
centrations of the silicon compound and higher concentra-
tion of the bisproline tetraanion led to precipitates) 29Si NMR
showed two singlets at –84.27 and –98.83 ppm, respectively.
It is challenging to assign putative structures to com-
pounds with these chemical shifts. Each exchange at silicon
of H by O or N leads to an upfield shift, as does each ex-
change of N by O. For example, the addition of the anionic
ligand of 7 to HSi(OEt)3 to give a pentacoordinate species
(HSi(OEt)3-N7)– would lead to an upfield shift of about
20 ppm. However, displacement of the EtO– by the same ni-
trogen to give a tetracoordinate species (HSi(OEt)2-N7)
would lead to a downfield shift of about 15 ppm (16). The
observed peaks are consistent with a pentacoordinate species
Mechanistic study
Silicon compounds undergo extracoordination in the pres-
ence of silaphilic nucleophiles, particularly oxygen, fluoride,
and aromatic amines (12). Coordination expansion is facili-
tated by electron-withdrawing groups on silicon, especially
fluoride and oxygen ligands. Thus, the facility of trialk-
oxysilanes to undergo extracoordination lies between that of
trialkyl- and trihalo-silanes (12). Tacke and co-workers (13),
in a beautiful series of papers, demonstrated that bidentate
nucleophiles are particularly efficacious in inducing coordi-
nation expansion. A broad variety of pentacoordinate amino
and hydroxy acid derivatives, exemplified by 11, have been
isolated in crystalline form (Scheme 5) (13, 14).
Complexes of 7 and HSi(OEt)3 were characterized by 29Si
NMR. The 29Si NMR of the neutral mixture gave a singlet at
(HSiX4 , –84.27 ppm) and an oxidized pentacoordinate spe-
–
–
2–
cies (SiX5 ) or a hydrido hexacoordinate species (HSiX5
,
© 2006 NRC Canada

Gan and Brook
1419
Fig. 2. ORTEP drawing of the structure of 12, a copper complex 13, and a possible structure of the hydridosiliconate 14.
O
N
N
N
_
O
Si
N
H
14
Table 1. Selected crystallographic data for ligand 7.
Table 2. Selected crystallographic data for 13.
Identification code
Empirical formula
CCDC 601366
C18H26N4O2
Identification code
Empirical formula
CCDC 601367
C17H24CuN4O4
Formula weight (g mol–1)
330.43
Monoclinic
C2
20.259(8)
8.751(3)
10.929(4)
90
113.066(6)
90
1782.6(12)
4
Formula weight
Space group
Crystal system
Crystal size (mm3)
a (Å)
411.94
Crystal system
Space group
a (Å)
b (Å)
P2(1)2(1)2(1)
Orthorhombic
0.20 × 0.18 × 0.06
8.3234(4)
11.7554(5)
18.5682(8)
90
c (Å)
b (Å)
c (Å)
α (°)
β (°)
α (°)
γ (°)
β (°)
90
90
Volume (Å3)
γ (°)
Volume (Å3)
Z
1816.80(14)
4
1.506
Z
Densitycalcd. (Mg/m3)
1.231
Densitycalcd. (Mg/m3)
Absorption coefficient (mm–1)
F(000)
0.082
712
0.38 × 0.18 × 0.08
2.03–26.48
7556
Absorption coefficient (mm–1)
F(000)
1.233
860
2.05–28.31
16 688
4359
Crystal size (mm3)
θ range for data collection (°)
Reflections collected
Independent reflections
Rint
θ range for data collection (°)
Reflections collected
Independent reflections
Rint
3346
0.0346
0.0891
Data, restraints, parameters
Goodness-of-fit on F2
Final R indices [I > σ(I)]
3346, 1, 218
1.009
R1 = 0.0419, wR2 = 0.0898
Completeness to θ = 28.31° (%)
Data, restraints, parameters
Goodness-of-fit on F2
98.00
4359, 0, 248
1.042
Final R indices [I > 2σ(I)]
R indices (all data)
Largest diff. peak and hole (e Å–3) 0.526 and –0.555
R1 = 0.0593, wR2 = 0.1036
R indices (all data)
Largest diff. peak and hole (e Å–3)
R1 = 0.0702, wR2 = 0.0993
R1 = 0.1041, wR2 = 0.1152
0.116 and –0.118
–98.83 ppm), respectively. Since extracoordinate hydrido-
siliconates are required to reduce ketones (see later), it is an-
ticipated that these peaks represent penta- and hexa-
coordinate silicon hydrides; after the ketone reduction,
29Si NMR showed only one peak at –82.39 ppm.
symmetric structures, such as 14, may be formed. Extensive
attempts to isolate various silicon complexes of 7 in crystal-
line form were unsuccessful.
Reductions of acetophenone
It did not prove possible to prepare crystals of sufficient
quality for an X-ray analysis. By contrast, the N,N-dimethyl
derivative 12 gave suitable crystals (Fig. 2, for crystallo-
graphic parameters and typical bond lengths and angles see
Table 1). To explore complexed ligand structures that would
be related to the reduction process, the copper complex 13
of ligand 7 was prepared by the reaction of the ligand with
copper(II) chloride in methanol in the presence of excess po-
tassium carbonate (Fig. 2). An X-ray crystal structure of the
compound showed a nearly square planar arrangement of the
C2-symmetric nitrogen ligands around copper (Tables 2 and
3). The ligand in 13 forms a compact complex with short
Cu—N bond lengths that brings the stereodirecting chiral
centres in closer proximity to the metal centre. This structure
was very encouraging as it suggests that analogous C2-
Previous work demonstrated that ketone reduction with
hydrosilanes could be initiated with carboxylate or other an-
ions to activate the silicon (7). A series of reductions of
acetophenone was undertaken to establish the key factors re-
quired for efficacy in the presence of 7 (Table 4). Negative
controls included a set of reactions in which each of the key
ingredients was selectively absent. Notable among the re-
sults is the reduction of acetophenone with the proline anion,
which resulted in 50% yield and 15% ee (Table 4, entry 3).
This is a result that is related to, but less efficient than, re-
ductions in the presence of anions of histidine and particu-
larly phenylalanine that occurred in yields typically of 80%
and ee up to 70% (7). A series of experiments demonstrated
that the best compromise for yield and ee occurred at 55 °C,
higher than would be expected for a reaction run under ki-
© 2006 NRC Canada

1420
Can. J. Chem. Vol. 84, 2006
Table 3. Selected bond lengths (Å) and angles
(°) for 13 (esds in parentheses).
tivate triethoxysilane to undergo the reduction (Table 4, en-
try 2) as was also shown by 29Si NMR experiments (see ear-
lier). By contrast, the most effective reduction took place
with the tetraanion of 7 (Table 3, entry 4). While the tetra-
anion of 7 can make a tight complex with silicon, it can do
so with loss of chirality because of amino acid epimeri-
zation.
While the yields of these reactions were acceptable, the ee
were marginal. Although the crystal structure of the copper
complex 13 shows that the stereochemistry of the amino ac-
ids are maintained in the complex, it is also conceivable that
α-amido epimerization occurs under the more basic condi-
tions used for these reductions. To reduce this possibility, the
efficacy of the reaction was tested as a function of the equiv-
alents of base added (from 1 to 4 equiv.). The most interest-
ing results came with 2 equiv. of base, which should
deprotonate the amide NHs, possibly leading to bidentate
complexes 15 (Table 4) and 16 (analogous to 9 and 10,
Fig. 3) without affecting the chiral centres. The reaction was
more sluggish and it can be seen that, in one case, the ee im-
proved, but at the expense of reaction yield (Table 4, entries
5–7).
Bond lengths (Å)
Cu(1)—N(1)
Cu(1)—N(4)
C(12)—C(13)
C(7)—C(8)
N(3)—C(8)
Cu(1)—N(2)
N(1)—C(7)
N(2)—C(2)
N(2)—C(12)
Cu(1)—N(3)
N(1)—C(1)
C(1)—C(2)
N(4)—C(13)
1.924(4)
2.006(4)
1.526(7)
1.517(7)
1.525(6)
1.925(4)
1.342(6)
1.413(6)
1.305(6)
1.997(4)
1.410(6)
1.426(6)
1.511(6)
Bond angles (°)
N(1)-Cu(1)-N(2)
N(1)-Cu(1)-N(4)
C(7)-N(1)-C(1)
C(6)-C(1)-N(1)
C(12)-N(2)-Cu(1)
N(2)-C(2)-C(1)
C(8)-N(3)-Cu(1)
C(13)-N(4)-Cu(1)
N(1)-C(7)-C(8)
C(9)-C(8)-N(3)
N(2)-C(12)-C(13)
C(15)-C(14)-C(13)
N(1)-Cu(1)-N(3)
N(2)-Cu(1)-N(4)
C(7)-N(1)-Cu(1)
N(1)-C(1)-C(2)
C(2)-N(2)-Cu(1)
C(11)-N(3)-C(8)
C(16)-N(4)-C(13)
O(1)-C(7)-N(1)
C(7)-C(8)-C(9)
O(2)-C(12)-N(2)
N(4)-C(13)-C(12)
N(2)-Cu(1)-N(3)
N(3)-Cu(1)-N(4)
C(1)-N(1)-Cu(1)
C(12)-N(2)-C(2)
C(3)-C(2)-N(2)
C(11)-N(3)-Cu(1)
C(16)-N(4)-Cu(1)
O(1)-C(7)-C(8)
C(7)-C(8)-N(3)
O(2)-C(12)-C(13)
C(12)-C(13)-C(14)
83.38(16)
168.95(17)
127.5(4)
127.5(4)
116.8(3)
114.4(4)
106.5(3)
107.2(3)
113.5(4)
103.8(4)
115.2(4)
103.8(5)
85.66(17)
85.60(16)
116.7(3)
113.0(4)
114.2(3)
106.4(4)
105.5(4)
128.0(4)
114.1(4)
127.3(5)
112.3(4)
166.91(16)
105.17(17)
115.1(3)
127.9(4)
125.8(4)
118.2(3)
117.7(3)
118.5(4)
113.0(4)
117.5(4)
114.3(4)
Hydrosilanes are very stable at neutral conditions, but sig-
nificantly less so away from neutrality, particularly under ba-
sic conditions. Exchangeable hydrogens under these conditions
serve as excellent electrophiles, with the result that H2 is
normally released (e.g., R3SiH + HY → R3SiY + H2) (17).
This process is particularly favoured when multidentate lig-
ands are utilized (14) and can be exploited as a method for
generating H2 in situ on demand (18).
In the current case, the design of the ligand is challenged
by this reactivity. Tetradentate complexation giving com-
pounds such as 14 could also result in loss of chirality
through epimerization 17. By contrast, a bidentate chiral C2-
symmetric complex such as 16 is subject to loss of hydride
through the processes just described (16 → 18, Fig. 3).
Si-H groups are significantly less reactive to acidic than
basic conditions (19). It was reasoned that these problems
could be mitigated or avoided by changing from basic to
acidic conditions. That is, the same ligand could be
complexed by a Lewis acid that would fit into the chiral
pocket of the ligand and direct reduction. An important pre-
cedent for this approach is the observation by Cozzi and co-
workers (20) that Lewis acidic titanium fluoride complexes
19, based on readily accessible chiral bisoxazoline com-
plexes of Evans, will catalyze carbonyl reductions (Scheme 6).
The titanium complex of ligand 7 is expected to be tetra-
dentate (Table 5) based on the structure of the copper com-
plex 13. Carbonyl complexation will preferentially occur at
the more Lewis acidic site (titanium) and the locus of the re-
duction reaction will be taken away from silicon. These pro-
posals were tested by complexing ligand 7 with titanium-
based Lewis acids and examining the reduction reaction in
the absence and presence of base (Table 5) in the presence
of 5 mol% of the chiral catalyst.
netic control. The reactions further confirmed that extra-
coordinate hydrosilanes are more reactive towards a variety
of electrophiles than their four-coordinate counterparts (12).
For example, neutral HSi(OEt)3 is not able to reduce
acetophenone in the absence of nucleophilic activation (Ta-
ble 4, entry 1). Neutral bisproline 7 is similarly unable to ac-
The relative Lewis acidity of simple titanium catalysts fol-
lows the order Ti(OiPr)4 < TiCl4 < TiF4. Replacement of
halides or alkoxy groups with amines will further moderate
Lewis acidity. No reduction was observed under any condi-
tions when the first two less acidic compounds were em-
ployed as catalysts (Table 5). When 2 equiv. of BuLi were
© 2006 NRC Canada

Gan and Brook
1421
Table 4. Basic reduction of acetophenone by (EtO)3SiH in the presence of 7.
_
O
i) BuLi (n equiv.)/–78 °C
H
N
H
N
R
R'
OH
H
N
H
N
NH
O
NH
O
N
N
ii) (EtO)3SiH, 55 °C
H
R
R'
O
O
Si
OEt
15
EtO
one proposed intermediate
Entry
A
Conditions
n (equiv. base)
Yield (%)
ee (%)
1
2
3
4
5
6
7
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
55 °C, 72 h
7, 55 °C, 12 h
proline, BuLi, 55 °C, 24 h
7, BuLi, rt, 12 h
7, BuLi, rt, 72 h
0
0
2
4
2
2
2
NRa
NR
50
85
35
—
—
15
5
64
20
5
2-Bromoacetophenone
4-Methoxyacetophenone
7, BuLi, rt, 72 h
7, BuLi, rt, 72 h
20
48
aNR = No reaction.
Fig. 3. Possible pentacoordinate intermediates prior to and following reduction.
O
O
-H2
O
O
OLi
N
N
N
_
N
O
N
N
O
N
N
_
N
LiO
N
_
_
Si
Si
Si
Si
EtO
OEt
HN
EtO
NH
NH
N
H
N
H
N
H
OEt
14
17
16
18
Scheme 6.
O
Ph
Ph
Ph
R'
Ph
O
O
O
O
O
O
OH
Ph
Ph
Ph
F
Ti
F
N
R
N
N
i) n-BuLi / THF
R'
N
N
ii) TiF4 / THF
N
Ph
R
Ph
Yield 50%–61%
ee 65%–85%
Ph
Ph
3–8 mol %
19
Ph
used to facilitate formation of the titanium–7 complex, only
marginal reduction yields were observed, in general worse
than in the absence of the titanium compound (Table 4). Of
the three reducing agents H2, Ph2SiH2, and HSi(OEt)3, only
the last was somewhat efficient. H2 was used as a negative
control. Of the two silanes, HSi(OEt)3 is generally more re-
active than Ph2SiH2. It has a greater facility for coordination
expansion, and as discussed earlier, silylhydrides are more
reactive as five- rather than four-coordinate silicon. Improved
results were obtained when 4 equiv. of base was used to cre-
ate the titanium–7 complex. Yields increased as did enantio-
selectivity as determined using Mosher ester synthesis (21),
although not to levels sufficient for practical application.
A bidentate adduct could form from addition of the
dianion 20 to TiF4 (Scheme 7), which will be a less rigid
structure than a tridentate complex such as 21 or the C2-
symmetric catalyst tetradentate titanium complex 22 that
should form when 4 equiv. of base are added (Scheme 7).
The more rigid structures with proximal chiral groups should
have improved enantioselectivity, as was observed with the
system derived from the tetraanion.
Several observations provide guidance about the role of
the titanium complex 20. Oxophilic titanium will preferen-
tially jettison nitrogen groups to form a complex with the
carbonyl oxygen to give a motif such as 21, which is widely
exploited in titanium-catalyzed aldol and related reactions
(22), but in doing so will lose C2-symmetry. The attempt to
crystallize 20 or carbonyl complexes of it were unfortunately
unfruitful. Hydrosilanes are normally insufficiently reactive
© 2006 NRC Canada

1422
Can. J. Chem. Vol. 84, 2006
Table 5. Enantioselective reduction of ketones using a bisproline-Ti catalytic system.
OH
O
O
i) BuLi/–78 °C
ii) TiF4
i) RCOR'
ii)(EtO)3SiH, 55 oC
O
N
N
N
N
O
F
N
H
N
H
R'
R
Ti
F
NH
HN
Metal catalyst Reaction
Temp. Reducing
n
Entry Ketone
7 (mol%) (equiv.)
time (h)
(°C)
agent
(equiv. BuLi) Yield ee
5
0
5
1
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
None
12
24
24
24
24
24
24
24
24
12
24
12
12
12
12
25
55
55
25
55
55
55
55
55
25
55
55
55
55
55
HSi(OEt)3
HSi(OEt)3
HSi(OEt)3
H2
4
0
2
2
2
2
2
4
4
4
4
4
4
4
4
85
5
—
—
—
—
—
—
—
—
2
2
TiF4 (5)
TiCl4 (10)
TiF4 (10)
None
NR
NR
NR
NR
17
3
4
10
5
5
5
5
5
5
5
5
5
5
5
5
Ph2SiH2
6
TiF4 (5)
TiF4 (5)
TiCl4 (5)
RhCl3 (5)
TiF4 (5)
TiF4 (5)
TiF4 (5)
TiF4 (5)
TiF4 (5)
TiF4 (5)
Ph2SiH2
7
(EtO)3SiH
(EtO)3SiH
HSi(OEt)3
HSi(OEt)3
HSi(OEt)3
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
10
8
NR
20
9
10
11
12
13
14
15
80
80
20
20
20
2
80
2-Bromoacetophenone
2-Methoxyacetophenone
60
40
trans-4-Phenyl-3-buten-2-one
90
2
Scheme 7.
2-
2-
2-
R
H
N
O
O
O
F
R'
O
O
O
N
N
N
F
O
F
N
N
Ti
Ti
Ti
F
F
NH
N
N
HN
F
F
N
N
F
20
21
22
to reduce such titanium carbonyl complexes. By contrast,
carbocations can be trapped to give C—H bonds (23).
While the specific role of the hydrosilane has not yet been
established in the Ti-catalyzed reductions, it seems likely, as
with the basic conditions, that extracoordinate silicon is re-
sponsible for reduction. The inability of the TiCl4 complex
of 7 to catalyze reduction is instructive in this context. The
formation of a Lewis acidic chiral complex will liberate the
halide Cl–, which is normally not able to facilitate extra-
coordination at silicon (12). Thus, while a chiral carbonyl–Ti
complex may form, the only reducing agent present is
HSi(OEt)3, which is a not viable reducing agent for ketones.
As reported by many researchers, fluoride activates silicon
hydrides to reduce carbonyls (24). Formation of compounds
such as 22 with TiF4 serves two purposes. It first provides a
chiral Lewis acidic pocket that serves as the locus of reduc-
tion and further liberates 2 equiv. of F–. Fluoride is key, as it
can convert the hydrosilane into an active reducing agent,
HSi(OEt)3F–. The obvious disadvantage of this process is
that the activated fluoride complex HSi(OEt)3F– can directly
reduce the ketone outside the sphere of the chiral ligand,
leading to a reduction in the overall enantioselectivity of the
process.
Of the two very mild approaches examined, the Lewis
acidic approach was more efficacious than the extra-
coordinate hydrosiliconate, with respect to both yields and
enantioselectivity. Our current focus is to develop ligands
that provide chirality and intramolecular activation to the
silicon. Such a system will constrain all reactions to the
proximity of the chiral environment.
Conclusion
A C2-symmetric bisproline ligand can be used as a cata-
© 2006 NRC Canada

Gan and Brook
1423
lyst to induce enantioselective induction as an anionic
extracoordinate silicon complex or after complexation with
TiF4. The Lewis acid catalyzed route led to high yields be-
cause side reactions are reduced and showed higher ee.
anisotropic thermal parameters and hydrogen atoms were
added as fixed contributors at calculated positions, with iso-
tropic thermal parameters based on the atom to which they
are bonded.
Data for 13 were collected on a three-circle D8 Bruker
diffractometer equipped with a Bruker SMART 6000 CCD
area detector (using the program SMART (25)) and a rotat-
ing anode utilizing cross-coupled parallel focusing mirrors
to provide monochromated Cu Kα radiation (λ = 1.541 78 Å).
Data processing and structure solving were carried out as
noted previously.
Experimental section
Reagents and physical methods
The following materials were obtained from Sigma-Aldrich
and were used without further purification: acetophenone, n-
butyllithium (1.6 mol/L solution in cyclohexane), (S)-(+)-α-
methoxy-α-(trifluoromethyl)phenylacetyl chloride (MTPA-
Cl (+)), 2-methoxyacetophenone, trans-4-phenyl-3-buten-2-
one, sodium sulfate, triethoxysilane, 1,2-diaminobenzene,
N-BOC-(S)-proline, hydroxybenztriazole (HOBt), 1-(3-
Preparation of the bis(L)prolinyl amide of 1,2-
diaminobenzene
A solution of 1,2-diaminobenzene (0.36 g, 3.3 mmol) and
N-(tert-butoxycarbonyl)-L-proline (1.5 g, 6.9 mmol) in
CH2Cl2–DMF (10:1, 30 mL) was treated at 0 °C with HOBt
(0.93 g, 6.9 mmol) and EDC (1.35 g, 6.9 mmol). The reac-
tion mixture was stirred at 0 °C for 2 h and allowed to warm
up to room temperature (rt) overnight. Solvents were re-
moved under reduced pressure. CH2Cl2 (20 mL) was added
to the yellow residue and stirred for 2 h. TFA (10 mL) was
added dropwise at rt to the solution, which was stirred for
another 2 h. Saturated K2CO3 solution (20 mL) neutralized
the solution (pH 9). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was dried
over anhydr. Na2SO4. After removing the solvents under re-
duced pressure, the product was recrystallized from metha-
nol and dichloromethane (20:1). The product, a colourless
crystal, was formed in 83% yield. 1H NMR (CDCl3,
500 MHz) δ: 1.73–1.80 (m, 4H, R1-CH-R2), 2.02–2.13 (m,
2H, NH), 2.18–2.24 (m, 4H, R2-CH-R3), 2.95–3.10 (m, 4H,
CH2-NH), 3.86–3.93 (q, 2H, CH-NH), 7.13–7.19 (m, 2H,
Ph-H), 7.65–7.70 (m, 2H, Ph-H). 13C NMR (d6-DMSO,
200 MHz) δ: 33.27, 37.76, 54.07, 67.92, 131.03, 132.11,
137.72, 181.25. LRMS (EI) m/z (%): 302 (M+, 13), 232 (62),
205 (53), 188 (100), 91 (92), 70 (83), 45 (87). HRMS (ES)
m/z calcd. for (C16H23N4O2)+: 303.1808; found: 303.1821.
dimethylaminopropyl)-3-ethylcarbodiimide
(EDC), rhodium(III) chloride, titanium(IV) fluoride, and ti-
tanium(IV) chloride.
hydrochloride
All solvents were thoroughly dried before use; THF was
dried from Na/benzophenone. All reactions were carried out
in flame-dried apparatus under an argon atmosphere with the
use of septa and syringes for the transfer of reagents.
1H and 13C NMR spectra were recorded on a Bruker AC-
200 (at 200 MHz for protons, 50.32 MHz for 13C) Fourier
transform spectrometer. 29Si NMR was performed on a
Bruker DRX-300 (at 75.44 and 59.60 MHz for carbon and
silicon, respectively). 1H-NMR was also performed on a
1
Bruker DRX-500 (at 500 MHz for hydrogen). H chemical
shifts are reported either with respect to tetramethylsilane as
an external standard set to 0 ppm or CDCl3 as an internal
standard set to 7.26 ppm. 13C NMR chemical shifts are re-
ported either with respect to CDCl3 as an internal standard
set to 77.26 or THF-d8 as an internal standard set to
67.57 ppm. Coupling constants (J) are recorded in Hertz
(Hz). The abbreviations singlet (s), doublet (d), triplet (t),
quartet (q), doublet of doublets (dd), doublet of triplets (dt),
multiplet (m) are used to report spectra.
Electron impact (EI) and chemical ionization (CI, NH3)
mass spectra were recorded at 70 eV with a source tempera-
ture of 200 °C on a Micromass GCT (Waters Corporation,
Milford, Massachusetts) mass spectrometer using a heated
probe. High-resolution mass spectral (HRMS) data were ob-
tained using the EI method calibrant with perfluorotributyl
amine. Molecular modeling calculations were undertaken us-
ing the MM2 molecular mechanics parameter set, using
Hyperchem 5.01 from Hypercube Inc. (Gainesville, Florida).
X-ray crystallographic data for 7 and 13 were collected
from suitable samples mounted with epoxy on the end of
thin glass fibers. Data collections were performed at 273 K.
Data for 7 were collected on a Bruker P4 diffractometer
equipped with a Bruker SMART 1K CCD area detector (us-
ing the program SMART (25)) and a rotating anode utilizing
graphite-monochromated Mo Kα radiation (λ = 0.710 73 Å).
Data processing was carried out by use of the program
SAINT (26), while the program SADABS (27) was utilized
for the scaling of diffraction data, the application of a decay
correction, and an empirical absorption correction based on
redundant reflections. The structures were solved by using
the direct methods procedure in the Bruker SHELXTL (28)
program library and refined by full-matrix least-squares
methods on F2. All non-hydrogen atoms were refined using
Preparation of the N,N′-dimethyl bis(L)prolinyl amide
of 1,2-diaminobenzene (12)
To a stirred solution of 7 (1 g, 3.3 mmol) and 37% aque-
ous formaldehyde (2 mL, 25 mmol) in 20 mL acetonitrile
was added sodium cyanoborohydride (0.8 g, 10 mmol). Gla-
cial acetic acid was added until the solution reached neutral-
ity. The reaction was stirred at ambient temperature for 3 h.
The reaction mixture was poured into 50 mL of ether and
washed with 3 × 30 mL portions of 1 N KOH and one
30 mL portion of brine. The ether solution was dried
(Na2SO4) and evaporated under reduced pressure. The de-
sired product was recrystallized from MeOH and ether
(1:10). The product, a colourless crystal, was formed in 80%
1
yield, mp 206 °C. H NMR (CDCl3, 300 MHz) δ: 1.77–1.80
(m, 4H, R1-CH2-R2), 1.82–1.99 (m, 2H, CH-CH2-CH2),
2.25–2.42 (m, 4H, CH-CH2-CH2), 2.46 (s, 6H, CH3-N), 3.02
(q, 2H, J = 5.1, 10.2 Hz, CH2-NHCH3), 3.14–3.19 (m, 2H,
CH2-NHCH3), 3.29–3.32 (m, 2H, CH-NCH3), 7.20–7.25 (m,
2H, Ph-H), 7.62–7.67 (m, 2H, Ph-H), 9.38 (s, 2H, CONH).
13C NMR (CDCl3, 200 MHz) δ: 24.38, 31.15, 41.79, 56.67,
69.23, 124.25, 125.80, 129.77, 173.43. LRMS (ES) m/z (%):
331.6 (M+, 100), 147.0 (5), 65 (10). HRMS (ES) m/z calcd.
© 2006 NRC Canada

1424
Can. J. Chem. Vol. 84, 2006
for (C18H27N4O2)+: 331.2134; found: 331.2139. For X-ray
data, see Table 1.
lution was stirred for 5 min at –78 °C and warmed to 0 °C
for 15 min. To this yellow solution was added TiF4 (6 mg,
0.05 mmol) and the mixture was vigorously stirred until the
salt was completely dissolved. The resulting yellow mixture
was stirred for 1 h at rt and triethoxysilane (0.38 mL,
2.06 mmol) and acetophenone (0.12 mL, 1.02 mmol) were
added. The solution was stirred at 55 °C and product devel-
opment was monitored by TLC. The reaction mixture was
diluted with ethyl acetate (5 mL) and carefully made basic
(pH 9) with 1 mol/L of sodium hydroxide (30). The solid
was separated by filtration and the organic phase was col-
lected. The aqueous phase was extracted with ethyl acetate
(3 × 10 mL). The organic layers were combined, dried over
sodium sulfate, and then concentrated to give the crude
product which was purified by column chromatography
eluting with hexanes – ethyl acetate (5:1).
Preparation of the copper complex of the bis(L)prolinyl
amide of 1,2-diaminobenzene (13)
Ligand 7 (0.03 g, 0.1 mmol) was dissolved in methanol
(5 mL) before the addition of anhydr. K2CO3 (0.055 g,
0.4 mmol) and CuCl2·2H2O (0.017 g, 0.1 mmol). The result-
ing system was stirred overnight, then the solid was filtered
off and the clear blue solution was layered with ether. After
2 weeks, purple crystals were isolated, mp 295 °C (dec.).
HRMS (ES) m/z calcd. for (C16H21N4O2Cu)+: 364.0961;
found: 364.0957. For X-ray data, see Tables 2 and 3.
General procedure for the 29Si NMR experiment
(example ligand 7–triethoxysilane, 1:2)
To a dry NMR tube was added 7 (0.039 g, 0.13 mmol)
and d8-THF (0.3 mL). This solution was cooled to –78 °C
and n-butyllithium (0.16 mL, 1.6 mol/L solution in hexanes,
0.26 mmol) was added dropwise. The resulting yellowish so-
lution was warmed to 0 °C for 15 min. To this yellow solu-
tion was added triethoxysilane (0.05 mL, 0.26 mmol). The
solution was allowed to stand at 0 °C then warmed up to rt
for 30 min. 29Si NMR was examined in proton decoupled
mode using the Bruker DRX-500.
2-Bromophenethyl alcohol
1H NMR (CDCl3, 200 MHz) δ: 2.69 (bs, 1H, OH), 3.69–
3.45 (m, 2H, CH2Br), 4.90 (dd, J = 3.5, 8.6 Hz, 1H,
PhCH(OH)), 7.36 (s, 5Harom). 13C NMR (CDCl3, 200 MHz)
δ: 40.12, 73.78, 125.95, 128.43, 128.65, 140.31. MS (EI) m/z
(%): 202 ((M + 2)+, 2), 200 (M+, 2), 185 (5), 183 (5), 121
(5), 107 (100), 91 (10), 79 (78), 51 (29).
trans-4-Phenyl-3-buten-2-ol
1H NMR (CDCl3, 200 MHz) δ: 1.38 (d, 3H, J = 6.4 Hz,
PhCH=CHCH(OH)CH3), 2.26 (bs, 1H, PhCH=CHCH(OH)CH3),
4.48 (dp, 1H, J = 0.9, 6.3 Hz, PhCH=CHCH(OH)CH3), 6.26
(dd, 1H, J = 6.3, 16.0 Hz, PhCH=CHCH(OH)CH3), 6.56 (d,
1H, J = 16.0 Hz, PhCH=CHCH(OH)CH3), 7.20–7.41 (m,
5Harom). 13C NMR (CDCl3, 200 MHz) δ: 23.27, 68.68, 126.34,
127.47, 128.44, 129.16, 133.51, 136.61. MS (EI) m/z (%):
148 (M+, 63), 131 (66), 115 (26), 105 (100), 91 (49), 77
(37), 55 (15), 43 (71).
General procedure for basic reduction of ketone in the
presence of 7 (example acetophenone) (Table 4)
To a dry 10 mL round-bottomed flame-dried flask pro-
tected by argon was added 7 (0.016 g, 0.05 mmol) and THF
(5 mL). This solution was cooled to –78 °C and n-
butyllithium (0.13 mL, 1.6 mol/L solution in hexanes,
0.2 mmol) was added dropwise. The resulting yellowish so-
lution was stirred for 5 min at –78 °C and then warmed to
0 °C for 15 min at which point (EtO)3SiH (0.38 mL,
2.06 mmol) was added. The resulting clear solution was
stirred for 1 h at rt, then acetophenone (0.12 mL, 1.02 mmol)
was added. The solution was stirred at rt and product devel-
opment was monitored by TLC. The reaction mixture was
acidified by adding 1 N HCl at 0 °C and carefully made to
pH 6 (29). The organic phase collected. The aqueous phase
was extracted with ethyl acetate (3 × 10 mL). The organic
layers weree combined, dried over sodium sulfate, and then
concentrated to give the crude product, which was purified
by column chromatography eluting with hexanes – ethyl ac-
4-Methoxyphenethyl alcohol
1H NMR (CDCl3, 200 MHz) δ: 1.41 (d, 3H, J = 6.4 Hz,
CH3O-C6H4CH(OH)CH3), 2.64 (bs, 1H, CH3OC6H4CH(OH)CH3),
3.74 (s, 3H, CH3OC6H4-CH(OH)CH3), 4.76 (q, 1H, J =
6.4 Hz, CH3OC6H4CH(OH)CH3), 6.85 (d, 2H, J = 8.0 Hz, 2 ×
CH3OC-CH-CH), 7.25 (d, 2H, J = 8.0 Hz, 2 × CH3OC-CH-
CH). 13C NMR (CDCl3, 200 MHz) δ: 24.88, 55.09, 69.61,
113.62, 126.53, 138.00, 158.70. MS (EI) m/z (%): 152 (M+,
6), 135 (37), 109 (78), 105 (50), 84 (17), 77 (74), 51 (42),
43 (100).
1
etate (5:1). H NMR (CDCl3, 200 MHz) δ: 1.56 (d, 3H, J =
6.5 Hz, PhCH(OH)CH3), 2.76 (bs, 1H, PhCH(OH)CH3),
4.94 (q, 1H, J = 6.5 Hz, PhCH(OH)CH3), 7.32–7.45 (m,
5Harom). 13C NMR (CDCl3, 200 MHz) δ: 24.97, 69.99,
125.24, 127.14, 128.24, 145.75. MS (EI) m/z (%): 122 (M+,
10), 121 (40), 104 (68), 79 (28), 57 (7), 43 (100). MS (CI)
m/z (%): 140 ((M + 18)+, 17), 122 (100), 105 (41), 78 (2),
52 (1), 44(1).
2-Methoxyphenethyl alcohol
1H NMR (CDCl3, 200 MHz) δ: 2.81 (s, 1H, OH), 3.43 (s,
3H, CH3O), 3.53 (dd, 2H, J = 1.2, 4.1 Hz, CH3O-CH2-
CH(OH)), 4.88 (dd, 1H, J = 1.2, 1.7 Hz, CH(OH)), 7.30–
7.40 (m, 5Harom). 13C NMR (CDCl3, 200 MHz) δ: 24.12,
26.89, 57.69, 115.62, 129.53, 139.00. MS (EI) m/z (%): 144
(M+, 9), 113 (31), 96 (68), 77 (78), 67 (70), 31 (100).
General procedure for Lewis acid catalyzed reduction
of ketone (example acetophenone) (Table 5)
General procedure for reduction of ketone using
rhodium chloride and titanium chloride
The general procedure for Table 5 was followed except
that RhCl3 (10 mg, 0.05 mmol) or TiCl4 (9.5 mg,
0.05 mmol) were used, respectively.
To a dry 10 mL round-bottomed flame-dried flask pro-
tected by argon was added 7 (0.016 g, 0.05 mmol) and THF
(5 mL). This solution was cooled to –78 °C and n-
butyllithium (0.13 mL, 1.6 mol/L solution in hexanes,
0.2 mmol) was added dropwise. The resulting yellowish so-
© 2006 NRC Canada

Gan and Brook
1425
13. (a) M. Mühleisen and R. Tacke. Organometallics, 13, 3740
(1994); (b) R. Tacke and M. Mühleisen. Angew. Chem. Int.
Ed. Engl. 106, 1431 (1994); (c) R. Tacke and M. Mühleisen.
Inorg. Chem. 33, 4191 (1994); (d) R. Tacke, M. Mühleisen,
and P.G. Jones. Angew. Chem. Int. Ed. Engl. 33, 1186 (1994);
(e) M. Mühleisen and R. Tacke. Chem. Ber. 127, 1615 (1994);
( f ) R. Tacke, J. Becht, A. Lopez-Mras, and J. Sperlich. J.
Organomet. Chem. 446, 1 (1993).
14. (a) M.J. Roth, M.A. Brook, and H.B. Penny. J. Organomet.
Chem. 521, 65 (1996); (b) M.A. Brook, D. Chau, M.J. Roth,
W. Yu, and H. Penny. Organometallics, 13, 750 (1994).
15. F.J. LaRonde and M.A. Brook. Inorg. Chim. Acta, 296, 208
(1999).
General experimental procedure for preparation of
Mosher esters (example (S)-1-phenylethanol)
(S)-1-Phenylethanol (2 mg, 0.02 mmol) and MTPA-Cl (+)
(4 µL, 0.02 mmol) were mixed with carbon tetrachloride (3
drops) and dry pyridine (3 drops). The reaction mixture was
allowed to stand in a stoppered flask for 12 h at ambient
temperature. Water (1 mL) was added and the reaction mix-
ture transferred to a separatory funnel and extracted with
ether (20 mL). The ether solution, after washing succes-
sively with HCl (1 mol/L, 20 mL), saturated sodium carbon-
ate solution (20 mL), and water (20 mL), was dried with
sodium sulfate, filtered, and the solvent was removed in
vacuo. The residue was dissolved in deuterated chloroform
for NMR analysis. The integration of the hydrogen on the
carbon bearing the hydroxyl group was used as a measure to
assess the enantioselection.
16. E.A. Williams. In The chemistry of organic silicon com-
pounds. Vol. 1. Edited by S. Patai and Z. Rappoport. Wiley,
Chichester, UK. 1989. Chap. 8. p. 524.
17. L.N. Lewis. J. Am. Chem. Soc. 112, 5998 (1990), and
refs. cited therein.
18. (a) J.M. Tour and S.L. Pendalwar. Tetrahedron Lett. 31, 4719
(1990); (b) J.M. Tour, J.P. Cooper, and S.L. Pendalwar. J. Org.
Chem. 55, 3452 (1990).
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© 2006 NRC Canada