Enantioselective reduction of ketones and imines catalyzed by (CN-Box)ReV-oxo complexes

Article abstract of DOI:10.1002/chem.201001164

The development and application of chiral, non-racemic Re^V-oxo complexes to the enantioselective reduction of prochiral ketones is described. In addition to the enantioselective reduction of prochiral ketones, we report the application of these complexes to 1) a tandem Meyer-Schuster rearrangement/reduction to access enantioenriched allylic alcohols and 2) the enantioselective reduction of imines.

Full text of DOI:10.1002/chem.201001164

FULL PAPER
DOI: 10.1002/chem.201001164
Enantioselective Reduction of Ketones and Imines Catalyzed by
(CN-Box)ReV–Oxo Complexes**
Kristine A. Nolin, Richard W. Ahn, Yusuke Kobayashi, Joshua J. Kennedy-Smith, and
F. Dean Toste*[a]
Abstract: The development and application of chiral, non-racemic ReV–oxo com-
plexes to the enantioselective reduction of prochiral ketones is described. In addi-
Keywords:
reduction
rearrangement · rhenium
enantioselective
hydrosilylation ·
tion to the enantioselective reduction of prochiral ketones, we report the applica-
tion of these complexes to 1) a tandem Meyer–Schuster rearrangement/reduction
to access enantioenriched allylic alcohols and 2) the enantioselective reduction of
imines.
·
Introduction
The enantioselective reduction of prochiral ketones and
imines by hydrogenation, hydroboration or hydrosilylation
has been extensively studied.[7] A number of different transi-
tion metals, including Zn,[8] Fe,[9] Ru,[10] Ir,[11] Ti,[12] Rh,[13]
and Cu,[14] have successfully been employed in the enantio-
selective hydrosilylation of prochiral ketones. A similar
array of transition-metal complexes have been employed as
catalysts for the enantioselective hydrosilylation of
imines.[15] Common to the majority of these catalysts is that
they are derived from low-valent transition metals. In this
report, we describe the development and application of
chiral, non-racemic ReV–oxo complexes to the enantioselec-
tive reduction of prochiral ketones and imines. This new
class of hydrosilylation catalyst offers opportunities for the
creation of novel transformations that take advantage of the
unique reactivity of the metal–oxo functionality.[16] To this
end, we also report the application of metal–oxo complexes
to a tandem Meyer–Schuster rearrangement/reduction to
access enantioenriched allylic alcohol.
Transition metal–oxo complexes are amongst the most im-
portant catalysts for oxidative transformations.[1] In contrast,
we reported the use of [(PPh3)2Re(O)2I] as a catalyst in the
hydrosilylation of aldehydes and ketones[2]—an overall re-
duction of these functional groups. This methodology and
those subsequently reported[3] have highlighted the air-,
moisture-, and reagent tolerant nature of these oxidized
transition-metal complexes. As a result, this class of com-
plexes have become an attractive and practical alternative
to many low oxidation state transition-metal complexes that
are more commonly employed as catalysts in reduction reac-
tions.
A number of rhenium[4] and molybdenum[5] complexes
have been shown to be efficient catalysts for hydrosilylation
reactions. Despite these recent reports, enantioselective
metal–oxo catalyzed reductions are still rare.[6] Having pre-
viously developed a catalytic system for the hydrosilylation
of carbonyls using a rhenium(V)–dioxo complex to yield
chiral, racemic silyl ethers, we focused our efforts on ex-
panding this reactivity to enantioselective reductions.
Results and Discussion
Catalyst design: Evaluation of the mechanistic of the hydro-
silylation
of
carbonyl
compounds
catalyzed
by
[a] Dr. K. A. Nolin, R. W. Ahn, Dr. Y. Kobayashi,
Dr. J. J. Kennedy-Smith, Prof. F. D. Toste
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
[(PPh3)2(O)2ReI] revealed that an open coordination site
must be available to allow for the complexation of the car-
bonyl.[17] Consistent with this hypothesis is the failure of
Re–oxo complexes with bidentate phosphine ligands to
affect the transformation. These neutral, bidentate phos-
phine ligands, which occupy all available dative (L-type) co-
ordination sites on the metal center, are not conducive to
Fax : (+1)510-666-2504
E-mail: fdtoste@berkeley.edu
[**] CN-Box = Cyanobis(oxazoline).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001164.
Chem. Eur. J. 2010, 16, 9555 – 9562
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9555

Table 1. Solvent Studies of ketone reductions.
the necessary ligand dissociation. This restriction was con-
sidered in the design of a chiral ReV–oxo complex for the
enantioselective hydrosilylation of ketones. As a result,
chiral monoanionic ligands were hypothesized to be suitable
ligands for the asymmetric ReV–oxo catalyzed hydrosilyla-
tion (Scheme 1).
Entry R1
R2 R3
Sub-
strate
Solvent
CH2Cl2
Yield Product ee [%]
[%]
1
2
3
4
5
6
7
8
-(CH2)3-
OMe 4a
90
5a
5a
5a
5a
5b
5b
5b
5b
88
86
93
89
70
40
77
22
-(CH2)3-
-(CH2)3-
-(CH2)3-
OMe 4a
OMe 4a
OMe 4a
benzene 36
EtOAc 71
dioxane 95
Me
Me
Me
Me
H
H
H
H
H
H
H
H
4b
4b
4b
4b
CH2Cl2
EtOAc
dioxane 90
neat 97
57
79
Scheme 1. Catalyst design.
ment was obtained when acetophenone was reduced in
CH2Cl2 (57% yield and 70% ee, entry 5). The neat reduc-
tion of 4b yielded the corresponding alcohol in excellent
yield, but with low enantioselectivity (22% ee, entry 8).
With improved yield compared to dichloromethane, 1,4-di-
oxane was identified as the optimal solvent for the reduction
of both substrates furnishing the resulting alcohols in high
enantiomeric excess (entries 4 and 7).
A number of mono- and polyhydridic silanes were exam-
ined in the enantioselective hydrosilylation of 5-methoxy-
tetralone (Table 2). High enantiomeric excess was also at-
tained with Et3SiH (60% yield and 85% ee, entry 2); how-
ever, a significant rate reduction was observed relative to
the reaction with Me2PhSiH (95% yield and 89% ee,
entry 1). Attenuation of reactivity was more pronounced
with Ph2MeSiH (23% yield and 82% ee, entry 3). The use
of dihydride Ph2SiH2 led to formation of 5a albeit in lower
yield and enantiomeric enrichment (43% yield and 72% ee,
entry 4). None of the desired product was observed when
bulky silanes (iPr3SiH and tBuMe2SiH), PMHS or the poly-
hydridic phenyl silane were incorporated as reducing agents.
Me2PhSiH was found to be the optimal stoichiometric re-
ducing agent and, based on these results, was utilized during
further reaction optimization.
C2-Symmetric bis(oxazoline) ligands are a privileged class
of ligands that have been utilized in numerous transition-
metal-catalyzed enantioselective transformations resulting in
high levels of selectivity.[18] However, these ligands are most
often coordinated to the metal centers as bidentate, neutral
ligands.[19] We envisioned that the addition of an electron-
withdrawing group on the bridging carbon of the bis(oxazo-
line) would increase the acidity of the ligand allowing for
facile deprotonation and complexation as the corresponding
anion ligand. Our investigations began with the commercial-
ly available cyanobis(oxazoline) ligand (4S)-(+)-phenyl-a-
[(4S)-phenyloxazolidin-2-ylidene]-2-oxazoline-2-acetonitrile
(1). Stirring 1 with [Re(O)Cl3ACHTUNGTRENN(GU OPPh3)ACHTUNTGRNE(NNGU SMe2)] (2) in CH2Cl2
at room temperature yielded (CN-box)ReV–oxo complex 3
as a emerald green solid [Eq. (1)].
The effect of temperature was probed in the reduction of
4a with Me2PhSiH catalyzed by 3. At 08C, no catalytic ac-
tivity was observed (Table 2, entry 7). An erosion of enan-
tioselectivity as well as reactivity was observed when the re-
action was heated to 608C (entry 8). At this elevated tem-
perature, a substantial amount of disilane and disiloxane
through silane decomposition was observed.[22]
Initial optimization: The ability of 3 to catalyze the asym-
metric hydrosilylation of ketones was examined. At room
temperature, 5-methoxytetralone (4) was reduced with
5 mol% 3 and 1.5 equivalents of Me2PhSiH in 0.5m CH2Cl2.
After TBAF deprotection of the silyl ether, the correspond-
ing alcohol was isolated in 90% yield with 88% enantiomer-
ic excess[20] (Table 1, entry 1).[21] In aromatic solvents, the re-
action proved sluggish with only 36% yield of 5a after 48 h
(entry 2). Good reactivity was observed in ethyl acetate;
however, the excellent selectivity observed with the reduc-
tion of 4a (93% ee entry 3) did not extend to acyclic ketone
4b (40% ee, entry 6). A higher level of enantiomeric enrich-
Ligand optimization: In an effort to increase the enantiose-
lectivity of the reaction, the effect of changes to steric and
electronic composition of the cyanobis(oxazoline) ligand
were investigated using the optimized reaction conditions
(Me2PhSiH and 3 in dioxane at room temperature). To do
so, a number of differentially substituted bis(oxazoline)
compounds were synthesized. The synthesis of these com-
9556
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9555 – 9562

Enantioselective Reduction of Ketones and Imines
Table 2. Effect of silane on ketone reductions.
FULL PAPER
Entry
Silane
T
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Me2PhSiH
Et3SiH
Ph2MeSiH
Ph2SiH2
RT
RT
RT
RT
RT
RT
08C
608C
95
60
23
43
nr
nr
nr
71
89
85
82
72
n/a
n/a
n/a
76
iPr3SiH
tBuMe2SiH
Me2PhSiH
Me2PhSiH
pounds was accomplished in two steps from the correspond-
ing chiral, non-racemic amino alcohol (Scheme 2). The
amino alcohols were 1) obtained through the reduction of
the corresponding amino acid or 2) synthesized by the meth-
ods developed by Sharpless[23] or Ellman.[24] The amino alco-
hols were condensed with diethyl malonimidate dihydro-
chloride to produce the corresponding bis(oxazoline). Fol-
lowing protocol developed by Corey and Wang, the bis(oxa-
zoline) was deprotonated with nBuLi and treated with p-tol-
uenesulfonyl cyanide to yield the aryl and alkyl substituted
cyanonbis(oxazolines) (Scheme 2).[25]
Figure 1. Cyanobis(oxazoline) ligands.
Cyanobis(oxazoline) ligands of varying electronic and
steric composition (6a–g) were readily synthesized from the
corresponding amino alcohols and complexed to the metal
center, as described above, to yield (CN-box) ReV–oxo com-
plexes (7a–g). These complexes were examined in the re-
duction of 5-methoxytetralone and acetophenone. Moderate
enantiomeric excesses were obtained in the hydrosilylation
reactions catalyzed by rhenium complexes incorporating cy-
anobis(oxazoline) ligands with alkyl (53% ee, Table 3,
entry 1), benzyl (53% ee, entry 2), and indenyl (30% ee,
entry 3) substitution. Tetraphenyl substituted ligand 6d led
to slightly improved levels of enantioenrichment of 5a
Scheme 2. Cyanobis(oxazoline) synthesis.
Complexation of the cyanobis(oxazolines) 6a–g (Figure 1)
was accomplished through dropwise addition[26] of the ligand
as a concentrated solution in CH2Cl2 to a dilute suspension
of 2 in CH2Cl2 [Eq. (2)]. The reaction underwent a gradual
color change to become a clear, emerald green solution.
Upon trituration with Et2O or hexanes, the corresponding
CN-box ReV–oxo complexes 7a–g were isolated as green
solids. While formation of complexes 7a–g proceeded readi-
ly, complexation of cyanobis(oxazolines) 6h–k to the metal
center was unsuccessful. Under the above described condi-
tions, these complexation reactions resulted in the formation
of unidentifiable black solids that were isolated and found
to be catalytically inactive.[27]
Table 3. Ligand effects on ketone reductions.
Entry R1 R2 R3
Ligand Catalyst Yield [%] Product ee [%]
1
2
3
4
5
6
7
8
-(CH2)3- OMe 6a
7a
7b
7c
7d
7e
3
7 f
7d
7e
3
23
88
71
26
83
95
97
35
68
90
87
60
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
53
53
30
67
96
89
94
73
82
77
86
71
-(CH2)3- OMe 6b
-(CH2)3- OMe 6c
-(CH2)3- OMe 6d
-(CH2)3- OMe 6e
-(CH2)3- OMe
1
-(CH2)3- OMe 6 f
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
6d
6e
1
6 f
6g
9
10
11
12
7 f
7g
Chem. Eur. J. 2010, 16, 9555 – 9562
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9557

F. D. Toste et al.
Table 4. Asymmetric reduction of aryl ketones.
(67% ee, entry 3) and good se-
lectivity in the reduction of 4b
(73%, entry 8). A substantial
increase in selectivity was ach-
ieved with 2-napthyl cyano-
bis(oxazoline) Re-oxo com-
plexes 7e (82% and 96% ee,
entries 5 and 9). However,
markedly improved reactivity
was observed with the phenyl
and 4-tert-butylphenyl catalysts
with consistently high level of
enantioselectivity (77–94% ee,
entries 6, 7, 10 and 11).
En-
try
Ketone
Substrate
Catalyst
Yield [%]
Product
ee [%]
(S)-3
(R)-7 f
90
92
78 (R)
86 (S)
1
4b
5b
(S)-3
(R)-7 f
(S)-3
59
89
70
88 (R)
86 (S)
83 (R)
2
3
8a: R=H
9a
9b
8b: R=OTs
(S)-3
(R)-7 f
69
61
87 (R)
86 (S)
4
8c
9c
Scope of enantioselective re-
duction of ketones: The scope
of the hydrosilylation was
probed using two equivalents of
Me2PhSiH, in dioxane, and
3 mol% of catalyst 3 or 7 f.
Good to excellent enantioselec-
tivities were obtained in the re-
duction of aromatic ketones.
Acetophenone was reduced
with good selectivity (Table 4,
entry 1). Good to excellent
enantiomeric excess was ob-
tained in the reduction of five-,
(S)-3
(R)-7 f
(S)-3
71
97
84
93 (R)
94 (S)
89 (R)
5
6
4a: R=OMe
8d: R=H
5a
9d
(S)-3
(R)-7 f
70
82
75 (R)
88 (S)
7
8
8e
8 f
9e
9 f
(S)-3
(R)-7 f
83
96
78 (R)
81 (S)
(S)-3
(R)-7 f
51
64
93 (R)
82 (S)
9
8g
8h
9g
9h
six-,
and
seven-membered
cyclic ketones (83–94% ee) (en-
tries 2–7). Heteroaromatic ke-
tones were also well tolerated
under the reaction conditions;
for example, alcohol 9g was ob-
tained in 93% ee (entry 9). In
most cases, the 4-tert-butylphen-
yl catalyst 7 f produced greater
enantioselectivities than phenyl
catalyst 3, although, in some
cases, the observed enhance-
10
(R)-7 f
80
84 (S)
11
12
8i
8j
(S)-3
94
67
9i
9j
15 (R)
6 (S)
(R)-7 f
ment was not dramatic and the effect can even be reversed
(entry 9). The reduction of non-aryl ketones proceeded in
good to excellent yield, however, with modest enantioen-
richment of the resultant alcohols (6–15% ee, entries 11 and
12).
A convenient, alternate protocol for the hydrosilylation
entails the in situ generation of the chiral catalyst. This was
achieved by pre-stirring 2 mol% of 2 and 6 mol% of the de-
sired cyanobis(oxazoline) ligand in CH2Cl2 for two hours
prior to addition of the ketone and silane. Under these con-
ditions, 4a was hydrosilylated and deprotected yielding the
corresponding alcohol 5a with identical enantioselectivity to
that observed with the pre-formed catalyst 3 [Eq. (3)].
The ReV–oxo catalyzed enantioselective hydrosilylation of
ketones was extended to the synthesis of chiral allylic alco-
hols. Modest enantioselectivities, 45–55% ee, were observed
in the hydrosilylation of a,b-unsaturated conjugated ketone
10a (Table 5, entry 1). Higher enantiomeric excesses, 55–
63% ee, were obtained with a-substituted enone 10b
(entry 2). It should be noted that 1,4-reduction of the
enones was not observed under these conditions.
Tandem 3,3-rearrangement–asymmetric reduction: In the
course of examining ReV–oxo complexes as catalysts in the
9558
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9555 – 9562

Enantioselective Reduction of Ketones and Imines
Table 5. Asymmetric reduction of enones.
FULL PAPER
Table 6. Tandem Meyer–Schuster rearrangement–hydrosilylation.
Entry Ketone
1
Substrate Catalyst Yield [%] Product ee [%]
Entry
R
Substrate Ligand Yield [%] Product [%] ee [%]
1
2
3
4
5
6
7
Ph
Ph
16a
16a
16b
1
43
38
42
85
25
42
73
18a
18a
18b
18c
18d
18e
18 f
49
82
92
64
50
63
65
10a
10b
(R)-7 f
90
11a
11b
55 (S)
6g
6g
6g
6g
6g
6g
(S)-3
(R)-7 f
87
47
63 (R)
55 (S)
2-Nap
2-Cl-Ph 16c
4-Cl-Ph 16d
tBu
nBu
2
3
16e
16 f
10c
(R)-7 f
71
11c
95 (S)
cohols 18a–f in the highest levels of enantiomeric excess
from the one-pot Meyer–Schuster rearrangement-reducion
of propargyl alcohols 16b–f.
etherification of propargyl alcohols,[16e] rearrangement of the
alcohol to enone, the Meyer–Schuster rearrangement, was
observed to be the prevailing reactivity in non-polar and ar-
omatic solvents.[28] It was envisioned that a ReV–oxo cata-
lyzed Meyer–Schuster rearrangement could be coupled with
the asymmetric reductions in a one-pot synthesis of chiral
allylic alcohols from racemic propargyl alcohols (Scheme 3).
To access a, b-unsaturated enones, the rearrangement of
allenyl alcohols was examined. Allenyl alcohols 19a–c were
subjected to the tandem reaction conditions [Eq. (5)]. Using
commercially available ligand 1, the one-pot reactions were
performed using Me2PhSiH as the stoichiometric reducing
agents. The allylic alcohols 20a–c were obtained in good
yields (63–71%) and moderate to good enantiomeric excess
(56–77%). As shown above, the ability to generate the
chiral catalyst in situ lends provides a highly tunable system
for the enantioselective synthesis of allylic alcohols from
racemic starting materials.
Scheme 3. Tandem Meyer–Schuster rearrangement hydrosilylation.
Chiral complexes 3 and 7 f were tested for there ability to
facilitate the Meyer–Schuster rearrangement. Propargyl al-
cohol 12 was treated with CN-box Re complexes 3 and 7 f in
toluene at 808C.[29] The reaction resulted in the formation of
cis and trans isomers of the desired enone (13 and 14) as
well as a dimerized by-product (15) [Eq. (4)].
Asymmetric reduction of imines: With a system in hand for
the asymmetric reduction of ketones, we next turned our at-
tention toward the reduction of imines.[6] While efficient sys-
tems have been developed, they generally utilize metals in
low oxidation states. Representative systems include those
catalyzed by low oxidation state late metal complexes[11,15]
and titanocene complexes.[15f,31] In order to demonstrate the
utility of this air and moisture tolerant catalyst for the syn-
thesis of chiral amines via reduction of the corresponding
imine, an appropriate protecting group needed to be select-
ed. Phosphinyl imines have been shown to be stable under
ambient conditions and proved suitable for the reaction con-
ditions. The phosphinyl group can easily be cleaved under
acidic conditions to yield the chiral amine.[32]
The reduction of methyl thiophene imine 21 in CH2Cl2
with Me2PhSiH proceeded with excellent yield and enantio-
selectivity at room temperature [Eq. (6)].[33] The reaction
proceeded with the same selectivity in a range of solvents
including THF, EtOAc, and toluene. The substitution of
Me2PhSiH with Ph2MeSiH did not alter the enantioselectivi-
Having observed that the chiral catalyst could be generat-
ed in situ (see above), we next examined Re–oxo complex
2, the chiral catalyst precursor, as a catalyst for the Meyer–
Schuster reaction.[30] Gratifyingly, 2 facilitated the rear-
rangement of the 16a to the corresponding enone (17a).
Without isolation of the enone, ligand 1 was added to the re-
action solution followed by 2 equivalents of Me2PhSiH.
Allyl alcohol 18a was isolated in 43% yield and 49% ee
(Table 6, entry 1). After further optimization, it was found
that in situ generation of chiral catalyst 7g provided allyl al-
Chem. Eur. J. 2010, 16, 9555 – 9562
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9559

F. D. Toste et al.
The synthesis of phenyl glycine derivatives was achieved
through the reduction of a-imino esters by 7 f. The reduction
of these imines proceeded in moderate to good yield with
excellent enantioselectivity (Table 8, entries 1–3). Non-aro-
matic a-imino esters bearing a-protons existed as the a-
amino acrylate and were unreactive (entries 4 and 5). Simi-
larly, b-imino ester 25 f did not yield the desired amine 26 f
(entry 6).
ty; however, Me2PhSiH generally resulted in higher yield of
the corresponding phosphinyl amine. No reactivity was ob-
served with Me2tBuSiH or iPr3SiH. Mild heating of the reac-
tion showed no measurable decrease in enantioselectivity
but did result in slightly higher yields (Me2PhSiH at 408C:
81% yield, 98% ee).
Table 8. Reduction of a-imino esters.
The reaction successfully led to the reduction of aryl
phosphinyl imines. Acyclic ketimines (Table 7, entries 1–7)
reduced good yield with excellent enantioselectivity. Similar
selectivity was observed with cyclic ketimines (entries 8–10).
Notably, imine 23j exists primarily as the enamine and the
reduction proceeded in 71% yield with 96% ee without any
additional reaction time or heating. Additionally, heteraro-
matic compounds performed well under the reaction condi-
tions and were reduced in very good yield with excellent se-
lectivity (entries 6 and 7). Interestingly, N-methylpyrrole
methyl ketimine was unreactive when subject to the reduc-
tion conditions. Aliphatic ketimines did not display the
same selectivity as the aryl imines. Cyclohexyl methyl imine
23k and isopropyl ethyl imine 23l were reduced with 32 and
17% ee, respectively (Table 7, entries 11 and 12). The bulky
tert-butyl methyl imine was unreactive (entry 13).
Entry Imine
Substrate
Yield Prod- ee
[%]
uct
[%]
1
2
25a X=Ph
25b 4-
OMePh
25c 2-MePh Me
R=Et 83
26a
26b
>99
95
Me
47
69
3
4
26c
26d
99
25d
nr
n/a
5
6
25e
25 f
nr
nr
26e
26 f
n/a
n/a
Synthesis of chiral allylic amines was achieved through
chemo- and enantioselective reduction of the corresponding
imine. Conjugated aromatic imines were reduced in good
yield with excellent selectivity (Table 9, entries 1–2). Uncon-
jugated vinyl imines were reduced with good enantioselec-
tivity in moderate yield. For this substrate, extension of the
reaction time led to reduction of the olefin to yield the alkyl
amine.
Table 7. Reduction of aryl and alkyl phosphinyl imines.
Entry Imine
Substrate
Yield
[%]
Product ee
[%]
1
2
3
4
5
23a X=H R=Me 51
24a
24b
24c
24d
24e
>99
98
98
99
>99
23b OMe
23c CF3
Me
Me
Me
Bu
61
78
71
68
Table 9. Synthesis of allylic amines.
23d
23e
I
H
6
7
23 f
23g
81
76
24 f
>99
Entry
Imine
Sub-
strate
Yield
[%]
Prod-
uct
ee [%]
>99
75
24g
99
1
2
3
27a
27b
27c
71
62
48
28a
28b
28c
8
9
10
23h n=1
23i
23j
X=H 89
24h
24i
24j
95
95
96
2
3
OMe
H
69
71
11
12
13
23k R=Me R’=Cy 69
23l Et
23m Me
24k
24l
24m
32
17
n/a
83
iPr
tBu
73
nr
9560
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9555 – 9562

Enantioselective Reduction of Ketones and Imines
FULL PAPER
followed by catalyst 7 f (3 mol%). The reaction was monitored by TLC.
Upon completion or 72 h, the reaction was chromatographed. The reac-
tion mixture was loaded directly on to a silica gel column and chromato-
graphed with the 10–50% acetone in CH2Cl2 to give the amine. Absolute
configurations were assigned by comparison of the HPLC retention times
to literature values.[33]
Conclusion
In summary, a series of chiral, non-racemic (CN-box)ReV–
oxo complexes have been prepared and employed as versa-
tile and efficient catalysts for the hydrosilylation of ketones
and imines. These reductions proceed under an ambient air
atmosphere without the need for exclusion of advantageous
water. The mild reaction is highly functional group tolerant
and has been extended to include the formation phenyl gly-
cine derivative, allylic alcohol and allylic amines. The (CN-
box)ReV–oxo complexes can be pre-formed and isolated as
benchtop stable solids or generated in situ from a single pre-
cursor. The utility of in situ generation of the chiral catalyst
and the unique reactivity of metal–oxo complexes was high-
lighted in tandem Meyer–Schuster hydrosilylation reactions
providing access to enantioenriched allylic alcohols from
racemic propargyl and allenyl alcohols.
Acknowledgements
We gratefully acknowledge NIHGMS (GM074774), the Camille and
Henry Dreyfus Foundation and Research Corporation (Research Innova-
tion Award) for financial support. K.A.N. thanks Novartis for a graduate
fellowship and Y.K. is grateful for a research fellowship from JSPS for
young scientists.
[1] R. Hua, J.-L. Jiang, Curr. Org. Synth. 2007, 4, 151–174.
[2] J. J. Kennedy-Smith, K. A. Nolin, H. P. Gunterman, F. D. Toste, J.
Am. Chem. Soc. 2003, 125, 4056–4057.
[3] a) A. K. Roy, Adv. Organomet. Chem. 2007, 55, 1–59. For a review,
see: b) G. Du, M. M. Abu-Omar, Curr. Org. Chem. 2008, 12, 1185–
1198; c) R. Sanz, M. R. Pedrosa, Curr. Org. Synth. 2009, 6, 239–263.
[4] For examples of reduction of various functional groups, with silanes,
catalyzed by rhenium–oxo complexes. Aldehyde/ketone: a) P. M.
Reis, B. Royo, Catal. Commun. 2007, 8, 1057–1059; b) G. D. Du,
M. M. Abu-Omar, Organometallics 2006, 25, 4920–4923; c) E. A.
Ison, J. E. Cessarich, G. D. Du, P. E. Fanwich, M. M. Abu-Omar,
Inorg. Chem. 2006, 45, 2385–2387. Sulfoxide: d) S. C. A. Sousa,
A. C. Fernandes, Tetrahedron Lett. 2009, 50, 6872–6876. Nitro:
e) R. G. de Noronha, C. C. Romao, A. C. Fernandes, J. Org. Chem.
2009, 74, 6960–6964.
[5] For examples of reduction with molybdenum–oxo complexes, see:
aldehyde/ketone: a) J. E. Ziegler, G. D. P. E. Fanwick, M. M. Abu-
Omar, Inorg. Chem. 2009, 48, 11290–11296; b) P. M. Reis, C. C.
Romao, B. Royo, Dalton Trans. 2006, 1842–1846; c) A. C. Fer-
nandes, R. Fernandes, C. C. Romao, B. Royo, Chem. Commun.
2005, 213–214. Imines: d) A. C. Fernandes, C. C. Romao, Tetrahe-
dron Lett. 2005, 46, 8881–8883. Amides: e) A. C. Fernandes, C. C.
Romao, J. Mol. Catal. A 2007, 272, 60–63. Esters: f) A. C. Fer-
nandes, C. C. Romao, J. Mol. Catal. A 2006, 253, 96–98.
Experimental Section
General procedure for synthesis of ReV–oxo complexes 3 and 7a–g:
ReV–dimethylsulfide (DMS) complex 2 (1 equiv) was added to a round-
bottom flask charged with a magnetic stir bar. CH2Cl2 was added to a re-
action flask to a concentration of 5 mm. In a scintillation vial, 1.2 equiv of
cyanobis(oxazoline) ligand 6 f was diluted in CH2Cl2 (5 mm). Ligand solu-
tion was added slowly to Re suspension. Reaction solution quickly
changes from light green to very dark green. Reaction stirred at RT for
~5 h at which time the solution is a bright emerald green. (Note: This re-
action time can be reduced to 30 min by adding one drop of DMSO;
however, isolation of the product becomes more difficult.) Solvent was
evaporated and the dark green film was diluted with a small amount of
CH2Cl2 then triturated with Et2O. Filtration with a Buchner funnel yields
Re complex 7 f, a bright green solid. The trituration was repeated 4 times
or until no significant material was isolated. The resultant solid was dried
in vacuo.
General procedure for asymmetric reduction of ketones with isolated
asymmetric catalyst: To a 7.4 mL Fischer vial charged with a solution of
ketone (50 mg, 1 equiv) in dioxane (1m), was added silane (2 equiv) fol-
lowed by catalyst 3 or 7 f (3 mol%). The reaction was monitored by
TLC. Upon completion or 72 h, the reaction was quenched with 1 equiv
of tetrabutylammonium fluoride (1.0m in THF). The reaction mixture
was loaded directly on to a silica gel column and chromatographed with
the 10–20% ethyl acetate in hexanes (9g: 50% ethyl acetate in hexanes)
to give the alcohol. NMR and HPLC analyses of the compounds listed
below were consistent with previously reported values.[34] Absolute con-
figuration of 5b, 9a, and 9d were assigned by comparison of the optical
rotation and HPLC retention times to literature values.[21]
[6] a) K. A. Nolin, R. W. Ahn, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
12462–12463; b) G. Du, M. M. Abu-Omar, Inorg. Chim. Acta 2008,
361, 3184–3192.
[7] a) H. Nishiyama, K. Itoh in Catalytic Asymmetric Synthesis (Ed.: I.
Ojima), Wiley, New York, 2000; b) T. Ohkuma, M. Kitamura, R.
Noyori in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima),
Wiley-VCH, Weinheim, 2000; c) T. Ohkuma, R. Noyori in Compre-
hensive Asymmetric Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz,
H. Yamamoto), Springer, Heidelberg, 1999, p. 199; d) O. Riant, N.
Mostefai, J. Courmarcel, Synthesis 2004, 2943–2958; e) S. Diez-Gon-
zalez, S. P. Nolan, Org. Prep. Proced. Int. 2007, 39, 523–559; f) C. G.
Arena, Mini-Rev. Org. Chem. 2009, 6, 159–162.
[8] a) V. M. Mastranzo, L. Quintero, C. Anaya de Parrodi, E. Juaristi,
P. J. Walsh, Tetrahedron 2004, 60, 1781–1789; b) V. Bette, A. Mor-
treux, D. Savoia, J.-F. Carpentier, Adv. Synth. Catal. 2005, 347, 289–
302; c) H. Mimoun, J. Y. de Saint Laumer, L. Giannini, R. Scopelliti,
C. Floriani, J. Am. Chem. Soc. 1999, 121, 6158–6166.
[9] a) H. Nishiyama, A. Furuta, Chem. Commun. 2007, 760–762;
b) N. R. Shaikh, S. Enthaler, K. Junge, M. Beller, Angew. Chem.
2008, 120, 2531–2535; Angew. Chem. Int. Ed. 2008, 47, 2497–2501;
c) T. Inagaki, L. T. Phong, A. Furuta, J. Ito, H. Nishiyama, Chem.
Eur. J. 2010, 16, 3090–3096.
[10] Y. Nishibayashi, L. Takei, S. Uemura, M. Hidai, Organometallics
1998, 17, 3420–3422.
[11] I. Takei, Y. Nishibayashi, Y. Arikawa, S. Uemura, M. Hidai, Organo-
metallics 1999, 18, 2271–2274.
General procedure for tandem Meyer–Schuster asymmetric reduction re-
action: Re–DMS complex 2 (2.5 mol%) was added to scintillation vial
charged with 1 equiv of propargyl alcohol in 0.5m dioxane. The reaction
solution is stirred at room temperature for 3 h. Upon complexation,
3 mol% of cyanobis(oxazoline) ligand was added and the reaction solu-
tion was stirred at room temperature for 5 h resulting in a clear solution
then 2 equivalents of Me2PhSiH were added. The reaction solution was
stirred at room temperature and monitored by TLC. After 60 h or reac-
tion completion, the silyl ether was deprotected with 1 equiv of tetrabuty-
lammonium fluoride (1.0m in THF). Direct purification reaction mixture
by column chromatography on a silica gel column with the 10–20% ethyl
acetate in hexanes gave the allylic alcohol. The enantiomeric excess was
determined by chiral HPLC.
General procedure for asymmetric reduction of phosphinyl imines with
asymmetric catalyst: To a 7.4 mL Fischer vial charged with a solution of
imine (50 mg, 1 equiv) in CH2Cl2 (1m), was added Me2PhSiH (2 equiv)
Chem. Eur. J. 2010, 16, 9555 – 9562
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9561

F. D. Toste et al.
[12] M. B. Carter, B. Schlott, A. Gutierrez, S. L. Buchwald, J. Am. Chem.
Soc. 1994, 116, 11667–11670.
[20] Enantiomeric excess of ketone reductions determined by chiral
HPLC.
[13] a) J.-F. Carpentier, V. Bette, Curr. Org. Chem. 2002, 6, 913–936;
b) R. J. Corriu, J. C. Poulin, T. P. Dang, H. B. Kagan, J. Chem. Soc.
Chem. Commun. 1973, 38–39; c) W. Dumont, J. C. Poulin, T. P.
Dang, H. B. Kagan, J. Am. Chem. Soc. 1973, 95, 8295–8299; d) I.
Ojima, M. Nihonyanagi, Y. Nagai, J. Chem. Soc. Chem. Commun.
1972, 938a; e) I. Ojima, T. Kogure, M. Nihonyanagi, Y. Nagai, Bull.
Chem. Soc. Jpn. 1972, 45, 3506; f) I. Ojima, T. Kogure, M. Nihonya-
nagi, Y. Nagai, Bull. Chem. Soc. Jpn. 1972, 45, 3722; g) B. Tao, G. C.
Fu, Angew. Chem. 2002, 114, 4048–4050; Angew. Chem. Int. Ed.
2002, 41, 3892–3894; Angew. Chem. Int. Ed. 2002, 41, 3892–3894;
h) Y. Nishibayashi, K. Segawa, K. Ohe, S. Uemura, Organometallics
1995, 14, 5486–5487.
[21] Absolute configuration of 5b and 9b assigned by comparison of
HPLC retention times to those reported by: J. Hannedouche, G.
Clarkson, M. Wills, J. Am. Chem. Soc. 2004, 126, 986. The absolute
stereochemistry of remaining products assigned by analogy.
[22] E. A. Ison, R. A. Corbin, M. M. Obu-Omar, J. Am. Chem. Soc.
2005, 127, 11938–11939.
[23] H.-T. Chang, K.-B. Sharpless, Tetrahedron Lett. 1996, 37, 3219–3222.
[24] T. P. Tang, S. K. Volkman, J. A. Ellman, J. Org. Chem. 2001, 66,
8772–8778.
[25] E. J. Corey, Z. Wang, Tetrahedron Lett. 1993, 34, 4001–4004.
[26] Faster addition results in a blackening of solution and the isolation
of an unreactive complex.
[14] B. H. Lipshutz, K. Noson, W. Chrisman, A. Lower, J. Am. Chem.
Soc. 2003, 125, 8779–8789.
[27] Modifications to the standard complexation conditions where unsuc-
cessful. (CN-box) Re–oxo complex synthesis was also attempted in
acetonitrile and THF albeit with similar results.
[28] C. Y. Lorber, J. A. Osborn, Tetrahedron Lett. 1996, 37, 853–856, and
references therein.
[15] a) O. Riant in Modern Reduction Methods (Eds.: P. G. Andersson,
I. J. Munslow), Wiley-VCH, Weinheim, 2008, pp. 321–337. Rh:
b) R. Becker, H. Brunner, S. Mahboobi, W. Wiegrebe, Angew.
Chem. 1985, 97, 969–970; Angew. Chem. Int. Ed. Engl. 1985, 24,
995–996; c) N. Langlois, T. P. Dang, H. B. Kagan, Tetrahedron Lett.
1973, 14, 4865–4868. Ir: d) D. Xiao, X. Zhang, Angew. Chem. 2001,
113, 3533–3536; Angew. Chem. Int. Ed. 2001, 40, 3425–3428. Ru:
e) Y. Nishibayashi, I. Takei, S. Uemura, M. Hidai, Organometallics
1998, 17, 3420–3422. Ti f) X. Verdaguer, U. E. W. Lange, M. T.
Reding, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 6784–6785.
Cu: g) B. H. Lipshutz, H. Shimizu, H. Angew. Chem. 2004, 116,
2278–2280; Angew. Chem. Int. Ed. 2004, 43, 2228–2230; Angew.
Chem. Int. Ed. 2004, 43, 2228–2230. Zn: h) B.-M. Park, S. Mun, J.
Yun, Adv. Synth. Catal. 2006, 348, 1029–1032.
[16] For examples non-oxidative transformation catalyzed by rhenium–
oxo complexes, developed in our group, see: a) R. V. Ohri, A. T. Ra-
dosevich, K. J. Hrovat, C. Musich, D. Huang, T. R. Holman, F. D.
Toste, Org. Lett. 2005, 7, 2501–2504; b) J. J. Kennedy-Smith, L. A.
Young, F. D. Toste, Org. Lett. 2004, 6, 1325–1327; c) B. D. Sherry,
R. N. Loy, F. D. Toste, J. Am. Chem. Soc. 2004, 126, 4510–4511;
d) M. R. Luzung, F. D. Toste, J. Am. Chem. Soc. 2003, 125, 15760–
15761; e) B. D. Sherry, A. T. Radosevich, F. D. Toste, J. Am. Chem.
Soc. 2003, 125, 6076–6077.
[29] Previous studies within the group found that toluene was a suitable
solvent for ReV–oxo catalyzed Meyer–Schuster reaction.
[30] During the course of this work, a related rhenium-,oxo,catalyzed re-
arrangement of propargyl alcohols was reported: M. Stefanoni, M.
Luparia, A. Porta, G. Zanoni, G. Vidari, Chem. Eur. J. 2009, 15,
3940–3944.
[31] a) M. C. Hansen, S. L. Buchwald, Org. Lett. 2000, 2, 713–715; b) X.
Verdaguer, U. E. W. Lange, S. L. Buchwald, Angew. Chem. 1998,
110, 1174–1178; Angew. Chem. Int. Ed. 1998, 37, 1103–1107.
[32] a) B. Krzyzanowska, Synthesis 1978, 521–524; b) S. Masumoto, H.
Usuda, M. Suzuki, M. Kanai, M. Shibaski, J. Am. Chem. Soc 2003,
125, 5634–5635; c) F. Spindler, H-U. Blaser, Adv. Synth. Catal. 2001,
343, 68–70; d) K. D. Sugi, T. Nagata, T. Yamada, T. Mukaiyama,
Chem. Lett. 1997, 493–494; e) D. J. Weix, Y. Shi, J. A. Ellman, J.
Am. Chem. Soc. 2005, 127, 1092–1093.
[33] Absolute configuration was assigned by comparison of HPLC reten-
tion times to those reported by: T. Yamada, T. Nagata, K. Sugi, K.
Yorozu, T. Ikeno, Y. Ohtsuka, D. Miyazaki, T. Mukaiyama, Chem.
Eur. J. 2003, 9, 4485–4509.
[34] a) H. C. Brown, J. Chandrasekharan, P. Ramachandran, J. Am.
Chem. Soc. 1988, 110, 1539–1546; b) E. J. Corey, R. Bakshi, S. Shi-
bata, C. Chen, V. Singh, J. Am. Chem. Soc. 1987, 109, 7925–7926;
c) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1996, 118, 2521–2522.
[17] K. A. Nolin, J. R. Krumper, M. D. Pluth, R. G. Bergman, F. D. Toste,
J. Am. Chem. Soc. 2007, 129, 14684–14696.
[18] G. Desimoni, G. Faita, K. A. Jorgensen, Chem. Rev. 2006, 106,
3561–3651.
[19] S. Dagorne, S. Bellemin-Laponnaz, A. Maisse-Francois, Eur. J.
Inorg. Chem. 2007, 913–925.
Received: May 1, 2010
Published online: July 7, 2010
9562
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9555 – 9562