Thiourea-catalyzed enantioselective cyanosilylation of ketones

Article abstract of DOI:10.1021/ja052511x

The new chiral amino thiourea catalyst 3d promotes the highly enantioselective cyanosilylation of a wide variety of ketones. The hindered tertiary amine substituent plays a crucial role with regard to both stereoinduction and reactivity, suggesting a coop

Full text of DOI:10.1021/ja052511x

Published on Web 06/04/2005
Thiourea-Catalyzed Enantioselective Cyanosilylation of Ketones
Douglas E. Fuerst and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02318
Received April 18, 2005; E-mail: jacobsen@chemistry.harvard.edu
Lewis acid catalysis stands as the traditional and proven strategy
for activation of carbonyl compounds toward enantioselective
reactions.1 Only recently, general acid catalysis with small-molecule
hydrogen-bond donors has emerged as a promising alternative for
electrophile activation in asymmetric synthesis.2 Catalysts that
function as H-bond donors exploit a mode of activation common
in enzymatic pathways,3 and may hold complementary reactivity
and scope relative to metal-based systems. Our own efforts in
general acid asymmetric catalysis have focused on chiral urea and
thiourea derivatives (e.g. 1, Figure 1) for activation of alkyl- or
acyl-substituted imines in Strecker,4 Mannich,5 hydrophophonyla-
tion,6 nitro-Mannich,7 and acyl Pictet-Spengler8 reactions.9 Ap-
plication of achiral urea and thiourea derivatives to carbonyl
activation reactions was demonstrated in seminal work by Curran10
and subsequent studies by Schreiner,11 but only very recently have
thiourea derivatives been applied with varying success to the
asymmetric catalytic activation of carbonyl compounds.12 We
describe here a significant new example of thiourea catalysis in
carbonyl 1,2-addition chemistry, in the highly enantioselective
cyanosilylation of ketones and aldehydes with a new bifunctional
thiourea-amine derivative.
The catalytic asymmetric cyanation of carbonyl compounds ranks
among the most important and well-studied reaction classes in
asymmetric catalysis, due in large part to the utility of the product
cyanohydrins as precursors to R-hydroxy acids, â-amino alcohols,
and other valuable chiral building blocks.13 Wheareas several
outstanding catalyst systems have been identified for cyanation of
aldehydes,14 ketones present a greater challenge as a substrate class,
and only recently have effective methods using chiral metal
complexes,15 cinchona alkaloids,16 and chiral oxazaborolidinium
ions17 been devised. The known Schiff base derivative 1 displayed
no measurable catalytic activity in the model cyanosilylation of
acetophenone with TMSCN (Table 1). However, primary amine
2, the immediate synthetic precursor to 1, proved highly active and
led to product formation in 25% ee. The modular nature of the
thiourea derivatives allowed straightforward and systematic opti-
mization of the catalyst structure.18 While tert-leucine proved to
be the optimal amino acid component, less sterically demanding
amide derivatives led to improved enantioselectivities, with second-
ary methyl amides (catalysts 3a-d) affording the best results.
Replacement of the primary amine in 3a with the corresponding
N,N-dimethyl tertiary amine (3b) resulted in complete suppression
of reactivity. However, introduction of CF3CH2OH for in situ
generation of HCN restored catalytic activity and led to product
formation in 90% ee.19
Figure 1. Thiourea catalysts.
Table 1. Optimization Studiesa
temp
C)
time
(h)
conv
(%)b
ee
catalyst
solvent
additive
(
°
(%)c
1
2
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
23
48
3
3
24
24
48
12
12
<5
100
100
0
80
30
-40
-40
-40
-40
-78
-78
-78
25
55
3a
3b
3b
3b
3c
3d
CF3CH2OHd
CF3CH2OHd
CF3CH2OHd
CF3CH2OHd
90
95
94
97
100
100
a Reactions were carried out on a 0.2 mmol scale with 1.3 equiv of
TMSCN in 0.5 mL of solvent, unless noted otherwise. b Determined by
GC relative to dodecane as internal standard. c Determined by GC analysis.
d 2.2 equiv of TMSCN and 1.0 equiv of CF3CH2OH were used.
demanding catalysts promoted silylcyanation with significantly
increased reaction rates, with complete substrate conversion within
12 h at -78 °C.20 Catalyst 3d also induced measurably improved
enantioselectivity (97% ee).21
Thiourea catalyst 3d proved to be general for the highly
enantioselective cyanosilylation of a wide range of ketones (Table
2). In most cases, useful reaction rates were obtained at 5 mol %
catalyst loading. Alkyl aryl ketones underwent reaction with high
enantioselectivity with only slight dependence on the size of the
alkyl group (entries 1-3) or the properties of the aromatic ring
(entries 4-10). Heteroaromatic ketones were also excellent sub-
strates, highlighting the tolerance of Lewis basic functionality with
thiourea catalysts (entries 11-13). In addition, a range of R,â-
unsaturated ketones were well-tolerated and afforded the 1,2-
addition products exclusively (entries 14-17). Although 3d was
optimized for the reaction of ketones, it was also found to be an
efficient catalyst for the cyanosilylation of aldehydes. Thus,
benzaldehyde and trans-cinnamaldehyde underwent cyanosilylation
with 3d (0.05 mol %) and CF3CH2OH (20 mol %) within 2 h in
96% ee and 93% ee, respectively. As an indication of the possible
Optimization of other reaction parameters (e.g. solvent, temper-
ature) led to further improvements in enantioselectivity with catalyst
3b, albeit at the expense of reactivity (95% ee and 30% conversion
at 48 h). The crucial role of the amine substituent on the catalyst
was evident upon comparison of N,N-dimethyl (3b), N,N-diethyl
(3c), and N,N-di-n-propyl (3d) derivatives. The more sterically
9
8964
J. AM. CHEM. SOC. 2005, 127, 8964-8965
10.1021/ja052511x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Cyanosilylation of Ketones Catalyzed
by 3da
racemic and enantiomerically enriched products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Reactions were carried out on a 1.0 mmol scale with 2.2 equiv of
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d
(see Supporting Information). Reaction carried out on 10 mmol scale.
e Reaction carried out using 10 mol % catalyst. f Reaction carried out with
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2′-methylacetophenone was carried out on 10 mmol scale (96%
yield, 98% ee) and the catalyst recovered in 96% yield by silica
gel chromatography (entry 4).
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(17) Riu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384-5387.
High enantioselectivities have been obtained only in cyanosil-
ylation of carbonyl substrates bearing one sp2-hybridized substitu-
ent.22 While the mechanism of catalysis with 3d remains under
investigation, electronic, rather than steric, differentiation of the
two ketone substituents is implicated strongly as the source of
asymmetric induction (compare entries 1-3 and 14-15).23 The
critical role of the Brønsted basic amine moiety in combination
with the thiourea unit suggests a cooperative mechanism for 3d
involving simultaneous nucleophile and electrophile activation.24
Thiourea 3d represents one of the most effective and general
carbonyl cyanation catalysts identified to date. Current work is
directed toward elucidating the mechanism of carbonyl activation
and discovering other carbonyl addition reactions catalyzed by chiral
thiourea derivatives.
(18) For a complete list of all urea and thiourea catalysts examined see the
Supporting Information.
(19) The role of the alcohol additive is presumably to generate HCN as the
active nucleophile in the addition reaction, as is the case in thiourea-
catalyzed Strecker reactions (ref 4). For other examples of the beneficial
effect of alcohol additives on cyanosilylation of carbonyls see: (a) Hayashi,
M.; Matsuda, N.; Oguni, N. J. Chem. Soc., Perkin Trans. 1 1992, 3135-
3140. (b) Brunel, J. M.; Legrand, O.; Buono, G. Tetrahedron: Asymm.
1999, 10, 1979-1984. (c) Reference 15d.
(20) The corresponding N,N-di-n-butylamine- and N,N-di-n-pentylamine-
substituted catalysts afforded comparable conversion to 3d, but with
slightly lower enantioselectivity (95%).
(21) For the preparation of 3d, see the Supporting Information.
(22) Dialkyl ketones are poor substrates in cyanosilylation reactions with 3d:
2-heptanone, 11% ee; cyclohexyl methyl ketone, <5% conversion.
(23) Ketone enantioface selectivity dictated solely by electronic differentiation
is well-precedented: (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995,
36, 9153-9156. (b) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M.
Tetrahedron 2004, 60, 10497-10504.
Acknowledgment. This work was supported by the NIGMS
through GM-43214 and P50 GM069721. We thank Mark S. Taylor
for helpful discussions.
(24) The cyclohexylamine-derived analogue of 3d, which lacks the tertiary
amine group, displayed no reactivity under the standard conditions.
Supporting Information Available: Complete experimental pro-
cedures, characterization data, and chiral chromatographic analyses of
JA052511X
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