Catalytic asymmetric protonation of silyl ketene imines

Article abstract of DOI:10.1021/ja312141b

An efficient catalytic and highly enantioselective protonation of silyl ketene imines is described. The reaction is catalyzed by the chiral phosphoric acids TRIP or STRIP in the presence of a stoichiometric amount of methanol as the proton source and silyl acceptor. A variety of substituted racemic silyl ketene imines have been transformed into highly enantioenriched nitriles.

Full text of DOI:10.1021/ja312141b

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Protonation of Silyl Ketene Imines
Joyram Guin, Georgy Varseev, and Benjamin List*
Max-Planck-Institut fur Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
Lewis acid mediated asymmetric Mannich reactions of SKIs
with acylhydrazones have been described by Leighton et al.14
We have recently introduced chiral disulfonimides (DSI) as
highly active and enantioselective pre-Lewis acid catalysts of
silicon-transfer-based carbon−carbon-bond forming reac-
tions.15 In the context of these studies, we also became
interested in exploring SKIs as nucleophiles. We quickly
realized that, in the presence of our DSI catalysts and diverse
electrophiles, often a small amount of the SKI underwent
decomposition to the parent nitrile. Remarkably, the obtained
material was enantioenriched implying participation of the
chiral catalyst. On the basis of this observation, we envisioned
that an enantioselective protonation of racemic SKIs could
possibly be occurring. Since asymmetric protonations of SKIs
had not been reported before and in light of the high synthetic
value of enantioenriched α-branched nitriles, we decided to
further investigate this remarkable transformation.
We began our studies by investigating the protonation of SKI
1a in the presence of a variety of chiral Brønsted acid catalysts
and methanol as a proton source (Table 1).16 A catalytic
amount of DSI-catalyst 2 (5 mol %) indeed promoted the
reaction in the presence of 1.2 equiv of methanol. Complete
conversion of imine 1a in a mixture of pentane and toluene at
room temperature was obtained in 2 h, but a very low
enantiomeric ratio (60:40 er) was observed (entry 1). We also
investigated alternative chiral acids including several BINOL-
derived phosphoric acids (3,4) and the spirocyclic variation
STRIP (5).17−19 The H8-BINOL phosphate 3 and BINOL
phosphates 4a and 4b with 3,5-(CF3)2C6H3- and 3,5-
(SF5)2C6H3-substituents proved to be highly active, but again,
only poor enantioselectivity was obtained (entries 2−4). SiPh3-
substituted catalyst 4c enabled the reaction with a promising
enantiomeric ratio (e.r.) of 77:23 (entry 5). A significant
improvement was obtained by using commercially available
TRIP (4d) (e.r. = 92:8, entry 6). Even slightly better
enantioselectivity (96:4 er) was achieved when using 5 mol %
of STRIP (5, entry 7). Importantly, the catalyst loading could
be reduced to only 2.5 mol % with catalyst 5 without erosion of
enantioselectivity and yield (entry 8). Decreasing the catalyst
loading further to 1 mol % was detrimental (entry 9). Even with
TRIP, excellent enantioselectivity could be achieved when the
reaction temperature was lowered to −78 °C (e.r. = 96:4, entry
10). However, the catalyst loading could not be further reduced
with this catalyst (entry 11). SKIs with different silicon
protecting groups were also prepared but gave inferior results
(entries 12, 13).
ABSTRACT: An efficient catalytic and highly enantiose-
lective protonation of silyl ketene imines is described. The
reaction is catalyzed by the chiral phosphoric acids TRIP
or STRIP in the presence of a stoichiometric amount of
methanol as the proton source and silyl acceptor. A variety
of substituted racemic silyl ketene imines have been
transformed into highly enantioenriched nitriles.
he nitrile functional group is a pharmacophore in
1
Tbiologically active compounds and a versatile precursor
of other functionalities such as carboxylic acids, ketones,
aldehydes, and amines.2 Enantiopure α-alkyl-α-arylnitriles are
particularly important as the corresponding carboxylic acids
have extensively been used as nonsteroidal anti-inflammatory
drugs.3 While few catalytic asymmetric syntheses of α-branched
nitriles have been reported, including olefin hydrocyanations,4
conjugate cyanations,5 and Negishsi cross-couplings,6 a mild,
organocatalytic approach may constitute an attractive and
complementary alternative. Herein we describe an efficient
catalytic and enantioselective protonation of silyl ketene imines
(SKIs), which are readily available from racemic nitriles. Our
method offers a straightforward entry to enantioenriched
secondary nitriles under mild reaction conditions (eq 1).
The asymmetric catalytic protonation of cyclic ketone-
derived enol silanes has been well investigated.7 However,
analogous protonations of enolsilanes derived of acyclic ketones
and carboxylic acid derivatives remain challenging.8,9 We
hypothesized that SKIs, which are easily obtained from the
corresponding branched nitriles via deprotonation and
silylation, and known to easily racemize,10a may undergo an
asymmetric protonation generating the corresponding enantio-
pure nitriles via dynamic kinetic resolution. Asymmetric
protonations of SKIs had previously been entirely unknown.
SKIs are currently being established as highly useful carbon
nucleophiles that have been employed in the construction of
challenging all-carbon quaternary stereogenic centers.10 While
the synthetic potential of SKIs is well appreciated,11 their use in
asymmetric catalysis has not been extensively studied. Fu et al.
described a catalytic asymmetric acylation of SKIs using a chiral
DMAP-type catalyst.12 Their implementation in chiral Lewis
base catalyzed asymmetric aldol reactions with aldehydes has
been reported by the Denmark group.13 Recently, chiral silicon
Received: December 12, 2012
Published: January 30, 2013
© 2013 American Chemical Society
2100
dx.doi.org/10.1021/ja312141b | J. Am. Chem. Soc. 2013, 135, 2100−2103

Journal of the American Chemical Society
Communication
a
a b c
, ,
Table 1. Catalyst Identification and Reaction Optimization
Table 2. Substrate Scope
a
Unless otherwise specified, all reactions were carried out at 0.1 mmol
scale of SKI 1a at room temperature in a 15:1 (v/v) mixture of
b
pentane and toluene. Reactions were performed at 0.2 mmol scale of
c
d
SKIs 1a-c. Reactions were performed at −78 °C. Determined by 1H
e
f
NMR analysis. Isolated yield. Enantiomeric ratio (e.r.) determined by
HPLC analysis on a chiral stationary phase. TBS = Dimethyl-tert-
butylsilyl. TIPS = Triisopropylsilyl. TES = Triethylsilyl.
We then directed our attention toward exploring the reaction
scope with different substituted SKIs. Several TBS-protected
SKIs with varying substituents at both the alkyl and aryl moiety
were prepared from the corresponding nitriles using literature
procedures (see Supporting Information (SI)).12,13c Either one
or the other of the two best reaction conditions, with 2.5 mol %
of STRIP at room temperature (condition A) or 5 mol % of
TRIP at −78 °C (condition B), was used. A broad range of
SKIs could be converted to the corresponding nitriles 34−60 in
high yields with good to excellent enantioselectivity (Table
2).20 Electron-rich SKIs bearing para-, meta-, and ortho-
methoxy substituted phenyl moieties delivered the correspond-
ing nitriles 34−37 in good yields (82−85%) and enantiomeric
ratios (94:6−96:4 er). Electron-deficient SKIs with a fluoro,
chloro, and bromo substituent at the phenyl ring were equally
well tolerated. Ester and ketone functionalized nitriles 43 and
44 were obtained with slightly lower enantioselectivity.
a
All reactions were carried out at 0.2 mmol scale of SKIs (7−33) in a
15:1 (v/v) mixture of pentane and toluene (8.0 mL, 0.025 M).
b
c
Isolated yield. Enantiomertic ratio (e.r.) determined by HPLC on a
d
chiral stationary phase. Enantiomertic ratio determined by GC on a
chiral stationary phase.
Gratifyingly, nitriles 45−47 with para-, meta-, and ortho-alkyl
substituents at the phenyl ring could also be obtained in good
yields (88−95%) and with good to excellent enantioselectivity
(90:10→99:1 er). A sterically demanding substrate bearing a
3,5-di-tert-butyl substituted phenyl moiety gave the desired
product 48 in excellent enantioselectivity (97:3 er). Thiophene
2101
dx.doi.org/10.1021/ja312141b | J. Am. Chem. Soc. 2013, 135, 2100−2103

Journal of the American Chemical Society
Communication
substituted SKIs could also be transformed efficiently to the
corresponding highly enantioenriched products 49−50. Naph-
thyl-substituted SKIs gave products 51−52 in slightly lower
enantioselectivity.
Scheme 2. Proposed Catalytic Cycle
We further expanded the utility of our reaction toward the
synthesis of highly enantioenriched α-alkyl-α-arylnitriles
bearing longer n-alkyl and α-branched alkyl substituents.
Indeed, nitriles 53−56 with ethyl and propyl substituents
could be prepared with good to excellent enantiocontrol.
Remarkably, sterically demanding α-branched alkyl substituted
racemic SKIs underwent an efficient protonation and furnished
nitriles 57−58 in good yields (90−97%) with an excellent
enantiomeric ratio of 98:2. α,α-Dialkyl substituted SKIs were
also examined in our transformation. Unfortunately, the
corresponding nitriles 59−60 were formed only in moderate
enantioselectivity under the optimized reaction conditions.
Absolute configurations of compounds 6 and 53 [both (S)]
were determined by comparing the optical rotation with
literature data (see the SI), and absolute configurations of all
others compounds were assigned by analogy.21
To illustrate the practical utility of our reaction, a preparative
scale experiment was performed. Accordingly, 1.8 g of SKI 61
was subjected to our catalytic asymmetric protonation protocol
and gave 0.83 g of corresponding nitrile 62 in 70% yield with an
e.r. of 93:7. A single recrystallization improved the e.r. to 98:2
(Scheme 1). The nitrile 62 was then transformed to the anti-
inflammatory drug Cicloprofen 63 in good yield with a high
enantiomeric ratio of 97:3.
stoichiometric proton source adds to the potential practical
value of our method. Several functionalized α-alkyl-α-
arylnitriles with varying substituents at both aryl and alkyl
chains were obtained in good yields and with excellent
enantioselectivity. A gram scale experiment has been performed
to illustrate practical aspects, and a mechanism has been
suggested.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
list@kofo.mpg.de
■
Scheme 1. Gram Scale Experiment and Enantioselective
Synthesis of Cicloprofen
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge generous financial support from the
Max-Planck-Society, the European Research Council (Ad-
vanced grant “High Performance Lewis Acid Organocatalysis,
HIPOCAT”), and the Alexander von Humboldt Foundation
(fellowship for J.G.).
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In order to obtain an insight into the reaction mechanism,
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