Lewis base catalyzed enantioselective additions of an N-silyl vinylketene imine

Article abstract of DOI:10.1002/anie.201108795

Outside the limits: In the title reaction the nucleophile 1 represents a synthetic equivalent of nucleophilic allylic nitriles and addresses some of the current limitations associated with reactions of allylic nitrile anions. Unsaturated nitriles containi

Full text of DOI:10.1002/anie.201108795

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DOI: 10.1002/anie.201108795
Asymmetric Catalysis
Lewis Base Catalyzed Enantioselective Additions of an N-Silyl
Vinylketene Imine**
Scott E. Denmark* and Tyler W. Wilson
The anions derived from metalation of allylic nitriles repre-
sent a promising class of nucleophiles for carbon–carbon bond
formation. The reactions of these species with electrophiles
can proceed through either a or g addition and provide access
to synthetically useful building blocks containing nitrile and
alkene functional groups (Scheme 1). Achieving high site
brønsted base, and a chiral phosphine ligand to achieve
activation/deprotonation of allyl nitrile. The enantioselective
addition of the resulting metalated nitrile to ketoimines[3a]
and aromatic ketones[3b,c] occurs with good yields, high site
selectivities, and moderate to high enantioselectivities.
Although this example represents an important advance for
asymmetric additions of this nucleophile class, the scope has
been limited to the reaction of allyl nitrile with carbonyl
compounds that do not readily undergo base-mediated self-
condensation reactions.[4] The reactions of allylic nitrile
nucleophiles with aldehydes remain an unsolved problem.
An alternative strategy for creating nucleophilic allylic
nitriles that avoids the use of anionic intermediates is to
employ N-silyl vinylketene imines (2; see Scheme 2). These
compounds could be prepared by selective N silylation of
allylic nitrile anions. Utilization of these nucleophiles in
catalytic, enantioselective, vinylogous aldol reactions would
generate d-hydroxy a,b-unsaturated nitriles (Scheme 2). The
Scheme 1. Activation and electrophilic trapping of allylic nitriles.
DMSO=dimethylsulfoxide.
Scheme 2. Vinylogous aldol reaction of N-silyl vinylketene imines.
selectivity in these reactions presents a significant challenge
for reaction development, especially when considering the
number of metalated intermediates that can form upon
activation of the allylic nitrile. Notable progress has recently
been made in site-selective additions of allyl and crotyl
nitriles to carbonyl compounds using pro-azaphosphatranes[1]
and palladium/pincer[2] catalysts. Despite these advances, and
the utility that nucleophilic allylic nitriles offer in carbon–
carbon bond-forming reactions, enantioselective processes
involving these species are rare.
synthetic benefit of unsaturated nitriles has been highlighted
by their ability to undergo new carbon–carbon bond-forming
reactions with organometallic compounds[5] as well as allow-
ing access to a,b-unsaturated aldehydes,[6] carboxylic acid
derivatives, and allylic amines through manipulation of the
nitrile.[3c] Interestingly, the vinylogous Mukaiyama aldol
reaction, which is a well-established method for controlling
site and stereoselectivity in the addition of ketone, ester, and
amide dienolates, has not previously been reported for
nitriles.[7] Herein, we describe a new approach for generating
nucleophilic allylic nitriles, through the intermediacy of a silyl
vinylketene imine, and the subsequent use of these reagents in
enantioselective, vinylogous aldol reactions.
To date, only the catalytic, enantioselective addition of
allyl nitrile has been realized.[3] The method, reported by
Shibasaki and co-workers, involves the cooperative catalytic
action of a soft CuI Lewis acid, a hard lithium alkoxide
The synthesis of silyl ketene imines derived from a,a-
disubstituted nitriles is well documented,[8] and previous
studies from these laboratories,[9] as well as others, have
demonstrated their efficacy in the enantioselective synthesis
of quaternary stereogenic centers.[10] However, only a single
report describes the synthesis and use of N-silyl vinylketene
imines. Ghosez and co-workers reported a method for
converting allyl nitrile into a bis-silyl vinylketene imine by
double deprotonation with lithium diisopropylamide (LDA)
and silylation with excess triisopropylsilyl chloride
(TIPSCl).[11] The resulting vinylketene imine is employed as
[*] Prof. S. E. Denmark, Dr. T. W. Wilson
Department of Chemistry, University of Illinois
Urbana, IL 61801 (USA)
E-mail: denmark@scs.uiuc.edu
Homepage: http://www.scs.uiuc.edu/denmark
[**] Financial support was provided by the National Science Foundation
(NSF CHE-0717989 and 1012663). The authors acknowledge Jeremy
Henle for the preparation of benzyloxy aldehydes.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108795.
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Table 1: Addition of N-silyl vinylketene imine 4 to aliphatic aldehydes.[a–c]
a diene in cycloaddition reactions with acetylenic esters, thus
affording anilines after desilylation and aromatization.
The challenge inherent to the synthesis of N-silyl vinyl-
ketene imines is achieving selective N silylation instead of Ca
or Cg silylation of the metalated allylic nitrile intermediate.
Foregoing studies have documented the tendency of meta-
lated nitriles to undergo competitive C silylation; however,
the use of bulky silylating agents typically results in kinetically
controlled silylation at the less hindered nitrogen atom.[8b,12]
The preliminary work of Ghosez and co-workers on the
synthesis of N-silyl vinylketene imines also supports this
trend.
Entry
1
Product
Yield [%][b]
e.r.[d]
Cognizant of the aforementioned precedents, studies
aimed at the preparation of N-silyl vinylketene imines from
allylic nitrile derivatives were initiated. 2-Methyl-3-butene-
nitrile (3; Scheme 3)[13] was chosen as the pronucleophile
65
95:5
7a
7b
7c
7d
7e
(82)[e]
(95:5)[e]
57
98.5:1.5
(98:2)[e]
2
3
4
5
(86)[e]
82
63
96.5:3.5
98.5:1.5
Scheme 3. Synthesis of N-silyl vinylketene imine 4.
75
92:8
because it is a readily available, inexpensive starting material,
and the methyl substituent at C2 should inhibit competitive
Ca silylation. Through optimization studies, it was found that
the N-silyl vinylketene imine 4 could easily be prepared in
good yield and selectivity by addition of nitrile 3 to a pre-
cooled solution of LDA and TIPSCl (Scheme 3). The result-
ing product was isolated as a thermally stable liquid that could
be purified by distillation and handled in air without
significant hydrolysis. When stored at À108C, 4 showed no
signs of decomposition even after storage for eight months.
Earlier reports from these laboratories have shown that
silyl ketene imines are susceptible to Lewis base catalyzed,[14]
SiCl4-mediated carbonyl addition reactions. In general, the
reactions are characterized by high yields and excellent
stereoselectivities and have provided novel methods for the
preparation of quaternary stereogenic carbon centers,[9a]
tertiary alcohols,[15] and cross-benzoin products.[15] One
major limitation for silyl ketene imine additions with this
catalyst system has been the difficulty of engaging aliphatic
aldehydes. The reaction of disubstituted silyl ketene imines
with aliphatic aldehydes has been thwarted by the added
strain energy that accrues from the formation of a quaternary
carbon center as well as the reduced reactivity observed for
aliphatic aldehydes in Lewis base catalyzed, SiCl4-mediated
aldol reactions.[16] We postulated that N-silyl vinylketene
imines would be able to react with aliphatic aldehydes
through the g-carbon atom of the ketene imine because this
site is relatively free of steric encumbrance. To test this
hypothesis, 4 was combined with hydrocinnamaldehyde using
reaction conditions similar to those reported previously for
Lewis base catalyzed, vinylogous aldol additions of enoxy-
silanes.[17] Gratifyingly, the reaction afforded selectively the
E-g-addition product 7a in moderate yield and with excellent
enantioselectivity (Table 1, entry 1). Further analysis
revealed that the moderate yield observed in the addition
(81)[e]
(90:10)[e]
55
88:12
6
7 f
(86)[e]
(87:13)[e]
7
8
7g
7h
74
90:10
54
77.5:22.5
(76:24)[e]
(78)[e]
[a] 1.0 mmol scale reaction. [b] Yields are for constitutionally and
analytically pure material. [c] g/a and E/Z ratios determined by 1H NMR
analysis of crude reaction mixtures. [d] Enantiomeric ratios determined
by CSP-SFC analysis. [e] Reaction performed at À558C.
resulted from incomplete consumption of the aldehyde. This
problem could be eliminated at slightly elevated reaction
temperatures (À558C) and nitrile 7a was isolated in a syn-
thetically useful yield and comparable enantioselectivity.
Other aliphatic aldehydes were also tested to explore the
substrate generality with regard to substitution pattern.
Overall, the addition was highly selective for formation of
E-a,b-unsaturated nitriles in moderate to good yields and
with good to excellent enantioselectivities. Aldehydes con-
taining b branching gave nitrile products 7a–c with the
highest levels of enantiomeric purity whilst aldehydes con-
taining a linear aliphatic chain, reacted with slightly reduced
enantioselectivity (Table 1, entries 5–8). Surprisingly, an even
more hindered aliphatic aldehyde containing a branching
underwent addition to give the E-a,b-unsaturated nitrile 7d in
moderate yield and excellent enantioselectivity (Table 1,
entry 4). The addition of 4 to aliphatic aldehydes containing
either isolated olefins or benzyloxy ethers were also tested.
The resulting g-nitrile products 7 f–g were obtained with
excellent site selectivity and good yields and stereoselectiv-
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Table 3: Addition of N-silyl vinylketene imine 4 to aromatic aldehydes.[a]
ities. However, for aldehydes containing ethereal linkages, the
enantioselectivity was sensitive to the position of the oxygen
atom in the alkyl side chain (Table 1, compare entries 7 and
8).
To further elaborate the scope of the electrophiles in this
reaction, a survey of a,b-unsaturated aldehydes was con-
ducted. These reaction partners present an additional chal-
lenge because the catalyst must control the site selectivity for
addition of both the nucleophile (g versus a) and the
electrophile (1,4 versus 1,2). Initial rate studies using in situ
IR monitoring showed a rapid consumption of the starting
material (see the Supporting Information), thus allowing
a dramatic reduction in the overall reaction time. Under these
modified reaction conditions, the addition of 4 to cinnam-
aldehyde was studied (Table 2, entry 1). Analysis of the crude
Entry
Product
Yield g/a[c] Stereo-
[%][b]
selectivity[c,d]
99:1 E/Z
93.5:6.5 e.r.
1
2
3
11a
11b
11c
97
98:2
99:1
95:5
99:1 E/Z
93:7 e.r.
97
85
87
93
92
92
95
93:7 E/Z
60:40 e.r. (E)
94:6 e.r. (Z)
1
reaction mixture by H NMR spectroscopy showed excellent
Table 2: Addition of N-silyl vinylketene imine 4 to aromatic enals.[a]
98:2 E/Z
92:8 e.r.
4
5
6
7
8
11d
11e
11 f
11g
11h
96:4
99:1
99:1
95:5
98:2
99:1 E/Z
97:3 e.r.
97:3 E/Z
93:7 e.r.
Entry
Product
Yield 1,2/ E/Z[c] e.r.[d]
[%][b] 1,4[c]
98:2 E/Z
94.5:5.5 e.r.
1
2
3
4
9a
9b
9c
9d
84
79
79
83
92:8
92:8
99:1 92:8
98:2 93:7
98:2 E/Z
92.5:7.5 e.r.
98:2 E/Z
91.5:8.5 e.r.
9
11i
11j
91
93
97:3
92:8
90:10 94:6 94:6
99:1 E/Z
77:23 e.r.
10
92:8
99:1 92:8
[a] 1.0 mmol scale reaction. [b] Yields are for the isolated, constitution-
ally and analytically pure material. [c] g/a and E/Z ratios determined by
1H NMR analysis of crude reaction mixtures. [d] Enantiomeric ratios
determined by CSP-SFC analysis.
[a] 1.0 mmol scale reaction. [b] Yields are for the isolated, constitution-
ally and analytically pure material. [c] g/a and E/Z ratios determined by
1H NMR analysis of crude reaction mixtures. [d] Enantiomeric ratios
determined by CSP-SFC analysis.
constitutional site selectivity for g attack of nucleophile 4 to
the carbonyl group of the enal (1,2-addition), thus producing
diene 9a in good yield and enantioselectivity. In view of this
promising result, other commercially available aromatic enals
were evaluated in the reaction and the diene products were
isolated in good yield. Electron-rich and electron-poor
aromatic enals underwent addition with similar rates yielding
diene products in excellent E/Z selectivity and good site and
enantioselectivity (Table 2, entries 2–4).
To investigate the generality of the vinylogous aldol
reaction with respect to aromatic aldehydes, various electron-
rich, electron-poor, and hindered aromatic aldehydes were
investigated (Table 3). Initial optimization studies revealed
that the catalyst loading could be reduced without significant
loses in the reaction rate or enantioselectivity. Hence, the
addition of 4 to various aromatic aldehydes was investigated
using 2.5 mol% of the Lewis base catalyst (R,R)-6. Electroni-
cally neutral aromatic aldehydes such as benzaldehyde and 2-
naphthaldehyde underwent addition in high yields and good
enantioselectivities (Table 3, entries 1–2). Electron-rich aro-
matic aldehydes exhibited the highest enantiomeric ratios, for
example the addition of
4 to 4-methoxybenzaldehyde
afforded nitrile product 11e in 97:3 e.r. (Table 3, entry 5). In
contrast, electron-poor aromatic aldehydes reacted with
attenuated enantioselectivities (Table 3, entry 9–10), thus
suggesting a competitive achiral background reaction is
ensuing for these more reactive substrates. The lowest
enantioselectivity observed in the survey was for the addition
to the sterically hindered aldehyde 1-naphthaldehyde
(Table 3, entry 3). Interestingly, in this case a significant
disparity was observed in the enantiomeric ratios of the
resulting E and Z nitriles. Previous studies with this catalyst
system have also shown higher observed enantioselectivities
in minor diastereomers, but the difference is typically not as
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dramatic. Importantly, additions to slightly less hindered
aromatic aldehydes, such as 2-methyl benzaldehyde and 2-
methoxybenzaldehyde, yielded nitrile products in good dia-
stereo- and enantioselectivity (Table 3, entries 4 and 7). In
general, unsaturated nitriles derived from selective g addition
of 4 to aromatic aldehydes were obtained in excellent yields
and with good to high enantioselectivities.
Received: December 14, 2011
Revised: January 23, 2012
Published online: February 20, 2012
Keywords: allylic compounds · asymmetric catalysis ·
.
enantioselectivity · ketenes · Lewis bases
The double-bond geometry of the alkene subunit was
unambiguously established to be E by single-crystal X-ray
analysis of compound 11b,[18] which resulted from addition of
4 to 2-naphthaldehyde. Correlation of the E-configured
double bond to nitriles derived from other classes of
aldehydes was confirmed by comparison of the diagnostic
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1
13C and H NMR spectra. The absolute configuration of the
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hydroxy-bearing stereogenic center in the nitrile products was
determined by chemical derivatization to known compounds
and comparison of their optical rotations (see the Supporting
Information). The absolute and relative configurations of the
nitrile products confirm that the N-silyl vinylketene imine 4
undergoes addition to the Re face of the aldehyde in an s-trans
conformation and is congruent with previous studies with this
catalyst system.[16,19] The high selectivity for formation of the
E-configured double bond likely results from unfavorable
steric interactions encountered in the approach of 4 to the
activated Lewis acid/aldehyde complex in an s-cis orientation
(Scheme 4).
[8] a) R. West, G. A. Gornowicz, J. Am. Chem. Soc. 1971, 93, 1714 –
1720; b) D. S. Watt, Synth. Commun. 1974, 4, 127 – 131.
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[13] 2-Methyl-3-butenenitrile, 70% was obtained from TCI America
($0.14/g) and was used without further purification. The
remainder is a mixture of consitutional and geometrical isomers.
All isomers converge to the product through either a or
g deprotonation.
Scheme 4. Proposed open transition structures for rationalization of
the E-configured double bond observed in the nitrile products.
LB=Lewis base.
In conclusion, a novel Lewis base catalyzed, Lewis acid
mediated vinylogous aldol addition of the N-silyl vinylketene
imine 4 has been described. This stable and storable silylated
nucleophile is easily prepared in a single step from 2-methyl-
3-butenenitrile. The Lewis base catalyzed reactions of 4 are
characterized by exceptionally high site selectivity for g addi-
tion to a diverse range of aldehyde acceptors. The resulting
a,b-unsaturated nitriles are obtained in good to high yield and
with excellent selectivity for formation of the E-configured
double-bond isomer. Furthermore, the products could be
prepared in good to excellent enantioselectivity by employing
Lewis base catalyst (R,R)-6 with loadings as low as 2.5 mol%.
Importantly, this method provides an alternative strategy to
existing methods for accessing nucleophilic allylic nitriles,
which allows addition to aldehydes.[3] Ongoing studies are
focused on expanding the scope of this reaction with respect
to the N-silyl vinylketene imine and examining their reactivity
with other classes of electrophiles such as ketones and imines.
[14] S. E. Denmark, G. L. Beutner, Angew. Chem. 2008, 120, 1584 –
1663; Angew. Chem. Int. Ed. 2008, 47, 1560 – 1638.
[15] S. E. Denmark, T. W. Wilson, Nat. Chem. 2010, 2, 937 – 943.
[16] In the presense of silicon tetrachloride and Lewis base, aliphatic
aldehydes form trichlorosilyl chlorohydrins that do not react
with enoxysilane nucleophiles, see: S. E. Denmark, G. L. Beut-
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[18] CCDC 852351 (11b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[19] S. E. Denmark, B. M. Eklov, P. J. Yao, M. D. Eastgate, J. Am.
Chem. Soc. 2009, 131, 11770– 11787.
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