Oxidative γ-addition of enals to trifluoromethyl ketones: Enantioselectivity control via lewis acid/n-heterocyclic carbene cooperative catalysis

Article abstract of DOI:10.1021/ja303618z

An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)₃ or combined Sc(OTf) ₃/Mg(OTf)₂] and NHC cooperative catalysis.

Full text of DOI:10.1021/ja303618z

Communication
pubs.acs.org/JACS
Oxidative γ-Addition of Enals to Trifluoromethyl Ketones:
Enantioselectivity Control via Lewis Acid/N-Heterocyclic Carbene
Cooperative Catalysis
Junming Mo,† Xingkuan Chen,† and Yonggui Robin Chi*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
γ-activation of α,β-unsaturated ketenes mediated by cinchona
ABSTRACT: An oxidative γ-functionalization of enals
under N-heterocyclic carbene (NHC) catalysis to give
unsaturated δ-lactones is disclosed. Enantioselectivity
control involving the relatively remote enal γ-carbon was
achieved via Lewis acid [Sc(OTf)3 or combined Sc-
(OTf)3/Mg(OTf)2] and NHC cooperative catalysis.
alkaloid and NHC-based nucleophilic catalysts was reported by
the groups of Peters and Ye.8 Our present work constitutes the
first study of NHC-catalyzed oxidative γ-functionalization of
enals.
The oxidation of enals to the corresponding α,β-unsaturated
esters as Michael acceptors under NHC catalysis has been
pioneered by the groups of Scheidt, Studer, You, and Gois.9 In
our reactions, the substituent at the enal β-carbon, introduced
to suppress typical NHC-catalyzed enal reactions,2−4,6 also
prevented the oxidatively generated unsaturated ester inter-
mediates from behaving as Michael acceptors. The seminal
work on NHC/Lewis acid co-operative catalysis is from Scheidt
and co-workers.10 In 2010, they found that Ti(OiPr)4 as a Lewis
acid could induce diastereoselectivity switching in NHC-
mediated reactions of enal homoenolates with chalcones.10a
They also reported that the Lewis acid [Mg(OtBu)2] could
induce relatively small (e.g., from 72 to 86%) but consistent
enantioselectivity improvements in NHC-catalyzed additions of
enal homoenolates to hydrazones.10b In 2011, the You group
found that the use of a sodium salt (NaBF4) could significantly
improve the ee of an NHC-catalyzed redox Michael reaction.7e
Very recently, during the preparation of our manuscript,
Scheidt and co-workers reported a large ee enhancement when
LiCl was used as a mild Lewis acid additive in NHC-catalyzed
additions of enal homoenolates to isatines.10c Our work
demonstrates that enantioselective control involving the
relatively remote enal γ-carbon can be nicely achieved through
the introduction of Sc(OTf)3 or Sc(OTf)3/Mg(OTf)2 as a
relatively strong Lewis acid cocatalyst. Sc-based Lewis acids
have been found to be effective in cooperative NHC catalysis
for the first time.
nantioselective activation of nonreactive C−H units that
E
are remote to activating groups is of fundamental and
practical significance but often challenging. Under N-hetero-
cyclic carbene (NHC) catalysis,1 for example, the activation of
enals offers homoenolate,2 enolate,3 and acyl anion equivalents4
for enantioselective reactions.5 These reactions primarily
involve β, α, and carbonyl carbons, respectively, as the
prenucleophiles.2−5 The activation of enal γ-carbons via NHC
catalysis, on the other hand, poses significant challenges and
remains underdeveloped. Examples of the apparent difficulties
in NHC-mediated γ-functionalization of enals include (a)
difficulties in activating the enal γ-carbons as nucleophiles; (b)
competing reactions of the homoenolate, enolate, and acyl
anion intermediates; and (c) the fact that chiral information
from the NHC catalyst may be relatively remote from the enal
γ-carbon, making stereocontrol difficult. Here we report the
first enantioselective γ-addition of enals to activated ketones via
oxidatively generated NHC-bounded vinyl enolate intermedi-
ates (eq 1). The typical NHC-mediated enal reactions,2−4,6
We first set out to develop an oxidative γ-addition of enals 1
to trifluoroacetophenone (2a) for the synthesis of unsaturated
δ-lactones 3. Quinone 4, previously explored in NHC-catalyzed
oxidations,9 was found to be a good oxidant in our studies. Not
surprisingly, β-monosubstituted enals (such as crotonaldehyde)
were not effective because of competing typical NHC-mediated
enal reactions2−4,6 such as those involving the homoenolate4
nucleophiles. Fortunately, the use of enal 1a, obtained by
installing a phenyl group at the β-position of butenal, afforded
the desired γ-addition and cyclization product 3a in 70%
such as those involving homoenolate intermediates as the
nucleophiles, were suppressed by introducing one substituent at
the enal β-carbon. The high enantioselectivity (∼90% ee) was
achieved via NHC and Sc- or Sc/Mg-based Lewis acid
cooperative catalysis. In the absence of the Lewis acid
cocatalyst, only 5−23% ee was observed in all cases. The
Lewis acid cocatalyst assists the stereocontrol at the enal γ-
carbon presumably by coordinating with the reaction partners
(eq 1). As an important note, relevant γ-functionalization of
some enals was previously realized via dienamine catalysis,7 and
Received: April 16, 2012
Published: May 9, 2012
© 2012 American Chemical Society
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Communication
isolated yield using NHC precatalyst A (Table 1, entry 1). We
next attempted to develop enantioselective catalysis by using
(entries 7−13). The use of the NHC and Lewis acid in 1:1
molar ratio gave optimal results in terms of both reaction yield
and enantioselectivity. Ethers were good solvents, and
tetrahydrofuran (THF) was the best among the solvents
screened in this study.11 It is worth noting that in the presence
of Sc(OTf)3, catalysts B (N-Ph) and C (N-Mes) showed similar
enantioselectivities (entries 7 and 8). Among the other Lewis
acids screened [Mg(OTf)2, Ti(OMe)4, ScCl3, Mg(OtBu)2,
MgSO4] that afforded good conversions, Mg(OTf)2 was the
only other one that offered similar benefits in remote
enantioselective control (entry 10). We next found that
Table 1. Development of the Oxidative Cooperative
a
Catalytic γ-Functionalization of Enals
12
K2CO3 was superior to Cs2CO3 and that catalyst C was
slightly better than B with K2CO3, affording 3a with 88% ee in
72% yield (entry 12). The combined use of the two effective
Lewis acids [Mg(OTf)2 and Sc(OTf)3, 10 mol % each] offered
a small (∼3%) but consistent additional ee enhancement (entry
13), for reasons that are unclear at this point. When the
reaction was carried out at 0 °C over a longer reaction time (48
h) in the presence of C and the two Lewis acid cocatalysts,
product 3a was obtained in 81% isolated yield and 94% ee
(entry 15). The exact mode of cooperative catalytic activation
remains unknown (also see Scheme 1).
Having established an optimal protocol for the reaction, the
scope of the enal substrate reacting with ketone 2a was
examined (Chart 1). To demonstrate the generality of the
Lewis acid effects, the ee’s of the products formed in the
presence and absence of the Lewis acid cocatalysts are included
for all of the reactions. Both electron-donating (3b and 3c) and
‑withdrawing (3d and 3e) substituents on the β-phenyl unit
b
c
entry NHC
Lewis acid
base
yield (%)
ee (%)
1
2
A
B
C
D
E
−
−
−
−
−
−
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
70
50
63
−
<5
67
52
64
−
59
55
72
69
84
81
−
21
29
−
3
4
5
−
6
C
B
C
E
16
64
73
−
60
55
88
91
91
94
7
Sc(OTf)3
8
Sc(OTf)3
9
Sc(OTf)3
10
11
C
C
C
C
C
C
Mg(OTf)2
Mg(OTf)2
12
Sc(OTf)3
d
13
Sc(OTf)3/Mg(OTf)2
Sc(OTf)3
e
14
de
a
,
Chart 1. Variation of the Enal 1
15
Sc(OTf)3/Mg(OTf)2
a
Reaction conditions: 1a (0.15 mmol), 2a (0.15 mmol), 4 (0.15
mmol), solvent (1.5 mL). Reaction times: entries 1−6, 12 h; entries
b
7−13, 24 h; entries 14 and 15, 48 h. Isolated yields based on 2a.
c
Enantiomeric excess of 3a, determined via chiral-phase HPLC
analysis. The absolute configuration was assigned on the basis of a
comparison of the optical rotation of 3a with the literature value:
observed, [α]2D0 = −80.3° (10 mg/mL, CHCl3); literature value, [α]D25
d
= −73.2° (10 mg/mL, CHCl3).8d Sc(OTf)3 (10 mol %), Mg(OTf)2
e
(10 mol %). 0.18 mmol of 1a at 0 °C; under these conditions without
Lewis acid, the product was obtained in 19% ee.
chiral NHCs that were previously found to be successful in the
related homoenolate, enolate, and acyl anion reactions. The
aminoindanol-based catalysts B and C could catalyze the
reactions in only 16−29% ee after extensive optimization with
respect to typical parameters such as base, solvent, and
temperature (entries 2, 3, and 6). Relatively bulky triazolium
compounds D and E led to little or no formation of 3a under
oxidative NHC catalysis (entries 4 and 5).
Instead of modifying the NHC catalysts, we decided to
introduce a second catalyst to interact with either or both of the
reaction partners (the ketone and the vinyl enolate
intermediate; see eq 1 or Scheme 1). Our efforts with chiral
hydrogen-bond-donating catalysts (e.g, thioureas, tartaric acids,
and BINOL derivatives) were unsuccessful. Encouraging results
emerged when Sc(OTf)3 was used as a Lewis acid cocatalyst.
The product ee jumped from 29 to 73% in the presence of
Sc(OTf)3 with C as the NHC precatalyst and Cs2CO3 as the
base (Table 1, entry 8 vs 3). The reaction with NHC
precatalyst B showed a similar ee enhancement (entry 7). In
general, the addition of the Lewis acid cocatalyst led to slower
reactions, and a longer reaction time (24 h) was necessary
a
b
Similar conditions as in Table 1, entry 15. The ee for the reaction
without the presence of the Lewis acid under otherwise identical
conditions is given in parentheses.
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were tolerated. Replacing the β-phenyl substituent with a
naphthyl (3f) or heteroaryl (3g−i) unit did not significantly
change the reaction yield or ee. When the β-aryl group of the
enal was changed to a vinyl substituent (3j and 3k), a slight
decrease in enantioselectivity to 77−79% ee was observed.
Replacing the β-phenyl group in enal 1a with an alkyl
substituent or the β-methyl unit of 1a with a longer carbon
unit (e.g., an ethyl group) led to little conversion to the δ-
lactone product. Instead, self-redox of the enal leading to the
corresponding carboxylic acid was observed as the major
reaction pathway.
Scheme 1. Postulated Reaction Pathway
The scope of the activated ketone substrate was also
examined (Chart 2). All of the (hetero)aryltrifluoroacetones
a
Chart 2. Variation of the Ketone 2
3a.13 The Sc(III) Lewis acid, which is known to have good
affinities for carbonyl oxygens and carboxylates,14 likely is
involved in multisite coordination to bring the ketone
electrophile into close proximity with intermediate III and
the chiral NHC catalyst, as illustrated by IV.15 This
coordination amplifies the otherwise weak chiral induction by
the chiral NHC catalyst.
In summary, we have disclosed the first oxidative generation
of vinyl enolates for γ-functionalization of enals under NHC
catalysis. The challenging remote chiral control was realized
through the introduction of a Lewis acid cocatalyst. Mechanistic
details, functionalization of less reactive sites of common
substrates such as enals and simple aldehydes, and further
exploration of the use of cooperative catalysis for remote
asymmetric control are under study in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
a
b
Similar conditions as in Table 1, entry 15. The ee for the reaction
without the presence of the Lewis acid under otherwise identical
conditions is given in parentheses.
AUTHOR INFORMATION
Corresponding Author
robinchi@ntu.edu.sg
■
examined in this work reacted well with good enantioselectiv-
ities. For example, installing a methyl (3l), bromo (3m), or
chloro (3n) on the phenyl unit of ketone 2a did not affect the
reaction outcome. Switching the phenyl group of 2a to a
heteroaryl substituent (3o) led to excellent results as well (75%
yield, 90% ee). Very encouragingly, replacing the aryl group of
ketone 2a with an alkyl substituent [methyl (3p), ethyl (3q)]
also led to effective reactions, albeit with decreased yields and
ee’s. Switching the phenyl group in 2a to an electron-
withdrawing ester unit (3r) afforded a good yield (65%) but
decreased enantioselectivity (60% ee) without further opti-
mization of this particular substrate.
Author Contributions
†J.M. and X.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support for this work was provided by
Singapore National Research Foundation, Singapore Economic
Development Board (EDB), GlaxoSmithKline (GSK), and
Nanyang Technological University. We also appreciate the
thoughtful comments from the referees.
A postulated reaction pathway is illustrated in Scheme 1. The
vinyl enolate intermediate (III) likely comes from γ-
deprotonation of the oxidatively generated unsaturated ester
intermediate (II), although direct oxidation of the enal γ-
carbon of the homoenolate intermediate I leading to III cannot
be completely ruled out. Vinyl enolate III then undergoes
nucleophilic addition to ketone 2a, eventually affording product
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78%; t-BuOMe, 83%; (n-Bu)2O, 54%; DME, 56%; 2,2,5,5-tetramethyl-
THF, 70%.
(12) The ee values for reactions using different bases: LiOH, 55%;
Na2CO3, 81%; NaHCO3, 84%; K2CO3, 88%; KOAc, 85%; K2HPO4,
85%; Et3N, low conversion, 14% ee. Organic bases (DBU, DMAP,
DABCO) gave little formation of 3a.
(13) A concerted pathway for this transformation (from IV to 3a)
cannot be ruled out.
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(15) For instance, the addition of acetate anions (1.0 equiv of
Bu4N+Ac−) to the reaction mixture (identical to that for Table 1, entry
13) led to a decreased ee of 79%, presumably due to competing
binding of the Lewis acid with Ac− vs the reaction partners (2a or III,
Scheme 1).
(6) For additional examples of NHC-mediated enal reactions, see:
(a) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org.
Lett. 2006, 8, 507. (b) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J.
Am. Chem. Soc. 2007, 129, 3520. (c) Chan, A.; Scheidt, K. A. J. Am.
Chem. Soc. 2007, 129, 5334. (d) Seayad, J.; Patra, P. K.; Zhang, Y.;
Ying, J. Y. Org. Lett. 2008, 10, 953. (e) Yang, L.; Tan, B.; Wang, F.;
Zhong, G. J. Org. Chem. 2009, 74, 1744.
(7) For selected examples of dienamine catalysis, see: (a) Bertelsen,
́
S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem.
Soc. 2006, 128, 12973. (b) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Huang, G.-F.; Su, C.-F.; Liao, J.-J. J. Org. Chem. 2007, 72, 8459.
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