Enantioselective N-Heterocyclic Carbene Catalysis by the Umpolung of α,β-Unsaturated Ketones

Article abstract of DOI:10.1002/anie.201510106

N-Heterocyclic carbene-catalyzed formation of β-anionic intermediates from enones has been employed in the enantioselective synthesis of 2-aryl propionates. The reaction was achievable using a homochiral 4-MeOC₆H₄ morpholinone cataly

Full text of DOI:10.1002/anie.201510106

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International Edition: DOI: 10.1002/anie.201510106
German Edition: DOI: 10.1002/ange.201510106
NHC Catalysis
Enantioselective N-Heterocyclic Carbene Catalysis by the Umpolung
of a,b-Unsaturated Ketones
Yuji Nakano and David W. Lupton*
Abstract: N-Heterocyclic carbene-catalyzed formation of b-
anionic intermediates from enones has been employed in the
enantioselective synthesis of 2-aryl propionates. The reaction
was achievable using a homochiral 4-MeOC6H4 morpholinone
catalyst allowing the first example of enantioselective catalysis
by umpolung of a,b-unsaturated ketones. The reaction is high
yielding, and shows robustness with reasonable generality. A
mechanism is proposed in which the enantiodetermining
protonation is achieved using either hexafluoroisopropanol
or the formed naphthol product.
triggers reactions by the resultant enolate (4).[6] Tautomeriza-
tion to reveal a b-anion is rare and, to our knowledge, unique
to NHC catalysis. Although b-anion 3 was introduced nearly
a decade ago, its utility remains unclear with limited studies
reported to date. Notably Matsuoka[7a,c–g] and Glorius[7b] have
introduced tail-to-tail dimerization of enolates, while Chen
has examined polymerization catalysis via intermediates 3
and 4.[8] Presumably, the paucity of studies on this inter-
mediate, compared to the plethora on the aforementioned
intermediates 1 and 2, is related to challenges in achieving
reaction discovery without triggering reactions of enolate 4,
which are known with NHCs.[6a–d]
C
entral to many N-heterocyclic carbene (NHC)-catalyzed[1]
reactions are the homoenolate (1)[2] or a,b-unsaturated acyl
azolium (2; Figure 1).[3] These form through initial 1,2-
addition to an a,b-unsaturated carbonyl, and have allowed
a wealth of chemical transformations to be discovered. In
contrast, b-azolium ylide 3, a species afforded through 1,4-
addition to a,b-unsaturated carbonyls followed by tautome-
rization,[4] as reported by Fu in 2006,[5] has been largely
overlooked in synthesis. While many nucleophilic catalysts
undergo 1,4-addition to conjugate acceptors, this usually
The underdeveloped chemistry of b-azolium ylide 3,
specifically as it relates to enantioselective catalysis, piqued
our interest in this area. To this end, we envisaged a cyclo-
isomerization of bis-conjugate acceptors (5) to 2-aryl prop-
ionates (6; Eq. 1) as a method to expand knowledge of these
neglected intermediates. Herein, we report the outcome of
these studies, which have allowed the discovery of the first
enantioselective reaction involving the b-anion 3 intermedi-
ate. The reaction provides a method to access 2-aryl
propionates in up to 91:9 e.r. and good yields. Mechanistic
studies, and a discussion of unsuitable substrates, provides
a picture of a reaction balanced between competing side
reactions, and with sensitivity to alcohol-containing additives.
In addition to providing information regarding b-anion 3, the
products contain the 2-aryl propionate motifs found exten-
sively in non-steroidal anti-inflammatory drugs (NSAIDs).[9]
Studies commenced with the preparation of diene 5a
using procedures modified from Gravel.[10] When exposed to
the Enders TPT[11] catalyst, we were pleased to isolate 2-aryl
propionate 6a in 92% yield (Table 1, entry 1). The discovery
of an enantioselective variant proved significantly more
challenging, and commenced with a survey of new and
known chiral catalysts. Based on previous success with
morpholinone-based NHCs,[12] a screen of six catalysts bear-
ing various N-substituents was undertaken (Table 1,
entries 2–7). This approach also reflected observations of
Chen who found that polymerization of acrylate derivatives
was sensitive to the nature of the azolium, and the
N-substitution pattern.[8,13] In this case, N-t-butyl (A1) and
N-C6F5 (A2) were not viable, while N-Mes (A3), N-Ph (A4),
N-4-MeOC6H4 (A5), and N-2,6-(MeO)2C6H3 (A6) all gave
the expected product with moderate enantioselectivity. The
highest selectivity of 74:26 e.r. was obtained with N-4-
MeOC6H4 (A5). Both the yield and the enantioselectivity
were depressed using alternate bases (Table 1, entries 8 and
9). The decrease with KHMDS was striking, and speaks to the
role of the conjugate acid (hexamethyldisilazane) in the
enantiodetermining protonation (see below). Introduction of
Figure 1. Overview of NHC reactions.
[*] Y. Nakano, Prof. Dr. D. W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria (Australia)
E-mail: david.lupton@monash.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510106.
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examined (results not shown),[14] with hexafluoroisopropanol
(HFIP) found to give the greatest improvement in enantio-
selectivity (Table 1, compare entries 6 and 17).[14h] Further
improvement to 87:13 e.r. was achieved by conducting the
reaction at slightly lower temperatures and with 30 mol% A5
(Table 1, entry 18). The reaction could also be achieved with
similar levels of enantioselectivity using 10 mol% catalyst at
408C (Table 1, entry 19).
Table 1: Selected optimizations.
Entry
1[c]
NHC
TPT
Base
Yield[a]
92
e.r.[b]
–
KOtBu
The generality of the reaction was examined initially by
modifying the ester functionality (Table 2). Use of i-Pr and
benzyl esters led to moderate decreases in enantioselectivity.
Similarly, perturbing the electronics of the aryl scaffold with
electron-releasing or -donating substituents decreased the
enantioselectivity (MeO, 79:21 e.r.; Cl, 71:29 e.r.). Extending
the alkyl side chain gave naphthol 6 f in 79:21 e.r., while the
use of non-aryl tethers was tolerated with the cyclopentane
derivative 6g forming in good yield and 81:19 e.r., while the
cyclohexyl variant 6h formed in a 74:26 e.r. The latter result
could be improved to 84:16 e.r. using naphthol 6a as an
additive rather than HFIP. Synthesis of partially saturated
anthracenyl propionate 6i was achieved in 83:17 e.r., while
isomeric 6j formed in 89:11 e.r. This could be improved to
91:9 e.r.[15] when preparing anthracene 6k, while biaryl 6l was
formed with reasonable enantioselectivity and good yield.
While the reaction was robust with substrates in which the
Michael acceptors were linked by annulation, the reaction
was not possible when this functionality was removed. For
2
3
4
5
6
7
8
9
A1, R=t-Bu
A2, R=C6F5
A3, R=Mes
A4, R=Ph
A5, R=4-MeOC6H4
A6, R=2,6-MeO2C6H3
A5, R=4-MeOC6H4
A5, R=4-MeOC6H4
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KHMDS
Cs2CO2
no rx
no rx
65
71
92
43
67
68
–
–
31:69
69:31
74:26
72:28
66:34
71:29
10
B, R=4-MeOC6H4
KOtBu
no rx
–
11
12
13
C1, R=4-MeOC6H4
C2, R=2,6-MeO2C6H3
C3, R=Ph
KOtBu
KOtBu
KOtBu
48
–
70
74:26
–
70:30
Table 2: Scope of the reaction.[a,b]
14
15
16
D1, R2 =Bn
KOtBu
KOtBu
KOtBu
59
69
trace
76:24
68:32
–
D2, R2 =CHPh2
D3, R2 =C(OH)Ph2
additive
17
A5
A5
A5
HFIP[d]
HFIP[d]
HFIP[d]
KOtBu
KOtBu
KOtBu
80
80
80
80:20
87:13
85:15
18[e,f]
19[c,f]
[a] Isolated yield following chromatography. [b] The e.r. was determined
by HPLC with chiral stationary phases. [c] 10 mol% TPT or A5·HBF4 and
base. [d] 1 equiv. [e] 30 mol% A5·HBF4 and base. [f] 408C.
a diphenyl group in the morpholinone scaffold (B) caused the
reaction to fail (Table 1, entry 10), while switching to the
indanol NHCs (C1–3) with the three most promising N-
substituents did not improve the enantioselectivity or yield
(Table 1, entries 11–13). Pyrrolidinone NHCs D1–3 were
examined, with benzyl-substituted catalyst D1 giving the
product with improved enantioselectivity, but modest yield
(Table 1, entry 14), while catalyst D2 decreased selectivity,
and D3 failed to provide 6a (Table 1, entries 15 and 16).
As detailed above the reaction showed significant sensi-
tivity to proton sources. Thus, alcoholic additives were
[a] Isolated yield following chromatography. [b] The e.r. was determined
by HPLC with chiral stationary phases. [c] Without HFIP, with 1 equiv 6a.
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example bis-Michael acceptor 7, rather than undergoing
more, in the absence of HFIP, the ee of naphthol 6a
cyclization, provided dimer 9, presumably through a reaction
analogous to those of Glorius and Matsuoka (Scheme 1,
eq. 3).[7] In addition, increasing the electrophilicity of the
second Michael acceptor, as in ketone 10, diverted the
reaction, with the competing Rauhaut–Currier product 11
being formed (eq. 4).
The sensitivity of the reaction to catalyst loading
prompted an examination of non-linear effects (NLE). In
this case, no NLE was observed (Scheme 2A), implicating
a single equivalent of catalyst A5 in the enantiodetermining
event. An alternate explanation for the sensitivity to catalyst
loading would involve the phenolic product 6 participating in
the enantiodetermining step, and thus the catalyst to substrate
ratio would impact the enantioselectivity. Support for this
scenario can be gleaned from the enhanced enantioselectivity
(84:16 vs. 74:16 e.r.) observed in the formation of 6h using
naphthol 6a as an additive (Table 2, footnote c). Further-
progressively increased from 28% after two minutes, to
54% at reaction completion (Scheme 2B). Reintroduction of
HFIP gave a reaction that proceeded at 70% ee for its
duration. Finally, support for this scenario was obtained when
the cycloisomerization was performed with deuterated sub-
strate d-5a. In addition to deuteration of the phenolic
hydrogen, around 25% deuterium incorporation was
observed at the 2-position (eq. 6). To determine whether
proton transfer between these positions occurs following
reaction completion, racemic 6a and enantioenriched 6a
were subjected to catalyst A5 and TPT respectively. In both
cases, no change in the optical purity was observed.[16] Thus,
a plausible mechanism (Scheme 3) for this reaction commen-
ces with NHC addition to the terminal olefin to afford enolate
I which, following tautomerization, provides the key b-
azolium ylide II. Conjugate addition proceeds through
intermediate II, with a trans arrangement between the
azolium and the acceptor, and the azolium positioned to
minimize steric interactions between the benzyl group and the
phenyl linker, to afford enolate III. Diastereoselective pro-
tonation of III then affords IV, which, following E1cB
reaction and tautomerization, affords propionate 6a. An
alternate explanation would involve E1cB prior to protona-
tion, a mechanistic scenario difficult to distinguish. When the
reaction was monitored by NMR, the only azolium-type
structure was the free NHC, indicating that this is likely the
resting state of the catalyst.
The kinetics of the reaction are finely balanced, with the
desired cyclization (II!III) moderately faster than reaction
with a second equivalent of substrate (that is, 7!9, eq. 3).
Furthermore, proton transfer to afford b-azolium ylide II is
slightly faster than Rauhaut–Currier cyclization (that is, 10!
11, eq. 4).
The umpolung of Michael acceptors by 1,4-addition of
NHCs is an unusual activation mode, in comparison to the
Scheme 1. Competing reactions.
Scheme 3. Plausible mechanism.
Scheme 2. Mechanistic studies.
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The authors thank Dr. Joel Hooper, Dr. Craig Forsyth and
Mr. Adam Ametovski (Monash University) for supporting
studies, and the Australian Research Council through the
Discovery
(DP120101315)
and
Future
Fellowship
(FT110100319) programs for financial support.
Keywords: 1,4-addition · 2-aryl propionates ·
enantioselective catalysis · N-heterocyclic carbenes ·
b-azolium ylides
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[16] This result also precludes Brønsted base-mediated chemistry as
being the origin of enantioselectivity.
Received: October 30, 2015
Revised: December 24, 2015
Published online: January 28, 2016
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