N-Heterocyclic Carbene-Catalysed Mukaiyama-Michael Reaction and Mukaiyama Aldol/Mukaiyama-Michael Three-Component Coupling Reaction

Article abstract of DOI:10.1071/CH16566

An N-heterocyclic carbene-catalysed Mukaiyama-Michael addition between several trimethylsilyl (TMS) enol ethers and chalcone derivatives has been discovered. In addition, a related reaction cascade involving dehydrative Mukaiyama aldol followed by a Mukaiyama-Michael addition process has been developed. The later reaction can also be achieved as a three-component coupling reaction. The enantioselective variant of these reactions has been examined with homochiral catalysts. Though these catalysts were active, they fail to achieve enantioinduction.

Full text of DOI:10.1071/CH16566

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Communication
http://dx.doi.org/10.1071/CH16566
N-Heterocyclic Carbene-Catalysed Mukaiyama–Michael
Reaction and Mukaiyama Aldol/Mukaiyama–Michael
Three-Component Coupling Reaction*
A
A B
,
Kim Nguyen and David W. Lupton
A
School of Chemistry, Monash University, Clayton 3800, Vic., Australia.
Corresponding author. Email: david.lupton@monash.edu
B
An N-heterocyclic carbene-catalysed Mukaiyama–Michael addition between several trimethylsilyl (TMS) enol ethers and
chalcone derivatives has been discovered. In addition, a related reaction cascade involving dehydrative Mukaiyama aldol
followed by a Mukaiyama–Michael addition process has been developed. The later reaction can also be achieved as a
three-component coupling reaction. The enantioselective variant of these reactions has been examined with homochiral
catalysts. Though these catalysts were active, they fail to achieve enantioinduction.
Manuscript received: 5 October 2016.
Manuscript accepted: 30 November 2016.
Published online: 20 January 2017.
In the preceding decades, N-heterocyclic carbene (NHC) orga-
nocatalysis has evolved as a powerful approach to discover and
develop reactions.[1,2] While catalysis by NHC addition to the
carbonyl is most common, several less developed modes of
catalysis have been reported.[1h] For example, studies led by
Song et al. at Boehringer Ingelheim have demonstrated novel
silyl transfer reactions[3–6] such as the NHC-catalysed
Mukaiyama aldol reaction (Eqn 1, Scheme 1)[5] and a silyl enol
ether synthesis (Eqn 2, Scheme 1).[6] Building on these early
observations, elegant studies, particularly regarding vinylogous
Mukaiyama chemistry, have since been reported.[7,8]
Our interest in NHC catalysis in many cases has focused on
the coupling of acyl fluorides and silicon-masked nucleo-
philes.[9,10] For example in 2009, we reported that IMes (A2)
catalysed the synthesis of dihydropyranone (1) from acyl
fluorides (i.e. 2) and silyl enol ethers (i.e. 3).[9a] This reaction
presumably proceeds via substitution at the acyl fluoride with
concomitantdesilylation to provide acyl azolium 4 and enolate5.
In those studies, a plausible mechanistic alternative involving
NHC addition to the silyl ether (i.e. 3), analogous to the
proposals of Song and others,[3–8] could also be evoked. To
allow clarification of mechanistic aspects of our earlier work, we
envisaged a study focused on NHC-mediated silyl addition
reactions. By gaining an appreciation of such chemistry, we
hoped that we could clarify the differences between NHC-
mediated silyl addition chemistry and our earlier work. Herein,
we report the outcome of these studies with the discovery of an
NHC-catalysed Mukaiyama–Michael addition (i.e. 6 1 99 - 7;
14 examples) and a related dehydrative Mukaiyama aldol/
Mukaiyama–Michael cascade (i.e. 8 þ 9 - [6] 1 99 - 7;
5 examples reported).[11] Both reactions have acceptable scope
with the later allowing three-component coupling reactions to be
achieved. Finally, while the transformations defined previously
are viable using homochiral NHC catalysts they proceed without
enantioselectivity using several catalysts. Completion of these
studies and comparison with our earlier work involving acyl
fluorides highlight that the conditions for these two types of
NHC catalysis are distinct and unlikely to compete with each
other.
Studies commenced by examining the reaction between
trimethylsily (TMS) enol ether 9a and chalcone (6a) in the
presence of 10 mol-% NHC catalyst (A1), which was generated
by deprotonation of the corresponding imidazolium salt.[12]
Though the reaction reached completion, a modest yield of
Michael adduct 7a was obtained (Table 1, entry 1); with
oligomeric by-products also observed. Changing the solvent to
benzene (Table 1, entry 2), toluene (Table 1, entry 3), or diethyl
ether (Table 1, entry 4), while maintaining the same temperature
(08C), failed to improve the yield of 7a. Similarly, alternate
bases for NHC generation had little impact on the yield (Table 1,
entries 5 and 6). At a lower temperature (i.e. ꢀ358C), the
reaction was sluggish and oligomerisation predominated, as
1
determined by H NMR spectroscopy analysis. This result is
presumably due to the occurrence of base-induced anionic
polymerisation (Table 1, entry 7). Using a higher temperature
(i.e. 668C), a slight increase in yield was observed (Table 1, entry
8). To retard oligomerisation, the reaction was performed at
higher dilution (0.017 M cf. 0.1 M). Though the higher dilution
used suppressed decomposition pathways, allowing the product
to be formed in 65 % yield (based on recovered starting
*Special issue dedicated to 7th Heron Island Conference.
Journal compilation ꢀ CSIRO 2017
www.publish.csiro.au/journals/ajc

B
K. Nguyen and D. W. Lupton
Song’s NHC-mediated silyl transfer reactions
O
0.5 mol-% A1, 0ꢁC,
THF, 65h
then HCl
OH
O
H
p-CH3C6H4
(1)
OTMS
ꢀ
p-CH3C6H4
74 % yield
Ph
Ph
N
N
A1
OTMS
CH3
H3CO
1 mol-% A1,
THF, 23ꢁC, 2.5h
OTMS
CH3
(2)
O
ꢀ
p-CH3C6H4
H3C
p-CH3C6H4
92 % yield
Dihydropyranone synthesis
O
F
10 mol-% A2, toluene,
Δ, 16h
TMSO
O
O
ꢀ
(3)
Ph
Mes
N
Ph
2
N
Mes
3
1, 84 % yield
A2
ꢀ
ꢃ
N
O
N
O
Mes
Mes
Ph
ꢀ
5
4
Herein
O
O
Ar1
H
O
cat. NHC
cat. NHC
OTMS
R
O
8
Ar2
OTMS
Ar1
ꢀ
Ar2
Ar1
7
Ar2
6
R
9ꢂ
9
Mukaiyama aldol/Michael cascade
5 examples 29–62 % yield
Mukaiyama–Michael
14 examples 40–81 % yield
Scheme 1. Project background.
materials), the reaction failed to reach completion (Table 1,
entry 9). A more useful modification involved performing the
reaction at a higher stoichiometry of 9a (1.3 cf. 1.2 equiv.),
affording 7a in 77 % isolated yield (Table 1, entry 10). This
result could not be improved further upon using alternate
imidazole-derived NHCs (A3ꢀA5); a maximum yield of 10 %
was obtained for adduct 7a under identical conditions (Table 1,
entries 11–13). Finally, performing the reaction at room tem-
perature with NHC A1 gave 7a in 80 % yield, and when closely
monitored, the reaction was found to reach completion after 3 h
(Table 1, entry 14).
The general scope of the NHC-catalysed Mukaiyama–
Michael addition was initially examined by exploring changes
to the TMS enol ether 9 (Table 2). Electron-poor acetophe-
none-derived enol ethers (i.e. 9b) and mildly electron-rich
variants (i.e. 9c) gave the expected products 7ab and 7ac in
79 % and 72 % yields, respectively. The TMS enol ether of
p-methoxyacetophenone (9d) reacted very slowly, thereby
requiring heating to give a modest yield of 7ad (40 %).
Acetonaphthone enol ether 9e gave the expected product 7ae
in 75 % isolated yield, whereas furan-containing 7af formed in
51 % yield when the reaction was heated. TMS enol ethers
bearing an a-substituent (i.e. 9g and h) reacted in acceptable
yield to form a 1 : 1 diastereomeric mixture of 7ag and a 2 : 1
mixture of 7ah favouring the syn adduct. Electron-poor b-aryl
groups about the chalcone were poorly accommodated, with
7ba (p-NO2) and 7ca (p-Br) formed in 26 % and 39 % yield
respectively. The former was prepared as a 2 : 1 isolable
mixture with cyclohexanol 10 (see below). In comparison, b-
tolyl-containing product 7da was formed in 81 % yield. Intro-
duction of a tolyl group as the acyl substituent also gave
positive results i.e. 7ea was produced in 63 % yield. However,
this yield was reduced when a p-BrC6H4 group (i.e. 7fa) was
used instead. Finally, a 2-napthyl group was incorporated into
this position in acceptable yield (i.e. 7ga).
The poor yield of Michael adduct 7ba from nitrochalcone 6b
(Table 2 and Eqn 6) arises due to a competing proton transfer
from the initially formed Michael adduct to give enolate 11 that
can then unite with a second equivalent of chalcone 6b, via
Michael addition and aldol cyclisation, to yield Kostanecki and
Rossbach-type cyclohexanol 10.[13] This pathway may account
for the modest yield observed with both chalcone 6b and 6c.

NHC-Catalysed Mukaiyama–Michael Reaction
C
Table 1. Selected reaction optimisation
OTMS
Ph
10 mol-% A1–A4·HBF4,
O
10 mol-% base, solvent,
temp., time
9a
ꢀ
O
Ph
O
(4)
Ph
Ph
Ph
Ph
R
7a
6a
Catalysts
R
A2, R ꢄ 2,4,6-(CH3)3C6H2
A3, R ꢄ 2,6-(iPr)2C6H3
A4, R ꢄ 2,6-(MeO)2C6H3
A1, R ꢄ
N
N
Entry
Catalyst
SolventA
Base
Reaction
Time [h]
YieldB [%]
temperature [8C]
1
2
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A3
A4
A5
A1
THF
KHMDS
0
0
5
9
47
34
38
39
46
50
24
50
65D
77
10
9
C6H6
CH3C6H5
Et2O
THF
KHMDS
KHMDS
KHMDS
NaHMDS
KOtBu
3
0
6
4
0
8
5
0
5
6
THF
0
5
7
THF
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
ꢀ35
66
66
66
66
66
66
rtF
13
1
8
THF
THFC
9
14
14
14
14
14
3
10E
11E
12E
13E
14E
THF
THF
THF
THF
10
80
THF
AAll reactions were performed at 0.1 M with respect to 6a except as noted. BIsolated yield following column chromatography. C0.017 M.
DBased on recovered starting material (45 % isolated). EThe amount of 9a used was 1.3 equiv. Frt, Room temperature.
Table 2. Scope for Mukaiyama–Michael additionA
OTMS
O
10 mol-% A1–A4·HBF4,
10 mol-% KHMDS,
THF, rt, 3 h
R1
R2
2
R1
Ar1
9a–9h
R
O
O
ꢀ
(5)
Ar1
Ar2
Ar2
7
6a–6g
Variation of 9
O
O
7aa, Ar ꢄ C6H5, 80 %
7ab, Ar ꢄ p-BrC6H4, 79 %
7ac, Ar ꢄ p-CH3C6H4, 72 %
7ad, Ar ꢄ p-MeOC6H4, 40 %B
O
Ar
O
Ph
Ph
Ph
Ph
7ae, 75 %
O
Me
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
7af, 51 %B
Variation of 6
7ah, 50 % (syn:anti 2:1)C
7ag, 71 % (syn:anti 1:1)C
O
O
O
O
Ph
O
Ph
O
Ph
Ar1
Ar2
Ph
Ph
Ph
7ba, Ar1 ꢄ p-NO2C6H4, 26 %
7ca, Ar1 ꢄ p-BrC6H4, 39 %
7da, Ar1 ꢄ p-CH3C6H4, 81 %
7ea, Ar2 ꢄ p-CH3C6H4, 63 %
7fa, Ar2 ꢄ p-BrC6H4, 42 %
7ga, 53 %
AIsolated yield following column chromatography. BHeating at 668C was used.
CDiastereomeric ratio determined by 1H NMR analysis.

D
K. Nguyen and D. W. Lupton
OTMS
10 mol-% A1·HBF4,
10 mol-% KHMDS,
THF, rt, 3 h
O
Ph
9a
Ph
O
O
ꢀ
(6)
Ph
p-NO2C6H4
p-NO2C6H4
Ph
6b
7ba, 26 %
ꢃ
O
p-NO2C6H4
PhOC
COPh
Ph
O
Ph
p-NO2C6H4
Ph
p-NO2C6H4
OH
10, 18 %
11
10 mol-%
OTMS
·
A1 HBF4,
O
10 mol-%
Ph
KHMDS, THF,
O
Ph
O
2.3 equiv. 9a
66ꢁC, 2 h
(7)
ꢀ
O
Ar
Ph
Ph
Ar
7aa, Ar ꢄ C6H5, 60 % yield
6a–h
Ar
H
7ea, Ar ꢄ p-MeC6H4, 62 % yield
7fa, Ar ꢄ p-BrC6H4, 50 % yield
7ha, Ar ꢄ p-MeOC6H4, 29 % yield
10 mol-%
OTMS
O
then
·
A1 HBF4,
OTMS
Ph
10 mol-%
KHMDS, THF,
ꢃ78ꢁC rt,
30 min
p-BrC6H4
9b
O
O
p-BrC6H4
1.1 equiv. 9a
(8)
ꢀ
O
Ph
Ph
Ph
Ph
7ab, 56 % yield
H
6a
Ph
Scheme 2). Using the more common N-C6F5-substituted NHC
(i.e. B2), the reaction failed. When the t-butyl N-substituent
was examined on the indanol (C1) and pyrrolidone (D1 and
E1) scaffolds, the reaction was viable but once more no
enantioselectivity was observed. Moreover, using an elec-
tron-rich aryl N-substituent D2 did not improve the outcome.
The lack of enantioselectivity either is related to poor control of
the chiral space, potentially due to a distal positioning of the
catalyst, or a mechanism in which the nucleophilic catalyst
dissociates the silyl group rather than providing a hypervalent
silicate.[14] Furthermore, a general base-induced retro-Michael/
Michael sequence may result in racemisation. To investigate
whether a dissociative pathway was operative and could be
suppressed, thereby allowing enantioinduction via either the
hypervalent silicate or an ion-paired silyl azolium enolate, the
reaction was performed in non-coordinating solvents. Unfortu-
nately, in all cases no product formed.
The NHC-catalysed Mukaiyama–Michael addition is a via-
ble transformation, albeit one sensitive to the electronics of both
the silyl enol ether and the Michael acceptor. The conditions for
this reaction are similar to those developed by Song et al. for the
related Mukaiyama aldol reaction, thereby allowing a dehy-
drative Mukaiyama aldol/Mukaiyama–Michael cascade to
develop. This can be executed as a three-component coupling
reaction. The observation of rapid dehydration in these studies,
when none is observed in the studies of Song et al.,[5] is
As the reaction conditions developed herein should be
compatible with the related aldol reaction, a cascade dehy-
drative aldol/Mukaiyama–Michael sequence was trialled.
Specifically, the reaction between 2.3 equiv. of TMS enol
ether 9a and either benzaldehyde, p-methylbenzaldehyde
p-bromobenzaldehyde, or p-methoxybenzaldehyde gave the
expected chalcone-derived Michael adducts 7aa, 7ea, 7fa, and
7ha in 60 %, 62 %, 50 %, and 29 % yields, respectively (Eqn 7).
A related three-component coupling reaction using different
silyl enol ethers was more challenging to develop. Using
various TMS enol ethers and aldehydes, non-selective cou-
pling occurred, presumably due to the similar rates of the
dehydrative aldol reaction to the Mukaiyama–Michael addi-
tion. To achieve selective coupling, a one-pot, two-step
sequence was developed in which benzaldehyde was reacted
initially with 1.1 equiv. of TMS enol 9a, then TMS enol ether
9b, to afford the dehydrative aldol/Mukaiyama–Michael
adduct 7ab in 56 % isolated yield (Eqn 8).
To expand the utility of the Mukaiyama–Michael trans-
formation, an enantioselective variant was examined. The use of
t-butyl N-substituted NHCs[9f] seemed an appropriate starting
place for optimisation due to the marked improvement in
reaction outcome with sterically demanding NHCs (i.e. Table 1,
entries 11–13 cf. 14). Gratifyingly, we found that by using
morpholinone-containing B1, the reaction proceeded in accept-
able yield, however no enantioselectivity was observed (Eqn 9,

NHC-Catalysed Mukaiyama–Michael Reaction
E
OTMS
O
10 mol-% B1–E1·HBF4,
10 mol-% KHMDS,
THF, 0ꢁC, 4 h
p-BrC6H4
9b
p-BrC6H4
O
O
ꢀ
(9)
Ph
Ph
Ph
Ph
6a
7ab
Catalysts
CH3
CH3
Bn
O
O
Ph
Ph
N
N
Bn
N
N
N
N
N
N
N
N
N
N
R1
t-Bu
R1
B1, R1 ꢄ t-Bu
t-Bu
D1, R1 ꢄ t-Bu
C1, 24 % yield, 0 % ee
E1, 41 % yield, 0 % ee
49 % yield, 0 % ee
B2, R1 ꢄ C6F5,
no reaction
40 % yield, 0 % ee
D2, R1 ꢄ p-MeOC6H4,
8 % yield, 0 % ee
Scheme 2. Studies on enantioselectivity.
striking, with the only differences in reaction conditions relat-
ing to the method of NHC generation (preformed or via in situ
deprotonation). This highlights the non-innocent effects of the
salt by-products formed upon NHC generation – something we,
and others, have documented.[15] Studies on the enantioselective
variant of this reaction could not expand the utility of the
reaction.
For cascade catalysis see: (e) A. Grossmann, D. Enders, Angew. Chem.,
Int. Ed. 2012, 51, 314. doi:10.1002/ANIE.201105415
(f) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511. doi:10.1039/
C2CS15333E
(g) J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A. Scheidt,
Angew. Chem., Int. Ed. 2012, 51, 11686. doi:10.1002/ANIE.201203704
(h) S. J. Ryan, L. Candish, D. W. Lupton, Chem. Soc. Rev. 2013, 42,
4906. doi:10.1039/C3CS35522E
A few observations can be made about the competition
between NHC-mediated desilylation and NHC-mediated
defluorination–desilylation as we have previously reported.[9]
First, the former reaction appears to only proceed in a useful
fashion at room temperature or above, whereas our previously
reported chemistry is viable at low temperatures in several
cases.[9] Second, while the former chemistry shows high sensi-
tivity to the nature of the N-substituent (i.e. Table 1, entries
11–13 cf. 14), the latter chemistry can be achieved with various
types of NHC. Thus, the two pathways for silyl enol ether
reactivity are likely to be easily selected for, based on catalyst
selection and other reaction conditions.
(i) S. De Sarkar, A. Biswap, R. C. Samanta, A. Studer, Chem. Eur. J.
2013, 19, 4664. doi:10.1002/CHEM.201203707
(j) J. Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696.
doi:10.1021/AR400239V
(k) P. Chauhan, D. Enders, Angew. Chem., Int. Ed. 2014, 53, 1485.
doi:10.1002/ANIE.201309952
(l) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014,
510, 485. doi:10.1038/NATURE13384
[2] B. Maji, M. Breugst, H. Mayr, Angew. Chem., Int. Ed. 2011, 50, 6915.
doi:10.1002/ANIE.201102435
[3] For trifluoromethylation with TMSCF3 see: J. J. Song, Z. Tan, J. T.
Reeves, F. Gallou, N. K. Yee, C. H. Senanayake, Org. Lett. 2005, 7,
2193. doi:10.1021/OL050568I
[4] For cyanation with TMSCN see: J. J. Song, F. Gallou, J. T. Reeves,
Z. Tan, N. K. Yee, C. H. Senanayake, J. Org. Chem. 2006, 71, 1273.
doi:10.1021/JO052206U
[5] J. J. Song, Z. Tan, J. T. Reeves, N. K. Yee, C. H. Senanayake, Org. Lett.
2007, 9, 1013. doi:10.1021/OL0630494
[6] J. J. Song, Z. Tan, J. T. Reeves, D. R. Fandrick, N. K. Yee, C. H.
Senanayake, Org. Lett. 2008, 10, 877. doi:10.1021/OL703025B
[7] For reviews focused on NHC catalysis with silicon-containing
compounds see: (a) M. J. Fuchter, Chem. Eur. J. 2010, 16, 12286.
doi:10.1002/CHEM.201001120
Supplementary material
Common procedures, experimental details and NMR spectra are
.
available for A1 HBF4, 7ab, 7ca, and 10 on the Journal’s
website.
Acknowledgements
The authors acknowledge financial support from the Australian Research
Council through the Discovery (DP120101315 and DP150101522) and
Future Fellowship (FT110100319) programs. The authors also thank Ms
Alison Levens (Monash University) for help in manuscript preparation and
Dr Joel Hooper (Monash University) for studies on enantioselectivity.
(b) L. He, H. Gao, Y. Wang, G.-F. Du, B. Dai, Tetrahedron Lett. 2015,
56, 972. doi:10.1016/J.TETLET.2015.01.034
For adamantly NHC-based catalysis see: (c) K. A. Agnew-Francis,
C. M. Williams, Adv. Synth. Catal. 2016, 358, 675. doi:10.1002/
ADSC.201500949
[8] For recent examples of NHC catalysis with silicon compounds, see for
vinylogous aldol (a) G.-F. Du, L. He, C.-Z. Gu, B. Dai, Synlett 2010,
16, 2513.
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[11] For a concise overview of the Mukaiyama aldol reaction and some
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