Enantioselective stetter reactions of enals and modified chalcones catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1002/anie.201105812

New trick for an old cat.: Triazolium-based N-heterocyclic carbenes (NHCs) catalyze the selective generation of acyl anion equivalents for the title reaction. The stereoelectronic properties of the enal-derived Breslow intermediates and the unique reactiv

Full text of DOI:10.1002/anie.201105812

Communications
DOI: 10.1002/anie.201105812
Organocatalysis
Enantioselective Stetter Reactions of Enals and Modified Chalcones
Catalyzed by N-Heterocyclic Carbenes**
Xinqiang Fang, Xingkuan Chen, Hui Lv, and Yonggui Robin Chi*
Organocatalytic activation of readily available substrates has
led to the rapid development of many enantioselective
reactions in the last decade.[1] In N-heterocyclic carbene
(NHC) catalysis,[2] reactions of enals with enones or enone
derivatives have been extensively investigated and are
reported to undergo a diverse set of transformations based
on the catalytically generated enolate and homoenolate
equivalents as intermediates.[3,4] In contrast, the NHC-cata-
lyzed enantioselective Stetter-type Michael additions[5] of
enals to enones remain challenging in part due to the
competing and often dominant homoenolate or enolate[3]
pathways. Herein we report an enantioselective Stetter
reaction of enals and modified chalcones using triazolium-
based NHC catalysts [Eq. (1)]. The previously reported
anion precursors, the Stetter products could be obtained in
good yields. The initial studies and optimization of the
reaction conditions for the enantioselective intermolecular
Stetter reaction using the enal 1a and modified chalcone 2a as
the model substrates with triazolium-based NHCs as the
catalysts are summarized in Table 1. The reaction proceeded
Table 1: Stetter reaction between enal 1a and modified chalcone 2a:
optimization of reaction conditions.[a]
Entry
NHC
Base
Solvent, T
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
A
B
B
B
B
B
B
C
C
D
E
DBU
DBU
Et3N
DIPEA
DMAP
LHMDS
DBU
DBU
DBU
THF, RT
THF, RT
THF, RT
THF, RT
THF, RT
THF, RT
THF, 08C
THF, 08C
Toluene, 08C
THF, 08C
THF, 08C
90
80
–
67
91
90
92
84
90
n.d.
29
n.d.
60
33[d]
30[d]
40[d]
22
typical homoenolate and enolate pathways[3,4] were largely
suppressed especially when b-alkyl enals were used as the acyl
anion precursors and alkylidene diketones as the Michael
acceptors. Enals having two b substituents can also behave as
effective acyl anion precursors. A relevant and elegant
enantioselective Stetter reaction between enals and nitro-
alkenes using NHC and catechol cocatalysts was reported by
Rovis and co-workers recently.[6]
Our development of the Stetter reaction with enals as
substrates was first initiated by an observation of a low
yielding Stetter adduct as a side product during our recent
study of Diels–Alder reactions of b-aryl enals with modified
chalcones.[7] We next found that by using b-alkyl enals as acyl
7[e]
8[e]
9[e]
10[e]
11[e]
86
22
54
16
DBU
DBU
43
[a] Reaction conditions: 1a (0.45 mmol), 2a (0.15 mmol), NHC (20
mol%), base (20 mol%), solvent (1.5 mL), 12 h. [b] Yield of isolated
product based on 2a. [c] Enantiomeric excess of 3a determined by chiral-
phase HPLC analysis; absolute configuration was determined by X-ray
structure analysis of its analogue 3i (Table 2; see the Supporting
Information).[11] [d] Diels–Alder products were also formed in about a 1:1
ratio with the Stetter products. [e] Used 30 mol% NHC, 20 mol% base.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Mes=2,4,6-trimethylphenyl,
DIPEA=N,N’-diisopropylethylamine, DMAP=4-(dimethylamino)-pyri-
dine, LHMDS=lithium bis(trimethylsilyl)amide, Mes=2,4,6-trimethyl-
phenyl, TBD=1,5,7-triazabicyclo[4.4.0]dec-5-ene, THF=tetrahydro-
furan, n.d.=not determined.
[*] Dr. X. Fang, X. Chen, Dr. H. Lv, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
Homepage: http://chigroupweb.org
efficiently with the achiral triazolium A as the pre-catalyst
and DBU as the base in THF to give Stetter product 3a in
90% yield upon isolation (Table 1, entry 1). The use of the
chiral pre-catalyst B resulted in an 80% yield with an
encouraging 67% ee (Table 1, entry 2). Additional optimiza-
tion to improve the reaction enantioselectivity by using
different bases (Table 1, entries 3–6) led to improved ee val-
[**] We acknowledge the generous financial support from the Singapore
National Research Foundation (NRF), Singapore Economic Devel-
opment Board (EDB), GlaxoSmithKline (GSK), and Nanyang
Technological University (NTU). We thank Dr. Y. Li and Dr. R.
Ganguly for the X-ray structure analysis (NTU).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105812.
11782
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Angew. Chem. Int. Ed. 2011, 50, 11782 –11785

ues, but with significantly reduced reaction yields. We then
realized that the relatively low enantioselectivity obtained
with the catalyst B was primarily caused by base-mediated
racemization of the Stetter product 3a. Thus by using a slight
excess of B (30 mol%, relative to 20 mol% DBU) and
decreasing the reaction temperature to 08C, the Stetter
product was obtained in 90% ee with 86% yield (Table 1,
entry 7). Attempts to use using the pre-catalysts C–E under a
range of reaction conditions (Table 1, entries 8–11) did not
lead to improvements in reaction yields or enantioselectiv-
ities. It is interesting to note that the choice of the NHC
catalyst is important to achieve the Stetter reactions. In our
previous work, by using the imidazolium-based bulky IMes
catalyst the reactions with the same sets of substrates
proceeded through an enal enolate pathway to give Diels–
Alder products.[7]
We next examined enals with b-aryl substituents. With the
b-aryl enals, the enolate pathway (giving Diels–Alder prod-
ucts)[7] dominated and was difficult to suppress using the
reaction conditions employed in Table 2 with B as the pre-
catalyst. The use of the less bulky NHC catalyst C did lead to
the Stetter adduct as the sole product, but with low yields and
poor enantioselectivities under various reaction conditions
(see the Supporting Information). We then went back to
catalyst B and extensively optimized the reaction conditions.
Although the enolate pathway[7] was still hard to eliminate
after much effort, the Stetter product could be obtained with
up to 49% yield and good enantioselectivities by using
toluene as the solvent at 08C (Table 3). The difference in
reactivity induced by the b substituents on the enals may
result from the relatively electron-rich and electron-poor
properties of the alkyl and aryl groups, respectively.
Next we used B with DBU as the base in THF at 08C
(Table 1, entry 7) to investigate the scope of the Stetter
reaction. We first studied the reaction using a series of b-alkyl
enal substrates and alkylidene diketones (Table 2). In all cases
Table 3: Scope of the Stetter reaction with b-aryl enals.[a]
Table 2: Scope of the Stetter reaction using b-alkyl enals.[a]
Entry
Ar
R2, R3
5
Yield [%][b]
ee [%][c]
1
2
3
4
5
Ph
3-OMeC6H4, Ph
Ph, Ph
Ph, 4-FC6H4
Ph, Ph
5a
5b
5c
5d
5e
40
33
39
47
49
85
82
88
87
92
4-BrC6H4
2-naphthyl
4-OMeC6H4
2-OMeC6H4
Entry R1
R2, R3
3
Yield [%][b] ee [%][c]
Ph, 4-BrC6H4
1
Me
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
3a
3b
3c
3d
3e
3 f
90
86
77
81
84
85
94
90
88
91
91
95
91
90
92
92
85
93
94
92
2
Et
[a] Reaction conditions: 4 (0.45 mmol), 2 (0.15 mmol), toluene (1.5 mL),
08C. Diels–Alder products were also formed in 20-40% yields. [b] Yield of
isolated product. [c] Enantiomeric excess of 5 determined by chiral-phase
HPLC analysis.
3
nPr
4
n-C5H11
5
n-C7H15
=
6
Me-CH CH Ph, Ph
7
Et
3-OMeC6H4, Ph
3g[d] 68
3h[d] 51
3i
3j
3k
8
9
Me
Me
Me
Me
Et
4-iPrC6H4, Ph
4-BrC6H4, Ph
4-FC6H4, Ph
Ph, 4-BrC6H4
3-OMeC6H4, 4-BrC6H4 3l
Ph, 4-ClC6H4
Ph, 4-FC6H4
The tolerance of b,b-disubstituted enals in the Stetter
reaction was also tested. Previously under NHC catalysis
these types of enals were mainly used in self-redox reac-
tions.[9] We reasoned that the additional b substituent (espe-
cially an alkyl group) might enhance the electron density of
the resulting enal acyl anions and thus make these enals
behave more effectively in the Stetter reaction than the
corresponding monosubstituted b-aryl enals. We first tested
the reaction between the b,b-disubstituted enal 6a and
modified enone 2a by using the reaction conditions employed
in Table 3. To our delight, the Stetter product 7a was obtained
in 89% yield with an acceptable enantioselectivity (Table 4,
entry 1). The substrate scope was then briefly examined
(Table 4). An enal having an electron-donating group on the
phenyl ring showed high reactivity and afforded products with
excellent yields, albeit with slightly decreased enantioselec-
tivities (Table 4, entries 3 and 4). The diaryl-substituted enal
reacted as well, but the yield was low even after attempted
optimization which included the use of catechol additives
(Table 4, entry 5). Good yield was achieved when the dialkyl-
substituted enal was used, but with decreased enantioselec-
tivity (Table 4, entry 6). The enone substrates having elec-
tron-withdrawing groups such as COMe or CO2Et were not
effective when using simple enals, but proved to be reactive
80
71
89
86
10
11
12
13
14
Me
Me
3m 64
3n 74
[a] Reaction conditions: 1 (0.45 mmol), 2 (0.15 mmol), THF (1.5 mL).
[b] Yield of isolated product. [c] Enantiomeric excess of 3, determined by
chiral-phase HPLC analysis; the absolute configuration was determined
by X-ray structure analysis of product 3i. [d] Catechol (100 mol%) was
used as an additive.
the reactions proceeded smoothly to afford the Stetter
products with good enantioselectivities and yields. The
Michael acceptor 2 having aryl groups (R2 and R3) with
different electronic properties was investigated (Table 2,
entries 7–14). Electron-donating groups on the phenyl rings
generally gave products with slightly decreased yields
(Table 2, entries 7 and 8); in these cases the addition of a
catechol additive[8] improved the yields without affecting
enantioselectivities. In all the examples studied in Table 2, the
reactions exclusively proceeded to give the Stetter products
without observable formation of the typical products arising
from either the enolate or homoenolate pathways.
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Communications
Table 4: Scope of the Stetter reaction with b,b-disubstituted enals.[a]
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Entry R1, R2
R3, R4, R5
7
Yield ee
[%][b] [%][c]
1
2
3
4
5
Ph, Me
Ph, Me
Ph, Ph, Ph
Ph, 4-BrC6H4, 4-BrC6H4 7b 90
7a 89
83
88
70
74
65
4-OMeC6H4, Me 4-BrC6H4, Ph, Ph
4-OMeC6H4, Me 4-iPrC6H4, Ph, Ph
4-MeC6H4,
4-MeC6H4
PhCH2CH2, Me
Ph, Me
7c 93
7d 91
7e 33
3-OMeC6H4, Ph, Ph
6
7
Ph, Ph, Ph
Ph, Me, Ph
7 f 81
7g 70
42
87
94[d]
97[e]
56
8
9
Ph, Me
Ph, Me
Ph, OEt, Ph
Ph(CH2)2, Ph, Ph
7h 65
7i
35
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[5] For racemic Stetter reactions with enals as acyl anion precursors
using thiazolium-based NHCs, see: a) H. Stetter, G. Hilboll, H.
[a] Reaction conditions: 6 (0.45 mmol), 2 (0.15 mmol), toluene (1.5 mL).
[b] Yield of isolated product. [c] Enantiomeric excess of 7 determined by
chiral-phase HPLC analysis. [d] The ee values of both diastereomers;
1.3:1 d.r. [e] The ee value of the major diastereomer; 2.8:1 d.r.
with b,b-disubstituted enals (Table 4, entries 7 and 8).[10]
Finally, an alkylidene diketone with an alkyl group (R3) also
afforded the corresponding Stetter product, albeit with low
yield and moderate enantioselectivity (Table 4, entry 9).
Notably, simple chalcones that were previously demon-
strated to be good electrophiles for reacting with enal-derived
enolate and homoenolate intermediates,[3] failed to undergo
the Stetter reaction with enals in our studies. We also noticed
that the use of simple aryl and alkyl aldehydes (e.g.
benzaldehyde and 3-phenylpropanal, respectively) as poten-
tial acyl anion precursors did not lead to an observable Stetter
reaction with these modified chalcones (e.g. 2a) under our
reaction conditions. Given the same set of substrates, the
choice of the NHC catalyst (e.g. imidazolium-based IMes and
the triazolium-based NHCs) can affect the reaction path-
way.[7] These results indicated that the stereoelectronic
properties of the enal-derived Breslow intermediates and
the unique reactivity of modified chalcones were crucial for
the enantioselective Stetter reaction to occur.
In summary, we have disclosed the enantioselective
Stetter reaction between enals and modified chalcones. The
reactions are believed to proceed through a Michael-type
addition of NHC-bound enal acyl anions to the modified
chalcones. Through an alteration of the reaction partners (the
electrophiles) and the proper choice of the NHC catalyst,
selective capturing of the enal acyl anion intermediates was
realized. Additional mechanistic studies for a specific under-
standing of the origins of the experimental observations with
respects to both substrate and catalyst effects are in progress.
Received: August 17, 2011
Published online: October 11, 2011
Keywords: asymmetric catalysis · N-heterocyclic carbene ·
.
organocatalysis · Stetter reaction · synthetic methods
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Angew. Chem. Int. Ed. 2011, 50, 11782 –11785

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[8] Phenol derivatives have been used as hydrogen-bonding addi-
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[10] Other Michael acceptors such as dimethyl 2-benzylidenemalo-
nate, (E)-2-benzoyl-3-phenylacrylonitrile, 2-benzylidenemalo-
nonitrile, (E)-1,2,3-triphenylprop-2-en-1-one were also tested,
but failed to afford Stetter products under our reaction
conditions.
[11] CCDC 839736 (3i) contains the supplementary crystallographic
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.
[6] D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011, 133, 10402 –
10405.
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