Enantioselective Stetter Reactions Catalyzed by Bis(amino)cyclopropenylidenes: Important Role for Water as an Additive

Article abstract of DOI:10.1021/acs.orglett.0c03879

The first highly enantioselective intermolecular Stetter reaction using simple enones is reported. A series of novel chiral BAC structures were designed and prepared. They were tested in the Stetter reaction with simple aldehydes and enones. The products were generated in excellent yields and enantioselectivities (up to 94% ee). Surprisingly, a substoichiometric amount of water was crucial to obtain high enantioselectivities. Chiral BACs were also shown to catalyze 1,6-conjugate addition reactions with paraquinone methides enantioselectively.

Full text of DOI:10.1021/acs.orglett.0c03879

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Letter
Enantioselective Stetter Reactions Catalyzed by
Bis(amino)cyclopropenylidenes: Important Role for Water as an
Additive
Mehran Rezazadeh Khalkhali, Myron M. D. Wilde, and Michel Gravel*
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ABSTRACT: The first highly enantioselective intermolecular Stetter
reaction using simple enones is reported. A series of novel chiral BAC
structures were designed and prepared. They were tested in the Stetter
reaction with simple aldehydes and enones. The products were generated
in excellent yields and enantioselectivities (up to 94% ee). Surprisingly, a
substoichiometric amount of water was crucial to obtain high
enantioselectivities. Chiral BACs were also shown to catalyze 1,6-
conjugate addition reactions with paraquinone methides enantioselectively.
ynthetic access to 1,4-dicarbonyl motifs is limited due to
impractical from the point of view of catalyst synthesis. Instead,
Stheir unusual polarity pattern. The Stetter reaction we opted to restrict rotation around the C−N bonds by the use
of bulky C2-symmetric amino substituents (Figure 1b). Most
chiral NHC catalysts are devoid of symmetry, leading to E/Z
isomerism of the corresponding Breslow intermediates, which
can negatively affect the enantioselectivity. The Breslow
intermediates derived from our new C2-symmetric pre-
catalysts do not feature E/Z isomerism, which limits the
number of available reaction pathways. Pre-catalysts 2 and 3
were prepared from the known chiral piperidine and
pyrrolidine, respectively. Following initial screening results
(vide infra), the bulkier pre-catalysts 4 and 5 were also
prepared. Pre-catalysts 1−5 were evaluated in a model Stetter
reaction (Table 1).
The reaction using piperidine-derived pre-catalyst 2 showed
a notable improvement in enantioselectivity compared to the
one using pre-catalyst 1, thereby validating the approach of
restricting C−N bond rotation through steric hindrance
(entries 1 and 2). Not surprisingly, this increase in
enantioselectivity was accompanied by a decrease in reactivity.
The level of enantioselectivity was maintained when using
pyrrolidine-derived pre-catalyst 3, but a much better
conversion of 92% was obtained (entry 3). It is not clear at
this point whether the improved reactivity profile of 3
compared to that of 2 is due to the size of the heterocycles
or to the presence of aromatic rings in 3. The tunability of
aromatic substituents allowed the exploration of other diaryl-
provides a direct and convergent synthetic route for
constructing 1,4-dicarbonyls using a strategic C−C bond
formation.1 Seminal work by Enders disclosed the first
intramolecular enantioselective Stetter reaction.2 Although
the intramolecular variant is well explored,3 highly enantiose-
lective intermolecular Stetter reactions have remained a
challenge.4 Representative examples are shown in Scheme 1.
Enders and colleagues first demonstrated an enantioselective
intermolecular Stetter reaction with aromatic aldehydes and
chalcone in which moderate yields and enantioselectivities
were obtained (Scheme 1a).4b Rovis and co-workers obtained
excellent results by using highly electrophilic glyoxamides and
arylidene malonates as reaction partners (Scheme 1b).4c We
later reported β,γ-unsaturated α-ketoesters as effective partners
in these reactions.4h Despite a number of other reports in this
area, a high level of enantioselectivity for the intermolecular
Stetter reaction involving simple enones and aldehydes
remains elusive.
BACs have proved to be quite stable carbenes.5 In 2013, we
showed that they are competent catalysts for the Stetter
reaction.6,7 However, when chiral pre-catalyst 1 was used, the
product was obtained with only a modest 36% ee (Scheme 1c).
The excellent reactivity profile of BACs motivated us to design
and synthesize new chiral backbones that would better impart
enantioselectivity for this challenging transformation.
We reasoned that the poor enantioselectivity observed when
using pre-catalyst 1 is due to the free C−N bond rotation
illustrated in Figure 1a. We hypothesized that more rigid
structures would lead to higher enantioselectivities due to a
better-defined chiral environment near the reaction center.
Rigidifying the catalyst’s structure via the introduction of
additional fused rings to the structure of 1 was deemed
Received: November 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03879
© XXXX American Chemical Society
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Scheme 1. Selected Examples of Enantioselective
Intermolecular Stetter Reactions
Figure 1. (a) Undesired C−N bond rotation. (b) C2-symmetric
design with hindered C−N bond rotation. (c) Chiral pre-catalysts
used in this study.
a
Table 1. Pre-Catalyst Screening
b
c
entry
pre-catalyst
conversion (%)
ee (%)
1
2
3
4
5
1
2
3
4
5
>99
45
92
82
32
10
55
57
85
60
d
a
Reactions were run with 1.2 equiv of aldehyde, 10 mol % of pre-
catalyst, and 0.7 equiv of Cs2CO3 in CH2Cl2 in the presence of 4 Å
b
molecular sieves for 4 h at rt under argon. Conversions determined
c
by 1H NMR analysis of the crude reaction mixture. ee determined by
d
HPLC analysis using a chiral stationary phase. 15% of pre-catalyst
was used.
Gratifyingly, a great improvement in the enantioselectivity
was obtained while maintaining a reasonable level of reactivity
(entry 4). Next, we turned our efforts to varying the electronic
properties of the catalyst. In the presence of electron-rich 5,
the enantioselectivity observed was similar to that using pre-
catalyst 3, but the conversion dropped significantly (entry 5).
Unfortunately, brief attempts to prepare a fluorinated version
of 3 failed. Nevertheless, the results obtained with 4 were
sufficiently encouraging to optimize this reaction and explore
its scope.
Of concern was that our initial results were not reproducible.
The enantioselectivity ranged from 85 to 94% ee and the
conversion from 30 to 90%. Interestingly, we observed a
correlation between enantioselectivity and conversion: a higher
yield led to a lower selectivity and vice versa (results not
shown). We suspected that adventitious water played a role in
the variability of our results, so we decided to carefully control
the amount of water present in the reaction vessel. We
screened the model reaction with various amounts of water,
and the best result was obtained in the presence of 20 mol %
water (80% conversion, 90% ee; see the Supporting
Information). More importantly, the results became highly
reproducible. We reasoned that the improvement of
enantioselectivity in the presence of water might be due to
hydrogen bonding. Various additives with hydrogen bonding
ability were therefore tested, but water proved to be optimal
(see the Supporting Information).
substituted pyrrolidine-derived pre-catalysts. We surmised that,
by modulating the steric and electronic properties of these aryl
substituents, an increase in enantioselectivity could be
obtained. To this effect, aryl groups with increased bulk
could possibly enhance the rigidity of the catalyst and/or the
facial selectivity on the acceptor. Simple visual inspection
suggested that ortho substituents or branched alkyl groups
(such as t-Bu and i-Pr) at the meta position are too bulky, and
they might shut down the reactivity of the catalyst. Meta-
methyl substitution therefore seemed to be a reasonable
choice. Thus, pre-catalyst 4 was synthesized and tested.
B
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a
Optimization of the other reaction parameters is presented
in Table 2. Lowering the temperature from −10 to −25 °C led
Scheme 2. Substrate Scope
a
Table 2. Optimization of the Reaction Conditions
b
entry
solvent
T (°C)
t (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
−10
−25
0
0
0
0
0
0
0
4
4
4
80
19
91
60
84
93
92
83
8
90
96
91
91
90
88
82
77
75
85
0
0.75
2
24
4
4
4
4
4
4
THF
9
10
11
CH3CN
p-dioxane
DMF
0
0
0
83
57
92
c
12
CHCl3
91
a
b
1
Reactions were run on a 0.07 mmol scale. Yield determined by H
c
NMR analysis using an internal standard. 0.3 equiv of Cs2CO3 was
used.
to an increase in enantioselectivity, but that was accompanied
by a dramatic drop in conversion (entries 1 and 2). Lower
solubility of the pre-catalyst at this temperature could be an
explanation for this observation.8 Surprisingly, the conversion
could be increased at 0 °C while maintaining the high level of
enantioselectivity (entry 3). Varying the reaction time showed
that very little racemization occurs over time (entries 4−6). A
solvent screen revealed that chloroform is superior to the other
solvents (entries 7−11). Finally, we found that the amount of
base could be lowered without a measurable impact on the
reaction outcome (entry 12).
With the optimized reaction conditions in hand, we set out
to explore the generality of this transformation (Scheme 2).
The reaction is tolerant to electron-withdrawing and mild
electron-donating groups on both reactants. The use of
electron-poor aromatic aldehydes leads to the highest
enantioselectivities (6−8), but the products derived from
benzaldehyde or electron-rich aromatic aldehydes are still
obtained in good enantiomeric excess (9, 10). The use of an
electron-rich acceptor led to the Stetter product in modest
yield but with very high enantioselectivity (11). Product 12
was formed from meta-anisaldehyde, implying that the reaction
is sterically tolerant to substituents at the meta position (12).
Further investigation demonstrated that heteroaromatic
aldehydes are well tolerated. The furfural-derived product 13
was formed in high yield and with high enantioselectivity.
Acceptors containing a heterocyclic substituent also led to the
desired products efficiently, although the product formed from
the β-heterocyclic acceptor only had a modest enantiomeric
excess (14, 15). The successful formation of furyl-containing
Stetter products is synthetically significant, as this moiety is
susceptible to further modifications such as photo-oxygen-
ation9 and Diels−Alder reactions.10 Other heteroaromatic
aldehydes were also tested and led to the desired products.
The use of 3-pyridinecarboxaldehyde and 2-thiazolecarbox-
aldehyde gave the Stetter products with excellent conversions
a
Reactions were run on a 0.15 mmol scale. Yields are of pure, isolated
products; yields indicated in parentheses were determined by 1H
NMR analysis using an internal standard.
and diminished enantioselectivities (16, 17). Benzofuran-2-
carboxaldehyde also coupled with chalcone but in the absence
of water. The reaction using this particular substrate proved to
be highly water sensitive. Lack of water led to a higher
conversion; however, the enantioselectivity was inferior,
confirming the significant influence of water on the
enantioselectivity of this reaction. It is worth noting that the
use of ortho-substituted aromatic aldehydes or aliphatic
aldehydes did not lead to the desired Stetter products.
Although an extensive survey of Michael acceptors was not
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carried out, β-alkyl-substituted acceptors were found to be
unreactive under the optimized conditions, as were β,γ-
unsaturated α-ketoesters. The absolute configuration of
product 9 was determined by polarimetry and comparison
with reported values.4b The absolute configuration of other
substrates was assigned by analogy.
Anand and co-workers recently reported a BAC-catalyzed
1,6-addition of aldehydes onto para-quinone methides to form
racemic α,α-diaryl ketones.7a Inspired by their report, we
wondered if the reported reaction can be done enantiose-
lectively using a chiral BAC catalyst. Gratifyingly, in the
presence of 4, the desired product 19 was formed in excellent
yield and good enantioselectivity (Scheme 3). No further
orcid.org/0000-0003-3656-7108; Email: michel.gravel@
usask.ca
Authors
Mehran Rezazadeh Khalkhali − Department of Chemistry,
University of Saskatchewan, Saskatoon, SK S7N 5C9,
Canada
Myron M. D. Wilde − Department of Chemistry, University of
Saskatchewan, Saskatoon, SK S7N 5C9, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03879
Notes
The authors declare no competing financial interest.
Scheme 3. Enantioselective 1,6-Addition
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada (RGPIN-2017-06230), the
Canada Foundation for Innovation (CFI), and the University
of Saskatchewan for financial support.
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03879.
Experimental procedures, characterization data, and
NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1−19 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
́
acetaldehyde. Org. Biomol. Chem. 2011, 9, 2069−2071. (h) Sanchez-
Larios, E.; Thai, K.; Bilodeau, F.; Gravel, M. Highly Enantioselective
Intermolecular Stetter Reactions of β-Aryl Acceptors: α-Ketoester
Moiety as Handle for Activation and Synthetic Manipulations. Org.
Michel Gravel − Department of Chemistry, University of
Saskatchewan, Saskatoon, SK S7N 5C9, Canada;
D
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