Oxidatively initiated NHC-catalyzed enantioselective synthesis of 3,4-disubstituted cyclopentanones from enals

Article abstract of DOI:10.1021/jacs.5b06390

An unprecedented N-heterocyclic carbene (NHC)-catalyzed annulation of enals to form 3,4-disubstituted cyclopentanones has been discovered. Aryl enals undergo dimerization in the presence of a single-electron oxidant to form C₂ symmetric cyclopentanones. A cross-reaction has also been developed, allowing for the synthesis of differentially substituted cyclopentanones. Mechanistically, the reaction is thought to proceed through radical intermediates, further establishing the synthetic utility of this class of reactivity.

Full text of DOI:10.1021/jacs.5b06390

Communication
pubs.acs.org/JACS
Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis
of 3,4-Disubstituted Cyclopentanones from Enals
Nicholas A. White and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: An unprecedented N-heterocyclic carbene
(NHC)-catalyzed annulation of enals to form 3,4-
disubstituted cyclopentanones has been discovered. Aryl
enals undergo dimerization in the presence of a single-
electron oxidant to form C2 symmetric cyclopentanones.
A cross-reaction has also been developed, allowing for
the synthesis of differentially substituted cyclopentanones.
Mechanistically, the reaction is thought to proceed through
radical intermediates, further establishing the synthetic
utility of this class of reactivity.
ver the past decade, N-heterocyclic carbene (NHC)-
Ocatalyzed reactions of the homoenolate equivalent have
been the focus of intense investigation.1 Glorius and Bode
reported the first examples of NHC-generated homoenolate
equivalents in 2004 independently and concurrently.2 These
seminal reports showed the synthetic utility of the homoenolate
in the context of synthesizing 2,3-disubstituted γ-lactones
(Figure 1, eq 1). Soon after these reports Bode and He showed
that γ-lactams are easily accessed via this pathway through the
coupling of an enal and an imine (Figure 1, eq 2).3 In 2006 Nair
et al. demonstrated the coupling of enals with chalcones to
furnish 1,3,4-trisubstituted cyclopentene (Figure 1, eq 3).4
Further developments in this field have broadened the partners
that participate in these annulations and investigated asymmetric
version of the reaction.5 These annulation reactions are all pre-
Figure 1. Background.
sumed to proceed via two-electron pathways.
Ultimately, NHC 3c proved optimal, providing the desired
product in 51% yield, 84% ee, as a single diastereomer. A high-
throughput experimentation (HTE) screen revealed that
trifluorotoluene was the best solvent and the beneficial effect
of lithium chloride on yield.11
With optimized conditions identified, we explored the scope
of the dimerization. Electron-rich and electron-deficient aryl
enals are tolerated in the reaction. Electron-rich substrates
proved to provide higher yields than their electron-poor
counterparts. The heteroaromatic 2-furylcinnamaldehyde
works in the reaction as well. Unfortunately, aliphatic enals
do not participate. To our delight, 4-bromocinnamaldeyde
provides product in reasonable yield and contains a potential
handle for cross coupling reactions. In all cases, the cyclo-
pentanone products are formed as a single diastereomer. The
remainder of the mass balance in these reactions is the
α,β-unsaturated acid, the result of a two-electron oxidation of
In 2014, we described the NHC-catalyzed conversion of
enals to aldols using nitroarenes as oxidants in methanol. The
net transformation converts enals and nitroarenes to β-hydroxy
esters. Evidence points to one-electron oxidation of the
homoenolate equivalent6 by an electron-deficient nitroarene
oxidant.7,8 During our investigations, we observed the formation
of cyclopentanone products9 when the reaction is conducted
in a non-nucleophilic solvent. For example, the reaction of
4-methoxycinnamaldehyde 1a with 4-nitropyridine N-oxide 2
in dichloromethane at room temperature in the presence of
NHC 3a forms cyclopentanone 4a in 49% yield as a single
diastereomer. Intrigued by this previously unknown reactivity,
we began to explore the reaction parameters.
An initial screen of chiral NHC catalysts at room temperature
proved discouraging with only backbone-fluorinated NHC 3b
providing any desired product in a meager 12% ee.10 Switching
the solvent to toluene afforded an increase to 60% ee (Table 1).
Increasing in the reaction temperature to 70 °C improved the
reactivity and allowed us to screen a variety of chiral catalysts.
Received: June 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b06390
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Reaction Optimization
Table 2. Dimerization Scope
b
c
entry NHC additive temp (°C)
solvent
yield (%)
ee (%)
1
3a
3b
3b
3c
3d
3e
3b
3c
3d
3e
3f
−
−
−
−
−
−
−
−
−
−
−
−
23
23
23
23
23
23
70
70
70
70
70
70
70
CH2Cl2
CH2Cl2
PhMe
49
25
28
<5
<5
<5
46
51
30
44
26
64
79
−
12
60
−
−
−
50
84
50
76
−78
84
84
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
5
6
7
8
PhMe
9
PhMe
10
11
12
13
PhMe
PhMe
3c
3c
PhCF3
PhCF3
LiCl
a
See footnotes a−c in Table 1.
Scheme 1. Proposed Catalytic Cycle
a
Reactions were conducted with 1.0 equiv of 1 and 0.66 equiv of 2.
Isolated yields after chromatography. Enantiomeric excess was
b
c
determined by HPLC analysis on a chiral stationary phase.
the Breslow intermediate to form the acyl azolium, followed by
attack by adventitious water (Table 2).
Mechanistically, we believe that this transformation is related
to the β-hydroxylation of enals that we previously reported.7
We postulate that the reaction proceeds by formation of
Breslow intermediate I,12 which transfers a single electron to
4-nitropyridine N-oxide 2 to generate a radical cation II and
radical anion III (Scheme 1). Radical cation II is then attacked at
the β-carbon by a second, native, Breslow intermediate I to form
IV.13 IV then undergoes a second single electron transfer to
radical anion III to form acyl azolium V. The acyl azolium is then
attacked intramolecularly by the pendant enolate azolium to
liberate one equivalent of NHC and form cyclopentanone VI.
This cyclopentanone is attacked by water to liberate the second
equivalent of NHC and form β-ketoacid VII. This β-ketoacid
then undergoes decarboxylation to furnish cyclopentanone
product 4.14 Once radical anion III abstracts the second electron
from IV, intermediate VIII is formed, which decomposes to
nitroso IX (observed by LCMS). This reactivity represents a rare
example of carbon turnover of the acyl azolium.15 Typically,
exogenous alcohol, a tethered alcohol, or a tethered amine
attacks the acyl azolium. Even in the case of the cyclopentene
forming reactions1 the acyl azolium is turned over by a tethered
alcohol to form a β-lactone, which then extrudes CO2.
for the acyl azolium, and 4-methoxycinnamaldehyde 1a to reaction
with carbene 3c but observed no cyclopentanone products.16 Fur-
ther, employing the known 2-electron oxidant phenazine 7 in the
reaction also does not lead to cyclopentanone products.17
In an effort to broaden the synthetic utility of the trans-
formation, we investigated the use of a heterocoupling partner
We also entertained the idea that the reaction proceeds by one
Breslow intermediate undergoing a two-electron oxidation to
form an acyl azolium which is in turn attacked via a [1,4] addi-
tion by a native Breslow intermediate (Scheme 2). To test this
hypothesis, we subjected 3-phenylpropiolaldehyde 5, a precursor
B
DOI: 10.1021/jacs.5b06390
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
To demonstrate the utility of the cylopentanone products,
a Baeyer−Villager oxidation and a Beckman rearrangement
were carried out. In both cases, retention of stereochemistry was
observed and lactone 8 and lactam 9 products were formed in
good yields (Scheme 3).
Scheme 2. Control Experiments
In conclusion, we have developed a methodology for the
enantioselective synthesis of 3,4-disubstituted cyclopentanones.
The protocol allows for the dimerization of aryl enals18 to form
C-2 symmetric cyclopentanones. Further, a cross reaction has
been developed to synthesize nonsymmetric 3,4-disubstituted
cyclopentanones. The proposed reaction mechanism invokes
radical intermediates. Furthering the substrate scope and
investigating new modes of reactivity enabled by these inter-
mediates is the subject of ongoing investigations.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b06390.
that would deliver unsymmetrical adducts. All attempts at using
other electron-deficient alkenes (such as nitroalkenes, enoates,
enones) met with failure; the reaction appears to require an enal
on both sides. As a partial solution, we found that biasing the
reaction with an excess of one of the enals delivers the cross
product in good yields. Best results are achieved when the more
electron-rich (more reactive) enal is used in excess. In these
reactions, the dimer of the more reactive enal is always formed,
but the dimer of the limiting enal is observed in only trace
amounts (Table 3).
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*rovis@colostate.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
ab
,
■
Table 3. Cross-Reaction
We thank NIGMS for generous support (GM72586) and Daniel
DiRocco (Merck Research Laboratories) for a generous gift of
aminoindanol. We thank Daniel Reuss (CSU) for help with
assaying CO2 levels. Funding by NIGMS (GM72586).
REFERENCES
■
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b
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Scheme 3. Derivatization
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Journal of the American Chemical Society
Communication
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prior to dimerization. However, given that we have seen overreduction
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(18) Under these conditions, aliphatic enals and dienals do not afford
dimer product. An yne-enal participates in the cross-reaction with
achiral catalyst, but not with chiral catalyst.
D
DOI: 10.1021/jacs.5b06390
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX