N-heterocyclic carbene-catalyzed generation of α,β-unsaturated acyl imidazoliums: Synthesis of dihydropyranones by their reaction with enolates

Article abstract of DOI:10.1021/ja905501z

(Chemical Equation Presented) Catalytic generation of α,β- unsaturated acyl imidazolium cations and enolates has been achieved, and their involvement in a Michael addition acylation sequence exploited, to provide a range of dihydropyranones. α,β-Unsaturat

Full text of DOI:10.1021/ja905501z

Published on Web 09/16/2009
N-Heterocyclic Carbene-Catalyzed Generation of r,ꢀ-Unsaturated Acyl
Imidazoliums: Synthesis of Dihydropyranones by their Reaction with Enolates
Sarah J. Ryan, Lisa Candish, and David W. Lupton*
School of Chemistry, Monash UniVersity, Clayton 3800, Victoria, Australia
Received July 3, 2009; E-mail: david.lupton@sci.monash.edu.au
Scheme 1. Proposed Catalytic Pathway for the Formation of 4
N-Heterocyclic carbene (NHC) catalyzed polarity reversal of the
carbonyl group is central to a number of organic transformations, most
notably the benzoin and Stetter reactions.1a,c More recently conjugated
or redox active substrates have allowed access to reactive intermediates
useful in reaction discovery.1b,d We have undertaken studies aimed at
extending this family to include R,ꢀ-unsaturated acyl azoliums (i.e.,
2). While these intermediates were reported by Scheidt in his MnO2
based oxidative esterification,2a their reactivity at the ꢀ-position is yet
to be investigated. In comparison to homoenolates, which react as
donors at the ꢀ-position (eq 1),1d,3 the cationic nature of the acyl
azolium, in combination with steric shielding, should generate an
intermediate ideally suited to act as a conjugate acceptor. In this
communication, we report the first conjugate addition reactions
involving R,ꢀ-unsaturated acyl azoliums (eq 2).
Table 1. Selected Optimization Studies
To investigate the reactivity of R,ꢀ-unsaturated acyl azoliums, a
method for their generation in the presence of an appropriate
nucleophile was required. While a number of approaches could be
envisaged, we chose to investigate the use of R,ꢀ-unsaturated enol
esters (i.e., 5).4 When such substrates are exposed to Lewis basic
catalysts,5 fragmentation should liberate enolate 3 and the required
R,ꢀ-unsaturated carboxylate 2.6,7 Conjugate addition into the acyl
azolium, providing enolate 6,8 followed by proton transfer and
acylation, should then afford pyranone 49,10 and regenerate the cat-
alyst (Scheme 1).
entry
catalyst (mol %)
temp/ time
base
yielda
1
2
3
4
5
6
7
A (100 mol %)
B1 (100 mol %)
B1 (10 mol %)
C1 (10 mol %)
C2 (10 mol %)
B2 (100 mol %)b
D (100 mol %)
reflux/16 h
-78 °C/1 h
-78 °C/1 h
reflux/16 h
reflux/16 h
reflux/16 h
reflux/16 h
KHMDS
-
19 (7)
41
trace
86
79
-
KOtBu
KOtBu
KOtBu
KOtBu
NR
NR
a Isolated yield following flash column chromatography. b Catalyst B2
Investigations began with the reaction of thiamine (A) and enol
ester 5a in refluxing toluene (Table 1, entry 1). This readily available
NHC fragmented enol ester 5a, however, rather than affording 4a
C-acylation provided 1,3-diketone 7.11 When 100 mol % of the
more nucleophilic tetramethyl carbene B1 was reacted with enol
ester 5a, pyranone 4a was obtained in 41% yield, accompanied by
22% of diketone 7 (Table 1, entry 2). Unfortunately, when carbene
B1 was used substoichiometrically no more than a trace of
dihydropyranone 4a was observed (Table 1, entry 3). To our delight,
when catalysts derived from IMes ·HCl C1 and IDip ·HCl C2,
recognized in both homoenolate and transesterification catalysis,3,6
were used, pyranone 4a formed in high yield with good catalytic
loading (Table 1, entries 4 and 5).
generated by deprotonation of the corresponding imidazolium chloride.
The reactions’ scope was investigated across a range of R,ꢀ-
unsaturated acceptors and enolates (Chart 1). Aromatic, heteroaro-
matic, and aliphatic R,ꢀ-unsaturated esters all reacted readily to
give the corresponding pyranones (4a-d). ꢀ-Disubstituted acyl
azoliums were found to be good substrates, allowing efficient
construction of quaternary carbon centers (4d, 4f, 4m). Ketone and
aldehyde enolates derived from cyclic, acyclic, aromatic, and 1,3-
diketones were investigated in the transformation providing good
yields of the expected dihydropyranones. In the case of 1,3-
diketones, the reaction preceded readily at 0 °C, even with a
ꢀ-disubstituted acyl azolium intermediate (4m).
Finally the suitability of imidazolium derived catalyst B2 and
triazolium precatalyst D was investigated. Unfortunately neither
proved suitable for this reaction (Table 1, entries 6 and 7).12
While the generation of acyl azoliums and enolates from enol
esters proved useful, these should also be accessible from R,ꢀ-
unsaturated acid fluorides 8 and TMS enol ethers 9 (eq 5). In this
9
14176 J. AM. CHEM. SOC. 2009, 131, 14176–14177
10.1021/ja905501z CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Chart 1. Scope of NHC Catalyzed Rearrangementa
of this reaction has been achieved with triazolium E. Exploration of
the utility of this new type of azolium intermediate and the application
of pyranones, known medicinal agents,17 and useful building blocks
in organic synthesis10a,b is ongoing.
Acknowledgment. We acknowledge financial support of the
ARC (DP0881137). Roche (Palo Alto) through donation of equip-
ment. The assistance of Prof. Cameron Jones, Dr. Andreas Stasch,
Simon Bonyhady, and Michael Blair is also acknowledged.
Supporting Information Available: Characterization data, NMR
spectra, and detailed experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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scenario addition of the NHC into the acid fluoride would instigate
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Chart 2. Scope of Intermolecular NHC Catalyzed Reactiona
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a Isolated yield. b Ratio determined by 1H NMR spectroscopy. c 10 mol
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Recently, highly enantioselective Stetter and benzoin reactions have
been achieved using chiral NHCs.1a When catalysts derived from either
chiral triazolium14 or imidazolium15 salts were exposed to enol ester
5a, pyranone 4a failed to form. However, when the reaction was
attempted with enol ester 5k and the catalyst derived from triazolium
E, pyranone 4k16 formed in good yield and 50% ee (eq 6). While this
level of induction is modest, it is comparable to the state-of-the-art
for reactions in which bond formation ꢀ to the carbonyl group occurs
(eq 1).2b,3a,12a
(12) Differing reactivity between imidazolium and triazolium NHCs: (a) Struble,
J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008, 10, 957. (b)
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J. L.; Rovis, T. J. Org. Chem. 2008, 73, 2033, and references therein.
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Lohre, C.; Fro¨hlich, R.; Bergander, K.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 8344, and references therein.
In summary, we have achieved the first conjugate addition reactions
into R,ꢀ-unsaturated acyl azoliums. A range of conjugate acceptors,
included those containing ꢀ-disubstitution, reacted smoothly with a
variety of enolates to afford the expected dihydropyranones in good
yields. This transformation complements NHC-catalyzed homoenolate
chemistry that involve ꢀ-donation (eq 1).1d,3 An enantioselective variant
(16) Absolute configuration inferred from studies with pyranone 4l and ref 10a.
(17) For medicinal lactones, see: Prisinzano, T. E. J. Nat. Prod. 2009, 72, 581.
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