Conversion of α-haloaldehydes into acylating agents by an internal redox reaction catalyzed by nucleophilic carbenes

Article abstract of DOI:10.1021/ja046991o

Reactivity umpolung allows us to consider nontraditional bond disconnections. We report herein that treatment of an α-haloaldehyde with a nucleophile in the presence of catalytic amounts of nucleophilic carbenes results in an internal redox reaction giving rise to a dehalogenated acylating agent as an intermediate by a new reaction manifold. A brief illustration of the scope of this reaction is presented along with evidence supporting the direct intervention of the carbene in the acylation step. Copyright

Full text of DOI:10.1021/ja046991o

Published on Web 07/09/2004
Conversion of r-Haloaldehydes into Acylating Agents by an Internal Redox
Reaction Catalyzed by Nucleophilic Carbenes
Nathan T. Reynolds, Javier Read de Alaniz, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received May 21, 2004; E-mail: rovis@lamar.colostate.edu
Scheme 1. Proposed Mechanism of the Internal Redox Reaction
of R-Haloaldehydes
Umpolung reactivity of functional groups allows chemists the
opportunity to view bond disconnections in nontraditional ways.1
A catalyzed umpolung reaction of aldehydes was first discovered
in the context of the benzoin reaction.2 The utility of the proposed
acyl anion equivalent was further extended when Stetter discovered
that this intermediate reacts with Michael acceptors, affording 1,4-
dicarbonyl compounds.3 The presence of a catalyst coupled with
the formation of a new stereocenter in the benzoin and Stetter
processes affords an opportunity for asymmetric catalysis of these
reactions, a concept that we4 and others5 have recently reduced to
practice. It has been reported that imidazolylidine carbenes catalyze
transesterification reactions, and intermediates such as IV (Scheme
1) have been implicated.6,7,8 In conjunction with our efforts aimed
at extending the utility of this umpolung reactivity, we envisioned
accessing these intermediates via an unlikely precursor. Herein, we
report a new reaction that transforms R-haloaldehydes into dehalo-
genated acylation agents catalyzed by nucleophilic carbenes.
The activation of aldehydes in the benzoin and Stetter reaction
manifolds is proposed to proceed through the nucleophilic alkene
intermediate II (Scheme 1). We envisioned that, should this
intermediate contain a â-leaving group, we may access the enol
III that, following tautomerization, should provide the acyl azolium
IV. Interception of this activated ester with an appropriate nucleo-
phile should regenerate the catalyst.
Table 1. Survey of Acylation Precursors
We initiated our investigations by examining R-bromodihydro-
cinnamaldehyde, easily prepared from hydrocinnamaldehyde and
NBS in the presence of proline.9 The haloaldehyde was treated with
benzyl alcohol and triethylamine in the presence of the carbene
precursor. Of the three common classes of azolium salts, thiazolium
A and triazolium B proved to be catalytically competent, while
imidazolium C provided only traces of product (eq 1). The
efficiency of this transformation is worth noting: the reaction
proceeds well with only one equivalent of alcohol, haloaldehyde,
and amine base at ambient temperatures to provide the ester in 80%
yield.
a Reactions conducted with one equivalent each of benzyl alcohol and
triethylamine in the presence of 20 mol % triazolium catalyst at ambient
temperature, unless otherwise stated.
With these results in hand, we examined the effect of various
haloaldehydes in this reaction. Bromoacetaldehyde provided the
desired ester in 60% yield (Table 1, entry 1). Secondary and tertiary
bromides were efficient substrates for this reaction (entries 2 and
4), with tertiary bromides requiring a longer reaction time (24 h).
As expected, R-bromoaldehydes are more reactive than the
chlorinated analogues (entry 2 vs entry 3).
Next, we surveyed the range of nucleophiles that would
participate in the reaction. Primary alcohols work well (Table 2,
entries 1-3) providing the desired esters in good yield. An increase
in reaction time was required to obtain similar yields with secondary
alcohols (entries 4-5, 8). Phenols are competent substrates in this
chemistry as are anilines, suggesting that imine formation is not a
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C O M M U N I C A T I O N S
Table 2. Effect of Nucleophile Structure on the Internal Redox
Reaction
hydrobenzoin with R-bromocyclohexanecarboxaldehyde in the
presence of catalyst D provides the monoacylated diol in 75% yield
and 83% ee. No trace of the corresponding diacylated product was
1
evident by H NMR.
In summary, we have discovered a new reaction pathway
available to R-haloaldehydes catalyzed by nucleophillic carbenes.
Efforts to utilize this reactivity in other transformations are currently
underway.
Acknowledgment. We thank the National Science Foundation
(CAREER) for partial support of this work. J.R.A. thanks Colorado
PEAKS AGEP for a fellowship. T.R. gratefully acknowledges
Merck Research Laboratories for unrestricted support, and
GlaxoSmithKline and Amgen for young investigator awards.
Note Added in Proof. While this manuscript was in review, a
conceptually similar transformation was reported by Bode and
Chow; see Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 8126-8127.
Note Added after ASAP Publication. After this paper was
posted ASAP on July 9, 2004, yield and ee data were added to
eq 5. The corrected version was posted July 14, 2004.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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The use of a chiral carbene as a catalyst allows us to desym-
metrize meso diols using this approach. Treatment of meso-
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