Rhodium-catalyzed reductive aldol reactions using aldehydes as the stoichiometric reductants

Article abstract of DOI:10.1021/ja056130v

Chelated acyl rhodium hydrides, generated from the addition of [Rh(dppe)]ClO₄ to β-sulfide-substituted aldehydes, can function as the stoichiometric reductants in reductive aldol processes. Unsaturated nitriles, esters, and ketones can be used as enolate equivalents, and a variety of simple α- and β-substituted aldehydes can be employed. The use of a second, more electrophilic, aldehyde allows three-component reactions to be performed. Copyright

Full text of DOI:10.1021/ja056130v

Published on Web 12/03/2005
Rhodium-Catalyzed Reductive Aldol Reactions Using Aldehydes as the
Stoichiometric Reductants
Michael C. Willis* and Robert L. Woodward
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, U.K.
Received September 6, 2005; E-mail: m.c.willis@bath.ac.uk
Transition metal catalyzed reductive aldol reactions are proving
to be valuable synthetic tools. They allow the required enolates to
be generated regioselectively in situ, can be catalyzed by a number
Table 1. Scope of the Rh-Catalyzed Reductive Aldol Reaction
Using â-Sulfide-Substituted Aldehydes as Reductants and
Electrophilesa
1
of different metals, and have recently been shown to deliver good
2
levels of diastereo- and enantioselectivity. Despite these attributes,
there still remain limitations stemming from the use of stoichio-
metric reductants, such as silanes or molecular hydrogen. In
particular, the formation of side products, such as enol silanes, or
C-C or C-O double-bond reduction products, can be responsible
3
for reduced efficiency. In this Communication, we report the
development of a versatile new reductive aldol process that employs
aldehydes as the stoichiometric reductants.
During a recent investigation into chelation-controlled Rh(I)-
catalyzed intermolecular hydroacylation reactions, we attempted to
generate ketone 1 through the union of â-methyl sulfide-substituted
4
propanal 2 and acrylonitrile (reaction 1). While none of the desired
ketone was generated, we isolated ester 3 in good yield (reaction
2). Despite the absence of a recognized reductant in the reagent
system, ester 3 represents the acylated version of the reductive aldol
5
product generated from aldehyde 2 and acrylonitrile. The lack of
precedent for this transformation prompted us to investigate the
scope and mechanism of this intriguing process.6
Under the conditions developed for our hydroacylation chemistry
4
([Rh(dppe)]ClO (10 mol %), DCE, 70 °C, 8 h), the reductive aldol
process proved to be tolerant of a variety of aldehyde and alkene
substrates (Table 1).7 Variation of the size and/or electronic
properties of the sulfide group proved to have little effect on the
reaction, with Me-, Et-, and Ph-sulfide-substituted aldehydes all
combining with acrylonitrile with comparable yields (entries 1-3).
The introduction of R- or â-methyl or â-phenyl substituents on the
aldehyde was also accepted well (entries 4-6). Similarly, the R,â-
dimethylated aldehyde combined with acrylonitrile to deliver the
acylated adduct in an excellent 93% yield (entry 7). We next
,8
a
Conditions: aldehyde (1.0 equiv), alkene (5.0 equiv), [Rh(dppe)]ClO4
9
explored variation in the nature of the electron-poor alkene. Both
(10 mol %), DCE, 70 °C. Catalyst generated in situ from [Rh(dppe)-
(
nbd)]ClO4 and H2. b Isolated yields. c See Supporting Information for
methyl- and phenylvinyl ketone could be combined with the simple
ethyl sulfide-substituted aldehyde to deliver the esterified aldol
adducts in good yields (entries 8 and 9). Although we have
previously shown that simple unsaturated alkyl esters undergo
d
diastereomeric ratios. Starting aldehyde used as a 1:1 mixture of diaster-
eomers. e With 3% of the hydroacylation adduct observed by 1H NMR.
catalyst loading. For example, reaction between aldehyde 2 and
acrylonitrile (reaction 2) can be achieved with only 1 mol % catalyst
in 36 h at 70 °C to deliver ester 3 in 77% yield.
Having demonstrated the utility of the process to deliver a range
of aldol adducts, we began to investigate potential mechanisms;
two possibilities are outlined in Scheme 1. Both commence with
4
hydroacylation chemistry, we were pleased to find that the use of
the more electron-poor phenyl acrylate allowed the reductive aldol
pathway to be followed (entry 10).
To provide convenient reaction times, we routinely employed
10 mol % of the catalyst; however, it was possible to lower the
18012
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J. AM. CHEM. SOC. 2005, 127, 18012-18013
10.1021/ja056130v CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
â-sulfide substituent is present, a variety of simple R- and
â-substituted aldehydes can be employed. The use of a second,
more electrophilic, aldehyde allows three-component reactions to
be performed. Although the diastereoselectivities observed were
poor, no effort at optimization was attempted during this initial
study, with the focus being to secure efficient bond construction.
Chelated acyl rhodium hydrides, such as 4, represent a new class
of hydrides for use in synthesis; this opening investigation has
demonstrated their reactivity and potential to act as alternatives to
traditional reducing systems. Further investigations exploring their
reactivity, alternative applications, and asymmetric variants are
underway.
Acknowledgment. This work was supported by the EPSRC.
The EPSRC Mass Spectrometry Service at the University of Wales
Swansea is also thanked for their assistance. We would like to thank
Helen Randell-Sly for assistance with catalyst preparation, and
Stephen McNally for preliminary results.
Supporting Information Available: Experimental procedures and
full characterization for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
the oxidative addition of Rh(I) into the aldehyde C-H bond to
generate chelated acyl rhodium hydride 4. Path A continues with
addition of the rhodium acyl across acrylonitrile in the manner of
a hydroacylation reaction, to generate ketone 5. Tischenko-like
reduction of ketone 5,11 involving a second equivalent of rhodium
acyl 4, then affords ester 3. Path B involves conjugate addition of
the hydride present in intermediate 4 to acrylonitrile, generating
rhodium enolate 6.12 Addition of the enolate to a further equivalent
of the starting aldehyde delivers aldolate 7, which can reductively
eliminate Rh(I) to provide the final esterified aldol adduct.
10
References
(
1) Rh: (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809-4812.
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Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985-
Scheme 2 a
1
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3) For relevant reviews, see; (a) Jang, H.-Y.; Krische, M. K. Acc. Chem.
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(
4) Willis, M. C.; McNally, S. J.; Beswick, P. J. Angew. Chem., Int. Ed. 2004,
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a
[Rh(dppe)]ClO4 (10 mol %), DCE, 70 °C, 16 h.
(5) For the formation of a similar acylated adduct in a Rh-catalyzed silane-
mediated reductive aldol, see ref 2b.
To test for the intermediacy of ketone 5, we independently
prepared this ketone and attempted to convert it to ester 3; exposure
of the ketone to the standard reaction conditions resulted in no
reaction. To investigate the possibility of an enolate intermediate,
we sought to trap the enolate with an alternative aldehyde; a three-
component reaction involving sulfide-substituted aldehyde 2, acry-
lonitrile, and tert-butyl glyoxylate provided acylated aldol adduct
(6) For a related Rh(I)-catalyzed alkynal redox process, see; Tanaka, K.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 1607-1609.
(7) See Supporting Information for details.
(8) The diastereoselectivities obtained in all reductive aldol reactions were
only modest, ranging from 1:1 to 3.3:1.
(
9) Using the present reaction conditions, we have been unable to utilize
substituted alkenes in the reductive aldol process.
(10) This requires the hydroacylation to provide the branched adduct. In
reactions with aldehyde 2, we have only observed this for a single electron-
poor alkene, phenylvinyl sulfone.
8
in good yield (Scheme 2). Alternatively, acrylonitrile could be
replaced with phenylvinyl ketone to provide adduct 9 in excellent
yield. Finally, the use of deuterated aldehyde 10 delivered ester
(
11) For examples of Rh-catalyzed Tischenko-like processes, see; (a) Bergens,
S. H.; Fairlie, D. P.; Bosnich, B. Organometallics 1990, 9, 566-571. (b)
Slough, G. A.; Ashbaugh, J. R.; Zannoni, L. A. Organometallics 1994,
11, in which deuterium incorporation occurred exclusively â to the
1
3, 3587-3593. (c) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
original ketone. Taken together, these preliminary investigations
124, 1674-1679. See also ref 2b.
are consistent with path B (Scheme 1).
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898. (c) Slough, G. A.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem.
Soc. 1989, 111, 938-949.
In conclusion, we have demonstrated that catalytically generated
chelated acyl rhodium hydrides can function as the stoichiometric
reductants in reductive aldol processes. Unsaturated nitriles, esters,
and ketones can be used as enolate equivalents, and provided a
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J. AM. CHEM. SOC.
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