Reductive generation of enolates from enones using elemental hydrogen: Catalytic C-C bond formation under hydrogenative conditions

Article abstract of DOI:10.1021/ja021163l

Exposure of enones to elemental hydrogen in the presence of a Rh(I) catalyst enables reductive enolate generation, as evidenced by electrophilic trapping of the enolate by appendant and exogenous aldehyde partners. The significance of these findings resides in the ability to regioselectivity generate and transform transition metal enolates under catalytic conditions that circumvent formation of stoichiometric byproducts. Copyright

Full text of DOI:10.1021/ja021163l

Published on Web 11/28/2002
Reductive Generation of Enolates from Enones Using Elemental Hydrogen:
Catalytic C-C Bond Formation under Hydrogenative Conditions
Hye-Young Jang, Ryan R. Huddleston, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received September 9, 2002
Scheme 1. Proposed Catalytic Cycle: Conjugate Reduction
versus Electrophilic Trapping
Enolates are among the most broadly utilized reactive intermedi-
ates in organic chemistry.1 Despite the fundamental significance
of enolate chemistry, there is a paucity of mechanistically distinct
methods for enolate generation. Most often, enolate formation is
accomplished through deprotonation of carbonyl compounds or acti-
vation of related enol derivatives. Seminal studies by Stork demon-
strate that stoichiometric generation of enolates may be achieved
via dissolving metal reduction of enones.2 Subsequently, catalytic
hydrometalative methods for the reductive generation of enolates
and enol derivatives from R,â-unsaturated carbonyl compounds have
emerged: catalytic enone 1,4-hydrosilation,3 1,4-hydroboration,4
1,4-hydroalumination,5 and 1,4-hydrostannylation.6,8e The avail-
ability of catalytic methods for reductive enolate generation has
enabled the development of an emerging family of catalytic C-C
bond-forming processes.7
While the conjugate reduction of enones under hydrogenation
conditions is well known,8 to our knowledge, the reductive gener-
ation of enolates from enones under hydrogenative conditions is
unknown and would represent a mild and atom economical means
of enolate generation. Here, we report a catalytic protocol for the
reductive generation of transition metal enolates using elemental
hydrogen as terminal reductant. Transition metal enolates generated
in this fashion are subject to electrophilic trapping by appendant
or exogenous aldehyde partners, enabling catalytic C-C bond for-
mation under hydrogenative conditions (eqs 1 and 2, respectively).
should result in formation of Rh-aldolate III, which upon oxygen-
hydrogen reductive elimination, should afford the aldol product
along with LnRh(I) to complete the catalytic cycle (Scheme 1).
To explore the feasibility of catalytic C-C bond formation under
hydrogenative conditions, solutions of phenyl-substituted mono-
enone monoaldehyde 1a in dichloroethane (DCE, 0.1 M) were ex-
posed to various Rh(I) sources under 1 atm of hydrogen. While the
majority of Rh-catalysts screened produce products of 1,4-reduction,
Rh(COD)2OTf/PPh3 gives roughly equal proportions of syn-aldol
cycloreduction product 1b and 1,4-reduction product 1c (Table 1,
entry 1). It was speculated that deprotonation of (hydrido)Rh species
I or II would disable the 1,4-reduction manifold. Indeed, transfor-
mations conducted in the presence of potassium acetate produce
1b in 59% yield, along with a 21% yield of 1,4-reduction product
1c (Table 1, entry 2). Exposure of conjugate reduction product 1c
to identical conditions does not produce 1b. Additionally, enone
1a is unreactive toward triarylphosphine addition, thus excluding
tandem Baylis-Hillman cyclization-conjugate reduction pathways
en route to 1b. It was speculated that enhanced Lewis acidity of
the metal would promote coordination of the appendant aldehyde,
in turn, promoting aldol cyclization. Accordingly, utilization of (p-
CF3Ph)3P as ligand, in the absence of base, results in a 53% yield
of 1b, along with a 22% yield of 1c (Table 1, entry 3). Taking
advantage of both potassium acetate and ligand electronic effects,
we found that the yield of 1b is increased to 89%, with only 0.1%
1,4-reduction (Table 1, entry 4). The latter conditions proved general
The generally accepted mechanism for Rh-catalyzed alkene
hydrogenation involves three fundamental steps: (1) oxidative addi-
tion of LnRh(I) to elemental hydrogen, (2) alkene hydrometalation
to afford LnRh(III)(alkyl)(hydrido) intermediates, and (3) alkyl-
hydrogen reductive elimination to provide the saturated product
along with LnRh(I) to complete the catalytic cycle.9,10 Hypotheti-
cally, in the presence of an exogenous electrophile, trapping of the
alkyl-rhodium intermediate might occur in competition with alkyl-
hydrogen reductive elimination. Moreover, were the electrophilic
trap appended to the nascent alkyl-rhodium intermediate, C-C bond
formation may fully intercede the reductive elimination event.
Predicated on this analysis, hydrogenative cycloreduction of mono-
enone monoaldehydes was deemed feasible. Enone hydrometalation
should produce Rh-enolate II. Addition to the appendant aldehyde
Table 1. Optimization of Rh-Catalyzed Hydrogenative Aldol
Cycloreduction of 1aa
entry
ligand
additive (mol %) yieldb aldol (syn−anti) yieldb 1,4-reduction
1
2
3
4
PPh3
21% (99:1)
59% (58:1)
57% (14:1)
89% (10:1)
25%
21%
22%
0.1%
PPh3
KOAc (30%)
(p-CF3Ph)3P
(p-CF3Ph)3P KOAc (30%)
a As product ratios were found to vary with surface-to-volume ratio of
the reaction mixture, all transformations were conducted on a 1.48 mmol
scale in 50 mL round-bottomed flasks. b Isolated yields after purification
by silica gel chromatography.
* To whom correspondence should be addressed. E-mail: mkrische@
mail.utexas.edu.
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J. AM. CHEM. SOC. 2002, 124, 15156-15157
10.1021/ja021163l CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Rh-Catalyzed Hydrogenative Aldol Cycloreduction of
Monoenone Monoaldehydes 1a-7aa
reductive aldol condensation of aromatic and heteroaromatic alde-
hyde partners (Table 4, entries 1-5). Aliphatic aldehydes participate
in the reaction, but their reduced rate of reaction exacerbates the
issue of competitive conjugate reduction, resulting in diminished
yields (Table 4, entry 6).
Tolerance with respect to variation of the nucleophilic partner
next was explored. Whereas ethyl acrylate exclusively provides pro-
ducts of 1,4-reduction, methyl vinyl ketone undergoes reaction with
p-nitrobenzaldehyde to provide a 70% yield of the aldol product.
substrate
product (syn:anti)
1,4-reduction
1a, n ) 2, R ) Ph
1b, 89% (10:1)
2b, 74% (5:1)
3b, 90% (10:1)
4b, 76% (19:1)
5b, 70% (6:1)
6b, 71% (24:1)
7b, 65% (1:5)
1c, 0.1%
2c, 3%
3c, 1%
4c, 2%
5c, 10%
6c, 1%
2a, n ) 2, R ) p-MeOPh
3a, n ) 2, R ) 2-naphthyl
4a, n) 2, R ) 2-thiophenyl
5a, n ) 2, R ) 2-furyl
6a, n ) 1, R ) Ph
7a, n ) 2, R ) CH3
a See Supporting Information for detailed experimental procedure.
for cycloreduction of aromatic, heteroaromatic, and aliphatic enone
substrates to form five- and six-membered ring products (Table 2).
Competitive conjugate reduction rendered the outcome of
intermolecular condensation uncertain. To assess the feasibility of
an intermolecular variant, initial studies focused on the reductive
condensation of phenyl vinyl ketone and p-nitrobenzaldehyde.
Remarkably, addition of 10 mol % catalyst and 50 mol % KOAc
to an equimolar solution of enone/aldehyde partners in dichloro-
ethane (0.5 M) under 1 atm of hydrogen gave a 53% yield of the
aldol product 8 (Table 3, entry 1). As competitive enone conjugate
In summary, we report a catalytic C-C bond formation under
hydrogenative conditions. The significance of these findings resides
in the ability to regioselectivity generate and transform transition
metal enolates under catalytic conditions that circumvent formation
of stoichiometric byproducts. Future studies will focus on the
development of related hydrogenative catalytic transformations
predicated on the use of enones as latent enolates.
Acknowledgment. We acknowledge the Robert A. Welch Foun-
dation (F-1466), the NSF-CAREER program (CHE0090441), the
Herman Frasch Foundation (535-HF02), the NIH (RO1 GM65149-
01), Eli Lilly Faculty Grantee Program, and the Research Corp.
Cottrell Scholar Award (CS0927) for partial support of this research.
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Table 3. Optimization of the Intermolecular Rh-Catalyzed
Hydrogenative Aldol Condensation
entry
enone (mol %)
catalysts (mol %)
conc. (mol/L)
KOAc (mol %)
yielda
References
1
2
3
4
5
100
150
150
150
150
10
10
10
5
0.5
0.5
0.1
0.1
0.5
50
50
50
50
53%
75%
85%
92%
79%
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5
a Isolated yields after purification by silica gel chromatography.
reduction accounted for the mass balance, the reaction was repeated
using 1.5 equiv of the enone. A 75% yield of the aldol 8 was
obtained (Table 3, entry 2). Under more dilute conditions (0.1 M),
the yield of 8 was increased to 85% (Table 3, entry 3). When the
amount of catalyst was reduced to 5%, the yield of 8 increased
further to 92% (Table 3, entry 4). Notably, omission of KOAc under
these conditions gave a 79% yield of aldol product 8 (Table 3,
entry 5). Exposure of propiophenone to the optimized conditions
does not result in aldolization. Additionally, phenyl vinyl ketone
does not engage in Baylis-Hillman chemistry under these condi-
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a See Supporting Information for detailed experimental procedure.
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