Catalytic addition of metallo-aldehyde enolates to ketones: A new C-C bond-forming hydrogenation

Article abstract of DOI:10.1021/ol030136c

The first catalytic cross-aldolization of metallo-aldehyde enolates with ketone acceptors is enabled via hydrogenation of keto-enals with cationic rhodium catalysts. These results, in conjunction with prior studies involving the catalytic hydrogen-mediate

Full text of DOI:10.1021/ol030136c

ORGANIC
LETTERS
2004
Vol. 6, No. 5
691-694
Catalytic Addition of Metallo-Aldehyde
Enolates to Ketones: A New C−C
Bond-Forming Hydrogenation
Phillip K. Koech and Michael J. Krische*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received November 25, 2003
ABSTRACT
The first catalytic cross-aldolization of metallo-aldehyde enolates with ketone acceptors is enabled via hydrogenation of keto-enals with cationic
rhodium catalysts. These results, in conjunction with prior studies involving the catalytic hydrogen-mediated reductive coupling of enones,
dienes, and diynes with carbonyl acceptors, support the feasibility of developing a broad new class of catalytic C−C bond formations based
on the electrophilic trapping of hydrogenation intermediates.
Recently, a method for the catalytic generation and aldoliza-
tion of transition metal enolates via enone hydrogenation was
disclosed from our lab.1 Applicability of this methodology
toward intra- and intermolecular condensation of aromatic
and aliphatic enones with aldehyde partners has been
established.1a Additionally, a more challenging variant of the
aldol reaction, which employs ketones as electrophilic
partners, proceeds readily under hydrogenation conditions
to give cyclic aldol products in diastereomerically pure
form.1b Finally, the generality of catalytic hydrogenation as
a conceptually novel approach to reductive C-C bond
formation is demonstrated by the capacity of diverse
π-unsaturated partners, such as enones,1 dienes,2 and diynes,3
to participate in catalytic hydrogen-mediated condensations
with carbonyl partners.
To assess the limits of catalytic hydrogen-mediated C-C
bond formation vis-a`-vis aldol condensation, the catalytic
hydrogenation-aldolization of enals was explored. Aldoliza-
tions that proceed through the intermediacy of metallo-
aldehyde enolates are among the most challenging variants
of the aldol reaction known.4 Catalytic cross-aldolizations
of this type have only been achieved through amine catalysis5
and the use of enol silanes.6 The catalytic addition of metallo-
aldehyde enolates to ketones is, to our knowledge, unprec-
edented, as only a single stoichiometric variant of such an
aldolization is reported.7 In this account, we disclose that
catalytic aldol cyclization of keto-enals proceeds readily
under hydrogenation conditions to provide the corresponding
(4) (a) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: New York,
1991; Vol. 2, p 133. (b) Alcaide, B.; Almendros, P. Angew. Chem., Int.
Ed. 2003, 42, 858.
(5) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798. (b) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785.
(6) Denmark, S.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40, 4759.
(7) Yachi, K.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 1999, 121,
9465.
(1) (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 15156. (b) Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5,
1143.
(2) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. Angew. Chem., Int.
Ed. 2003, 42, 4074.
(3) Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 11488.
10.1021/ol030136c CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/30/2004

five- and six-membered ring products, along with modest
quantities of simple 1,4-reduction products.
moving to more electron deficient phosphine ligands, 2b is
obtained in greater than 70% yield (Table 1, entries 5 and
6). To ensure the cycloreductions proceed in accordance with
the postulated mechanism, several control experiments were
performed. Exposure of the conjugate reduction product to
the reaction conditions does not produce 2b. Conversely, 2b
does not undergo retro-aldolization upon exposure to the
reaction conditions. Enal 2a is unreactive toward triarylphos-
phine addition, excluding tandem Morita-Baylis-Hillman
cyclization-conjugate reduction pathways. Finally, upon
omission of hydrogen, no reaction is observed. The structural
assignment of 2b was corroborated by single-crystal X-ray
diffraction analysis of the corresponding carboxylic acid
(Table 1).
Under these optimized conditions, the scope of the
catalytic aldol cycloreduction of keto-enals was explored.
As demonstrated by the catalytic cycloreduction of substrates
1a and 2a, five-membered-ring formation proceeds well to
provide the bicyclic aldol products 1b and 2b in 72% and
73% yield, respectively. As illustrated by substrates 3a and
4a, cyclization to form six-membered rings occurs in slightly
diminished yield due to increasing levels of conjugate
reduction. Here, aldol products 3b and 4b are produced in
63% and 59% yields, respectively. The structural assignment
of 4b was corroborated by single-crystal X-ray diffraction
analysis (Scheme 1).
The primary issues limiting the utility of aldehyde enolates
in cross-aldolizations with ketone partners involve polyal-
dolization along with a diminished thermodynamic driving
force.8 It was recognized that intramolecular aldolization
should attenuate polyaldolization. Additionally, as aldoliza-
tion is primarily driven by chelation,9 intramolecular al-
dolization should also favorably bias the enolate-aldolate
equilibria. Predicated on this analysis, catalytic hydrogena-
tion-aldolization of keto-enal 2a was attempted. Exposure
of a solution of keto-enal 2a in dichloroethane (DCE) at 40
°C to RhI(COD)2OTf under an atmosphere of hydrogen (1
atm) in the presence of triphenylphosphine and potassium
acetate gave the aldol product 2b in 23% yield, accompanied
by a 50% yield of the product of simple conjugate reduction
(Table 1, entry 1). The conjugate reduction manifold should
Table 1. Optimization of the Catalytic Aldol Cycloreduction of
Keto-Enal 1aa
solvent
(concn)
yieldb
Scheme 1. Catalytic Aldol Cycloreduction of Keto-Enals
1a-4a
entry
ligand
Ph3P
Ph3P
Ph3P
Ph3P
(p-CF3Ph)3P
(2-furyl)3P
additive
(1,4-reduction)
1
2
3
4
5
6
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DCE (0.1 M)
DCE (0.1 M)
DCE (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
23% (50%)
40% (28%)
59% (29%)
65% (32%)
73% (22%)
73% (21%)
a Procedure: Toa25mLround-bottomedflaskchargedwithRh(COD)2OTf
(24 mg, 0.052 mmol, 10 mol %) and ligand (0.12 mmol, 24 mol %) was
added solvent. The mixture was stirred for 10 min under an argon
atmosphere, at which point 2a (100 mg, 0.52 mmol, 100 mol %) and base
(0.52 mmol, 100 mol %) were added. The system was purged with hydrogen
gas and the reaction was allowed to stir at 40 °C under 1 atm of hydrogen
until complete consumption of substrate. b Isolated yields after purification
by silica gel chromatography.
be attenuated by base-assisted entry into the monohydride
catalytic cycle (vide supra). Accordingly, substituting potas-
sium carbonate for potassium acetate, the yield of 2b is
increased to 40% (Table 1, entry 2). Reactions performed at
higher dilution provide 2b in 59% yield (Table 1, entry 3).
Under otherwise identical conditions, but in THF solvent,
the yield of 2b is increased to 65% (Table 1, entry 4). Finally,
To further explore the scope of this new catalytic variant
of the aldol reaction, a range of other substrates were
subjected to conditions for hydrogenation-aldolization. As
demonstrated by the cycloreduction of the indanedione
containing substrates 5a and 6a, aromatic ketones are viable
electrophilic partners. Keto-enals 7a and 8a highlight the
chemoselectivity of aldolization with regard to the use of
nonequivalent ketone acceptors. For 7a, steric bias in the
form of geminal dimethyl substitution induces addition to
the less encumbered ketone partner. In the case of 8a,
addition to the ketone occurs smoothly in the presence of
(8) As reported in ref 7, ab initio calculation (RHF/6-31G) revealed that
∆Hf for the â-hydroxyaldehyde (CH3)2C(OH)CH2CHO derived from
acetaldehyde and acetone is +21.155 kcal/mol, while ∆Hf for the isomeric
â-hydroxyketone CH3CH(OH)CH2COCH3 also derived from acetaldehyde
and acetone is -10.455 kcal/mol.
(9) The failure of tris(dialkylamino)sulfonium enolates to react with
aldehydes is attributed to unfavorable enolate-aldolate equilibria: Noyori,
R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc. 1980, 102,
1223.
692
Org. Lett., Vol. 6, No. 5, 2004

of the aldol products to the reaction conditions does not result
in retro-aldolization, the formation of 1,4-reduction products
is attributed to a modest enolate-aldolate equilibrium ratio
with kinetic trapping from the equilibrium mixture via
oxygen-hydrogen reductive elimination. Finally, modest
syn:anti ratios are consistent with the well-established lack
of stereoselectivity inherent to aldol additions employing
aldehyde enolates (Scheme 2).10
Scheme 2. Catalytic Aldol Cycloreduction of Keto-Enals
5a-9a
Mechanistically, we speculate that a key feature of these
catalytic C-C bond-forming hydrogenations involves het-
erolytic activation of elemental hydrogen to yield (mono-
hydrido)metal intermediates.11 Heterolytic activation of
hydrogen, which may be achieved through the deprotonation
of cationic rhodium dihydrides,12,13 enables monohydride-
based catalytic cycles that circumvent direct enolate-
hydrogen reductive elimination. The veracity of this analysis
is now borne out by a large body of empirical data (Scheme
3).1-3
In summation, the first catalytic addition of metallo-
aldehyde enolates to ketones is achieved through hydrogena-
tion-aldolization. Future studies will be devoted to the
development of related catalytic C-C bond-forming hydro-
genations, including the hydrogen-mediated reductive cou-
pling of simple alkenes to diverse electrophilic partners.
Acknowledgment. The authors thank to the Robert A.
Welch Foundation (F-1466), the NSF-CAREER program
(CHE0090441), the Herman Frasch Foundation (535-HF02),
the NIH (RO1 GM65149-01), the donors of the Petroleum
Research Fund, administered by the American Chemical
Society (34974-G1), the Research Corporation Cottrell
Scholar Award (CS0927), the Alfred P. Sloan Foundation,
the Camille and Henry Dreyfus Foundation, Eli Lilly, and
the N-benzyl amide. Notably, hydrogenolytic cleavage of the
N-benzyl amide is not observed. As illustrated by the
cycloreduction of enal ketone 9a, addition to an appendant
monoketone proceeds with levels of efficiency comparable
to that of related 1,3-dione partners. In all cases, the
formation of aldol products is accompanied by significant
quantities of simple 1,4-reduction products. As resubmission
Scheme 3. A Possible Catalytic Mechanism for the Aldol Cycloreduction of Keto-Enals under Hydrogenation Conditions
Org. Lett., Vol. 6, No. 5, 2004
693

the UT Austin Center for Materials Research for partial
support of this research.
crystallographic data file in CIF format for the carboxylic
acid derived from 2b and the cis-decalone aldehyde 4b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
Supporting Information Available: H NMR, 13C NMR,
IR, and HRMS data for all new compounds and X-ray
OL030136C
(10) Heathcock et al. reveal that the kinetic stereoselectivity in the
addition of both Z- and E-lithium enolates of propanal to benzaldehyde
gives 1:1 mixtures of syn- and anti-aldol products. Given that Z-lithium
ketone enolates generally exhibit good levels of syn-diastereoselectivity in
aldol additions, this result underscores the lack of stereoselectivity inherent
to aldol additions employing aldehyde enolates: Heathcock, C. H.; Buse,
C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org.
Chem. 1980, 45, 1066.
(12) Initiation of monohydride-based hydrogenation cycles via depro-
tonation of cationic Rh(III)-dihydrides is known: (a) Schrock, R. R.; Osborn,
J. A. J. Am. Chem. Soc. 1976, 98, 2134. (b) Schrock, R. R.; Osborn, J. A.
J. Am. Chem. Soc. 1976, 98, 2143. (c) Schrock, R. R.; Osborn, J. A. J. Am.
Chem. Soc. 1976, 98, 4450.
(13) For a review on the acidity of metal hydrides, see: Norton, J. R. In
Transition Metal Hydrides; Dedieu, A., Ed.: VCH Publishers: New York,
1992; Chapter 9.
(11) For a review on the heterolytic activation of elemental hydrogen,
see: Brothers, P. J. Prog. Inorg. Chem. 1981, 28, 1.
694
Org. Lett., Vol. 6, No. 5, 2004