Enolate generation under hydrogenation conditions: catalytic aldol cycloreduction of keto-enones.

Article abstract of DOI:10.1021/ol0300219

[reaction: see text] Formal heterolytic activation of elemental hydrogen under Rh catalysis enables the reductive generation of enolates from enones under hydrogenation conditions. Enolates generated in this fashion participate in catalytic C-C bond formation via carbonyl addition to aldehyde and, as demonstrated in this account, ketone partners. Notably, the use of appendant dione partners enables diastereoselective formation of cycloaldol products possessing 3-stereogenic centers, including 2-contiguous quaternary centers.

Full text of DOI:10.1021/ol0300219

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1143-1146
Enolate Generation under Hydrogenation
Conditions: Catalytic Aldol
Cycloreduction of Keto-Enones
Ryan R. Huddleston and Michael J. Krische*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received February 11, 2003
ABSTRACT
Formal heterolytic activation of elemental hydrogen under Rh catalysis enables the reductive generation of enolates from enones under
hydrogenation conditions. Enolates generated in this fashion participate in catalytic C−C bond formation via carbonyl addition to aldehyde
and, as demonstrated in this account, ketone partners. Notably, the use of appendant dione partners enables diastereoselective formation of
cycloaldol products possessing 3-stereogenic centers, including 2-contiguous quaternary centers.
While the significance of metalloenolates as reactive inter-
mediates in organic chemistry is universally appreciated,
preparatively useful protocols for enolate generation are
largely restricted to the deprotonation and derivatization of
carbonyl compounds.1 Recently, a method for the production
and catalytic transformation of transition metal enolates via
enone hydrogenation was disclosed by our lab.2 This method
effects regioselective enolate formation under mild conditions
(ambient temperatures and pressures) and has led to the first
completely atom economical catalytic reductive aldol proc-
ess.3,4 Applicability of this methodology vis-a`-vis intra- and
intermolecular condensation with aldehyde partners has been
established.2 The outcome of related condensations employ-
ing ketone partners was rendered uncertain, as competitive
conjugate reduction in response to reduced reactivity of the
electrophilic partner was anticipated. In this account, we
report that catalytic intramolecular aldol cycloreduction under
hydrogenative conditions proceeds readily with ketone
partners to provide the corresponding five- and six-membered
ring products.5 Through the use of dione acceptors, 3-stereo-
genic centers, including 2-contiguous quaternary centers, are
(3) For related catalytic reductive aldol processes, see: (a) Revis, A.;
Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi,
K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331. (c) Isayama, S.; Mukaiyama,
T. Chem. Lett. 1989, 2005. (d) Kiyooka, S.; Shimizu, A.; Torii, S.
Tetrahedron Lett. 1998, 39, 5237. (e) Ooi, T.; Doda, K.; Sakai, D.; Maruoka,
K. Tetrahedron Lett. 1999, 40, 2133. (f) Taylor, S. J.; Morken, J. P. J. Am.
Chem. Soc. 1999, 121, 12202. (g) Taylor, S. J.; Duffey, M. O.; Morken, J.
P. J. Am. Chem. Soc. 2000, 122, 4528. (h) Zhao, C.-X.; Duffey, M. O.;
Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829. (i) Baik, T.-G.; Luiz,
A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112. (j)
Emiabata-Smith, D.; McKillop, A.; Mills, C.; Motherwell, W. B.; White-
head, A. J. Synlett 2001, 1302.
(1) For selected reviews on the generation and utilization of enolates,
see: (a) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917. (b) Hughes, D. L. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, 1999; Vol. III, p 1273. (c) Evans, D. A.
Asymmetric Synth. 1984, 3, 1. (d) Jackman, L. M.; Lange, B. C. Tetrahedron
1977, 33, 2737. (e) Mekelburger, H. B.; Wilcox, C. S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Permagon: New York, 1991; Vol.
II, p 99.
(2) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 15156.
(4) For a review on the use of enones as latent enolates in catalysis, see:
Huddleston, R. R.; Krische, M. J. Synlett 2003, 12.
10.1021/ol0300219 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/06/2003

Scheme 1. Formal Heterolytic Activation of Elemental Hydrogen Mitigates Competitive Conjugate Reduction Manifolds by Enabling
Monohydride-Based Catalytic Cycles.
formed with control of the relative stereochemistry in a
completely atom economical fashion.
under hydrogenation conditions was studied using (COD)2-
RhI(OTf) as a precatalyst. A mechanism was envisioned
whereby enolate-hydrogen reductive elimination pathways
are disabled through deprotonation of the (hydrido)metal
intermediates LnRhIII(H)2 or (enolato)RhIII(H)Ln (Scheme 1).
The principal challenge in using elemental hydrogen for
reductive enolate generation involves circumventing 1,4-
reduction.6 To overcome this pitfall, it was speculated that
hydrogenative enolate generation might be achieved upon
formal heterolytic activation of elemental hydrogen to yield
(monohydrido)metal intermediates.7 Formal heterolytic ac-
tivation of hydrogen may occur through tandem oxidative
addition of hydrogen, followed by reductive elimination of
HX, which may be assisted by base. Unlike the mechanism
for alkene hydrogenation involving Wilkinson’s catalyst,8,9
cationic rhodium complexes appear to operate through formal
heterolytic hydrogen activation pathways.7,10,11 This is likely
due to the enhanced acidity of cationic rhodium hydrides
with respect to their neutral counterparts.12 Predicated on this
analysis, and given the established efficiency of aldol
additions involving rhodium enolates,13 aldol cycloreduction
To probe the viability of ketones as electrophilic partners,
the cycloreduction of monoenone monoketone 1a was
explored. Exposure of 1a to conditions related to those
employed for intra- and intermolecular condensation with
aldehyde partners resulted in formation of the desired aldol
product, accompanied by substantial quantities of conjugate
reduction product 1c. While these reactions proceed readily
at room temperature, decreased variation in the ratio of
cycloreduction to conjugate reduction products was observed
at higher temperatures, presumably due to an attendant
decrease in the concentration of hydrogen in solution. Under
these conditions, syn-1b was obtained in 72% isolated yield
as a single diastereomer as determined by 1H NMR analysis,
along with a 20% isolated yield of conjugate reduction
product 1c. The structural assignment of 1b was corroborated
by single-crystal X-ray diffraction analysis.5 For this and
other transformations, a series of control experiments were
routinely performed to ensure the cycloreductions proceed
in accordance with the postulated mechanism. Exposure of
conjugate reduction product 1c to the reaction conditions does
not produce 1b. Conversely, aldol product 1b does not
undergo retro-aldolization upon exposure to the reaction
conditions. Additionally, â-substituted enones are unreactive
toward triarylphosphine addition, thus excluding tandem
Morita-Baylis-Hillman cyclization-conjugate reduction
pathways. These conditions proved to be general for the syn-
(5) Borane-mediated aldol cycloreduction of keto-enones was recently
reported by our lab: Huddleston, R. R.; Cauble, D. F.; Krische, M. J. J.
Org. Chem. 2003, 68, 11.
(6) For selected reviews on the conjugate reduction of enones via catalytic
hydrogenation, see: (a) Keinan, E.; Greenspoon, N. Partial Reduction of
Enones, Styrenes and Related Systems. In ComprehensiVe Organic Syn-
thesis; Trost, B. M., Ed.; Permagon: New York, 1991; Vol. III, p 523. (b)
House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park,
CA, 1972. (c) James, B. R. Homogeneous Hydrogenation; Wiley-Inter-
science: New York, 1973. (d) Rylander, P. N. Hydrogenation Methods;
Academic Press: London, 1985. (e) Rylander, P. N. Catalytic Hydrogena-
tion in Organic Synthesis; Academic Press: New York, 1979. (f) Freifelder,
M. Catalytic Hydrogenation in Organic Synthesis; Wiley-Interscience: New
York, 1978.
(7) For a review on the heterolytic activation of elemental hydrogen,
see: Brothers, P. J. Prog. Inorg. Chem. 1981, 28, 1.
(8) (a) Tolman, C. A.; Meakin, P. Z.; Lindner, D. L.; Jesson, J. P. J.
Am. Chem. Soc. 1974, 96, 2762. (b) Halpern, J.; Okamoto, T.; Zakhariev,
A. J. Mol. Catal. 1976, 2, 65.
(9) For a review, see: Marko, L. Pure Appl. Chem. 1979, 51, 2211.
(10) Monohydride formation by deprotonation of a dihydride intermediate
is known for cationic Rh complexes: (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.
(11) Direct heterolytic activation of hydrogen by RhCl(CO)(PPh3)2 has
been suggested, but the mechanism likely involves an intermediate
dihydride: Evans, D.; Osborn, J. A.; Wilkinson, G. J. Chem. Soc., A 1968,
3133.
(13) For a review, see: Burkhardt, E. R.; Doney, J. J.; Slough, G. A.;
Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988,
60, 1.
(14) Procedure: To a 13 × 100 mm test tube charged with Rh(COD)2OTf
(0.0462 mmol, 10 mol %) and Ph3P (0.111 mmol, 24 mol %) was added
DCE (0.185 M, 2.5 mL). The mixture was stirred for 10 min under an
argon atmosphere, at which point the substrate (0.462 mmol, 100 mol %)
and K2CO3 (0.37 mmol, 80 mol %) were added. The system was purged
with hydrogen gas for 3 min, and the reaction was allowed to stir at 80 °C
under 1 atm of hydrogen until complete consumption of the substrate. Yields
represent averages of three runs. Cycloreductions to produce compounds
6b, 12b, and 13b-18b were conducted at 25 °C.
(12) For a review, see: Norton, J. R. In Transition Metal Hydrides;
Dedieu, A. Ed.; New York, 1992, Chapter 9.
1144
Org. Lett., Vol. 5, No. 7, 2003

selective aldol cycloreduction of aromatic and heteroaromatic
enone substrates to form six-membered ring products. In all
cases, formation of the cycloreduction product was ac-
companied by 8-20% isolated yield of the corresponding
conjugate reduction product. As product ratios were found
to vary with surface/volume ratio of the reaction mixture,
all transformations were conducted on 1.48 mmol scale in
13 × 100 mm sealed test tubes (Figure 1).
The structural assignment of 15b was corroborated by single-
crystal X-ray diffraction analysis. With the exception of
substrate 18a, which affords strained cis-decalone 18b, 1,4-
reduction products were not produced. This method enables
diastereoselective formation of 3-contiguous stereogenic
centers, including 2-contiguous quaternary centers (Scheme
2).
Scheme 2. Catalytic Hydrogenative Cycloreduction of
Dione-enones14
Figure 1. Catalytic hydrogenative cycloreduction of keto-enones:
six-membered ring formation.14
The formation of five-membered rings also proceeds
smoothly for both aromatic and heteroaromatic enone
substrates under these conditions. Cycloreduction products
7b-12b were obtained as single diastereomers, as deter-
1
mined by H NMR analysis. Again, due to the reduced
To corroborate the mechanism proposed in Scheme 1 and
further explore the effect of ketone electronics on the extent
of conjugate reduction, the aldol cycloreduction of ether-
containing substrate 19a was explored under catalytic
hydrogenation conditions employing molecular deuterium
(98% isotopic purity). The syn-aldol cycloreduction product
19b was obtained in 83% yield. Conjugate reduction was
not observed. For 19b, deuterium was exclusively incorpo-
rated at the â-position. In addition to monodeuterated
material (81% composition), doubly deuterated (8% com-
position) and nondeuterated materials (11% composition)
were also observed. These data suggest that enone hydro-
metalation is reversible, i.e., â-hydride elimination of the
Rh-enolate occurs.
electrophilicity of the ketone acceptor, the formation of each
cycloreduction product was accompanied by 8-24% isolated
yield of the corresponding conjugate reduction product
(Figure 2).
In summary, elemental hydrogen represents a clean and
cost-effective reductant for the catalytic generation and
transformation of rhodium-enolates. Unlike reductive C-C
bond formations employing silane, borane, alane, and stan-
Figure 2. Catalytic hydrogenative cycloreduction of keto-enones:
five-membered ring formation.14
Scheme 3. Catalytic Cycloreduction Employing Elemental
The cycloreduction of monoenone monoketones 1a-12a
was accompanied by significant quantities of conjugation
reduction (8-24%). Conjugate reduction pathways should
be attenuated in the case of more reactive ketone electro-
philes. Dione-containing substrates 13a-18a should be more
reactive by virtue of inductive effects and relief of dipole-
dipole interactions. Indeed, exposure of enone-diones 13a-
18a to catalytic hydrogenation conditions at ambient tem-
perature led to formation of the corresponding bicyclic aldol
products 13b-18b in >95:5 d.e. as determined by 1H NMR.
Deuterium
Org. Lett., Vol. 5, No. 7, 2003
1145

nane as terminal reductants, the use of elemental hydrogen
circumvents formation of stoichiometric byproducts. Enolate
nucleophiles generated under hydrogenation conditions readily
participate in catalytic C-C bond formation via carbonyl
addition to aldehyde and, as demonstrated in this account,
ketone partners. Notably, the use of appendant dione partners
enables diastereoselective formation of cycloaldol products
possessing 3-stereogenic centers, including 2-contiguous
quaternary centers. Future studies will be devoted to the
development of related C-C bond formations induced
through catalytic hydrogenation of alkene pronucleophiles.
program (CHE0090441), the Herman Frasch Foundation
(535-HF02), the NIH (RO1 GM65149-01), 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 and Eli Lilly for partial support of this research.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS) and X-ray
crystallographic data for 15b. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-1466), the NSF-CAREER
OL0300219
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Org. Lett., Vol. 5, No. 7, 2003