Hydrogen-mediated aldol reductive coupling of vinyl ketones catalyzed by rhodium: High syn-selectivity through the effect of tri-2-furylphosphine

Article abstract of DOI:10.1021/ol052859x

Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of diverse aldehydes at ambient temperature and pressure using tri-2-furylphosphine-ligated rhodium catalysts enables formation of aldol products with high l

Full text of DOI:10.1021/ol052859x

ORGANIC
LETTERS
2006
Vol. 8, No. 3
519-522
Hydrogen-Mediated Aldol Reductive
Coupling of Vinyl Ketones Catalyzed by
Rhodium: High Syn-Selectivity through
the Effect of Tri-2-furylphosphine
Cheol-Kyu Jung, Susan A. Garner, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received November 25, 2005
ABSTRACT
Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of diverse aldehydes at ambient temperature
and pressure using tri-2-furylphosphine-ligated rhodium catalysts enables formation of aldol products with high levels of syn-diastereoselectivity.
A progressive increase in diastereoselectivity is observed upon sequential replacement of phenyl residues for 2-furyl residues (Ph3P, FurPh2P,
Fur2PhP, Fur3P). Hydrogen-labile functional groups, including alkynes, alkenes, benzylic ethers, and nitroarenes, remain intact under the
coupling conditions.
The aldol reaction has been known for over a century.1
Stimulated by the observation that Z- and E-enolates may
react stereospecifically to provide syn- and anti-addition
products,2 several catalyzed aldol additions have been
developed that address relative and absolute stereocontrol.3
Much less attention has been devoted to catalytic systems
that attend to regio- and stereoselective enolization in aldol
additions involving ketones as nucleophilic partners.4 As first
demonstrated by Stork, regiospecific enolate formation may
be achieved through stoichiometric enone reduction,5 en-
abling generation of enolate isomers that cannot be formed
exclusively through acid-base-mediated enolization. Sub-
sequently, the direct metal-catalyzed reductive coupling of
enones to aldehydes was achieved, termed the “reductive
aldol reaction.” 6 To date, catalysts for reductive aldol
coupling based on cobalt,7 rhodium,8,9 iridium,10a palladium,10b
copper,10c,d and indium10e have been reported. In two cases,
(4) A classical example of the subtle factors governing regioselective
enolization of nonsymmetric ketones involves the deprotonation of steroidal
ketones. Whereas cholesteran-3-one exhibits a thermodynamic preference
for formation of the ∆3-enolate, with little kinetic selectivity for formation
of ∆2-enolate, introduction of 7,8-unsaturation results in a thermodynamic
preference for formation of the ∆2-enolate, with little kinetic selectivity
for formation of ∆3-enolate. (a) Velluz, L.; Valls, J.; Nomine, G. Angew.
Chem., Int. Ed. Engl. 1965, 4, 181. (b) Corey, E. J.; Sneen, R. A. J. Am.
Chem. Soc. 1955, 77, 2505. (c) Berkoz, B.; Chavez, E. P.; Djerassi, C. J.
Chem. Soc. 1962, 1323. (d) Mazur, Y.; Sondheimer, F. J. Am. Chem. Soc.
1958, 80, 6296.
(1) Though largely attributed to Wu¨rtz, the aldol reaction was reported
first by Borodin: (a) von Richter, V. Ber. Deut. Chem. Ges. 1869, 2, 552
(Borodin’s earliest results are cited in this article). (b) Wu¨rtz, A. Bull. Soc.
Chim. Fr. 1872, 17, 436.
(2) (a) Dubois, J.-E.; Dubois, M. Tetrahedron Lett. 1967, 8, 4215. (b)
Dubois, J.-E.; Fort, J.-F. Tetrahedron 1972, 28, 1653. (c) Dubois, J.-E.;
Fort, J.-F. Tetrahedron 1972, 28, 1665.
(3) For selected reviews on stereoselective aldol additions, see: (a)
Heathcock, C. H. Science 1981, 214, 395. (b) Heathcock, C. H. ACS Symp.
Ser. 1982, 185, 55. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top.
Stereochem. 1982, 13, 1. (d) Machajewski, T. D.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1352. (e) Palomo, C.; Oiarbide, M.; Garc´ıa, J.
M. Chem. Soc. ReV. 2004, 33, 65.
(5) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83,
2965. (b) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. J.
Am. Chem. Soc. 1965, 87, 275.
10.1021/ol052859x CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/31/2005

wherein acrylates are used as nucleophilic partners and
hydrosilanes serve as terminal reductant, diastereo- and
enantioselective aldolization has been achieved.8c,d,h
poor diastereoselectivity is observed in the reductive coupling
of MVK with p-nitrobenzaldehyde using triphenylphosphine
as ligand (Table 1, entry 1), the use of tri-2-furylphosphine
Here, using elemental hydrogen as terminal reductant, we
disclose the first highly diastereoselective reductive aldol
couplings of Vinyl ketones, which are achieved by virtue of
the unique properties of tri-2-furylphosphine.11 Specifically,
hydrogenation of methyl or ethyl vinyl ketone (MVK or
EVK) in the presence of structurally diverse aldehydes using
tri-2-furylphosphine-modified rhodium catalysts results in
reductive coupling to afford aldol products with exceptionally
high levels of syn-diastereoselection. Notably, the diaste-
reoselectivities observed in the present hydrogen-mediated
aldol additions, which are conducted at ambient temperature
and pressure, are comparable to and in many instances rival
those observed in related low-temperature aldol additions of
preformed lithium enolates.3a-c,12
Table 1. Optimization of the Diastereoselective
Hydrogen-Mediated Reductive Aldol Coupling To Afford 1aa,b
entry
ligand
PPh3
(2-Fur)Ph2P Li2CO3
(2-Fur)2PhP Li2CO3
(2-Fur)3P
AsPh3
(2-Fur)3P
(2-Fur)3P
additive
Li2CO3
[DCM], M yield, % dr
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
0.1
0.1
0.3
0.3
31
24
52
74
17
63
88
91
3:1
6:1
15:1
19:1
7:1
19:1
16:1
16:1
Li2CO3
Li2CO3
It was reasoned that a diastereoselective variant of the
rhodium-catalyzed hydrogen-mediated reductive aldol coup-
ling9a might be attained through use of the weakly coordinat-
ing, π-acidic ligand tri-2-furylphosphine.11 This ligand may
render the rhodium center more Lewis acidic by virtue of
its π-acidity, thus conferring heightened levels of stereo-
control by “tightening” the Zimmerman-Traxler-type transi-
tion structure.3 Alternatively, Fur3P may dissociate to
promote formation of enolate haptomers that embody enyl
(σ + π) character, which may influence the stereochemical
outcome of addition (vide supra).13 In the event, whereas
Li2CO3
Li2CO3 (10%)
w 8 (2-Fur)3P
a Optimized Procedure. To a 13 mm × 100 mm test tube charged with
Li2CO3 (5 mg, 0.066 mmol, 10 mol %), Fur3P (18 mg, 0.079 mmol, 12
mol %), Rh(COD)2OTf (16 mg, 0.033 mmol, 5 mol %), and aldehyde (100
mg, 0.66 mmol, 100 mol %) was added dichloromethane (1.0 M). The test
tube was sealed, and the reaction mixture was sparged with Ar(g) followed
by H2(g) for 20 s each. The reaction was placed under one atmosphere of
hydrogen using a balloon, and MVK (81 µL, 0.99 mmol, 150 mol %) was
added. The reaction mixture was allowed to stir until consumption of
aldehyde was observed, as revealed by TLC analysis. The reaction mixture
was evaporated onto silica, and the aldol product 1a was isolated by flash
chromatography (SiO2: EtOAc/hexane). b The cited yields are of isolated
material and represent the average of two runs.
(6) For reviews encompassing catalytic reductive aldol coupling, see:
(a) Motherwell, W. B. Pure Appl. Chem. 2002, 74, 135. (b) Huddleston, R.
R.; Krische, M. J. Synlett 2003, 12. (c) Jang, H.-Y.; Huddleston, R. R.;
Krische, M. J. Chemtracts 2003, 16, 554. (d) Jang, H.-Y.; Krische, M. J.
Eur. J. Org. Chem. 2004, 3953. (e) Jang, H.-Y.; Krische, M. J. Acc. Chem.
Res. 2004, 37, 653. (f) Chiu, P. Synthesis 2004, 2210.
(7) For cobalt catalyzed reductive aldol couplings, see: (a) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005. (b) Baik, T.-G.; Luis, A. L.; Wang,
L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112. (c) Wang, L.-C.;
Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische, M. J.
J. Am. Chem. Soc. 2002, 124, 9448.
(8) For rhodium catalyzed reductive aldol couplings mediated by silane,
see: (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b)
Matsuda, I.; Takahashi, K.; Sata, S. Tetrahedron Lett. 1990, 31, 5331. (c)
Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121, 12202. (d) Taylor,
S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528. (e)
Emiabata-Smith, D.; McKillop, A.; Mills, C.; Motherwell, W. B.; White-
head, A. J. Synlett 2001, 1302. (f) Freir´ıa, M.; Whitehead, A. J.; Tocher,
D. A.; Motherwell, W. B. Tetrahedron 2004, 60, 2673. (g) Fuller, N. O.;
Morken, J. P. Synlett 2005, 1459. (h) Nishiyama, H.; Siomi, T.; Tsuchiya,
Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972.
(9) For rhodium catalyzed reductive aldol couplings mediated by
hydrogen, see: (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. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6,
691. (d) Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org.
Chem. 2004, 69, 1380.
(10) For reductive aldol couplings catalyzed by other metals, see the
following references. (a) Iridium: Zhao, C.-X.; Duffey, M. O.; Taylor, S.
J.; Morken, J. P. Org. Lett. 2001, 3, 1829. (b) Palladium: Kiyooka, S.;
Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237. (c) Copper: Ooi,
T.; Doda, K.; Sakai, D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133.
(d) Lam, H.-W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. (e) Indium: Miura,
K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985.
(11) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(b) Farina, V. Pure Appl. Chem. 1996, 68, 73. (c) Anderson, N. G.; Keay,
B. A. Chem. ReV. 2001, 101, 997.
(12) As a point of reference, the lithium Z(O)-enolate of 3-pentanone
aldolizes with benzaldehyde under kinetically controlled conditions to
provide a 9:1 syn/anti-ratio. Upon equilibration, a 44:56 syn/anti ratio results.
For further examples, see ref 3a-c.
under otherwise identical conditions provides the aldol
product 1a in 74% yield with a remarkable 19:1 syn/anti
ratio (Table 1, entry 4). Systematic replacement of phenyl
moieties with 2-furyl residues (Ph3P, FurPh2P, Fur2PhP,
Fur3P) results in a progressive increase in yield and stereo-
selectivity (Table 1, entries 1-4). In the absence of Li2CO3,
coupling performed with the tri-2-furylphosphine ligated
rhodium catalyst retains the 19:1 syn/anti ratio (Table 1, entry
6), revealing the tri-2-furylphosphine effect does not involve
transmetalation to lithium. Indeed, the weakly coordinating,
π-acidic ligand triphenylarsine also promotes enhanced
stereocontrol (Table 1, entry 5). Finally, it was found that a
modest increase in concentration enables acquisition of 1a
in 91% yield with a 16:1 syn/anti ratio at only 10 mol %
loadings of Li2CO3 (Table 1, entries 7 and 8).
Using commercially available MVK and EVK as pronu-
cleophiles, these optimized conditions were applied across
a diverse set of aldehydes. High levels of syn-diastereose-
lection were observed using aromatic aldehydes, R,â-
unsaturated aldehydes, acetylenic aldehydes, and aliphatic
aldehydes. Aldol additions involving EVK occur with higher
levels of diastereoselection, presumably due to an enhanced
kinetic and thermodynamic preference for formation of the
(13) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581 and
references therein.
520
Org. Lett., Vol. 8, No. 3, 2006

Table 2. Diastereoselective Hydrogen-Mediated Reductive Aldol Coupling of MVK/EVK to Assorted Aldehydesa-c
a Reductive couplings were performed at ambient temperature and pressure in 13 × 100 mL test tubes in accordance with the procedure described in
Table 1. The following transformations employed slightly different conditions. For aldols 1a,b, the reaction was conducted at 0.3 M concentration using 150
mol % of enone. For entries 2a,b, 3a,b, 5a,b-7a,b, and 9a,b, the reaction was conducted at 1.0 M concentration using 300 mol % of enone. For compounds
4a,b, the reaction was conducted using 4 mol % of Li2CO3, 4.8 mol % of Fur3P, 2 mol % of Rh(COD)2OTf, and 500 mol % of enone. Finally, for entry 8a,b,
the reaction was conducted using 20 mol % of Li2CO3, 24 mol % of Fur3P, and 10 mol % of Rh(COD)2OTf. b The cited yields are of isolated material and
1
represent the average of two runs. c Diastereomeric ratios were established by H NMR or HPLC analysis.
Z(O)-enolate due to increased A1,2-strain. Additionally, for
lithium Z(O)-enolates, it has been observed that diastereo-
selection increases with increasing size of the acyl substitu-
ent.3 The chemoselectivity of this catalytic system is
underscored by the formation of 7a,b and 4a,b, which
embody alkene and alkyne functionality, yet are not subject
to “over-hydrogenation” under the reductive coupling condi-
tions. Further, hydrogen labile functional groups such as
benzylic ethers and nitroarenes remain intact, as demonstrated
by the formation of 2ab/5ab and 1ab/7ab, respectively
(Table 2).
It is well established that additions of Z(O)-enolates to
R-chiral aldehydes proceeding through Zimmerman-Traxler-
type transition structures may exhibit anti-Felkin-Anh se-
lectivity, thus avoiding syn-pentane interactions evident in
the alternate Felkin-Anh mode of approach.14 Hence, it is
noteworthy that the hydrogen-mediated coupling to form 10a
occurs with a distinct anti-Felkin preference accompanied
by high levels of syn-diastereoselection.15 While chelation
controlled addition cannot be ruled out, this result does
suggest intervention of Z(O)-enolates and Zimmerman-
Traxler-type transition structures in the present rhodium
catalyzed reductive aldol additions (Scheme 1).
The collective results suggest the following features of
the catalytic mechanism: (a) high kinetic selectivity for Z(O)-
enolate formation, likely by means of internal hydride
delivery to the enone s-cis conformer,16 (b) high kinetic
selectivity for syn-aldolization through addition of the Z-
(15) The stereochemical assignment of 10a is based upon single crystal
X-ray diffraction analysis of the corresponding 3,5-dinitrobenzoate. The
8:1 diastereomeric ratio refers to the major isomer versus all other isomers
combined.
(16) Enones constrained in the s-trans configuration, such as cyclohex-
enone, do not participate in reductive coupling.
(14) Roush, W. R. J. Org. Chem. 1991, 56, 4151.
Org. Lett., Vol. 8, No. 3, 2006
521

Scheme 1. Diastereoselective Addition of MVK to an R-Chiral
Scheme 2. Reductive Coupling under a Deuterium
Aldehyde
Atmospherea
(O)-enolate to the aldehyde through a Zimmerman-Traxler-
type transition structure, and (c) preservation of kinetic syn-
selectivity via irreversible enolization and aldolization.17 The
dissociation of Fur3P to form enolate haptomers that embody
enyl (σ + π) character may assist in preserving the kinetic
selectivity of enolization by retarding haptomeric equilibria,
as observed in related regio- and stereoretentive rhodium
catalyzed allylic substitutions.13
To gain further insight into the reaction mechanism, the
reductive coupling of MVK and p-nitrobenzaldehyde was
performed using elemental deuterium. The coupling product
deuterio-1a incorporates a single deuterium atom at the
former enone â-position. Deuterium incorporation at the
R-carbon of the product is not observed, excluding Morita-
Baylis-Hillman pathways en route to product. The strict
incorporation of a single deuterium atom is consistent with
irreversible enolization via enone hydrometalation (Scheme
2).
hydrogenation. This suggests an equally powerful approach
to reductiVe C-C bond formation mediated by elemental
hydrogen. Inspired by this prospect, hydrogen-mediated C-C
bond formation has become the focus of research in our
laboratory.6e,9 The present hydrogen-mediated couplings
represent the first diastereoselective reductive aldol additions
involving vinyl ketones and provide regio- and stereoselec-
tivities rivaling those obtained through the low-temperature
reaction of preformed lithium enolates. Future studies will
focus on the development of enantioselective variants of the
transformations reported herein and the discovery of new
“C-C bond forming hydrogenations”.
Acknowledgment is made to the Welch Foundation,
Johnson & Johnson, and the NIH-NIGMS (RO1-GM69445)
for partial support of this research.
Supporting Information Available: Spectral data for all
new compounds, including single-crystal X-ray diffraction
data for 6a and the dinitrobenzoate of 10a. This material is
available free of charge via the Internet at http://pubs.acs.org.
More than half of the chiral compounds produced industri-
ally from prochiral substrates are made via asymmetric
(17) High levels of diastereoselectivity do not preclude reversible
aldolization, provided aldolization proceeds with sufficiently high levels
of kinetic stereoselectivity.
OL052859X
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Org. Lett., Vol. 8, No. 3, 2006