Highly regioselective, catalytic asymmetric reductive coupling of 1,3-enynes and ketones

Article abstract of DOI:10.1021/ol051075g

(Chemical Equation Presented) Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts of Ni(cod)₂ and a P-chiral, monodentate ferrocenyl phosphine ligand. The

Full text of DOI:10.1021/ol051075g

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3077-3080
Highly Regioselective, Catalytic
Asymmetric Reductive Coupling of
1,3-Enynes and Ketones
Karen M. Miller and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tfj@mit.edu
Received May 10, 2005
ABSTRACT
Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts
of Ni(cod)2 and a P-chiral, monodentate ferrocenyl phosphine ligand. These couplings represent the first examples of catalytic, intermolecular
reductive coupling of alkynes and ketones, enantioselective or otherwise, and afford synthetically useful 1,3-dienes possessing a quaternary
carbinol stereogenic center in up to 70% ee.
Catalytic, stereoselective, multicomponent coupling reactions
facilitate the efficient construction of complex organic
molecules by forming multiple bonds in a single synthetic
operation.1 Examples of such reactions include transition
metal catalyzed intermolecular reductive or alkylative cou-
pling of alkynes with common functional groups, such as
aldehydes,2,3 epoxides,4 and imines.5 In contrast, due to their
greatly attenuated reactivity relative to aldehydes, the use
of ketones as coupling partners in reactions of this type has
yet to be reported.6-9 In fact, ketones have been employed
as electrophiles only rarely in any catalytic multicomponent
coupling reactions,10 and the vast majority of these are
intramolecular processes.11-13
We recently reported catalytic reductive couplings of
aldehydes and 1,3-enynes2g (and other alkynes2i) in which a
pendant alkene enhanced both the reactivity and selectivity
of the alkyne. We now disclose that catalytic intermolecular
reductive couplings of 1,3-enynes and ketones also proceed
(1) (a) Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-
VCH: Weinheim, Germany, 2005. (b) Ramo´n, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602-1634.
(3) Rhodium: (a) Huddleston, R. R.; Yang, H.-Y.; Krische, M. J. J. Am.
Chem. Soc. 2003, 125, 11488-11489. (b) Jang, H.-Y.; Huddleston, R. R.;
Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4664-4668. (c) Review: Jang,
H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653-661.
(4) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076-
8077.
(2) Nickel: (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997,
119, 9065-9066. (b) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett.
2000, 2, 4221-4223. (c) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003,
68, 156-166. (d) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5,
653-655. (e) Miller, K. M.; Huang, W. S.; Jamison, T. F. J. Am. Chem.
Soc. 2003, 125, 3442-3443. (f) Miller, K. M.; Molinaro, C.; Jamison, T.
F. Tetrahedron: Asymmetry 2003, 14, 3619-3625. (g) Miller, K. M.;
Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004,
126, 4130-4131. (h) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am.
Chem. Soc. 2004, 126, 3698-3699. (i) Miller, K. M.; Jamison, T. F. J.
Am. Chem. Soc. 2004, 126, 15342-15343. (j) Review: Montgomery, J.
Angew. Chem., Int. Ed. 2004, 43, 3890-3908.
(5) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364-
1367. (b) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43,
3941-3944.
(6) For an example of the nickel-catalyzed intramolecular reductive
coupling of an alkyne and a ketone, see: Chan, J.; Jamison, T. F. J. Am.
Chem. Soc. 2004, 126, 10682-10691.
(7) For a recent report of nickel-catalyzed intermolecular alkyne insertions
into cyclobutanones, see: Murakami, M.; Ashida, S.; Takanori, M. J. Am.
Chem. Soc. 2005, 127, 6932-6933.
10.1021/ol051075g CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

efficiently in high regioselectivity and modest enantioselec-
tivity when conducted in the presence of catalytic amounts
of a P-chiral, ferrocenyl monodentate phosphine ligand
(Scheme 1).
more direct approach, as both alkyne reduction and C-C
bond formation occur in the same catalytic pathway and the
stoichiometric use of a transition metal is avoided.
Initial attempts to promote the catalytic reductive coupling
of 1-decen-3-yne (1) and acetophenone using triethylborane
(Et3B) as a stoichiometric reductant and catalytic amounts
of both Ni(cod)2 and tricyclopentylphosphine (Cyp3P), a
ligand that had proven particularly effective in promoting
reductive couplings of 1,3-enynes and aldehydes, were
completely unsuccessful. Only a trace of the desired coupling
product was observed, even at elevated temperature (Table
1, entry 1). Similar results were obtained with both tris(o-
Scheme 1
The enantioselective generation of quaternary stereocenters
is generally a formidable challenge. Recently, several
catalytic, asymmetric methods that achieve this goal have
been developed,14 and addition reactions to ketones have
attracted significant attention, as they provide access to
enantiomerically enriched tertiary alcohols.15 Walsh has
reported highly enantioselective, catalytic additions of alk-
enylzirconium reagents (prepared by in situ hydrozirconation
of a terminal alkyne) to ketones.16,17 The catalytic, asym-
metric reductive coupling of alkynes and ketones reported
herein allows for the use of internal alkynes and affords a
Table 1. Ligand Evaluation in Catalytic Reductive Couplings
of 1,3-Enynes and Acetophenonea
yield (%),
regioselectivityb eec (%)
entry R1
R2
R3P
1
2
3
4
5
6
7d
8e
H
H
H
H
H
Me
Me
Me
n-Hex (1)
Cyp3P
<2 (n.d.)
<2 (n.d.)
<2 (n.d.)
68 (>95:5)
44 (>95:5)
79 (>95:5)
89 (>95:5)
69 (>95:5)f
n-Hex (1) (o-anisyl)3P
n-Hex (1) CyPPh2
n-Hex (1) (+)-NMDPP
n-Hex (1)
Et (3)
17
FcPPh2
FcPPh2
(S)-4
Et (3)
Et (3)
58
64
(S)-4
(8) Transition metal mediated reductive coupling of alkynes and ketones
(stoichiometric in transition metal): (a) Buchwald, S. L.; Watson, B. T.;
Huffman, J. C. J. Am. Chem. Soc. 1987, 109, 2544-2546. (b) Kataoka, Y.;
Miyai, J.; Oshima, K.; Takai, K.; Utimoto, K. J. Org. Chem. 1992, 57,
1973-1981. (c) Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.;
Nakajima, K.; Negishi, E. J. Org. Chem. 1998, 63, 6802-6806. (d) Ozerov,
O. V.; Brock, C. P.; Carr, S. D.; Ladipo, F. T. Organometallics 2000, 19,
5016-5025.
(9) Reductive cyclizations of alkynes and ketones promoted by samarium
diiodide. Reviews: (a) Molander, G. A. Chem. ReV. 1992, 92, 29-68. (b)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371-
3403. Examples: (c) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989,
111, 8236-8246. (d) Berndt, M.; Gross, S.; Ho¨lemann, A.; Reissig, H.-U.
Synlett 2004, 422-438. (e) Ho¨lemann, A.; Reissig, H.-U. Synlett 2004,
2732-2735.
(10) For example, see: (a) Tejedor, D.; Garcia-Tellado, F.; Marrero-
Tellado, J. J.; de Armas, P. Chem. Eur. J. 2003, 3122-3131. (b) Bharadwaj,
A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465-2468.
a See Scheme 1. Standard procedure: To Ni(cod)2 (0.05 mmol), R3P
(0.1 mmol), acetophenone (1.0 mmol), and Et3B (1.0 mmol) at 50 °C was
added dropwise the enyne (0.5 mmol) over 6 h. After an additional 12 h,
silica gel chromatography afforded dienols 2 and 5 as mixtures with
acetophenone. b Yield and regioselectivity determined by 1H NMR integra-
tion. c Determined by HPLC analysis, Chiralcel OJ column. d Reaction
conducted at 35 °C. e Reaction conducted at 23 °C. f Isolated yield of 5
following treatment of crude reaction mixture with NaBH4 at 0 °C. n.d. )
not determined.
methoxyphenyl)phosphine ((o-anisyl)3P, entry 2) and cyclo-
hexyldiphenylphosphine (CyPPh2, entry 3). To our delight,
however, the use of (+)-neomenthyldiphenylphosphine
(NMDPP, Figure 1) led to an efficient catalytic reductive
(11) Titanocene-catalyzed intramolecular alkene-ketone cyclocarbony-
lation: (a) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 4424-4431. (b) Mandal, S. K.; Amin, S. R.; Crowe, W. E.
J. Am. Chem. Soc. 2001, 123, 6457-6458.
(12) Catalytic intramolecular allene-ketone cyclizations: (a) Kang, S.-
K.; Yoon, S.-K. Chem. Commun. 2002, 2634-2635. (b) Kang, S.-K.; Ha,
Y.-H.; Ko, B.-S.; Lim, Y.; Jung, J. Angew. Chem., Int. Ed. 2002, 41, 343-
345. (c) Kang, S.-K.; Hong, Y.-T.; Lee, J.-H.; Kim, W.-Y.; Lee, I.; Yu,
C.-M. Org. Lett. 2003, 5, 2813-2816.
(13) Rh-catalyzed carbometallative aldol cycloreduction: (a) Cauble, D.
F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110-
1111. (b) Bocknack, B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5421-5424.
(14) Reviews: (a) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (b) Corey,
E. J.; Guzma´n-Pe´rez, A. Angew. Chem., Int. Ed. 1998, 37, 388-401. (c)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
(d) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. (e)
Ramo´n, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149-183. (f) Douglas,
C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363-
5367.
Figure 1. Chiral monodentate phosphines effective at promoting
the catalytic reductive coupling of 1,3-enynes and ketones.
coupling, affording the desired dienol 2 in 68% yield and
>95:5 regioselectivity, albeit in only 17% ee (entry 4).
P-Chiral, ferrocenyl monodentate phosphines are effective
in catalytic asymmetric coupling reactions of alkynes with
both aldehydes2 and imines.5b Accordingly, we evaluated this
family of phosphines in the ketone coupling reaction
described above. Unlike the other achiral ligands evaluated,
(15) Review: Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43,
284-287.
(16) (a) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538-6539.
(b) Anaya de Parrodi, C.; Walsh, P. J. Synlett 2004, 2417-2420.
(17) For diastereoselective additions of alkenylzirconocenes to ketones
and R-keto esters, respectively, see: (a) Chavez, D. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2001, 40, 3667-3670. (b) Wipf, P.; Stephenson,
C. R. J. Org. Lett. 2003, 5, 2449-2452.
3078
Org. Lett., Vol. 7, No. 14, 2005

In addition to acetophenone, a variety of aromatic and
heteroaromatic ketones undergo efficient catalytic asym-
metric reductive coupling with 2 under these conditions
(Table 2).20 Electron-donating substituents (entries 3 and 4)
and electron-withdrawing aromatic esters are compatible
(entry 5). Both 1- and 2-acetylnaphthalene couple effectively
(entries 7 and 8), although ortho substitution leads to
somewhat diminished enantioselectivity (entries 3 and 7).
Heteroaromatic ketones 2-acetylfuran and benzofuran-2-yl
methyl ketone can also be employed (entries 9 and 10).
Interestingly, an R,â-unsaturated ketone, 1-acetyl-1-cyclo-
hexene, affords the best enantioselectivity observed (70%
ee), albeit in moderate yield (entry 12).21 The unique
reactivity of 1,3-enynes relative to other classes of alkynes
and the high regioselectivity in these reactions suggests that
these transformations may be directed by the neighboring
alkene.2g,22
Table 2. Catalytic Asymmetric Reductive Coupling of
1,3-Enynes and Ketonesa
The products of these coupling reactions are enantiomeri-
cally enriched chiral 1,3-dienes, a class of compounds whose
utility in Diels-Alder cycloaddition reactions has been
intensively studied.23,24 As shown in Scheme 2, a site-
Scheme 2
selective Rh-catalyzed hydrogenation of these dienols previ-
ously reported in our laboratory2g provides access to enan-
a See Scheme 1 and the Supporting Information for details. Standard
procedure: To Ni(cod)2 (0.05 mmol), (S)-4 (0.1 mmol), the ketone (1.0
mmol), and Et3B (1.0 mmol) at 23 °C, the enyne (0.5 mmol) was added
dropwise over 6 h. After an additional 12 h, the reaction was stirred 30
min open to air to promote oxidation of the catalyst and treated with NaBH4
(1.0 mmol) at 0 °C. b Isolated yield (SiO2 chromatography). c Determined
(18) P-Chiral ferrocenyl phosphines with other substitution patterns on
this aromatic ring displayed reduced efficacy (e.g., 2-biphenyl, 28% yield,
18% ee; 2,5-dimethylphenyl, 76% yield, 50% ee; 2-i-Pr-phenyl, 13% yield,
70% ee).
(19) Superior yields were typically obtained in these reactions when
conducted in the absence of an additional solvent. However, when solid
ketones were employed, toluene was used as a cosolvent.
1
by H NMR. d Determined by HPLC analysis (Chiralcel OJ or Chiralpak
AD-H column). e (R)-4 (0.1 mmol) was employed. f Absolute configuration
determined to be S by conversion to the known R-hydroxy ketone 15
(Scheme 2). g Toluene (0.2 mL) was added as a cosolvent.
(20) Ketones containing two alkyl substituents, such as cyclohexyl methyl
ketone or cyclopropyl methyl ketone, afforded coupling products in very
low yield (<10%), and R-keto esters were completely ineffective.
(21) The yield was improved by conducting this reaction at 35 °C: 55%
yield, >95:5 regioselectivity, 63% ee.
(22) Alkynes that lack an alkenyl substituent, such as 1-phenyl-1-propyne
or 4-octyne, and 1,3-enynes bearing an aromatic substituent, such as
1-phenyl-3-buten-1-yne, did not undergo coupling under these conditions.
(23) For leading references on related chiral 1,3-dienes in intermolecular
Diels-Alder reactions, see: (a) Tripathy, R.;. Franck, R. W.; Onan, K. D.
J. Am. Chem. Soc. 1988, 110, 3257-3262. (b) Fisher, M. J.; Hehre, W. J.;
Kahn, S. D.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4625-4633.
(c) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J.; Huang, L.;
Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990, 112, 8472-8478. (d) Adam,
W.; Glaser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc. 1995, 117, 9190-
9193. (e) Barriault, L.; Thomas, J. D. O.; Clement, R. J. Org. Chem. 2003,
68, 2317-2323;
ferrocenyldiphenylphosphine (FcPPh2) was effective at pro-
moting the catalytic reductive coupling of 1 and acetophe-
none (entry 5), and the yield of the reaction of the
commercially available 2-methyl-1-hexen-3-yne (3) under the
same conditions was significantly higher (entry 6). The
introduction of a methyl group at the ortho position of one
of the phenyl rings of FcPPh2, i.e., P-chiral ferrocenyl
phosphine 4,2c not only improved the reaction yield, but also
afforded the corresponding dienol 5 in 58% ee (entry 7).18
The enhanced reactivity observed with phosphine 4 allowed
this coupling reaction to be conducted efficiently at room
temperature, affording a further increase in enantioselectivity
(64% ee, entry 8).19
(24) In intramolecular Diels-Alder reactions, see: (a) Bols, M.; Skryd-
strup, T. Chem. ReV. 1995, 95, 1253-1277. (b) Keck, G. E.; Romer, D. R.
J. Org. Chem. 1993, 58, 6083-6089. (c) Shiina, J.; Nishiyama, S.
Tetrahedron 2003, 59, 6039-6044;
Org. Lett., Vol. 7, No. 14, 2005
3079

tiomerically enriched, trisubstituted allylic alcohols such as
14 that possess a quaternary carbinol stereogenic center, a
class of allylic alcohols not previously accessible via any
catalytic method (Scheme 2).25 Ozonolysis of these com-
pounds affords R-hydroxy ketones such as 15, the TMS ether
of which has been employed by Masamune in asymmetric
aldol reactions.26 This two-step procedure also allowed
assignment of the configuration of the major enantiomer of
dienol 5 as S.27
In summary, we have developed the first catalytic asym-
metric reductive coupling of alkynes and ketones, a trans-
formation in which 1,3-enynes are uniquely effective sub-
strates. This transformation is highly regioselective and
affords synthetically useful 1,3-dienes with an adjacent
quaternary carbinol stereogenic center in moderate enanti-
oselectivity. Finally, the P-chiral monodentate ferrocenyl
phosphine that promotes this coupling reaction may find use
in other asymmetric, nickel-catalyzed transformations. Our
efforts toward this end will be described in due course.
Acknowledgment. Support for this work was provided
by the National Institute of General Medical Sciences (GM-
063755). We also thank the NIGMS (GM-072566), NSF
(CAREER CHE-0134704), Amgen, Boehringer-Ingelheim,
Bristol Myers-Squibb, GlaxoSmithKline, Johnson & Johnson,
Merck Research Laboratories, Pfizer, the Sloan Foundation,
Wyeth, and the Deshpande Center (MIT) for generous
financial support. We are grateful to Dr. Li Li for obtaining
mass spectrometric data for all compounds (MIT Department
of Chemistry Instrumentation Facility, which is supported
in part by the NSF (CHE-9809061 and DBI-9729592) and
the NIH (1S10RR13886-01)).
(25) For the singular example of the preparation of such compounds via
antibody-catalyzed resolution, see: List, B.; Shabat, D.; Zhong, G.; Turner,
J. M.; Li, A.; Bui, T.; Anderson, J.; Lerner, R. A.; Barbas, C. F., III. J. Am.
Chem. Soc. 1999, 121, 7283-7291.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for compounds
2 and 5-15. This material is available free of charge via
the Internet at http://pubs.acs.org.
(26) Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angew.
Chem., Int. Ed. Engl. 1980, 19, 557-558.
(27) Harder, T.; Lohl, T.; Bolte, M.; Wagner, K.; Hoppe, D. Tetrahedron
Lett. 1994, 35, 7365-7368.
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