ORGANIC

LETTERS

Highly Selective Catalytic Intermolecular 2000

Vol. 2, No. 26
Reductive Coupling of Alkynes and 4221-4223
Aldehydes
Wei-Sheng Huang, Johann Chan, and Timothy F. Jamison*

Department of Chemistry, Massachusetts Institute of Technology,

Cambridge, Massachusetts 02139
[email protected]

Received October 26, 2000

ABSTRACT

Alkynes (internal and terminal) and aldehydes (aromatic and aliphatic) are reductively coupled in a single catalytic reaction to yield di- and
trisubstituted allylic alcohols with high stereoselectivity and regioselectivity. In most cases, a 1:1 ratio of alkyne to aldehyde is sufficient for
efficient coupling. The yield and regioselectivity are strongly dependent on the phosphine ligand, but the allylic alcohols formed are invariably
the products of cis addition to the alkyne.

Transition metal-catalyzed coupling reactions enable con- of one or more transition metals. For example, the Nozaki-
vergent synthesis and are among the most efficient methods Hiyama-Kishi reaction effects the addition of an alkenyl
of assembling complex organic molecules from simpler halide to a carbonyl with a nickel catalyst and an excess of
fragments.1 Very complex structures have been prepared CrCl2, Mn, or Zn.4 Alternatively, as alkynes are often
using an allylic alcohol as the site of fragment coupling,2 convenient intermediates, many reliable one-pot methods for
and addition of an alkenylmetal reagent to a carbonyl is a effecting their reductiVe coupling with aldehydes to give
commonly used method that features carbon-carbon bond allylic alcohols have been developed.5-7 In one approach,
formation and the creation of a stereogenic center. an alkyne-metal complex is prepared and then treated with
Many of the alkenylmetal reagents required for these the carbonyl compound.5 Another commonly used sequence,
preparations of synthetically useful allylic alcohols3 are especially for terminal alkynes, involves stoichiometric
generated in situ using stoichiometric amounts or excesses
(4) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. Soc. 1977, 99, 3179. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am.
J., Eds.; Wiley: New York, 1997. Chem. Soc. 1986, 108, 5644. (c) Takai, K.; Tagashira, M.; Kuroda, T.;
(2) For examples in Kishi’s palytoxin synthesis, see: Armstrong, R. W.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W.-H.; Hawkins, (d) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (e) Fürstner,
L. D.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWorter, W. W.; A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
Mizuno, M.; Nakata, M.; Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino, (5) (a) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem.
J. A.; Ueda, K.; Uenishi, J.; White, J. B.; Yonaga, M. J. Am. Chem. Soc. Soc. 1987, 109, 2544. (b) Van Wagenen, B. C.; Livinghouse, T. Tetrahedron
1989, 111, 7525. Lett. 1989, 30, 3495. (c) Takai, K.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
(3) Reviews: Sigmatropic rearrangements: (a) [2,3]: Brückner, R. Iin 1990, 55, 1707. (d) Takagi, K.; Rousset, C. J.; Negishi, E. J. Am. Chem.
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, Soc. 1991, 113, 1440. (e) Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.
1991; Vol. 6, Chapter 4.6. (b) Hill, R. K. In ComprehensiVe Organic Utimoto, K. J. Org. Chem. 1992, 57, 1973. (f) Takayanagi, Y.; Yamashita,
Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 5, Chapter K.; Yoshida, Y.; Sato, F. J. Chem. Soc., Chem. Commun. 1996, 1725.
7.1. (c) [3,3]: Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., (6) (a) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170.
Ed.; Pergamon: New York, 1991; Vol. 5, Chapter 7.2. (d) Directed (b) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593.
reactions: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, (7) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf, P.;
1307. Ribe, S. J. Org. Chem. 1998, 63, 6454.

10.1021/ol006781q CCC: $19.00 © 2000 American Chemical Society

Published on Web 11/21/2000
hydroboration,6 or hydrozirconation,7 followed by transmeta-
lation and addition of an organic ligand to promote carbonyl Table 1. Effects of Phosphine, Solvent, and Temperature on
addition. Intermolecular Reductive Coupling of 1-Phenylpropyne and
Here we report the first catalytic method for intermolecular Aldehydesa
reductive coupling of alkynes and aldehydes (eq 1).8 Enjoy-

ing a broad substrate scope (terminal and internal alkynes;

aliphatic and aromatic aldehydes), having many of the entry aldehyde phosphine product yieldb regioselectivityc
hallmarks of an efficient fragment coupling, and exhibiting 1 2a Cy3P 3a 76% 77:23
high stereo- and regioselectivity, this catalytic reaction 2 Et3P 3a 46% 91:9
combines the features of many “tried-and-true” methods of 3 (n-Bu)3P 3a 77% 92:8
intermolecular reductive couplings of alkynes and aldehydes 4 2b (n-Bu)3P 4a 49% 95:5
that use stoichiometric amounts of transition metals.5-8 A 5d (n-Bu)3P 4a 86% 90:10
6e (n-Bu)3P 4a 85% 92:8
related process is that of Montgomery, who reported a nickel-
7d,e (n-Bu)3P 4a 88% 92:8
catalyzed, intermolecular alkylatiVe coupling of terminal
a Except where noted, all reactions were conducted using the conditions
alkynes and aldehydes that prepares trisubstituted allylic
indicated in eq 2 (initial concentration of alkyne and aldehyde ) 0.16 M,
alcohols with a substitution pattern different than that which Ar atmosphere, THF). b Combined isolated yield of regioisomers. c Minor
we obtain.9 The Montgomery method does not effect regioisomers (3b, 4b) not shown. Regioselectivity was determined either
by separation of regioisomers (silica gel chromatography) or with a 1H NMR
intermolecular reductive coupling of alkynes and aldehydes spectrum of the product mixture. d Reaction conducted at 40 °C. e Reaction
but is useful for the reductive cyclizations of alkynals to give conducted in toluene.
five- or six-membered rings.9,10
The technical challenge of this catalytic reaction is its
intermolecular nature and the requirement for a stoichiometric ered that the phosphine and solvent choices are critical but
reducing agent. The starting materials and products are all that the complete (E)-selectivity observed in the reaction is
subject to reduction, and undesired oligomerization of the invariant (eq 2 and Table 1).15,16 Notably, smaller trialky-
alkyne11 and reductive dimerization (pinacol formation) of lphosphines exhibited the highest regioselectivities (entries
the aldehyde12 can also be competitive. We examined many 2-3) while larger ones gave the highest yields (entries 1
combinations of transition metal salt, reducing agent, and and 3),17 with Bu3P providing the best combination (entries
other additives and indeed found alkyne polymerization and/ 3-7).18 In contrast to THF (Table 1, entries 4-5), toluene
or simple reduction of the alkyne and/or aldehyde to be the gave nearly identical results at different temperatures (entries
most common undesired reactions.13 Exceptional in these 6 and 7).
experiments, however, was the use of a low-valent nickel The efficiency, scope, and high selectivity of this trans-
catalyst along with tricyclohexylphosphine and triethyl- formation are summarized in Table 2. In most cases, 100
borane,14 which afforded the desired allylic alcohol in good mol % of the alkyne and 100 mol % of the aldehyde are
yield and high stereoselectivity, but with only moderate sufficient for good to high yields. No trace of (Z) isomer is
regioselection (eq 2 and Table 1, entry 1). In our investiga- ever observed,16 and only one regioisomer can be detected
tions directed toward improving regioselectivity, we discov- in many cases. Both internal and terminal alkynes can be
reductively coupled with aliphatic and aromatic aldehydes,
(8) Excess SmI2 effects intermolecular reductive coupling of alkynes and even those possessing moderate steric hindrance (entries
ketones.: Inanaga, J.; Katsuki, J.; Ujikawa, O.; Yamaguchi, M. Tetrahedron
Lett. 1991, 32, 4921. 8-10).
(9) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. The presence of a trimethylsilyl group in the alkyne yields
(b) Review: Montgomery, J. Acc. Chem. Res. 2000, 33, 467.
(10) (a) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. allylic alcohols with near perfect regioselectivity and ste-
(b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950. (c) reoselectivity in good to high yields (entries 3-4, 6, and 9).
Crowe has reported a Ti-catalyzed alkynal cyclization: Crowe, W. E.; The diastereoselectivities obtained in entries 8 and 9 are
Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
(11) Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: New York, (15) Identity established by comparison with known compounds and/or
1995; Vol. 12, Chapter 7.3. by appropriate NOE NMR experiments. See Supporting Information. Similar
(12) Brettle, R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; regioselectivity trends were observed with terminal alkynes.
Pergamon: New York, 1991; Vol. 3, Chapter 2.6. (16) As the Cahn-Ingold-Prelog priority of Si is higher than that of C,
(13) For example, we tested silanes and boranes in concert with salts of the allylic alcohol products in entries 3, 4, 6, and 9 (Table 2) are assigned
Mg, Cr, Rh, Cu, and Zn. the (Z) configuration. As in all other cases, they are nevertheless the products
(14) Trace amounts of desired allylic alcohols were observed using of cis addition to the alkyne.
triethylsilane as the reducing agent. For examples of uses of triethylborane (17) While Ph3P afforded trace amounts of allylic alcohol, neither (t-
in Ni(II)-catalyzed reactions see: (a) Kimura, M.; Ezoe, A.; Shibata, K.; Bu)3P nor BINAP was an effective additive in these reactions.
Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (b) Kimura, M.; Fujimatsu, (18) Equivalent results are obtained with the less expensive “tribu-
H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. tylphosphine” (contains isomers) as with the more expensive “tri-n-
Chem., Int. Ed. 1999, 38, 397. (c) Kimura, M.; Shibata, K.; Tamaru, Y. butylphosphine” (isomerically pure). The former was used in all subsequent
Tetrahedron Lett. 2000, 41, 6789. experiments.

4222 Org. Lett., Vol. 2, No. 26, 2000

 3-pentanone undergoes reductive coupling suggests applica-
Table 2. Intermolecular Catalytic Reductive Couplings of tions of this method in site-selective fragment coupling
Internal and Terminal Alkynes with Aromatic and Aliphatic reactions.
Aldehydesa Highly selective, of wide scope, and using commercially
available catalysts and reagents, this catalytic transformation
joins two common functional groups by effecting a reduction
and an intermolecular carbonyl addition reaction without
undesired reductions of either the aldehyde or the alkyne.
As a 1:1 ratio of alkyne to aldehyde is sufficient for high-
yielding reductive couplings in most cases, this reaction may
also find use in joining late-stage intermediates in complex
molecule synthesis,20 with the concomitant benefits of
creating a highly substituted alkene and a stereogenic
center.21 Our efforts in these and related areas are ongoing.22

Acknowledgment. We thank MIT for financial support

of this work and S. L. Buchwald and G. C. Fu for helpful
discussions.

Supporting Information Available: Experimental pro-

cedures and physical, spectrometric, and chromatographic
properties of compounds 3-12. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL006781Q

(19) Hydrozirconation of 1b, transmetalation with ZnMe2, and addition

to 2d affords 10a as a 64:36 ratio of diastereomers. See Supporting
Information and ref 6a.
(20) See ref 10 for examples of Ni-catalyzed reductive alkynal cycliza-
tions in natural product synthesis.
(21) Access to enantiomerically enriched allylic alcohols is possible in
two catalytic reactions by combining this method with an efficient kinetic
resolution. (a) Sharpless asymmetric epoxidation (review): Johnson, R. A.;
Sharpless, K. B. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
a Except where noted, all reactions were conducted using the conditions Pergamon: New York, 1991; Vol. 7, Chapter 3.2. (b) Ruble, J. C.; Latham,
indicated in eq 2 (1 mmol of alkyne, 1 mmol of aldehyde, toluene, Ar H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492. (c) Vedejs, E.;
atmosphere). b Combined isolated yield of regioisomers. c Minor regioiso- Daugulis, J. Am. Chem. Soc. 1999, 121, 5813. (d) Bellemin-Laponnaz, S.;
mers (3b-12b) not shown. Regioselectivity (a:b) was determined either Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C. J. Chem. Soc., Chem.
by separation of regioisomers (silica gel chromatography) or with a 1H NMR Commun. 2000, 1009.
spectrum of the product mixture. d THF used as solvent. e 200 mol % used. (22) Elucidation of the mechanism of this transformation will require
f Reaction conducted under reflux. g Reaction conducted at 0 °C. further experiments, as irreversible hydrometalation of the alkyne does not
occur in the absence of aldehyde and no substrate conversion occurs in the
absence of Et3B (see Supporting Information). See also refs 9 and 10 for
discussions of possible mechanisms of related intramolecular reactions using
comparable to that obtained in a related alkenylzinc addition Et3SiH as the reducing agent and ref 14 for discussions of the role of Et3B
to the same aldehyde.19 That neither acetophenone nor in Ni(II)-catalyzed reactions.

Org. Lett., Vol. 2, No. 26, 2000 4223