Monophasic catalytic system for the selective semireduction of alkynes

Article abstract of DOI:10.1021/ol4001679

A highly efficient semireduction of alkynes has been developed. Using 0.5-2 mol % of a copper catalyst, semireduction can be accomplished with a wide range of substrates, including both internal and terminal alkynes without over-reduction. The new method has excellent chemoselectivity, and the semireduction can be accomplished even in the presence of nitro and aryl iodo groups. Finally, commercial availability of a catalyst precursor adds to the appeal of the new catalytic system.

Full text of DOI:10.1021/ol4001679

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Monophasic Catalytic System for the
Selective Semireduction of Alkynes
Aaron M Whittaker and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195,
United States
lalic@chem.washington.edu
Received January 20, 2013
ABSTRACT
A highly efficient semireduction of alkynes has been developed. Using 0.5À2 mol % of a copper catalyst, semireduction can be accomplished with
a wide range of substrates, including both internal and terminal alkynes without over-reduction. The new method has excellent chemoselectivity,
and the semireduction can be accomplished even in the presence of nitro and aryl iodo groups. Finally, commercial availability of a catalyst
precursor adds to the appeal of the new catalytic system.
One of the most important transformations of alkynes is
their semireduction to alkenes, a transformation usually
accomplished using Lindlar1 or P2 nickel2 catalysts. How-
ever, both catalysts havesignificant limitations. P2 nickel is
not selective in reductions ofterminalalkynes and hastobe
prepared fresh before each reaction.2b Lindlar catalyst
induces EÀZ isomerization and further reduction of the
alkene products, thus, strict monitoring of the reaction
progress is necessary.3 Over-reduction is even more pro-
nounced with terminal alkynes and alkynes that adsorb
well to the catalyst surface, such as arylacetylenes, and
alkynescontaining polarfunctionalgroups.3b,4 Finally, the
notorious batch variability further complicates the use of
the Lindlar catalyst.4b
To address these problems, numerous attempts have
been made to control the reactivity of solid-state catalysts
by modifications of the catalyst surface.5 Although sig-
nificant progress has been made in the reduction of
arylacetylenes with this approach,5rÀt few reports also
describe selective reduction of terminal alkynes,5b,s which
is still a major challenge.5mÀo Similarly, few catalysts have
been used for the reduction of alkynes in the presence of
nitro or aryl iodo groups.5b
Considerable effort has also been devoted to the devel-
opment of molecular catalysts of rhodium,6 chromium,7
palladium,4b,8 vanadium,9 and other metals.10 Although
(5) Selected examples: (a) Campos, K. R.; Cai, D.; Journet, M.;
Kowal, J. J.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2001, 66, 3634. (b)
Yabe, Y.; Yamada, T.; Nagata, S.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Adv. Synth. Catal. 2012, 354, 1264. (c) Gruttadauria, M.; Noto, R.;
Deganello, G.; Liotta, L. F. Tetrahedron Lett. 1999, 40, 2857. (d) Khan,
N. A. J. Am. Chem. Soc. 1952, 74, 3018. (e) Nitta, Y.; Imanaka, T.;
Teranishi, S. Bull. Chem. Soc. Jpn. 1981, 54, 3579. (f) Brunet, J. J.;
Gallois, P.; Caubere, P. J. Org. Chem. 1980, 45, 1937. (g) Gallois, P.;
Brunet, J. J.; Caubere, P. J. Org. Chem. 1980, 45, 1946. (h) Brunet, J. J.;
Caubere, P. J. Org. Chem. 1984, 49, 4058. (i) Yoon, N. M.; Park, K. B.;
€
Lee, H. J.; Choi, J. Tetrahedron Lett. 1996, 37, 8527. (j) Armbruster, M.;
€
Kovnir, K.; Behrens, M.; Teschner, D.; Grin, Y.; Schlogl, R. J. Am.
Chem. Soc. 2010, 132, 14745. (k) Gruttadauria, M.; Liotta, L. F.; Noto,
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R.; Deganello, G. Tetrahedron Lett. 2001, 42, 2015. (l) Mastalir, A.;
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€
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Kiraly, Z.; Szollosi, G.; Bartok, M. J. Catal. 2000, 194, 146. (m) Nishio,
R.; Sugiura, M.; Kobayashi, S. Org. Biomol. Chem. 2006, 4, 992. (n)
Alonso, F.; Osante, I.; Yus, M. Adv. Synth. Catal. 2006, 348, 305. (o)
Shao, Z.; Li, C.; Chen, X.; Pang, M.; Wang, X.; Liang, C. ChemCatChem
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2010, 2, 1555. (p) Mastalir, A.; Kiraly, Z. J. Catal. 2003, 220, 372. (q)
Panpranot, J.; Phandinthong, K.; Sirikajorn, T.; Arai, M.; Praserthdam,
P. J. Mol. Catal. A: Chem. 2007, 261, 29. (r) Weerachawanasak, P.;
Mekasuwandumrong, O.; Arai, M.; Fujita, S.-I.; Praserthdam, P.;
Panpranot, J. J. Catal. 2009, 262, 199. (s) Hori, J.; Murata, K.; Sugai,
T.; Shinohara, H.; Noyori, R.; Arai, N.; Kurono, N.; Ohkuma, T. Adv.
Synth. Catal. 2009, 351, 3143. (t) Dominguez-Dominguez, S.; Berenguer-
Murcia, A.; Pradhan, B. K.; Linares-Solano, A.; Cazorla-Amoros, D.
J. Phys. Chem. C 2008, 112, 3827.
(1) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446. (b) Lindlar, H.;
Dubuis, R. Org. Synth. Coll. 1973, 5, 880.
(2) (a) Brown, C. A. Chem. Commun. 1970, 139. (b) Brown, C. A.;
Ahuja, V. K. J. Org. Chem. 1973, 38, 2226.
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(3) (a) Molnar, A.; Sarkany, A.; Varga, M. J. Mol. Catal. A: Chem.
2001, 173, 185. (b) Ulan, J. G.; Maier, W. F.; Smith, D. A. J. Org. Chem.
1987, 52, 3132.
(4) (a) van Laren, M. W.; Elsevier, C. J. Angew. Chem., Int. Ed. 1999,
38, 3715. (b) Kluwer, A. M.; Koblenz, T. S.; Jonischkeit, T.; Woelk, K.;
Elsevier, C. J. J. Am. Chem. Soc. 2005, 127, 15470.
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r
10.1021/ol4001679
XXXX American Chemical Society

most homogeneous catalysts developed so far are inferior
to Lindlar, some show remarkable selectivity such as those
developed by Trost8b and Shibaskaki.7 Unfortunately, low
yields of the alkene8b or high temperature and hydrogen
pressure7 make these catalysts impractical. The most sig-
nificant progress has been achieved using palladium4,8a
and copper10a complexes in the semireduction of aryl- and
diarylacetylenes.
using conditions similar to the stoichiometric reactions
by Sadighi.11 Unfortunately, we observed only 12% of
the desired alkene product 3. Through a combination of
stoichiometric and competition experiments, we identified
three side reactions responsible for the low yield of the
catalytic reaction (Scheme 1). The major problem was the
formation of catalytically inactive copper acetylide 4 by
deprotonation of the alkyne, by the copper alkoxide 2, or
by the alkenyl copper complex 5. Another obstacle was the
protonation of the copper hydride by i-PrOH. Although
the copper isopropoxide 7 formed in this reaction is cataly-
tically active, this side reaction consumes both the silane and
the alcohol.
Overall, while significant progress has been made in
developing both homogeneous and heterogeneous cata-
lysts for the semireduction of alkynes, none offer a prac-
tical alternative to Lindlar catalyst in terms of substrate
scope, selectivity, and the ease of use. As a result, and
despite the associated problems, Lindlar catalyst remains
the reagent of choice for the semireduction of most alkynes.
Our approach to the development of a selective catalyst
for semireduction of alkynes was inspired Sadighi’s report
describing transmetalation of copper alkoxide with silane,
followed by hydrocupration of an alkyne.11 Prompted
by these stoichiometric reactions, we decided to explore
an alkyne semireduction strategy using hydrometalation
followed by protonation of the resulting alkenyl copper.
The most appealing aspect of this approach is that it is
fundamentally different from the standard delivery of
hydrogen through alkyne insertion then reductive elimina-
tion. Furthermore, hydrocupration has barely been ex-
plored in the context of the semireduction of alkynes.
Stryker has reported a stoichiometric reduction of alkynes
using 0.5 equiv of ((PPh3)CuH)6 and water.12 However,
over-reduction was a significant problem, while derivatives
of propargylic alcohols primarily gave allene products.
Recently, the first report of a catalytic semireduction of
alkynes involving copper hydride was reported.13 Tsuji
showed that a bisphosphine copper complex can be used as
a catalyst in a selective semireduction of activated aryl and
diaryl acetylenes. Unfortunately, this catalyst was ineffec-
tivein reductions of less reactivesimple alkynes. For the six
simple substrates examined, three catalysts and four sets of
conditions were used, reflecting the difficulties associated
with the development of a general catalytic system.
In this paper, we present the development of a copper
catalyst that can serve as a practical alternative to Lindlar
and P2 nickel catalysts in semireduction of both terminal
and internal alkynes.
Scheme 1. Catalytic Reduction of Alkynes and Side Reactions
Through optimization of several components of the
catalytic system we were able to suppress all three side
reactions. The formation of hydrogen could be suppressed
by the use of sterically demanding NHC ligands. For example,
in stoichiometric reactions with silane, alcohol, and alkyne,
the use an ICyCuO-t-Bu complex resulted in silane con-
sumption by the formation of hydrogen gas (Scheme 2, eq 5),
while a complex supported by a sterically demanding IPr
ligand suppressed hydrogen formation, and produced
alkene as the major product (Scheme 2, eq 6). As shown
in eqs 7 and 8 (Scheme 2), the choice of silane had a
significant effect on the formation of the copper acetylide.
With highly reactive PMHS (polymethylhydrosiloxane)
the copper alkoxide is engaged in a fast transmetalation,
and deprotonation of the alkyne is completely suppressed.
The results of the experiments shown in Scheme 2 guided
our optimization of the catalyst and the silane and allowed
us to achieve the complete conversion in the catalytic
semireduction of alkyne 8 (Table 1, entries 1À6). Increas-
ing the amount of t-BuOH to 10 equivalents resulted in an
increase in the rate of the reduction (entry 7), but for the
complete conversion, 2 mol % of the catalyst was still
necessary. We suspected that the side reaction shown in
eq 3, although slow, was responsible for removing the
active catalyst from the reaction mixture. Indeed, we found
that in the presence of a stronger acid (i-BuOH) that
increases the rate of protonation of alkenyl copper intermedi-
ate, 0.5 mol % of the catalyst was sufficient for the complete
reduction of the alkyne in less than 1 h (Table 1, entry 8).
In initial experiments, we focused on the reduction of
terminal alkynes and decided to explore the reduction of 1
(8) (a) Hauwert, P.; Maestri, G.; Sprengers, J. W.; Catellani, M.;
Elsevier, C. J. Angew. Chem., Int. Ed. 2008, 47, 3223. (b) Trost, B. M.;
Braslau, R. Tetrahedron Lett. 1989, 30, 4657. (c) Li, J.; Hua, R.; Liu, T.
J. Org. Chem. 2010, 75, 2966.
(9) La Pierre, H. S.; Arnold, J.; Toste, F. D. Angew. Chem., Int. Ed.
2011, 50, 3900.
(10) (a) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv.
Synth. Catal. 2012, 354, 1542. (b) Belger, C.; Neisius, N. M.; Plietker, B.
Chem.;Eur. J. 2010, 16, 12214.
(11) Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics
2004, 23, 3369.
(12) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. Tetrahedron Lett.
1990, 31, 2397.
(13) During our work on this project, Tsuji reported selective reduc-
tion of a wide range of mostly aryl and diaryl acetylenes using the same
approach. See ref 10a.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Optimization of the Catalytic System
Scheme 3. Catalytic Semireduction of Terminal Alkynesa
Table 1. Reaction Optimization
catalyst
(mol %)
time
yieldb
(%)
entrya
L
silane
ROH
(h)
1
ICy
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.5
(EtO)3Si t-BuOH
(EtO)3Si t-BuOH
(EtO)3Si t-BuOH
(EtO)3Si t-BuOH
8
8
8
8
8
8
1
1
1
19
69
a Reactions were performed on 1 mmol scale. Yields of isolated
products are reported, unless otherwise noted. b Determined by GC
analysis. c IPrCuOtBu (2 mol %). d From 5-phenoxy-pent-3-ene-1-yne.
2
IMes
SiPr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
3
61
4
90
5
Et3Si
t-BuOH
t-BuOH
t-BuOH
t-BuOH
i-BuOH
<5
6
PMHS
PMHS
PMHS
PMHS
>98
>98
65
reagents. A propargylic alcohol and a variety of its
derivatives, were reduced to the corresponding allylic
derivatives (18À21) without any overreduction, a common
problem with most catalysts.4,5a,5b,5n,5s The formation
of the corresponding allene product was not observed
either, although similar conditions have been used in
transformations of propargylic carbonates to allenes.17
Finally, terminal 1,3-enynes are selectively reduced to
1,3-dienes (22). Overall, the remarkable chemoselectivity
of our catalytic system is complementary to the chemos-
electivity of catalysts currently used for the semireduction
of alkynes. It is important to note that we did not observe
the formation of alkane products in any of the reactions
shown in Scheme 3. Even with prolonged exposure of
1-phenyl-1-butene to the standard reaction conditions no
over-reduction occurred (eq 9).
7c
8c
9d
>98
a ROH (2.0 equiv), R3SiH (2.0 equiv), 25 °C, toluene. b Determined
by GC. c 10 equiv of t-BuOH used. d i-BuOH (1.2 equiv), PMHS
(1.2 equiv), 25 °C, toluene.
Optimal results are obtained using just 0.5 mol % of the
catalyst and a slight excess (1.2 equiv)14 of PMHS and
isobutyl alcohol, which facilitates product isolation. It is
worth noting that PMHS is readily available, air stable,
cost-effective, and nontoxic and has a minimal environ-
mental impact.15 Under optimized reaction conditions,
selective semireduction of a wide range of terminal alkynes
is accomplished within one hour at room temperature
(Scheme 3). The semireduction can be achieved in the
presence of nitroarenes, aryl halides, esters, sulfonates,
carbamates, imides, alcohols, and ethers.
Although very similar conditions have been used for the
reduction of ketones,16 they are also well tolerated in this
reaction (14). Terminal alkynes are selectively reduced in
the presence of both strained alkenes and internal alkynes
(15 and 17). These two transformations are particularly
difficult to accomplish using the currently available
We also found that by using a closely related set of
reaction conditions we could accomplish a stereoselective
semireduction of internal alkynes. The major difference is
that t-BuOH was the preferred proton source and that the
reduction had to be performed at the slightly elevated
temperature (45 °C). Under the optimal conditions inter-
nal alkynes could be reduced in the presence of benzyl
ethers, nitro arenes, nitriles, aryl bromides, alkyl chlorides,
imides, esters, alkenes, and alcohols (Scheme 4). Again, the
derivatives of propargylic alcohols could be reduced to
(14) Equivalents of PMHS refer to the equivalents of Si-H units
present in the amount of PMHS used in the experiment.
(15) (a) Klyaschitskaya, A. L.; Krasovskii, G. N.; Fridlyand, S. A.
Gig. Sanit. 1970, 35, 28. (b) J. Lawrence, N.; D. Drew, M.; M. Bushell, S.
J. Chem. Soc., Perkin Trans. 1 1999, 3381. (c) Jacquet, O.; Das Neves
Gomes, C.; Ephritikhine, M.; Cantat, T. J. Am. Chem. Soc. 2012, 134,
2934.
ꢀ
(16) Dı
´
ez-Gonzalez, S.; Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan,
(17) Deutsch, C.; Lipshutz, B. H.; Krause, N. Org. Lett. 2009, 11,
S. P. J. Org. Chem. 2005, 70, 4784.
5010.
Org. Lett., Vol. XX, No. XX, XXXX
C

allylic alcohol derivatives. With all substrates, we observed
the exclusive formation of the Z alkene, and we did not
observe further reduction of the alkene products. It is
important to note that at elevated temperatures aryl
acetylenes are the only substrates with which we observed
the formation of the alkane product. However, at 25°C the
Z alkene was the only product observed.
experiments by Tsuji10a and Lipshutz19 and suggests that
there is no exchange between copper hydride and t-BuOH.
Scheme 5. Proposed Mechanism
Scheme 4. Catalytic Semireduction of Internal Alkynesa
We have also explored the difference in the reactivity of
terminal and internal alkynes. In a reduction of terminal
alkyne 8performed in the presence of 10 mol % of IPrCuO-t-
Bu and t-BuOH monitored by in situ 1H NMR, only alkenyl
copper was observed throughout the course of the reaction,18
indicating an alkenyl copper catalyst resting state. In a similar
experiment performed with 6-dodecyne, we only observed
copper hydride as the catalyst resting state.18
Overall, the difference in the rate of hydrocupration of
terminal and internal alkynes allows us to understand the
use of two different alcohols. With terminal alkynes, a less
acidic proton source results in rate-limiting protonation of
the alkenylcopperintermediateand can leadtothe catalyst
deactivation according to eq 3 (Scheme 1). In reactions
of internal alkynes, hydrocupration is rate-limiting, and
faster protonation of the alkenyl copper intermediate is
unimportant. Instead, protonation of the copper hydride
intermediateisamajor concern, andthelessacidict-BuOH
is the optimal proton source.
a Reactions were performed on a 1 mmol scale. Yields of isolated
products are reported, unless otherwise stated. b t-BuOH (3.5 equiv),
PMHS (3 equiv), R, β-unsaturated aster also reduced in the process.
c GC yield. d Reaction performed at 25 °C.
To demonstrate the synthetic utility of the new method,
we have performed gram-scale reactions using commer-
cially available and air stable IPrCuCl as a catalyst pre-
cursor. As shown in eqs 10 and 11, both terminal and
internal alkynes can be reduced to the corresponding
alkenes using this procedure.
In conclusion, we have developed a highly efficient cata-
lytic method for the selective semireduction of alkynes.
Essential for the reaction development was an understand-
ing of the mechanism and the competing processes. The
new method can be used with a wide range of substrates,
including both internal and terminal alkynes. Further-
more, the new method has exellent chemoselectivity,
complementary to Lindlar and P2 nickel catalysts.
Finally, practical reaction conditions (25 or 45 °C, low catalyst
loading, monophasic mixture), together with the commercial
availability of a catalyst precursor add to the systems appeal.
We propose that the mechanism of the semireduction
involves copper hydride formation, hydrocupration of the
alkyne, then protonation of the alkenyl copper intermedi-
ate by the alcohol to form the copper alkoxide and
the desired product (Scheme 5). Stoichiometric reactions
performed by Sadighi,11 Tsuji,10a and us18 support each of
these elementary steps. We have also shown that any of the
three proposed intermediates can be used as catalysts in the
reaction. Furthermore, a deuterium labeling experiment
resulted in high deuterium incorporation (>97%) and
regioselectivity (Scheme 5, eq 12). This observation
contrasts lower deuterium incorporation observed in
Acknowledgment. We thank the University of Washington
and NSF (CAREER Award 1254636) for financial support.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) See the Supporting Information for details.
(19) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc.
2004, 126, 8352.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX