Evolution of efficient strategies for enone-alkyne and enal-alkyne reductive couplings

Article abstract of DOI:10.1021/ja9083607

Strategies for the reductive coupling of enones or enals with alkynes have been developed. The reducing agents employed include organozincs, organoboranes, organosilanes, and methanol. The latter of these strategies is simple, cost-effective, and tolerant

Full text of DOI:10.1021/ja9083607

Published on Web 11/02/2009
Evolution of Efficient Strategies for Enone-Alkyne and
Enal-Alkyne Reductive Couplings
Wei Li, Ananda Herath, and John Montgomery*
Department of Chemistry, 930 North UniVersity AVenue, UniVersity of Michigan,
Ann Arbor, Michigan 48109-1055
Received October 1, 2009; E-mail: jmontg@umich.edu
Abstract: Strategies for the reductive coupling of enones or enals with alkynes have been developed. The
reducing agents employed include organozincs, organoboranes, organosilanes, and methanol. The latter
of these strategies is simple, cost-effective, and tolerant of many functional groups. Isotopic labeling
strategies have provided supporting evidence for the mechanistic proposals.
Scheme 1. Progression of Strategies for Effecting Conjugate
Addition
Introduction
Conjugate additions to enones, enoates, and their derivatives
are among the most widely used reactions in the preparation of
functionalized carbonyl derivatives.1 The installation of alkene
functionality by conjugate addition is well established, with
many powerful variants. Traditional vinyl cuprate additions
require prior synthesis of a vinyl halide, followed by lithium
halogen exchange, cuprate formation, and then addition to the
electrophilic alkene substrate (Scheme 1).1 Alkyne hydrometa-
lation strategies provide a powerful alternative to reagents
derived from metal halogen exchange, but the stoichiometric
generation of an alkenyl metal species is nonetheless still
required.2 Catalytic methods for the direct reductive coupling
of enones and alkynes have attracted considerable recent study
including work from our lab, and such methods enjoy the
advantage of avoiding the stoichiometric assembly of vinyl
organometallic reagents.3 While this feature provides an im-
portant advance, the choice of reducing agent employed becomes
an important defining feature of the practicality of the method.4
enyne product.6 More recent advances from our laboratories
illustrated conceptually similar couplings of enones and enals
employing organoborane and silane reducing agents.7 In concur-
rent studies, Cheng illustrated that cobalt-catalyzed processes
involving zinc-mediated reductive couplings provide an effective
procedure for enoate conjugate additions, which is an especially
useful observation given the poor reactivity of enoates in the
nickel-catalyzed processes.8 A recent report from our labora-
tories then illustrated that reducing agents may be omitted
Early reports from our lab illustrated that intramolecular
reductive couplings of enones and alkynes were possible by
utilizing ZnEt2 as the reducing agent in the presence of a Ni(0)
catalyst.5 This work built upon the important earlier studies of
Ikeda, who illustrated that alkynylstannane reagents could
participate in enone-alkyne alkylative coupling processes that
transfer the alkynyl unit during coupling to generate a conjugated
(1) Lipshutz, B. H.; Sengupta, S. In Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, 1992; Vol. 41, pp 135-631.
(2) (a) Loots, M. J.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 8045. (b)
Wipf, P.; Smitrovich, J. H. J. Org. Chem. 1991, 56, 6494. (c) Lipshutz,
B. H.; Wood, M. R. J. Am. Chem. Soc. 1994, 116, 11689. (d) Lipshutz,
B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 7440. (e) El-
Batta, A.; Hage, T. R.; Plotkin, S.; Bergdahl, M. Org. Lett. 2004, 6,
107. (f) Yanagi, T.; Sasaki, H.; Suzuki, A; Miyaura, N. Syn. Commun.
1996, 26, 2503.
(5) (a) Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118,
2099. (b) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am.
Chem. Soc. 1997, 119, 4911. (c) Montgomery, J.; Chevliakov, M. V.;
Brielmann, H. L. Tetrahedron 1997, 53, 16449. (d) Montgomery, J.;
Seo, J.; Chui, H. M. P. Tetrahedron Lett. 1996, 37, 6839.
(6) (a) Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975. (b) Ikeda,
S.; Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics 1995, 14,
5015. (c) Ikeda, S. Acc. Chem. Res. 2000, 33, 511.
(3) (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (b)
Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (c) Montgomery, J.;
Amarasinghe, K. K. D.; Chowdhury, S. K.; Oblinger, E.; Seo, J.;
Savchenko, A. V. Pure Appl. Chem. 2002, 7, 129.
(7) (a) Herath, A.; Thompson, B.; Montgomery, J. J. Am. Chem. Soc.
2007, 129, 8712. (b) Herath, A.; Montgomery, J. J. Am. Chem. Soc.
2008, 130, 8132.
(4) For a recent review highlighting the progression from the use of
stoichiometric metallated species to contemporary catalytic methods:
Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J. Angew. Chem.,
Int. Ed. 2009, 48, 34.
(8) (a) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H. J. Am. Chem. Soc. 2002,
124, 9696. (b) Chang, H.-T.; Jayanth, T. T.; Wang, C.-C.; Cheng,
C.-H. J. Am. Chem. Soc. 2007, 129, 12032. (c) Jeganmohan, M.;
Cheng, C.-H. Chem.sEur. J. 2008, 14, 10876.
9
17024 J. AM. CHEM. SOC. 2009, 131, 17024–17029
10.1021/ja9083607 CCC: $40.75  2009 American Chemical Society

Strategies for Enone-Alkyne Reductive Couplings
A R T I C L E S
Table 1. Scope of Triethylborane-Mediated Reductive Couplingsa
altogether from enal-alkyne couplings by engineering an internal
redox pathway.9 This strategy provides a means to access ester-
containing products starting from enal via the unusual redox
interchange inherent in the process. Alkenes have recently been
recognized by Jamison as useful inputs for the generation of
γ,δ-unsaturated carbonyls by the three-component addition of
enones, alkenes, and silyl triflates, and as noted herein, the
alkene addition method illustrates complementary characteristics
to alkyne addition methods.10 A variant involving alkene-enone
additions from Ogoshi recently illustrated that the silyl triflate
may be omitted under more forcing conditions.11
Considering the increase in practicality of conjugate additions
dating back to early developments in organocuprate chemistry
up to the current state of procedures described above, we were
motivated to further advance methods for enone-alkyne reduc-
tive couplings to the highest possible level of practicality. Recent
developments from Krische12 and Sigman13 in the development
of C-C bond-forming reductive coupling processes that utilize
alcohols as the reducing agent have had a major impact on the
underlying efficiencies of aldehyde addition processes and cross-
couplings, respectively. These important advances motivated us
to consider this strategy as means for accessing γ,δ-unsaturated
carbonyls by the reductive couplings of enones and alkynes.
The ability to carry out conjugate addition reactions in simple
hydroxylic solvents in the absence of any other reducing agent
would provide an important advance toward avoiding the
limitations and inefficiencies of alternate methods for effecting
conjugate addition. In this report, we provide a full account of
our recent studies on the intermolecular reductive coupling of
enones or enals with alkynes and describe for the first time the
use of methanol as the reducing agent in couplings of this type.14
Results and Discussion
Development of Triethylborane-Mediated Enone-Alkyne
Reductive Couplings. Although efficient reductive cyclizations
of alkynyl enones employing diethylzinc in anhydrous THF as
the reducing agent were developed by our lab in the mid 1990s,5
two critical changes in reaction setup are required to allow
efficient intermolecular processes to proceed. By employing a
methanol/THF cosolvent system, and employing triethylborane
as reducing agent, a variety of simple enones and alkynes
undergo efficient reductive coupling in the presence of
Ni(COD)2 (10 mol %) and PBu3 (20 mol %). The scope of this
procedure is relatively broad, and a representative sampling of
effective substrate combinations are depicted below (Table 1).7a
As shown, effective variants include couplings of R-substituted
a Reactions were carried out in MeOH/THF (8:1) using 1.0 equiv of
enone, 1.5 equiv of alkyne, 3.0 equiv of Et3B, 0.1 equiv of Ni(COD)2,
and 0.2 equiv of PBu3 at 50 °C. A product ratio of >95:5 indicates that
no other stereo- or regioisomer was detected at a level greater than 5%.
and ꢀ-substituted enones, cyclic or acyclic enones, R′-silyloxy-
enones, and enones that possess free hydroxyls. Similarly,
terminal alkynes, aromatic and nonaromatic internal alkynes,
and ynoates were efficiently tolerated. Regioselectivities are high
with aromatic and terminal alkynes, whereas regioisomeric
mixtures are observed with nonaromatic internal alkynes. As
the examples illustrate, several features are particularly note-
worthy. First, the method tolerates unprotected hydroxyls and
ester functionality, which would be problematic for many
alternate methods including the use of organolithium-derived
cuprates. Second, the combination of enones and ynoates is
interesting from the standpoint of chemoselectivity. Both starting
components are effective Michael acceptors, yet no homocou-
pling is observed for either component. Only a modest excess
of the ynoate is required, and slow addition techniques are not
required.
(9) Herath, A.; Li, W.; Montgomery, J. J. Am. Chem. Soc. 2008, 130,
469.
(10) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F. Angew. Chem., Int. Ed. 2008,
47, 1893.
(11) Ogoshi, S.; Haba, T.; Ohashi, M. J. Am. Chem. Soc. 2009, 131, 10350.
(12) (a) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009,
48, 6313. (b) Patman, R. L.; Chaulagain, M. R.; Williams, V. M.;
Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066. (c) Han, S. B.;
Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
6916. (d) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc.
2009, 131, 5054. (e) Kim, I. S.; Han, S. B.; Krische, M. J. J. Am.
Chem. Soc. 2009, 131, 2514. (f) Bower, J. F.; Skucas, E.; Patman,
R. L.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 15134. (g) See
also Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A.; Zhao,
Y.-M.; Xia, W. J. J. Am. Chem. Soc. 2005, 127, 10836.
Our studies illustrate that the methanol component in the
solvent mixture is required. This effect may be attributed to
the role of methanol in promoting alkyl transfer of the
organoborane, as well as in promoting hydrolysis of a transiently
generated nickel enolate motif. The likely mechanism for this
transformation involves complexation of the enone 3 and alkyne
(13) (a) Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am. Chem.
Soc. 2007, 129, 14193. (b) Iwai, Y.; Gligorich, K. M.; Sigman, M. S.
Angew. Chem., Int. Ed. 2008, 47, 3219. (c) Gligorich, K. M.; Iwai,
Y.; Cummings, S. A.; Sigman, M. S. Tetrahedron 2009, 65, 5074.
(14) For a preliminary account of portions of this work, see ref 7.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 17025

A R T I C L E S
Li et al.
Scheme 2. Mechanism of Triethylborane-Mediated Reductive
Couplings
Scheme 3. Divergent Behavior of Enones and Enals
Scheme 4. Suppression of [3 + 2] Cycloaddition by the Use of
Organosilanes
4 to a Ni(0)/PBu3 species, followed by oxidative cyclization to
nickel metallacycle 6 or 7 (Scheme 2).15 Involvement of the
organoborane may accelerate this oxidative cyclization. The role
of Et3B in promoting metallacycle formation in aldehyde-alkyne
couplings was recently computationally evaluated by Houk and
Jamison,16 and proposals of this Lewis acidic role of Et3B were
depicted by Tamaru in aldehyde-diene couplings.17 The role
of organozincs in promoting metallacycle formation was studied
in our collaborative work with Schlegel,18 and experimental
demonstrations of rate acceleration promoted by other Lewis
acids were documented by Ogoshi for other classes of metal-
lacycles.19 The species generated upon stirring Et3B in methanol
has been characterized as Et2BOMe,20 and we assume that this
species is likely generated under the mixed solvent system
employed in our studies. The enolate derived from oxidative
cyclization may be viewed as either a boron or nickel enolate
6 or 7, simply depending upon whether the Ni-O interaction
is maintained. After the formation of 6 or 7, protonation of the
enolate by methanol would generate species 8, followed by ethyl
transfer from boron to nickel to generate 9, ꢀ-hydride elimina-
tion to produce 10, and reductive elimination to produce the
observed conjugate addition product 5.
cyclopentenol product via [3 + 2] reductive cycloaddition is
observed.21 We envision the mechanism of enone-alkyne
reductive coupling and enal alkyne [3 + 2] reductive cycload-
dition as being closely related. With vinyl nickel species 8
serving as a common intermediate, (Scheme 3), reduction by
Et3B leads to formation of acyclic product 5 via intermediates
9 and 10 as depicted above (Scheme 2). However, in the enal
variant, intermediate 8 (R1 ) H) now possesses an electrophilic
aldehyde still complexed to the alkenyl nickel unit. Direct
addition of the nickel alkenyl functionality to the aldehyde then
occurs to initiate five-membered ring closure leading to the [3
+ 2] cycloaddition product 11.
The [3 + 2] reductive cycloaddition reaction is an interesting
process in its own right as previously communicated,21 and
related processes have since been reported by Cheng22 and Toste
and Bergman.23 However, the need for an efficient reductive
coupling of enals and alkynes still remained. The mechanistic
analysis described above suggested that suppression of the [3
+ 2] reductive cycloaddition pathway might be difficult for any
set of conditions that proceeded through intermediate 8. For
this reason, we were attracted to the use of silane reducing agents
in aprotic solvents. In the absence of organoboranes, metalla-
cycle 12 could be directly produced by oxidative cyclization
(Scheme 4). σ-Bond metathesis of 12 would generate intermedi-
ate 13, followed by generation of enol silane product 14 by
C-H reductive elimination. The absence of methanol in the
solvent composition would ensure that metallacyclic enolate
protonation does not occur under the reaction conditions, and
the formation of the enol silane functionality generated by the
σ-bond metathesis event would ensure that the aldehyde is not
Development of Trialkylsilane-Mediated Enal-Alkyne
Reductive Couplings. One class of reactions that fails using the
above protocol is the reductive coupling of enals with alkynes.
Whereas simple conjugate addition products are not obtained,
instead, efficient conversion of the enal and alkyne to a
(15) Amarasinghe, K. K. D.; Chowdhury, S. K.; Heeg, M. J.; Montgomery,
J. Organometallics 2001, 20, 370.
(16) (a) McCarren, P. R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk,
K. N. J. Am. Chem. Soc. 2009, 131, 6654. For development of the
synthetic procedures related to this study, see: (b) Huang, W.-S.; Chan,
J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (c) Miller, K. M.; Huang,
W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
(17) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K; Shimizu, M.;
Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 397.
(18) Hratchian, H. P.; Chowdhury, S. K.; Gutierrez-Garcia, V. M.;
Amarasinghe, K. K. D.; Heeg, M. J.; Schlegel, H. B.; Montgomery,
J. Organometallics 2004, 23, 4636.
(19) (a) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126,
11802. (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem.
Soc. 2005, 127, 12810.
(21) Herath, A.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 14030.
(20) (a) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 1923. For the use of
Ni(COD)2/Et3B in methanol, see: (b) Patel, S. J.; Jamison, T. F. Angew.
Chem., Int. Ed. 2003, 42, 1364.
(22) Chang, H.-T.; Jayanth, T. T.; Cheng, C.-H. J. Am. Chem. Soc. 2007,
129, 4166.
(23) Schomaker, J. M.; Toste, F. D.; Bergman, R. G. Org. Lett. 2009, 11,
3698.
9
17026 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Strategies for Enone-Alkyne Reductive Couplings
A R T I C L E S
Table 2. Scope of Trialkylsilane-Mediated Reductive Couplingsa
Scheme 5. Complementarity of Enal-Alkyne and Enal-Alkene
Couplings
functional groups including alcohols, esters, ketones, aldehydes
and secondary amines. The only alternate procedure for enol
silane synthesis that has demonstrated this range of functional
group tolerance is the Trost Ru-catalyzed alkene-alkyne
coupling procedure that selectively generates E-enol silanes,24
thus making the Ni- and Ru-catalyzed processes entirely
complementary.
The consistently observed Z-enol silane stereochemistry
provides evidence that the η1 O-bound nickel metallacyclic
enolate 12 is involved as a productive intermediate (Scheme
5). The seven-membered metallacycle with an η1 enolate
requires formation of the Z-enolate that is maintained in
subsequent mechanistic steps to ultimately produce Z-enol silane
14. This outcome can be contrasted with the recent studies of
Jamison on enone-alkene couplings using silyl triflate promot-
ers.10 That method provides similar products, but with the E-enol
silane 16 being selectively produced. The mechanism proposed
by Jamison for his method involves formation of η3 nickel
enolate species 15, and indeed, it is likely the differing hapticity
of the metallacyclic enolates derived from otherwise similar
couplings of alkenes and alkynes that leads to this profound
change in enol silane stereochemistry, thus establishing the two
methods as complementary. In addition, the positions where
functionality may be installed is different between the two
methods. Notably, an enone-alkyne-derived nickel metallacycle
was previously characterized by our lab as the η1 O-enolate
species, as evidenced by both crystallographic and NMR
characterization.15,18 In contrast, a cyclic nickel enolate derived
from enone-cyclopropyl ketone coupling was characterized by
Ogoshi as the η3 nickel enolate.25 Based on these precedents, it
appears likely that the hybridization of atoms within the
metallacycle framework, the ring size, and the resulting ring
strain differences result in the key hapticity change that
ultimately reverses the observed enol silane geometry.26
Development of Methanol-Mediated Enone-Alkyne Reduc-
tive Couplings. With efficient methods in hand for the reductive
couplings of enones and alkynes using trialkylboranes and of
enals and alkynes using trialkylsilanes, we next considered the
a Reactions were carried out in THF using 1.0 equiv of enone, 1.5
equiv of alkyne, 2.0 equiv of silane, 0.1 equiv of Ni(COD)2, and 0.2
equiv of PCy3 at 50 °C. A product ratio of >98:2 indicates that no other
stereo- or regioisomer was detected at a level greater than 2%. b Isomer
ratio refers to the regiochemistry of alkyne insertion. c Me2PhSiH was
used as reducing agent. d Isomer ratio refers to relative stereochemistry
of the two stereocenters.
liberated during the integral mechanistic steps. These features
should suppress the competing [3 + 2] cycloaddition manifold.
As envisioned by this analysis, the silane-mediated reductive
coupling of enals and alkynes employing a catalyst from
Ni(COD)2 (10 mol %) and PCy3 (20 mol %) in THF provides
a straightforward and versatile entry to enol silanes. Representa-
tive examples are depicted below (Table 2).7b The process is
efficient with acrolein as well as enals that possess ꢀ-alkyl- and
ꢀ-aryl substitution. In all cases, control of stereochemistry of
both newly formed alkenes is highly selective, and the Z-enol
silane stereochemistry is always observed. A variety of orga-
nosilanes efficiently participate in the process, and while most
lead to isolable enol silanes, couplings with Me2PhSiH afford
products that undergo complete hydrolysis upon purification to
afford the aldehyde product. Of particular note is the remarkable
functional group tolerance compared with other methods for
enol silane preparation. Whereas electrophilic silicon reagents
are typically employed in the synthesis of enol silanes, the use
of organosilanes instead allows tolerance of a variety of
(24) (a) Trost, B. M.; Surivet, J. P.; Toste, F. D. J. Am. Chem. Soc. 2001,
123, 2897. For an overview of related methods, see: (b) Trost, B. M.;
Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067.
(25) Tamaki, T.; Nagata, M.; Ohashi, M.; Ogoshi, S. Chem.sEur. J. 2009,
15, 10083.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 17027

A R T I C L E S
Li et al.
Scheme 6. Reductive Couplings Using Methanol as Reducing
Agent
Table 3. Scope of Methanol-Mediated Reductive Couplings
possibility of increasing the practicality and cost of the enone-
alkyne coupling procedure by directly using methanol as the
reducing agent, thereby avoiding the use of a pyrophoric
reducing agent. The analysis leading to this possibility comes
from considering the mechanism proposed for Et3B-based
reductive couplings. As noted above, Et3B-based reductive
couplings required the use of a methanol-THF cosolvent system,
to allow the production of intermediate 8 by protonation of the
metallacyclic enolate motif (Scheme 2). We reasoned that
species 17, generated in the absence of Et3B, could potentially
be coaxed to undergo ꢀ-hydride elimination directly to form
nickel hydride species 10, ultimately leading to product 5
(Scheme 6). For the Et3B-free pathway to succeed, not only
must intermediate 17 undergo ꢀ-hydride elimination, but the
oxidative cyclization to generate metallacycle 12 must proceed
in the absence of the borane Lewis acidity.
Upon initiating studies to explore the possibility of reductive
couplings employing methanol as the reducing agent, our initial
experiments using the precise protocol used in Et3B-based
couplings, but in the absence of Et3B, led to inefficient
couplings. While the Et3B-based procedure used a Ni(0)/PBu3
catalyst, we quickly found that PCy3 and PPh3 complexes of
Ni(0) in THF/methanol do efficiently catalyze enone-alkyne
reductive couplings of internal alkynes in the absence of Et3B
(Table 3). The scope of this procedure is somewhat analogous
to the related Et3B-based procedure described above, with the
notable exceptions that cyclic enones participated efficiently only
when Et3B was employed. Otherwise, examples employing
methyl vinyl ketone, R-substituted, or ꢀ-substituted enones were
generally efficient in the Et3B-free variant, as were couplings
with a range of internal alkynes bearing various functional
groups. Although PCy3 and PPh3 may be used interchangably
in some cases, PCy3 was generally preferred with R- or
ꢀ-substituted enones, whereas PPh3 was generally preferred with
enones that lack R- and ꢀ-substitution.
Terminal alkynes are an important class of substrates that
are often problematic in reductive couplings due to rapid
trimerization of the terminal alkyne under the reaction condi-
tions. In a coupling of phenylacetylene, the standard conditions
with PCy3 afforded the desired product in 59% isolated yield.
However, syringe-drive addition of the alkyne improved the
yield to 94%. In our prior studies of aldehyde-alkyne reductive
couplings, N-heterocyclic carbene (NHC) ligands were relatively
inefficient in the trimerization of alkynes compared with the
desired reductive coupling pathway.27 This observation proved
a Reactions were carried out in MeOH:THF (8:1) using 1.0 equiv of
enone, 1.5 equiv of alkyne, 0.1 equiv of Ni(COD)2, and either 0.2 equiv
of PPh3 or PCy3, or 0.1 equiv of IMes [from 1,3-bis(2,4,6-trimethyl-
phenyl)imidazolium chloride and t-BuOK] at 50 °C. A product ratio of
>95:5 indicates that no other stereo- or regioisomer was detected at a
level greater than 5%. b Alkyne was added by syringe drive.
c Additionally, 13% yield of the alcohol derived from deprotection of
the product acetate was obtained, giving an overall 60% yield for the
desired coupling.
useful here as well in the reductive coupling of enones and
terminal alkynes. For example, a coupling of cyclohexyl
acetylene proceeded in only 24% isolated yield even when
employing slow addition of the alkyne. However, the use of
the NHC IMes as ligand improved the yield to 47%. When using
internal alkynes, NHC’s were generally less satisfactory than
PCy3 or PPh3. In summary, three complementary ligands are
identified for the methanol-based procedure: PCy3 for R- or
ꢀ-substituted enones with internal alkynes, PPh3 for unsubsti-
tuted enones with internal alkynes, and NHC’s for couplings
of terminal alkynes. Examples provided in Table 3 illustrate
the optimum conditions for each example shown.
(26) For interconversion of C- and O-enolates of nickel, see: Campora, J.;
Maya, C. M.; Palma, P.; Carmona, E.; Gutie´rrez-Puebla, E.; Ruiz, C.
J. Am. Chem. Soc. 2003, 125, 1482.
(27) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004,
126, 3698.
9
17028 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Strategies for Enone-Alkyne Reductive Couplings
Scheme 7. Deuterium-Labeling Studies
A R T I C L E S
reducing agent. In the variant employing Ni(COD)2, PBu3, and
Et3B, a reaction in CD3OD/THF afforded product with 3%
incorporation of deuterium at the alkenyl position (Scheme 7).
An experiment with Ni(COD)2 and PCy3 performed in CD3OD/
THF, in contrast, afforded >97% deuteration at the alkenyl
position. A third experiment with Ni(COD)2 and PCy3 performed
in CH3OD/THF afforded no measurable deuteration at the
alkenyl position. Deuteration at the methylene position R to the
phenyl ketone was observed at levels exceeding 1 unit of
deuterium due to the combination of initial enolate kinetic
protonation in addition to H/D exchange occurring in this acidic
position. The above experiments clearly indicate that the variant
using Et3B employs the borane, not methanol, as the reducing
agent. In contrast, the Et3B-free procedure clearly employs
methanol as the reducing agent by transferring a hydrogen atom
from the CH3 group to the product.
a Percent D incorporation of the CH2 moiety R to the ketone is given
relative to 2 hydrogen atom units.
Conclusions
In summary, a group of protocols has been developed for
the reductive couplings of enones or enals with alkynes. The
procedures provide simple and environmentally friendly alterna-
tives to the use of vinyl cuprate reagents in conjugate addition
processes. The developments described present a progression
of practicality, wherein the reducing agent required may include
organozincs, organoboranes, silanes, or methanol. The latter of
these developments, namely the procedure that utilizes methanol
as a cosolvent and reducing agent, provides an especially
attractive procedure that avoids the stoichiometric generation
of metalated species and reactive or flammable reducing agents
that classical alternatives require.
The failure of cyclic enones to participate when using methanol
as the reducing agent may originate from the beneficial interaction
of oxygen and nickel during metallacycle formation with acyclic
enones, leading to the O-enolate 12, which is postulated to be a
key intermediate in the reactions. Cyclic enones, which are locked
in the S-trans orientation, cannot adopt an orientation that allows
the O-enolate to form. Instead formation of a five-membered
C-enolate would be required for cyclic enones. The Lewis acidity
of Et3B may therefore become especially important with cyclic
enones since the Ni-O interaction is not allowed to develop during
metallacycle formation.
The similar scope and relative rates of couplings in the
presence and absence of Et3B raise the question of whether the
borane is actually functioning as reducing agent at all in the
Et3B variant, or whether it is simply functioning as a Lewis
acidic promoter. This question can be addressed by isotopic
labeling studies, and a series of experiments were carried out
to clarify this question. Using trans-chalcone as a test case, three
experiments were performed to elucidate the nature of the
Acknowledgment. We acknowledge receipt of NSF grant CHE-
0718250 in support of this work. Ben Thompson is thanked for
preliminary contributions described in ref 7a.
Supporting Information Available: Full experimental details
and copies of NMR spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA9083607
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 17029