Published on Web 06/23/2007
Catalytic Intermolecular Reductive Coupling of Enones and Alkynes
Ananda Herath, Benjamin B. Thompson, and John Montgomery*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received May 9, 2007; E-mail: jmontg@umich.edu
Scheme 1. Divergent Pathways for Reductive Couplings of
Alkynes with Enals or Enones
Conjugate addition reactions have long been recognized as a
powerful tool for assembly of functionalized ketones, and a variety
of copper-promoted processes involving enone alkenylation have
been widely used to prepare γ,δ-unsaturated carbonyls.1 Typical
strategies involve either stoichiometric preparation of alkenyl copper
reagents that directly add to enones, or alternatively, stoichiometric
formation of a vinyl metal species (zirconium in the most prominent
cases) that undergoes addition to enones in the presence of a copper
or nickel catalyst.2 Earlier studies from our laboratory illustrated
that alkynyl enones undergo nickel-catalyzed reductive cyclization
processes using diethylzinc as reducing agent.3 Unfortunately, the
scope of this process was limited to five-membered ring cyclizations
on very simple substrates, and the use of triethylborane under aprotic
conditions was also ineffective. Attempts with intermolecular
versions, sterically hindered cyclizations, or larger ring cyclizations
were entirely unsatisfactory. More recent studies from Cheng
involving cobalt catalysis provided an efficient method for
the reductive coupling of enoates and alkynes,4 and Micalizio
reported titanium-promoted alkene/alkyne reductive couplings
involving nonactivated alkenes.5 However, although powerful
copper-based methods for conjugate addition of terminal alkyne-
derived vinyl organometallics are known,2 the highly desirable direct
catalytic intermolecular reductive coupling of enones and alkynes
without requiring vinyl organometallic preparation has not been
reported.
A number of features of the above examples, particularly the
range of alkyne substitution patterns and the tolerance of free
hydroxyls, illustrate complementarity to alternative copper-based
procedures. However, the unique characteristics of this new process
are perhaps best illustrated by the chemoselective coupling of
ynoates and enones (Table 2). Whereas both ynoates and enones
are potential Michael acceptors, they undergo highly regio-, stereo-
and chemoselective heterocouplings at room temperature without
requiring a large excess of either reagent or careful control of
reagent addition (entries 1-4). Failure to observe products derived
from homocoupling of either starting material is perhaps surprising
given the potentially similar reactivity of both components. Ad-
ditionally, with ynoates being excellent Michael acceptors, hydro-
metallation strategies have potential to exhibit lack of chemose-
lectivity or reversed regioselectivity.7 Finally, strategies for
organocuprate formation via traditional lithiation sequences are
typically difficult in the presence of electrophilic functional groups
such as esters.8 Avoiding each of these potential complications in
a simple, catalytic protocol renders the ynoate/enone reductive
coupling particularly valuable.9
In the course of studying catalytic [3 + 2] reductive cycload-
ditions of enals and alkynes recently developed in our lab,6 we
observed that simply utilizing an enone rather than an enal allowed
catalytic intermolecular reductive couplings to instead proceed
(Scheme 1). Recognizing the potential impact of this transformation
as a complement to organocuprate technology, we set out to
examine the scope of this new reductive coupling process, and the
results are described herein.
The divergent reactivity of enals compared with enones (Scheme
1) can be explained within the same mechanistic framework of
catalytic [3 + 2] reductive cycloadditions (Scheme 2). Oxidative
cyclization of enone 1 and alkyne 2 with Ni(0) would afford
metallacycle 7 or related borane adduct 8.10 Details of how the
reducing agent (Et3B in this report) may accelerate the oxidative
cyclization was described in a computational study of organozinc-
mediated alkylative couplings of alkynyl enones.11 Once structure
7 or 8 is formed, enolate protonation would afford structure 9. From
this intermediate, using an enal starting material (R1 ) H), vinyl
nickel addition to the tethered aldehyde would afford boron alkoxide
10 en route to [3 + 2] reductive cycloaddition product 3.
Alternatively, if carbonyl addition is sterically impeded in ketone
derivatives when an enone is used (R1 ) aryl or alkyl), then ethyl
transfer from boron to nickel to produce 11, followed by â-hydride
elimination to 12 and reductive elimination would generate acyclic
reductive coupling product 4. An experiment using CD3OD afforded
product 4 with no deuterium incorporation at the alkenyl position,
consistent with this proposed pathway (eq 1).
A series of examples were examined to illustrate the scope of
enone/alkyne reductive couplings, and an attractive range of enones
and alkynes were found to participate efficiently. A variety of
enones were first examined in couplings of 1-phenyl propyne (Table
1). With this representative alkyne, efficient couplings were
demonstrated with a range of enones including methyl vinyl ketone
(entry 1), a longer chain simple vinyl ketone (entry 2), aromatic
vinyl ketones with â-alkyl or â-aryl substitution (entries 3 and 4),
an R-alkyl enone (entry 5), an R′-silyloxy(vinyl)ketone (entry 6),
a â-substituted enone bearing a free hydroxyl (entry 7), and a cyclic
enone (entry 8). To examine the range of alkynes that efficiently
participate, additional examples were then carried out. Couplings
were observed with diaryl alkynes (entry 9), terminal alkynes (entry
10), nonaromatic internal alkynes (entry 11), and a hydroxyl-bearing
alkyne (entries 12 and 13). Couplings with aromatic or terminal
alkynes proceeded with excellent regioselection (entries 1-8, 10),
whereas nonaromatic internal alkynes afforded mixtures of regioi-
somers (entries 12 and 13).
9
8712
J. AM. CHEM. SOC. 2007, 129, 8712-8713
10.1021/ja073300q CCC: $37.00 © 2007 American Chemical Society