Deoxygenative C-C bond-forming processes via a net four-electron reductive coupling

Article abstract of DOI:10.1021/jacs.5b08448

The nickel-catalyzed coupling of enones or enals with alkynes in the presence of silane and titanium alkoxide reductants provides direct access to skipped diene products. The process involves a net four-electron reductive coupling and proceeds with deoxyg

Full text of DOI:10.1021/jacs.5b08448

Communication
pubs.acs.org/JACS
Deoxygenative C−C Bond-Forming Processes via a Net Four-Electron
Reductive Coupling
David P. Todd, Benjamin B. Thompson,† Alex J. Nett, and John Montgomery*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
the presence of a reductant, wherein a net two-electron
ABSTRACT: The nickel-catalyzed coupling of enones or
enals with alkynes in the presence of silane and titanium
alkoxide reductants provides direct access to skipped diene
products. The process involves a net four-electron
reductive coupling and proceeds with deoxygenation of
the starting enone or enal. A new class of well-defined
nickel(0) precatalysts bearing an unhindered N-hetero-
cyclic carbene ligand, which was developed in optimization
of the process, is essential for the efficiency of the
transformation. The strategy allows the high reactivity of
α,β-unsaturated carbonyl substrates to be utilized in
couplings with simultaneous extrusion of the oxygen
atom, thus enabling a traceless strategy for alkene
installation.
reduction of the starting components occurs during the
coupling event. Examples of this type of process include the
coupling of enones and alkynes to produce γ,δ-unsaturated
ketones (product 2, Scheme 1),5 the coupling of aldehydes and
alkynes to produce allylic alcohols,5 and the coupling of allylic
alcohols with alkynes to produce skipped dienes.6 These
processes share the characteristic of a net two-electron
reduction accompanying the coupling event. In the course of
exploring the development of catalytic reductive coupling
methods, we observed an unexpected conversion of enones and
alkynes to skipped diene products with complete deoxygena-
tion of the enone substrate (product 3, Scheme 1). This
process possesses the unique characteristic of a net four-
electron reduction accompanying the coupling event. The
discovery, optimization, and mechanistic study of this process is
described herein.
vast array of catalytic methods have been developed for
Prior reports from our laboratory described the efficient
reductive coupling of enals and alkynes in the presence of silane
reductants and Ni(COD)2 (COD = 1,5-cyclooctadiene) with
PCy3 to produce (Z)-enol silanes 4 (Scheme 2).7 During efforts
to extend this reactivity to enones rather than enals, exploration
of a range of phosphine and N-heterocyclic carbene (NHC)
ligands afforded low yields of the expected trisubstituted enol
silanes, with alkyne hydrosilylation being the major side
reaction. However, attempting the reaction with the un-
hindered NHC ligand ITol (5) while using Ti(O-i-Pr)4 with
Et3SiH8 led to the unexpected production of skipped diene 7 in
37% isolated yield.9 Omission of Ti(O-i-Pr)4 or replacement of
ITol with more common NHC ligands bearing ortho
substituents on the N-aryl group such as IMes (N-mesityl) or
IPr (N-[2,6-diisopropylphenyl]) failed to produce more than
trace quantities of the skipped diene product 7. Replacement of
Ti(O-i-Pr)4 with isopropanol10 or the use of catalytic Ti(O-i-
Pr)4 with excess isopropanol did result in production of 7, but
in considerably lower isolated yield than when 1.1 equiv of
Ti(O-i-Pr)4 was used.
Among the many classes of NHC complexes of nickel that
our group has explored in various contexts, ligands such as ITol
that lack ortho substituents on the N-aryl group typically lead
to low-yielding and inconsistent reactions compared with the
substantially more robust analogous catalysts derived from
IMes or IPr. Given this limitation and the unique behavior of
ITol in promoting the formation of skipped diene 7, we
examined the preparation of stable precatalysts of Ni(0)
A
the union of two π components via carbon−carbon bond
formation. The majority of such methods involve the
redistribution of atoms without a net change in the oxidation
state in the components. For example, the coupling of an
alkene and an alkyne to produce a diene (product 1, Scheme
1),1 the hydrovinylation of alkenes,2 and the hydroacylation of
Scheme 1. Redox Description of Catalytic Coupling
Processes
an alkyne or alkene with an aldehyde3 are representative
examples of processes of this type. The participation of
substrates lacking π bonds in processes of this type has more
recently been made possible by sequential hydrogen transfer/
C−C coupling events, as illustrated by the coupling of an
alcohol and an allene to produce a homoallylic alcohol.4 All of
the above-mentioned processes share the characteristic of being
completely atom-economical without a net formal change in
oxidation state of the reactants.
A second group of processes that similarly enable the union
of two π components involves catalytic methods conducted in
Received: August 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b08448
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Journal of the American Chemical Society
Communication
Scheme 2. Catalyst Optimization in Skipped Diene
Formation
Table 1. Scope of Skipped Diene Formation
coordinated with ITol.11 Among several classes of well-defined
catalysts examined, Ni(0) complex 6 derived from methyl
methacrylate, ITol·HBF4, and Ni(COD)2, had the desirable
attributes of ease of preparation, moderate air stability, and high
reactivity in the production of skipped dienes, as evidenced by
the production of 7a in 90% isolated yield (Scheme 2). On the
basis of this outcome, the utility of catalyst 6 was employed in
our further exploration of skipped dienes via the four-electron
reductive coupling of enones and alkynes.
Scheme 3. Evaluation of Potential Intermediates
Utilizing the optimized procedure with catalyst 6, Et3SiH,
and Ti(O-i-Pr)4, the production of skipped diene products
from a range of alkynes (2.0 equiv) with enones and enals (1.0
equiv) was examined (Table 1). From a range of enone
substrates, products 7a−i were obtained in good yields with
>95:5 regioselectivity. Within these examples, the enone
substrates included phenyl and methyl ketones with aromatic
or aliphatic substituents at the enone β-position. The alkyne
could be varied to include symmetrical or unsymmetrical
alkynes, including aromatic alkynes, terminal alkynes, and
alkynes bearing phthalimido or silyloxy functionality. Notably,
cyclic enones such as cyclohexenone (not shown) were
generally ineffective substrates in this transformation. The
process was very effective with enal substrates to produce
products 8a−e, including enals possessing aromatic or aliphatic
β-substituents. Notably, an enal lacking β-substituents was an
efficient substrate (giving product 8c), whereas enones lacking
a β-substituent were ineffective in the transformation.
the C−OSiEt3 bond was the likely operative mechanistic
pathway.12 However, attempts to reduce compound 4a under
the reaction conditions failed to produce skipped diene 8a. A
second alternative considered was that enal 1,2-hydrosilylation
was followed by alkyne addition to the resulting silylated allylic
alcohol.6 However, exposure of the silylated allylic alcohol
derived from cinnamaldehyde to the reaction conditions also
failed to produce skipped diene product 8a.
Important insight was gained from deuterium-labeling studies
in the production of d-4a and d-8a from cinnamaldehyde and 1-
phenylpropyne (Scheme 4). Using the previously published
procedure with PCy3 as the ligand and Et3SiD as the
reductant,7a the deuterium label is exclusively introduced on
the alkyne-derived terminus of the product d-4a, as expected.
However, in the skipped diene production using catalyst 6 with
Et3SiD, deuteration of the enal-derived terminal methylene
group exclusively cis to the central carbon was observed in
Because of the novelty of the four-electron reductive
coupling and the unusual combination of reactive components,
a series of experiments were conducted to better understand
the mechanism of this process (Scheme 3). Given the
precedent for two-electron reductive couplings to generate
enol silane products (i.e., product 4, Scheme 2),7 we envisioned
that enol silane production followed by reductive cleavage of
B
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Journal of the American Chemical Society
Communication
bipyridine metallacycles.13 While stereoselective formation of
the 1,2-trans-alkene generated by enone couplings (product 7,
Table 1) could potentially be biased by the thermodynamic
stability of the trans-alkene, the stereochemical outcome of
aldehyde coupling [product (5-d)-8a, Scheme 4] using Et3SiD
removes this bias. Starting from the known stereochemistry of
9, syn addition to (Z)-enol silane 11 followed by anti silyloxy
elimination in the conversion of 13 to 14 explains the net
stereochemical outcome. The overall positional selectivity using
Et3SiD and Ti(O-i-C3D7)4 [comparing products (5-d)-8a and
(1-d)-8a, Scheme 4] is fully consistent with the proposed
mechanistic pathway. In particular, the diverging mechanisms
from intermediate 10 leading to changes in position of
deuterium incorporation explain the labeling outcomes in the
production of d-4a and d-8a.
Scheme 4. Deuterium-Labeling Studies
In summary, a new synthetic entry to skipped dienes
involving deoxygenative coupling of enones or enals with
alkynes has been developed. The process is formally a four-
electron reductive coupling, which enables the high reactivity of
unsaturated carbonyl substrates to be utilized while providing
products that are free of the carbonyl functionality. Deuterium-
labeling studies documented an unusual outcome in which
Et3SiH and Ti(O-i-Pr)4 both play key roles as reductants in the
transformation. Future studies will explore the utility of this
new mechanistic pathway in other classes of transformations.
product (5-d)-8a, and no label incorporation in the alkyne-
derived terminus was observed. With Ti(O-i-C3D7)4, 91%
deuterium incoporation in the alkyne-derived terminus was
observed in product (1-d)-8a, and no label incorporation at the
enal-derived terminus was observed.
On the basis of these experiments, a mechanism that explains
the surprising outcome of these labeling experiments can be
formulated (Scheme 5). Oxidative cyclization of the enone and
alkyne with Ni(0) provides seven-membered metallacycle 9
with an η1 nickel O-enolate motif,13,14 and σ-bond metathesis of
the silane with the Ni−O bond provides nickel hydride
intermediate 10 bearing an enol silane functionality. This
intermediate serves as a common intermediate leading to two-
electron or four-electron reductive coupling pathways. With
PCy3 as the ligand, reductive elimination of the C−H bond
provides the observed enol silane product 4 in analogy to
previous reports.7 However, the unique reactivity illustrated by
the unhindered NHC ligand ITol likely suppresses the
efficiency of reductive elimination while allowing coordination
and insertion of the tethered enol silane functionality via
species 11 to provide intermediate 12. Bond rotation in 12 to
produce rotamer 13 is then followed by anti elimination of the
silyloxy group, promoted by the Lewis acid Ti(O-i-Pr)4,15 to
provide intermediate 14 with isopropoxy transfer from Ti to Ni.
Extrusion of acetone10 to generate 15 and reductive elimination
of the C−H bond provide the observed product 7/8.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b08448.
X-ray crystallographic data for catalyst 6 (CIF)
Experimental details and copies of spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*jmontg@umich.edu
Present Address
†B.B.T.: Eastman Chemical Company, 730 Worcester St.,
Springfield, MA 01151.
Notes
The authors declare no competing financial interest.
Several experimental observations support the above-
postulated mechanistic pathway. The η1 nickel O-enolate
form of metallacycle 9 (Scheme 5) is supported by the
observed (Z)-enol silane stereochemistry of 4 and is consistent
with prior crystallographic analysis of the analogous tmeda and
ACKNOWLEDGMENTS
■
This work was supported by NSF Grant CHE-1265491. The
authors thank Jeff Kampf for the crystallographic analysis of
Scheme 5. Operative Mechanistic Pathways
C
DOI: 10.1021/jacs.5b08448
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Communication
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assistance in the synthesis and evaluation of catalyst 6.
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DOI: 10.1021/jacs.5b08448
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