Fully intermolecular nickel-catalyzed three-component couplings via internal redox

Article abstract of DOI:10.1021/ja0781846

Two distinct nickel-catalyzed fully intermolecular three-component couplings are described. The catalytic addition of enals, alkynes, and alcohols provides γ,δ-unsaturated esters, whereas the catalytic addition of enones, alkynes, and aldehydes provides s

Full text of DOI:10.1021/ja0781846

Published on Web 12/15/2007
Fully Intermolecular Nickel-Catalyzed Three-Component Couplings via
Internal Redox
Ananda Herath, Wei Li, and John Montgomery*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received October 25, 2007; E-mail: jmontg@umich.edu
Scheme 1. Divergent Reaction Pathways
Transition-metal-catalyzed reductive couplings have seen exten-
sive developments in recent years and have been demonstrated with
a broad array of catalysts and substrate combinations. In reactions
of this type, two π-systems such as aldehydes, enones, alkynes,
dienes, or allenes are typically combined with a reducing agent
such as elemental hydrogen, silanes, boranes, or organozincs. During
the coupling event, the two π-systems are joined via C-C bond
formation and undergo a net two-electron reduction, while the
reducing agent undergoes a net two-electron oxidation.1 Whereas
many transition-metal-catalyzed processes such as enyne cycloi-
somerizations do not require a reducing agent, the nature of the
catalysts and substrate combinations are often very different from
the catalysts and substrate combinations that undergo reductive
couplings. The vast majority of cycloisomerization processes
involve olefin formation via â-hydride elimination of a metal alkyl.2
The nickel-catalyzed [3+2] reductive cycloaddition of enals and
alkynes with various reducing agents to afford cyclopentenol 3 was
recently described by our laboratories (Scheme 1).3 When enones
rather than enals were employed, simple reductive coupling to afford
γ,δ-unsaturated ketone 4 was instead observed.4 Formation of
metallacycle 1 followed by protonation to afford alkenyl nickel
species 2 was a key step in both pathways, whereas the fate of
intermediate 2 diverged to either product 3 or 4 depending upon
whether enals or enones were used as starting materials. During
the course of these investigations, we found that a third minor
pathway was possible for enals, wherein methyl ester 5 was
produced in low yield when PCy3 was used as ligand.
Whereas the formation of 3 or 4 is formally a reductive
cycloaddition or coupling, the generation of 5 instead involves an
internal redox process, wherein the aldehyde is oxidized and the
alkyne is reduced.5 We therefore anticipated that a reducing agent
may not be required for the formation of compound 5. Attempting
its formation in the absence of Et3B illustrated that the reducing
agent is indeed not required. Reaction optimization suggested that
optimal conditions for formation of compound 5 involve treatment
of an enal and alkyne with Ni(COD)2 and IPr in a methanol/THF
solvent system (Table 1). Using this optimized procedure, a number
of examples of the procedure were carried out. As illustrated, the
process tolerates substitution at either the R- or â-position of the
enal as well as aryl or alkyl functionality on the alkyne.
Table 1. Three-Component Enal, Alkyne, Alcohol Additionsa
% yield
entry
R1
R2
R3
R4
(regioselectivity)
1
2
3
4
5
H
H
H
Me
H
n-Pr
n-Pr
n-Pr
H
Ph
Et
n-Pent
Ph
Et
Me
Et
Me
Me
Et
75 (53:47)
52
76 (73:27)
85 (75:25)
45
(CH2)2Ph
a Reaction conditions: enal (1.0 equiv), alkyne (1.5 equiv), Ni(COD)2
(0.1 equiv), IPr‚HCl (0.1 equiv), KO-t-Bu (0.1 equiv), MeOH/THF (8:1),
50 °C, 2 h.
Scheme 2. Mechanism of Enal, Alkyne, Alcohol Couplings
In light of the previously proposed mechanism for generation
of compounds 3 and 4, we suggest that metallacycle 6 is a key
intermediate in the generation of product 5 (Scheme 2).6 Protonation
of the enolate moiety of 6 by methanol would generate species 7,
followed by the addition of MeO- to the complexed aldehyde to
produce hemiacetal 8. Aldehyde insertion into a nickel methoxide
species could also be involved in the formation of 8. â-Hydride
elimination of this species would then afford nickel hydride 9, which
would produce the observed product 5 upon reductive elimination.7
Alternatively, addition of uncomplexed N-heterocyclic carbene to
the aldehyde of 7 could be responsible for hydride transfer to nickel,
followed by acyl transfer to methanol.5 As noted in Scheme 2,
incorporation of deuterium at the aldehyde carbon leads to
deuteration of the alkene C-H in product 5 by the mechanism
depicted, and this result was confirmed with >95% deuterium
incorporation at the expected alkene position in the Table 1, entry
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J. AM. CHEM. SOC. 2008, 130, 469-471
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C O M M U N I C A T I O N S
Scheme 3. Strategies for Oxametalacycloheptadiene Synthesis
Table 2. Three-Component Enone, Alkyne, Aldehyde Additionsa
% yield
entry
R1
R2
R3
R4
R5
ligand
(regiosel)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Me
H
H
H
H
H
H
H
H
Me
Me
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
2-furyl
2-furyl
Ph
Ph
Ph
Ph
i-Pr
i-Pr
Cy
Et
Et
Et
Et
Me
Ph
H
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
IPr
PCy3
IPr
PCy3
IPr
PCy3
IPr
PCy3
IPr
PCy3
IPr
PCy3
PCy3
PCy3
PCy3
66
70
5 example. This deuterium-labeling analysis unambiguously rules
out the possibility that methanol serves as a hydride source
concomitant with formaldehyde generation.
n-Pent
n-Pent
n-Pent
n-Pent
Me
Me
Me
Me
Me
Ph
Me
Ph
H
Ph
Me
Ph
Me
Ph
Me
Me
Me
Me
61 (72:28)
76 (>95:5)
60 (>95:5)
56 (90:10)
86 (80:20)
77 (>95:5)
47 (61:39)
65 (87:13)
72 (80:20)
79 (>95:5)
50 (>95:5)
42 (>95:5)
46 (>95:5)
Upon considering the proposed mechanism for the formation of
compound 5 (Scheme 2), we anticipated that other structurally
related nickel alkoxide species could potentially participate in
mechanistically related processes. A requirement for the proposed
mechanistic pathway is the generation of a metallacyclic alkoxide
that possesses an accessible â-hydrogen. We reasoned that an aldol
addition reaction of metallacyclic enolate 6 would generate species
10,8 which bears structural similarity to the key hemiacetal 8
proposed in the generation of 5 (Scheme 3).
Me
n-Pent
Et
H
H
Et
a Reaction conditions, IPr variant: enone (1.0 equiv), alkyne (1.5 equiv),
aldehyde (2.0 equiv), Ni(COD)2 (0.1 equiv), IPr‚HCl (0.1 equiv), KO-t-Bu
(0.1 equiv), toluene, 90 °C, 1 h. PCy3 variant: enone (1.0 equiv), alkyne
(1.5 equiv), aldehyde (2.0 equiv), Ni(COD)2 (0.1 equiv), tricyclohexyl
phosphine (0.2 equiv), toluene, 90 °C, 1 h.
Our exploratory experiments thus focused on the catalytic
addition of enals, alkynes, and aldehydes with Ni(0) catalysts in
the absence of protic solvents in order to avoid undesired enolate
protonation. At the outset, avoiding undesired pathways (such as
homocoupling) in a fully intermolecular catalytic coupling of three
π-components appeared to be a daunting task.9 This is particularly
true since nickel-catalyzed couplings of enones with alkynes,
aldehydes with alkynes, and alkyne trimerizations are all well
precedented processes.1 Thus we were very pleased to observe that
treatment of a mixture of an enone, an aldehyde, and an alkyne to
Ni(COD)2 with either PCy3 or IPr as ligand in toluene directly
afforded 1,3-diketone products 11 in good yield with a high degree
of chemoselectivity. Using these optimized procedures, a number
of illustrations of this three-component coupling of enones, alkynes,
and aldehydes were carried out (Table 2). The enone may be
functionalized with a variety of groups at the carbonyl carbon and
at the R-position, although â-substitution on the enone is not
tolerated. The alkyne may be aromatic, nonaromatic, or terminal.
As illustrated by entries 1-12, the alkyne regioselectivities are
reversed depending on the choice of ligand (PCy3 vs IPr). Whereas
regiochemical reversals had been noted in reductive couplings
involving similarly substituted alkynes,10 the reversal of regiose-
lectivity with aromatic and terminal alkynes is unprecedented in
non-directed nickel-catalyzed reductive couplings.11 Finally, both
aromatic and aliphatic aldehydes are tolerated depending on ligand
structure. The participation of aliphatic aldehydes requires PCy3,
whereas aromatic aldehydes participate with either PCy3 or IPr-
derived catalysts.
Scheme 4. Mechanism of Enone, Alkyne, Aldehyde Couplings
π-Complexes 12a and 12b are accessible via complexation of the
enone and alkyne to Ni(0) (Scheme 4). The sterically demanding
environment of the IPr ligand may favor orientation of the small
alkyne substituent proximal to the ligand as in 12b, whereas the
smaller size of PCy3 may favor the opposite orientation 12a to
minimize interactions of the large alkyne substituent with the enone
â-carbon.10 Oxidative cyclization to metallacycle 13 is followed
by aldol addition of the nickel enolate to the aldehyde.6 The resulting
nickel aldolate 10 undergoes â-hydride elimination to nickel-hydride
14,13 which then affords product 11 upon reductive elimination.
Notably, a prior report from our laboratory described a stoichio-
metric process involving aldol reactions of bicyclic metallacycles
derived from alkynyl enals;8a,b however, by changing to an
intermolecular process with enone starting materials and a different
ligand environment, the catalytic generation of structurally different
products by a distinct mechanistic pathway now becomes possible.
Deuterium-labeling experiments are again useful in evaluating
the proposed mechanism (Scheme 5). Upon carrying out the Ni-
(COD)2/PCy3-catalyzed coupling of d1-benzaldehyde, methyl vinyl
ketone, and 1-phenyl propyne, deuterated product 15 was obtained
With respect to synthetic utility of this transformation, we note
that allylations of 1,3-dicarbonyls provide straightforward entries
to the substructures prepared in Table 2. However, the unsym-
metrical 1,3-diketones and the stereodefined allylic electrophiles
required for synthesis of the products in Table 2 typically require
prior preparation (often multistep), and the direct catalytic union
of enones, alkynes, and aldehydes represents a greatly improved
method for preparation of the compounds depicted. Additionally,
the O-acylation that sometimes plagues attempts at enolate C-
acylation in conjugate addition/acylation strategies is avoided by
the procedure described herein.12
We suggest that the mechanism of the enone, alkyne, aldehyde
three-component couplings proceed by a similar pathway to that
proposed above for enal, alkyne, alcohol three-component couplings.
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C O M M U N I C A T I O N S
Scheme 5. Deuterium-Labeling Studiesa
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.
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a Yields are based upon methyl vinyl ketone.
in 73% yield with >95% deuterium incorporation at the expected
alkenyl position. The same result was obtained with the Ni(COD)2/
IPr catalyst system with the reversed regioselectivity as expected.
To probe the molecularity of the formal 1,5-hydrogen migration, a
crossover experiment was performed. Beginning with 1.25 equiv
each of d1-benzaldehyde and 2-furaldehyde, methyl vinyl ketone
(1.0 equiv) and 1-phenyl propyne (1.5 equiv), a catalytic coupling
involving the Ni(COD)2/PCy3-based conditions was performed.
Product 15 was obtained in 25% yield with >95% deuterium
incorporation, whereas product 16, obtained in 40% yield, possessed
<5% deuterium incorporation. A related crossover experiment with
3-hexyne and the Ni(COD)2/IPr catalyst system also afforded >95%
deuterium incorporation in the phenyl-containing product. These
experiments unambiguously establish an intramolecular hydrogen
migration and rule out alternate mechanisms that could involve a
preformed nickel-hydride active catalyst.14
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Cannizzaro15 and Evans-Tishchenko16 reactions involve a hydride
transfer event from hemiacetal intermediates to an electrophilic unit.
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4) involves a conceptually related hydride transfer event, but the
hydride transfer to an alkyne is now allowed by these new
procedures. Therefore, the developments in this paper may be
viewed as unusual extensions of these classical reactions, albeit
with very different mechanisms involved.
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In summary, two distinct three-component catalytic processes
have been discovered: the coupling of alcohols, alkynes, and enals,
and the coupling of aldehydes, alkynes, and enones. Both of the
processes involve internal redox and proceed in the absence of
reducing agents that have previously been required in many nickel-
catalyzed couplings of these classes of reagents. The high extent
of chemoselectivity is unusual, particularly for aldehyde, enone,
alkyne couplings that involve three different π-components. We
believe that engineering internal redox into reactions of this type
will constitute a strategy of broad utility.17
Acknowledgment. The authors wish to acknowledge receipt
of NSF Grant CHE-0718250 and a Pfizer Michigan Green
Chemistry Award in support of this work.
(17) For a recent illustration in a different context, see: Bower, J. F.; Skucas,
E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc. 2007 129, 15134.
JA0781846
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