RESEARCH
cycloaddition (Fig. 1C). In an initial survey of re-
action parameters, the use of a polar solvent such
as N-methyl-2-pyrrolidone was found to promote
high conversions of the 1,1-dichloroalkene. The
catalyst generated from Ni(dme)Br2 (10 mol %)
(dme, 1,2-dimethoxyethane) and L3 (5 mol %)
afforded cyclopentene product 2 in up to 52%
yield. The steric profile of the catalyst proved to
be a critical determinant of reaction efficiency.
When the isopropyl (i-Pr) substituents of the
flanking N-aryl groups were replaced with methyl
(Me) or ethyl (Et) (L1 or L2, respectively), the
yield of 2 decreased to 22% or less. Conversely,
the more-hindered cyclopentyl-substituted ligand
(L4) provided a near-quantitative yield of 2.
There was no competing [2 + 1]-cycloaddition to
generate a vinylcyclopropane, nor did the cata-
lyst isomerize the skipped diene of product 2
into conjugation. The importance of the dinuclear
catalyst structure was examined by comparing
the efficiency of catalysts generated using related
mononucleating ligands (L5 to L9). In no case
did we observe substantial yields of cyclopentene
2 using a mononickel catalyst.
ORGANIC CHEMISTRY
Catalytic reductive
[4 + 1]-cycloadditions
of vinylidenes and dienes
You-Yun Zhou and Christopher Uyeda*
Cycloaddition reactions provide direct and convergent routes to cycloalkanes,
making them valuable targets for the development of synthetic methods. Whereas
six-membered rings are readily accessible from Diels-Alder reactions, cycloadditions
that generate five-membered rings are comparatively limited in scope. Here, we
report that dinickel complexes catalyze [4 + 1]-cycloaddition reactions of 1,3-dienes.
The C1 partner is a vinylidene equivalent generated from the reductive activation
of a 1,1-dichloroalkene in the presence of stoichiometric zinc. Intermolecular and
intramolecular variants of the reaction are described, and high levels of asymmetric
induction are achieved in the intramolecular cycloadditions using a C2-symmetric
chiral ligand that stabilizes a metal-metal bond.
atural products display a variety of carbo-
cyclic structures that are readily assembled
within the active sites of cyclase enzymes
but are challenging to prepare de novo in
the laboratory (1). It is also common for
preparatively useful variants of this process re-
quire an activating substituent, an additional
strain element, or a catalyst to accelerate the
rearrangement step (12–17)—the rearrangement
of the parent vinylcyclopropane molecule oc-
curs at >300°C and has an activation energy of
~50 kcal/mol (18, 19). In light of these challenges,
transition metal–catalyzed [4 + 1]-cycloadditions
have also been explored, culminating in the
discovery of methods that allow for the addition
of CO to various cumulene-containing dienes
(20–23).
We recently reported a dinickel catalyst that
promotes the [2 + 1]-cycloaddition of vinylidenes
and alkenes to form methylenecyclopropane
products (24). 1,1-Dichloroalkenes, which are
conveniently prepared from the corresponding
aldehyde or ketone in a single step, serve as
vinylidene precursors (25), and Zn is used as a
stoichiometric reductant. Experiments using
stereochemically labeled alkenes were sugges-
tive of a stepwise mechanism for cyclopropane
formation. The intermediacy of a metallacycle
generated from the addition of a Ni2(C=CHR)
species to the alkene could account for this
observation. Subsequent C–C reductive elim-
ination would then close the three-membered
ring. We reasoned that such a process might be
adapted to 1,3-dienes as a means of circumvent-
ing the electronic constraints of the pericyclic
[4 + 1]-cycloaddition pathway. In this scenario,
the partitioning between vinylcyclopropane and
cyclopentene products would be dictated by the
relative facility of the two possible C–C reductive
eliminations. Here, we report that dinickel cat-
alysts induce highly selective [4 + 1]-cycloadditions
of vinylidenes and simple 1,3-dienes, provid-
ing a direct synthetic entry into polysubstituted
cyclopentenes.
The substrate scope of the reductive [4 + 1]-
cycloaddition reaction is summarized in Fig. 2.
A variety of common functional groups are tol-
erated, including thioethers, trifluoromethyl
groups, nitriles, esters, ethers, protected amines,
epoxides, acetals, and boronate esters. Products
containing exocyclic vinyl ethers (20) are acces-
sible, albeit in moderate yield owing to competing
reductive decomposition of the alkoxy-substituted
1,1-dichloroalkene. Aryl bromides (7), which are
often employed in Ni-catalyzed cross-coupling
reactions, are left untouched in the cycloaddition
because of the comparatively rapid oxidative
addition of the 1,1-dichloroalkene by the cat-
alyst. Butadiene is a viable substrate (22 to 24),
and the relatively unhindered alkene in the prod-
uct is not susceptible to a secondary methylene-
cyclopropanation. 1,1-Dichloroethylene provides
a source of the parent vinylidene fragment (25
and 26), yielding cyclopentene products with no
substituents on the exocyclic methylene. Products
containing tetrasubstituted alkenes are gener-
ated using ketone-derived 1,1-dichloroalkenes
(27 and 28). Representative 1-substituted (32),
2-substituted (33), 1,2-disubstituted (34), and
1,3-disusbstituted (35) dienes were found to react
efficiently with a model 1,1-dichloroalkene. In the
case of 1,3-disubstituted dienes (35 to 40) the
cycloadditions proceeded with high E selectivity
(9:1 to >20:1 ratio of stereoisomers).
To explore the synthetic utility of this method,
the 4-methylene-1-cyclopentene products were
converted into other classes of cyclopentane
derivatives commonly featured in organic and
organometallic compounds (Fig. 3A). The direct
products of the [4 + 1]-cycloaddition possess
the same degree of unsaturation as a cyclo-
pentadiene motif. Accordingly, deprotonation
of 41 with n-BuLi afforded a cyclopentadienyl
anion equivalent that was quenched with FeBr2
(0.6 equiv) to yield a hexasubstituted ferrocene
(42). Additionally, the two trisubstituted alkenes
in 41 could be readily differentiated in a reaction
N
synthetic molecules to incorporate ring systems
to impose geometric constraints or to arrange
functional components at well-defined positions
in three-dimensional space. For these reasons,
methods that provide convenient access to com-
mon cycloalkanes are of substantial value to
synthetic chemists. Whereas six-membered rings
may be prepared using the Diels-Alder reaction,
no cycloaddition of equivalent generality is avail-
able for the synthesis of five-membered rings.
Current leading approaches include transition
metal–catalyzed [2 + 2 + 1]-cycloadditions, such
as the Pauson-Khand reaction (2), and [3 +
2]-cycloadditions using trimethylenemethane
equivalents (3).
It is attractive to consider an alternative route
to five-membered rings (4, 5) that would rely on
a [4 + 1]-cycloaddition between a 1,3-diene and
a suitable C1 partner (Fig. 1A). A major impedi-
ment to realizing such a reaction by a concerted
mechanism is the competing [2 + 1]-cycloaddition,
which is often favored and generates vinyl-
cyclopropanes as products (Fig. 1B). Quantum
mechanical models for the reaction between
singlet methylene and 1,3-butadiene attribute
this selectivity to excessive closed-shell repulsion
between the carbene lone pair and the filled
Y1 orbital of the diene in the symmetry-allowed
transition state geometry (6–8). Consequently,
direct [4 + 1]-cycloadditions are exceedingly
rare beyond specialized classes of substrates
(9–11). A viable alternative is to carry out a
sequential [2 + 1]-cycloaddition followed by a
vinylcyclopropane 1,3-rearrangement; however,
The Ni2 catalyst 3 was previously shown to
promote the reductive methylenecyclopropa-
nation reaction and thus served as a starting
point for our investigations of a model [4 + 1]-
Department of Chemistry, Purdue University, West Lafayette,
IN 47907, USA.
*Corresponding author. Email: cuyeda@purdue.edu
Zhou et al., Science 363, 857–862 (2019)
22 February 2019
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Zhou, You-Yun
