Catalytic Reductive Vinylidene Transfer Reactions

Article abstract of DOI:10.1021/jacs.7b05901

Methylenecyclopropanes are important synthetic intermediates that possess strain energies exceeding those of saturated cyclopropanes by >10 kcal/mol. This report describes a catalytic reductive methylenecyclopropanation reaction of simple olefins, utilizing 1,1-dichloroalkenes as vinylidene precursors. The reaction is promoted by a dinuclear Ni catalyst, which is proposed to access Ni₂(vinylidenoid) intermediates via C - Cl oxidative addition.

Full text of DOI:10.1021/jacs.7b05901

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Catalytic Reductive Vinylidene Transfer Reactions
Sudipta Pal, You-Yun Zhou, and Christopher Uyeda
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05901 • Publication Date (Web): 14 Aug 2017
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Catalytic Reductive Vinylidene Transfer Reactions
Sudipta Pal,‡ You-Yun Zhou,‡ and Christopher Uyeda*
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Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
Supporting Information Placeholder
readily available and indefinitely stable 1,1-dihaloalkanes. In
ABSTRACT: Methylenecyclopropanes are important syn-
thetic intermediates that possess strain energies exceeding
those of saturated cyclopropanes by >10 kcal/mol. This report
describes a catalytic reductive methylenecyclopropanation
reaction of simple olefins, utilizing 1,1-dichloroalkenes as
vinylidene precursors. The reaction is promoted by a dinu-
clear Ni catalyst, which is proposed to access
Ni2(vinylidenoid) intermediates via C–Cl oxidative addition.
this context, we recently described a dinuclear Ni catalyst
that promotes the cyclopropanation of alkenes using CH2Cl2
as a carbene source and Zn as a terminal reductant.11 Here,
we report the reductive transfer of vinylidenes from 1,1-
dichloroalkenes (Figure 1). This method provides direct ac-
cess to methylenecyclopropanes, a class of synthetic inter-
mediates valued for their ability to engage in strain-induced
ring-opening reactions.2d,2e,12
Vinylidenes (methylidene carbenes) are reactive interme-
diates comprising a divalent carbon atom incorporated into a
C=C double bond.1 Like their saturated carbene counterparts,
vinylidenes undergo reactions that allow the valence-
deficient carbon to increase its coordination number—for
example, through cheletropic reactions with π-systems or
insertions into C–H bonds.2 Free vinylidenes are accessible
from the decomposition of transiently generated diazo-
alkenes.3 Alternatively, (R2C=C)(M)(X) species (vinyli-
denoids) serve as R2C=C: surrogates, eliminating metal hal-
ides as stoichiometric byproducts.1d A key challenge associat-
ed with developing efficient transfer reactions of vinylidenes
is their susceptibility to competing Fritsch–Buttenberg–
Wiechell (FBW) rearrangements that form alkynes (Figure
1).4 The rate of the 1,2-shift varies as a function of the migrat-
ing group, but when one of the alkene substituents is an H
atom, the rearrangement becomes nearly barrierless.5 This
process underlies the well-known Corey–Fuchs and Seyferth–
Gilbert alkyne syntheses.6
Transition metal catalysis may provide an avenue to ad-
dress the instability of vinylidenes, allowing group transfer
reactions to be favored over competing FBW rearrangement.
Nevertheless, current carbene transfer catalysts are largely
unsuitable for vinylidene transfer due to their reliance on
diazoalkane decomposition as an activation strategy.7 Diazo-
alkenes, the equivalent vinylidene precursors, are not known
to be isolable and undergo N2 elimination spontaneously at
room temperature.1d,3a Transition metal-bound vinylidenes
are accessible by an alternative route involving a metal-
induced isomerization of an alkyne.8 Buono described a Pd-
catalyzed methylenecyclopropanation reaction that operates
by this pathway and is effective for a range of norbornene-
derived substrates.9,10 Other classes of alkenes are not cur-
rently viable in catalytic vinylidene [2 + 1]-cycloadditions.
Figure 1. Vinylidenes as reactive intermediates and design
principles for a catalytic reductive vinylidene transfer reac-
tion.
In our initial studies, we arrived at an optimal set of condi-
tions for a model methylenecyclopropanation reaction based
on our previously reported CH2 transfer method.11 The Ni2
catalyst 113 promotes the addition of 2 to styrene in 94% yield
using Zn as a reductant (Table 1, entry 1). Of note, none of
the 1,1-dichloroalkene is lost to polymerization, reductive
dehalogenation, or FBW rearrangement, allowing the reac-
tion to be conducted with near-equimolar quantities of the
two reaction partners. The [i-PrNDI]Ni2Cl2 complex 4 is also a
high-yielding catalyst, demonstrating efficient entry into the
catalytic cycle from multiple oxidation states of the Ni2 com-
plex (entry 2). The reaction is amenable to in situ catalyst
Our group is interested in developing new modes of car-
bene generation based on the reductive dehalogenation of
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generation using the free i-PrNDI ligand (5, 5 mol%) and
cyclopropanated products (33–37). More hindered alkenes
1
2
3
4
5
6
7
8
Ni(DME)Cl2 (10 mol%) in the place of preformed 1 (entry 3).
Decreasing the steric profile of the imine aryl substituents
leads to rapidly diminishing yields (entries 4–5). Finally, the
importance of the dinuclear catalyst structure was assessed
using a series of mononickel complexes bearing structurally
related N-donor ligands. In these cases, there is significant
consumption of the 1,1-dichloroalkene (2) but no productive
vinylidene transfer to form 3 (entries 6–9).
than those shown in Table 2 are a current limitation and
generally result in low yields. In accordance with these ob-
servations, the selectivity properties of the reaction are high-
ly sensitive to steric effects. For example, norbornene and
norbornadiene are selectively cyclopropanated on the exo
face (37–38), and polyalkene substrates are monocyclopro-
panated at the less substituted alkene (39–40).
Unexpectedly, attempts to carry out the methylenecyclo-
propanation of ethylene (1 atm) yielded 1,3-diene products
(41–43), a reaction that constitutes a formal vinylidene inser-
tion into a C(sp2)–H bond (Figure 2). We reasoned that these
products may be forming in a catalyst-promoted ring-
Table 1. Catalyst Structure–Activity Relationshipsa
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opening
of
a
transient
methylenecyclopropane
intermediate.14 At partial conversions, the reaction to form 42
contains significant amounts of the corresponding meth-
ylenecyclopropane, the concentration of which decreases as
the reaction approaches completion.
entry catalyst
yield
94%
87%
92%
50%
<2%
<2%
<2%
<2%
E/Z ratio
1
[
i-PrNDI]Ni2(C6H6) (1)
i-PrNDI]Ni2Cl2 (4)
1:5
1:5
1:5
1:1
–
Figure
isomerization reactions.
2.
Tandem
methylenecyclopropanation–
2
[
3b
4b
5b
6
i-PrNDI (5) + Ni(DME)Cl2
EtNDI (6) + Ni(DME)Cl2
MeNDI (7) + Ni(DME)Cl2
Experiments pertaining to the mechanism of the catalytic
methylenecyclopropanation are summarized in Figure 3a. By
cyclic voltammetry, the Ni2Cl2 complex 4 exhibits two re-
versible reduction events at –1.15 and –1.72 V relative to the
Fc/Fc couple.11 Zn is capable of accessing only the first of
+
[
[
i-PrPDI]NiCl2 (8)
i-PrIP]Ni(COD) (9)
–
these two reductions, suggesting that the Ni2Cl complex 44 is
the most reduced state of the catalyst that is accessible. Next,
we questioned whether the role of Zn is restricted to catalyst
reduction15 or whether it might be more intimately involved
in the cyclopropane-forming steps of the mechanism—for
example, through the generation of Zn vinylidenoid species.16
This latter possibility was ruled out by conducting a cyclo-
propanation in the absence of Zn, where the Ni2Cl complex
44 was used stoichiometrically as the only source of reducing
equivalents. Accordingly, the reaction between β,β-
dichlorostyrene (1.0 equiv), p-methoxystyrene (1.0 equiv),
and 44 (2.0 equiv) provided 32 in 67% yield (1:2 E/Z ratio).
7
–
8
[BPY]Ni(COD) (10)
i-PrDAD]Ni(COD) (11)
–
9
[
<2%
–
aYields and E/Z ratios were determined by H NMR integra-
tion. Reaction conditions: 2 (0.21 mmol), styrene (0.2 mmol),
catalyst (5 mol%), 24 h, 22 °C. Reactions were conducted
with 5 mol% of the NDI ligand and 10 mol% of Ni(DME)Cl2.
1
b
The substrate scope of the catalytic methylenecyclopropa-
nation is summarized in Table 2. 1,1-Dichloroalkenes bearing
alkyl, aryl, or heteroaryl substituents afford high yields in
their reactions with styrene (12–18). With regard to the al-
kene partner, monosubstituted terminal alkenes are effective
substrates (19–32), and a variety of common functional
groups are tolerated, including esters, ethers, nitriles, boro-
nate esters, aryl chlorides, sulfonyl protecting groups, ace-
tals, primary amides, and ketones. The observed E/Z ratios
vary over a range of values and are dependent on the identity
of the alkene substituent: alkyl groups with α-branching fa-
vor the E-isomer, linear alkyl groups afford low stereoselec-
tivity, and aryl groups favor the Z-isomer.
Finally, there is substantial evidence to support a stepwise
mechanism for the cyclopropanation. The E- and Z-
stereoisomers of β-deuterated p-methoxystyrene react with
incomplete retention of the alkene stereochemistry, yielding
product 32-d1 as a mixture of cis and trans diastereomers. In
principle, this loss of stereochemical fidelity may be due to
an off-path, catalyst-promoted E/Z isomerization of the p-
methoxystyrene starting material. This possibility was tested
by running these reactions to partial conversion and examin-
ing the stereochemistry of the recovered alkene. At a reac-
tion time of 20 min, the recovered alkene is diastereomerical-
ly pure, suggesting that stereochemical scrambling is intrin-
sic to the mechanism of cyclopropane formation.
Relatively unhindered internal alkenes, such as cyclopen-
tene, 2,5-dihydrofuran, and norbornene, also react to form
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Table 2. Substrate Scope for the Catalytic Methylenecyclopropanation Reactiona
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aIsolated yields were determined following purification and are averaged over two runs. See Supporting Information for experi-
mental details. bThe alkene partner was used in excess (4–10 equiv).
A proposed catalytic cycle based on these data is outlined
in Figure 3b. Two-electron oxidative addition of the 1,1-
dichloroalkene using the Ni2Cl complex 44 would require an
additional reducing equivalent provided by either a second
molecule of 44 or by Zn. The resulting Ni2(1-chloroalkenyl)Cl
intermediate 45 could then engage the alkene partner and
form the corresponding methylenecyclopropane product. An
alternative possibility is that 45 first isomerizes by α-chloride
migration to produce the Ni2(vinylidene)Cl2 species 46.17
According to DFT models (BP86/6-311G(d,p)), this isomeriza-
tion is moderately endothermic but potentially accessible
under the reaction conditions (ΔG = 10.5 kcal/mol, 298 K). In
both scenarios, the Ni2Cl2 complex 4 is generated following
vinylidene transfer, and a one-electron reduction closes the
catalytic cycle.
dene transfer predominates over competing rearrangement
to the alkyne despite the presence of a β-hydrogen. Our cur-
rent efforts are directed at generalizing this catalytic vinyli-
dene transfer strategy to other classes of cycloadditions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Attempts to obtain characterization data on the postulated
vinylidenoid intermediate 45/46 proved unsuccessful due to
its instability. In order to access a more stable structural sur-
rogate, the Ni2(μ-styrenyl)Br complex 47 was prepared from
Corresponding Author
*cuyeda@purdue.edu
Author Contributions
‡These authors contributed equally.
an oxidative addition reaction between
1
and β-
bromostyrene. This complex lacks the additional halogen at
the β-position and is thus incapable of engaging in vinyli-
dene transfer. A notable feature of the solid-state structure is
the η2-coordination of the alkenyl π-system to the second Ni.
This interaction constrains the orientation of the β-hydrogen
substituent and may contribute to the absence of FBW rear-
rangement side products in these reactions.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by Purdue University. We thank
Dr. Matthias Zeller for assistance with XRD experiments and
Ravikiran Yerabolu for assistance with mass spectrometry
experiments. C.U. is an Alfred P. Sloan Foundation Research
Fellow.
In summary, the Ni2 catalyst 1 has proven to be uniquely
effective relative to analogous mononickel complexes in
promoting reductive methylenecyclopropanation reactions
using 1,1-dichloroalkenes. Of particular significance, vinyli-
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Figure 3. (a) Mechanistic studies probing the relevant catalyst oxidation states, the role of Zn, and the concertedness of the cy-
clopropanation. (b) A proposed catalytic mechanism. (c) A structurally characterized model (47) for the proposed Ni2 vinyli-
denoid intermediate (45).
C. Chem.–Eur. J. 2006, 12, 6450-6456; (d) Bruneau, C.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2006, 45, 2176-2203; (e) Bruneau, C.; Dixneuf,
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