Reductive Cyclopropanations Catalyzed by Dinuclear Nickel Complexes

Article abstract of DOI:10.1002/anie.201511271

Dinuclear Ni complexes supported by naphthyridine-diimine (NDI) ligands catalyze the reductive cyclopropanation of alkenes with CH₂Cl₂ as the methylene source. The use of mild terminal reductants (Zn or Et₂Zn) confers significant functional-group tolerance, and the catalyst accommodates structurally and electronically diverse alkenes. Mononickel catalysts bearing related N chelates afford comparatively low cyclopropane yields (≤20 %). These results constitute an entry into catalytic carbene transformations from oxidized methylene precursors.

Full text of DOI:10.1002/anie.201511271

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International Edition: DOI: 10.1002/anie.201511271
German Edition: DOI: 10.1002/ange.201511271
Carbene Transfer Reactions
Hot Paper
Reductive Cyclopropanations Catalyzed by Dinuclear Nickel
Complexes
You-Yun Zhou and Christopher Uyeda*
Abstract: Dinuclear Ni complexes supported by naphthyri-
dine-diimine (NDI) ligands catalyze the reductive cyclopropa-
nation of alkenes with CH2Cl2 as the methylene source. The use
of mild terminal reductants (Zn or Et2Zn) confers significant
functional-group tolerance, and the catalyst accommodates
structurally and electronically diverse alkenes. Mononickel
catalysts bearing related N chelates afford comparatively low
cyclopropane yields (ꢀ 20%). These results constitute an entry
into catalytic carbene transformations from oxidized methyl-
ene precursors.
T
ransition-metal-mediated carbene transfer processes have
emerged as the preeminent catalytic approach for selective
cyclopropane synthesis.[1] The most established subclass of
these reactions revolves around the controlled decomposition
of diazoalkanes, which undergo facile N2 extrusion to
=
generate transient M CR2 species (Figure 1a). Since the
seminal studies on using homogeneous Cu complexes,[2] this
manifold has provided a rich arena for catalyst discovery, and
much of the d block has now been surveyed in pursuit of
efficient cyclopropanation catalysts.[1] Despite the collective
synthetic utility of these reactions, a persistent limitation is
the scope of carbene precursors. Diazoalkane reagents are
inherently unstable in the absence of electron-withdrawing
substituents. Consequently, diazoacetates, and their deriva-
tives, are the most common class of substrates in reported
methods. Given the abundance of natural products, pharma-
ceutical compounds, and fine chemicals containing cyclo-
propanes with one or more unsubstituted carbon atoms,
a general catalytic approach for the transfer of the parent CH2
group would be of significant value.[3]
In principle, the use of diazomethane in carbene transfer
reactions[4] could be circumvented by accessing reactive
methylene equivalents reductively from dihalomethanes.
Indeed, the Simmons–Smith cyclopropanation, which was
first reported in 1958, operates in this way and continues to
represent the most viable method for CH2 transfer (Fig-
ure 1b).[5] The active intermediate is formulated as an
(ICH2)ZnI species, which is generated in situ from the
reduction of CH2I2 with Zn. In contrast to their redox-neutral
counterparts, reductive cyclopropanations have been remark-
ably resistant to catalysis. Previous efforts have focused on the
use of Lewis acids[6] or organic additives[7] to intercept the
Figure 1. Noncatalytic and transition-metal-catalyzed alkene cyclopro-
panation reactions.
intermediate (XCH2)Zn species and accelerate the methylene
transfer step. This approach has been successfully applied to
allylic alcohols, culminating in enantioselective variants;
however, few methods have extended this mode of activation
more generally to substrates without directing groups.[8]
We envisioned an alternative catalytic strategy for reduc-
tive carbene transformations centered on the use of transition
metals to facilitate carbon–halogen bond activation (Fig-
ure 1c). In our proposed scheme, a low-valent metal complex
engages the dihalomethane reagent in an oxidative addition,
forming a (XCH2)MX species. Methylene transfer to an
organic substrate yields an oxidized MX2 complex, which then
undergoes two-electron reduction to close the catalytic cycle.
Whereas carbon(sp3)–halogen bond activations are well-
precedented in Ni-catalyzed cross-coupling[9] and reductive
cross-coupling reactions,[10] little is known about the ability of
(XCH2)M intermediates to undergo efficient methylene
transfer. Herein, we report an entry into transition-metal-
catalyzed reductive carbene transfer processes in the context
of a cyclopropanation mediated by the dinuclear Ni com-
plexes 1–3 (Figure 2).[11] The procedure allows CH2Cl2,[12]
[*] Dr. Y.-Y. Zhou, Prof. C. Uyeda
Department of Chemistry, Purdue University
560 Oval Dr., West Lafayette, IN 47907 (USA)
E-mail: cuyeda@purdue.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201511271.
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room temperature. In the presence of 4-methoxystyrene
(20 equiv), the CH2 equivalent is trapped in 54% efficiency as
the cyclopropanated product. The intermediate species
responsible for methylene transfer is fleeting under these
conditions. When complex 1 is premixed with CH2Cl2 for
20 min prior to the addition of the alkene, only traces of the
cyclopropane are obtained. The one-electron-oxidized mono-
chloride complex 2 is also competent at effecting the
reductive cyclopropanation and provides a slightly dimin-
ished yield of 33%. With (E)- or (Z)-b-methyl-(4-methoxy)-
styrene, the cyclopropanation is stereospecific, affording the
trans- or cis-configured products, respectively (Figure 3b).
This stereochemical outcome excludes mechanisms that
involve stepwise ring formation through long-lived radical
intermediates.
Figure 2. Dinuclear Ni catalysts for reductive cyclopropanations.
The remaining criterion for catalytic turnover was the
identification of a suitable reductant to regenerate either 1 or
2 from dichloride complex 3 (Figure 3c). Cyclic voltammetry
experiments indicated a chemically reversible one-electron
reduction for 3 at À1.15 V vs. Cp2Fe/Cp2Fe+. The large peak-
to-peak separation (530 mV at a scan rate of 100 mVsÀ1) is
consistent with halide dissociation upon reduction. Based on
this electrochemical behavior, we hypothesized that a variety
of mild chemical reductants, particularly those that efficiently
sequester chloride, might be capable of converting 3 into 2.
Accordingly, treatment of 3 with excess Zn powder cleanly
effects the one-electron reduction to monochloride complex
2. Et2Zn (1.0 equiv) also reduces 3 to 2 with concomitant
evolution of ethane and ethylene. With ꢁ 2.0 equiv of Et2Zn,
the monochloride complex 2 is further reduced to 1.
a previously inert substrate in the Simmons–Smith reaction,
to function as a methylene source when used in combination
with Zn or Et2Zn as terminal reductants. Structurally and
electronically diverse classes of alkenes are cyclopropanated
in high yield under these conditions.
In the initial stages of reaction development, key steps of
the proposed catalytic cyclopropanation were validated by
examining the ability of the low-valent [i-PrNDI]Ni2(C6H6)
complex 1 to stoichiometrically activate CH2Cl2 and promote
methylene transfer (Figure 3a). Complex 1 is rapidly oxidized
by CH2Cl2, generating the dichloride complex 3 in 10 min at
Collectively, these preliminary studies revealed a viable
strategy for achieving catalytic cyclopropanations. At 5 mol%
loading, complex
1 catalyzes the cyclopropanation of
4-methoxystyrene in CH2Cl2 using Zn as a terminal reductant
(Table 1, entry 1). No background conversion was observed
without the catalyst under otherwise identical conditions
(entry 2). Several noteworthy observations were made during
our optimization studies. First, the inclusion of N,N-dimethyl-
acetamide (DMA) in the solvent mixture is critical to
obtaining high product yields as it presumably serves to
activate the heterogeneous Zn surface. Second, mononickel
catalysts bearing structurally related N chelates (complexes
4–8) uniformly afforded low yields, despite significant con-
sumption of the alkene starting material (entries 4–8).[13] For
these catalysts, the appearance of broad resonances in the
1H NMR spectrum is consistent with polymerization being
a dominant side reaction. Third, the halide complexes 2 and 3
were equally efficient catalysts compared to 1, indicating
facile entry into the cyclopropanation manifold from a variety
of oxidation states (entries 9 and 10).
Under the optimized catalytic conditions, the scope of
styrene derivatives was examined (Table 2). Common elec-
tron-withdrawing and electron-donating substituents are
tolerated. It is significant that 2-chlorostyrene is cyclopropa-
nated in high yield, demonstrating that CH2Cl2 activation
outcompetes reduction or reductive coupling of the aryl
chloride. Furthermore, a boronate ester and a trialkoxysilane,
functional groups commonly used in cross-coupling reactions,
are compatible with the cyclopropanation conditions.
Figure 3. Stoichiometric reactivity of [NDI]Ni2 complexes relevant to
catalytic cyclopropanation. Ar=4-MeOC6H4.
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Table 1: Catalyst comparison.[a]
Table 3: Scope of alkenes in the catalytic cyclopropanation.[a]
Entry
Catalyst
i-PrNDI]Ni2(C6H6) (1)
Conversion [%]
Yield [%]
1
2
[
>99
0
69
0
–
3
4
5
6
7
8
9
10
Ni(COD)2
35
2
[
[
[
i-PrPDI]NiCl2 (4)
i-PrPDI]NiCl (5)
i-PrIP]Ni(COD) (6)
>99
>99
52
82
38
19
20
19
8
2
76
64
[BPY]Ni(COD) (7)
[
[
[
i-PrDAD]Ni(COD) (8)
i-PrNDI]Ni2Cl (2)
>99
>99
i-PrNDI]Ni2Cl2 (3)
[a] Reactions were run on a 0.5 mmol scale in CH2Cl2 (0.4 mL) and DMA
(50 mL). Conversions of the starting material and yields of the cyclo-
propane product were determined by 1H NMR integration against an
internal standard.
Table 2: Scope of styrene derivatives in the catalytic cyclopropanation.[a]
Ar
Yield [%]
74[b]
Ar
Yield [%]
60
74
80
66
70
[a] Reactions were conducted on a 0.5 mmol scale. Full procedures are
reported in the Supporting Information. Yields of isolated products after
purification are given. [b] Yields determined by 1H NMR integration
against an internal standard. [c] CD2Cl2 instead of CH2Cl2.
84
73
69
83
disubstituted cyclopropanes from their corresponding alkene
stereoisomers (entries 1–6). For these substrates, the use of
Et2Zn instead of Zn has a beneficial impact on rate and yield.
A diene (entry 7) is selectively cyclopropanated at the less
hindered terminal double bond. 1,1-Disubstitued alkenes
(entries 8–11), carbocyclic (entries 12–14) and heterocyclic
(entries 15 and 16) alkenes, and a,b-unsaturated carbonyl
compounds (entries 17–19) also react efficiently under the
catalytic conditions. a-Cyclopropylstyrene reacts to form the
dicyclopropane product without rearrangement, providing
further support for a non-radical pathway (entry 11). Ali-
phatic terminal alkenes are a current limitation, undergoing
competing hydrogenation with Et2Zn as the reductant.
Finally, cyclopropanes with deuterium substitution are gen-
erated using CD2Cl2 (entries 20 and 21).
70
65
[a] Reactions were conducted on a 0.5 mmol scale in CH2Cl2 (0.4 mL)
and DMA (50 mL). Yields of isolated products after purification are given.
[b] Yield determined by 1H NMR integration against an internal stan-
dard.
The catalytic cyclopropanation using 1 can be extended to
other classes of alkenes (Table 3). Internal alkenes react
stereospecifically, affording access to both cis- and trans-
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The Ni-catalyzed cyclopropanation and the uncatalyzed
Simmons–Smith reaction exhibit distinct selectivity profiles.
Simmons–Smith-type (XCH2)Zn reagents are generally elec-
trophilic,[5] reacting sluggishly with electron-deficient
alkenes.[14] For example, the cyclopropanation of chalcone
with CH2I2 and Et2Zn produces low yields of the cyclo-
propane (16%), and the reaction is accompanied by extensive
decomposition of the starting material (Figure 4a). By con-
In summary, we have shown that the dinuclear Ni catalysts
1–3 directly engage CH2Cl2 in cyclopropanation reactions in
the presence of mild reductants, such as Zn or Et2Zn, to
achieve turnover. These complexes enable the catalytic
transfer of unsubstituted methylene, providing a useful com-
plement to cyclopropanation methods that employ diazoal-
kane reagents bearing stabilizing electron-withdrawing sub-
stituents. In principle, this mode of reductive dihalomethane
activation might be extended to other catalytic carbene
transformations. The application of the [NDI]Ni2 platform to
these reactions is currently studied in our laboratory.
Acknowledgements
This work was generously supported by Purdue University.
We thank Ian Powers for assistance with X-ray crystallog-
raphy.
Keywords: alkenes · carbene transfer · cyclopropanation ·
nickel catalysis · reductive cycloaddition
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3171–3175
Angew. Chem. 2016, 128, 3223–3227
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Received: December 4, 2015
Published online: January 28, 2016
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