Methylenespiro[2.3]hexanes via Nickel-Catalyzed Cyclopropanations with [1.1.1]Propellane

Article abstract of DOI:10.1021/jacs.9b10689

[1.1.1]Propellane is a highly strained tricyclic hydrocarbon whose reactivity is dominated by addition reactions across the central inverted bond to provide bicyclo[1.1.1]pentane derivatives. These reactions proceed under both radical and two-electron pathways, hence, providing access to a diverse array of products. Conversely, transition metal-catalyzed reactions of [1.1.1]propellane are underdeveloped and lack synthetic utility, with reported examples generally yielding mixtures of ring-opened structural isomers, dimers, and trimers, often with poor selectivity. Herein, we report that nickel(0) catalysis enables the use of [1.1.1]propellane as a carbene precursor in cyclopropanations of a range of functionalized alkenes to give methylenespiro[2.3]hexane products. Computational studies provide support for initial formation of a Ni(0)-[1.1.1]propellane complex followed by concerted double C-C bond activation to give the key 3-methylenecyclobutylidene-nickel intermediate.

Full text of DOI:10.1021/jacs.9b10689

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Article
Methylenespiro[2.3]hexanes via Nickel-Catalyzed
Cyclopropanations with [1.1.1]Propellane
Songjie Yu, Adam Noble, Robin B. Bedford, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Nov 2019
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Methylenespiro[2.3]hexanes via Nickel-Catalyzed Cyclopropanations
with [1.1.1]Propellane
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Songjie Yu, Adam Noble, Robin B. Bedford,* and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
Supporting Information Placeholder
ABSTRACT: [1.1.1]Propellane is a highly strained tricyclic hydrocarbon whose reactivity is dominated by addition reactions
across the central inverted bond to provide bicyclo[1.1.1]pentane derivatives. These reactions proceed under both radical and two-
electron pathways, hence providing access to a diverse array of products. Conversely, transition metal-catalyzed reactions of
[1.1.1]propellane are underdeveloped and lack synthetic utility, with reported examples generally yielding mixtures of ring-opened
structural isomers, dimers, and trimers, often with poor selectivity. Herein, we report that nickel(0) catalysis enables the use of
[1.1.1]propellane as
a
carbene precursor in cyclopropanations of
a
range of functionalized alkenes to give
methylenespiro[2.3]hexane products. Computational studies provide support for initial formation of a Ni(0)-[1.1.1]propellane
complex followed by concerted double C–C bond activation to give the key 3-methylenecyclobutylidene-nickel intermediate.
bonds and their lack of interaction with transition metal
catalysts. Typically, catalytic C–C bond activation protocols
require the use directing groups10 or activated strained ring
systems, including cyclopropanes11,12 or cyclobutanones,13 and
proceed via cleavage of a single C–C bond to generate a
metallacycle intermediate. Conversely, access to metal
carbene complexes requires a double C–C bond activation of
cyclopropanes, via a formal retro-cyclopropanation. While the
use of simple cyclopropanes as carbene precursors is rare,14
systems that impart additional ring-strain as a crucial driving
force have been exploited to promote the challenging double
C–C bond activation.15,16 For example, bicyclo[1.1.0]butanes
have been employed as metal carbene precursors under
1. Introduction
Catalytic cyclopropanation is a powerful method for
generating three-membered carbocycles from alkenes and
appropriate carbene precursors.1 Key to the catalytic process is
the formation of a transition metal carbene intermediate
(Scheme 1), which then reacts with an alkene in either a
concerted manner (pathway A),2,3 wherein the alkene attacks
the carbene moiety directly to form two C–C bonds
simultaneously, or in a stepwise fashion via the formation of a
metallacyclobutane intermediate (pathway B).4–6 Irrespective
of the pathway adopted, the formation of a carbene complex is
regarded as pivotal to the transformation. Typically, this is
accomplished by taking advantage of highly reactive
compounds, such as diazoalkanes,7 containing weak C–X
bonds that are easily cleaved by the metal catalyst.8
rhodium17
and
nickel
catalysis.18
In
contrast,
[1.1.1]propellane,19 which is considerably more strained than
bicyclo[1.1.1]butane, has found little application as a metal
carbene precursor.
Scheme 1. Generalized mechanisms for catalytic alkene
cyclopropanation with a metal carbene complex
[1.1.1]Propellane (1) is
a highly strained tricyclic
hydrocarbon, with a calculated strain energy of between 98
and 113 kcal/mol.20 This is attributed to the unusual ‘inverted’
central σ-bond between its bridgehead carbons. As a result, the
reactivity of 1 has been dominated by strain-release, wherein
additions
across
the
bridgehead
bond
yield
bicyclo[1.1.1]pentane derivatives either via single-electron21
or two-electron pathways (Scheme 2a).22,23 Despite the
growing number of synthetic methods for accessing
functionalized bicyclo[1.1.1]pentanes from 1, reports of
transition metal-catalyzed reactions of 1 are rare. However, its
high ring-strain should provide the required driving force to
facilitate metal-catalyzed retro-cyclopropanation, in which
double C–C bond activation furnishes a metal carbene species.
A less common approach to metal carbenes is via C–C bond
activation,9 which is challenging due to the inertness of C–C
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Scheme 2. Transformations of [1.1.1]propellane
precursor (Scheme 2c). The reaction proceeds via double C–C
bond activation of 1 to generate nickel carbene 6 and provides
access to methylenespiro[2.3]hexanes through
7
4
5
6
7
cyclopropanation of a broad array of alkenes. Density
functional theory (DFT) calculations provide insight into the
key interaction between 1 and the Ni(0) catalyst and support
the formation of the proposed 3-methylenecyclobutylidene
nickel complex 6.
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2. Results and Discussion
Initial investigations focused on cyclopropanation of
4-vinylbiphenyl (8a) with 1 in the presence of various
transition metal catalysts (Table 1). In line with the report by
Wiberg,26 a Rh(I) catalyst resulted in rapid formation of the
dimerization product bis(3-methylenecyclobutylidene) (2)
with no observable cyclopropanation (entry 1). Similarly, Ir(I),
Pd(0), and Cu(I) catalysts failed to promote cyclopropanation
(entries 2–4). Pleasingly, switching to Ni(cod)2 as the catalyst
with the N-heterocyclic carbene (NHC) ligand SIMes
(generated
in
situ
from
1,3-bis(2,4,6-
trimethylphenyl)imidazolinium chloride [SIMes∙HCl] and
NaOtBu) suppressed the dimerization pathway and resulted in
formation of methylenespiro[2.3]hexane derivative 7a in 64%
yield after 20 h at 50 °C (entry 5).27 Further evaluation of the
Table 1. Optimization studiesa
To date, the limited reports of carbene formation from 1
have resulted in mixtures of isomerization and oligomerization
products, thus lacking synthetic utility. Thermal ring-opening
entry
catalyst (mol%)
x (mol%)
base
3 (%)b
1
2
Rh(cod)2Cl (5)
Ir(cod)2Cl (5)
Pd(dba)3 (5)
Cu(MeCN)4PF6 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
-
-
-
-
-
0
0
of
dimethylenecyclopropane,24 a reaction subsequently shown to
occur via free carbene intermediate
1 under flow conditions at 430 °C yields 1,2-
-
a
3
-
0
(methylenecyclobutylidene) with an activation energy of 39.6
kcal/mol.25 Wiberg explored ring-opening reactions of 1 in the
presence of various transition metal catalysts (Scheme 2b).26
With Rh(I) or Pd(II) an almost instantaneous reaction occurred
to give the ring-opened dimer 2, whereas Ag(I), Ir(I), Pt(II),
and Pt(0) led to slower reactions to produce varying amounts
of dimer 2, methylene cyclobutene (3), and various trimeric
products. The authors proposed that these were formed via
metal carbene intermediates 4. This was supported by a
cyclopropanation reaction with methyl acrylate catalyzed by
[Rh(CO)2Cl]2, which gave methylenespiro[2.3]hexane 5 as a
1:1.5 mixture with 2. However, formation of 5 required the
use of methyl acrylate as the solvent, presumably to make
cyclopropanation competitive with the rapid dimerization of
the carbene intermediate.
c
4
-
-
0
5
12
12
12
12
20
12
12
-
NaOtBu
LiOMe
LiOtBu
KOtBu
LiOMe
LiOMe
LiOMe
-
64
6
81
7
67
8
69
9
87 (76)
(89)d
(65)d,e
(75)d
0
10
11
12
13
12
LiOMe
a Reaction conditions: 8a (0.20 mmol), 1 (0.7–0.9 M in Et2O,
0.40 mmol), catalyst (5–10 mol%), SIMes∙HCl (0–20 mol%), base
We envisaged that the carbenes generated by metal-
mediated ring-opening of 1 could be exploited more generally
in cyclopropanation reactions with alkenes. Key to achieving
this would be to suppress undesired isomerization and
oligomerization reactions of the metal carbene intermediate.
Herein, we report that nickel catalysis efficiently promotes
cyclopropanation reactions of alkenes using 1 as a carbene
b
(20 mol%), and solvent (3 mL) at 50 °C for 20 h. Yields were
1
determined by H NMR analysis using 1,3,5-trimethoxybenzene
as an internal standard. Numbers in parenthesis are isolated yields
c
of
the
purified
product.
2,2-Bis((4S)-4-
d
isopropyloxazoline)propane (12 mol%) was used as the ligand.
e
With 4.0 equiv 1. Using IMes∙HCl (12 mol%) in place of
SIMes∙HCl.
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base used to generate the NHC ligand revealed LiOMe to be
alkenes were tolerated, such as pyridine (7n), quinoline (7o),
2
3
optimal, affording 7a in 81% yield (entries 6–8). Using a
higher ligand loading of 20 mol% resulted in marginal
indole (7p), furan (7q), and benzothiophene (7r), undergoing
cyclopropanation in good to excellent yields. In addition to
alkenes with aromatic substituents, conjugated 1,3-diene and
1,3-enyne substrates were also tolerated. These substrates
displayed higher reactivity and reactions proceeded efficiently
at room temperature, delivering alkenyl or alkynyl-substituted
spirocyclic products 7t–7x in good yield and with complete
regioselectivity for reaction at the terminal alkene. We also
investigated the reaction of terminal alkynes with 1 (Scheme
4
5
6
7
8
9
increase in yield (entry 9). However,
a
significant
improvement was observed upon increasing the amount of 1
from 2 equiv to 4 equiv, which allowed isolation of 7a in 89%
(entry 10). Changing the NHC ligand to 1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene (IMes) resulted in
a
slightly decreased yield (entry 11). Interestingly, Ni(cod)2 in
the absence of NHC ligand was still an effective catalyst for
cyclopropanation, providing 7a in a slightly reduced yield of
75% (entry 12). Finally, a control experiment demonstrated
the importance of the Ni(0) catalyst as no product was
observed in its absence (entry 13), which is in line with the
high energy barrier to free carbene formation via thermal
rearrangement of 1.25
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4). Interestingly, 4-ethynylbiphenyl (9) reacted via
a
carbene/alkyne metathesis rather than the expected
cyclopropanation,29 giving bis(3-methylenecyclobutylidene)
product 10 in 20% yield.
Scheme 4. Reaction of terminal alkynes
With optimal conditions for the nickel-catalyzed
cyclopropanation established, the scope of the reaction was
assessed (Scheme 3). A wide range of styrene derivatives
reacted efficiently to provide cyclopropanes 7a–7k in 47–89%
yield, including those bearing electron-donating (7c) and
electron-withdrawing substituents (7d–7g). It is notable that
several reactive functional groups, including a pinacol boronic
ester (7h), chloride (7i and 7j), and fluoride (7k), are tolerated
under the reaction conditions, despite them being known to
The presence of a conjugated π-system on the alkene
substrate was found to be crucial for productive
cyclopropanation, as alkyl-substituted alkenes (e.g.,
allylbenzene) were unreactive under our optimized conditions.
Unfortunately, the cyclopropanation reaction also failed for α-
and β-substituted styrenes. Therefore, we sought alternative
alkene substrates that would undergo cyclopropanation while
providing a synthetic handle that would allow subsequent
substitution reactions. Boronic esters are highly versatile
undergo
nickel-catalyzed
transformations.28
Alkenes
substituted with electron-rich aromatic groups, such as
naphthyl and ferrocenyl gave the spirocyclic products 7l and
7m in 84% and 44% yield, respectively. Heteroaromatic
moieties are ubiquitous in bioactive molecules but their
functionalization can be challenging using transition metal
catalysis due to the potentially strong ligation to metal centers.
In this catalytic system, a broad range of heteroaryl substituted
Scheme 3. Alkene scopea
a
Reaction conditions: alkene (0.20 mmol), propellane (0.7–0.9 M in Et2O, 4.0 equiv), Ni(cod)2 (10 mol%), SIMes∙HCl (12 mol%),
LiOMe (20 mol%), and toluene (3 mL) at 50 °C for 20 h. Yield are of isolated products. b Reaction performed at room temperature.
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moieties that can readily be transformed into a diverse array of
hydroboration,35 providing alkenylboronic ester 14 and
alkylboronic ester 15, respectively. Spiro[2.3]hexan-5-one
derivative 16 could be prepared in excellent yield via
ozonolysis. Finally, spirocyclic propagations were performed
functional groups.30 Thus, we examined the nickel-catalyzed
cyclopropanation reaction with alkenylboronic esters 11
(Scheme 5).31 We were pleased to find that vinylboronic acid
pinacol ester underwent productive reaction, providing
borylated methylenespiro[2.3]hexane 12a in good yield.32
Furthermore, in contrast to the styrene derivatives,
alkenylboronic esters with β-substitution were also suitable
substrates. Various alkyl groups at the β-position were
tolerated, providing products 12b–12f in moderate to good
yields and with excellent diastereoselectivity when E-alkene
substrates were used. The stereospecificity of the reaction was
examined by using (Z)-1-propenylboronic acid pinacol ester,
which selectively provided the syn diastereomer of 12b but
only with a modest 32:68 trans/cis ratio (see below for further
discussion). In addition to β-substitution, α-substituted
alkenylboronic esters were efficiently cyclopropanated,
providing tertiary benzylic (12g) and tertiary non-benzylic
(12h and 12i) cyclopropylboronic esters in good yields.
Unfortunately, trisubstituted alkenes proved unreactive, with
1-cyclohexenylboronic ester pinacol ester failing to yield
tricyclic product 12j. Finally, the use of benzyl acrylate
provided cyclopropyl carboxylate ester 13 in 40% yield.
to access different sized heterocycles, including
a
carboalumination/thioetherification36
to form
tetrahydrothiophene 17, and a [2+2] cycloaddition with
chlorosulfonyl isocyanate to give β-lactam 18.33c
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Scheme 6. Products derivatizations
Scheme 5. Alkenylboronic ester scopea
a
Prop-1-en-1-ylboronic acid pinacol ester, Grubbs 2nd
generation catalyst (5 mol%), CH2Cl2, 50 °C. b Products formed in
c
52:48–56:44 d.r. CuCl (5 mol%), DTBM-segphos (6 mol%),
KOtBu (20 mol%), HBpin (1.2 equiv), toluene, r.t.
O3,
d
e
MeOH/CH2Cl2, then PPh3 (1.5 equiv). Cp2ZrCl2 (5 mol%),
Et3Al (1.2 equiv), toluene, then sulfur (2.4 equiv).
f
Chlorosulfonyl isocyanate (1.0 equiv), Et2O, r.t.
3. Mechanistic Studies
Our investigations into the mechanism of this nickel-
catalyzed cyclopropanation initially focused on elucidating if
the reaction proceeded via a single-electron pathway. This was
considered due to the propensity of the bridgehead bond of 1
to react with free radicals37 and because nickel-catalyzed
reactions commonly involve single-electron transfer
processes.28 Furthermore, Wiberg has previously shown that 1
undergoes cyclopropanation reactions with highly activated
electron-deficient π-systems and proposed that they proceed
via a radical mechanism.26,38 In our nickel-catalyzed process, if
a stepwise radical mechanism was operative, cyclopropanation
of 1,2-disubstituted alkenes would be expected to proceed
with poor stereocontrol, whereas two-electron pathways of a
metal carbene intermediate (e.g., pathways A and B in Scheme
1) should be stereospecific. Therefore, we investigated the
stereospecificity of the cyclopropanation reaction using both
(E)- and (Z)-β-deutero-4-vinylbiphenyl (19) (Schemes 7a and
7b). Reaction of (E)-19 (>99:1 E/Z) with 1 under the standard
conditions afforded trans-20 as the major product with a 95:5
ratio of isotopomers, while the reaction of (Z)-19 (>99:1 Z/E)
gave cis-20 as the major product in a 97:3 ratio. The high
stereoselectivity of these reactions support a stereoretentive
cycloaddition of a nickel carbene rather than a radical
pathway. We postulated that the small drop in selectivity in
the reactions of (E)-19 and (Z)-19, and the poor
diastereoselectivity observed with (Z)-11b (see product syn-
12b, Scheme 5), could be caused by isomerization of the
a
Yields are of isolated products. The trans:cis ratio was
b
determined by GC/MS.
Using (E)-1-propenylboronic acid
pinacol ester. c Using (Z)-1-propenylboronic acid pinacol ester
We next sought to highlight the synthetic utility of the
methylenespiro[2.3]hexane
skeleton
(Scheme
6).
Methylenecyclobutanes have previously found application in
natural product total synthesis due to the versatility of the
exocyclic alkene.33 Thus, we used this moiety as a handle for
diversification
of
cyclopropanation
product
7a.
Transformation into synthetically useful organoboronic ester
products was achieved via cross metathesis34 and
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starting alkene prior to cyclopropanation. Indeed, submitting
IB (IB*) was explored but was found to be too high in energy to
be relevant (see Supporting Information for full details). The
propellane adduct IB then undergoes a concerted ring-opening
where two C–C bonds are cleaved to generate the carbene
intermediate IC via transition state TSBC. The subsequent
cyclopropanation was found to proceed through a stepwise
pathway (see pathway B, Scheme 1), with C–C bond
(E)-19 and (Z)-11b to the standard reactions conditions but in
the absence of 1 resulted in substantial isomerization, giving a
50:50 ratio of isomers of 19 and a 91:9 E/Z ratio for 11b
(Schemes 7c and 7d). In addition, when 8a was treated with
the nickel catalyst in the presence of methanol-d4,
approximately 5% deuterium incorporation was observed in
the recovered alkene (Scheme 7e), which reveals the alkene
isomerization stems from a nickel-hydride species generated
from oxidative addition of Ni(0) to methanol.39 Based on these
experiments, we concluded that the cyclopropanation proceeds
via a two-electron pathway involving reaction of the alkene
substrate with a nickel carbene intermediate, as shown in
Scheme 1.
formation,
via
transition
state
TSCD
,
giving
metallacyclobutane intermediate ID. The regioselectivity of the
formation of metallacyclobutane ID favored C–Ni bond-
formation at the benzylic carbon, as the alternative transition
state TSCD’, in which C–C bond-formation occurs at the
benzylic carbon, is 3.5 kcal/mol higher in free energy than
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transition state TSCD
.
Reductive elimination of the
cyclopropane moiety, via TSDE, then yields IE, the Ni(0)
adduct of the product, 7b, which is in turn liberated by
reaction with styrene, regenerating IA.43 It appears that π-
coordination of the arene during the reductive elimination
Scheme 7. Mechanistic experiments
facilitates the process,
a finding in accord with the
experimental observation that replacing the arene with a more
strongly coordinating alkene function allows the reaction
temperature to be lowered (Scheme 3), whereas no reaction
occurs when the coordinating group is removed (e.g., alkyl-
substituted alkenes).
While metal carbenes have been proposed as intermediates
in transition metal-catalyzed reactions of [1.1.1]propellane,26
their mechanism of formation and subsequent reactivity has
not been studied. Therefore, we used DFT (B3LYP-D3/6-
311++G**//B3LYP-D3/6-31+G*; SMD, solvent = toluene,
see Supporting Information for full details) to model the nickel
catalytic cycle,40 where the smaller NHC ligand L was used as
a representative catalyst (Figure 1).41,42 Loss of a styrene from
the 16-electron Ni(0) species RS, generating the 14-electron
intermediate IA, is an endergonic process, consistent with RS
acting as an off-cycle resting state. With intermediate IA + 1 +
styrene defining the free-energy zero point of the cycle,
coordination of propellane to IA to give the Ni(0) intermediate
IB is thermodynamically favorable, with a ΔG of –8.3
kcal/mol. An alternative diradical ground state for the adduct
Figure 1. DFT-calculated catalytic cycle and associated free en-
ergy level diagram. *The individual ligand substitution steps (IE
to IA) were not modelled.
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Intermediate IB can also undergo smooth, reversible
typical C–C single bond, Cb–Cc is significantly longer than a
oxidative addition to give an off-cycle metalla-
[2.1.1]propellane intermediate IF, a process calculated to be
thermodynamically and kinetically competitive with the
concerted ring-opening to form IC (Figure 1). While two
alternative pathways for cyclopropanation that proceed via IF
may be envisaged, these were found to be energetically less
likely, at least in our model system (see Supporting
information for full details).
The calculated intermediate IB represents a rare example of
a coordinated [1.1.1]propellane,44 while intermediate IF can
formally be considered as a metalla-[2.1.1]propellane. To the
best of our knowledge, while rare examples of transition
metal-based metalla-[1.1.1]propellanes are known,45 [2.1.1]-
analogues have not been reported. The nature of the ‘inverted’
C–C bonds of small ring propellanes has been the subject of
much debate in the literature,20a,46 with recent ab initio valence
bond calculations by Wu and co-workers revealing that the
inverted bond has predominant ‘charge-shift’ bonding
character with little or no diradical contribution.47,48
Accordingly, a closer examination of the electronic structures
of intermediates IB and IF (geometry optimization at the
B3LYP/6-311++G** level of theory) was of interest.
double bond, even one coordinated to Ni, as highlighted by the
calculated C–C bond length of 1.361 Å for the coordinated
styrene ligand in IF. Taken together, these bond metrics favor
the metalla-[2.1.1]propellane form A, which would be
expected to have an inverted Ca–Cb bond. Indeed, the
separation of these carbon atoms is very similar to that
calculated for [2.1.1]propellane at the same level of theory
(Figure 3). An NBO analysis shows a σ-symmetry bonding
orbital located between Ca and Cb while the equivalent MO has
further density associated with the metal–Cc fragment. The
WBI of the Ca–Cb bond clearly indicate a bonding interaction,
however, an AIM analysis does not identify a bond critical
point (bcp) between these two carbon atoms. This is perhaps
not surprising in view of the extended nature of the MO, and
the observation that organometallic ligands with such
conjugation to metal centers do not always reveal bcp’s.54 In
contrast, the delocalization index (δ(AB)) for this interaction,
also obtained from the AIM calculation, is clearly indicative of
significant bonding.
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The calculated C–C bond length of the inverted bond of the
propellane ligand in IB of 1.600 Å is marginally longer than
either that calculated for free propellane at the same level of
theory (1.582 Å) or measured for a closely related derivative
(1.579 Å),49 but is significantly shorter than the bridgehead
carbon distance in bicyclo[1.1.1]pentane (1.845 Å),50 which is
indicative of a C–C bonding interaction. The coordination of
the propellane in IB is offset from linear, with a calculated
angle between the inverted C–C bond axis and the nickel
center of 151. Meanwhile, the calculated Ni–C bond length to
the propellane ligand (2.042 Å) is longer than that of the Ni–C
bond for the carbene ligand (1.935 Å). Figure 2 shows both
the bonding molecular orbitals (MO) between the propellane
ligand and a d-orbital on nickel – an orbital that also shows
significant involvement of the NHC donor – and a summary of
key topological data, calculated using the Atoms in Molecules
(AIM) method,51 along with Wiberg Bond Indices (WBI) for
key bonds in IB and propellane. Comparing the data, it is clear
that the inverted C–C bond of propellane remains largely
intact on coordination. The positive value for the Laplacian,
2ρ, is atypical of covalent C–C bonds, which tend to return
negative values, but is in line with the charge-shift description
of propellane inverted bonds.49
The intermediate IF could be viewed as containing either a
metalla-[2.1.1]propellane (form A in Figure 3) or, at the other
extreme, a nickel carbene complex with an intramolecularly
coordinated alkene moiety (form B). Indeed, as described in
the introduction, metal carbene intermediates are ubiquitous in
catalytic cyclopropanations. However, the calculated Ni–Ca
bond length (1.968 Å) is too long for any significant carbenic
character, indeed it is longer than the Ni–C(NHC) bond (1.926
Å), which is generally accepted to be a single bond with very
little retro-donation. By comparison, structurally characterized
Ni(II) carbene complexes without heteroatom functionality on
the carbene carbon display Ni=C bond lengths in the range
1.844 – 1.906 Å,52 while the Ni–C bond lengths of the very
limited number of nickelacyclobutanes reported are 1.927 –
1.956 Å.53 Meanwhile, despite being marginally shorter than a
Figure 2. MO of the Ni-propellane σ-bond of intermediate IB
(isovalue = 0.05 (electron/bohr3)1/2); AIM-calculated bond critical
points (bcp, small green spheres), associated electron density (ρ)
and Laplacian (2ρ) values at the bcp’s and Wiberg Bond Indices
(WBI) of the bonds.
Figure 3. NBO and MO associated with the inverted C-C bond of
intermediate IF (isovalue = 0.05 (electron/bohr3)1/2); WBI and
AIM-calculated metrics (as defined in Figure 2) as well as AIM-
derived delocalisation index ((AB)) values.
4. Conclusions
We
have
developed
a
new
approach
to
methylenespiro[2.3]hexane derivatives via a nickel-catalyzed
cyclopropanation of alkenes with [1.1.1]propellane. The
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(2) (a) Bonge, H. T.; Hansen, T. Computational Study of
reaction involves a rare example of double C–C bond
activation of [1.1.1]propellane to provide
2
Cyclopropanation Reactions with Halodiazoacetates. J. Org. Chem.
2010, 75, 2309. (b) Hansen, J.; Autschbach, J.; Davies, H. M. L.
Computational Study on the Selectivity of Donor/Acceptor-
Substituted Rhodium Carbenoids. J. Org. Chem. 2009, 74, 6555. (c)
Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A.
Isotope Effects and the Nature of Selectivity in Rhodium-Catalyzed
Cyclopropanations. J. Am. Chem. Soc. 2003, 125, 15902.
a
3
4
5
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methylenecyclobutylidene-metal intermediate. Nickel catalysis
proved essential in preventing deleterious side reactions of the
metal-carbene and enabled the successful application of a wide
range of alkene substrates, including styrenes, 1,3-dienes, 1,3-
eynes, and alkenyl boronic esters. The formation of a nickel
carbene was supported both experimentally, by the high
stereospecificity of the cyclopropanation of 1,2-disubstituted
alkenes; and computationally, with DFT calculations showing
the carbene is formed via a concerted double C–C bond
cleavage of a nickel-[1.1.1]propellane complex. Given that
transformations of propellane are dominated by additions
across the bridgehead σ-bond to form bicyclo[1.1.1]pentanes,
this nickel-catalyzed process unveils a new reaction mode that
will enhance the application of [1.1.1]propellane in the
synthesis of complex molecules.
(3) (a) Suenobu, K.; Itagaki, M.; Nakamura, E. Reaction Pathway
and Stereoselectivity of Asymmetric Synthesis of Chrysanthemate
with the Aratani C1-Symmetric Salicylaldimine−Copper Catalyst. J.
Am. Chem. Soc. 2004, 126, 7271. (b) Fraile, J. M.; Garcꢀa, J. I.; Gil,
M. J.; Martꢀnez-Merino, V.; Mayoral, J. A.; Salvatella, L. Theoretical
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Insights into the Role of
a Counterion in Copper-Catalyzed
Enantioselective Cyclopropanation Reactions. Chem. Eur. J. 2004,
10, 758. (b) Fraile, J. M.; Garcꢀa, J. I.; Martꢀnez-Merino, V.; Mayoral,
J. A.; Salvatella, L. Theoretical (DFT) Insights into the Mechanism of
Copper-Catalyzed Cyclopropanation Reactions. Implications for
Enantioselective Catalysis. J. Am. Chem. Soc. 2001, 123, 7616.
(4) (a) Berthon-Gelloz, G.; Marchant, M.; Straub, B. F.; Marko, I.
E. Palladium‐Catalyzed Cyclopropanation of Alkenyl Silanes by
Diazoalkanes: Evidence for a Pd0 Mechanism. Chem. Eur. J. 2009,
15, 2923. (b) Bernardi, F.; Bottoni, A.; Miscione, G. P. DFT Study of
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, full characterization data for new com-
pounds, and details of computational studies are supplied in the
Supporting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.
the
Palladium-Catalyzed
Cyclopropanation
Reaction.
Organometallics 2001, 20, 2751.
(5) Rosenberg, M. L.; Krapp, A.; Tilset, M. On the Mechanism of
Cyclopropanation Reactions Catalyzed by a Rhodium(I) Catalyst
Bearing
a
Chelating Imine-Functionalized NHC Ligand:
A
AUTHOR INFORMATION
Corresponding Author
Computational Study. Organometallics 2011, 30, 6562.
(6) Wang, F.; Meng, Q.; Li, M. Density Functional Computations
of the Cyclopropanation of Ethene Catalyzed by Iron (II) Carbene
Complexes Cp(CO)(L)Fe=CHR, L = CO, PMe3, R = Me, OMe, ph,
CO2Me. Int. J. Quantum Chem. 2008, 108, 945.
* r.bedford@bristol.ac.uk
* v.aggarwal@bristol.ac.uk
(7) (a) Doyle, M. P.; McKervey M. A.; Tao, Y. In Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides. Wiley-VCH: Weinheim, 1998, pp. 1–
65. (b) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire A. R.;
McKervey, M. A. Modern Organic Synthesis with α-Diazocarbonyl
Compounds. Chem. Rev. 2015, 115, 9981. (c) Mix, K. A.; Aronoff M.
R.; Raines, R. T. Diazo Compounds: Versatile Tools for Chemical
Biology. ACS Chem. Biol. 2016, 11, 3233.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the EPSRC (EP/S017801/1) for financial support. S.Y.
thanks the EU for an H2020 Marie Skłodowska-Curie Fellowship
(grant no. 792439).
(8) Jia, M.; Ma, S. New Approaches to the Synthesis of Metal
Carbenes. Angew. Chem. Int. Ed. 2016, 55, 9134.
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