Simplifying nickel(0) catalysis: An air-stable nickel precatalyst for the internally selective benzylation of terminal alkenes

Article abstract of DOI:10.1021/ja3116718

The synthesis and characterization of the air-stable nickel(II) complex trans-(PCy₂Ph)₂Ni(o-tolyl)Cl is described in conjunction with an investigation of its use for the Mizoroki-Heck-type, room temperature, internally selective coupling of substituted benzyl chlorides with terminal alkenes. This reaction, which employs a terminal alkene as an alkenylmetal equivalent, provides rapid, convergent access to substituted allylbenzene derivatives in high yield and with regioselectivity greater than 95:5 in nearly all cases. The reaction is operationally simple, can be carried out on the benchtop with no purification or degassing of solvents or reagents, and requires no exclusion of air or water during setup. Synthesis of the precatalyst is accomplished through a straightforward procedure that employs inexpensive, commercially available reagents, requires no purification steps, and proceeds in high yield.

Full text of DOI:10.1021/ja3116718

Article
pubs.acs.org/JACS
Simplifying Nickel(0) Catalysis: An Air-Stable Nickel Precatalyst for
the Internally Selective Benzylation of Terminal Alkenes
Eric A. Standley and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: The synthesis and characterization of the air-
stable nickel(II) complex trans-(PCy2Ph)2Ni(o-tolyl)Cl is
described in conjunction with an investigation of its use for
the Mizoroki−Heck-type, room temperature, internally
selective coupling of substituted benzyl chlorides with terminal
alkenes. This reaction, which employs a terminal alkene as an
alkenylmetal equivalent, provides rapid, convergent access to substituted allylbenzene derivatives in high yield and with
regioselectivity greater than 95:5 in nearly all cases. The reaction is operationally simple, can be carried out on the benchtop with
no purification or degassing of solvents or reagents, and requires no exclusion of air or water during setup. Synthesis of the
precatalyst is accomplished through a straightforward procedure that employs inexpensive, commercially available reagents,
requires no purification steps, and proceeds in high yield.
Scheme 1. Regiochemistry of the Mizoroki−Heck Reaction
INTRODUCTION
■
Among the multitude of methods for the synthesis of alkenes,
the Mizoroki−Heck reaction continues to find frequent use in
organic synthesis.1 Though the first reported couplings of this
type employed electron deficient alkenes such as styrenes and
acrylates (Scheme 1, eq 1),2 there have also been efforts to
expand the scope to include electron rich alkenes such as
enamides and enol ethers (Scheme 1, eq 2).3 In contrast to
either of those two alkene classes, however, electronically
unbiased alkenes such as α-olefins have seen considerably less
attention in the context of the Mizoroki−Heck reaction.3a In
this report, we describe the preparation and use of the first air-
stable nickel precatalyst for internally selective Heck reactions
of terminal, electronically unbiased alkenes and benzyl
chlorides. The reaction proceeds at room temperature to
provide 1,1-disubstituted alkenes; no exclusion of air or
moisture is required during the setup of each reaction, and
no drying, degassing, or purification of any reagents is required,
in stark contrast to what is typically required for nickel(0)-
catalyzed reactions.
One factor contributing to the historical lack of attention to
aliphatic alkenes is likely the difficulty in controlling the
regiochemical outcome of such reactions, given that the two
carbons of the alkene are not electronically differentiated.
Certain privileged alkenes, such as allylic alcohols and amines,
are biased significantly enough through electronic and/or
chelation effects to allow for high terminal or internal
selectivity, depending on the appropriate choice of metal,
ligand, and solvent (Scheme 1, eq 3).4
behavior of benzyl electrophiles in the Mizoroki−Heck reaction
remains much less well-studied than aryl and vinyl electro-
philes, despite the inclusion of benzyl halides in Heck’s seminal
1972 report.7 This may be due in part to the propensity for
alkene isomerization observed with these types of electrophiles,
However, in addition to our own work in this area,5
developments from several other laboratories have begun to
allow high selectivity for substitution at either the terminal or
internal position of unbiased, aliphatic alkenes with aryl
electrophiles (Scheme 1, eqs 4 and 5).6 Furthermore, the
Received: December 2, 2012
Published: January 14, 2013
© 2013 American Chemical Society
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though a number of methods have indeed been developed
employing benzyl halides and benzyl trifluoroacetates as
coupling partners, including one enantioselective variant
(Scheme 1, eq 6).8
Treatment of complex 2 with benzyl chloride, Et3N, and
TESOTf facilitates the benzylation of ethylene to yield
allylbenzene and (PCy2Ph)2Ni(0) (3), which is believed to
be the catalytically active species.12 Even at half the catalyst
loading (5 mol % instead of 10 mol % employed in our
previously published method), the coupling of benzyl chloride
with 1-octene proceeds faster than when Ni(COD)2 and
PCy2Ph are used as the catalyst, which we construe as evidence
that COD is reducing the rate of reaction. Furthermore,
addition of COD to a reaction catalyzed by 2 retards the rate
relative to a control experiment in which no COD was added.
Thus, we had clearly established the detrimental effect the
presence of COD has on this coupling reaction.
These results provide the first definitive evidence showing
the COD ligands in Ni(COD)2 are not innocent in a reaction
such as this coupling. Given the widespread use of Ni(COD)2
as a precursor to homogeneous Ni(0) species in organic
synthesis, this result has significant implications for a variety of
aspects of nickel catalysis. As researchers continue to seek more
highly active catalysts to allow more challenging couplings or
lower catalyst loadings, this finding is likely to shape the
development of new catalysts and reactions.
Though precatalyst 2 had proven interesting and had
provided valuable information regarding the role of COD in
the reaction, it still required inert-atmosphere techniques for its
synthesis, storage, and usage. As such, we began to examine
other possible precatalysts that would possess the same
properties, but also tolerate storage under air. A number of
complexes of the form trans-(PR3)2Ni(aryl)X (where R = Ph,
Cy, Et; and X = Cl, Br) have been demonstrated to be air stable
with prudent choice of the substituents on the aryl ring, for
example, when the aryl group is an o-tolyl or 2-napthyl moiety.
Though first reported in 1960 by Chatt and Shaw,13 there have
been relatively few reported uses for these complexes.14
With this inspiration, we attempted the synthesis of the
complex trans-(PCy2Ph)2Ni(o-tolyl)Cl (1) and determined that
it can be conveniently synthesized in a two-step procedure
beginning from NiCl2·6H2O and PCy2Ph, followed by addition
of 1 equiv of o-tolylmagnesium chloride to yield 1 as a yellow,
diamagnetic, air-stable solid (Scheme 3).15 Alternatively, the
As a part of our laboratory’s ongoing work in the area of
stereo- and regiocontrolled synthesis of alkenes via coupling
reactions, we were interested in further developing our
previously reported method5 for the coupling of benzyl
chlorides to terminal alkenes catalyzed by Ni(COD)2 and
PCy2Ph (COD = 1,5-cyclooctadiene). We sought to make the
reaction operationally simpler by removing the need for the use
of inert-atmosphere techniques (glovebox or glovebag) to set
up each reaction. Furthermore, the cost of Ni(COD)2 is
considerably higher than many Ni(II) sources,9 its quality from
commercial suppliers varies significantly (even between batches
from the same supplier), and it has a limited shelf life if not
stored cold and under an inert atmosphere. Of course, the
laboratory synthesis of Ni(COD)2 is well established,10 but it
requires Schlenk or glovebox techniques and does not obviate
the need for storage and use under an inert atmosphere. Thus,
we sought to reduce the cost and operational complexity of this
method by devising an air-stable precatalyst, which would
enable this chemistry to be carried out on the benchtop with no
use of a glovebox or even any air-free techniques required.
RESULTS AND DISCUSSION
■
During early investigations of this reaction, we observed that
catalysts comprising the combination of Ni(COD)2 and
PCy2Ph effected benzylation of the COD ligands themselves
in preference to the intended alkene substrate in some
instances. This observation led us to hypothesize that COD
was coordinating to nickel with greater affinity than the
intended alkene, effectively acting as a competitive inhibitor,
causing a rate reduction of the desired transformation. Thus,
removing COD from the reaction could allow for a greater
turnover frequency and/or a reduced catalyst loading and
potentially allow for the use of more sterically hindered alkenes
or even disubstituted alkenes as viable substrates.
A search of the literature brought the stable and isolable,
though air-sensitive, complex (PPh3)2Ni(η2-C2H4) to our
attention.11 This complex is readily synthesized by combining
Ni(COD)2, PPh3, and ethylene in diethyl ether; analogously,
(PCy2Ph)2Ni(η2-C2H4) (2) was produced by the combination
of Ni(COD)2, PCy2Ph, and ethylene in ether to form a yellow
solid in excellent yield, as illustrated in Scheme 2. We had
hoped the additional steric hindrance of PCy2Ph (compared to
PPh3) would endow the complex with greater stability toward
oxygen; however, although more tolerant of exposure to oxygen
than (PPh3)2Ni(η2-C2H4), 2 still decomposes in air within a
few minutes of exposure, so its use still requires inert-
atmosphere techniques.
Scheme 3. Synthesis of trans-(PCy2Ph)2Ni(o-tolyl)Cl
a
Scheme 2. Synthesis of (PCy2Ph)2Ni(η2-C2H4)
ligand PCy2Ph can be easily synthesized from dichlorophenyl-
phosphine and cyclohexylmagnesium chloride, which can either
be made from chlorocyclohexane or purchased commercially.
No purification steps are required in this sequence, making the
synthesis of precatalyst 1 remarkably convenient.
Precatalyst 1 as well as the intermediate complex trans-
(PCy2Ph)2NiCl2 (4)16 have both been characterized by single-
crystal X-ray diffraction (see thermal ellipsoid representations
in Figure 1); 4 adopts a nearly ideal square planar geometry
with trans stereochemistry. This complex is diamagnetic and
a
Complex 3 was not isolated; its yield was determined indirectly to be
>98% based on the amount of allylbenzene formed (measured by gas
chromatography).
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dimethylbiphenyl (6, 97% yield by gas chromatography) is
formed rather than styrene 5. Indeed, treatment of the
precatalyst with TMSOTf effects reduction to a nickel(0)
species and 6 even in the complete absence of any alkene. This
suggests that, following chloride abstraction from 1, trans-
metalation with another molecule of 1 to produce 1a and 1b
occurs. Subsequently, reductive elimination of 6 from complex
1a is evidently the means by which production of nickel(0)
takes place. This in turn suggests that only half of the
precatalyst is ultimately reduced; presumably, the other half is
converted to the catalytically inactive (PCy2Ph)2Ni(Cl)(OTf)
(1b) unless reduction of 1b through another mechanism is
concurrently active.18
Entry into a nickel(0) manifold from nickel(II) promoted by
an additive such as a silyl triflate is unprecedented. In the vast
majority of cases, reduction of a nickel(II) species to the
catalytically active form is effected in one of four ways:19 (1) by
consumption of an organometallic reactant present in the
reaction, such as a boronic acid;20 (2) by an exogenous
reductant such as zinc, manganese, or sodium−mercury
amalgam, which is added to carry out the reduction by electron
transfer; (3) by addition of an organometallic reagent such as
AlMe3, Et2Zn, or MeMgBr, which can effect reduction through
two successive transmetalations to yield a dialkylnickel(II)
complex, which undergoes reductive elimination to yield an
alkane and a nickel(0) species;21 or (4) by addition of a hydride
donor such as DIBAL, methanol, or isopropanol.22,23 The
ability to enter into a nickel(0) catalytic cycle at room
temperature and without the use of pyrophoric or strongly
basic reagents represents a new and potentially valuable means
of entry into nickel(0) species that could be employed for a
wide variety of nickel(0)-catalyzed reactions.
Figure 1. Thermal ellipsoid representations of trans-(PCy2Ph)2Ni(o-
tolyl)Cl (1, top) and trans-(PCy2Ph)2NiCl2 (4, bottom) with
ellipsoids at 50% probability level. Hydrogen atoms and disorder on
ligands not shown for clarity; see the Supporting Information for full
representations, including disorder.
Having established the competence of precatalyst 1 for this
coupling reaction, we began optimizing the reaction, ultimately
arriving at the conditions described in Table 1, with the
conditions in entry 4 being chosen as our fully optimized
air-stable and can be stored exposed to air at room temperature
indefinitely. Likewise, complex 1 assumes a trans stereo-
chemistry and square planar geometry and is stable toward air.
The geometry of 4 is somewhat distorted toward a tetrahedral
arrangement, as indicated by the observed P−Ni−P bond angle
of 161.7° and Cl−Ni−C bond angle of 170.4°, both noticeably
shy of the ideal 180°.17
Upon treatment of complex 1 with an alkene, silyl triflate,
and base, reduction from the Ni(II) precatalyst to the
catalytically active Ni(0) species occurs within minutes at
room temperature. Initially, we hypothesized this to occur by
arylation of the alkene as illustrated in Scheme 4; however, 2,2′-
a
Table 1. Optimization of Reaction Parameters
% yield at time (h)
entry
change from above conditions
1
3
24
1
neat
1
3
11
92
76
96
84
79
68
73
54
95
12
95
2
PhMe
2
40
16
68
52
40
38
11
8
3
PhMe, 10 mol % 1,5-COD added
CH2Cl2
2
4
51
35
21
19
1
Scheme 4. Activation of Precatalyst 1
5
CH2Cl2, 2 equiv of 1-octene
CH2Cl2, 1.3 equiv of 1-octene
CH2Cl2, 1 equiv of 1-octene
PhMe, 3.5 equiv of 1-octene
PhMe, 2 equiv of 1-octene
CH2Cl2, TESOTf inst. TMSOTf
CH2Cl2, EtiPr2N instead of Et3N
6
7
8
9
1
10
11
12
48
2
65
6
b
purified and degassed reagents
59
76
a
All yields were determined by GC against a calibrated internal
standard. All reagents were used “as received” except where explicitly
stated. Many reactions were complete prior to 24 h but were run for
b
the full 24 h for comparison purposes. Liquid reagents and solvents
were dried over a suitable drying agent and distilled followed by three
cycles of freeze−pump−thaw degassing.
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a
Scheme 5. Substrate Scope of the Nickel-Catalyzed Coupling of Benzyl Chlorides to Terminal Alkenes
a
Yields listed are isolated yields. Ratios reported represent the ratio of the major (branched) product to the sum of all other isomers as determined
b
c
by GC. Ratios reported as >95:5 were determined by NMR. TBSOTf and 3 equiv of 3-buten-1-ol used in place of TMSOTf. 3 equiv of alkene
used. TESOTf used in place of TMSOTf. Excess TMSOTf used to effect in situ protection. TESOTf and 3 equiv of allyl alcohol used in place of
TMSOTf. Ratio was 78:22 prior to purification. The linear and branched products were separable by column chromatography. Reaction carried
out on a 10 mmol scale. Product contained an inseparable byproduct (ca. 10% by mass) formed by the oligomerization of 2-methyl-1,5-hexadiene.
d
e
f
g
h
i
conditions. With our previously published conditions5 (10 mol
% Ni(COD)2, 20 mol % PCy2Ph, 6 equiv of Et3N, 1.75 equiv of
TESOTf) as a starting point, we began by investigating the
reaction under solvent-free (neat) conditions, and we observed
that these conditions performed quite poorly. We attribute this
to the low solubility of precatalyst 1 in triethylamine, which
causes very slow activation. However, even in toluene,
activation of the precatalyst is not facile, as entry 2 highlights:
even after 1 h, only 2% of product has been produced, and
although the reaction ultimately does reach completion, it
requires nearly 24 h to do so. At this time, we also confirmed
once more that the addition of COD to the reaction mixture
does indeed reduce the rate of reaction (entry 3).
Intriguingly, changing the reaction solvent to dichloro-
methane facilitated rapid activation of the catalyst and a greatly
accelerated coupling, requiring only 4 h for the reaction to
reach complete conversion (cf. entries 2 and 4), which
corresponds approximately to a 5-fold rate enhancement. At
present, we are unaware of any nickel(0)-catalyzed cross
couplings carried out in a solvent of dichloromethane, making
this reaction unique in that regard.24,25 The change from
toluene to CH2Cl2 also allows for a reduction of the excess of
alkene required (cf. entries 4−9). In toluene, changing from 5
to 2 equiv of alkene caused a marked decrease in the yield, even
after 24 h of reaction time (92% vs 54%). However, in CH2Cl2,
changing from 5 to 2 equiv of alkene ultimately affords the
product in only a slightly diminished yield (96% vs 84%),
though the reaction rate is decreased. As the excess further
decreases, however, the yield begins to drop considerably,
ultimately to 68% when a 1:1 stoichiometry of benzyl chloride
and alkene is used.
Also interesting is the marked reduction in yield observed
when Hunig’s base (EtiPr N) is used instead of triethylamine
̈
2
(cf. entries 4 and 11). Though of similar thermodynamic
basicity, this likely suggests that the sterically less hindered
Et3N is capable of deprotonating the nickel hydride (formed
after β-hydride elimination, Scheme 7, vide infra) much more
efficiently.
Prior to beginning this optimization process, one of the
changes we investigated was whether the use of dried and
degassed solvents and reagents is necessary to obtain
satisfactory results. Preliminary trials showed that using
reagents and solvents “as received” had no negative effects on
the yield of the reaction; however, a direct comparison was
carried out to rigorously verify this observation. As the
comparison between entries 4 and 12 indicates, the reaction
does appear to proceed more rapidly when purified and
degassed reagents are employed, but ultimately, the same yield
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is achieved in both cases. We attribute this difference in rate to
the oxygen-mediated decomposition of some portion of the
catalyst when unpurified reagents are employed, causing the
effective catalyst loading to be slightly less than the nominal
loading.26 Having verified the absence of negative effects, we
opted to carry out the remainder of the optimization without
purification or degassing of any reagents, taking the conditions
described in entry 4 as our optimized conditions.
Having satisfactorily optimized the conditions for the
coupling reaction, we next examined the scope of the reaction,
the results of which are shown in Scheme 5. Several aspects are
noteworthy: first, the reaction is highly selective for the
branched product over the linear product across a wide variety
of electronically and sterically differentiated benzyl chlorides
and alkenes. The selectivity, described by the ratio between the
branched product and the sum of all other isomers observed, is
greater than 95:5 in nearly all instances, which not only
indicates an intrinsically high selectivity for the branched
product over the linear product but also shows that
isomerization of the product after its formation is extremely
minimal.27
Substitution in the ortho, meta, and para positions of the
benzyl chloride is well tolerated, including fluorine, chlorine,
bromine, and iodine substituents (e.g., 11, 12, 14, 15, 17).
Some addition of nickel into the C−I bond was observed, but
the yield of the corresponding desired product (11) was not
significantly diminished. The tolerance of aryl halides is a
significant feature of this method, since this enables the
construction of halogen-substituted allylbenzene derivatives,
which can then be directly used in further cross-coupling
reactions, if desired. Oxidative addition of Ni(0) phosphine
complexes into aryl fluorides,28 chlorides,29 bromides, and
iodides30 is well established, so the excellent chemoselectivity of
the oxidative addition into the benzyl sp3C−Cl bond in
preference to the sp2C−X bonds suggests the former occurs
significantly faster than the latter.
(12, 22), phenols (24), and following aqueous workup, free
carboxylic acids (21) and amines (25). As illustrated by
example 17, allyltrimethylsilane is a competent alkene coupling
partner, though some protiodesilylation does occur (ca. 15%).
In this particular example, the protiodesilylated material was
separable by column chromatography, allowing clean isolation
of 17, though in modest yield.
Also of considerable interest is the marked unreactivity of
styrenes compared to α-olefins, as evidenced by the formation
of 18 in high yield from 4-vinylbenzyl chloride and 3-
butenylbenzene with no observable reaction at the styrene.
Gratifyingly, sulfur-containing functional groups, such as
sulfones (19, 26) and benzothiophene (27) are tolerated
with no apparent poisoning of the catalyst. Lastly, methylene
acetals (26, 29) are compatible with the reaction conditions.
While most reactions proceed in good to excellent yield, a
reduction in yield typically results from substitution on the
ortho positions of the benzyl chloride or substitution adjacent
to the olefin. Examples 8, 9, 14, and 28 demonstrate this trend,
since all four are obtained in a lower yield than substrates
containing similar functional groups but connected in different
positions. Additionally, there are several other specific
conditions that greatly reduce the yield of the reaction or in
some cases completely prevent product formation. Such
examples are outlined in Chart 1.
Chart 1. Substrates That Did Not Provide the Desired
Benzylation Products
As examples 23, 27, 29, and 31 demonstrate, primary alkyl
chlorides, bromides, and tosylates are all tolerated; again, this
speaks to the excellent chemoselectivity of the oxidative
addition into the benzyl sp3C−Cl bond in preference to
primary sp3C−Cl, sp3C−Br, and sp3C−OTs bonds. As with
their aryl counterparts, oxidative addition by nickel(0) into
these types of bonds is well documented.31 Construction of
these 1° alkyl electrophiles could prove useful, whether it be for
nucleophilic substitution reactions, for cross couplings, or in the
preparation of nucleophilic organometallic reagents such as
Grignard, organolithium, or organozinc reagents.
Additionally, as a part of our efforts to increase the
convenience and flexibility of this method, we also explored
the use of alternative silyl triflate additives. In the majority of
cases, TMSOTf can be used in place of the more expensive
TESOTf with no detrimental effects, though there are some
instances in which the greater Lewis acidity of TMSOTf
compared to that of TESOTf causes partial decomposition of
substrates. Likewise, TBSOTf is also a competent silyl triflate
additive for this reaction. Given the interchangeability of these
additives, researchers may find it convenient to be able to use
any of these silyl triflates, depending on what is readily
available.
An ester moiety at the ortho position appears to completely
prevent catalytic turnover; intriguingly, this functional group is
well tolerated in the 4-position of the aromatic ring, suggesting
it may be interfering with the catalytic cycle through chelation
to the nickel center after oxidative addition. Substitution of
both the 2- and 6-positions of the benzyl chloride with fluorine
(34) prevents product formation, leading to exclusive
formation of the homocoupled product 1,2-bis(2,6-
difluorophenyl)ethane. However, 2,4-difluorobenzyl chloride
(30, 32) is a competent substrate, indicating that the
combination of the steric hindrance and the electron poor
nature of 2,6-difluorobenzyl chloride is problematic, especially
given that 2,4,6-trimethylbenzyl chloride is a competent
substrate (28). Additionally, 4-(chloromethyl)pyridine (34, as
the HCl salt) does not provide any product; it is unclear if this
is due to reaction with the silyl triflate or because the nitrogen
is able to coordinate to nickel, disrupting the catalytic cycle.
Finally, 4-(chloromethyl)-N,N-dimethylbenzamide (36) did
not provide any of the desired product, likely due to reaction
of the amide with the silyl triflate.
Using these three different silyl triflate additives, we
demonstrated that in situ protection of free alcohols, carboxylic
acids, and amines is possible on both the alkene and benzyl
chloride coupling partners, directly yielding protected alcohols
A number of alkenes also provided very little or no product;
allyl phenyl ether (37) underwent coupling but also reacts with
TESOTf, as does the coupling product, both of which
decomposed to a significant extent. Diene 38 decomposed
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a
under the reaction conditions, and the rate of reaction of
cyclohexene (39) was extremely low, with only traces of
product formed, even after 48 h of reaction time.
Scheme 7. Hypothesized Mechanism
The profound selectivity for reaction with terminal,
electronically unbiased alkenes in preference to styrenes (as
evidenced by example 18) is a surprising and interesting
outcome, which we felt warranted further investigation. As
shown in Scheme 6, the reaction between benzyl chloride and
a
Scheme 6. Comparison of Styrene and α-Olefins
a
Reaction conditions: precatalyst 1 (5 mol %), 5 equiv of alkene (1-
octene or styrene), Et3N (6 equiv), TMSOTf (1.5 equiv), 2 M in
CH2Cl2. Yields and ratios determined by GC.
1-octene proceeded in high yield as expected; however, the
analogous reaction with styrene provided 40 in only 8% yield.
Of further interest is the regiochemical outcome of the reaction
with styrene: though not as selective as with aliphatic alkenes,
substitution at the internal position is still favored in a 78:22
ratio. To date, the highest regioselectivity reported for styrene
is 40:60 in favor of the linear product, making this a significant
improvement from a theoretical standpoint, despite the low
yield.32
During NMR spectroscopic characterization of complex 1,
we observed that dissolution in CD2Cl2 caused the solution to
take on a markedly red color compared to the pure yellow color
observed in benzene. This difference is also reflected in the
NMR spectra of the complex in C6D6 compared to CD2Cl2; the
31P NMR spectrum in C6D6 shows only a single peak at 16.1
ppm, whereas the spectrum in CD2Cl2 shows three signals: one
at 15.0 ppm, corresponding to 1, as well as a signal at 3.1 ppm
for free PCy2Ph and one downfield signal at 44.9 ppm,
presumably (PCy2Ph)Ni(o-tolyl)Cl or a CD2Cl2 adduct thereof
(spectra are included in the Supporting Information). On this
basis, it is reasonable to suggest that dichloromethane promotes
or stabilizes dissociation of one PCy2Ph ligand, which we
hypothesize is necessary during the course of the reaction to
allow coupling to occur, as outlined in the proposed mechanism
(Scheme 7).
The proposed mechanism begins with reduction of the
precatalyst 1 to the NiL2 species 41 (via the mechanism
presented in Scheme 4), followed by rapid oxidative addition to
yield 42, which is in equilibrium with 42′. Abstraction of
chloride by the silyl triflate yields cationic nickel species 43,
which facilitates alkene coordination to yield 44.33 This species
undergoes β-migratory insertion with the indicated regiochem-
istry to produce 45, with nickel bonded to the less substituted
of the two carbons comprising the alkene. The migratory
insertion step is likely irreversible, and it also determines the
regiochemical outcome of the reaction: insertion as shown (44
to 45) will ultimately provide the branched (desired) product,
whereas insertion with the opposite regiochemistry will lead to
formation of the linear product.
a
Migratory insertion (44 to 45) occurs to form the new nickel−carbon
bond to the less substituted carbon of the alkene, which is marked with
a red circle for emphasis.
association, and deprotonation by Et3N complete the catalytic
cycle. One commonly observed side product (43′), formed by
the formal protonation of benzyl nickel species 43, is often
produced in small quantities during the course of the reaction.
As the concentration of alkene decreases, the equilibrium
between 43 and 44 shifts more toward 43, which results in a
higher concentration of 43 at any given time, causing reduction
product 43′ to be formed in greater amounts. We suspect this is
the root cause for the decrease in yield observed as the amount
of alkene used in the reaction is reduced or when more
sterically hindered alkenes are used.
We hypothesize that the principal factor responsible for
formation of the branched product in preference to the linear
product is the steric differentiation of the two ends of the
alkene, which manifests itself as a difference in energy between
the incipient 1° C−Ni and 2° C−Ni bonds formed during
migratory insertion (44 to 45). The less hindered 1° C−Ni
bond is lower in energy, and as such, the transition state leading
to its formation is also lower in energy. The uniformly high
selectivity observed across a range of electronically diverse
substrates supports this hypothesis, suggesting that electronic
factors are of secondary importance in determining the
regiochemical outcome of the migratory insertion and thus of
the reaction. The comparison between styrene and an aliphatic
olefin (Scheme 6) further supports this hypothesis: while the
branched product is still the major product, the selectivity is
indeed reduced compared to electronically unbiased alkenes.
CONCLUSIONS
■
In summary, we have developed a convenient protocol for the
internally selective benzylation of terminal alkenes using the air-
stable precatalyst trans-(PCy2Ph)2Ni(o-tolyl)Cl (1). This
precatalyst is easily prepared from commercially available
NiCl2·6H2O, PCy2Ph, and o-tolylmagnesium chloride in a high-
Following migratory insertion, β-hydride elimination to form
nickel hydride 46 takes place. Product release, ligand
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(4) (a) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem.
1992, 57, 3558−3563. (b) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi,
R. J. Org. Chem. 1993, 58, 7421−7126. (c) Olofsson, K.; Larhed, M.;
Hallberg, A. J. Org. Chem. 2000, 65, 7235−7239. (d) Olofsson, K.;
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(5) Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem. Soc.
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(6) (a) Qin, L.; Ren, X.; Lu, Y.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed.
2012, 51, 5915−5919. (b) Werner, E. W.; Sigman, M. S. J. Am. Chem.
Soc. 2011, 133, 9692−9695. See also (c) Zheng, C.; Wang, D.; Stahl,
S. S. J. Am. Chem. Soc. 2012, 134, 16496−16499.
(7) See ref 2c as well as (a) Wong, P. K.; Lau, K. S. Y.; Stille, J. K. J.
Am. Chem. Soc. 1974, 96, 5956−5957.
(8) (a) Wu, G.-z.; Lamaty, F.; Negishi, E.-i. J. Org. Chem. 1989, 54,
2507−2508. (b) Yi, P.; Zhuangyu, Z.; Hongwen, H. Synth. Commun.
1992, 22, 2019−2029. (c) Yi, P.; Zhuangyu, Z.; Hongwen, H. Synthesis
1995, 245−247. (d) Kumar, P. Org. Prep. Proced. Int. 1997, 29, 477−
480. (e) Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000,
41, 725−727. (f) Narahashi, H.; Yamamoto, A.; Shimizu, I. Chem. Lett.
2004, 33, 348−349. (g) Narahashi, H.; Shimizu, I.; Yamamoto, A. J.
Organomet. Chem. 2008, 693, 283−296. (h) Yang, Z.; Zhou, J. J. Am.
Chem. Soc. 2012, 134, 11833−11835.
(9) Based on prices from Strem Chemicals, Inc., Ni(COD)2 is
approximately 200 times more expensive than NiCl2·6H2O on a mole
for mole basis or approximately 80 times more expensive than
Ni(acac)2 hydrate.
yielding, two-step procedure and can be stored open to air at
room temperature with no measurable loss of purity or activity.
Furthermore, all reagents used in the reaction can be used “as
received” with no purification or even any degassing necessary.
The reaction is tolerant of substitution on both the benzyl
chloride and alkene coupling partners, allowing rapid access to
a wide variety of substituted allylbenzene derivatives. Addition-
ally, this study has provided useful information regarding the
commonly employed nickel(0) source Ni(COD)2, demonstrat-
ing that the COD ligands are not innocent under all
circumstances. This finding has wider implications for the
field of nickel(0) catalysis, where Ni(COD)2 is frequently used
as a precursor to a variety of Ni(0) complexes. More detailed
studies of the mechanism of activation of precatalyst 1 and of
the mechanism of the coupling reaction are underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data (1H, 13C, 31P as
applicable) for all new compounds and X-ray crystallographic
data (CIF) for complexes 1 and 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tfj@mit.edu
■
(10) (a) For the first reported synthesis of Ni(COD)2, see Wilke, G.
Angew. Chem. 1960, 72, 581−582. (b) The crystal structure was
determined and reported in Dierks, H.; Dietrich, H. Z. Kristallogr.,
Kristallgeom., Kristallphys., Kristallchem. 1965, 122, 1−23. (c) For a
representative synthetic procedure using Et3Al as the reductant, see
Notes
The authors declare no competing financial interest.
́
Bogdanovic, B.; Kroner, M.; Wilke, G. Justus Liebigs Ann. Chem. 1966,
̈
699, 1−23. (d) A modification was devised and reported in
Semmelhack, M. F. Org. React. 1972, 19, 115−198. (e) A detailed,
further modified procedure was later reported: Schunn, R. A. Inorg.
Synth. 1974, 15, 5−9. (f) A more convenient preparation using
DIBAL as the reductant was reported in Krysan, D. J.; Mackenzie, P. B.
J. Org. Chem. 1990, 55, 4229−4230.
(11) Herrmann, G.; Wilke, G. Angew. Chem. 1962, 17, 693−694.
(12) It is likely that (PCy2Ph2)Ni(0) exists in solution coordinated to
solvent or allylbenzene, rather than as a discrete species. There is
evidence that two-coordinate nickel(0) species do exist in solution but
only with very large NHC ligands such as IPr. For an example, see
Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J. Am. Chem.
Soc. 2002, 124, 15188−15189.
ACKNOWLEDGMENTS
■
Support has been provided by the NIGMS (GM63755) and by
an NSF Graduate Research Fellowship (E.A.S.). We gratefully
acknowledge Georgiy Teverovskiy and Prof. Stephen L.
Buchwald for helpful discussions and for a sample of trans-
(PPh ) Ni(o-tolyl)Cl for initial experiments. Dr. Peter Muller
̈
3
2
(MIT) is kindly acknowledged for X-ray crystallography, which
was carried out on instrumentation purchased with the help of
NSF grant CHE-0946721. Li Li (MIT) is acknowledged for
HRMS data, which was obtained on an instrument purchased
with the assistance of NSF grant CHE-0234877. NMR
spectroscopy was carried out on instruments purchased in
part with funds provided by the NSF (CHE-9808061 and
CHE-8915028).
(13) (a) Chatt, J.; Shaw, B. L. J. Chem. Soc. 1960, 1718−1729.
Further examples can be found in (b) Cross, R. J.; Wardle, R. J. Chem.
Soc. A 1970, 840−845. (c) Cassar, L.; Ferrara, S.; Foa, M. In Advances
́
in Chemistry Series; American Chemical Society: Washington, DC;
1974; Vol. 132, pp 252−273. (d) Brandsma, L.; Vasilevsky, S. F.;
Verkruijsse, H. D. Application of Transition Metal Catalysts in Organic
Synthesis; Springer: New York, 1998; pp 3−4.
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(33) Based on the observation that the rate of the reaction is
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(18) A control experiment using 5 mol % of trans-(PCy2Ph)2NiCl2 as
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experiment with no catalyst added produced no product; this suggests
that it is possible for trans-(PCy2Ph)2NiCl2 to mediate this reaction,
though evidently not in a catalytic fashion.
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(26) A reaction carried out using 1 mol % of precatalyst 1 and
unpurified reagents provided a 0% yield of the desired product,
suggesting that the amount of dissolved oxygen in the reagents is
sufficient to destroy all of the catalyst.
(27) Nickel hydrides (such as complex 47, Scheme 7) are known to
isomerize alkenes, which can under some circumstances cause a small
amount of isomerization of the starting alkene to form the
corresponding cis- or trans-2-alkene. In these instances, between 0%
and 5% of the recovered starting alkene is isolated as this isomer. For a
recent example of a nickel hydride used for alkene isomerization, see
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