Nickel-catalyzed heck-type reactions of benzyl chlorides and simple olefins

Article abstract of DOI:10.1021/ja209235d

Nickel-catalyzed intermolecular benzylation and heterobenzylation of unactivated alkenes to provide functionalized allylbenzene derivatives are described. A wide range of both the benzyl chloride and alkene coupling partners are tolerated. In contrast to analogous palladium-catalyzed variants of this process, all reactions described herein employ electronically unbiased aliphatic olefins (including ethylene), proceed at room temperature, and provide 1,1-disubstituted olefins over the more commonly observed 1,2-disubstituted olefins with very high selectivity.

Full text of DOI:10.1021/ja209235d

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pubs.acs.org/JACS
Nickel-Catalyzed Heck-Type Reactions of Benzyl Chlorides
and Simple Olefins
Ryosuke Matsubara, Alicia C. Gutierrez, and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
We address herein several of the aforementioned deficiencies.
The nickel-catalyzed intermolecular benzylation of simple, un-
activated olefins (eq 1) represents the first example of an alkene
benzylation method that (a) utilizes α-olefins as substrates,
including ethylene and propylene, (b) displays high selectivity
for 1,1-disubstituted olefins, (c) avoids isomerization of the
desired allylbenzene derivatives to the styrenyl products, and
finally, (d) proceeds smoothly at room temperature.
We initially examined the nickel-catalyzed coupling reaction of
ethylene (1 atm) and benzyl alcohol (1 equiv) in the presence of
Et3SiOTf (1.75 equiv) and triethylamine (6 equiv).12 In stark
contrast to our previously reported nickel-catalyzed olefin
allylation,12d methyl ether and methyl carbonate derivatives
exhibited no conversion, indicating that they failed to undergo
oxidative addition.13 Benzyl bromide afforded the product in
poor yield and underwent undesired side reactions with the
triethylamine.14 Ultimately, benzyl chloride (1) proved to be a
suitable substrate (Table 1).
For these initial studies with ethylene, PCyPh2 provided super-
ior reactivity and yields (entries 1 and 2). Only 1 mol % of the
nickel complex derived from Ni(cod)2 and PCyPh2 is required to
catalyze the reaction, affording the product in quantitative yield.
Using 5 mol % of the catalyst drastically increases the reaction rate,
reducing the time required for complete conversion from 16 to 2 h
(entry 3). Decreasing the catalyst loading beyond 1 mol % sig-
nificantly lowers the conversion (entry 4). No reaction took place
with the exclusion of Ni(cod)2 and only a trace amount of the
product was formed without addition of Et3SiOTf (entry 5). In
the latter case, the consumption of benzyl chloride is believed to be
caused by a change in mechanism from the desired manifold (vide
infra) to one which favors homocoupling.
A particularly noteworthy feature of this method is the regio-
selectivity observed when 1-alkyl-substituted (R ¼ H) alkenes are
used. Excellent regioselectivity in favor of the unusual 1,1- over 1,2-
disubstituted olefins (the exclusive regioisomer observed in all
previously reported cases) is obtained under these nickel-catalyzed
conditions. Furthermore, styrene and acrylate (excellent substrates
in other Heck-type analogues) are poor substrates in this catalytic
system, rendering this methodology complementary in both
regioselectivity and reactivity to its palladium analogues. In con-
trast to ethylene, for the α-olefins, higher conversion (100%) was
obtained with PCy2Ph compared to PCyPh2 (59% conversion,
entries 6 and 7). A catalyst loading of 5 mol % was sufficient to
catalyze the reaction, but improved yields were obtained when the
loading was increased to 10 mol % (entries 7 and 8). The reactions
ABSTRACT: Nickel-catalyzed intermolecular benzyla-
tion and heterobenzylation of unactivated alkenes to
provide functionalized allylbenzene derivatives are de-
scribed. A wide range of both the benzyl chloride and
alkene coupling partners are tolerated. In contrast to
analogous palladium-catalyzed variants of this process,
all reactions described herein employ electronically un-
biased aliphatic olefins (including ethylene), proceed at
room temperature, and provide 1,1-disubstituted olefins
over the more commonly observed 1,2-disubstituted
olefins with very high selectivity.
he HeckꢀMizoroki reaction1 is a powerful carbonꢀcarbon
T
bond-forming process that couples alkenes with a wide
scope of aryl, alkenyl, and alkyl halides.2 When benzyl3 chlorides
are employed, the coupling provides useful allylbenzene deriva-
tives, a versatile functional group in organic synthesis. Despite the
fact that the first coupling of methyl acrylate using benzyl chloride
was described by Heck nearly 40 years ago,4 the intervening years
have witnessed only sporadic reports of couplings with benzyl
halides or related derivatives.5,6 Of these, the chief limitation is
substrate scope; most examples utilize olefins bearing substituents
that facilitate coupling electronically, such as acrylates, styrenes,
and N-vinyl amides. The benzylation of widely available aliphatic
olefin feedstocks7 has not yet been realized. Moreover, the
products obtained in these reactions are subject to olefin isomer-
ization, and the previously reported examples generally afford a
mixtureofallylbenzenederivatives (kineticproducts) and isomeric
styrenes. This problem can be difficult to control at the high
reaction temperatures (100ꢀ130 °C) employed. A further un-
solved problem is regioselectivity; to the best of our knowledge, no
examples of Heck-type olefin couplings of simple alkenes that give
1,1-disubstituted products have been reported.8 While the ruthe-
nium-catalyzed eneꢀyne coupling developed by Trost is a notable
example,9 there are far fewer methods for the direct assembly of
1,1-disubstituted olefins compared to 1,2-disubstituted olefins,
despite the fact that 1,1-disubstituted olefins are prevalent in many
biologically active compounds10 and are very useful intermediates
in target-oriented syntheses.11
Received: March 10, 2011
Published: November 08, 2011
r
2011 American Chemical Society
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Table 1. Optimization of Olefin Benzylation Conditions
Table 2. Nickel-Catalyzed Benzylation of Ethylenea
a Determined by GC. b Et3SiOTf not used.
with 1-octene proceeded readily at ambient temperature, albeit at a
slower rate that was observed for ethylene. For 1-octene, 2 equiv of
olefin was required for complete conversion (entry 9), but with a
slightly diminished yield compared to the reaction in which 5 equiv
was used (entry 7).
Given the rapid rate with which the coupling of ethylene
proceeded, we used this simple olefin to examine the scope of the
reaction with regard to the benzyl chloride partner. Gratifyingly,
good to excellent yields were observed across a broad range of
substrates under these optimized conditions (Table 2).15 Various
benzyl chloride derivatives were tolerated, including those with
para- (2aꢀf), meta- (2gꢀl), hetero- (2 mꢀr), and ortho-
substitution (2sꢀt). Both electron-rich and electron-deficient
benzyl chlorides were coupled within 2 h at room temperature.
Highyields werealso observed when halogen-substituted aromatic
substrates were used. Even an ortho-iodo benzyl chloride was
successfully employed, to afford the desired product (2t) in good
yield. In this case, only 4% of the product derived from oxidative
addition into the carbonꢀiodide bond was concomitantly formed.
Cyano (2c) and ester (2f) functional groups on the aromatic rings
were also tolerated, and α,α0-dichloroxylenes (meta and para) were
efficient substrates for the preparation of diallylbenzenes (2b and
2k). It is noteworthy that nitrogen-protecting groups, Boc and Ts
(2n, 2q, and 2r), located β to the benzylic carbon, did not interfere
with the reaction.
Having examined the substrate scope of functional groups on
the benzyl chloride with ethylene, we next turned our attention to
the substituted olefins. A variety of functionality on the α-olefin is
tolerated, including silyl ethers (3h and 3k), phthalimides (3f and
3l), and alkyl groups with α-branching (3d) (Table 3. An alkene
containing a pendant alkyl bromide underwent the coupling with
noobservablesidereactions, furnishing3i in 97%yieldand thereby
demonstrating the excellent chemoselectivity of this reaction.
Propylene, a gaseous olefin, afforded the desired product (3j) in
excellent yield. Notably, α-olefins containing pendant olefins (3b)
a Isolated yield unless otherwise noted. b Determined by GC (internal
standard). c Determined by 1H NMR spectroscopy (internal standard).
d Yield obtained with 10 mol % catalyst. e 2,3-Dihydro-1H-indene (4%)
observed as inseparable byproduct. f Yield obtained with 20 mol %
catalyst loading. g 4-Cyano-β-methylstyrene (5%) obtained as an in-
separable byproduct. h Obtained with 2.5 equiv Et3SiOTf.
are also tolerated. As was observed for ethylene, aryl bromides
are compatible with the reaction conditions (3c). A trifluoro-
methyl substituent was also tolerated under the reaction
conditions. Despite the presence of three fluorine atoms at a
benzylic position, no evidence of fluoride substitution was
detected (entry 3l).16
Attempts to employ more highly substituted benzyl chlorides
revealed the limits of this reaction (Figure 1). No reaction was
observed upon exposure of 5, containing a methyl substituent at
the benzylic position, to the reaction. Further examination of scope
revealed that nitro-substituted aromatic groups were not compa-
tible, despite the compatibility of nitrile- and ester-substituted
benzyl chlorides. No conversion was observed when a pyridine
was present (7) as the heterosubstituent, further revealing the limits
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Table 3. Nickel-Catalyzed Benzylation of 1-Substituted
Olefinsa,b
Figure 1. Substrates that did not undergo the desired benzylation.
Scheme 1. Proposed Catalytic Cycle and ORTEP Drawing of
η3-Nickel Complex 14a
a All yields are isolated yields. b rr = Regioisomeric ratio (3/4). c Reac-
tions carried out neat in olefin (5 equiv) except for the examples that
employ a gaseous or solid olefin; for these entries, toluene was used as a
solvent. d Twenty mole percent of the catalyst. e Total yield of 3 and 4.
f Toluene (1.4 M) used as solvent; 1.5 equiv of olefin. g Propylene
introduced via balloon (1 atm); toluene (0.2 M) used as solvent.
h Toluene (1.2 M) used as solvent.
of this catalyst system. We also examined the functional group
tolerance with regard to the alkene partner. The steric limit is
reached with tert-butyl ethylene 8, for which no reaction was
observed. While no reaction was observed for carbamate 9,
carbonate 10 formed an intractable mixture of products. To probe
the compatibility of substrates containing enolizable protons, ester
11 was examined; the ester failed to undergo complete conversion
even when more than 2 equiv of Et3SiOTf was used.
We propose the reaction mechanism shown in Scheme 1.
Nickel(0) complex 12, possibly in equilibrium with alkene
(substrate or cyclooctadiene) complex 13, adds oxidatively to
benzyl chloride without mediation of Et3SiOTf, affording a
mixture of nickel(II) complex 14, bearing an η3-benzyl ligand
and one phosphine, and 15 bearing an η1-benzyl ligand and two
phosphines.17 In solution at room temperature, a rapid equi-
librium exists between complexes 14 and 15, but favors
complex 14.18 As depicted, Ni(η3-CH2C6H5)(PCy2Ph)Cl
(14) has been characterized by X-ray crystallography. Coun-
teranion exchange from Clꢀ to TfOꢀ mediated by Et3SiOTf
provides cationic nickel complex 16,19 which then undergoes
olefin coordination. Subsequent migratory insertion, the carbonꢀ
carbon bond-forming step in which the regioselectivity is deter-
mined, gives alkyl-nickel species 17. This is followed by β-hydride
elimination, affording the 1,1-disubstituted olefin product and nickel
a P = PR3.
complex 18. Nickel(0) complex 12 is then regenerated by triethy-
lamine, completing the catalytic cycle.
In Heck reactions catalyzed by palladium, the selectivity of the
olefin insertion step is governed by a combination of electrostatic
and frontier orbital effects, yet which effect is dominant in this
reaction is unclear at this time. In the proposed mechanism, the
productive pathway is the one that places the metal on the less
substituted olefinic carbon. Given the relatively shorter nickelꢀ
carbon bond lengths (compared to the analogous palladium
system), it is conceivable that steric effects are the dominant
factor in this reaction. The ease with which ethylene undergoes
the reaction compared to substituted olefins (2 vs 16 h), despite its
significantly lower relative concentration (1 atm in 0.2 M toluene vs
neat in 5 equiv olefin), lends support to this argument. However, the
most sterically demanding olefin tolerated by the reaction, vinyl
cyclohexane, was also the only substrate that afforded any of the
linear adduct.
The observation that 36% of the benzyl chloride is converted
to the homo dimer in the absence of Et3SiOTf (Table 1, entry 5)
can also be rationalized using this mechanism. Unable to form
allyl complex 16, it is likely that two molecules of the nickel chloride
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(14, 15) undergo disproportionation to the catalytically incom-
petent Ni(II)Cl2 and a Ni(II)Bn2 intermediate. The latter would
then afford the self-coupled product (dihydrostilbene) via re-
ductive elimination.
Yamamoto, A.; Shimizu, I. Chem. Lett. 2004, 33, 348. (g) Narahashi, H.;
Shimizu, I.; Yamamoto, A. J. Organomet. Chem. 2008, 693, 283. Pd-
catalyzed intermolecular Heck reaction of simple olefins was reported.
(6) To the best of our knowledge, there is only one example of
intermolecular benzylation of a simple olefin, where a styrene-type
product derived from olefin isomerization of the initially formed product
was obtained. See ref 5a.
(7) Alpha olefins are regarded as a chemical feedstock. Alpha Olefins
Applications Handbook; Lappin, G. R., Sauer, J. D., Eds.; Marcel Dekker:
New York, 1989.
(8) Cross-coupling reactions of benzyl halides (or their derivatives)
and alkenyl organometallics have been reported, although very few
methods to synthesize 1,1-disubstituted olefins were reported. For
selected examples, see:(a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc.
1979, 101, 4992. (b) Kamlage, S.; Sefkow, M.; Peter, M. G. J. Org. Chem.
1999, 64, 2938. (c) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org.
Chem. 1999, 64, 2796. (d) Pꢀerez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am.
Chem. Soc. 2001, 123, 4155. See also refs10a and 11.
(9) For initial reports describing branch selectivity in the ruthenium-
catalyzed intermolecular eneꢀyne coupling, see:(a) Trost, B. M.; Toste,
F. D. Tetrahedron Lett. 1999, 40, 7739–7743. (b) Trost, B. M.; Machacek,
M.; Schnaderbeck, M. J. Org. Lett. 2000, 2, 1761–1764. (c) Trost, B. M.;
Pinkerton, A. B.; Toste, F. D.; Sperrle, M. J. Am. Chem. Soc. 2001,
123, 12504–12509.
In conclusion, we have described a novel nickel-catalyzed
intermolecular benzylation of simple, widely available α-
olefins and ethylene. The functional group tolerance seen across
the broad range of substrates studied rivals that observed for
analogous reported palladium-catalyzed methods. The ob-
served selectivity favoring 1,1- versus 1,2-disubstituted olefins is
a unique and significant feature of this methodology. Addi-
tionally, the relatively low temperature at which these reactions
proceed (room temperature) is unique. The above study represents
an important advance in catalytic reactions using simple olefins
as substrates. We are currently investigating Et3SiOTf-free processes
as well as other types of catalytic reactions using simple olefins as
nucleophiles in carbonꢀcarbon bond-forming reactions.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
tral data for all unknown compounds and CIF file for complex 14.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(10) For examples, see:(a) Miller, J. A.; Negishi, E.-i. Tetrahedron
Lett. 1984, 25, 5863. (b) Sabarre, A.; Love, J. Org. Lett. 2008, 10, 3941.
(11) For examples, see:(a) Taber, D. F.; Christos, T. E.; Neubert,
T. D.; Batra, D. J. Org. Chem. 1999, 64, 9673. (b) Tiefenbacher, K.;
Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548.
’ AUTHOR INFORMATION
(12) The combination of Et3N and a silyl triflate has been found in
our laboratory to mediate nickel-catalyzed reactions of simple olefins.
(a) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 14194. (b) Ho,
C.-Y.; Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362. (c) Ho,
C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782. (d) Matsubara,
R.; Jamison, T. F. J. Am. Chem. Soc. 2010, 132, 6880.
Corresponding Author
tfj@mit.edu
’ ACKNOWLEDGMENT
Support for this work was provided by the NIGMS (GM 72566
and GM 63755). We are grateful to Dr. Peter M€uller (MIT) and
Dr. Michael Takase (MIT) for X-ray diffraction analysis. R.M. thanks
JSPS Postdoctoral Fellowships for Research Abroad for financial
support and Dr. Akemi Moriyama (Children’s Hospital Boston,
deceased March 2011) for encouragement and support. A.C.G.
thanks the NIH for financial support.
(13) See Supporting Information for details.
(14) The discrepancy between the high (100%) conversion of the
benzyl bromide and the low (20%) yield of product is believed to be due
to nucleophilic displacement of the benzyl bromide by Et3N to form the
insoluble triethylammonium salt.
(15) GC or NMR yields are given for cases where product volatility
made isolation difficult.
(16) The successful use of m-CF3C6H4CH2Cl in a nickel(0)-cata-
lyzed cross-coupling reaction has been reported previously:(a) Lipshutz,
B. H.; Bulow, G.; Lowe, R. F.; Stevens, K. L. J. Am. Chem. Soc. 1996, 118,
5512.
(17) For experimental details and NMR spectra, see Supporting
Information.
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M. L. Organometallics 1987, 6, 1757. (c) Carmona, E.; Paneque, M.;
Poveda, M. L. Polyhedron 1989, 8, 285.
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