Palladium-catalyzed carboiodination of alkenes: Carbon-carbon bond formation with retention of reactive functionality

Article abstract of DOI:10.1021/ja110377q

We report a palladium-catalyzed carbon-carbon bond-forming reaction between aryl iodides and alkenes. In contrast to traditional cross-coupling reactions, two new bonds are formed, and all of the atoms in the starting materials are incorporated into the p

Full text of DOI:10.1021/ja110377q

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Palladium-Catalyzed Carboiodination of Alkenes: Carbon-Carbon
Bond Formation with Retention of Reactive Functionality
Stephen G. Newman and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario,
Canada M5S 3H6
S Supporting Information
b
Scheme 1. Reaction Pathways of Alkyl Palladium Halides
and Proposed Reductive Elimination
ABSTRACT: We report a palladium-catalyzed carbon-
carbon bond-forming reaction between aryl iodides and
alkenes. In contrast to traditional cross-coupling reactions,
two new bonds are formed, and all of the atoms in the
starting materials are incorporated into the product. The use
of a palladium catalyst with bulky phosphine ligands is found
to be crucial for reactivity.
he efficient formation of carbon-carbon bonds is the most
T
important and most challenging aspect of organic chemistry.
Transformations such as the aldol, Friedel-Crafts, Diels-Alder,
and Grignard reactions, all of which were developed over 80 years
ago, still constitute the most useful reactions we have today for
preparing the core of complex natural products, pharmaceuticals,
and novel materials. Perhaps the dominant advance in carbon-
carbon bond construction is the emergence of transition-metal
catalysis.1 By utilizing precious metals, new bonds can be made
between readily accessible organic molecules efficiently and
reliably.
Scheme 2. Effect of Catalyst in Intramolecular Carboiodination
of Alkenes
Among transition metals, palladium has stood out due to its
ability to catalyze diverse reactions and its applicability to
practical synthesis.2 The Mizoroki-Heck reaction is one such
coupling transformation, which unites an aryl halide and an
alkene with the loss of HX (X = halide or pseudohalide)
(Scheme 1). Significant attention has been devoted to increasing
the efficiency of coupling reactions by using domino processes.
For example, the alkyl Pd(II) halide intermediate in the Heck
reaction can undergo an anion capture event to form a second
new bond.3 This transformation typically requires an alkyl Pd(II)
halide intermediate with no syn-β-hydrogens.
We speculated a direct reductive elimination of an alkyl
palladium halide would be possible to provide an alkyl halide.
The resulting reaction would provide a new carbon-carbon
bond while retaining the reactive halide of the starting material.
Similar processes have been explored by Heck4 and more
recently greatly improved by Sanford,5 utilizing an organo-
metallic reagent and stoichiometric oxidant. Other carbohalo-
genation reactions are known but are usually radical-type pro-
cesses, which imparts limitations on the scope.6
iodides. Both intra- and intermolecular reactions take place when
exceptionally bulky phosphine ligands are used. The products
contain a new carbon-carbon and carbon-iodine bond, and no
stoichiometric waste is formed in the reaction.
We began our studies by analyzing the use of well-defined
Pd(0) catalysts with bulky phosphine ligands for the intramole-
cular cyclization of substrate 1a (Scheme 2). At 90 °C in toluene,
carboiodination complex 2a could be obtained in up to 82% yield
by using 5 mol % Pd(Q-phos)2 as a Pd(0) source.8 Other bulky
ligands such as P(t-Bu)3 and PhP(t-Bu)2 gave lower conversion,
while less bulky ligands such as PCy3 and P(o-tol)3 gave no
detectable product.
Running the reaction at 100 °C with 2.5 mol % of Pd(Q-phos)2
gave full conversion of starting material after 4 h and a 95% isolated
yield of 2a. With these optimized conditions, a number of intramolecular
Carbon-halogen reductive elimination has only recently
been identified as a plausible elementary step in Pd(0)/Pd(II)
catalytic cycles, and no carbon-carbon bond-forming reaction
has utilized this step.7 Herein, we report the development of a
palladium-catalyzed carboiodination reaction of alkenes with aryl
Received: November 18, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja110377q J. Am. Chem. Soc. 2011, 133, 1778–1780
|

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Table 1. Scope of Palladium-Catalyzed Intramolecular
Carboiodinationa
Scheme 3. Intermolecular Carboiodination of Norbornene
are present in the cyclized alkyl Pd(II) halide intermediate.
Instead, olefin isomerization or Heck-type products are formed.
To investigate an intermolecular variant of this transfor-
mation, we chose norbornene as our model alkene, as the inter-
mediate alkyl palladium halide species cannot undergo syn-β-
hydride elimination. Reoptimization revealed Pd[P(t-Bu3)]2
to be the best catalyst. Treating 3-fluoroiodobenzene and
1.3 equivalents of norbornene with 5 mol % catalyst gave the
carboiodination adduct 4a in 66% yield as the major product,
along with small quantities of unidentified side products
(Scheme. 3). Similar reactivity was found for other aryl iodides.
Product 4b, derived from 4-nitroiodobenzene, was a crystalline
solid, and single-crystal X-ray diffraction confirmed the syn,
exo stereochemistry of the major product (see Supporting
Information).
While it is premature to make strong mechanistic implications,
an oxidative addition, carbopalladation, reductive elimination
pathway seems most likely.9 Reductive elimination of alkyl
halides from Pd(II) has not been studied; however, oxidative
addition of alkyl halides to Pd(0) has been investigated and is
generally considered to occur by either an SN2 or nonchain
radical mechanism, depending on the catalyst, substrate, and
conditions.10 The intramolecular reaction is found to be un-
inhibited by radical scavengers such as TEMPO or galvinoxyl,
while the intermolecular reaction was found to be partially
inhibited by these species. Further mechanistic studies into the
corresponding reductive elimination are currently underway. It is
noteworthy that the catalytic cycle suggested was first proposed
almost 30 years ago by Ban and co-workers in their palladium-
catalyzed ene-halogenocyclization reactions.11 This mechanism
was subsequently shown by Curran and co-workers to actually be
a radical atom transfer process.12
The ability of bulky phosphine ligands to induce reductive
elimination of Pd(II) complexes has been frequently utilized in
the past decade to increase the scope of many known C-C- and
C-X-forming reactions. Further support for alkyl palladium
halide reductive elimination as a novel elementary step for
catalytic cycles will open a wide door for new coupling reactions.
We are currently working to further our knowledge of the
reaction mechanism and ligand requirements for carbohalogena-
tion. Extensions to a diverse range of unsaturated substrates are
also underway.
a Reaction conditions: Substrate 1 (0.1 or 0.2 mmol scale), Pd(Q-Phos)2
(2.5 or 5 mol %), 0.2 M in toluene, 100 °C, sealed tube. b 0.05 M in
toluene.
cyclizations were explored (see Table 1). Both 5- and 6-mem-
bered rings could be formed to produce various oxygen- and
nitrogen-containing heterocycles as well as a carbocycle in high
yields. Reactions that formed 5-membered rings generally
required lower catalyst loading and shorter times than those that
formed 6-membered rings. The analogous reaction with an aryl
bromide or chloride does not give the corresponding carboha-
logenation product, suggesting the sp3 C-Cl and C-Br reduc-
tive elimination may be more difficult than C-I reductive
elimination. Thus far, the reaction does not work if β-hydrogens
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mlautens@chem.utoronto.ca
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’ ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the University of Toronto, and
Merck-Frosst Canada for an Industrial Research Chair for
financial support. S.G.N. thanks NSERC for a postgraduate
scholarship. Margot Lautens is thanked for aiding in the synthesis
of starting materials. We thank Johnson Matthey for donation of
palladium catalysts and Alan J. Lough (Chemistry Department,
University of Toronto) for obtaining the crystal structure of 4b.
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