Oxidatively intercepting heck intermediates: Pd-catalyzed 1,2- and 1,1-arylhalogenation of alkenes

Article abstract of DOI:10.1021/ja0782798

This communication describes the development of two Pd-catalyzed reactions for the arylchlorination of diverse α-olefins by oxidatively intercepting Heck intermediates. Depending on the nature of the oxidant and the reaction conditions, these transformati

Full text of DOI:10.1021/ja0782798

Published on Web 01/30/2008
Oxidatively Intercepting Heck Intermediates: Pd-Catalyzed 1,2- and
1,1-Arylhalogenation of Alkenes
Dipannita Kalyani and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109
Received October 30, 2007; E-mail: mssanfor@umich.edu
Table 1. Substrate Scope for Phenylchlorination Reactionsa
Palladium-catalyzed cascade reactions are widely used for the
assembly of complex organic molecules.1 These transformations
frequently involve σ-alkyl PdII intermediates that are formed by
Heck-type olefin insertion into a Pd-aryl bond (A in eq 1).1 Such
intermediates are typically intercepted by olefin/alkyne insertion2
or CO insertion2 to afford valuable functionalized products. In
contrast, selective and high yielding approaches to the direct
oxidative functionalization of Heck intermediates remain rare.3 Such
reactions would be particularly valuable, as they would allow direct
conversion of the Pd-C bond of A into diverse C-X bonds (X )
Cl, Br, I, F, O, N, and/or C, eq 1b).
An early report by Heck described the oxidative halogenation
of intermediates of general structure A to form 1,2-arylhalogenated
compounds (C, X ) Cl).3a However, competing formation of alkene
products (via â-hydride elimination followed by olefin dissociation,
eq 1a) severely limited the scope, yields, and overall synthetic utility
of these transformations. Recently, we and others have demonstrated
that Pd-alkyl species generated through C-H activation,4 olefin
a Conditions: 10 mol % of PdCl2(PhCN)2, 2-4 equiv of PhICl2, 2.6
equiv of PhSnBu3, CH2Cl2, -78 to 25 °C or 10 mol % of PdCl2(PhCN)2,
4 equiv of CuCl2, 1.3 equiv of PhSnBu3, Et2O, -78 to 25 °C. b Reaction at
0 °C in CH3NO2/Et2O (1:1). c Isolated yields and selectivities.
aminopalladation,5 or enyne cyclization6 can be oxidatively inter-
cepted using iodine(III) reagents. Importantly, with appropriate
selection of oxidant and reaction conditions, these transformations
proceed with little to no formation of â-hydride elimination
products.4-6 On the basis of this work, we reasoned that highly
reactive iodine(III) oxidants such as PhICl2 might be effective at
out-competing â-hydride elimination from Heck intermediates. We
describe herein the successful application of this strategy to the
Pd-catalyzed 1,2-arylchlorination of R-olefins. In addition, we
report that isomeric 1,1-arylchlorinated products can be obtained
in high yields simply by tuning the electrophilic chlorinating
reagent. This report discusses the scope, mechanism, and origin of
the intriguing reversal of selectivity in these reactions.
substrates. In all cases, the 1,2-phenylchlorinated compounds were
obtained with good to excellent selectivity, and <10% of products
derived from â-hydride elimination/alkene dissociation were ob-
served. Furthermore, these reactions were compatible with many
common organic functional groups, including amides, silyl ethers,
esters, and benzylic hydrogens, as well as alkyl and aromatic
halides.
As discussed above, 1,1-arylchlorinated isomers were observed
as minor side products in the reactions with PhICl2. However,
intriguingly, when PhICl2 was substituted with less reactive
electrophilic chlorinating reagents such as N-chlorosuccinimide or
CuCl2,7a the reaction of 1-octene and PhSnBu3 afforded only the
1,1-phenylchlorinated product 1b, albeit in low (4 and 13%) yields.7
Subsequent optimization revealed that, with CuCl2 as the oxidant,
simply changing the solvent from CH2Cl2 to Et2O resulted in
exclusive formation of 1b in 50% isolated yield.8 Furthermore, this
Pd-catalyzed 1,1-phenylchlorination with CuCl2 was also general
and highly selective across a wide range of functionally diverse
R-olefins (Table 1). Importantly, only minimal (<10%) amounts
of alkenes derived from â-hydride elimination/olefin dissociation
were observed. These results show that two different, synthetically
useful products can be accessed selectiVely simply by changing the
oxidant in these reactions.
Our initial studies focused on the Pd-catalyzed reaction of
1-octene and PhSnBu3 (eq 2). We were delighted to find that under
optimal conditions (10 mol % of PdCl2(PhCN)2, 4 equiv of PhICl2,
and 2.6 equiv of PhSnBu3 in CH2Cl2 at -78 °C) this reaction
provided the desired 1,2-phenylchlorinated product 1a in 72% yield
(as determined by 1H NMR spectroscopy). Remarkably, only traces
(<2%) of alkene product 1c were observed in the crude reaction
mixture. Instead, the major side product was the corresponding 1,1-
isomer 1b (obtained in 6% yield by 1H NMR). As shown in Table
1, this reaction could be applied to a wide variety of R-olefin
We propose the mechanistic manifold outlined in eq 3 to account
for the formation of 1,2- and 1,1-arylchlorinated products C and
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C O M M U N I C A T I O N S
C-I in these transformations. With highly reactive PhICl2 as the
electrophilic chlorinating reagent, the oxidative halogenation of
Heck intermediate A is believed to be significantly faster than
competing â-hydride elimination, providing isomer C as the
predominant product. We hypothesize that the small quantity of
isomer C-I observed in these reactions is formed from Pd-alkyl
intermediate A-I via â-hydride elimination from A, reinsertion to
generate A-I, and finally oxidative functionalization of A-I with
PhICl2.9
complexes are both more thermodynamically stable and more
kinetically reactive than the corresponding π-benzyl species.11c As
such, this large difference between vinylnaphthalene and styrene
provides support for π-aryl stabilization as a key factor in the
selectivity of these CuCl2-mediated arylchlorinations.
In summary, we have developed two Pd-catalyzed reactions for
the arylchlorination of R-olefins by oxidatively intercepting Heck
intermediates. Depending on the nature of the oxidant and the
reaction conditions, both 1,1- and 1,2-arylchlorinated products can
be obtained in good yield and selectivity. Furthermore, the
selectivity of these reactions can be rationally tuned by controlling
the relative rates of oxidative functionalization versus â-hydride
elimination from equilibrating PdII-alkyl species and by π-benzyl
stabilization of Pd intermediates. Future work will apply insights
from these studies to a broad scope of oxidants and transmetalating
reagents. In addition, studies are underway to gain further insights
into the mechanism of these transformations.
In contrast, we propose that with less electrophilic oxidants (e.g.,
CuCl2)7a the rate of â-hydride elimination is significantly faster
than that of oxidative functionalization, allowing rapid equilibration
between A and A-I. In this scenario, the observed selectivity for
the 1,1-product (C-I) would derive from selective chlorination of
Pd-benzyl intermediate A-I versus Pd-alkyl intermediate A.10
Initial support for this proposal was obtained by studies of the Pd-
catalyzed reaction between CuCl2 and 1-octene-(1,1-d2). The
isolated product 1b-d2 contained a single D at the 1-position and a
single D at the 2-position, as predicted based on a â-deuteride
elimination/reinsertion/oxidative cleavage pathway such as that in
eq 3 (see Supporting Information for full details).
To further probe this hypothesis, we examined the Pd-catalyzed
phenylchlorination of 4-(4-chlorophenyl)-1-butene (10) with CuCl2
under our standard conditions. As shown in eq 4, this reaction
afforded two isomeric phenylchlorinated productss1,1-function-
alized 10b and 1,4-functionalized 10csin a 4:1 ratio. The formation
of 10c (which requires the Pd to migrate two carbons down the
alkyl chain) provides strong evidence in support of equilibrating
â-hydride elimination/reinsertion steps prior to oxidative cleavage.
In addition, the sole formation of 10b and 10c (as opposed to
isomers resulting from chlorination at other positions along the alkyl
chain) further supports the proposed preference for benzylic
functionalization with CuCl2.
Acknowledgment. We thank the NIH NIGMS (GM073836)
and the Dreyfus, Beckman, and Sloan Foundations for funding.
D.K. also thanks Bristol Myers Squibb for a graduate fellowship.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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We hypothesized that the selectivity for benzylic chlorination
in the CuCl2 reactions might arise from equilibration of σ-benzyl
Pd intermediate A-I with the corresponding π-benzyl Pd species
(A-Iπ).11 A π-benzyl interaction could lead to increased amounts
of the 1,1-product by shifting the equilibrium between σ-alkyl
complex A and A-I/A-Iπ to the right and/or by increasing the rate
of oxidative chlorination of A-I/A-Iπ versus A.11 To investigate
this further, the Pd-catalyzed reactions of styrene and of 2-vinyl-
naphthalene with p-Cl-PhSnBu3 and CuCl2 were compared under
identical conditions (eq 5). In both cases, initial alkene insertion
would directly generate a Pd-benzyl or Pd-naphthyl intermediate;
therefore, significant quantities of 1,2-arylchlorinated products 11a
and 12a were expected (and observed) in both transformations.
However, while the ratio of 1,2-/1,1-products with styrene was 2:1,
the corresponding reaction with vinylnaphthalene provided a >50:1
ratio of 12a/12b. Literature reports have shown that π-naphthyl
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