Catalytic coupling of haloolefins with anilides

Article abstract of DOI:10.1021/ja050366h

A strategy in which C-H activation reactions promoted by Pd(II) have been combined with β-heteroatom elimination to create a catalytic cycle achieving the arylation of haloacrylates is reported. The catalytic cycle can be subdivided into four parts: (1) C

Full text of DOI:10.1021/ja050366h

Published on Web 03/03/2005
Catalytic Coupling of Haloolefins with Anilides
Vladimir G. Zaitsev and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
Received January 19, 2005; E-mail: olafs@uh.edu
Scheme 1. Proposed Mechanistic Scheme
Extensive synthetic methodology has been developed based on
oxidative addition reactions of C-X bonds (X ) halogen, hetero-
atom).1 Catalytic C-C bond-forming reactions arising from C-H
bond activations are less common despite the wider availability,
price, and environmental advantages of the starting hydrocarbons
compared to functionalized compounds.2 The focus of many recent
studies has moved from investigations of the C-H bond activation
step to the application of these findings in catalytic processes.
An example illustrating the catalytic C-C bond-forming reaction
is palladium-catalyzed oxidative coupling of benzene derivatives
with alkenes bearing electron-withdrawing groups.3 This process
requires a stoichiometric reoxidant, usually oxygen, peroxides, or
Cu(II) since in the functionalization step, Pd2+ is reduced to Pd0.
The reoxidation step quite often is inefficient or turnover limiting,
and there are relatively few examples where high catalyst turnovers
have been demonstrated.3 Presence of Pd0 in the reaction mixture
may bring about side reactions if the arene contains halogen
substituents thus limiting the synthetic potential of this reaction.3a
Additionally, use of high pressures of the cheapest reoxidant
(oxygen) is unsafe in combination with flammable organic com-
pounds and elevated temperatures requiring special equipment.
We report here a strategy in which C-H activation reactions
promoted by Pd(II) have been combined with â-heteroatom
elimination to create a catalytic cycle (Scheme 1) and achieve the
arylation of haloolefins. The catalytic cycle can be subdivided into
four parts: (1) C-H activation; (2) the functionalization step,
migratory insertion of the olefin into a metal-carbon bond; (3)
â-heteroatom elimination; and (4) exchange of metal halide (if X
) halogen) for a less coordinating anion. In these processes, the
oxidation state of the metal does not change in the catalytic cycle,
and an oxidant is not required. A few Pd(II)-catalyzed reactions
employ â-acetate or â-halide eliminations as the terminating step.4
These examples demonstrate the viability of â-heteroatom elimina-
tion as a method to regenerate the catalytic species. This process
may be called a “reverse” Heck reaction with the heteroatom-
carbon bond breaking being the terminating and not the initiating
step.1a
was as follows: cis-chloro < trans-chloro ∼ cis-iodo < cis-bromo
< trans-bromo.6 As a consequence, all following reactions were
performed using trans-bromo ester.
A number of N-acylated anilines were found to be good
substrates for this reaction (Table 1). In some cases, better results
were obtained using pivaloylated substrates instead of acetanilides.
The yields and conversions are good for anilides possessing
substituents that are more electron donating than hydrogen. An
m-chloro substituent is compatible with the reaction conditions; in
this case, however, reduction of yield is observed. Even bromo
substituents are tolerated (entry 6), which would be problematic if
the reaction involved a Pd(0)-Pd(II) couple.3a Free phenolic
hydroxyl is also tolerated, and the coupling product was obtained
in 65% yield (entry 7). Interestingly, the N-methylated derivatives
were also found to be reactive, and the coupling products were
isolated in 40 (entry 8) and 98% (activated 3-methoxy substrate,
entry 9) yield. N-Alkylated anilides have been reported to be
unreactive if methyl acrylate is used as the olefin component.3b
No reaction was observed with 2-trifluoromethylacetanilide. With
more active substrates, it was possible to use cis-1-phenyl-3-bromo-
2-propenone as the olefinic component (entry 10). cis-3-Bro-
moacrylonitrile produced no desired coupling product under our
conditions.
We have carried out preliminary mechanistic investigations of
this coupling process. There are other mechanistic possibilities
besides the suggested one. First, elimination of HHal from the
haloalkene may produce the alkyne which may react with the
palladated anilide similar to the method of Fujiwara.7 A control
experiment was carried out by substituting the bromoalkene by
methyl propiolate. Under the usual reaction conditions, no product
was observed.
Second, simple Lewis acid-catalyzed electrophilic aromatic
substitution may be excluded based on the regioselectivity (exclu-
sive ortho-substitution) of the reaction.9 A reaction mechanism
proposed by Tremont for Pd-promoted alkylation of anilides and
N-benzilidene imines is unlikely.10 The intermediate palladated
The initial experiments were carried out with acetanilide deriva-
tives since these compounds are easily ortho-palladated, and the
palladated anilides readily react with acrylates (Scheme 1).5
3-Haloacrylates were chosen as the olefin components. The reaction
of ortho-palladated anilides with 3-chloroacrylate esters is very fast
in trifluoroacetic acid. However, the precipitated palladium halide
is virtually insoluble in the reaction medium, and thus the reaction
could not be rendered catalytic. Reaction in acetic acid produced
3-acetoxyacrylate ester in competition with the desired C-C
coupling process. Use of trifluoroethanol or methanol resulted in
production of Pd black. Efficient and relatively fast reaction was
observed in DMF, which was chosen as a solvent for further
investigations.
Next, reaction of preformed palladated anilide 1 with several
haloacrylates was investigated. The observed order of reactivity
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10.1021/ja050366h CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Coupling of Haloolefins with Anilidesa
Scheme 2. Kinetic Isotope Effects
almost the same as that in the intermolecular (3.6 vs 3.7) and is
within the expected range for a C-H activation process.11 These
data suggest that C-H bond cleavage occurs in the turnover-limiting
step.
In conclusion, we have developed a new alkene arylation process
based on C-H activation. The method is more functional group
tolerant compared with the existing alkene-arene coupling methods
based on electrophilic C-H activation. Efforts are underway to
extend this methodology to other classes of arenes and alkenes.
Acknowledgment. We thank the Welch Foundation (Grant No.
E-1571) and the University of Houston Small Grants Program for
supporting this research. We also thank Prof. Maurice Brookhart
for helpful comments.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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(6) Comparative haloacrylate reaction rates are provided as Supporting
Information.
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instead of AgOTf (about 1.5 turnovers observed). The use of AgOAc leads
to the production of acetoxyacrylate.
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a Substrate (1 equiv), olefin (1-1.5 equiv), AgOTf (1 equiv), Pd(OAc)2
(5 mol %). Piv ) pivaloyl. Yields are isolated yields. Silver was recovered
almost quantitatively as AgBr.8 See the Supporting Information for details.
b The starting anilide partially recovered after the reaction. c cis-1-Phenyl-
3-bromo-2-propenone was used as the olefin component.
anilides react with haloacrylate esters at room temperature, produc-
ing the coupling products. This all points to an alkene coordination-
insertion mechanism as opposed to other possible pathways. The
reaction is inhibited by the coupling products. If 1 equiv of 2 was
added to the reaction mixture, only 15% conversion to the product
was observed. Under similar conditions, 50% conversion was
observed with no starting material added. This may be the reason
for lower conversion in the case of less reactive substrates (entries
4 and 8). Both inter- and intramolecular deuterium isotope effects
were obtained for the reaction of p-toluanilide with methyl
bromoacrylate (Scheme 2). The intramolecular isotope effect is
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