Angewandte
Communications
Chemie
Synthetic Methods
Oxidative Coupling of Aryl Boron Reagents with sp3-Carbon
Nucleophiles: The Enolate Chan–Evans–Lam Reaction
Patrick J. Moon, Heather M. Halperin, and Rylan J. Lundgren*
Abstract: Reported is a versatile new oxidative method for the
arylation of activated methylene species. Under mild reaction
conditions (RT to 408C), Cu(OTf)2 mediates the selective
coupling of functionalized aryl boron species with a variety of
stabilized sp3-nucleophiles. Tertiary malonates and amido
esters can be employed as substrates to generate quaternary
centers. Complementing either traditional cross-coupling or
SNAr protocols, the transformation is chemoselective in the
presence of halogen electrophiles, including aryl bromides and
iodides. Substrates bearing amide, sulfonyl, and phosphonyl
groups, which are not amenable to coupling under mild
Hurtley-type conditions, are suitable reaction partners.
bond-forming reactions with aryl boron reagents under
oxidative conditions remain sparse.[11,12] To the best of our
knowledge, enamine annulation[13] and vinylation[14] represent
the closest known reports towards an enolate Chan–Evans–
Lam reaction. Currently available oxidative arylation strat-
egies employing organoboron reagents and activated meth-
ylenes require stoichiometric amounts of Pb(OAc)4 in
combination with mercury additives.[15] Motivated by this
methodological gap and the opportunity to access compound
classes not easily prepared by existing protocols, we report
herein the first copper-mediated oxidative coupling reactions
between either aryl boroxines or boronic esters and in situ
formed enolates to generate a-aryl carbonyl compounds
(Figure 1). The reaction is chemoselective in the presence of
halogen electrophiles (including aryl iodides) and can be
employed for substrate classes which are not amenable to
Hurtley-type reactions under mild reaction conditions
(< 708C), such as amides and tertiary malonate esters.
C
ross-coupling reactions between two distinct nucleophilic
partners have emerged as valuable transformations which
display reactivity and selectivity orthogonal to classical metal-
catalyzed couplings of electrophiles with nucleophiles.[1]
Oxidative coupling reactions often proceed under exception-
ally mild reaction conditions, employ base-metal mediators or
catalysts, and in ideal cases, tolerate electrophilic function-
ality useful for subsequent transformations. The copper-
mediated union of aryl boronic acids and heteroatom
nucleophiles exemplifies the power of such coupling mani-
folds.[2] First reported by Chan, Lam and co-workers,[3] and
Evans etal.,[4] functionalized aniline and phenol derivatives
can be prepared from stable, readily available aryl boron
species at room temperature by employing simple copper
salts and mild organic bases. In addition to N- and O-based
nucleophiles, sulfur, selenium, tellurium, and halogen nucle-
ophiles are also suitable partners in these reactions.[2,5,6]
Despite the success of Chan–Evans–Lam-type reactions
in carbon–heteroatom bond construction processes, as well as
an increasing appreciation for the mechanism of these
transformations,[7] a general method for the copper-mediated
arylation of stabilized sp3-carbon-based nucleophiles with
organoboron reagents has not been established. This is
particularly noteworthy in light of the importance of a-aryl
carbonyl compounds in synthetic organic and medicinal
chemistry, and the considerable body of literature concerning
transition-metal-based methods for their synthesis by the
coupling of sp2 electrophiles.[8–10] Indeed, in comparison to
Figure 1. Overview of the copper-mediated oxidative coupling of hetero-
atom nucleophiles and the oxidative carbonyl a-arylation developed
herein.
With the aim of developing copper-mediated oxidative
À
À
heteroatom nucleophiles, reports of copper promoting C C
C C bond formation between an aryl boron species and an
activated sp3-nucleophile, reaction conditions similar to those
established for heteroatom arylations were investigated,
generally without success. Typical side products arising from
protodeborylation, aryl–aryl homocoupling, and acetoxyla-
tion were observed under standard Chan–Evans–Lam con-
ditions.[2,14] The use of aryl boronic anhydrides (boroxines),
however, provided a breakthrough in reactivity (Table 1A).
Under standard reaction conditions, both aryl boronic acids
[*] P. J. Moon, H. M. Halperin, Prof. R. J. Lundgren
Department of Chemistry, University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
E-mail: rylan.lundgren@ualberta.ca
Supporting information and ORCID(s) from the author(s) for this
1894
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1894 –1898