Palladium‐Catalyzed Suzuki–Miyaura Cross‐Coupling of α‐Halomethyl Oxime Ethers and Site‐Selective Cross‐Coupling of Dihalo Derivatives

Abstract

The cross‐coupling reaction of chloro‐ and bromomethyl oxime ethers with a wide range of aryl‐, heteroaryl‐ and vinylboronic acids in the presence of catalytic palladium complexes with different phosphines has been carried out with good yields (60–98%, 40 examples). Regioselective cross‐coupling reactions differentiating between an alkyl or aryl position are achieved from dihalo oxime ethers containing Csp2‐ and Csp3‐halogen bonds using mono‐ or dicoordinated palladium catalysts such as Pd(dba)2/P(o‐tolyl)3 or Pd(PPh3)4. The selective orthogonal functionalization of dihalo oxime ethers is also described. Site‐selective transformations allow the introduction of the biaryl motif into dihalo oxime ethers preserving the highly activated alkyl halide moiety vicinal to the oxime group for further transformations. In this context, Z‐ and E‐oxime ethers could be considered as synthetic equivalents of ketones in palladium‐catalyzed Suzuki reactions.magnified image

Transition Metal‐Catalyzed Reactions Involving Oximes

“…In 2013, Medio‐Simon et al. developed a palladium‐catalyzed Suzuki–Miyaura cross‐coupling reaction of halomethyl oxime ethers with aromatic boronic acids . Various Z ‐α‐chlorinated oxime ethers with aryl‐, heteroaryl‐ and vinylboronic acids were examined, providing quite good yields (Scheme ).…”

Influence of the Ligand of Palladium(0) Complexes on the Rate of the Oxidative Addition of Aryl and Activated Alkyl Bromides: Csp2−Br versus Csp3−Br Reactivity and Selectivity

“…From the comparison of the reactivity of 8 and 3 , it is clear that the oxidative addition is much faster with the Csp 3 −Br bond in 8 than with the Csp 2 −Br bond in 3 (by a factor 7×10 4 ; Scheme ). Whenever these both occur in the same molecule, for example, that in Scheme b, the reactivity should be similar to that of 8 (a Br substituent on the aryl group of 3 should not significantly affect the reactivity of 3 ) with a favored Csp 3 −Br bond activation (Scheme ). This is in agreement with the regioselectivity at the Csp 3 −Br bond observed experimentally if Pd 0 (PPh 3 ) 4 is used as the catalyst (Scheme b, reaction to the right) …”

“…Therefore, although the reactivity of the aryl bromides 3 and 5 is enhanced by changing PPh 3 to P( o ‐Tol) 3 , the reactivity of compounds 8 and 9 at the Csp 3 −Br if P( o ‐Tol) 3 is used, remains high enough to preclude an efficient control of the regioselectivity in the corresponding dibromo‐derivatives (Scheme ) …”

“…Satisfactory ligand‐controlled regioselective Suzuki–Miyaura reactions at the Csp 3 −X position on related substrates bearing both Csp 3 −X and Csp 2 −X groups were also reported (Scheme a and b) ,,…”

A General Metal‐Assisted Synthesis of α‐Halo Oxime Ethers from Nitronates and Nitro Compounds

“…Nucleophilic substitution of the halogen in oxime ethers 1 provides an easy route to various functionalized oxime derivatives 3. Furthermore, α‐halo oxime ethers 1 are convenient substrates for palladium‐catalyzed C–C cross‐coupling,4a catalytic carbonylation,4b and aza‐Reformatsky reactions,4c,4d as well as for coupling with organic cuprates 4e…”