Mechanistic Details of Pd(II)-Catalyzed C–H Iodination with Molecular I₂: Oxidative Addition vs Electrophilic Cleavage

Abstract

Transition metal-catalyzed C-H bond halogenation is an important alternative to the highly utilized directed-lithiation methods and increases the accessibility of the synthetically valuable aryl halide compounds. However, this approach often requires impractical reagents, such as IOAc, or strong co-oxidants. Therefore, the development of methodology utilizing inexpensive oxidants and catalyst containing earth-abundant transition metals under mild experimental conditions would represent a significant advance in the field. Success in this endeavor requires a full understanding of the mechanisms and reactivity governing principles of this process. Here, we report intimate mechanistic details of the Pd(II)-catalyzed C-H iodination with molecular I2 as the sole oxidant. Namely, we elucidate the impact of the: (a) Pd-directing group (DG) interaction, (b) nature of oxidant, and (c) nature of the functionalized C-H bond [C(sp(2))-H vs C(sp(3))-H] on the Pd(II)/Pd(IV) redox and Pd(II)/Pd(II) redox-neutral mechanisms of this reaction. We find that both monomeric and dimeric Pd(II) species may act as an active catalyst during the reaction, which preferentially proceeds via the Pd(II)/Pd(II) redox-neutral electrophilic cleavage (EC) pathway for all studied substrates with a functionalized C(sp(2))-H bond. In general, a strong Pd-DG interaction increases the EC iodination barrier and reduces the I-I oxidative addition (OA) barrier. However, the increase in Pd-DG interaction alone is not enough to make the mechanistic switch from EC to OA: This occurs only upon changing to substrates with a functionalized C(sp(3))-H bond. We also investigated the impact of the nature of the electrophile on the C(sp(2))-H bond halogenation. We predicted molecular bromine (Br2) to be more effective electrophile for the C(sp(2))-H halogenation than I2. Subsequent experiments on the stoichiometric C(sp(2))-H bromination by Pd(OAc)2 and Br2 confirmed this prediction.The findings of this study advance our ability to design more efficient reactions with inexpensive oxidants under mild experimental conditions.

Nickel(II)‐Mediated Regioselective CH Monoiodination of Arenes and Heteroarenes by using Molecular Iodine

“…However, the method also suffers from a limitation as it provides bis‐iodinated products when both the ortho positions are unsubstituted. The mechanistic investigation carried out by Yu et al14 regarding the CH iodination with molecular I 2 revealed that the iodination could take place via either an oxidative addition or an electrophilic cleavage pathway depending on (i) the extent of interaction between metal and directing group and (ii) the nature of the CH bond [C( sp 3 )H vs. C( sp 2 )H]. Theoretical calculations revealed that a strong directing group donor ability favors the oxidative addition pathway.…”

“…D regenerates the catalyst by releasing the product 3a . However, a redox‐neutral process via an electrophilic cleavage pathway cannot be ruled out 14. In such a case, complex B will coordinate with iodine and then electrophilic attack on the NiC bond occurs by II to yield ionic complex G which further rearranges to the thermodynamically favored D .…”

Rhodium‐Catalyzed C(sp2)‐ or C(sp3)−H Bond Functionalization Assisted by Removable Directing Groups

“…[154][155][156][157][158][159] TheR h III -catalyzed C À Hb romination or iodination of benzamides with N-bromosuccinimide (NBS) or Niodosuccinimide (NIS), respectively was reported by Glorius and co-workers (Scheme 47 a). Major progress in CÀHh alogenation was achieved by using various electrophilic halogenating reagents,although in afew cases ad ihalogen (e.g.I 2 )w as used as the halogen source.…”

Modern Transition-Metal-Catalyzed Carbon–Halogen Bond Formation

“…The mechanism of this transformation was later studied computationally by these authors in collaboration with the Musaev group. 140 In 2013, Yu and co-workers contributed the first example of an asymmetric C−H iodination via the desymmetrization of diarylmethylamines (Scheme 51). 141 By employing the chiral monoprotected amino acid (MPAA) ligands developed in their laboratory, they were able to obtain exquisite enantioselectivities of the chiral iodinatined diarylmethylamine products.…”