Directed ortho‐Metalation of Aryl Amides, O‐Carbamates, and Methoxymethoxy Systems: Directed Metalation Group Competition and Cooperation

Abstract

A systematic study on the competitive metalation of derivatives containing four directed metalation groups (DMGs), namely, Cl, OMe, methoxymethoxy (OMOM), and CONEt2, in comparison with the OCONEt2 DMG is described. In addition, the anionic ortho‐Fries (AoF) rearrangement, the double metalation–electrophile quench of 1,2‐ and 1,4‐O‐carbamates, and iterative metalation procedures are presented. The results provide new methodologies for the synthesis of contiguously functionalized 1,2,3‐ and 1,2,3,4‐substituted aromatic derivatives of difficult accessibility and potential broad utility. A comparison of the present methodology with previously developed routes is provided for selected examples with emphasis on such substituted compounds.

Directed ortho‐Metalation of O‐Aryl N,N‐Dialkylcarbamates: Methodology, Anionic ortho‐Fries Rearrangement, and Lateral Metalation

“…The OCONR 2 group also participates in directed remote metalation reactions [45] and Ni-catalyzed Suzuki-Miyaura [46] and Kumada-Corriu [47] cross-coupling reactions and has been the subject of mechanistic studies. [49] These combined studies extend the preliminary results [7] substantially in all aspects above and provide new avenues for the diverse utility of the OCONR 2 DMG in DoM reactions of potential synthetic value. In an accompanying paper, we present intramolecular competition studies of the O-carbamate with several other prominent DMGs and illustrative iterative DoM chemistry.…”

“…In an accompanying paper, we present intramolecular competition studies of the O-carbamate with several other prominent DMGs and illustrative iterative DoM chemistry. [49] These combined studies extend the preliminary results [7] substantially in all aspects above and provide new avenues for the diverse utility of the OCONR 2 DMG in DoM reactions of potential synthetic value.…”

“…In the complementary study, [49] the comparative and synergistic effects of the O-carbamate with respect to several other DMGs in DoM reactivity are investigated.…”

“…On the basis of this result and the relative reactivity, a variety of electrophiles were introduced to give products 6-22 in good-to-excellent yields; the exceptions were 12 and 15, possibly because of the presence of acidic C-H bonds in the electrophile and single electron transfer (SET) reactions, respectively. Compounds 10 and 11 are poised for further DoM reactions, [49] whereas products 16, 17, 19-21, and 22 are basic substrates for further modern synthetic manipulations. Products with ortho-sulfur (17 and 18), -halo (19)(20)(21), and -hydroxy (22) substituents were also obtained cleanly, and the latter result shows the differentiation of catechol hydroxy groups.…”

“…Products with ortho-sulfur (17 and 18), -halo (19)(20)(21), and -hydroxy (22) substituents were also obtained cleanly, and the latter result shows the differentiation of catechol hydroxy groups. Compounds 10 and 11 are poised for further DoM reactions, [49] whereas products 16, 17, 19-21, and 22 are basic substrates for further modern synthetic manipulations.…”