Chemistry of Tertiary Carbon Center in the Formation of Congested C−O Ether Bonds

Abstract

Nucleophilic substitutions, including SN1 and SN2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An SRN1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non‐chiral or chiral α‐bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Carboxamide-Directed Stereospecific Couplings of Chiral Tertiary Alkyl Halides with Terminal Alkynes

“…In this case, the main coupling product, 3h , was the only product. Very recently, Kürti’s group and our group reported the alkoxylation of nonchiral α-bromocarboxamides as tertiary alkyl sources in the presence or absence of a Cu catalyst. These results indicated that the main intermediate was not an aziridinone.…”

Cu-Catalyzed C(sp3)–N Coupling and Alkene Carboamination Enabled by Ligand-Promoted Selective Hydrazine Transfer to Alkyl Radicals

“…According to previous reports, the nucleophilic substitution of sterically hindered alkyl bromides, especially those with electron-withdrawing groups, is difficult to proceed through either S N 1 or S N 2 pathways. , For example, no product was observed when 2e was treated with 3a under weakly basic conditions that were applied to Cu-catalyzed reactions (eq ). When a stronger base, a polar aprotic solvent, and higher temperature that benefit S N 2 reactions were applied, compounds 12 and 13 were produced instead, presumably through an elimination/Michael addition sequence (eq ).…”

Pd-Catalyzed C–O Bond Formation Enabling the Synthesis of Congested N,N,O-Trisubstituted Hydroxylamines

“…Among them, the congested C−O ether bond is very difficult to construct using Williamson ether synthesis 14 or other S N 2 15 or S N 1 16 reactions. Recent progress in this area has been made by Kurti, 17 Gong, 18 and Nishikata, 19 et al via cross-coupling tertiary alkyl electrophiles with alcohols for the synthesis of a quaternary carbon center. In spite of the above achievements, efficient C−O bond formation between hydroxylamines and tertiary or secondary alkyl halides remains rare, potentially due to the intrinsically low nucleophilicity of OH-hydroxylamine and the rather labile N−O bond.…”

“…Among them, the congested C–O ether bond is very difficult to construct using Williamson ether synthesis or other S N 2 or S N 1 reactions. Recent progress in this area has been made by Kürti, Gong, and Nishikata, et al. via cross-coupling tertiary alkyl electrophiles with alcohols for the synthesis of a quaternary carbon center.…”