Dearomatizing Amination Reactions

Abstract

Dearomatization reactions allow the direct synthesis of structurally complex sp 3 -rich molecules from readily available "flat" precursors. Established dearomatization processes commonly involve the formation of new CÀ C bonds, whereas methods that enable the introduction of CÀ N bonds have received less attention. Because of the privileged position of nitrogen in drug discovery, significant recent methodological efforts have been directed towards addressing this deficiency. Consequently, a variety of new processes are now available that allow the direct preparation of sp 3 -rich amino-containing building blocks and scaffolds. This review gives an overview of CÀ N bond forming dearomatization reactions, particularly with respect to scaffold assembly processes. The discussion gives historical context, but the main focus is on selected methods that have been reported recently.

Skeletal Transformation of Unactivated Arenes Enabled by a Low-Temperature Dearomative (3+2) Cycloaddition

“…Some features of the formal (3+2) cycloaddition between DAAA + II and arenes distinguish it from previously reported aminative cycloadditions of arenes or heteroarenes. 31 Though azaoxallyl and diazaoxallyl cations undergo (3+2) or (4+3) cycloadditions with less aromatic heteroarenes such as furans or indoles, 29,30 no such reactions with monocyclic aromatic hydrocarbons have been reported. The cycloaddition of DAAA + II is also distinct from the photocycloadditions of TADs, which favor a (4+2) mode as excitedstate arenophiles, whereas formal (3+2) adducts were exclusively observed with II.…”

A Metal‐Free C−H Amination‐Based Strategy for N‐Amino Indole Synthesis

“…Then, the other two commonly used hypervalent iodine-(III) oxidants, PIDA and PIFA were tested. PIDA was found to be less effective than PIFA (entries [14][15][16][17][18][19][20][21][22][23]. While the use of fluoroprotic solvents as TFE or HFIP was crucial to achieve high conversion of 1 a, the addition of PivOH or BF 3 •Et 2 O [21] failed to improve the yield of 2 a (entries 24 and 25).…”

Synthesis of spirocyclic 1,2-diamines by dearomatising intramolecular diamination of phenols

“…1,2 In order to create diverse sp 3 -rich scaffolds for the synthesis of lead-like molecules 3 and fragments, 4 we were interested in developing a method that would allow the concise synthesis of highly functionalised 1,2diaminocyclohexanes, motifs that are embedded in a wide range of natural and non-natural bioactive skeleta. The formation of nitrogen-containing spirocycles by dearomatisation reactions 5 may be triggered by reaction of phenol with external oxidants 6 or electrophilic reagents…”

“…The formation of nitrogen-containing spirocycles by dearomatisation reactions 5 may be triggered by reaction of phenol with external oxidants 6 or electrophilic reagents 7 followed by attack by a pendant nitrogen nucleophile, or alternatively by direct intramolecular attack of the arene on an electrophilic nitrogen species. 8 We envisioned that by performing an oxidative cyclisation using a urea as the nucleophile, we might be able to effect a subsequent aza-Michael addition on the resulting spirocyclic dienone derivative, leading to formation of a spirotricyclic derivative containing an embedded 1,2-diamine in a single operation (Fig.…”