Direct Deaminative Functionalization

Abstract

Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset of functional groups dominates this landscape, while others, despite their abundance, are sorely underdeveloped. Amines epitomize this dichotomy; they are abundant but otherwise intransigent toward direct interconversion. Here, we report an approach that enables the direct conversion of amines to bromides, chlorides, iodides, phosphates, thioethers, and alcohols, the heart of which is a deaminative carbon-centered radical formation process using an anomeric amide reagent. Experimental and computational mechanistic studies demonstrate that successful deaminative functionalization relies not only on outcompeting the H-atom transfer to the incipient radical but also on the generation of polarity-matched, productive chain-carrying radicals that continue to react efficiently. The overall implications of this technology for interconverting amine libraries were evaluated via high-throughput parallel synthesis and applied in the development of one-pot diversification protocols.

Mutagenicity of N-acyloxy-N-alkoxyamides – QSAR determination of factors controlling activity

“…The skeletal editing agent 42 has recently been shown to be a direct-acting mutagen in the Ames II assay. [108] Qualitative results from the Ames II method, which detects point mutations in a mix of S. typhimurium strains, are generally in good agreement with those from the full plate Ames methodology using TA100. [109] Contrary to Levin's recently published view, [108] quantitative Ames II results for 42 with S. typhimurium TA7001-7006 cannot be compared meaningfully to predicted plate counts from the standard Ames test with S. typhimurium TA100.…”

Site‐Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines**

“…Based on the aforementioned results and preceding reports, [28b,29,30a,b] a mechanistic scenario has been proposed to rationalize the observed reaction outcomes, as illustrated in Scheme 4. The reaction commences with the nucleophilic substitution of amines 1 with Levin's reagent 2 , producing intermediate A .…”

“…Subsequently, this intermediate can undergo thermal homolytic N 2 extrusion to form a geminate radical pair, which can undergo either in‐cage radical recombination or out‐cage radical trapping to form the final products. Inspired by these elegant works and the recent deaminative functionalization studies from the groups of Levin, Kelly, and Gutierrez, [30a] we hypothesized that…”

Harnessing Sulfur(VI) Fluoride Exchange Click Chemistry and Photocatalysis for Deaminative Benzylic Arylation

“…Benzylic ammonium salts have been coupled with boronic acids; however, the need for strongly alkylating agents potentially limits the scope of suitable substrates. Katritzky-type pyridinium salts have been employed in several photocatalytic and metal-catalyzed cross-coupling reactions, affording a powerful platform to activate primary amines bearing moderate steric hindrance. − Electron-rich trimethoxyphenyl imine provided an alternative approach, complementary in scope (α-tertiary primary amines) to the pyridylation activation. , Finally, a nitrogen-deletion strategy promoted by anomeric amides in the presence of secondary amines has been reported and subsequently expanded to deaminative functionalizations of primary amines, , albeit not in C–C cross-couplings. A common trade-off for these elegant strategies is the use of large activating groups, which lowers the activation barrier for C–N bond cleavage but creates large amounts of waste.…”