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.

Figure 1.

Introduction. (A) State-of-the-art deaminative functionalization methods requiring preactivation. TMP = trimethoxyphenyl. (B) Previously reported direct deamination. (C) Challenges for radical trapping and successful direct deaminative functionalization relying on productive chain carrier generation.

Figure 2.

Scope of the deaminative bromination and high-throughput screening data. Conditions: 1 (aliphatic amines −1.2 equiv, aromatic amines −1.5 equiv), CBr₄ (2 equiv), CH₃CN (0.1 M), 23 °C, 3 h (aliphatic) or 10 h (aromatic). Isolated yields unless otherwise indicated. ^aNMR yield. ^bDeamination also observed. ^cIsolated as TFA salt. ^d24 h. ^eSee the Supporting Information for details.

Figure 3.

Implications of deaminative bromination for downstream diversification. See the Supporting Information for detailed reaction conditions. [Si] = diisopropylammonium bis(catechol)silicate.

Figure 4.

Beyond bromination: aromatic phosphonylation, aromatic thiolation, chlorination, iodination, and aliphatic hydroxylation. See the Supporting Information for detailed reaction conditions. ^aNMR yield. ^b50 °C.

Figure 5.

Mechanistic and computational study. (A) Proposed mechanism with computed energetics. (B) Experimental mechanistic evidence. (C) Rationalization of the generality of CBr₄.