Umpolung Amide Synthesis Using Substoichiometric N-Iodosuccinimide (NIS) and Oxygen as a Terminal Oxidant

Abstract

Umpolung Amide Synthesis (UmAS) provides direct access to amides from an α-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C–N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of α-bromo nitroalkane donors, this protocol realizes the goal of enantioselective α-amino amide and peptide synthesis based solely on catalytic methods.

Metal‐Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles

“…In conclusion, our mechanistic rationales, as depicted in Figure 2a nd Figure3,a re consistent with all of the reported data and observations that have been obtainedd uring previously published umpolung amide synthesis (UmAS) studies [5,6] and our recent work. [7] Critically, the key differences in our conclusionsi nclude:1 )the intermediacy of ar eactive tetrahedral dihalogenated speciesl ike 6,a nd not a-amino halonitroalkane 3';2 )the halogen bondingo fN IS with amines to form iodonium complexes like 2,a nd not electrophilic N-iodoamine 2'; and 3) the late-stagen ucleophilic addition of amines to oxygenatedi ntermediates like 7 or 8,o ras ubsequently derived traditional acyl precursor 13,tog ive the amide products 4.…”

“…[6] The differenceh erein is that we propose tetrahedral a-iodo-a-halonitroalkane 6 instead of aamino-a-halonitroalkane 3' as the key intermediate that reacts with oxygen.F urther evidencep resented in the UmAS-labeling study [6] also showed that the residual H 2 18 Oa nd N 18 O 2 -labeled a-halonitroalkanes 3 do not result in significantly 18 O-enriched amides 4 under 16 O 2 .T hus, having the dioxygen directly reacting with the anion of 3,t wo UmAS-like pathways to form the amide 4 were reasoned to occur by the tetrahedral a,a-diiodonitroalkane 6,a nd not by its a-amino-a-bromo counterpart 3' [6] (Scheme 4). [6] The differenceh erein is that we propose tetrahedral a-iodo-a-halonitroalkane 6 instead of aamino-a-halonitroalkane 3' as the key intermediate that reacts with oxygen.F urther evidencep resented in the UmAS-labeling study [6] also showed that the residual H 2 18 Oa nd N 18 O 2 -labeled a-halonitroalkanes 3 do not result in significantly 18 O-enriched amides 4 under 16 O 2 .T hus, having the dioxygen directly reacting with the anion of 3,t wo UmAS-like pathways to form the amide 4 were reasoned to occur by the tetrahedral a,a-diiodonitroalkane 6,a nd not by its a-amino-a-bromo counterpart 3' [6] (Scheme 4).…”

“…[7] Without the amine under O 2 , carboxylic acid 5 was generated from 3 (Scheme 1b). [5][6][7] mediate (vide infra) and the isolated deiodinated compound 1. [6] This wouldl ogically produceah itherto unobservedd iiodide inter- Figure 1.…”

“…Considering such types of dihalogenated species 6 as reactive tetrahedral intermediates to the amide 4,a sa lternatives to a-amino-a-bromonitroalkanes 3', [6] we prepared and compared the reactivity of dihalonitroalkanes 6 (X 1 ,X 2 = Cl, Br,a nd/or I) under both Ar and O 2 (Table 1; see the SupportingI nformation for X-ray of bromo/iodo 6). The experiments clearly showed that the amide 4 formed directly from the dihalide intermediate 6,w hereby higher reactivity and yield resulted with the introduction of at least one iodine substituent.…”

A one-pot amidation of primary nitroalkanes

“…19 Our attempts began with the most straightforward embodiment (Scheme 2), wherein two representative primary nitroalkanes (1,5) were treated using the standard UmAS conditions; one equivalent of halogen would be required for a-halogenation, and as little as 5 mol% is required for efficient amidation (based on a-bromonitroalkanes). 20 Both cases led to low yields of the desired amide product, but established the viability of a single-pot amidation of primary nitroalkanes. In addition to unreacted nitroalkane in these attempts, varying amounts of carboxylic acid were noted, consistent with the findings of Kornblum.…”