Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine

Abstract

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine–iodonium complex first forms through N−halogen bonding. This complex reacts with aci‐nitronates to give both α‐iodo‐ and α,α‐diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I+ under O2. In particular, evidence supports α,α‐diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.

Sterically Demanding Oxidative Amidation of α‐Substituted Malononitriles with Amines Using O2

“…Adding to such challenges is a drive to develop new ways to make amide bonds by activating nontraditional substrates oxidatively, as represented by the methods from the groups of Milstein, Rovis, Johnston, Bode, Lei, and Garg, as well as ours . Stemming from recent mechanistic insights, into the umpolung amide synthesis (UmAS) method of Johnston and co‐workers, we now present our oxidative advancement of the masked acyl cyanide (MAC) method to make amides, which was introduced by Yamamoto and co‐workers in 1990 and elegantly exploited in 2013 by the group of Rawal . Specifically, we disclose the direct, oxygen‐based conversion of 1,1‐dicyanoalkanes to make hindered amides and peptides in high yield and stereochemical integrity.…”

“…The stimulus for this work began during our discovery and development of the base‐promoted Nef oxidation of nitroalkenes or nitroalkanes to form their ketones with oxygen (Figure a) ,. During the further development of a direct halogenative method to form amides under aerobic conditions, we isolated α,α‐diiodinated nitroalkanes (Figure b) and recognized the mechanistic need to make intermediates that bear two electron‐stabilizing groups, X and Y (Figure c) . These substituents can thus not only stabilize transient radicals and anions, but also act as one‐ or two‐electron leaving groups.…”

“…On the basis of our previous mechanistic studies into making ketones and amides, from nitroalkanes, one plausible pathway for the oxidative amidation of malononitriles with amines is proposed in Figure . Thus, the α‐substituted malononitrile first deprotonates to generate the anion 11 , which is then capable of SET and addition with molecular oxygen, either directly or indirectly.…”

“…Mechanistic studies support an initial SET pathway between the anion 11 of the α‐substituted malononitrile and O 2 (via radical 12 ) to form the α‐peroxide adduct 13 as a precursor to the dioxirane 14 , which generates acyl cyanide ( 16 ) via the formation and fragmentation of bis(tetrahedral) adducts 15 (Figure ). Notably, our method does not require the formation of either congested pre‐oxidized hydroxy malononitriles as masked acyl cyanides (MAC), or congested halogenated nitroalkanes as precursors to activated esters,, and therefore offers good substrate scope for sterically hindered systems. It is thus reasoned that the SET induced addition of O 2 to 11 proceeds in a relatively unencumbered way to generate the acyl cyanide 16 , which is known to react readily with amines (or alcohols) in a mild manner .…”

Halogen Bonding of N‐Halosuccinimides with Amines and Effects of Brønsted Acids in Quinuclidine‐Catalyzed Halocyclizations

“…Concerns in this area arose during our development of an efficient oxidative amidation of primary nitroalkanes by the reaction of amines and NIS under O 2 , as well as our cyanoalkane oxidative studies [49–54] . During our mechanistic interrogations, we observed and isolated a previously unknown 1 : 1 adduct 1 between allylamine and NIS instead of the N ‐iodo‐amine, which is the generally expected species according to traditional reaction modes ( Scheme 1 ,C ).…”