Iron‐Catalyzed C_αH Oxidation of Tertiary, Aliphatic Amines to Amides under Mild Conditions

Abstract

De novo syntheses of amides often generate stoichiometric amounts of waste.Thus,recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities.H owever,s imple tertiary alkyl amines cannot be used as starting materials in these protocols. The researchd escribed herein enables the oxidative synthesis of amides from simple,n oncyclic tertiary alkyla mines under synthetically useful, mild conditions through ab iologically inspired approach:F e-catalyzed C a ÀHf unctionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of amild C a ÀHcyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine,d emonstrating the potential utility of the developed chemistry for metabolite synthesis.

Oxyfunctionalization of the Remote C−H Bonds of Aliphatic Amines by Decatungstate Photocatalysis

“…[1] While the most prevalent site of CÀH oxidation is a to the nitrogen atom, [2] achieving efficient distal oxidation of unactivated C(sp 3 )ÀHbonds has proven to be considerably more challenging.R ecently,e ffective hydroxylation of remote C(sp 3 ) À Hs ites within unprotected amines was found to be accessible through the deactivation of the amine C a ÀHb onds by protonation, [3] thus allowing the less activated and remote CÀHbonds to undergo oxidation. [1] While the most prevalent site of CÀH oxidation is a to the nitrogen atom, [2] achieving efficient distal oxidation of unactivated C(sp 3 )ÀHbonds has proven to be considerably more challenging.R ecently,e ffective hydroxylation of remote C(sp 3 ) À Hs ites within unprotected amines was found to be accessible through the deactivation of the amine C a ÀHb onds by protonation, [3] thus allowing the less activated and remote CÀHbonds to undergo oxidation.…”

“…Functionalized aliphatic amines represent ac ommon and important class of chemical building blocks for complexmolecule synthesis.A saconsequence,d iscovering new approaches for accessing functionalized amine building blocks in adirect and cost-effective manner is of considerable importance.One of the most well-studied approaches for the direct functionalization of aliphatic amines is through C(sp 3 ) À Ho xidation. [1] While the most prevalent site of CÀH oxidation is a to the nitrogen atom, [2] achieving efficient distal oxidation of unactivated C(sp 3 )ÀHbonds has proven to be considerably more challenging.R ecently,e ffective hydroxylation of remote C(sp 3 ) À Hs ites within unprotected amines was found to be accessible through the deactivation of the amine C a ÀHb onds by protonation, [3] thus allowing the less activated and remote CÀHbonds to undergo oxidation. [4] Despite the great strides in amine CÀHh ydroxylation, the ability to convert simple and unprotected aliphatic amines into ketone products by 4e-oxidation of amethylene remains an unsolved problem.…”

Supported Gold Nanoparticles for Efficient α‐Oxygenation of Secondary and Tertiary Amines into Amides

“…However,the a-oxygenation of amines has generally been carried out using stoichiometric organic or inorganic oxidants,s uch as tBuOOH, [6] RuO 4 (generated in situ by reaction of RuO 2 and NaIO 4 ), [7] iodosobenzene, [8] and PhCO 3 tBu. [9] Therefore,t he a-oxygenation of amines using O 2 as the terminal oxidant is ah ighly attractive,yet challenging task.…”

“…When morpholine (1e)w as used as as ubstrate,i tw as exclusively oxygenated in the 3-position to give the corresponding amide,and oxygenation did not occur at the 2-position (Table 1, entry 5). Furthermore,t he a-oxygenation of tetrahydroisoquinoline derivatives (1f and 1g)e ffectively proceeded at the benzylic positions ( [9][10][11][12]. [17] Thep resent catalytic system was also applicable to the a-oxygenation of tertiary amines.A ss hown in Table 2, various kinds of cyclic and linear tertiary amines were efficiently oxygenated to give the corresponding amides.…”

“…Cloperastine,acough suppressant, [19] was also selectively oxygenated to give the corresponding amide,l eaving chloride and ether functional groups intact (Table 2, entry 6). As for the ester group substituted amine 1s,t he oxygenation proceeded efficiently, although the ester group was hydrolyzed into the corresponding carboxylic acid functional group ( [9][10][11]. [17] It should be noted that the aforementioned a-oxygenation of tertiary amines proceeded in ah ighly regioselective manner and exclusively gave one regioisomer.…”