Reductive Cleavage Of The N-O Bond: Elemental Sulfur-Mediated Conversion Of N-alkoxyamides To Amides

Primary amides are a class of important compounds which widely exist in natural products,pharmaceutical agents and biomolecules.Naturally occurring drugs Geldanmycin,Tetrahydroindazole,Tetracycline and Temozolomide all possess the primary amide moiety in their chemical structure.Because of the importance of the primary amides,many research efforts have been devoted to the development of synthetic methodology for preparing various primary amides.So far,methods have been developed mainly including:1)ammoniation of carboxylic acids and their derivatives;2)oxidation of terminal alkynes,aryl methyl ketones,aryl cabinols or primary amines;3)aminocarbonylation of aryl halides;4)hydration of nitrile compounds.N-Alkoxyamides are kind of carboxylic acid derivatives.Usually,the-CONHOCH₃ moiety in N-alkoxyamides is used as the directing group for the direct and stereo selective functionalization of aromatic rings.However,the transformation from N-alkoxyamides to amides is much less exploited.The existing methods reported in literature are:1)reductive cleavage of N-O bonds promoted by samarium di-iodide,2)lithium/DTBB-induced reduction of N-alkoxyamides,3)ruthenium-catalyzed reduction of N-alkoxyamides in the presence of Zn-Cu alloy.Although these methods are effective,in each of their own respect,they suffer the disadvantages of the costly reagents and severe side reactions.Furthermore,all these approaches involve metallic reagents.Herein,we developed a metal free transformation that by treatment with S₈ in the presence of a base,N-alkoxyamides could be efficiently converted into corresponding amides.The reaction conditions including:reaction solvent,base,temperature and concentration were fully studied.And we obtained the optimal conditions as S₈ for the reductive reagent,DABCO（0.3 equiv）for the base and DMSO used as the solvent.Applying the optimal reaction conditions to a series of N-alkoxyamides,we set out the investigations of the scope and generality of this newly established method.And the results of all experiments showed that both the electron-donating and electron-withdrawing groups on the aryl group were well tolerated.The numbers of substituents on the aryl group couldn’t affect the reaction results.Both the aromatic and aliphatic groups were well tolerated.As N-alkoxyamide substituent has been widely utilized as a directing group in many transition metals catalyzed C-H activation and functionalization reactions,our method opens up a convenient synthetic route to access the functionalized aromatic amide by C-H functionalization directed by the N-alkoxyamide group followed with the N-O bond cleavage.We completed the synthesis of ortho-substituted arylformamides through a two-step procedure of first installing the ortho-substituent using the N-methoxyamide as the directing group,followed by our method to yield the primary amide.Based on previous reports and all the experimental results,both from the condition-optimization studies and control experiments,we proposed the mechanistic pathway for our reaction.And the mechanism could suggest the process of cleavage of the N-O bond mediated by elemental sulfur and could well account for the yield of aldehyde in the reactions,as well as the role DMSO played in forming the amide in the product.In summary,we have developed an efficient approach for preparing primary amides through reductive cleavage of the N-O bond in N-alkoxyamides realized by treatment with elemental sulphur and DABCO.Compared with previously reported methods,the novel approach is metal free and selective.It has been shown that the method was applicable for the synthesis of ortho-alkylated benzamide derivatives.