Manganese-Catalyzed Direct Conversion of Ester to Amide with Liberation of H 2 Akash Mondal, Murugan Subaramanian, Avanashiappan Nandakumar, and Ekambaram Balaraman* Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune-411008, India * S Supporting Information ABSTRACT: A simple and efficient Mn-catalyzed acylation of amines is achieved using both acyl and alkoxy functions of unactivated esters with the liberation of molecular hydrogen as a sole byproduct. The present protocol provides an atom- economical and sustainable route for the synthesis of amides from esters by employing an earth-abundant manganese salt and inexpensive phosphine-free tridentate ligand. A mides are common in nature and have found widespread applications in the pharmaceutical industry. 1 Amide linkages (or peptide bonds) are omnipresent in biomolecules, fine chemicals, and drug candidates. For instance, approx- imately 25% of drug molecules contain an amide moiety in their structural composition. 2 The classical approach to prepare amides involves coupling of carboxylic acids with amines at elevated temperature or aminolysis of activated carboxylic acid derivatives such as halides, anhydrides, and azides. 3 However, such protocols are limited by a narrow substrate scope, poor atom economy, need of reactive substrates, and cumulative waste generation. In this regard, catalytic aminolysis of esters is one of the elegant methods for the construction of amides, as this protocol involves the direct conversion of ubiquitous esters into biologically significant amides. 4 Indeed, aminolysis of esters results in alcohols as undesired byproducts, limiting the scope of the process. An efficient and newer strategy for amide synthesis that avoids byproduct formation and utilizes earth- abundant resources is highly demanding and challenging in chemical production. In 2007, the pioneering work on highly atom-economical and direct synthesis of amides from alcohols and amines was reported by the research group of Milstein. 5 This reaction is catalyzed by a dearomatized PNN-Ru pincer complex and operates via the acceptorless dehydrogenative coupling (ADC) pathway with the liberation of molecular hydrogen as the sole byproduct. Subsequently, several interesting reports on ADC for the preparation of amides were developed using expensive and less-abundant noble-metal-based catalytic systems. 6 In continuation of earlier work, Milstein and co-workers reported the direct synthesis of amides by dehydrogenative coupling of esters and amines with the liberation of hydrogen gas using the same PNN-Ru(II) catalytic system. 7a However, the ester substrates had to be purified prior to the reaction in order to eliminate carboxylic acid impurities that were responsible for catalyst deactivation even in the presence of the amine partner. In contrast to conventional approaches, the dehydrogenative coupling of esters with amines provides a sustainable protocol for the synthesis of amides since both the acyl part and the alkoxy part of the ester are incorporated into the product amide. 7 Though unprecedented progress has been achieved on catalytic aminolysis of esters using the ADC strategy with expensive, less abundant, toxic noble metals, the use of a catalytic system derived from and earth-abundant, economical, and biorelevant system is highly desirable in contemporary science. 8,9 In this regard, we report a facile protocol for the direct conversion of esters to amides with the liberation of molecular hydrogen using a base metal (manganese) as a catalyst featuring an inexpensive phosphine-free tridentate ligand. 10 The present protocol was successfully applied for various unactivated esters and amines (Scheme 1). Received: April 25, 2018 Scheme 1. Strategies for Amide Bond Formation Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.8b01305 Org. Lett. XXXX, XXX, XXX-XXX