Metal-Free Oxidative Amidation of 2‑Oxoaldehydes: A Facile Access to α‑Ketoamides Nagaraju Mupparapu, †,‡ Shahnawaz Khan, †,‡ Satyanarayana Battula, †,‡ Manoj Kushwaha, § Ajai Prakash Gupta, § Qazi Naveed Ahmed,* ,†,‡ and Ram A. Vishwakarma* ,†,‡ † Medicinal Chemistry Division, ‡ Academy of Scientific and Innovative Research (AcSIR), § Quality Control and Quality Assurance (QC & QA), Indian Institute of Integrative Medicine (IIIM), Jammu, Jammu and Kashmir 180016, India * S Supporting Information ABSTRACT: A novel and efficient method for the synthesis of α-ketoamides, employing a dimethyl sulfoxide (DMSO)- promoted oxidative amidation reaction between 2-oxoalde- hydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion- based intermediate as a central feature of reaction wherein C 1 -oxygen atom of α-ketoamides is finally derived from DMSO. α-Ketoamides, a well-known structural element of many natural products, pharmaceuticals and synthetic agents, have attracted considerable attention for their synthesis using different starting materials. 1-8 Not only have these compounds been optimized for their remarkable biological and pharmacological activities, but also they are known with wide application in a wide variety of functional group transformations as well. 9,10 Consequently, a number of synthetic methods for construction of this important unit have been established in the past decades. Nevertheless, most of these methods described synthesis under (1) harsh conditions (use strong oxidizing conditions) or (2) metal salt catalytic conditions. Recently chemistry around 2-oxoaldehyde (OA) has been explored by two different groups for the construction of α-ketoamides (Scheme 1). 7 It is a well familar fact that OA possessing adjacent aldehyde and ketone functional groups with different reactivity shows interesting chemical properties. The higher reactivity of aldehyde of OA in comparison to normal aldehyde is attributed to existence of an electron-withdrawing ketone group and has been well explored to produce different important structures. 11 Because of the importance of α-ketoamides and broad synthetic applications of OA, we developed a unique, alternative, convenient, and efficient method to access α-ketoamides using a metal-free oxidative amidation approach (Scheme 1). The present method employing a dimethyl sulfoxide (DMSO) promoted oxidative amidation reaction between OA and amine under metal-free conditions has clearly demon- strated the unusual behavior of OA toward amine in a DMSO environment. Interestingly, it was observed that reaction of phenylglyoxal 1a with pyrrolidine 2a in DMSO at 60 °C for 12 h afforded the desired product 3j in 10% yield (entry 1, Table 1). Same reaction when kept for 24 h could not increase the yields to that extent (12%, entry 2). To improve upon the yields of α- ketoamides, a preliminary set of reaction between 1a and pyrrolidine 2a under different condition has been carried out (entry 3-22). The effects of reaction temperature on the yields of 3j at different time intervals (pyrrolidine taken at 0.75 mmol) were subsequently examined. A higher conversion rate was obtained when the reaction was performed at 80 °C for 1.5 h (80%, entry 4). No further increase in yield was observed when the reaction temperature was >80 °C and time more than 1.5 h. The same reaction when tried at 45 °C for 48 h failed to produce desired product (entry 8 and 9). Next, various concentrations of amine were screened at 80 °C (entry 10-16). 0.97 mmol of pyrrolidine 2a was subsequently determined as the best concentration for the reaction. Finally as observed, the optimal reaction conditions for the reaction turned out to be phenylglyoxal 1a (0.75 mmol) with pyrrolidine 2a (0.97 mmol) at 80 °C in DMSO (95%, entry 11). Since the reaction was carried out in air atmosphere, it was necessary to perform reaction in different solvent conditions so as to ascertain the role of DMSO (entry 17-22). Reaction of 2a with 1a in different solvents under reflux conditions failed to produce desired product. Furthermore test reaction between 1a and 2a failed to produce α-ketoamides in DMSO/THF solution (DMSO taken in 10 equiv) as well. These results clearly Received: January 3, 2014 Published: February 3, 2014 Scheme 1. 2-Oxoaldehyde-Based Methods for Synthesis of α- Ketoamides Letter pubs.acs.org/OrgLett © 2014 American Chemical Society 1152 dx.doi.org/10.1021/ol5000204 | Org. Lett. 2014, 16, 1152-1155