Transition-Metal-Free Quinoline Synthesis from Acetophenones and Anthranils via Sequential One-Carbon Homologation/Conjugate Addition/Annulation Cascade Sandip Balasaheb Wakade, †,‡ Dipak Kumar Tiwari, †,‡ Pothapragada S. K. Prabhakar Ganesh, † Mandalaparthi Phanindrudu, †,‡ Pravin R. Likhar, ‡ and Dharmendra Kumar Tiwari* ,†,‡ † Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India ‡ Academy of Scientific & Innovative Research (AcSIR), New Delhi 110001, India * S Supporting Information ABSTRACT: A transition-metal-free method for the con- struction of functionalized quinolines from readily available acetophenones and anthranils is reported. This one-pot reaction cascade involves in situ generation of α,β-unsaturated ketones from the acetophenone via one-carbon homologation by DMSO followed by the aza-Michael addition of anthranils and subsequent annulation. DMSO acted in this reaction not only as solvent but also as one carbon source, thus providing a highly atom-economical and environmentally benign approach for the synthesis of 3-substituted quinolines. T he 3-substituted quinolines are ubiquitous in various pharmacologically and medicinally relevant molecules displaying a broad range of biological activities (Figure 1). 1,2 In addition, they have been exploited as synthetic intermediates in the preparation of drugs and functional materials. 3 Over the past few years, numerous quinoline syntheses have been developed, but most of the existing methods suffer from the requirement of highly functionalized starting materials and expensive transition metals. 4-6 Therefore, development of new synthetic methods for the quinoline synthesis in green, efficient, and metal-free fashion is highly desirable. α,β-Unsaturated ketones are frequently encountered in various bioactive compounds and generally regarded as versatile synthetic intermediates in the syntheses of fine chemicals, pharmaceuticals, and materials. 7,8 Traditionally, the synthesis of α,β-unsaturated ketones required multiple steps 9,10 and equimolar amounts of reagents such as 2-iodoxybenzoic acid (IBX) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). 11,12 Over the past few years, transition-metal-catalyzed (Pd, Ru, Ir, Ni, and Cu) oxidation of saturated ketones has proven to be a concise, efficient, and atom-economical method for the synthesis of α,β-unsaturated ketones. 8 To eliminate the need for the troublesome isolation of α,β-unsaturated ketones they are in situ subjected to various organic transformations such as arylation, amination, and conjugate addition to get β- functionalized ketones. 13 Very recently, we developed a copper- catalyzed α,β functionalization of saturated ketones with anthranils via sequential dehydrogenation/aza-Michael addi- tion/annulations cascade reactions in one pot (Scheme 1). 13f Although this method allows a convenient access to 3- ketoquinolines, the requirements of a transition metal and the commercial unavailability of phenylethyl ketones are the key limitations. In the recent past, both the acetophenone and anthranils have been recognized as good substrates for several organic Received: August 7, 2017 Figure 1. Biologically active molecules containing 3-substituted quinolines. Scheme 1. Synthesis of 3-Ketoquinolines Letter pubs.acs.org/OrgLett © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.7b02429 Org. Lett. XXXX, XXX, XXX-XXX