A Formal [4 + 4] Complementary Ambiphile Pairing Reaction: A New Cyclization Pathway for ortho-Quinone Methides

Abstract

A formal, one-pot, [4+4] cyclization pathway for the generation of 8-member sultams via in-situ generation of an ortho-quinone methide (o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are merged with insitu-generated o-QM in a formal [4+4] cyclization pathway to afford 5,2,1-dibenzooxathiazocine-2,2-dioxide scaffolds under microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4+4] cyclization.The development of chemical methodologies allowing ready access to novel heterocyclic scaffolds in a minimal number of steps is a key facet of drug discovery. Single pot, multicomponent reaction (MCR) strategies in particular have gained high value in this regard. 1 The great majority of these reactions involve the combination of reactive partners possessing single nucleophile-electrophile interactions, followed by subsequent merging in domino, cascade or tandem pathways to produce heterocyclic moieties. In comparison, synthons containing both electrophilic and nucleophilic sites (ambiphilic synthons) 2,3,4 have great potential in developing new reaction pathways with high step economy, 5 but remain underdeveloped. Interest in the development of chemical methodologies for the production of diverse sultam libraries has led to the exploration of complementary ambiphile pairing (CAP) pathways as part of a general strategy for the production of benzofused sultams in a facile manner ( Figure 1).At the heart of the titled method is the complementary pairing of two ambiphilic synthons, ofluoro benzenesulfonamides and ortho-quinone methide (o-QM) in a formal one-pot [4+4] approach to afford the novel 5,2,1-dibenzooxathiazocine-2,2-dioxide ring system. This route augments a recently reported [4+3] epoxide cascade strategy developed in our laboratory and others using the ambiphilic character of o-fluorobenzenesulfonamides for the synthesis of benzofused sultams. 6 phanson@ku.edu. Supporting Information Available: Experimental details and spectral charactization for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org. The aforementioned dibenzooxathiazocine ring system represents a new subclass within sultams that have not been reported to-date. Sultams are a class of non-natural heterocycles that have gained prominence in recent years due to their activity against a wide spectrum of biological targets. 12,13 Their acyclic precursors, sulfonamides, are highly versatile synthons due to the tunability of the SO 2 NH pKa. 14 In this regard, o-fluorobenzene sulfonamides are particularly attractive due to the highly electron withdrawing nature of the SO 2 functionality, in conjunction with the o-fluoro substituent, which impart enhanced electrophilicity at the ortho-carbon as well as attenuated acidity/nucleophilicity of the sulfonamide NH ( Investigations commenced with the production of an array of 2° o-fluorobenzenesulfonamides under modified Schotten-Bau...

Origin of the Base‐Dependent Facial Selectivity in Annulation Reactions of Nazarov‐Type Reagents with Unsaturated Indolo[2,3‐a]quinolizidine Lactams

“…Ethyl (or methyl) 3‐oxo‐4‐pentenoate ( 1 ), known as the Nazarov reagent, is a versatile annulating agent that is widely used in a variety of Robinson‐type annulations, in which it sequentially acts as an electrophilic reagent in a Michael addition and as a nucleophile to promote the cyclization, (Scheme ). The fact that 1 is unstable under basic conditions and polymerizes rapidly at room temperature has stimulated the development of more stable analogues of 1 bearing alkyl substituents on the vinyl moiety, such as 2 .…”

Rapid, Scalable Assembly of Stereochemically Rich, Mono- and Bicyclic Acyl Sultams

“…4 Among several approaches, the build-couple-pair 5a and functional group pairing 5b strategies have featured prominently in advancing DOS. We recently reported the concepts of complementary ambiphile pairing (CAP) 6 and reaction pairing 7 as DOS strategies for the facile generation of diverse sultam scaffolds. In this regard, the complementary union of ambiphilic 8 synthons, in a formal [m+n] fashion ([4+3] and [4+4]), allows access to diverse cyclic heterocycles in a step-economical approach.…”

“…In this regard, the ambiphilic nature of vinyl sulfonamides were previously reported to readily undergo hetero-Michael additions as well as N -alkylations, 10 and participate in a [4+3] epoxide-opening/Michael protocol. 6a Likewise, amino acids can be conceptually classified as ambiphilic synthons where they represent ideal starting materials as they allow for encoding stereochemical, skeletal and peripheral diversity. Furthermore, while aza-Michael addition of unprotected amino acids to acrylonitrile, 11 acrylate esters, 12 acrylaldehyde, 13 sulfones, 14 and vinylphosphoryl compounds 15 have been reported, to the best of our knowledge aza-Michael addition of unprotected amino acids to vinyl sulfonamides are absent in the literature.…”

Sulfonilamidometilación intramolecular de 2-naftilmetan y 2-(2-naftil)etansulfonamidas

“…(202) Se transformó el clorosulfonilacetato de metilo en la sulfonanilida 221 por reacción con anilina. La hidrólisis del grupo éster y posterior tratamiento con ácido polifosfórico produjo el correspondiente ácido carboxílico que cicló para producir la 1H-2,1-benzotiazin-4-ona (222). Esta cetona se trató con tosilhidrazina para obtener la tosilhidrazona 223, que por reacción de Bamford-Stevens en EtONa/EtOH se convirtió en el correspondiente sulfostirilo 224 con buenos rendimientos globales.…”

“…Página -79 -generación in situ de una metilenciclohexanona con estructura de orto-quinona. (222) El tratamiento de o-fluorbencensulfonamidas (288) con acetato de oterbutildimetilsililoxibencilo en presencia de TBAF e irradiación de microondas produjo en primer lugar la estructura o-quinoide (289) por parte del acetato de osililoxibencilo que cicla en una reacción [4+4] con el anión de la sulfonamida. El producto formado es la correpondiente benzooxosultama de 8 miembros (290) con buenos rendimientos.…”