A Sequential Pummerer−Diels−Alder Route for the Generation and Trapping of Furo[3,4-c]pyridines:  Synthesis of Heterocyclic Analogues of 1-Arylnaphthalene Lignans

• Published in: Journal of organic chemistry 2003-09, Vol.68 (18), p.6919-6927
• Main Authors: Sarkar, Tarun K, Panda, Niranjan, Basak, Sankar
• Format: Article
• Language: English
• Subjects: Chemistry; Crystallography, X-Ray; Exact sciences and technology; Heterocyclic compounds; Heterocyclic Compounds - chemical synthesis; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indicators and Reagents; Lignans - chemical synthesis; Magnetic Resonance Spectroscopy; Naphthalenes - chemical synthesis; Organic chemistry; Preparations and properties; Pyridines - chemistry; Spectrophotometry, Infrared; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0344081

The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an α-thiocarbocation, the interception of which by a neighboring keto functionality produces an α-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels−Alder cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and the entire sequence can be run in one pot. The facility of the sequential Pummerer−Diels−Alder reaction hinges on the experimental conditions, the best results being obtained with heptafluorobutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer−Diels−Alder reaction is further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration of the resulting hydoxylated isoquinoline derivative.