The Thionium/N-Acyliminium Ion Cyclization Cascade as a Strategy for the Synthesis of Azapolycyclic Ring Systems Albert Padwa * and Alex G. Waterson Department of Chemistry, Emory University, Atlanta, GA 30322, USA Received 28 October 1999; accepted 27 January 2000 Abstract ÐA series of amidosulfoxides were prepared by the addition of thiophenol to the appropriate alkenoic acid p-bond, and this was followed by reaction of the in situ generated acyl chloride with 3,4-dimethoxyphenethyl amine. The silicon-induced Pummerer reaction of these amidosulfoxides was carried out using 1-(dimethyl-tert-butylsiloxy)-1-methoxyethylene in dry acetonitrile in the presence of a catalytic amount of ZnI 2 and led to the very clean formation of 2-thiophenyl substituted lactams. Iminium ion-aromatic p-cyclization was accomplished by treatment of the initially formed thiophenyl lactams with BF 3 ´2AcOH which resulted in the generation of an N-acyliminium ion. Cyclization of the iminium ion onto the tethered aromatic ring led to various azapolycyclic ring systems. A related cyclization sequence also occurred with amidosulfoxides that possess simple ole®nic tethers. The method was applied toward the synthesis of a member of the protoberberine alkaloid family. q 2000 Elsevier Science Ltd. All rights reserved. Nitrogen containing heterocycles are widely distributed in nature and many of these compounds display important biological activity. 1 A vast number of natural and synthetic N-heterocyclic compounds have found applications as pharmaceutical and agricultural chemicals. 2 Accordingly, novel methods of preparing N-heterocycles has attracted much interest in recent years. 3±9 A variety of synthetic methodologies have been developed and many reviews, monographs, and reports have been released. 1 Despite the wide availability of different methods, there still exists a need for developing more ef®cient procedures which allow the ready synthesis of complex azapolycyclic ring systems. In recent years, the Pummerer reaction followed by a p-cyclization has been found to be a very effective and general method for the preparation of many diverse azapoly- cyclic ring systems. 10±12 By positioning a nitrogen atom in the tether between the electrophilic thionium ion and a nucleophile p-system, the Pummerer reaction has been used to generate numerous nitrogen heterocycles. 13±19 Another exceptionally viable strategy that has also been employed to prepare a variety of ®ve and six-membered nitrogen heterocycles involves the addition of nucleophiles to N-acyliminium ions. In particular, the intramolecular reaction of cyclic N-acyliminium ions has been successfully utilized for the preparation of various azabicyclic ring systems found in natural products. 20±31 Our interest in indolizidine/quinolizidine alkaloid synthesis led us to explore the thionium/N-acyliminium ion cascade as a key strategy for the assembly of these ring systems. 32 The approach we had in mind was based on our previous success using a tandem Pummerer/Mannich cyclization sequence for synthesis of the erythrinane alkaloid skeleton. 33 We envisioned that thionium ion 2, derived from a Pummerer reaction of sulfoxide 1, would readily react with the neighboring amido nitrogen atom to provide the 2-thiophenyl substituted lactam 3 (Scheme 1). Subse- quent elimination of the thiophenyl group should ultimately lead to the azabicyclic lactam 5 via cyclization of a transient N-acyliminium ion (i.e. 4). In this paper, we report an account of our efforts dealing with this unique tandem cyclization sequence. 34 We began our investigations of the sequential Pummerer/ N-acyliminium ion cascade by ®rst examining the intra- molecular thionium ion cyclization reaction of amido- sulfoxide 8. Treatment of isatoic anhydride (6) with the anion of dimethyl sulfoxide furnished o-amino-v-methyl- sul®nylacetophenone (7). 35 Heating a sample of 7 with acetic anhydride at 808C in benzene for 12 h afforded the desired amidosulfoxide 8. 36 The Pummerer cyclization of 8!9 requires (1) an electrophile to activate the sulfoxide and to transform the oxygen into a good leaving group, (2) a general base to remove the proton, and (3) the amido nitrogen atom to preferentially attack the thionium ion inter- mediate to give the cyclized 1,2-dihydroindolone. The Pummerer reaction has been initiated with a variety of electrophilic reagents (Pummerer promoters). 37 Acetic anhydride is by far the most commonly used promoter and is often utilized as the solvent at re¯ux temperature or in combination with other solvents or cocatalysts. We found Tetrahedron 56 (2000) 10159±10173 Pergamon TETRAHEDRON 0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00861-9 Keywords: thionium/N-acyliminium; azapolycyclic ring system; Pummerer reaction. * Corresponding author. Tel.: 11-404-727-0283; fax: 11-404-727-9418; e-mail: chemap@emory.edu