The Nazarov cyclization of substituted ethyl 3-(cyclohepta-1,3,5-trien-1-yl)-2-methylen-3-oxopropionates, prepared from cyclohepta-1,3,5-triene in three steps, gave solely 2,3-disubstituted 1,2,3,8-tetrahydroazulen-1-ones without any detectable formation of its double bond regioisomer.We recently reported a convenient synthesis of tetrahydroazulen-1-ones 1 which can be used as synthetic intermediates for azulenes, 2 homoazulenes, 3 bridged homotropylium cations, 4 and guaiazulene type sesquiterpenes. 5 The method involves the Nazarov cyclization 6,7 of 1-acryloylcyclohepta-1,3,5-triene, prepared from commercially available cyclohepta-1,3,5-triene in four steps, as a key step for constructing the bicyclic carbon framework. We have now extended our investigations with the aim of providing further synthetic applications for the substituted derivatives and wish to report here an efficient synthesis of 2,3-disubstituted 1,2,3,8-tetrahydroazulen-1-ones starting from cyclohepta-1,3,5-triene (Scheme).Reaction of 1-acetylcyclohepta-1,3,5-triene ( 1 ), which can be easily prepared from cyclohepta-1,3,5-triene by FriedelÐCrafts acylation, 8 with diethyl carbonate in the presence of sodium hydride gave the ester derivative 2 in 77 % yield. The Knoevenagel condensation of 2 with aryl aldehydes under the influence of piperidine and p -toluenesulfonic acid 9 gave the arylidene derivatives 3aÐd in good yields (81Ð93%). This condensation reaction gave only one of the geometrical isomers for all aldehydes used 10 and their structures were assigned by NMR analysis of long range coupling constants between carbonyl carbons and the neighboring hydrogens as shown in Figure 1. 9,10,11 The Nazarov reaction of 3aÐd was carried out in the presence of a mixture of phosphoric acid and formic acid, stannic chloride, or trimethylsilyl triflate. The reaction conditions and the results are summarized in the Table. All the reactions afforded the sole cyclization products 4aÐd in moderate to good yields. The gross structural features of 4aÐd were well characterized by their spectral data. The stereochemical relationship of two substituents in 4aÐd was determined to be anti to each other by the vicinal coupling constants between hydrogens at the 2 and 3 positions 12 and NOE experiments as shown in Figure 2. Scheme Figure 1 CÐH Long Range Coupling Constants (in Hz) of 3a Figure 2 Results of NOE Experiments of 4a Downloaded by: Chinese University of Hong Kong. Copyrighted material.
