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Experimental Section l,3,octan-5-one (9). Piperitenone (7) was prepared by the method of Beerebom9 from 178 g of methyl vinyl ketone and 686 g of mesityl oxide, giving 112 g of crude petroleum [90-125 °C bp (10 mm)], which was stirred with 28% aqueous ammonium hydroxide for 120 h at room temperature, saturated with sodium chloride, extracted in ether, extracted with 3 M HC1, dried, and concentrated to a 22% yield (based on MVK) of ca. 90% pure 8. Pulverized 85% potassium hydroxide (20 g) was dissolved in 200 mL of diethylene glycol by heating to 70 °C, and after the solution cooled to 35 °C, 14 g of hydrazine hydrate and 14 g of crude 8 were added. The solution was heated at 230 °C for 3 h and while the distillate produced was collected and cooled to room temperature. After addition of 250 mL of water, the pot solution was extracted three times (9) Beerebom,

A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.

2‐Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2‐a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.

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