The Formation of Spiro-β-lactams and Amides from Reaction of Cyclic Ketenes with Imines

Abstract

Spiro-β-lactams are interesting compounds due to their antiviral, and antibacterial properties, ability to inhibit cholesterol absorption, and the enzymes responsible for the cleavage of the amyloid precursor protein. Most synthetic efforts to form spiro-β-lactams utilize cycloaddition reactions. The cycloaddition usually uses ketene-imine. In this paper, we present a novel synthesis of spiro-βlactam derivatives 3 and amide derivatives 4, from cyclic acid chloride 1 with imine 2 (Scheme 1). We will describe the effects which govern selectivity in the formation of 3 and 4, and show that the size of the ring in 1 has the largest influence in this process. The spiro-β-lactams 6 and 8 were prepared by reaction of either cycloheptyl acid chloride 5 or cyclohexyl acid chloride 7 with imine 2, respectively (Scheme 2). In a typical procedure, the acid chloride was added to a stirred, refluxing solution of the imine and triethylamine in toluene. After refluxing the solution overnight and an aqueous work-up, spiro-β-lactams 6 and 8 were obtained in moderate yields and trash amount of side products were detected in TLC. The spiro-β-lactams 6 and 8 are the expected products of the [2+2] cycloadition reaction of imine 2 with the cyclic ketenes intermediate. We next examined the formation of spiro-β-lactams 10, from the reaction of cyclopentyl acid chloride 9 and imine 2. Under the same reaction conditions described above, spiroβ-lactams 10 was obtained in 55% yield and small amount of side products were observed in TLC. On the other hand, the amide 11 was obtained when the reaction was performed