N-carboethoxy-N-alkyl-propargylamines react with iodine, silver tetrafluoroborate and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride to give N-alkyl-S(E)-iodomethylidene-oxazolidin-2-ones which can be converted to the corresponding Salkynylidene-oxazolidin-2-ones by palladium chloride catalyzed coupling with alkynes.
The importance of human leukocyte elastase (HLE) as an agent in a variety of disease states has stimulated interest in the design and synthesis of potent synthetic inhibitors of this enzyme2. In earlier reports3, we described the preparation of a series of ynenol-lactones (1) that were shown to be potent, mechanism based inhibitors of HLE. We were therefore interested in assessing the biological activity of a series of 3-aza-analogs of (l), the .5alkynylideneoxazolidin-Zones (2).
The synthesis of 5-alkynylidene-oxazolidin-2-one (2) is shown in Scheme I. Reaction of propargylamine (3) with ethyl chloroformate in the presence of sodium bicarbonate in chloroform at 25OC afforded the urethane (4).
Compound (4) reacted with iodine, silver tetrafluoroborate and EDCI (1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in methylene chloride at 25oc to give a mixture of two isomers ( 5) and ( 6). In all cases studied, the E-isomer (5) was formed as the major product. The Z-isomer accounted for less than 10% of the product. Compound
(5) was converted to a mixture of ( 5) and (6) (approx. 95 : 5) under the conditions employed to effect the cyclization.
To our knowledge, the halo-cyclization of propargyl carbamates is unprecedented4. In the 12/AgBF4/EDCI cyclization of (4) to (5), all three reagents are essential for optimal yields. The 12/AgBF4 pair alone gave poor yields of (5), along with other decomposition products. The EDCI serves as a water scavenger in this reaction. Other conditions such as 12,12/AgBF4/DCC, 12/EDCI also effect the halo-cyclization of (4) to ( 5), but the yield of ( 5) is slightly lower under these conditions.