Morpholines alkylative cyclization

Zhou et al. reported on the ring opening of A -Ts aziri-dines followed by C—N alkylative cyclization with aryl propargyl alcohols in the presence of BuOK to afford dihy-droxazine derivatives 272 in moderate-to-good yield.It was hydrogenated with TFA and EtaSiH to produce 3,5-disubstituted morpholine derivatives 273 with excellent yield and high diastereoselectivity (Scheme 40.60). 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

The Stork variation was pioneered by Stork and co-workers in 1963. It entails the reaction of pyrrolidine or morpholine enamine derived from unsymmetrical cyclohexanones with methyl vinyl ketones. The alkylation is directed to the less substituted carbon opposite to the alkylation regioisomer formed by the standard Robinson annulation conditions. Cyclization to the corresponding octalone then occurs. The morpholine enamine is less reactive than the pyrrolidine and hence pyrrolidine enamine has been mostly used for this approach. An example of such annulation is shown in the s mthesis of 8-methyl-2-oxo-A octalone (19). The pyrrolidine enamine of 2-methylcyclo-hexanone is refluxed in benzene with MVK for 24 h followed by the addition of an acetate buffer and reflux for 4 h, and after the reaction is worked up purification gives 19 in 45% yield. 

---