The synthesis in Box 24.2 shows that N-alkylated analogues can be synthesized by N-alkylation directly or by a two-stage process involving N-acylation. Why might a two-stage process be preferred to direct N-alkylation? What sort of products could not be synthesized by the two-stage process? Is this likely to be a problem? BOX 24.2 Synthesis of N-alkylated morphine analogues The synthesis of N-alkylated morphine analogues is easily mide, but is now more conveniently carried out using a achieved by removing the N-methyl group from morphine to chloroformate reagent such as vinyloxycarbonyl chloride give normorphine, then alkylating the amino group with an The final alkylation step can sometimes be profitably alkyl halide. Removal of the N-methyl group was achieved replaced by a two-step process involving an acylation to give originally by a von Braun degradation with cyanogen bro- an amide, followed by reduction Me N-Me + MeOH N-H Morphine VOC-CI Normorphine R\'COC? Acid chloride R2x Alkyl Halide L?AI Ha R R3 N-R2 N-Alkylated morphine N-Acylated morphine N-Alkylated morphine Demethylation and alkylation of the basic centre. Solution N- Alkylation of amine is a nucleophilic substitution reaction. When an alkyl halide is used as an alkylating reagent, it forms alkyl carbocation intermediate which is prone to rearrangement resulting in a mixture of products. Thus the preferred method is acylation and then reduction. Primary amine alone can be synthesized by this two-step process. It will be a problem if we need to synthesize a secondary or tertiary amine. .

1. The synthesis in Box 24.2 shows that N-alkylated analogues can be synthesized by N-alkylation
directly or by a two-stage process involving N-acylation. Why might a two-stage process be
preferred to direct N-alkylation? What sort of products could not be synthesized by the two-stage
process? Is this likely to be a problem?
BOX 24.2 Synthesis of N-alkylated morphine analogues The synthesis of N-alkylated morphine
analogues is easily mide, but is now more conveniently carried out using a achieved by removing
the N-methyl group from morphine to chloroformate reagent such as vinyloxycarbonyl chloride
give normorphine, then alkylating the amino group with an The final alkylation step can
sometimes be profitably alkyl halide. Removal of the N-methyl group was achieved replaced by
a two-step process involving an acylation to give originally by a von Braun degradation with
cyanogen bro- an amide, followed by reduction Me N-Me + MeOH N-H Morphine VOC-CI
Normorphine R'COC? Acid chloride R2x Alkyl Halide L?AI Ha R R3 N-R2 N-Alkylated
morphine N-Acylated morphine N-Alkylated morphine Demethylation and alkylation of the
basic centre.
Solution
N- Alkylation of amine is a nucleophilic substitution reaction. When an alkyl halide is used as an
alkylating reagent, it forms alkyl carbocation intermediate which is prone to rearrangement
resulting in a mixture of products. Thus the preferred method is acylation and then reduction.
Primary amine alone can be synthesized by this two-step process. It will be a problem if we need
to synthesize a secondary or tertiary amine.