H2O2. Our retro-synthetic analysis of EPM (74) is shown in Scheme 109. This approach involves first synthesising the pre-cursor from cheap, readily (97) N-allylmaleimide available, maleic anhydride (45) and (256), before subsequent epoxidation of N-allylamine the allyl group using a suitable oxidising agent. Scheme 109: The retro-synthetic analysis of EPM (74) from cheap, readily available starting materials maleic anhydride and (45) (256). N-allylamine Literature Methods for the Synthesis of (97) N-Allylmaleimide The traditional method for the synthesis of maleimides is to first generate the N-substituted maleamic acid derivative from maleic anhydride (45) and a suitable primary amine, before closing the 5-membered ring through heating. For example, this method was used by Jones and co-workers in 2011, whereby they prepared (97) in 31% yield N-allylmaleimide (Scheme 110); compound 97 was subsequently used as a substrate in their efforts to investigate stereoselective intermolecular Friedel-Crafts reactions.154 The low yield of (97) achieved using this procedure can be attributed to the sensitivity of the allyl group to the harsh acidic conditions required for the 5-exo-trig cyclisation. Scheme 110: The synthesis of (97), as reported by Jones and N-allylmaleimide In a 1992 paper,155 Braish and Fox reported another route towards the synthesis of maleimides, which involved the use of inexpensive reagents and mild reaction conditions to afford the maleimide products in good yields. This method also involves the reaction of maleic anhydride (45) with a suitable primary amine, to form the maleamic acid in quantitative yield (Scheme 111). A subsequent reaction using oxalyl chloride (257) and DMF (258) affords a chlorinated-succinimide intermediate, which was transformed into the maleimide product upon treatment with triethylamine (157). Yield of Maleimide R Product / % -CH2CH=CH2 (97) 68
H2O2. Our retro-synthetic analysis of EPM (74) is shown in Scheme 109. This approach involves first synthesising the N-allylmaleimide (97) pre-cursor from cheap, readily available, maleic anhydride (45) and N-allylamine (256), before subsequent epoxidation of the allyl group using a suitable oxidising agent. Scheme 109: The retro-synthetic analysis of EPM (74) from cheap, readily available starting materials maleic anhydride (45) and N-allylamine (256). Literature Methods for the Synthesis of N-Allylmaleimide (97) The traditional method for the synthesis of N-substituted maleimides is to first generate the maleamic acid derivative from maleic anhydride (45) and a suitable primary amine, before closing the 5-membered ring through heating. For example, this method was used by Jones and co-workers in 2011, whereby they prepared N-allylmaleimide (97) in 31% yield (Scheme 110); compound 97 was subsequently used as a substrate in their efforts to investigate stereoselective intermolecular Friedel-Crafts reactions.154 The low yield of (97) achieved using this procedure can be attributed to the sensitivity of the allyl group to the harsh acidic conditions required for the 5-exo-trig cyclisation. Scheme 110: The synthesis of N-allylmaleimide (97), as reported by Jones and In a 1992 paper,155 Braish and Fox reported another route towards the synthesis of maleimides, which involved the use of inexpensive reagents and mild reaction conditions to afford the maleimide products in good yields. This method also involves the reaction of maleic anhydride (45) with a suitable primary amine, to form the maleamic acid in quantitative yield (Scheme 111). A subsequent reaction using oxalyl chloride (257) and DMF (258) affords a chlorinated-succinimide intermediate, which was transformed into the maleimide product upon treatment with triethylamine (157). R Yield of Maleimide Product / % -CH2CH=CH2 (97) 68
PhD_Thesis_4-10-12.docx