Peter G. Houghton

Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677

Abstract The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.

Intramolecular reaction between nitro and carbodi-imide groups; a new synthesis of 2-arylbenzotriazoles

1-(2-Nitrophenyl)-5-phenyltetrazole (5b) decomposes when heated to give nitrogen, carbon dioxide, and 2-phenylbenzotriazole (6) in high yield. This new molecular rearrangement proceeds via 2-nitrophenyl(phenyl)carbodi-imide (8). Other precursors of this carbodi-imide, i.e. oxadiazolone (10), oxadiazolethione (11), oxathiadiazole 2-oxide (12), and the aminimide (16), and carbodi-imide itself, all give 2-phenylbenzotriazole (6) on thermolysis, the last three in high yield. This reaction is general for diarylcarbodi-imides with an ortho nitro group, and their precursors, and it provides a useful new route to 2-arylbenzotriazoles. A sequence of electrocyclic ring closing and opening reactions (Scheme 5) is proposed as the mechanism of this process. The key intermediate, 2-phenyl-1,2,4-benzotriazin-3-one 1-oxide (19), has been isolated from a careful thermolysis of (12) in toluene; in solution it is in reversible equilibrium with the ring-opened form (20). This new nitro-carbodi-imide group interaction has been extended to the more stable nitrobiphenyl(phenyl)carbodi-imide (25) and nitronaphthyl(phenyl)-carbodi-imide (24) which, on flash vacuum pyrolysis, give benzimidazo[1,2-f]phenanthridine (29) and benz[cd]indazole 1-oxide (32) respectively, in new rearrangements.

Reactions of formylchromone derivatives. Part 1. Cycloadditions to 2- and 3-(aryliminomethyl)chromones

The reactions of several 2- and 3-(aryliminomethyl)chromones with various chloroketens have been investigated. Whereas the 2-substituted chromones gave 2-(4-oxoazetidin-2-yl)chromones, the 3-substituted chromones yielded fused pyridone derivatives.

Enantiospecific synthesis of the (4R)-1-azabicyclo[2.2.1]heptane ring system

An enantioselective synthesis of (4R)-1-azabicyclo[2.2.1]heptane derivatives is described commencing from readily available trans-4-hydroxy-L-proline which is converted into the key intermediate (3R)-N-(tert-butoxycarbonyl)-3-methylsulfonyloxypyrrolidine 4. Reaction of the sulfonate ester 4 with an enolate anion yields a mixture of (3R)-pyrrolidinylacetic esters 8 and 9 which are reduced to the corresponding alcohols 10 and 11. Conversion of the alcohols into the sulfonate esters 12 and 13 followed by deprotection of the pyrrolidine nitrogen leads to cyclisation yielding the (4R)-1- azabicyclo[2.2.1 ] heptane derivatives 14 and 15.

Synthesis of 5,6-dihydro-4H-imidazo[1,5-a][4,1]benzoxazepin-6-ones and their transformation into 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-ones

Novel 5,6-dihydro-4H-imidazo[1,5-a][4,1]benzoxazepin-6-ones have been prepared from benzoxazepindiones by 1,3-dipolar cycloadditions. Ring opening of the oxygen analogues with amines, chlorination followed by base promoted recyclisation provided 5,6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepin-6-ones by a novel route.

Reactions of formylchromone derivatives. Part 2. Addition reactions of 3-(aryliminomethyl)chromones

Whereas chromones are usually cleaved by amines. 3-(aryliminomethyl)chromones undergo nucleophilic addition with aromatic primary amines to give 2-amino-3-(arylaminomethylene)chroman-4-one derivatives. The 3-(aryliminomethyl) group also facilitates addition to the system of a variety of alcohols and thiols, and certain thiol adducts can be cyclised to thiazepine derivatives. The action of manganese dioxide on 3-(aryliminomethyl)chromones leads to 3-(arylaminomethylene)chroman-2,4-diones.