Richard C. Storr

The generation of 2,3-dihydro-2,3-bis-(methylene)thiophenes from 4,6-dihydrothieno[3,4-b]thiophene 5,5-dioxides

Abstract On heating in sulpholane 4,6-dihydrothieno[3,4-b]thiophene 5,5-dioxides give 2,3-dihydro-2,3-bis(methylene)thiophenes which can be intercepted in Diels-Alder reactions. Sulphur dioxide is a very efficient trap for these thiophene xylylenes giving the cyclic sulphones by cheletropic addition.

Generation and reactions of 2,3-dihydro-2,3-bis-(methylene)thiophenes

Abstract 2,3-Dihydro-2,3- bis -(methylene)thiophene and its benzo derivative, generated flash-pyrolytically, polymerise or are trapped with HCl and PhSH but only the latter gives Diels-Alder adducts; electrocyclisation of the 3-phenylmethylene derivative is accompanied by skeletal rearrangement to give naphtho[1,2- b ]thiophene.

Heterocyclic fused 2,5-dihydrothiophene S,S-dioxides as precursors to heterocyclic o-quinodimethanes☆

2,5-Dihydrothiophene 5,5-dioxides 8 and 6 have been obtained by interception of flash-pyrolytically produced 2,3-dihydro-2,3-bis(methylene)thiophene with sulfur dioxide and from methyl 4,5-bischloromethylthiophene-2-carboxylate by reaction with sodium sulfide and oxidation. Pyrazole fused analogues 15 and 16 (R = Me and COPh) were prepared from 3-phenylsulfonyl-2,5-dihydrothiophene S,S-dioxide by cycloaddition of diazomethane, base induced aromatisation and N-substitution of the sulfone 14. Reaction of 3-acetyl-4-phenylthio-2,5-dihydrothiophene S,S-dioxide with hydrazine and interception of 1-methyl-4,5-dihydrobis(methylene)pyrazole also gave pyrazole fused sulfones. On heating at 200°C, the heterocyclic fused sulfones underwent extrusion of sulfur dioxide and the resulting heterocyclic o-quinodimethanes were trapped with a range of dienophiles.

A CARBONYL OXIDE ROUTE TO ANTIMALARIAL YINGZHAOSU A ANALOGUES : SYNTHESIS AND ANTIMALARIAL ACTIVITY

Abstract Ozonolysis of R-carvone and in situ trapping with primary alcohols ROH (R= Me, Et, Bu, Pent, Oct) produces hydroperoxy ketals (5a-e) as a 1:1 mixture of diastereomers. Cyclisation of these intermediates with catalytic sodium methoxide in methanol produces the corresponding endoperoxide derivatives (6a-6e). The pentyl and octyl endoperoxide derivatives demonstrate reasonable antimalarial potency in vitro against the HB3 strain of Plasmodium falciparum . A mechanism for antimalarial action involving the formation of a C-centred radical is proposed.

Generation and reactions of azaxylylenes

Abstract Azaxylylenes produced by flash vacuum pyrolysis of 2-aminobenzyl alcohols, dihydrobenzoxazinones and dihydrobenzoxazines undergo intramolecular cyclisation, H-shifts or Diels-Alder reactions, depending on their substituents.

Heterocyclic o-xylylenes: Thiazole, oxazole and imidazole analogues

Abstract Oxazole, thiazole and imidazole analogues of o-xylylene have been generated flash pyrolytically and trapped with thiophenol and sulphur dioxide and in the case of the oxazole derivative with methyl acrylate.

Pyrimidine ortho-quinodimethanes

Abstract The pyrimidine sulfones 10 , R = Me; Nu = OMe, NEt 2 , SPh, H and 11 , R = Ph; Nu = OMe were synthesised from the dihydrothienopyrimidones 7 , R = Me, Ph by conversion to the chloro derivatives 8 followed by oxidation with mCPBA and reaction with the appropriate nucleophile or hydrogen and Pd. Heating of the sulfones in 1,2,4-trichlorobenzene gave the pyrimidine o -quinodimethanes which were intercepted in Diels-Alder reactions to give tetrahydroquinazolines.

The biomimetic iron-mediated degradation of arteflene (Ro-42-1611),an endoperoxide antimalarial: Implications for the mechanism of antimalarial activity

Abstract Arteflene 4 reacts with FeCl 2 .4H 2 O in acetonitrile or with hemin / N-acetylcysteine (heme Fe(II)) in acetonitrile to produce the diol 5 and the enone 6 . Treatment of arteflene with Zn AcOH , a model of NADH dehydrogenase, results in the formation of the diol 5 in 80% yield. The formation of the enone 6 indicates that arteflene fragments to a non-stabilised carbon-centred radical. This radical intermediate is proposed to mediate the potent antimalarial activity of 4 .

Generation and trapping of 5,6-dimethylenepyrimidin-4-ones in Diels-Alder and Michael additions

Abstract Pyrimidone fused sulfones 5 – 7 were obtained from the reaction of amidines with 3-methoxycarbonyl-4- oxotetrahydrothiophene followed by N-methylation and oxidation with mCPBA. On heating in solution at 150°C, extrusion of SO 2 occured to give the highly reactive 5,6-dimethylenepyrimidin-4-ones which were intercepted in situ in Diels-Alder reactions to give the adducts 24 – 28 and in conjugate addition reactions with thiol nucleophiles to give the thioethers 29 and 30 .

Synthesis of the 8-aminoquinoline antimalarial 5-fluoroprimaquine

Several approaches to the synthesis of 5-fluoro-6-methoxy-8-nitroquinoline 5, the key intermediate required for the synthesis of 5-fluoroprimaquine, were investigated. In one approach, 5-chloro-6-methoxy-8-nitroquinoline was synthesised and treated with a variety of nucleophilic sources of fluoride. In another approach, electrophilic substitution of 6-methoxy-8-nitroquinoline with (N-fluorosulfonimide, NFSI) was investigated. The final approach to 5 involved a modified Skraup reaction of 5-fluoro-4-methoxy-2-nitroaniline which gave the required intermediate in 30% yield.