Philip E. Brown

Studies of chromenes. Part 4. Oxidation of hexahydro-5H-chromeno[3,4-c]-pyridazines and conformational isomerism in tetra-and hexa-hydro-N,N′-dialkoxycarbonyl-5H-chromeno[3,4-c]pyridazines

3,4-Bis(t-butoxycarbonyl)- and 3,4-bis(methoxycarbpnyl)-8-methoxy-5,5-dimethyl-2,3,4,4a-tetra-hydro-5H-chromeno[3,4-c]pyridazines and their 2,2-dimethyl analogues were hydrogenated to give hexahydrochromenopyridazines possessing only a trans-ring junction. Removal of the t-butoxy-carbonyl groups from the trans-products afforded the corresponding 1,2,3,4,4a,10b-hexahydro-5H-chromeno[3,4-c]pyridazines which were oxidised first to 1,2,3,10b-tetrahydro- and then 1,2-dihydro-5H-chromenopyridazines. The last-named dihydro compounds possess an unusual [3,4]pyridazine hydrogenation pattern. The dialkoxycarbonyl derivatives of both the tetra- and hexahydrochromenopyridazines exist as pairs of conformational isomers whose interconversion is acid catalysed. The isomerism is considered to be due to restricted rotation about the less hindered N(3)–CO bond, the N(4)–CO bond being locked in one conformation by 1,3 interactions.

Studies of chromenes. Part 10. Oxiranes of nitrochromenes

Syntheses of stable oxiranes of 5- and 7-nitro-, and 5,7-dinitro- 2,2-dimethyl(chromenes and of 7–2H-ethoxycarbonylamino)-2,2-dimethyl-5-nitro-2H-chromene are described. Thermal cyclisation of the precursor phenyl prop-2-ynyl ethers proceeds in good yield but in the case of the dinitrophenyl ether the products are highly solvent dependent. The compounds are of interest as possible antitumour alkylating agents that are activated by bioreduction to extremely reactive oxiranes.

Analogues of antijuvenile hormones

Several analogues of precocenes I and II have been synthesized, including derivatives of 6,7-dihydroxy-2,2-dimethylchromen, 7,8-dihydroxy-2,2-dimethylchromen, 7-hydroxy-2,2-dimethyl-6-nitrochromen, and 6-amino-7-hydroxy-2,2-dimethylchromen. 5,6-Dimethoxy-3,3-dimethylindene was also synthesized. Improved procedures for the dehydration of chroman-4-ols to chromens and for the reduction of chroman-4-ones to chroman-4-ols are reported. Analogues have been tested for activity in the brown planthopper Nilaparvatus lugens Stal. None had significant morphogenetic effects, but two possessed insecticidal activity and showed both antagonism and synergism when used in conjunction with permethrin.

Studies of chromenes. Part 11. 3-Substitution of 7-methoxy-2,2-dimethylchroman-4-one without ring opening via 3-bromination

3-Bromination of 7-methoxy-2,2-dimethylchroman-4-one 3a stabilises the anion 2a obtained on deprotonation with LDA sufficiently for 3-alkylation to take place without the usual ring-opening. Methylation in the presence of copper(I) bromide results in 3,3-dimethylation in good yield.

Studies of chromenes. Part 5. Reaction of the Vilsmeier reagent with 7-methoxy-2,2-dimethylchroman-4-ones. 4-Chloro-7-methoxy-2,2-dimethyl-2H-chromenes and their nitration products.

Action of the Vilsmeier reagent on 7-methoxy-2,2-dimethylchroman-4-one and its 6-bromo and 6-methoxy analogues gave low yields of 4-chlorochromene-3-carbaldehydes. 4-Chloro-2H-chromenes, which are not precursors of the carbaldehydes, were obtained in high yields. 4-Chloro-7-methoxy-2,2-dimethyl-6-nitrochroman was too labile to allow a dehydrogenation to the 6-nitrochlorochromene but the latter was obtained by regioselective nitration of 4-chloro-7-methoxy-2,2-dimethyl-2H-chromene. 6-Amino-7-methoxy-2,2-dimethylchroman-4-one, protected as the N-ethoxycarbonyl derivative, gave the 6-aminochlorochromene. The 6-amino-5-chloro analogue largely underwent N-formylation. The chlorochromenes have potential synthetic value since those without electron-withdrawing substituents are readily hydrolysed back to the chroman-4-one.

Studies of chromens. Part 2. Synthesis of 7-methoxy-2,2-dimethylchromen-3-carboxylic acid

The preparation of the title compound (1a) is described. Effects of C-2 methyl groups on ring opening and alkylation of chroman-4-ones under basic conditions are discussed. The reaction of hydrazine with 3-ethoxycarbonyl-7-methoxy-2,2-dimethylchromen (1d) and 3-ethoxycarbonyl-7-methoxy-2,2-dimethylchroman-4-one (3f) failed to give the pyrazolidinone or pyrazolinone.

Studies of chromenes. Part 9. Syntheses of chromenequinones

Syntheses of 2,2-dimethylchromene-5,8-quinone, 2,2-dimethylchromene-6,7-quinone, and 6,7-dimethoxy-2,2-dimethylchromene-5,8-quinone are described. Being easily bioreducible to electron-rich chromenes these compounds, and their oxirane derivatives, are of interest as possible anti-tumour alkylating agents.

Studies of chromenes. Part 8. Addition versus rearrangement in silver ion-assisted solvolyses of trihalogenocyclopropa[c]chromenes

Silver ion-assisted solvolysis of the trichlorocyclopropa[c]chromene (1) at 80 °C proceeds by addition to give the 3-dichloromethylenechroman-4-one (2). At higher temperatures solvolysis involves cyclopropyl-allyl rearrangement and yields derivatives of the 4-dichloromethylenechroman-3-ol. The 7b-bromo-1,1-dichlorocyclopropa[c]chromene (9) reacts by rearrangement even at 80 °C.

Studies of chromens. Part 3. Routes to 2,2-dimethylchroman-3-ones and 4-ethyoxycarbonyl-2,2-dimethylchromens. Synthesis of a stable chromenopyrazolinone

2,2-Dimethyl-3,4-epoxychroman (6a) was converted into 2,2-dimethylchroman-3-one which readily underwent ethoxycarbonylation to 4-ethoxycarbonyl-2,2-dimethylchroman-3-one (5c). The derived 4-ethoxycarbonyl-2,2-dimethylchromen (1b) reacted with hydrazine to give the pyrazolidinone (4a), oxidation of which gave the stable pyrazolinone (11). Lead tetra-acetate acetoxylation of 7-methoxy-2,2-dimethylchroman-4-one, followed by metal hydride reduction, afforded the 3,4-diol as a mixture of isomers. The relative proportions of cis and trans isomers could be varied from 1:1 to 5:1, respectively, by the choice of reducing conditions. Acid-catalysed dehydration of the diol mixture gave 7-methoxy-2,2-dimethylchroman-3-one (5b). This was unstable and could not be ethoxycarbonylated, but 4-ethoxycarbonyl-7-methoxy-2,2-dimethylchroman-3-one (5d)/(1j) was obtained by a standard synthesis.