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5,11,17,23-Tetrabromo-25,26,27,28-tetrahydroxycalix[4]-arene (31). A solution of 0.5 g of 5,11,17,23-tetrabromo-25,26,27,28-tetramethoxycalix[4]arene (15) in 40 mL of benzene was treated dropwise with 15 mL of BBr?' in CH2C12, and the mixture was stirred at r c " temperature for 18 h in an atmosphere protected from moisture. The reaction mixture was poured into 100 mL of H20, stirred for 1.25 h, and the organic layer was evaporated and triturated with acetone to leave 0.39 g (84%) of a white powder. Crystallization from pyridine/toluene yielded a yellow powder as the first fraction and a white powder as the second fraction: mp >480 "C; IR (KBr) 3135 cm-' (OH stretching); 'H NMR (pyridine-d,) b 9.72 (s, 4, OH), 7.25 (s, 8, Ar H), 4.0 (br (37) Tashiro, M.; Yoshiya, H.; Fukatas, G.Methods for the preparation of a variety of para-substituted calix[4]arenes via the Claisen rearrangement route are described. Starting with the readily available p-tert-butylcalix[4]arene 1, the tert-butyl groups are removed by an AlCl,-catalyzed retro-Friedel-Crafts reaction, and the calix[4]arene 2 that is formed is converted to the tetraallyl ether 3. This compound undergoes a heat-induced Claisen rearrangement to yield p-allylcalix[4]arene 4, which is a useful starting material for the introduction of functional groups. Along one route, the tosylate of 4 is ozonized to the aldehyde 7, the aldehyde is reduced to the alcohol 8, the alcohol is converted to the bromide 10 and then to the azide 11, and the azide is reduced with diborane to p-(2-aminoethyl)calix[4]arene 12, a compound of interest as a chelating species. Along a second route, the tosylate of 4 is rearranged to p-(l-propenyl)calix[4]arene 16 and ozonized to p-formylcalix[4]arene 17 from which the oxime 18 can be prepared.

Described are studies directed toward the chemical research and development of an alternative synthesis to 9, the penultimate intermediate of clofencet (1), a novel wheat-hybridizing agent. Retrosynthetic analyses as well as the results obtained from feasibility studies are detailed, leading to the successful development of an alternative process. The key features of the novel route are a method for preparing on-scale ethyl diazoacetate (28) in a safe and effective manner, and the Lewis acidcatalyzed reaction of 28 with hydrazonoacetaldehyde 29, affording β-ketoester 30. The synthesis is completed via propionylation of 30, acid-catalyzed cyclization of 31 to pyridazinecarboxylic acid ester 32, followed by saponification and isolation of carboxylic acid 9. The results and challenges of eight pilot-plant runs are reported. The baseline process developed produced over 45 kg of 9 in 43-45% yield.

A series of gamma-butyrolactones and gamma-thiobutyrolactones possessing a variety of alkyl groups and alkyl-substitution patterns was prepared and evaluated for anticonvulsant and convulsant activity. Behavioral studies performed on these compounds suggest that maximal anticonvulsant activity (against maximal electroshock and pentylenetetrazol) results when three or four carbon atoms are present at the alpha-position. For convulsant potency, a similar dependence on the size of the alkyl chain at the beta-position was observed. Additional gamma-dimethyl groups were found to increase the convulsant potency of a beta-substituted compound and to cause an alpha-substituted anticonvulsant to become a convulsant. In general, sulfur for oxygen heteroatom substitution in the alpha-substituted lactones resulted in improved anticonvulsant potency and spectrum of activity. Binding of these compounds to the picrotoxin site of the GABA receptor complex was demonstrated with a [35S]-tert-butylbicyclophosphorothionate radioligand binding assay. Measurements of brain concentrations for selected compounds supports a hypothesis that correlates binding to the picrotoxin site with the pharmacological effects of these compounds.