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Novel halogenated chrysanthemic acid analogues have been prepared and the interesting properties of their esters are described. Among this group are the most active insecticides yet reported.

The preparation and stereochemical characterization of alpha- and beta-isomers of 1,2-dimethyl-4-m-hydroxyphenyl-4-propionyloxypiperidine are described. Both the alpha (axial 4-aryl/chair) and beta (equatorial 4-aryl/chair) isomers were of low potency or inactive in mice antinociceptive tests. Shortcomings of the alpha-isomer as a model for the 4-arylpiperidine moiety of morphine are discussed.

The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3 alpha-m-hydroxyphenyl chair conformations, is described. The former were secured from tropan-3-one in a sequence of reactions involving cyanide attack, hydrolysis, Grignard attack and then rearrangements. The reversed ester was obtained by treating tropan-3-one with lithium phenyl, followed by acylation. Configurational and conformational assignments follow from NMR analysis. The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine.

The stereochemistry of diastereoisomeric propionyl esters of 4-(2-furyl)-3-methyl-l-phenethylpiperidin-4-ols has been established by "C N M R analysis. Both isomers, after acid-catalysed ethanolysis, are converted to the corresponding 4-ethoxy derivative of configuration (t-3-Me, rc4-0Et) that correlates with its analgesic properties.In 1961, the easy conversion of the propionyl esters of 4-(2-furyl)-l-phenethylpiperidin-4-0ls (1) to the corresponding 4-alkoxy derivatives (2) by alkyl-oxygen2b R = H , R'=Et 2c R=Me. R = E t heterolysis was reported.' The 4-ethoxy ether derived from the 3-methyl ester l b proved to be a potent narcotic analgesic (1.2-2.5 times more active than morphine in mice).' As the stereochemical course of these reactions was unestablished in the original work, and in view of the critical influence of molecular geometry on interactions of opiate ligands with their receptor^,^ information of this type has now been obtained by a 13C NMR study. Reference compounds that lacked methyl substituents at C-3 of the piperidine ring were required.The ester l a was obtained as the hydrochloride salt by careful neutralization of the product of reaction of the lithium salt of 4-(2-furyl)-l-phenethylpiperidin-4-01 and propionic anhydride. The ether salts 2a and 2b separated when the ester hydrochloride l a was treated with excess of methanol-HC1 and ethanol-HC1, respectively. 13C NMR features of these compounds are given in Table 1 (entries 1-3), the conventional labelling system for the piperidine ring being employed (see 1). Assignments are based on comparisons with model compounds, established chemical shift parameters and off -resonance decoupled spectra as in related Evidence for replacement of acyloxy by alkoxy is * Author to whom correspondence should be addressed.provided by the upfield shifts of the C-4 resonances (removal of the acyl function of esters of 4-aryl-4-piperidino14" and 1-methylcycl~hexanols~ shifts the C-4 resonance upfield by about 10 ppm, cf. C-4 shifts of entries 1 and 4) and downfield shifts of saturated carbons attached to the C-4 function in products isolated from acidic media. The 13C NMR spectrum of the total base derived from treating 3-methyl-lphenethyl-4-piperidone first with 2-furyllithium and then propionic anhydride displayed multiple signals typical of a mixture. Fractional crystallization of the base after neutralization with ethanol-HC1 yielded first a hydrochloride identical (m.p., mixed m.p.) with that of the original report and designated the 0-form (see below), while later crops provided the second ( a -) diastereoisomer. 13C NMR comparisons showed the two esters to be the main components of the total base, with the a-isomer in slight excess, as judged by the relative intensities of C-3' and C-5 resonances and 0 (t-3-Me, r -0 ) of the diastereoisomers (see A) follows from the relative C-5 (0 27.8, a 31.8, l a 34