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Exhaustive direct fluorination of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate leads to dimethyl pentafluorobicyclo[1.1.1]pentane-1,3-dicarboxylate (2) and hexafluorobicyclo[1.1.1]pentane-1,3-dicarboxylate (3). The latter was hydrolyzed to the diacid (4) and converted to the 1,3-dibromo and 1,3-diiodo analogues (5 and 6) by the Hunsdieker reaction followed by treatment with SmI2. Na/NH3 reduction of the disodium salt 10 causes cage C−C bond cleavage. Single-crystal X-ray diffraction analysis of 3 revealed very short nonbonded F−F separations of 2.41 Å and an interbridgehead distance of 1.979 Å, long compared with 1.875 Å in 1,3-diacetylbicyclo[1.1.1]pentane [19; cf. 1.954 Å calculated (MP2/6-31G*) for 2,2,4,4,5,5-hexafluorobicyclo[1.1.1]pentane (13)]. Calculation suggests a strain energy of 101 kcal/mol (MP2/6-31G*) for the hexafluorinated cage, compared with 68 kcal/mol for the parent bicyclo[1.1.1]pentane (20). The remarkably low pK a values of 4 [0.73 and 1.34; cf. 3.22 and 4.26 for the parent diacid 24] originate in a direct field effect of fluorine atoms, combined with an increased s character of the exocyclic hybrid orbital on the bridgehead carbon in 4 (calculated 34% in 13) relative to 24 (calculated 30% in 20). Analysis of the strongly coupled nuclear spin systems of 2 and 3, based on a combination of two-dimensional NMR, spectral simulations, and GIAO-HF/6-31G* calculations of chemical shifts, revealed large and stereospecific long-range 1H−13C, 1H−19F, 13C−19F, and 19F−19F spin−spin coupling constants.

A series of isosteres of 3-benzoyltrifluoromethanesulfonanilide involving alternatives to the carbonyl linking group was synthesized and screened for antiinflammatory activity in the carrageenan rat paw edema test. The systems examined were of the type m-CF3SO2NH-C6H4-X-C6H5, where X was -CROH-, -CHR-, -CH(OH)CH2-, -COCH2-, -CH2CO-, greater than C equal to CR2, -CR equal to CH, -C identical to C-, -CH2CH2-, CONH-, -NR-, -O-, -S(O)n- (n equal to 0,1,2), and carbon-carbon single bond. Many ortho and para derivatives were also tested. Several of these new trifluoromethanesulfonanilides proved equipotent with phenylbutazone. The effects on the anticarrageenan activity of both the nature and ring position of X are discussed.

R-830, a di-tert-butylphenol, has been shown to be anti-inflammatory in a number of animal models. These include conventional systems such as carrageenan-induced edema and adjuvant arthritis of the rat and ultraviolet-induced erythema in the guinea pig in which the acidic nonsteroidal anti-inflammatory drugs (e.g., indomethacin) are effective. The anti-inflammatory activity of R-830 has also been demonstrated in other models (e.g., graft vs. host reaction and reversed passive cutaneous Arthus reaction in the rat, contact sensitivity in the mouse) in which the acidic nonsteroidal drugs are not effective. In vitro, R-830 inhibits guinea pig lung lipoxygenase and bovine seminal vesicle cyclo-oxygenase. The antioxidant properties of R-830 were demonstrated in two in vitro systems. We speculate that the antioxidant activity of this molecule might be related to its unusual profile of pharmacological activity.

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