5-Acyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and the homologous pyridine and azepine derivatives were synthesized and assayed for antiinflammatory and analgesic activity. 5-Benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid and the corresponding p-methoxy compound 74 were selected for evaluation as analgesic agents in humans on the basis of their high potency in the mouse phenylquinone writhing assay as well as on their minimal liability to elicit gastrointestinal erosion in rats on chronic administration. Extensive quantitative structure-activity relationship (QSAR) studies of the benzoylpyrrolopyrrolecarboxylic acids have demonstrated that the analgesic (mouse writhing) and antiinflammatory (rat carrageenan paw) potencies of these compounds are satisfactorily correlated with the steric and hydrogen-bonding properties of the benzoyl substituent(s). The 4-vinylbenzoyl compound 95, which was correctly predicted to be highly active in both assays on this basis, is undergoing advanced pharmacological evaluation in animals as a potential antiinflammatory agent.
. Can. J. Chem. 60,2295Chem. 60, (1982. Several syntheses of the previously unknown 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid and various 5-and 6-substituted derivatives thereof have been devised. Some of these processes have been extended to the heretofore unreported 5,6,7,8-tetrahydropyrrolo[l,2-a]pyridine-8-carboxylic acid and 5,6,7,8-tetrahydro-9H-pyrrolo[l,2-a]azepine-9-carboxylic acid derivatives.Two new processes were developed for the conversion of pyrroles into the corresponding pyrrol-2-acetic acid esters. Both processes were based on the use of the readily available ethoxalylpyrrole derivatives as the starting material. One sequence involved saponification of the a-keto ester, followed by Wolff-Kishner reduction of the crude a-keto acid salt and subsequent esterification of the acetic acid derivative thus produced. The second synthesis commenced with reduction of the 2-ethoxalpyrrole with sodium borohydride to the a-hydroxy ester, which was further reduced to the acetic acid ester with an equimolar mixture of triphenylphosphine and triphenylphosphine diiodide.
Parallel reaction conditions employing tetrabutylammonium iodide (19.4 g, 52.5 mmol, Aldrich) as the halide source for 16 h afforded the l-iodo-4-pentanol (3)5 in 32% yield after chromatography (silica gel, eluted with ether). Standard treatment of this alcohol (16 h, 21 °C) with acetic anhydride (15 mL) and pyridine (3 mL) with a catalytic amount of 4-(dimethylamino)pyridine (15 mg) afforded the acetate 4; 3.26 g (80%); IR (film) 1735 (0=0) cm'1; NMR (CDC13) 1.20 (d, 3 H, J = 6 Hz, CflgCHOAc), 1.35-2.05 (m, 4 H, CH2CH2), 2.05 (s, 3 H, CH3C=0), 3.21 (t, 2 H, J = 7 Hz, CH2I), 4.85 (m, 1 H, HCOAc).Reactioin of 2-methyltetrahydrofuran with anhydrous lithium bromide and boron trifluoride etherate in dichloromethane for 44 h gave 5 and 8 in approximately equal amounts on the basis of the integration of the methyl doublets at 1.29 and 1.40 in the NMR spectrum.1 -Acetoxy-4-bromopentane (9). Acetyl bromide (12.3 g, 100 mmol) in a pressure-equalizing dropping funnel was added dropwise over 20 min to a solution of 2-methyltetrahydrofuran (10.3 g, 120 mmol) containing zinc chloride (4 mg) maintained at 0 °C by an external ice bath. After addition was complete the ice bath was removed, the reaction stirred at 21 °C for 0.5 h and refluxed for 2.5 h. The reaction mixture was cooled, diluted with ether (130 mL), washed with 5% aqueous sodium bicarbonate solution, water, and brine, dried and the product purified by distillation to give 9: 19.6 g (93%); bp 65-68 °C (2.5 mm) [lit.12 bp 60 °C (0.01 mm)]; NMR (CDC13) 1.73 (d, 3 H, J = 6 Hz, CtfgCHBr), 1.7-1.9 (m, 4 H, CH2CH2), 2.00 (s, 3 H, CH3OC=0), 4.01 (m, 3 H, CHBr, CH2OAc). A weak doublet at 1.23 indicated the presence of ~10% of the positional isomer 6.
NOR 88CFurazan N-oxides with a strained ring bridging the 3and 4-positions are progressively deoxygenated by trialkyl phosphites, forming furazans, which can in some cases be isolated, and dinitriles. Heating in the presence of an acetylene forms bis(nitrile oxide) adducts (isoxazoles). with the more highly-strained types.IT has been known for many years that it is difficult to prepare the furazan or furazan N-oxide ring system directly fused to another five-membered ring. In his definitive re vie^,^ Boyer pointed out that only two examples were known in the furazan N-oxide (furoxan) series [(la) or (lb)4 and (3) 5], and one in the furazan series (4).6 Since then, a few ring-D-fused steroidal furoxans have been reported.'We undertook an investigation into strained furazan N-oxides, in order to confirm that ring strain is re-1 Earlier papers on this topic have appeared under the broader heading of ' N-Oxides and Related Compounds ' (see, e.g., Part XXXVI, ref. 15 below).
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