Antiviral agents. I. Bicyclo[2.2.2]octan- and -oct-2-enamines

Abstract

Yol. ¡:i 1 .(i-dibi'oinohexane in 100 ml of THF maintained tinder X2 al rtz. -0°was added dropwise over 0.7.5 hr a solution of 42..5 ml of 20') PhLi solution (70:30 C«H6-Et20). The resultant solution was allowed to mine to room temperatnre over a 2l)-br period. Hit) (.70 ml) was slowly added to destroy the unreaeted PhLi.The two phases were separated, the aqueous phase was discarded and the organic phase was washed ill.(haml dried iCaChi. The solvent, was evaporated tinder reduced pressure and the residue was distilled by means of a spinning-band column. The product, bp 79-81°(0.4.5 mm) [lit.10 bp 160-161°(17 mm ij, 27 1..52.52 1..528.5, weighed 4.13 g (34' ). Anal. (( , ) Br. Method B.-Equimolar quantities of an .V-alkylaminoethyi halide hydrohalide and Xa2S2( >:1 ,5IE() in H2() or HsO-EtOH, depending on the solubility of the former reactant, were heated on a steam hath for ra. 0..5 hr. When the reaction was complete. as indicated by failure of S to precipitate from a strongly acidified aliquot, the thiosulfuric acids crystallized from the cooled and, in some instances, concentrated reaction mixtures. The .Y-alkylaminoelhaiiethiosulfuric acids which were recrystallized until they were free of halide ion showed characteristic peaks in the ir near 8.1.5, 8.40, and 9.80 µ.2-(5-PhenylpentylaminoJethanethiosulfuric Acid. T he following exemplifies the procedure used when a carboxylic acid was the precursor of the .V-alkyl group. A mixture of 100 g (0.50 mol) of 5-phenylvaleric acid and 34.3 g (0.50 molt of 2-aminoethanol was heated gently at first, followed by a gradual inn-ease in the application of heat until the temperature was maintained 1 i .1. von Braun. Her., 44, 2877 i 19 i 1 ;, at 100 200Y The H.<) which formed in the course of the reactim. was collected in a Dean-Stark trap fitted atop a Yigreaux column The mide .Y-2-hydro.xyethyl t-5-phenylvaleramide w as used n, the next step wiihont further purification.A THK solution 20u ml i of the .Y-(2-hydroxyelhyl i-.5-plienylvaleranudc wn-added over 2.5 hr to a cooled and stirred slurry of 22.s g .0 uni of . and 500 ml of THF. After the mixture was hcined under reflux for 1 1 hr, 2.50 ml of 112() was cautiously added the moled and stirred mixture to destroy excess I.AH. The AnOHi:, which formed was filtered from the mixture and washed .Ei2()j. The aqueous phase of the filtrate was ex: meted •• F.tn ) , t lie et her anti TIIF solutions were combined, and dried -MgSI>. . and the solvents were evaporated on a rolar) evaporator. The ie-idue was distilled at reduced pressure to give 52 g .50' , of 2-• 5-phenylpentylamino iethanol. Treatment of the latter with 4s' , HBr by the method of ('órlese" gave .58 g t()9', of •>-.5-1 dieiivlpentylnmiii<>iethy 1 bromide -HBr which was converted into the thiostilfuric acid bv the reaclion with Xa-S-O 511.

6-(Trifluoromethyl)-2H-pyran-2-ones: Promising CF3-bearing conjugated cyclic diene and electrophilic building-blocks

“…and diethyl malonate (the first method was described earlier: Scheme 1 [7]). It was shown that 18a reacted with diethyl malonate in MeCN in the presence of MgCl 2 / Et 3 N. After treatment of the reaction mixture with p-TsOH in toluene, CF 3 -pyrone 2 was isolated (67%) (Scheme 5) [13].…”

“…The first representative of 6-CF 3 -2-pyrones, ethyl 6-(trifluoromethyl)-2H-pyran-2-one-3-carboxylate 2, was obtained (10%) by treatment of diethyl ethoxymethylenemalonate 1 with trifluoroacetone in the presence of EtONa (Scheme 1) [7]. This reaction is the only described example when trifluoroacetone was used as an active methylene compound for the preparation of a 6-CF 3 -2-pyrone.…”

“…The first synthesis of a representative of 6-CF 3 -2-pyrones, ethyl 6-(trifluoromethyl)-2H-pyran-2-one-3-carboxylate (10%), was described in 1970 [7]. It was shown there that this 6-CF 3 -2-pyrone reacted with nonactivated alkene ethylene as a cyclic diene to give the corresponding cycloadduct [7].…”

“…The first synthesis of a representative of 6-CF 3 -2-pyrones, ethyl 6-(trifluoromethyl)-2H-pyran-2-one-3-carboxylate (10%), was described in 1970 [7]. It was shown there that this 6-CF 3 -2-pyrone reacted with nonactivated alkene ethylene as a cyclic diene to give the corresponding cycloadduct [7]. Only twelve years later, in 1982, two other representatives of 6-CF 3 -2-pyrones, 3,4-dimethyl-5,6-bis(trifluoromethyl)-2H-pyran-2-one [8] and 4-hydroxy-3-(trifluoroacetyl)-6-(trifluoromethyl)-2H-pyran-2-one [9] were described.…”

“…The main objectives of this review are integrating data on the synthesis and chemical properties of 6-CF 3 -2-pyrones, presentation of these compounds as promising CF 3 (trifluoromethyl)-2H-pyran-2-one-3-carboxylate [7], which was synthesized as the first representative of 6-CF 3 -2-pyrones.…”