trans-2-Acetamidocyclohexanol (1; n = 2, R = CH,) on addition to thionyl chloride in chloroform at 0" was converted rapidly and quantitatively to D,L-2-methyl-4,5-cis-cyclohexanooxazoline hydrochloride (2; n = 2, R = CH,) judging from shifts in the methyl proton resonances of the n.m.r. spectra of the amide and the reaction solution. The intermediate chlorosulfinate was estimated to have a half-life of less than 2.25 min. The oxazoline salt was isolated in 98% yield by sublimation of the crude product in vacuo and was identified by its i.r. and n.m.r. spectra and by its facile and almost quantitative hydrolysis to cis-2-aminocyclohexanol hydrochloride. The oxazoline salts 2 (n = 1, R = CH3, C6H4-pN02 and n = 2, R = C6H5, C6H4-pNO2) were readily obtained in 95% yield or better by the same general method and it was shown that the trans-2-acetamidocyclanols are the preferred starting materials for conversion to cis-2-aminocyclanol derivatives by the thionyl chloride inversion reaction. The oxazoline bases 4 (n = 1, R = CH,, C6H4-pN02 and n = 2, R = CH,, C6H4-pNO2) were readily obtained in high yield from the corresponding salts and differences in the i.r. and n.m.r. spectral characteristics of the salts and bases are reported.La D,L-mtthyl-2 cyclohexano-4,5-cis oxazoline (2; n = 2, R = CH3) est rapidement et quantitativement produite en ajoutant le chlorure de thionyle & 0 "C A I'acttamido-2 cyclohexanol-tram (1; n = 2, R = CH,) dans du chloroforme. On estime que le demi temps de vie du chlorosulfinate intermtdiaire est moins que 2.25 min. Ce rtsultat est mis en Bvidence par un glissement dans le signal des protons du groupement mtthyle dans les spectres r.m.n., de I'amide et de la solution rtactionnelle. Le chlorhydrate de I'oxazoline est isolt avec un rendement de 98% par la sublimation sous vide du psoduit brut. On a Btabli la structure du compod en se servant de donntes obtenues par spectroscopie i.r. et r.m.n. et on I'a vkrifite par une mtthode d'hydrolyse simple qui conduit avec un rendement pratiquement quantitatif au chlorhydrate de I'amino-2 cyclohexanol-cis. On obtient facilement les chlorohydrates des oxazolines 2 (n = 1, R = CH,, C6H4-pNO2 et n = 2, R = C6H,, C6H4-pNO2) avec des rendements d'au moins 95% en utilisant la mkme mtthode gCntrale et on a ddmontrt que les acttamido-2 cyclanols-trans sont les produits de dtpart les plus utiles pour obtenir les dBrivts d'aminocyclanol-2-cis par la rtaction d'inversion & l'aide du chlorure de thionyle. On obtient facilement les bases oxazolines 4 (n = 1, R = CH,, C6H4-pNO2 et n = 2, R = CH3, C6H4-pN02) avec de bons rendements & partir des sels correspondants et on dkrit des diffkrences dans les spectres r.m.n. et i.r. des sels et des bases.

Interaction of potassium 1-phenylcyclopentanecarbosylate and 2-diethylaminoethyl chloride in a b s o l~~t e ethanol proveti the most satisfactory of four nietllods esami~ied for the preparation of 2-diethylaminoethyl 1-phenylcyclopentanecarbosylate hydrochloride (Parpanit). This procedure was used to obtain 2-(ethyl-2'-tluoroethyla11~i11o)ethyl ( I ) , 2-(ethylisopropyla~~~i~io)-ethyl (II), 3-diisopropylaminoetli~~l (III), 2-pyrrolidinoethyl (IV), and 2-pipericlinoeth).1 (V) 1-phenylcyclopentanecarbox~~1nte hyclrochloridcs. 2-Dicthylaminoethyl 1-(p-nitrophenyl)-cyc!opentanecarbos).late hydrochloride (111) was also preparcd in this way but was obtained Inore coliveniently by direct nitration of 2-diethyla1ninoeth).I l-pl~enylcyclopentanccarboxy-late. The preparation of intermediates required in thesc syntheses is described.P r e l i~n i n a r~ results are glven on the potency of these compounds as substitutes for atropine sulphate in the llsual osime and atropine sulphate treatment of mice which have bcen poisoned with Sarin.I n connection with extension of our studies on the usefulness of substitutes for atropine in the treatment of Sari11 poisoning (1,2) it became necessary to prepare certain analogues of 2-dietliylaminoetl1>~l 1-phenylcyclopentanecarboxylate hydrochloride, which is ltnown co~nmercially as Parpanit, Panparnit, Caranliphe11 hydrochloride, or Pentaphen. i\/Iany compounds of this type have been synthesized previously and the method nzost frequeiltly employed has been interaction of the acid chloride with the requisite aminoalcohol in a n aromatic solvent (3-8) (method 1). Other procedures which have bee11 utilized less frequelltly include transesterification of ethyl 1-phenylc~~clope~~tai~ecarbosylate with an an~inoalcohol and sodium in xylene (8-11) (method 2 ) ; interaction of an alltali ~n e t a l salt of the acid and an aminoalltyl halide in a hyclrocarbon s o l v e~~t (5,7, 12-14) (method 3); treatment of the acid chloride with an a~~~i n o a l c o h o l hydrochloride in a llydrocarbo~i solveilt ( 5 ) (method 4 ) ; and heating the acid with an aminoalltyl chloride hydrochloride in an alcohol (5) (method 5). J/Iethod 2 was considered unsuitable for preparation of the co~llpounds required because it sometimes furnishes very poor yields (11). I t was not clear, however, which of the other four procedures referred to above ivoulcl be most satisfactory. Accordingly, the merits of methods 1, 3, 4, and 5 were briefly exa~ni~zecl with respect to yield and ma~lipulative c o~~v e~~i e n c e for preparation of 2-dietl~ylarninoetl~~~l 1-phenylcyclopenti~~~ecarboxylate hg~drochloride (3).Interaction of equi~nolar quantities of 1-phenylcyclopentanecarboxylic acid chloride and 2-dietllylami11oetl1a1~0l in anhydrous benzene under reflux for 2 hours furnished the ester hydrochloride in 65y0 yield. Prolonging the period of reflus did not improve the yield (method 1).When potassium I-pl1e1~ylcyclopentnnecarboxy1ate was heated under reflux in absolute ethanol for 18 hours with a 20 mole% excess of 2-diet...

In preceding papers of this series (1, 2) the preparation of several analogues of 5'-diethylaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride (Parpanit) and certain of their quaternary salts was described. These coinpounds were required for evaluation of their efficacy as substitutes for, or adjuncts to, atropine in the treatment of sari11 poisoning (3-5). T h e preparation of fifteen additional analogues of Parpailit and four N-methyl-4'-piperidyl 1-arylcycloall~anecarboxylate hydrochlorides required for extensioil of these studies is reported herein. The compounds prepared and their properties are listed in Tables I to VI, and representative preparations are described in the Experimental section.The majority of the Parpanit analogues (Table IV) was prepared by the interaction of potassiuin 1-phenylcyclopentanecarboxylate \\-it11 the appropriate diall;ylai~~inoalkyl chloride, followed by treatment with dry hydrogen chloride netho hod F) in ethanol ( 1 , 6 , 7 ) .This was the most useful synthetic method when the requisite internlediate dialliylaminoalliyl chloride hydrochloride could be readily prepared, or ~vhen prepared, could be brought into reaction. 3'-Diethylaminopropyl 1-phenylcyclopentanecarboxylate hydrochloride, for example, was obtained in 62y0 yield from 3-diethylaminopropyl chloride and potassium 1-phenylcyclopentanecarboxylate, whereas the interaction of 3'-cl~loropropyl 1-phenylcyclopentanecarboxylate with diethylamine according to the general method of Weston (8) furnished only a 30% yield (nlethod 13).The potassiuin salt method proved impractical for the synthesis of 3'-quinuclidinyI 1-phenylcyclopentanecarboxylate hydrochloride. 3-Quinuclidinyl chloride hydrochloride is readily prepared by the action of thionyl chloride upon 3-quinuclidinol (9). 3-Quinuclidinyl chloride (lo), however, could not be induced to react with potassium 1-phenj lcyclopentanecarboxylate, presuinably because the rigidity of the ring system prevents the SKI reaction by inhibiting carbonium ion formation and also shields the 3-position fro111 SN2 attack. This compound was therefore prepared by interaction of l-phenylcyclopentanecarbonyl chloride and 3-quinuclidinol in anhydrous benzene (cf. refs. 1, 8 , 11-13; method I<), or by transesterification of methyl 1-phenylcyclopentanecarboxylate with 3-quinuclidinol in toluene using a catalytic amount of sodium, followed by treatment with dry hydrogen chloride (cf. refs. 13, 14, 16; method J ) . Transesterification of 3-quinuclidinol with ethyl 1-phenylcyclopentanecarboxylate (17) was unsuccessf~~l. 2'-t-ButylmethyIaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride was prepared by the interaction of 2'-t-butylaminoethyl 1-phenylcyclopentanecarboxylate with ethyl iodide in benzene, folIo\ved by ion exchange (method G).T h e N-methyl-4-piperidyl hydrochloride esters of 1-phei~ylc~~clopentanecarboxylic, 1-phenylcyclobutanecarboxylic, 1-p-n~ethylphen~~lcyclobutanecarboxylic, and l-p-methoxyphen~~lcyclobutanecarboxylic acids were prepared by treatment of the appropriate...

The syntheses of cis-and trans-2-aminocyclohexanols and of cis-and trans-2-ethylaminocyclohexanols are described. The cis isomers were prepared by treatment of the corresponding trarzs-2-acetamidocyclohexanols with thionyl chloride followed by hydrolysis of the resulting intermediate oxazolines. The 2-aminocyclohexanols were converted to 2'-(cis-and trans-2"-hydroxycyclohexyl)aminoethyl I-phenylcyclopentanecarboxylate hydrochlorides (1 and 2, R = H) by treatment with 2'-bromoethyl I-phenylcyclopentanecarboxylate, but attempts to convert the 2-ethylaminocyclohexanols to 1 and 2 (R = C,H,) by a similar reaction were unsuccessful. The anticholinesterase activities of several of the compounds are discussed, as are the potencies of 1 and 2 (R = H) in protecting nice and rats from sarin poisoning.

potassium methane disulphonate. The e.s.r. spectra are similar for all these compounds, consisting of a single absorption line with a g value of 2.004. The authors (3) present evidence indicating that the e.s.r. spectra are due to the presence of sulphite free-radical ions. The g values found in the present work are significantly higher than the value of 2.004 reported by Chantry et al. Hence it would appear that if the interpretation of these authors is correct the spectra obtained in the present work are not due to sulphite freeradical ions. Clark et al. (4) suggested that the SOz-free-radical ion was responsible for the e.s.r. spectra obtained by them from X-irradiated sodium and potassium dithionites. The spectra obtained in the present work for y-irradiated thiosulphates are similar to those obtained by Clark et al. As a check, a sample of sodium dithionite was irradiated with CoGo y rays. The e.s.r. spectra of the irradiated sample, a t room temperature and a t liquid nitrogen temperature, were obtained. At the lower temperature the sample could be readily power saturated. At both temperatures the g value of the peak was 2.005 and the line width was 10.4 gauss. The values reported by Clark et al. are 2.005 and 11.5 gauss, respectively.On the basis of the similarity of the e.s.r. spectra of irradiated dithionites and thiosulphates it seems safe to tentatively assume that Sop-free-radical ions are produced in the gamma irradiation of thiosulphates.T h e g value for the low-field shoulder of the low-field structure observed in the e.s.r. spectra of anhydrous IKazSp03 is 2.032. Free radicals in which the odd electron is mainly involved with the sulphur atom may be responsible for this structure ( 2 ) . Low-field structures a t a similar g value have been noted in the e.s.r. spectra of sulphur dissolved oleum (5) and of chilled sulphur vapor (6). Such a conclusion is consistent with the observation that colloidal sulphur is formed when gamma-irradiated thiosulphates are dissolved in water. ACKNOIVLEDGMENTThe authors gratefully acknowledge financial assistance from the Sational Research Council of Canada in the form of a research grant.1.