While the ureas1,2,3 and thioureas4,5 have served in many instances in the synthesis of heterocyclic rings, the use of the thio ethers CH3S-C /NR (H) Nnhr (H) has been very limited. Wheeler and Johnson1 23456 ' From o-phenylenediamine and the methyl thio ethers of o-and £-di-tolylthiourea, besides toluidine. The hydrochloride of XXIV melted at 174°and of XXV at 89-90°.1 From ethyl phenylaminoacetate and methyl isothio-di-jb-tolylurea.°From the hydrolysis of XL, and the original reaction mixture.h From the glycine and methyl isothio-di-e-tolylurea. * From the original reaction mixture and the hydrolysis of XLIII. ' From the ethyl ester of £-tolylglycine and the methyl thio ether. k From the reaction product in XLV.

Kava (Piper methysticum) extract products have been implicated in a number of severe hepatotoxicity cases. However, systematic toxicological studies regarding kava consumption have not been reported. In this study, 6 major kavalactones and different solvent fractions of kava roots, leaves, and stem peelings were evaluated for their mutagenic potential. None of the kavalactones was found to be positive in the experimental concentration ranges tested by the umu test (a sensitive test for point mutations). However, among the different solvent fractions, the n-butanol fraction of kava leaves was positive. Further investigations using bioassay-directed isolation and analysis indicated that 2 C-glycoside flavonoid compounds accounted for the positive mutagenic results. Two isolated compounds were identified as 2''-O-rhamnosylvitexin and schaftoside by NMR and MS techniques.

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Pyrrolylmagnesium bromide and chloride react with 4-chlorobutanenitrile to yield a mixture of 2-and 3-(3-cyanopropyl)pyrrole, with the former predominant, and not 2-pyrrol-2-yl-2-pyrroline as reported in the literature. The isomer distribution is similar to that obtained in the reaction of pyrrolylmagnesium chloride with butyl chloride, heptyl chloride, and l-chloro-4-methoxybutane. The constitution of pyrrolylmagnesium chloride in tetrahydrofuran is the same as in ethyl ether. In the alkylation with 4-chlorobutanenitrile initial complexing of the Grignard reagent with an unshared electron pair of the nitrile group occurs.Isomeric 1-, 2-, and 3-alkylpyrroles and those alkyl-substituted derivatives examined can be distinguished by their infrared absorption in the in-plane deformation region.Pursuant to the synthesis of 2,2'-bipyrroles2-6 it was of interest to attempt the synthesis of the parent unsubstituted bipyrrole by the dehydrogenation of the compound reported7 as 2-pyrrol-2-yl-2-pyrroline, which was synthesized from the reaction of pyrrolylmagnesium bromide with 4-chlorobutanenitrile. Since the earlier report describing this synthesis, a number of studies8-15 have established that the isomeric 1pyrroline is actually to be expected. As a consequence of our examination of the pyrrole Grignard reagenthalonitrile product and the variety of observations recorded in the literature14•16-21 for related studies we have been led to initiate an extensive investigation. In this first paper some features of the study of the reaction of the pyrrole Grignard reagent with 4chlorobutanenitrile and associated results are described. Results and DiscussionProduct from Pyrrole Grignard Reagent and 4-Chlorobutanenitrile.-Attempts on our part to dehydrogenate this product (I), which was obtained as an oil, by heating with platinum on charcoal22 were unsuccessful as were those with the formyl derivative (II) obtained from I via the Vilsmeier-Haack reaction.23 Direct comparison of the oil (I) from the Grignard re-(1) (a) Presented in part before the Division of Organic Chemistry, 139th