On phthalides and 1,3-indandiones. LIIL* Phthalides and 1,3-indandiones from (arylthio)acetic and aryloxyacetic acids

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1 On phthalides and,3-indandiones. LIIL* Phthalides and,3-indandiones from (arylthio)acetic and aryloxyacetic acids. LÄCOVÁ Department of Organic Chemistry and Biochemistry, Faculty of Natural ciences, Komenský University, Bratislava Received 0 November 97 Accepted for publication 30 ay Aryloxymethylenephthalides and 3-arylthiomethylenephthalides were prepared from phthalic anhydride and aryloxy- or (arylthio)acetic acids by the Gabriel modification of the Perkin synthesis []. Rearrangement of these phthalides led to 2-arylthio-,3-indandiones and to 2-aryloxy-,3- -indandiones, which afforded bis(2-aryloxy-,3-indandiones). o far, little attention has been paid to the Gabriel modification of the Perkin synthesis of phthalides and,3-indandiones from (arylthio)acetic acids; this contribution extends our previous papers [2, 3]. The goal of this study was to examine the possible herbicidal (aryloxyacetic and in lesser extent also (arylthio)acetic acids were reported to be significant herbicides) and hypotrombinemic activity [4]. These substances are also potential starting materials for further syntheses. Phthalic anhydride when reacting with aryloxyacetic or (arylthio)acetic acids according to cheme afforded 3-aryloxymethylenephthalides (I XX) or 3-arylthiomethylenephthalides (XXI XXXIV). The rearrangement of phthalides (I XX) in sodium methoxide led to 2-aryloxy-,3-indandiones (XXXV XLVI), which gave bis(2-aryloxy- -,3-indandiones) (XLVI LX). Phthalides XXI XXXIV rearranged to 2-arylthio- -,3-indandiones (XLVII-LV). When contrasting yields of phthalides from arylacetic acids with those from aryloxyand (arylthio)acetic acids, it becomes evident that the best yields were found with arylacetic acids which gave, in 60% yield, preferentially trans isomers of benzalphthalides (the trans to cis ratio 00 : ) [5, 6]. Under optimal conditions ( C, reaction time 3 4 hours) the yields of phthalides from (arylthiojacetic acids were about 50% (trans to cis isomer ratio was estimated to be 9 : ) and from aryloxyacetic acids about 30% at C (cis to trans isomer ratio was approximately 2 : ). 3-Aryloxymethylenephthalides (I XX) are under the temperature conditions of the reaction unstable and after a certain period of time (50 or more minutes depending on the nature of the substituent) they underwent decomposition and turned brown. The best reaction time was found to be minutes. * Part LI I: Collect. Czech. Chem. Commun., in press. Chem. zvesti 27 (4) (973)

2 . LÁCOVÁ R сн-х- R3 l~xx(x=0) R5 /?4 XXI- XXXIV (X-) : LVI-LX(X = 0) XXXV- XLVI (X = 0) XLvii - LV fx=s; R R 5 = hydrogen, halogen,, N 2, alkyl, aryl, or their combinations. cheme The different solubility in organic solvents was utilized to separate the geometric isomers (I XXI), which were characterized by melting points, spectral methods [7], and gas chromatography [3]. Both isomers were converted into 2-aryloxy-l,3-indandione as a sole product. In ethanol better soluble isomers assumed to have the cis configuration, having lower melting points and a lower C = 0 stretching frequency (prepared usually also in lower yields), rearrange into trans isomers of higher melting points. The shift of the carbonyl band in the i.r. spectra is substituent R dependent. A linear relation of those shifts with a constants has been observed; both isomers differ in the slope [7]. From among the sulfur analogs we succeeded to isolate only the cis-3-phenylthiomethylenephthalide (XXI). It has been found that nitrophenoxyacetic acids give the corresponding phthalides in very low yields and therefore, it is convenient to synthesize them according to [8]. s XVI XVIII and XXX having a nitro group could be reduced with zinc in acetic acid to yield amino derivatives, which gave, by diazotization and andmayer reaction, products XXIX and XXXI-XXXIV. Whereas the rearrangement of sulfur analogs of phthalides is almost quantitative, that of oxygen derivatives varies between 40 50%. Indandiones XLVII LV are more stable than the oxygen analogs thereof which, either during crystallization or when allowed to stand, gave bis(2-aryloxy-.3-indandione) in about 30% yield, this being further decomposed to furnish the corresponding substituted phenol. The yield of indandiones LVI LX could be raised by heating the solutions, or by addition of hydrogen peroxide at 00 C. It is noteworthy that substituents revealing the + effect 526 Chem. zvesti 27 (4) (973)

3 i Table Characteristic data of 3-aryloxymethylenephthalides (I XX) о 3 W Ьэ R % с %.p. w J cis I trans II cis II trans III cis C 3 C 3 C, Cie 2 C C 2 Cie- 2 C , fe! 5 b и о и t* д III trans C 3 ^'юн-^г^'з IV C 3 C, C I V trans C 3 с 7 н 4 о V cis C 2 5 C V trans с,н 5 C , VI cis С 5 Н,ОзС VI trans Ci U) VII cis С 5 Н С

4 Table (Continued) R %c % М.р. VII trans VIII cis VIII trans IX cis IX trans X cis X trans XI cis XI trans XII cis XII trans XIII trans XIV cis C 3 C 3 C 3 F F 0 O 3 u 0 O 3 Ci Ci n O s Ci e n O a C 6 a F с 5 н,о 3 г

5 Table (Continued.) R %c %.p. XIV trans XV cis X V trans XVI cis X VI trans X VII cis X VII trans XVIII cis XVIII trans XIX cis XIX trans XX cis XX tr -C 3 7 г-с 3 Н 7 F I I с 0 н б C G 5 C 3 C 3, F O 3 I С 5 Н, í( 0 5 N e 0 5 N N C lft u 0 5 N ít 0 5 N 0 O 5 N C 2 4 C 2 4 ^9 8 <;

6 ел со о Characteristic Table 2 data of 3-аг} dthiomothylenephthalidcs (XXI XXXI V) R R 5 % C % o/ 0.p. 2 К} * w > XXI trans XXI cis XXII XXIII XXIV XXV XX VI XX VII XX VIII XXIX XXX XXXI XXXII XXXIII XXXIV C 3 NO a N a Ы C, Br L O C3CON C50O2 Ci B 0 O 2 Ciei C С б Н 0 2 С8 Ci C 5 0 O.,Br C l5 ().,I с 5 и ол т «c\r, ln o 3 s C N C ]5,0 4 N n 0 2 N8 244.^ г t- 0

7 Table 3 Characteristic data of 2-aryloxy-l,3-indandiones (XXX V XLVl) R % с %.p. XXXV C, la () XXX VI ^!iei 2 () XXX VII C, Cie"-2^ XXX VIII C 3 C 3 C XXXIX CI e XL C le,0, XLI CI C lft XLII CI Ci XLIII Ci e n XLIV С в Н и С XLV C fl ft с 2 н 4 о XLVl -с 3 н 7 C, ^!)

8 Table 4 Characteristic data of 2-arylthio-l,3-indandiones (XLVII LV) R R 5 %c % %s.p. XLVII 0 C) XLVIII C 3 Ciei XLIX C 3 Ci6i L b LI Br Br LII CI LIU CI C deccmp. LIV N LV N

9 Tabic 5 Characteristic data of bis (2-aryloxy-l,3-indandioncs) (LVl LX) Aryl % c % М.р. v(c = 0) [cm- ] L VI Phenyl CWieOe 4Л4А s 748 m L Vil 3-ethylphenyl ^32-"-22^в s 746 m L Vlil 4-ethylphonyl ^32 -*"*-2 2^ в s 747 m ЫХ 2,5-Dimethylphenyl Сз4-Н-2вСв s LX 0-Naphthyl ^38-"-22^ s 747 m s strong; m medium,

10 . LACOVA stimulate the formation of bis derivatives, which have not been hitherto prepared. There are oxidation reactions leading to bis(2-aryl-l,3-indandiones) [9 ]; nevertheless no spontaneous formation of those substances at room temperature was reported Infrared spectra [7], p.m.r. spectrometry [2], and polarography [3, 4] were the tools we used to investigate the phthalides in more detail. everal substances (I XX) were found to possess a herbicidal activity [5], other (XXI-LV) are much less effective [6]. s IV, X-XII, XVI, XVIII, XXI, XXVI, XLIII, XLIV, XLVII, and LII were tested to inhibit the bacteriostatic and fungistatic activity. No inhibition of growth up to 500 [Lg/ ml was observed with Escherichia coli, almonella typhi murium, taphylococcus pyogenes aureus, Candida albicans. Trichophyton rubrum, Trichophyton flaviformae, Trichophyton violaceum, Trichophyton gypseum, Trichophyton Kaufman Wolf, icrosporum gypseum, and icrosporum cooked. Experimental Infrared spectra were measured with a UR-20 Zeiss spectrophotometer in nujol mull. 3-Aryloxymethylenephthalides (I XX) and 3-arylthiomethylenephthalides (XXI XXXIV) were prepared according to [ 3, 5], 2-aryloxy-l,3-indandiones (XXXV XLVI) and 2-arylthio-l,3-indandiones (XLVII LV) according to [2, 3]. Bis(2-aryloxy-l,3-indandiones) (LVI LX) 2-Aryloxy-l,3-indandione (4.2 mmoles) was refluxed 0 hours at 0 C. The decomposition product was allowed to cool, then diluted with diethyl ether and filtered. The crystalline residue was washed with the same solvent until it was yellow, and then it was crystallized from dimethylformamide. Characteristic data of synthesized substances are surveyed in Tables 5. Acknowledgements. Elemental analyses were determined by Dr E. Greiplová (Chemical Institute, Komenský University), i.r. spectra by Dr A. Perjéssy (Department of Organic Chemistry and Biochemistry, Komenský University), and biological tests by Dr F. Volná (Research Institute for Epidemiology and icrobiology) to whom I wish to express my thanks. References. Gabriel,., Ber. 4, 92, 925 (88). 2. Furdík,., Lácová,., and Livař,., Acta Facult. Rer. Natur. Univ. Comenianae (Chimia), Tom XII, Fase. 2 (968). 3. Furdík,., Lácová,., Livař,., and rivnák, J., Chem. Zvesti 20, 834 (966). 4. rnčiar, P., Lácová,., and Kovalcík, V., Pharmazie 23, 499 (968). 5. Berti, G., Gazz. Chim. Ital. 86, 655 (956). 6. Rigaudy, J., Bull. oc. Chim. Fr. 4, 482 (965). 7. Perjéssy, A. and Lácová,., Collect. Czech. Chem. Commun. 36, 2944 (97). 8. Lácová,. and Furdík,., Acta Facult. Rer. Natur. Univ. Comenianae (Chimia), TomlF, Fasc. (97). 9. Ozol, J., Tsiklicheskie ß-Diketony, p. 95. Izd. Akad. Nauk Latv. R, Riga, rnčiar, P., Chem. Zvesti 6, 673 (962).. Zalukaeva, L. and Evseeva, I. L, Zh. Obshch. Khim. 33 (2), 4025 (963). 534 Chem. zvesti 27 (4) (973)

11 OX PTALIDE AND.3-TXDAXDIONE. LIII 2. Perjéssy. A.. Vida, A., rnčiar, P., and Lácová,., Collect. Czech. Chem. Commun. 37, 39 (972). 3. Beňo, A.. rnčiar, P., and Lácová,., Collect. Czech. Chem. Commun. 37, 3295 (972). 4. Perjéssy, A., Kalavská, D., and Lácová,., Collect. Czech. Chem. Commun. 37, 60 (972)/ 5. Lácová,. and Priehradný,., Czechoslov. Patent (969). 6. Lácová,., preliminary results. Translated by Z. Votieký Chem. zvesti 27 (4) (973) 535