In connection with the investigations of tuberculostatic activity of arylthiosemicarbazides and arylthiosemicarbazones new 4-substituted thiosemicarbazides (I-XVIII) were synthesized. Condensation of these with aldehydes or ketones afforded the corresponding 4-substituted thiosemicarbazones (XIX-LVI). The attempted \u27acetylation of p-nitrobenzaldehyde-4-phenylthiosemicarbazone and o - chlorobenzaldehyde - 4 - phenylthiosemicarbazone gave besddes acetanilide N,N.-diacetyl-p-nitrobenzylidenhydrazine (LVII) ,and N,N-dia cetyl-chlorobenzylidenehydrazine (LIX) .The 4-substituted thiosemic arbazides and thiosemiearbazones were tested for their tuberculostatic activity

M. Tišler

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CROATICA CHEMICA ACTA 28 (1956) 147 CCA-22 547.497.I Syntheses in the 4-Substituted Thiosemicarbazide Series M. Tisler Institute of Organic Chemistry, Technical Faculty, University of Ljubljana, Slovenia, Yugoslavia Received July 28, 1956 In connection with the investigations of tuberculo.static activity of arylthiosemicarbazides and arylthiosemicarbazones new 4-substituted thiosemicarbazides (I-XVIII) were synthesized. Con-densation of these with aldehydes or ketones a fforded the cor-responding 4-substituted thiosemicarbazones (XIX-LVI). The attempted 'acetylation of p-nitrobenzaldehyde-4-phenylthiosemi-carbazone and o - chlorobenzald P.hyde - 4 - phenylthiosemicarbazone gave besddes acetanilide N,N.-diacetyl-p-nitrobenzylidenhydrazine (LVII) ,and N,N-diacetyl-o-chlorobenzylidenehydrazine (LIX) . The 4-substituted thiosemicarbazides and thiosemiearbazones were tested for their tuberculostatic activity. · Preliminary imrestigations in the s eries Qf 4-s•u.hstituted 1Jhiosemi.rcar1baimdes· :and thiosemicar'baizoin.es have shown that some of these Sll!bsta1nces poosess a r ema1rika1ble tubercmlostatk acti'V1itv24.-Therefore it was decided to P'repare other bitherto unlkrnown 4-substituted thiosemicarbazides and theiT der.ivati<ves and investigate thei,r acti'V'ity. Thiosemkwba,zides coiuld be synuhesized by one otf the following genera 1 · methods20 : by action of hydraizine hydrate om. isothiocyanates OT by action of bydrnizine hydrate on substituted thio1UTeas. A:s the latter reaction in many cases does no.t ipToceed smO'othly and is accompanied by did'ferent by-pll'Od1Ucts, we harve chosen the first route which, if conducted under proper conditions, 1ea:ds to thiosemica:ribaizides in excellent yields. R-NCS + NH2NH2 = R-NH-CS-NH-NH2 FoT the pr.eparation of iisothiocyanates we haive chosen the method of -decomposing the arrnmoniium saHs of dithioca11bamic acids with lead 1nitrate, as iJhis method is simple and <requi'Tes !IlO special precautions (as irn the case of thirophosgenatiQn). The formation of am.mQillium salts of dithioca11bamic acids :£rom m-'Iti.itroanillline amid o-chlrnroanili:ne failed because of the low basicity ·of bo,th amines. It is interes:ti'111g that p-ohloroaniline (pKb 12,0) wi.th almost the same tbasicity as o-chl.oxoaniline (PKb 12,05) COIU·1d be 1readi,ly converted into the salt of dii1ihiocarbam.ic acid. Both befor·e mentioned isothiocyanates were therefore prepared frrom the coll'Tesiponding diisiulbsUtuted thioiu;r-eas15• 23. The 4-'Stllbsitituted thiosemicarbazides were easily ipiTepared kom the cor-responding isothiocyanates, by di&solvillllg the latter oompo1U!!1;ds dn ethanol and 148 M. TISLER addinig .aqiueOllIB hydrazine hydrate in S1IT1aJl excess. The yields were almost quantitative. 4-( 4'-methoxy:phenyl)- and 4-( 4'-chlorophenyl)-thiosemicarbazide have ibeen already described iill the literature but they were prepared in a diffeTent way, e. g. k.om d:isuJbstiJ1Juted thirnITeas. Also 4~(2'-m.a.phtyl)-thiosemi­cairbazide has been mentioned in lite:rature7 rbut neither method oif pireparation nor meltilng-voint have been mentii.'OIIled. The 4-sUJbstituted thiosemicarbazides · are s taible .and crystahliine S1U1bstainces which readily undergo condensations with .aldehydes and ketones to form staible 4-sll.l'bstituted thiosemica'!'lba.zones. Some of the 4-siubstituted thiosemicarbazides have been aJ1r eady pToiposed for the Q.den.tifilcation and cha-raderis:ation oif aildehydes anid ketones8• 25• 26• 27 .as the obtained derivatives arre wehl~ystallised SUJbstances with high m elting-:points and are thernfOLre veiry s:ui1ta1ble for the identification of ca11boinyl compounds. We ihaive tried to acetyJate some of the eairLier synthesized 4-substituted thiosemicaTbazones under md.1ld co!l1ditio1I1JS with acet:iic .arnhydride, but the reaction failed ailld iills:tead of the expected .acetylated comporuruds the molecule has split in two parts. Thus we have obtained from p-nitroibenzaldehyde-4-phenylthiosemicairbazone acetand.lide and N,N-diacetyl-;p-nitrobenzylidenehydra-zine (L VII), identified by an authentic specimen whi1ch has been synthesized by .acetylation of known p-nitroiben"1:ylidenehydr.azine. Similarly we obtained from o-chiloirobenzaldehyd~-vhenylthiosemica'!'lbazone aceta111.i.ldde and N,N-di-acetyl~~chlorobenzylidenehydrazine (LIX). /COCHs R-CH = N-N" COCHs LVII R: p-N02C6H4-LIX R: o-Cl-CaHr It has been found that sUJbstituted hydrazines possess strong physiologicaI action :and isomcotinic acid hydra:zide has been found very effective in treat-ment of tubercl\lJlosis. Afiter the discove ry of tuberculostatic activity of thio-semica~barz:ones3• 4• 5• 12, p-acetylaminobenzaldehyde thiosemicarbazone (Con-teben, 'llibiolile) has bee111 introd111ced as clinic.ally effective tm1bercuJostatic agent and many ·related thiosemica'I'lbaz:ones were made and tested (inter alia:2, 6, 10. 13. 14, I&, 18, 19, 22). Among them hi:ghest tUJberculosfatic activity was found to reside in a seiries of p--substit•uted benizaldehyde d eriv.atives21 • We haive found that als o· some of the synthesized compo!UI1ids exhibit remarik.aible tuiberculostatic effect. The tubercu1ostatic actd.vi1ty was measured in vitro on the liquid cuJtiure medium Sul.a with the strain of Mycobacterium tuberculosis H 37 Rv. As reference srubstance So·lrvoteben ~diethylammornum salt of the thiiosemicairbazone of benizaldehyde-4-caivboxylic acid) was used. The samples weire prepared as descrilbed b efore24• The inCUJbation t€.mperature was 37° and the inaubation time was 14 days. We found that some of the tested swbstances showed complete inihi1bition in the co>ncentratiol!l of 5 y/ml. No definii·te patte:rn of structu;re-actiJvity r elatioll1JSlhirp oould be established. c TABLE I 4-Substituted thiosemicarbazi<les R~NH-CS-NH-NH2 ompound No. R Yield, O/o I 2' -methoxyphenyl- 96.5 II 4' - methoxyphenyl- 90.3 III 2' -ethoxyphenyl- 90.6 IV 4' - ethoxyphenyl- 91.2 v 4'-dimethyla minoiphenyl- 88.5 VI l '-naphtyl- 85.5 VII 2'-naphtyl- 89.5 VIII Benzoyl- 83.5 IX 2',3' -dimethylphenyl- 87 x 2',4' -dimethylphenyl- 92 XI 2',5' -dimethylphenyl- 86 XII 3',4' -dim ethylphenyl- 77.2 XIII 3' -nitrophenyl- 87 XIV 2' - chlorophenyl- 87 xv 3' -chlo rophenyl- 89 XVI 4' -chlorophenyl- 90 XVII Benzyl- 85.5 XVIII Cy clohexyl- 90.8 <a) Busch and Ulmer(9) give m . p. 1440 (b) Guha and Ray(l7) give m . p . 1300 (cl Bu,;ch and Ulmer(9) give m . p . 1800 - ---M.p., Formula •c 159 CsH110N3S 154(a) CsH110NaS 137,5 CoH1aONaS 149-50 C9H1aON3S 171-2 CuH14N4S 139 C11H11NaS 172-3 CuHuN3S 151-2 CsH oON3S 160 C9H1aN 3S 152 CuH1aN 3S 162 CuH1aN3S 119 CuH1aNaS 175 C1Hs0 2N4S 130-1 C1HsNaSCl 120(b) C1HsNaSCl 187-8(C) C;HsN 3SCl 129 CsH 11NaS I 147 C1H1sNsS Analyses, 0/o N calc'd I found 21.30 21.34 21.30 21.34 19.89 19.80 19.89 19.92 26.64 26.48 19.34 19.29 19.34 19.58 21.52 21.57 21.52 21.70 21.52 21.29 21.52 21.78 21.52 21.59 26.40 26.21 20.84 20.89 20.84 21.00 20.84 20.84 23 .18 23.24 24.25 24.16 Inhibition effect (y/ml) I -----5 --> 5 > 5 > 5 > 5 5 --5 --.... I (/J c:: b:I (/J >-3 ..... >-3 c::: >-3 M ti >-3 ::I1 0 (/J M ~ ..... 0 ;i. ~ b:I ;i. N ..... t:J M (/J M ~ ..... M (/J ~ ~ c.o TABLE II · 4-Substituted thiosemicarbazones R----NH-CS-NH-N=CH-R' I Compound M.p., I R R' Formula No. oc XIX 2' -methoxypheny 1- phenyl- · , 183 C1sH1sONaS xx 2' -methoxyphenyl- p-methoxyphenyl- 164 C1aH1102NaS XXI 4' -methoxyphenyl- phenyl- 189-90 C1sH1sONaS XXII 4'-methoxyphenyl- p-methoxyphenyl- 168 Cl6H1102NaS XXIII 2' -ethoxyphenyl- phenyl- 157 C1aH110NaS XXIV 2' -ethoxyphenyl- p-methoxyphenyl- 192 C17H1902NaS ! xxv 4'-ethoxyphenyl- phenyl- 190 C1aH110NaS XXVI 4' -ethoxyphenyl- p-methoxy-phenyl- '164 C11H1902NaS xxvn 4' -dimethylaminophenyl phenyl- \ 219-20 Cl6H1sN4S XXVIII 4' -dimethylaminophenyl p-methoxyphenyl- 189-90 C11H200N4S XXIX . l '-naphtyl- n-pentyl-. :! ! 113.5 C11H21NaS xxx 1'-naphtyl- m-methoxy-p-hy-droxyphenyl 209 C19H1102NaS XXXI 1'-naphtyl- p-methoxyp~enyl- 209 I C19H110NsS XXXII l'-naphtyl- phenyl- 210 I C1sH1sNaS XXXIII 2'-naphtyl- phenyl- 203 C1sH1sNaS XXXIV 2'-naphtyl- p-methoxyphenyl- 182 C19H110NaS xxxv 2',3'-dimethylphenyl- phenyl- 206 Cl6H11NaS XXXVI 2',3'-dJmethylphenyl- p-methoxyphenyl• 218 C17H190NaS XXXVII 2',4'-dimethylphenyl- phenyl- 208 C1aH11NaS XXXVIII 2',4'-dimethylphenyl- p-meth.oxyphenyl- 193 C11H190NaS XXXIX 2',5'-dimethylphenyl- .. phe:1:1yl- 177 C16H11NaS XL 2',5'-dimethylphenyl- p-methoxyphenyl- 176 C11H190NaS XLI 3',4'-dimethylphenyl- phenyl- 191 C10H11NaS Analyses, 0/o N . calc'd \ found 14.73 14.78 13.32 13.15 14.73 14.88 13.32 13.40 14.04 14.00 12.76 12.88 14.04 13.89 ' 12.76 12.73 18.78 18.64 17.06 17.17 13.94 14.14 11.96 11,87 12.53 12.47 13.76 13.95 13.76 13.78 12.53 12.38 14.83 14.88 13.41 13.18 14.83 14.73 13.41 13.41 14.83 14.89 13.41 13.30 14.83 14.75 I I Inhibition effect (y/ml) ----------> 5 5 -----------I ....... °' 0 ~ >'l H [/}. t"' M ::a XLII 3', 4' -dimethylphenyl- j p-methoxyphenyl- I 170 I C11H190N3S XLIII 3' -nitrophenyl- p-methoxyphenyl- 199 C1;H1403N4S XLIV 2' -chloro.phenyl- phenyl- 188 C14H12N 3SCl XLV 2' -chloro.phenyl- p-methoxyphenyl- 202 C1sH140N3SCl XLVI 3' -chloro.phenyl- phenyl- 148 C14H12N 3SCI XL VII 3' -chlorophenyl- p-methoxyphenyl- 168 C15H140N3SCl XL VIII 4' -chloro.phenyl- phenyl- 200-1 C14H12N 3SCl XLIX 4' -chloro.phenyl- p-methoxyphenyl- 192-3 C1sH140N3SCl L Benzyl- phenyl- 136 C15H1sN3S LI Benzyl- p-methoxyphenyl- 155 C1aH110NaS LII Cyclohexyl- phenyl-I 176 C14HrnNaS Liil Cyclohexyl- p-methoxyphenyl-I 179 C1sH210NaS 4-Substituted thiosemicarbazones R-NH-CS- NH-N = R ' LIV 11'-naphtyl-I Cyclopentyl-I 191 I CrnH11NaS /R1 4-Substituted thiosemicarbazones R-NH-CS-NH-N "' R2 Compound R Ri R2 M. p., Formula No. oc LV 1'-naphty1- methyl- methyl- 179 C14H1sNaS LVI l' -naphtyl- methyl- ethyl- 126 C1sH11NaS 13.41 13.43 16.96 16.79 14.50 14.66 13.14 13.21 14.50 14.46 13.14 13.26 14.50 14.42 13.14 13.14 15.60 15.47 14.04 14.06 16.03 16.32 14.42 14.30 I 14.831 15.oi I Analyses, 0/o N calc'd I found 16.33 16.07 15.49 15.53 >5 Inhibition effect (y/ml) 5 >5 .... I [/J q to [/J >-,] .... t-'l c::: ~ tJ >-,] ~ .... 0 [/J trj ~ .... () ;i. ::0 to ;i. N 8 t'l [/J t'l ::0 .... trj [/J ,_. OJ ..... 152 M. TISLER EXPERIMENTAL All melting-points were determined with Kofler's heating microscope. All compounds decompose at the melting-point. Preparation of isothiocyanates Isothiocyanates were prepared from the corresponding amines using a generally applicable procedure2s. The only exception was made in the case of preparation of 2-naphtylisothiocyanate where the necessary quantity of ethanol was doubled because of the low solubil<ity of 2-naphtyiamine. m-Nitrophenyl- 23 and o-chloro-phenylisothiocyanate15 were prepared from the corresponding disubstituted thio-ureas. For the preparation of benzoylisothiocyanate the procedure of Ambelang and Johnson1 was used. General procedure for the preparation of 4-substitUJted thiosemicarbazides Isothiocyanate (0.1 mole) was dissolved "in 960/0 ethanol (40-80 ml. are usually necessary). In the case of p-etho.xyphenyl-, p-dimethylami!Ilophenyl-, 1-naphtyl-2-naphtyl-, m-nitrophenyl- and p-chlorophenyl-isothiocyanate gentle warming was applied to bring the isothiocyanate in solution but the temperature should not exceed 5'0°. To the alcoholic solution of isothiocyanate hydrazine. hydrate (8 g. of 500/o aqueous solution) was added in one portion. The solution was thoroughly mixed and cooled with water. For the preparation of 4-(1'-naphtyl)- , 4-(3',4'-dimet·hyl-phenyl)-, 4-benzyl- and 4-cyclohexyl-thiosemicarbazide efficient cooling with ice should be applied because of the exothermic reaction and good solubility of the formed thiosemicarbazide in ethanol. The obtained precipitate was filtered and ·recrystallised from ethanol. General procedure for the prepamtion of 4-substituted thiosemicarbazones Equimolar quantities of a ldehyde or ketone and 4-substituted thi,osemicarbazide (quantities corresponding to 0.0025 mole of reactants were used) were refluxed with 960/o ethanol (7-10 ml.) for 5-10 min. on a water bath. After cooling, the precipitate was filtered and recrystallised from ethanol. N,N-dia_cetyl-op-nitrobenzylidenehyd.razine (L VII) p-Nitrobenzaldehyde-4-iphenylthiosemicarbazone25 (350 mg.), fused ·sodium ace-tate (400 mg.) and freshly distilled acetic anhydride (4 ml.) were refluxed on water bath for 15 min. After cooling, the solution was poured in water and the resulting oil solidified after standing some time. Any solid material was filtered off and recrystallised from ethanol giving colourless microneedles of L VII (35 mg.) with m. p. 163-40, undepressed in admixture with the synthesized specimen. Anal. 6.265 mg. subst.: 0.946 ml. N2 (250, 743 mm) C11H1104N3 (249.22) calc'd: N 16.86°/o found: N 16.910/o The filtrate was made alkaline and continuously extracted with ether for 8 hr. The solvent was then evaporated to dryness, a few ml. of water added, warmed on water bath until a solution was obtained and filtered . After cooling a crystalline precipitate was obtained which, after sublimation at 90-1000/1 mm. had m. p. 1150, not depressed in admixture with an authentic specimen of acetanilide.· An authentic specimen of LVII was prepared by acetylating p-nitrobenzal-hydrazine11 for 15 min. as described above. After recrystallisati-on from ethanol it had m . p. 1640. If the acetylation was carried in the same way but without heating, N-acetyl-p-nitrobenzylidenehydrazine (LVI'll) was obtained. After recrystallisation from ethanol the colourless microneedles had m. p. 197-80. Anal. 4.588 mg. subst.: 0.825 ml. N2 (250, 743 mm) C9H903N3 (207.19) calc'd: N 20.280/o found: N 20.20°/o 4-SUBSTITUTED THIOSEMICARBAZIDE SERIES 153 N,N-diacetyl-o-chlorobenzylidenehydrazine (LIX) o-Chlorobenzaldehyde-4-phenylthiosemicarbazone25 (200 mg.), fused sodium ace-tate (200 mg.) and freshly distilled acetic a.nhydride (2.0 ml.) were refluxed ·on water bath for 15 min. After cooling the excess of acetic anhydride was destroyed by addition of water. The supernatant solution was decanted •and the residual pasty mass recrystallised from ethanol giving colourless needles of LIX (20 mg.) with m. p. 1550. Anal. 5.995 mg. subst.: 0.628 ml. N 2 (280, 740 mm) C11H1102N2Cl (238.67) calc'd: N 11.740/o found: N 11.570/o The decanted solution was made alkaline and continuously ·extracted with ether for 8 hrs., the ethereal solution evaporated to dryness and the pasty residue sublimed at 100-1100/0.5 mm. giving acetanilide with m. p. 1150, not depressed with an authentic specimen. · Acknowledgments. The author is very much indebted to Professor M. Perpar for her interest in this work and to Dr. S. Banic of the Microbiological Institute of the Faculty of Medicine in Ljubljana for testing the compounds. REFERENCES 1. J. C. Am be 1 an g and T . B. Johnson. J. Am. Chem. Soc. 61 (1939) 632. 2. F. E . Anderson, C. J. Duca and J. V. Scud i, J. Am. Chem. Soc. 73 (1951) 4967. 3. R. Behn is c h, F. Mietzsch and H. Schmidt, Naturwiss., 53 (1946) 31. 4. R. Behn isc h , F. Mietzsch and H . Schmidt, Angew. Chem. 60 (1948) 113. 5. R. Behn is c h , F. Mietzsch and H. Schmidt. Am. Rev. Tuberc. 61 (1950) 1. 6. J. Bernstein, H. L. Yale, K. Losee, M. Holsing, J. Martins and W. A. Lott, J. Am. Chem. Soc. 73 (1951) 906. 7. P. K. Bo se, Quart. J. Indian Chem. Soc. 2 (1925) 95. 8. R. W. Bost and W. F . Smith, J. Am. Chem. Soc. 53 (1931) 652. 9. M. Busch and T. U 1 me r. Ber. '35 (1902) 1710. 10. N. P. B u u - Ho i, N. D. Xu on g, J. M. Gaza v e, L. Schembri, N. H . Nam and C . T . 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Sa h and H. H . Lei, J . Chinese Chem. Soc., 2 (1934) 153; cit. from c. A. 29 (1935) 461. J54 M. TISLER 24. M. T i s 1 e r, Experientia 12 (1956) 261. 25. M. Ti s 1 er, Z . anal. Chem. 149 (1956) 164. 26. M. Ti s 1 er, Z. anal. Chem. 150 (19'56) 345. 27. M. Ti s 1 er, Z. anal. Chem. 151 (1956). 187. 28. A. I. Voge 1, A Text-book of practical organic Chemistry, London 1!}48, p. 616. IZVOD Sinteze u redu 4-supstituiranih tiosemikarbazida M. Tisler U vezi s istraziv,anjem tuberkulostaticne aktivnosti tiosemikarbazida pri-pravljeni su 4-supstituirani tiosemikarbazidi (1-XVIII) te produkti kondenzacije s nekim aldehidima i ketonima (XIX-LVI) . Pri pokusaju acetiliranja p-nitrobenzal-dehid- i o-klorbenzaldehid-4-feniltiosemikarbazona dobiveni su, pored acetanilida ,. i N ,N-diacetil-p-nitrobenzilidenhidrazin (L VII) i N,N-diacetil-o-klorbenzilidenhidra-zin (LIX). Kod 4-supstituiranih tiosemikarbazida i tiosemikarbazona ispitivana je· njihova ·tuberkulostatiena aktivnost. INSTITUT ZA ORGANSKU KEMIJU TEHNICKOG FAKULTETA UNIVERZE U LJUBLJANI, SLOVENIJA Primlj eno 28. srpnj a 1956. 

Syntheses in the 4-Substituted Thiosemicarbazide Series

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