THE UNTVERSITY OF FJAI,TTTOBA STTIDIES ON TSOTHTÁ.ZOIIU}.I SÂLTS AND REIATED CO},IPOUI{DS by GART ED}¡ARD BACIIERS A T}MSIS SIMÌ,1TTTED TO TI{E FACULTY OF GR]I.DUÀTE STIIDIES ÏN PIIRÎI/iL FULIi'TIJ'&Til'r OF TI# REQUTREI.Tiü{TS TÇR TI.III DEGREE I'IÂSTER 0F SCIEÎIICE DEPARTI'ÎE]VT 0F CI{EI,IISTRY WIIINIPEG, I{ANI1.oBA October 1971 üF fi "*i¡l,''ÉËR$$iY LT BRARY ACIOTOIILEDGH,ÍTÍüTS : The research degcribed in thís thesis has been undertaken at tho suggestion of Dr. D. Id. McKínnon, for v¡hose guidance, advice, æd ass*stance ï exprees r¡\y sincere appreciation" My gratitud.e ie also due the National Research CounciÌ of Canada for the scholarships provid.ed. d.uring the course of this research, and the University of }ianitoba for the provisíon of laboratory facilities. Finally, I should like to thank rny colleaguee, I'fiss Sheena Loosmore, Ivlr. Joe Buchsbriber, Iilr. Pat Ma, a¡rd. Mr. Jack Wong. Their forbearance during several unusually od.or-ous experiments was admirable. 11 TA3I,E 0F.coNTlNTS ABSTRACT.......... o.. ó..... o. ...:. r. o õ i.. o.... o.......iii INTRODUCTION Ggngial.. - - . ô. :.' ..... o. ... .. .. .. .. r. .. o. .. .... 1 fsothiazoles. o r . c o. o . ... .. o. ¡. 2 ' I s o thi azo 1 um s s i al t . c . o . c . , . , . , o . ! 4-rsothiazoline-3-thiones... o... ô........ o.... r........ 13 . 3-Isothiazoline-l-thiones....o.....,r........er........18 Thiothiophthenes and an aza arialogue.. o...... c o. o... .,.19 DISCUSSION Purpose of resgarch...... c.. o...^... r.............. o., o..2J Reaction of isothiazolium salts ç¡ittr sutf:p¡ ¡ o o. c . .. .24 Ðirect approaches to 3-thioacylmetirylene isothiazoles. .{l concIusions...... ........... o. ........ .. ..... o..... ....49 EXPERII'TENTAL Ggngrall ¡ ¡ ¡ o........... o... .. e... r.,.... o...... ...51 starting materials...'.............oc........... .....,.52 Isothiazolium salts/sulfur/pyríd.ine Reactions, r . .., .. j9 Attempted d-irect syntheses...... .. o.. o.. e... ,.... .6, Approach to 2rd-diphenylisothiazolium perchlorate....,.TO RE'FERENOES. '.. '............... Ò o r. r...........,..,.... ....,.74 SPEOTRA... ... o... r. r....... o r o .. ... ....... ............8c t 11 ABSTIACT: The reactions of various isothiazolium salt.s with sulfur in refluxing pyrid.ine have been stud.ied. to d.etermine the prod.ucts and. mechanistic pathways involved. ln the course of these investigations, three pre- viously unreported. isothiazolium salts and. a ner.r l-isothiazotine*!- thione have been synthesized. Various approaches to 3-thioacylmethylene isothrazoles a:ed l-acylmetþ- lene isoxazoles have been investigated.. Hor*ever, ring d.econposition has so far prevented the synthesis of such a:ia.logues to the thiothioph- thene system by these synthetic routes A potentially useful approach to 3-unsubstituted-3-isothiazoline-)- thiones has been investigated and should. prove cond.ucive to the synthesis of these compound-s. INTRODUCTTON ï . GÐ{ERAL ÅNTROpUCTION : This thesis concerns s¡rnthetic routes to a number of compounds con- taining the isothiazole nucleuÊ v¡hich were required for severaÌ studies being undertaken in this laboratory. Such compound.s t+ould be usefuÌ in tbe investigation of lrl-dipolar reactionsr oxidation reactioner æd in the eynthesis of 3-thioacyl.nretl¡rlene Ísothiazoles, which are azã analoguee of the thiothiophthenes. These stud.íes willr whore appropriate, be mentioned in a later section. II" ISOTHÏAZOLES: d--P-esç rlp-tÈp n g{_!h q--}!-q r-ess}-e. : Isothiazoleo Ia, is a five-membered. heterocyclic molecule containing adjacent nitrogen and. sulfur atoms. A number of resonance forms may be drawn for the isothiazole molecute (ta - Ij), both requiring s-N +s-N- +s-N $o-Ö.ÇÇ.öööl)ö.+ Ia Tb Ic ïd Ie If Ig Ih Ii ïj (ff - f¡) and not requiríng (fa - fe) the partícipation of sulfur d--orbitale, Both iscthiazol.e and thiazo-1.e, TI, are chemically and physically simi-lar to pyridineo ïïï, s-r 2\' I \ f il uupportins the Longuet*Higgins theory \/* \*"/ of isoeteriu*1 rvhich claims that in II IïI an aromatic systemo the group -CH=CH- is electronically similar to the for- mally bivalent -S-. Taking into account the participation of sulfur d-orbitals, the repì.acement of =S= for =CIí-CH= is also possible. b):lyn th e sSe_g!fl IgoJI) ig¿,o l_çe : The first method of preparing isothiazol-e, described by Adams Slack2t3 involved the oxidation of !-arninobenz[d]isothiazole: Kt'1no¿" ]T[) :"..Ð =*tQ,, -" Û Although both benz[c]isothiazo]es and benz[d]isothiazoles with ben- zene rings containing an arnino group can thus be converted. to isothia- zoles, tho preparations are ted.ious and unsuitable for general synthe- ses, l\n improved reaction3 involves the cyclization of p-iminothio- butyramide v¡ith chlorine or þydrogen peroxrde: HrH¡V¡,¡e This reaction has been extended by Goerdeler4t5'6 to varíous substi- tuted. )-aminoisothiazoles. In a similar reaction, variously subetitu- ted. thioketones afford J-hyd.ro4ye 3-methoxy, and 3-arninoisothiauol""T, ¡ = 0H, Oldo, or ldH, Ph\,Åx An efficient synthetic method for isothiazoles has been developed by Hübenett a¡rdcowork"t*8, involving the catalytic reaction of sulfur dioxide, arnmonia, and an olefin. Thus, from propylene, isothiazolo may be obtained in good. yield. The catalys'b in this case is activated 4 3cl{¿*c}-lcH3 +4S0¿+ 3ruH, 3 * SHao + H¿s -----Þ Çi arumina. simirarryr 4-phenyl-isoihiazole can be synthesized. from a-metþlstyrene, and 4-rnetÌ:ylisothi azore from isobutyrene. The stabílity of the isothiazole ring is evidenced. by the use of reac- tion temperatures in the 200oC to loCo0 "rngu.g Isothiazoles have been obtained. from the reaction of 1,2-dithiolir¡.m salts with anmonía in etha¡roI10 or with.a¡nmoniurn acetate in acetic acid-11. Th" postulated mechanism proceed.s via nucleophilic attack at carbon atom 3 or l: -:þ-,,"*. s-s s-N -\,klq *, *V*' W* R, The utilization of aciùic nret\rne groups to prod.uce isothiazoles is illustrated by the formation of metþl 3-metþt-d-isothiazole carbory- late from thiophosgene and- mettryl p-anrinocrotonâte in absolute etþ1 ether r+ith trietl¡rlamine as cataly"trl2 *\ /NH.. .c:G. + \an, ,:{" ry* u3co2c/ v.*, co2cFl3 .4. second. use of an acidic metþne group was shown by l{ille and co- rho found. that the ad.dition product of acetylenÍc carbonyl "ork*rs13 compounds wÍth sodium thiosulfate would. cyclize in liquid- amrnonia to yield isothiazoles: o NHa S NaO, S-S-CH:Cf+ ë n \,Å.-¡$ However, the instability of the intermediate cis-thiocyanate aclduct regults in low yield.s. Nevertheless, the reaction is of value since it ca¡r be ad-ap'eecl to the s¡rnthesis of isose}"n"rolu".14 The cyclization of d.icyanoet$rlened"ithiolate to give an isothiazole vuas d.emonstrated, by Soed.erbaeckl5 tnd. Hatchardl6: NC, SNa s s-N rucf\stuo tras\./snr, CN A similar reaction has recently been reported by llakagav.'a et al17 *ho found that benzylid.enemalononitriles v¡ouId react v¡ith sulfur chlorícles or thio4yÌ chloride in pyridine to give an isothiazole by an as-yet unelucidated- mechani sm: s¿cl¿ sctz s_N A**cFl:c'€ \ or SOCl¿ /Pyr n'\.n" CN A nurnber of other isothiazole syntheses have been based on the active nucleophiì-ic methylene groups as found in malononitrile or phenylaceto- nitrile' these are generatly used. to form intermed.iates in the presence of base, v¡hich on treatr¡ent rrith sulfur yield. isothiaøole,s, Di(triethyl- eunnonio)rnetþlenenralononitrile lras formea in the reaction of acetoni- trile rvith rnalononitrile in trietþlaraine/carbon disutfid.e. Oxidation with sulfur in methenol followed. by treatment vrith methyl iod.id.e af- 1 B forded 3, 5-di( thiomethyl) -d-c;,¿noisothiazolu, pN etrÑs l'.4eCN l.l^C + t", ,sÑur. 1. S/r¡eol l-ir¡ t'ct+ Eñ* NC c MesVsr'1e CN {¡Cyano-l-amino-1, 2-d-ithiole-3-thione, obtained from malononitril-e, sulfurr and carbon disulfíd.e in the presonce of triettrylanine, under- went ring-opening and S-S bond. scission on treatment with potassium þdroxide. fsomerization and. ring-closure yielded dipotassiun-3 r4- dithio-4-cyanoisothiazole, which on methylation gave 1,5-di( thiomethyl)- 1 4-cya¡roi sothi azo le 9 : EbtN n-tru (tn + csr o s - Î-Ì Koll Þ î-il ttu¿soa- -u.*Ys-o*t\r/'--î.r$.*, Sod"ium viqyl srrlfidee, obtained by thioaoylatÍng malononitrile with esters of d.ithiocarbovlicr thionocarborylic, trithionocarborylic, or xanthic acid.s in anhydroìs ethanol with soclium ethoxid.e as catalyst, rqhen treated. with chloramine yieldecl 3-amino-4-cyanoisothiazotes20: ,cN Mes.. Naogb, N ca_75Na H.cr + NHaCI , CN Þ'^/rcR ff-- N.F.\RFIC' .R E¿o,¡¿v -* *\rÅ*n, CN Cyanothioacetamide, produced from the reaction of þd"rogen sulfide and malononitrile, reacts v¡ith carbon d.isulfid.e in the presence of a sodium alkoxide to give, on metÏ¡rlation, an intermediate which can be oxidized with iodine in ethanol to yield 3,5-di(thiomethyf)-+- cyanoisothiazole2l ¡ S il ,CN ¡. CS*/NaoEb õ s + H¿S NCeHaChlHe Ñu, T- Hrco -+ CN -N Dithioic acid. sal-ts, produced by treating phenylacetonitrile r.¡ith carbon disulfÍd.e in the presence of sod.ium þdrid.e and dimetþyì-for- mamide, can be cyclized r.rith eulfur in ethanol, Acidification yields 22: {-pheny}i sothiazo Ie-l , !-d i thiol s_N PhcH?cht +cs¿ lrflL' fi iìi rslELoFr u*-*rrvl m* usVsH Ph The oxiclative cyclization of p-mercaptopropionitrile with halogen B to yield, 3-haloisothiazoles23 in,rollres the lose of three proions by a mechanism which, as yet, is unclearS xu o X=CIorBr u, =Çï- 'p -iminoketones, such as p-imino-p-moz'pholinoetþI phenyl ketone, may be sulfurized- with sulfur and.