W I I! I \ 1 “I'll I J ) f WI! | I ’III 00—: ‘ 00-h 004:- l TH _ S?UDIES ON THE FORMATION CF 4-:WINOYR1AZOLE DERIVATWES FROM ACYL HYDRAZIN‘ES Thesis :‘or {he Dogma a? M. S. MiCHQGAN STATE COLLEGE iamss firi‘hur Garzsiwn ms ‘me1.- mg”, .7 5 A; ' ,- ‘ Auchigan Stars 0;, Univcrsit'y LWm-Fr- .. v- , 'F'Wx..._t'....'j. "'1 ' ' - “. ., I," ' -.L I}: A A R Y “"‘ STUDIES ON THE FORMNTION 0F iqAMTNOTRIAZOLE DERIVNTIVES FRO“ ACYL HYDFMIHSS By Junee Arthur Garrison A TErSSIS Submitted to the School of Graduate Studies of Michigan stein College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1951 AC W’OI’HE DC“ 1131‘ The author would like to express his gratitude to Dr. Robert M. Herbst, under whose direction this research was carried out and without Ihose inspiration and help- on suggestions this thesis would not have been possible. sessseeeee seesstes tsetse t test to s: ‘.'/ul;(“'"u;(} _‘.4,..1 STUDIES on THE FOR’I‘M‘ION OF 4-A‘iIVOTRIAZOLE DERIVATIVES FRO“ ACYL HYDRAZINBS BY James Arthur Garrison In the curse of study of high nitrogen compounds it use of interest to prepare a series of 8.6-dialkyl-4—amino-l,2,4—triasoles. A search of the literature disclosed the facts taut no one person had prepared a con- timous series ¢ these compounds and mat no si ngle method had been applied to their synthesis. It as. theredore. desirable to find a shorter and a simpler method or preparation. This thesis and the experi- ments discussed herein are the realts of investigations toward this goal. A convenient method of preparation of 3.5-dia1kyl-4-amino—1.2.4- triasoles he been found. When the allql groups are below three carbon atom, it is possible to prepare the triaseles from the free new acid and hydrazine hydrate solution in an ordinary distillation apparatus. Higher mlemhr weight aminotriasolee can be prepared by heating the diacyl hydrasine and hydrazine hydrate in a sealed tube. In Table I are compared the yields of 8.5-dialkyl-4-emine-l.z.4~triasoles obtained by the distillation method and the intersection of the diacyl hydrazines and aqueous hydrazine hydrate in sealed tubes. A mechanism for the formtion of sminotriasoles has been proposed. The mechanism involves (1) formation of a hydraziniun salt. (2) the de- hydration of the hydrazinium salt to form the monoacyl hydrazine. (3) decomposition of the monoacyl hydrazine to form a diaoyl hydrazine -1- and liberate hydrazine. (4) rearrangement of the diacyl hydrazine to the 'lactim" form and reaction of the lactim form and hydrazine in one or more of three ways; direct formation of the aminotriasoleg fomation of a dihydrotetrasine which rearranges to the aminotriasole; or forma- tion of an acyl hydrasidine followed by formation of the aminotriazole or of a dihydrotetrasine diich subsequently rearranges to the amino- triasole. TABLE I FORWAT ION 0F 3 , 5-DIALKY1a-4aAMIT’O-l , 2 , 4-T T-{IAZOLES l '3 N-WHZ ““ % Yield r b‘fr‘hnnfi on Soar ed ”'m'b“. : R Technique Technique C‘H3 75 .. 0235 68 64 C3H7( n) 48 59 03H7( i so) 0 62 cent 10 53 .2 .. TABLE OF {‘OT‘VI‘ENTS mmDUCTIONOOOOOOOOO0.00.0...0.....-0.0.0.0..0.00.0.0...0.00.0... HISTORICHICQOOOOOIIIOOOOOOOOOOOOOOO0.0.0.0....OOOIOIOOOOIOOOOOOOC‘O DISCUSSIONOO0.0000COOOOOCOIOOOOQOO00.0.00...000......0.0.0.00.0... EXPERI‘ENTAIIOOOOOOOOOOOOOOQOCssseeeeeeeeeeeseessseeseeeeeeonOOOOO Reagents..................................................... Preparation Of 4qkmino-1,2,4-triasole........................ Preparation of 3.6-Dimethy1-4-aminwlfi ,4otriasole. . . .. . . . . . . Preparation of 3 .5-Diethyl-4-mflno-1,2 .4-triasole. . . . . . . . . . . .- Preparation of 8 .5-Di-m-propyl-4-amino-lfi . 4-t riasole. . . . . . . . Reaction of Isobutryrio Acid and ITydrasine.. . . . . .. . . . . . .. . ... Reaction Of BOEIOlC'AOid find Hydrazlne.....o................o Fol-nation of Diisobutyryl Hydrasine from \(onoisobutyryl Hydrasine................................................. Formation of Dibensoyl Hyd rasine from Monobensoyl Hydrasine. . Preparation Of 3,5CD19thy104-CM1HOOI.2.4‘tf133010eeeeeeeeeeee Preparation of 3,5-Di-n-oropyl-4-arnino-l,2,4-triazole... ..... Preparation of 3.6-Di-isopropy1-4-amino-l ,2 ,4-triasol e. . . . . . . Preparation of 3.5-Dipheny1-4-amino-1,2,4-triazole. . . . . . . . . . . sn‘fl‘A-RYCOOUOOOOOOC.OCOOCCOOOOIQOCOOIIOOIOOOII00.0....0.00.00.00.00 LIST OF RgFEREHCESeeeeeeeeeeee6e.ee.eeeeeeee.eeeeeeeeeeeoeeoeeeeee PAGE 15 15 16 18 20 20 22 23 23 24 24 25 25 26 27' 28 TABLE II III IV LIST OF TABLES FORMATIOH OF 3.5oDIAIKYL-4-NHHO-1,2 , 4~TRIAZOLBS. . . e . . . . . EXP‘RI‘ENTAL DATA FOR THE PREPARATION (F 4-AMINO-1.2,4- TRIMOLEOeeOeoeeeeeeeeeeeeeeeeeeseeeseeeeeeeeeeeeeeees EXPERI‘ENTAL DATA FOR THE PIESPARATION OF 3.5-M‘ETan4. Am0-1.2.4.TRIAZOLEeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee EXPERI‘IENTAL DATA FOR THE PREPARATION OF 3.5-DI-N-PROPYIp “AMIHOCI.2.4.TRIAZOLEeeeseeeeeeeeeeeeeeeeeseeeeeeeeee PAGE 17 19 21 INTRODUCTION INT RODUCI ION In the course of stuck? of high nitrogen compounds it me of interest to prepare a series of 3.5-dialkyl-4-amino-l.2,4-triasoles. A search of the literature disclosed the facts that no one person had prepared a continuous series of these compounds and that no single method had been applied to their synthesis. The most general reaction was the condensation of tie molecules of a nonoacyl hydrasine to give the amino triasoles and water (Reaction 1). This reaction as used by Pellissari (6). Stoll‘ (9) (10). an! Silherrad (13). However, this Hzmm . 4712 Reaction 1. method was undesirable because the preparation of the monoacyl hydra- sines involved long periods of refluxing. It was, therefore. desir- able to find a shorter and a simpler method of preparation. This thesis and hue experiments discussed herein are the results of investi- gatiens toward this goal. -1- HI ST ORICAL HISTORICAL The first 4-amino-l.2.4-triasole derivative was described by Curtius and Lang (1) in 1888. It was prepared from ethyl diasoacetate in aqu ecu s alkali . (Noon) f_' -—cocoon 2 hzcn-Cooczns ‘ If: C-CCOH ——-C_""H V’N3’2 = a \ H)- ‘Hz £003 Curtius. however. through faulty molecular weight determinations. as- signed the sumirical formula Czflefis to the compound. Several years later Hantssch and Silberrad (2) found mat the salts of this compound contained 1.5 moles of acid for each mole of base. This cast some doubt on the molecular weights as determined by Curtius. Upon redetemination of the molecular weight. Rantzsch found the correct fonmla to be 03H4N4, to inch he assigned the name H-dihydrotetrazine (Structure I). H—-——FH\ l H—N>CH (I) Pinner (3) considered the possibility that compounds of this type could be amdno triazoles, but he did not attempt to prove their structure. In 1906. 3310: (4) proposed the 4-anino-l,‘2.4-triascle structure (Struc- ture II) on the basis of the reactions with ‘ -diketones and aromatic aldehydes. I! OH \CK/P «#7112 (II) The controversy concerning the correct structure for these compounds was settled in 1907. when Stolle; who had been originally a vigorous supporter of the dihydrotetrasine structure (5). proved quite conclu- sively that the amino triascle structure was correct (6). The foun- dation of his proof rested on the following series of reactions: n-Ic/c 6H5 \01 1 ”(can __ .CGHE /n.mc 6H5 e a Cellsm-I-lmz cam 5 655 Reaction 2a ‘cefis *6 I . cons 7 .Nncsns 1. (CH3C0)20 a .. + 071300011 c H 6 6 one 6H5 Reaction 2b The products of reaction 2b and reaction 5 were identical. If a structure analogous to structure I were correct, reaction 3 would not have taken place because there is no available hydrogen on the nitrogen carrying the phenyl group. Therefore. the 4-avnino-l,2,4-triasole structure (II) was correct. The synthesis of 4-mino—1,2,4-triasole, the first member of the series of 3.5-dia1kyl-4-amino-l,2,dotriasoles discussed in this thesis. has been described in Organic Syntheses (7). The method described involves. first. the preparation of monofornyl hydrazine by refluxing ethyl formate and hydrazine hydrate on a steam bath for 18 hours. The monoacyl hydrazine was isolated and then heated to 180° C. for three hours. The yield of the amino triazole was about 80 percent. 1165;? 4 nan-r1112 ___......,, H ) Izns 1 11-21312 H 2 H < -———-—-) 113-an {Ming 4 2 H20 The 3.5-dimthyl-4-amino-1,2.4-triascle has been prepared by a 4 921150}! variety of methods. It was first obtained by Pellissari (r?) by heating monoacstyl hydrazine for 7-8 hours at 180° C. Another method o «:33 a mag , Hm: """""" 4mg + 2 320 He described in the same paper involved heating diacetyl hydrazine at 180-»1900 C. to form d-aceramino-flfl-dimsthyl-lfi,4-triesole. The amide was hydrolysed with sulfuric acid. 5 ‘ s——c.___ 43E / 2 CH3< >013 _____. 3 H.» mecca-:3 . H o 1. Ca; coon Ha 1:1- ..CH = t, L, Dedichsn (9) heated acetonitrile with hydrazine hydrate in a sealed tube at 180° C. for 48 hours to obtain the triasole. a Charm {- ran-1311202120 i $-05, \ "“172 + “20 CH 8 Bilberrad (10) heated n-acetylacetsnilide and hydrazine hydrate at 260° c. for four hours and got a good yield of the triazole. -5... OCH 1. 66H6<0 3 + 2 “ZN-EH2 ___.._’ ‘l . “a Tim: CH: §j/}I-NH2 1' CGHE’NH‘Z I: A 3 Dedichen (9) also prepared 3,5-disthyl-4-amino-l,2,4~triasole by the method mentioned above using propionitrile in place of acstonitrile. The 3,5-di-n—propyl and di-ieopropyl 4-aminotriasoles*were prepared by Stall? and his students (11) (12) by refluxing an alcohol solution of theLsthyl ester of the appropriate acid and hydrazine hydrate for three days on a steam.bath. The product of this reaction is the mono- acyl hydrazine. The acyl hydrasine was then placed in a bomb and heated to 270° C. The yield of triasole was not reported in either re- action. The 3.5-diphenyl-4-amino-l.2,4dtriasole was prepared first by Curtius and Dedichen (13). who heated bensonitrile with hydrazine hydrate at 150° c. In 1897, Pinner (3) found that bonsamidrasone on standing gave off azmnonia and condensed to form the 3,5-diphenyl-4- aminotriasole. —- -c n m 6 5 2 06H5< ? _ Jug e 2 11:13 -.H- TH2 ' . 635 He also found that the ethyltxnsimdno other on standing for eight days with hydrazine hydrate formed the triazolo. Presumably the first step in this reaction is the formation of the amidrazone with the liberation of ethyl alcohol. The amidrasone'then undergoes the elimination of -6- )H 2 CGHSC\OC + 2 sz'mz —--) 236 HOE ammonia and condensation mentioned above. Silberrad (14) prepared this triasole in the best yield reported by any of the investigators for any of the compounds under discussion. He reported yields of 96 percent by heating nonobensoyl hydrasine at 230° C. with enough hydrasine hydrate to prevent tomtion of the dibmsoyl hydrazine. }) “3535 2 carscim‘m “ms 2:120 ‘ 2 More recently. Curtius and his oodworkers (15) (16) prepared the 3.6-di-isobutyl, di-isoamyl. and a di—isohuyl-i-aminotriasole. Thq found that the triasoles could be prepared by heating the properly sub- stituted mlonylamidic acid with hydrazine at 150° 0. for one day. In 1933. Oberhumer (17) used a case 2 (c.3) “on on? as 2.4::2 e 200 o OOH Mfg/I'fifiz 20.3112 cfiis(i'°) Ian-Ne method similar to that described by Pinnor to prepare 3,5-dimethyl-4- amino-1,2,4-triasole. This was the first preparation of N‘— -CH3 4112 2 Hfigfxmz -—-—-——-——§ ; Lama L 2 nan-mg 3H,, -7- an aliphatic triasole by this method. - In the same year, Aspelund and Angustson (18) heated ethyl acetate and hydrasine hydrate at 130° C. for only four hours and obtained a good yield of the dimethyl amino triu°1°e -8‘ DISCUSSION DISCUSSION The simplest precedure for the preparation of 4-aminotriasole derivatives involved simply heating a mixture of a lower fatty acid and hydrazine hydrate solution. The water originally present in the mixture and the Inter formed during the reaction were removed continu- cusly by distillation. The successive steps in the reaction involved (1) formation of the hydraziniun salt. (2) dehydration of the hydrasin- inn salt. (3) decomposition of the monoacyl hydrazine. and (4) forms;- tion of the triasole. All the methods described in the historical section involving acyl Mdrasines remire the isolation of these com- pounds as intermediates. a step which is not essential in all instances. The distillation method of preparation of the triazoles gave good yields of the compounds in which the alkyl side chains were shorter than three carbon atoms. When the carbon chain contained three carbon atoms. or ehen the benzene ring; replaced. the alkyl side chain, the yields dropped considerably. In attempts to prepare the diisopropyl and diphanyl aminotriasoles by this technique. the diacyl hydrazine was the principal product. This suggests the following mechanism: Step 1. Formation of the hydraziniun salt. it-coon 4 Frau-«rm2 .._...._... R-COO“ man-Hg Step 2. Dehydration of the hydraninium salt to form the nonoacyl hydrazine. ‘ R-<. + 11311-13742 .._..... R-Lj + H20 ‘NH-rm 2 -9- Step 3. Decomposition of the nonoacyl hydrazine to form the diaoyl hydrazine and liberate hydrazine. /° %’ Q) a n w _..___+ R -R 4- H mm “(NE-NH Kin-NH 3 3 2 Step 4. (a) The rearrangeaent of the diacyl hydrazine to the "lalbim" fem. H H :H-N K This is supported by the fact that on treatment with phosphoms pentachloride the diacyl hydrazine forms a diimino chloride.(6). The reaction of the lactim form of the diacyl hydrazine with hydrazine may follow one or more of the paths indicated. 7 IR DH 4b ? ”R H «l HZN-ITHB ..___'.. + 2 H20 . k -an ““9 I OH 4° ‘N H .q. 11211qu -—---—-'-3' R. --R e 2 H20 .10.. _ [2411-in2 xxx-<11 R on v 4d. a HzflJflz ..............p- e H 0 <2“ '