. ,4) r], A) " H \ h“ 1er31 SEN SLATE UNIVERSITY EAST LANSlNG, MICHIGAN THE SYSTHESIS OF SOME ALKYL AND ALKOXEA TEL M~IEIOIETRAZOLES All D TEEIR AHCYTATICI‘I By JOSEPH w. HORTON A TIES IS Submitted to the School of Graduate Studies of Hichigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY .r Department of Chemistry 1960 ACKNOWLEGEMENT The writer wishes to express his appreciation for the most helpful counsel and guidance extended to him by Dr. Robert M. Herbst during the course of this work and to Parke, Davis and Company for finan- cial assistance in the form of a fellowship. TIE SINTLESIS OF SOKE ALKYL AID ALKOXYA {1 AKIHOTETRAZOLES AID TLEIR ALKYLATION By JOSEPr-Z w. HORTON AN ABSTRACT Submitted to the School of Graduate Studies of Kichigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1960 Approved [QM/”4 /W ABSTRACT The alkylation of l-substituted-S-aminotetrazoles by the method of Herbst, Roberts and Harvill (1) has been shown to yield l,H-disubstituted-S-iminotetrazolines (2), with the original substituent remaining in the l-position and the alkylating agent attacking the h-position to form the appropriate disubstituted iminotetrazoline. However, in the alkylation of l-(l',1‘,3',3'-tetramethylbutyl)-5- aminotetrazole with p-chlorobenzyl chloride, the product was not the expected l-(l',l',3',3'-tetramethylbuty1)-h- (p-chlorobenzyl)~5-iminotetrazoline. The tertiary alkyl group was displaced during the course of the reaction with ' the formation of l,H-di-(p-chlorobenzyl)-5-iminotetrazoline. Tb show the fate of the tertiary alkyl group and also to determine if the reaction is characteristic of l-terti- ary alkyl-S-aminotetrazoles, l-tertiary butyl-S-aminotetra- zole was prepared and alkylated with benzyl chloride; two products were isolated. The solid product of the reaction was l,H-dibenzyl-S-iminotetrazoline; the displaced tertiary butyl group appeared as isobutylene. l-(l',l',3',3'-Tetramethylbutyl)-S-aminotetrazole was alkylated with benzyl chloride and the products of the reaction shown to be l,H-dibenzyl-S-iminotetrazoline and a mixture of 2,H,H—trimethyl-l-pentene and 2,H,#-trimethyl—2- pentene closely corresponding to the commercial mixture of 2 the two isomeric trimethylpentenes known as "diisobutylene". To demonstrate that the displacement reaction is a function of tertiary alkyl groups only, and not merely one of size, l-(3'-heptyl)-§-aminotetrazole was synthesized and alkylated with benzyl chloride. Normal alkylation occurred with the formation of 1-(3'-heptyl)~4-benzyl-5-iminotetrazo- line. The displacement of tertiary alkyl groups on alkylation was shown to be a general reaction by the use of ethyl p- toluenesulfonate as an alkylating agent for l-tertiary butyl- S-aminotetrazole. Isobutylene and l,H-diethyl-5-iminotetra- zoline were the products of the alkylation. 5-Hydroxytetrazoles have hitherto been prepared from tetrazoles containing a sulfur atom attached to the S-posi- tion of the tetrazole ring. An attempt to prepare l-substi- tuted-5-hydroxytetrazoles by proceeding through the l-alkyl- h—benzyl-S-ketotetrazolines was made. Also investigated at the same time were the preparation and properties of a group of l-alkoxyalkyl and l-aryloxyalkyl-S-aminotetrazoles. The following tetrazoles were prepared using a proce- dure adapted from Garbrecht and Herbst (3): l-(3‘-isopro- poxypropyl)-5~aminotetrazole, l-(3'-methoxypropyl)-5-amino- tetrazole, 1-(2'-methoxyethyl)-S-aminotetrazole, 1-(2'- phenoxyethyl)-5-aminotetrazole and l-(3'-phenoxypropyl)-5- aminotetrazole. The tetrazoles were prepared from the cor- responding alkoxyalkyl or aryloxyalkylamines by interaction with cyanogen bromide in aqueous ethanolic solution, fol- lowed by treatment with hydrazoic acid. All of the above compounds, except l-(3'-methoxypro- pyl)-5-aminotetrazole were benzylated to form the corres- ponding l-alkoxyalkyl-H-benzyl-S—iminotetrazolines. 1-(3'- Methoxypropyl)-S—aminotetrazole was alkylated with 2-phen- oxyethyl bromide to form 1-(3'-methoxypropyl)-H-(2'-phen- oxyethyl)-5-iminotetrazoline. Conversion of the iminotetrazolines to the correspond- ing ketotetrazolines was done by acetolysis in a manner similar to the method of Percival (h). Attempted hydro- genolysis of 1-(2'-phenoxyethyl)-H-benzyl-5-ketotetrazoline failed to cleave the benzyl group from the ketotetrazoline and produce the desired S-hydroxytetrazole. 2. 3. LITERATURE CITED Herbst, c. Roberts, and E. Harvill, J. Org. Chem., ;§ 139 (1951). Herbst and D. Percival, J. Org. Chem., lg, #39 (195%). Garbrecht and R. Herbst, J. Org. Chem., lfl, 101% (1953). Percival and R. Herbst, J. Org. Chem., gg, 925 (1957). To my wife Jo An TABLE OF CO} I T31? TS TAJLE PF COUTEJTS HISTORICAL IUTRCDUCTTON........................... PART ;.E TIE ALKYLATTCH OF l-iJRT ARY AIKYL-S-AKIHC— fivfinvj’xrv T*3T .LLJALAKJM “LJooooo-oooooooccoco-coco000.000.00.000... ~° 19nfl'r- LSLJ..DJ-LKJnooo00000000000ooooooooooooooooooooooo ’) "' f3“? _‘1"' JS‘VJ-c-htt.’ s.“ oooooooooo-oo-coo-00.040.000.000... “"b u, .‘o' '-. A ‘p- H 1 u — fi/\.'-fi - H Synthesis o; l-alnyl- ,-a;inx--tr wales...... 1-(1' ,l',3‘,3'-Tetra:e t-vloutvl) 5-a1ino- tet; flaZOlOCCOCOOOOOOOOOOOIOO0.000000... l-Tertiary butyl-E ~arin033trazole........ 1-(3'-Heptyl)-E-arinotetrazolo........... A. -ut‘yliction (.f l— (l', ' ,3',3'-totranethvl— outyl)—j-:xfn.tatiu:cl; with pmchloro- Allcylatio n of l—(l', ,3' J' +etraremyl- butyl)-f -;Iino tetrazole with benzyl CthTluO.............................. tertiary butyl—5-111Hm- .- LIL]. a")-.. v.....\,,. .‘.-.‘-K.oooooooo F.) C) .3 VL'At‘ ,1 .1 1_va V’—a 'JJ- . .1 .L totlazo le Jiji e.hy 7 p 1(71930111 ‘ J-~ " \ .-' Jr n31! “Jr-1.-...-v . :g. {J AlLlfl Ji033. Of l-(R'~IOELf1)-_-iv: -9t3tr - at .J- v :rl 3013 with bonzjl Ciloriéc............... Idont ifioa tion of the {as eons product iron the berz”lation of l-t3rti9 ry butyl-5- al.2illot0traZOle.0.0000000000000000000jiC. Identification of the gzlsoous product from the alkylatiol of l- tertiary butyl-S- aninotetrazolc w ith etliyl p-toluenesul- fOl‘lateOOOOOOO0.0.000000000000000000COOCO Identification of the volatile product fr m Lothyloutyl)-)-uuinototrazole with ben- Z171Chlorj.l;;-COO0.0...OOOOOOOOOOOOOOOOOOOO A. OXidatiVe degradaticll. O O O 0 O O O O O 0 O O O O O B. Dog-oc of unsaturation 3nd Bromine IIunlberOOOOOOOOOOOOIOO0.00.0.0.0000... C. Infrarai spnctra comparison.......... PART TWO THE SYNTHESIS AED PROPERTIES OF VARIOUS l-MKOXYIXLKYL-5-AIIETOTETRAZOIAESQQcoco.oocoo.ooooooo. Discussion....................................... Experiz.1ol'1tal..................................... Synt.3 osis of p13t1191iriooal’Vl ph311 :1 etiors... 2-Pht1371ridoot3Vl phonyl ethor............ V 3-Phthaliuidopropyl phonyl 3t33r......... Syncio sis of D30A3xV“lg“l ni3o hy 1n< + 112 R-CN + m< ——> R-fi-N< ———> R-I‘I=C=NH NH R-U"; C=NH HN3 R-N= c-Imz R-E— 'C'I-I-IHZ ‘3’ -———> Herbst, Roberts and Harvill (8), proposed a mechanism 'which.did not involve the use of 'he free imine radical first postulated by Schmidt (9) and used in the mechanism of VCHI Braun and Keller. The mechanism suggested by Herbst, fifi.élp, involved the addition of hydrazoic acid to the H nitrile, followed by an acid catalyzed rearrangement similar to a Curtius rearrangement of acid azides. The rearrange- ment, accompanied by the loss of nitrogen, resulted in the same carbodiimide postulated as an intermediate by von Braun and Keller. Upon the addition of another molecule of hydra- zoic acid, the substituted carbcdiimide was converted to a substituted guanyl azide which cyclized to form the l-sub- stituted-S-aminotetrasole. R-CN + 31113 ——>R-C|J==NH HpsoLL’ R-II= =NH + 1-12 N3 12-1-1: =er + m3 ——-> R—N=c|:-NH2 ——.. R-N———C-IIH2 N3 N§§N//N The work of Hantzsch and vagt (n) has been expanded by Garbrecht and Herbst (10), who found that the reaction of monosubstituted cyanamides with hydrazoic acid in ethereal or aqueous alcoholic solution resulted in the formation of l-substituted-S-aminotetrazoles. R-NH-CN + m3 ———> R-IiI—fi-E-IH2 N 1' \N/ \ Herbst, Roberts and Harvill (5, 11) have developed several methods for alkylation of l-substituted-S-amino- tetrazoles. Alkyl or aralkyl halides, alkyl sulfates or alkyl sulfonates are used as alkylating agents to produce 1,4-disubstituted-S-iminotetrazolines. The first preparation of S-hydroxytetrazole was re- ported by Freund and Paradies (12) in 1901, who prepared the compound by fusion of 5-tetrazolesulfonic acid with potassium hydroxide. The S-tetrazolesulfonic acid was pre- pared through a series of reactions from S-methylthiosemi- carbazide. The complete reaction sequence is as follows: IIHg-NH-C-S-CH HNOZ H-N—C-S-CH HI ll 3 a I ll 3 HOAc ’ H—I'V— Eli-SH King“ H-IIJ—fi-SO3K KQH , Hui.T (IV-OH Stolle (5) also prepared S-hydroxytetrazole, but used fifixminotetrazole as his starting material. The diazonium sulfate formed by diazotization of S-aminotetrazole was treated.successively with cupric hydroxide, hydrogen sulfide and barium chloride. Stolle also prepared S-hydroxytetra- Zole by'the hydrolysis of 5-iodotetrazole with 60% sodium hydroxide . Freund and Hempel (13) prepared l-phenyl-S-mercapto- tetrazole from thiocarbanilic acid aside and partially con- verted it to l-phenyl-S-hydroxytetrazole by oxidation with basic permanganate. C6H5-1~IH-CII=S = C6H5-N=(|3-SH 11:12003’ C6H5-llI———IC':-SH N3 N3 N§§N//N CéHg—N-———-C-SH KMhOh ‘ 06H5-?-————fi-OH C6H5-? K2C037 " r N N\ N 1‘ N - \\N’/ §§N/’ N\ \N/ In an analogous manner, Stolle and Hanke-Stark (1%) ;prepared l-phenyl-5-mercaptotetrazole and converted it to Il-phenyl—S-hydroxytetrazoleby preparing the S-methyl ether smith diazomethane; oxidizing the thioether with acid per- muznganate to the sulfone and hydrolyzing the sulfone with 10% sodium hydroxide. 063154.: C-SH 2. 16323129 06H5-1%———fi-802-CH3 - 01+ N\\ N N N C6H5-IiI-——- fi-soz-crg neon , C6H5-I'J fi-OH 7 Stolle and Henke-Stark (1%) also prepared l—methyl-S- hydroxytetrazole from 1-methy1-5-mercaptotetrazole by oxi- dation to l-methyl-S-tetrazolesulfonic acid with basic per- manganate and cleaving the sulfonate with concentrated potas- sium hydroxide. 1-methyl-5-mercaptotetrazole was obtained by interaction of methyl isothiocyanate and sodium azide. CH3 -N: C :: S + NaN3 C02 CH3-IIJ——— ("i-SH atm. \N CH3-I~|I-——-C-SH 1?:ng CH3-N————(|Ll'-SO3K KOH CH3-Il€————fi-OH N\N/N N\N/N N\N/N Percival (15) treated 1,4-dibenzyl-g-iminotetrazoline saith acetic anhydride and obtained, instead of the expected axzetylimino compound, l,M-dibenzyl-S-ketotetrazoline. c6 H5CH2-N——— B-IiI—fi-NHZ N\ N \ N/ R: tertiary butyl The alkylation of 1-tertiary butyl-S-aminotetrazole was carried out by the procedure of Herbst, Roberts and Harvill (8, 11). The S—aminotetrazole was treated with enough benzyl chloride not only to alkylate the compound to a 1,h-disubstituted-S-iminotetrazoline, but also to re- place the tertiary butyl group, if it could be replaced. The apparatus in which the alkylation was carried out was modified in such a way that any effluent gases would be con- densed in a trap which was cooled in a dry ice-acetone bath. The reaction mixture was maintained at a temperature of 140- 1450 C. for five and one half hours, during which time the mixture became homogeneous. A gas was evolved and condensed in the cold trap as a clear colorless liquid. The volatile Iraterial absorbed bromine with the formation of a produc :identical with an authentic sample of isobutylene dibromine. Zflie solid product of the reaction proved to be 1,4-dibenzyl- 53—iminotetrazeline, which was isolated nd identified as the hpndrochloride. A mixture melting point with an authentic Salnple of l,H-dibenzyl-F-iminotetrazoline hydrochloride Shcnved no depression of melting point. The elemental analy- sis of the benzylation product was in conformity with the dibenazyl derivative. The results of this sequence of reactions led to the hypOthesis that a tertiary allzyl group would be displaced durillg? the course of the benzylation and would appear as the corresxponding olefin. Accordingly, the benzylation of 10 l-(l',l‘,3',3'-tetramethylbutyl)~5-aminotetrazole was car- ried out under similar circumstances; the dry ice-acetone bath was replaced with a salt-ice bath; the temperature held between IHS-ISOO C. The reaction mixture turned to a clear melt and the volatile product evolved was caught in the cold trap. The solid product of the benzylation proved to be l,H-dibenzyl-S-iminotetrazoline hydrochloride. The melting point of the pure compound isolated from the alkylation mixture and a mixture melting point with an authentic sample of l,H-dibenzyl-S-iminotetrazoline hydrochloride were iden- tical. Thus benzyl chloride was also capable of displacing the tertiary octyl group from the E-aminotetrazole. The volatile product from the alkylation decolorized a solution of bromine in carbon tetrachloride; the rapid de- <3olorization of the solution suggested an unsaturated pro- ciuct, possibly a hydrocarbon. Therefore, the material was «Dacidized with permanganate to determine, if possible, the Iacnsition of the double bond. After refluxing the olefin- ‘pexrnmnganate mixture for thirty minutes (17), the reaction mistture was slowly distilled into a solution of 2,M-dinitro- phcnaylhydrazine in perchloric acid. A precipitate formed, Whixah on recrystallization from 95% ethanol melted at 123- 1260 C. The melting point corresponded to that of acetone 2ahwfliinitrOphenylhydrazone, demonstrating that the end of the (blefin consisted of an isoprOpylidene unit. 11 Since the olefin was produced by the diSplacement of the l,l,3,3-tetramethylbutyl group from the E-aminotetrazole, it was assumed to have the molecular formula of C8H16, and the molecular structure corresponding to either‘2,4,h-tri- methyl-l-pentene or 2,h,4-trimethyl-2-pentene. Accordingly, a determination of the decree of unsaturation and bromine number was performed. A modification of McIlhiney's tech- nique (18) was used. A bromine number of 1hh was obtained as the average of four determinations, compared to the theo- retical bromine number of lh3 for a C8H16 hydrocarbon. The average molecular weight of the hydrocarbon calculated from the bromine number, assuming one double bond, was 111 com- pared to a molecular weight of 112 for an octene. Infrared spectra of 2,H,h-trimethyl-l-pentene and 2,h,h- 'trinethyl-2-pentene were compared with the spectrum of the tuaknown hydrocarbon. Similar bands in the spectra of all tfrree hydrocarbons led to the conclusion that the displaced ll,Zl,3,3-tetramethylbutyl group from l-(l',l',3',3'-tetra- merbhylbutyl)-5;aminotetrazole'was a mixture of the two iso- mezric hydrocarbons. A comparison with the Spectrum of di- isobutylene, a commercially available mixture of the two iscuneric octenes, also showed the same bands. To demonstrate that the displacement of the alkyl group Was £1 function of the tertiary character of the group and not nuarely'one of size, a primary amine with a large_second- 12 ary alkyl group was prepared and the corresponding l-sec- ondary alkyl-S-aminotetrazole was synthesized. The primary amine chosen was 3-aminoheptane and was synthesized from 2-ethylhexanoic acid by the following sequence of reactions. The amide of 2-ethylhexanoic acid was prepared from the acid by first making the acid chloride by interaction with thionyl chloride and treating the acid chloride with concentrated aqueous ammonia. CH -CH -CH -CH -CH——C-OH SOCl CH -CH -CH -CH -CH-—C-Cl 2 2 2 2 2 2 3 I ll -—="-> 3 I ll CH3-CH2 0 CH3-CH2 0 CH3-CH2-CH2 -CH2-(l:H- (Ii-C1 NH3 CH -CH2-CH2-CH2-CfH-— (Ii-NHg CH3-CH2 0 CH3-CH2 0 The amide was then caused to undergo a Hofmann rear- Iuangement using bromine and sodium methoxide to form the Inerthyl carbamate; the carbamate was hydrolyzed by refluxing for l’+ hours with constant boiling hydrochloric acid. Q+H9\ /CH-C-NH2 NaOCHa ; cs-wn-g-o-cm, 0 || 7 " C2H5 o Bra CZHE /CH-NH-‘C-O-CH3 HCl 5 /CH-NH2 - HCl 13 The l-(3'-heptyl)-§-aminotetrazole was prepared from the 3-aminoheptane by interaction with cyanogen bromide in aqueous ethanol, followed by treatment with sodium azide and hydrochloric acid. C ”Hams-MHZ men a q+H9>CH-NH-CN as max“ )CH-NH-CN m1 /CH-N —— C-NH2 c H 02% . 2 5 N\ N When the benzylation of l-(3'-heptyl)-S-aminotetrazole vnas carried out in a fashion similar to the previous cases, txiking similar precautions to trap volatile_products, the ricxrmal benzylation product, l-(3'-heptyl)-h-benzy1-5-imino- 'tertrazoline, was obtained and characterized as the hydro- <3k£loride. No volatile material was evolved. This indicates tkmit the displacement reaction observed in the cases of 1- telftiary butyl-S-aminototrazole and l-(l',l',3',3‘-tetra- HEBtfrylbutyl)-5-aminotetras.le is due to the presence of the teI"tiamy'alkyl group on the l-position of the tetrazole rinéi, and not merely due to the size of the alkyl group. Tb further demonstrate that the displacement of the tertixrry alkyl groups is a characteristic of the alkyl group”; only, and not dependent in part upon the benzyl 1% group, the following experiment was performed. Ethyl p-tol- uenesulfonate was used in the alkylation of l-tertiary butyl- S-aminotetrazole. When the alkylation mixture was heated to a temperature of lho-lRSO C., the evolution of a gaseous material was observed, and on subsequent analysis, the gas was shown to be isobutylene. The l,H-dialkyl-S-iminotetrae zoline proved to be l,h-diethyl-S-iminotetrazoline. A mix- ture melting point with an authentic sample of l,H-diethyl- S-iminotetrazoline hydrochloride showed no depression. The above alKVlations of l-tertiary alkyl-S-aminotetra- zoles with various alkylating agents indicate that the dis- placement of the tertiary alkyl group is a function of the tertiary character of the group alone, and not a function cxf the alkylating agent or the size of the alkyl group of Gaither reactant. This conclusion is borne out by the find- fillgs that both tertiary butyl and "tertiary octyl" (l,l,3,3- q 'teatranethylbutyl) groups are displaced with equal facility u. 03’ alkylating agents such as ienzyl chloride, p-chlorobenzyl chloride and ethyl p-toluenesulfonate. A possible mechanism which could be postulated for the alignination of the tertiary alkyl group with the formation Of an: olefin and a symmetrically dialkylated iminotetrazoline Can.'be illustrated using l-tertiary butyl-S-aminotetrazole as all example. The l-tertiary butyl-S-aminotctrazole could '.' De aljrylated according to the mechanism proposed by Percival (15). This mechanism involves the l-substituted-fi-amino- 15 tetrazole in its polar resonance form, which is converted to the 1,4-disubs tituted-S -im biotetra Cline salt. i CH I 3 | 3 (+) c1r3-c—r———c-m~:2 0133-0—21 C—NH2 ' 1‘I (IIH IlI CH3\ 1‘.\ VN/ 3 IT/ ( 3 CH CH | 3 (+) | 3 (+) (-y CH3-(i—IiT—(ll-1-NII2 RX ; CH3-cl: —- 3'1 cl:= mg + x CH3 N§N/N 3 (-) CH3 N\ \N/ N-R x = (:1, p-CH3-cgmso3 The cation of the l-tertiary a ll:yl-H-al}:yl-S-imino- 'tertrazcline salt dissociates into a tertiary alkyl carbonium ice: and a molecule of l-alkyl-S-aminotetrazole. This step Imasr be explained by an electronic shift brought about by the :haffluence of the positively charged imino group and aided tU’ Th-e known tendency of tertiar alkyl compounds to under- go 1xnaic dissociation to form the relatively stable terti- Y’cxarbonium ion and associated anion. The tertiary butyl Garb ocniium ion ca n stabilize itself by ‘he ejection of a pro- ton 811d the formation of the corresponding olefin. 16 + CH3~C-—-N——-C=NH2 , CH3-CG) + II==C-NH2 I l l <——— l IT 1 CH3 N\N/N-R 0E3 I.\N/N-R CH CH CH3-C‘9 ——> Cn3-fi + H CH3 CH2 After a resonance shift into the dipolar ionic form, the l-alkyl-S-aminotetrazole could undergo a second alkyla- tion in the manner suggested by Percival to form a symmetri- cally substituted l,M-dialkyl-S-iminotetrazcline salt. H m (+3 <-) I'v=.—_c|:-NH__ E a :1}: C=NHZ Rxa R-IIV—--('J=NH2 + x N\ N/N-R N\N/N-R I\N/N-R The above mechanism can be used to explain the fact truat the elimination of tertiary alkyl groups is independent Of' the size of the alkyl group in the l-tertiary alkyl-S- aminotetrazole or the nature of the alkylating agent. DEFERIMENTAL PART ONE Experimentall’2 SYNTHESIS OF l-ALKYL-SQAKINOTETRAZOLES These compounds were prepared by methods only slightly different than those used by Garbrecht and Herbst (lo). Egeparation of l- 1'41',3}33'-tetramethylbutyllzjfiaming- tetrazole. A solution of 129 g. (1 mole) of l,l,3,3-tetramethyl- butylamine in 800 ml. of 95% ethanol was cooled to about 5° C. in‘a three liter three necked flask equipped with a :stirrer, dropping funnel, alcohol thermometer and an exit tnibe. With continued stirring and cooling, a solution of 1136 g. (1 mole) of cyanogen bromide in 200 ml. of 95% ethanol and 200 ml. of distilled water was added at such a rate that the temperature of the reaction mixture did not rise above 10° C. Subsequently a solution of ‘+0 g. (1 mole) of“ sodium hydroxide in 100 ml. of water was added with cocfiling and stirring again at such a rate that the tempera- 1. Microanalyses were done by Micro-Tech Laboratories, Skokie, Illinois. 22. Melting points were taken in open capillary tubes and were uncorrected. l8 ture did not rise above 10° C. The resulting solution was stirred in the ice bath for two and one half hours, after which a solution of 81 g. (1.2 moles) of sodium azide in 250 ml. of water was added, followed by 103 ml. of concen- trated hydrochloric acid diluted with 100 ml. of water, both at such a rate that the temperature of the reaction mixture remained below 100 C. The reaction flask was then transferred to a steam bath, equipped with an efficient reflux condenser and boiled under reflux for six hours. On cooling the mixture, the product separated as a mass of needles, which were separated on a Buchner furnel. Cbncentratioa of the mother liquor gave a further quantity (If crude product. The combined crude fractions (lMO g.) xvere recrystallized from one liter of 75% isopropyl alcohol, idsom which the product separated first as long, glistening .nxzedles that changed to heavy, glistening rods on further cooling. A total of 117 g. (60% of theory) of product, 21.3). 201-2020 C. was recovered. The analytical sample was recrystallized again from 99% isopropyl alcohol and melted at 202-20250 C. The Prcniuct is moderately soluble in hot alcohols and aqueous alccfldol, only very slightly soluble in water, benzene, ether or Ffetroleum ether. ltnalysis. Calculated for C9H19N5: C, Sh.8; H, 9.7; N, 35'. 5. Found: C, 5R9; H, 9.6; N, 35.8. 19 Preparation of 1-tertiary butyl-5-aminotetrazole. A solution of 73.1 g. (1 mole) of tertiary butylamine in 800 m1. of 95% ethanol was treated dropwise, while stir- ring and cooling, with a solution of 106 g. (1 mole) of cyanogen bromide in 200 m1..of'95% ethanol and 200 m1. of distilled water. The cyanogen bromide solution was added at such a rate that the temperature did not exceed 100 C. After the cyanogen bromide had been added, a solution of #0 g. (1 mole) of sodium hydroxide in 100 m1. of distilled water was added, keeping the temperature below 100 C. Following the addition of the sodium hydroxide, the reaction mixture was stirred for one and one half hours, Imaintaining the low temperature. Next, a solution of 78 g. (1.2 moles) of sodium azide in 240 ml. of distilled water unas added over a period of five minutes, followed by 100 nnl. (1.2 moles) of concentrated hydrochloric acid diluted wristh 100 m1. of distilled water. Addition was done at such ea :rate that the temperature did not exceed 100 C., and the reaction mixture was stirred for one hour after the addition 0f“ the hydrochloric acid, keeping the temperature below 10° 0, The reaction mixture was boiled under reflux for six houums and allowed to stir at room temperature for an addi- tionmil eight hours, at which time approximately one liter of solvenit was removed by distillation. After cooling, the CTUdea product separated and was collected by filtration. 20 The crude 1-tertiary butyl-S-aminotetrazole was washed with 500ml. of distilled water and was recrystallized from dis- tilled water. The yield was 10% g., 73% of the theoretical, and the purified compound melted at 185-1860 C. Analysis. Calculated for C5H11N5: C, H2.5; H, 7.9; N, 49.6. Found: C, 42.7; H, 7.8; N, 49.8. The acetyl derivative of l-tertiary butyl-S-aminotetra- zole was prepared by heating one gram of the tetrazole with 10 ml. of acetic anhydride for two hours. The compound, l-tertiary butyl-S-acetylaminotetrazole, was recrystallized from a mixture of ethyl acetate and petroleum ether and .meltcd at 98.5-99.50 C- Analysis. Calculated for C7H13N50: C, #5.9; H, 7.2; IV, 38.2. Found: C, #6.0; H, 7.2; N, 38.0. A one liter three necked flask was fitted with a con- cieaiser, mechanical stirrer and dropping funnel and placed in.ea water bath. Two hundred sixty-eight grams, (2.25 molxes) of thionyl chloride was placed in the flask and 288 5.3- (2 moles) of 2-ethy1hexanoic acid was added dropwise ‘Witkl stirring, using the cold water bath as a means of ab- sarbdllg the initial heat of the reaction. After all of the acid Ives added, the cold water bath was replaced by a heat- ing Bwuatle and the reaction mixture was heated at 85° C. for 21 30 minutes. At the end of the heating period, no more fumes of hydrogen chloride and sulfur dioxide were evolved; there- fore the reaction mixture was cooled to room temperature. The apparatus was modified for distillation under reduced pressure and the 2-ethylhexanoy1 chloride distilled at 7’+--76o C. at 16 mm. pressure (19). The yield of acid chloride was 278.5 g., 853.875 01 the theoretical amount. E. Prepapatiop of 2-gphylhexanamidg. A three liter three necked flask was fitted with a Inechanical stirrer, dropping funnel and thermometer. In the flask was placed 800 m1. of concentrated aqueous ammonia, 81nd the flask was cooled in an ice bath to 100 C. Then 278.5 g. (1.71 moles) of 2-ethylhexanoy1 chloride was added drwopwise while stirring, keeping the temperature below 15° C. AIFter all the acid chloride was added, the reaction mixture war; stirred for one hour at 100 C. The contents of the flarik were filtered with suction and washed with three 500 mlojportions of ice cold distilled water to remove ammonium chlrxride; the 2-ethylhexanamide was recrystallized from dis- tilledw'ater and dried overnight in the oven at a temperature of aliproximately 700 C. The yield of 2-ethylhexanamide was 210 E? (86” of theory) of material melting at 101-1020 C. (20). 22 C Prenarat'on of not N- '-he t carbamate. A modified Hefmann reaction (21) was used to prepare methyl H-3'-heptyl carbanate. A three liter three necked "tted with a reflux condenser, dropping funnel and a mechanical stirrer. Anhydrous methanol (1500 ml.) was placed in the flask and 67.h g. (2.93 moles) of metallic sodium was dissolved in tae methanol. After the sodium had dissolved, 210 g. (l.%7 moles) of 2-ethylhexanamide Cissolved in 1000 m1. of anhydrous methanol was added. At this point, 223% g. (1.47 moles) of bromine was added dropwise with con- :stant stirring, and the reaction mixture was boiled under stflux for 30 minutes on the steam bath after the addition of? the bromine. The reaction mixture was acidified with atnetic acid and the methanol was removed by distillation uruier diminished pressure. The residue in the flask was a Paxsty mixture of methyl N-3'-heptyl carbamate, sodium bro- Ufixie and sodium acetate. The mixture was washed with two 5OC>1m1. portions of distilled water to remove the inorganic salts. The crude urethane was a light yellow oil. ..._D Preparation of 3—aminoheptane hvdrochloride. The crude methyl N-3'-heptyl carbamate was boiled under refllxx for approximately 1% hours with 20% hydrochloric acid. At tfue end of the reflux period, almost all of the crude uretkmine had gone into solution. The aqueous layer was sepa- rated.znnd evaporated almost to dryness under diminished pres- 23 sure. The remaining water was removed by azeotropic distil- lation with anhydrous ethanol. The crude 3-aminoheptane hydrochloride was dissolved in absolute ethanol and precipi- tated by the addition of anhydrous ether. Yield was 109 g. (72% of theory). A two liter three necked flask was fitted with an alco~ .hod.thermometer, mechanical stirrer, dropping funnel and re- :flux condenser. In the flask was placed a solution of 75.8 5'. (0.5 mole) of 3-aminoheptane hydrochloride in #00 ml. of 95% ethanol and the resulting solution was cooled to 0° C. fill an ice-salt bath. A solution of 53 g. (0.5 mole) of cynanogen bromide in 100 ml. of 95% ethanol and 100 ml. of diastilled water was added while stirring, keeping the tem- Peznature of the reaction below 100 C. Stirring was con- tirnied during the whole sequence of the reaction. After the addition of the cyanogen bromide solution, ’+0 g. (1 mole) of SOdium hydroxide, dissolved in 100 ml. of distilled water, was sadded while the temperature of the reaction mixture was helabelow 100 C. Following the addition of the sodium hydrcxxide solution, the reaction mixture was stirred for one Eund one half hours, keeping the temperature below 100 C. .A.solution of 39 g. (0.6 mole) of sodium azide in 120 m1. of distilled water was then added over a five minute pericxi, followed by the addition of 50 ml. (0.6 mole) Of 2% concentrated hydrochloric acid diluted with 50 ml. of dis- tilled water. During the addition of the sodium azide solu- tion and the hydrochloric acid, the temperature of the reac- tion mixture was not allowed to rise above 100 C. The ice bath was removed and the reaction mixture was stirred at room temperature for three hours, followed by boiling under reflux on the steam bath for three hours, after which the reaction mixture was allowed to stand for eizht hours. The ethanol was removed by distillation and the reac- ‘tion mixture was stirred in an ice-salt bath until crystal- Zlization occurred. The crude 1-(3'-hepty1)-E-aminotetrazole twas recrystallized from heptane. The yield was MS.2 g. (LI-9.5% of theory) of material which melted at 1’+5-1’+60 C. (8). No depression in melting point was observed on admix- inxre with an authentic sample of 1-(3'-heptyl)-5;aminotetra- sole. ALKYLATICN 0F l-ALKYL-5AAMINOTETRAZOLES The 1-substituted-S-aminotetrazoles were alkylated by DPOCHedures only slightly modified from those of Herbst, Roberts and Harvill (8). A¥E¥juation of l-(l'.1'.3[$3'-tetramethy1butxl2-5-amino- 4K tragole with p-chlorobenzyl chloride. ‘A.nnxture of 9.9 g. (0.05 mole) of 1-(1',l',3',3'- 25 tetramethylbutyl)-S—aminotetrazole and 8.9 g. (0.055 mole) of p-chlorobenzyl chloride was heated in an oil bath at 135-1H00 C. for 18 hours. The reactants liquified com- pletely to form a two phase system in which there was ebul- lition and apparently gas evolution. After cooling, the crude solid product was taken up in about 100 ml. of hot 95% ethanol, the solution diluted with 500 ml. of water and distilled to remove ethanol and excess p-chlorobenzyl chlo- :ride. The aqueous solution was made alkaline with 15 g. of :sodium hydroxide to liberate the iminotetrazoline base. The latter was extracted with two 100 ml. and two TO 131. portions of warm.benzene. Warm ex ractien was neces- soury to prevent crystallization of the base. Evaporation (31‘ the combined benzene extracts left the base as a solid residue. One gram of the crude base was recrystallized first frcnn toluene-cyclohexane mixture, then from 99% isoprepyl alcnahol and then from toluene-cyclohexane mixture again. The jpure base was obtained as coarse, glistening prisms, I"an. 11+8-1Lt90 0. Analysis. alculated for C15H13C12N5: Cl, 21.2; N, 21.CL. Found: Cl, 21.1, 20.9; N, 21.2, 21.2. 'The composition of the base indicated, in addition to the exxpected ring benzylation, that the l,1,3,3-tetramethyl- buty]_ group had been displaced by a p-chlorobenzyl group. 26 The remainder of ‘hc crude base was taken up in 50 ml. of 99% isopropyl alcohc and converted into the hydrochloride by the addition of 15 ml. of concentrated hydrochloric acid. The crude hydrochloride, 12.5 g, of tan crystals. was sus- pended in 50 ml. of boiling toluene. After cooling, the solid was filtered off by suction; 9 g. of hydrochloride, m.p. 2l’+-2l5O C. remained. The material was recrystallized from 80% iscpropyl alcohol from which it separated as glis- tening needles of a dihydrate, m.p. 21H~215° C. Analysis. Calculated for C15HIuCl3N5.2 H20: C1, 26.2; N, 17.2; H20, 7.9. Found: c1, 26.6, 26.5; N, 17.5, 17.5; H20, 7090 A sample of the dihydrate was dried at 800 C. in a \nicuum; the melting point was not changed. Analysis. Calculated for 015B1H013N5‘ C1, 28.7; N, 18.9. Found: Cl, 28.6; N, 18.9. 6‘2? ole wit be c.lo do. ‘A mixture of 9.85 g. (0.05 mole) of l-(l',l',3',3'- tetrwamethylbutyl)-5;aminotetrazole and 15 g. (0.12 mole) of Innizgfil chloride was placed in a side-arm test tube fitted with: a mechanical stirrer and connected to a trap which was Coolxad by a crushed ice-water bath. The reaction mixture was theated to a temperature of IhS-ISSO C. in an 011 bath for 1130 hours. The reaction mixture first turned to a clear 27 melt and a volatile product distilled into the cold trap. After slightly more than an hour, the melt began to solidify and at the end of two hours, the reaction mixture was solid and no more material could be distilled into the cold trap. The cold trap was disconnected, sealed and stored in the refrigerator for further work-up. The solid material was dissolved in hot 95% ethanol and placed in a one liter three necked flask fitted with a Inechanical stirrer, a distillation head and a dropping :funnel. Five hundred milliliters of distilled water was zidded to the approximately 300 ml. of 95% ethanol and the (ethanol was removed by distillation; after which roughly LHDO ml. of water was steam distilled to remove the excess tnanzyl chloride. When the distillate was no longer cloudy, tflle reaction mixture was cooled in an ice bath, 25 g. of scfilid potassium hydroxide was added and the mixture stirred fcu? two hours. The cold suspension was stirred for one half horrr with 150 ml. of other and the ether layer was separated. Tbs? aqueous portion was extracted with three 50 ml. portions 0f (ather and the ethereal extracts were combined and dried OVGI‘ anhydrous potassium carbonate. The ether solution was decanted from the potassium Carinanate and evaporated to dryness on the steam bath with the caid of an air jet. The oil which remained was taken up I'm loo ml. of benzene and was treated with hydrogen chloride 28 gas to precipitate the l,H-dialkyl-S-iminotetrazoline as the hydrochloride. The crude tetrazoline hydrochloride was a light tan solid and was recrystallized from 50% ethanol. The material had the same melting point as l,H-dibenzyl-S—iminotetrazoline hydrochloride and the melting point was not depressed on admixture with an authentic sample of 1,4-dibenzyl-5-imino- tetrazoline hydrochloride (l5). kylation of l-tert'arr butyl-E-aminotetrazole with baggy; ch19; ide . A mixture of 7's. (0.05 mole) of l-tertiary butyl-5- auninotetrazole and 15 g. (0.12 mole) of benzyl chloride vnas placed in a urea tube which was connected to a cold truip immersed in a dry ice-acetone bath. he urea tube wars heated in an oil bath to a temperature of lkO-IHEO C. fox' five and one half hours. During the heathld period, the: reaction mixture liquified to a clear melt and a gas W815 evolved, which condensed in the cold trap to a clear, COJJIrless liquid. The melt solidified in the later stages of idle heating period. The solid material was dissolved in 250 ml. of hot 95% ethaxiol and the resulting solution was placed in a flask fitteui for steam distillation. Three hundred milliliters 0f diAstilled water was added; he alcohol distilled, and apprcucimately 500 ml. of water was distilled to remove any 29 excess benzyl chloride. After cooling, 25 5. of solid potassium hydroxide was added and the reaction mixture was stirred for one and one half hours, followed by extraction of the free base with three 100 ml. portions of ether. The ether extracts were combined and dried over anhydrous potas- sium carbonate. The ether extract was decanted from the potassium car- bonate and evaporated to dryness. The dark brown residue ‘was taken up in benzene and the benzene solution was parti- aally decolorized with Norite. Gaseous hydrogen chloride teas passed into the benzene solution until precipitation was (namplete. The crude l,%-dibenzyl-5-iminotetrazoline hydro- cflaloride was recrystallized from 70% ethanol. The purified compound melted at 212-2130 c. with densomposition and showed no depression in melting point when mixed with an authentic sample of l,1r-dibenzyl-5-iminotetra- zoline hydrochloride (15). Much of L-tertiary but EzlaDluenesulfonate. A mixture of 7 g. (0.05 mole) of l-tertiary butyl-5- a-‘I11:ln<;)tetrazole and 25 g. (0.125 mole) of ethyl p-toluene- Sulfonate was placed in a urea tube which was connected to a CCfild trap immersed in a dry ice-acetone bath. The urea tUbGE‘Was placed in an oil bath and heaced for six hours at a. temperature of 1140-1160 C. During the course of the 30 heating period, the reaction mixture turned to a clear melt and after a few minutes at 11400 C., evolution of {as com- menced. The volatile material was condensed in the cold trap and preserved for further study. At the end of the heating period, the reaction mixture vras poured into 200 ml. of distilled water. A brown oil separated, which was found to be excess ethyl p-toluene- suli‘onate. Fifteen grams of sodium hydroxide was added to the reaction mixture in order to free the l,’+-dialkyl-5- iminotetrazoline from its p-toluonesulfonic acid salt, fol- lowed by the addition of 100 g. of potassium carbonate which was added in one portion to salt out the free base. The free base was extracted from the water by two 100 ml. per- tions and two 50 2:11. portions of ether. The ethereal ex- tracts were dried over anhydrous potassium carbonate. After evaporation of the solvent, the l,’+-dialkyl-5-iminotetrazo- line remained as an oily residue. The material was dissolved in isopropyl alcohol, de- colorized with carbon, treated with 10 ml. of concentrated hydrochloric acid, and the solution evaporated to drzmess. The resulting solid was recrystallized from an isopropyl alcohol-ether mixture. . The melt ing point of the, L13. tar ial .‘J.ac‘ ’3 f) n r "i C O C n w‘ (n, [V “ \y 7 ”Q v‘ A A" M ,‘d v. i I. s-~ J. .3. . - ' Q *«L— / . /"'<_QU . , 9.41“ oilxxiex . ilk; 0.311).: 0.28 .LOl‘. Ox 1 -0 Lillg pC’li-t when nixed with an authentic sample of 1,L+-diethyl-5-in;ino- 4. , 4'“r\ A fl .0 ‘ o 1 fl oe Lu «.th -:-ine 11‘7"].I‘OC‘71C1“.1510 (u ) . ~. 31 Alizylation oi‘ l-B'~h-cth‘l)-§-..;:1inctetrazele with benzyl 1 ' ' I 1110:... ‘3. ) i A side-arm test tube was placed in an oil oat: ce-salt 111ixture . Po cor1ected to a trap which was cooled by an T1 0 side- -:.m: test tube was charng with 9.2 g. (0.05 mole) 01“ 1-(3'-hcptfl)-5-an1i1otetre_. eel" and 15 g. (0.12 mole) of benzyl chloride. A 1::echa11ical stirrer sealed the top of the test tube and the reaction mixture was heated, while stir- ring, for five hours. No gaseous product evolved, even though the tenperature of the oil bath was held at 11150 C. a clear melt which later par Q a. The reaction 1;;ixture fort; tially solidified. The partially solidified reaction nixture was dissol— ed in hot 95% ethanol and placed in a one liter three nee}: zed flask which was fitted with a distillation apparatus, dropping funnel and mechanical stirrer. Enough alcohol was added to make a volume of 300 ml. Five hundred milliliters of distilled water was added and the solution was slowly distilled to remove the alcohol and the excess benzyl chlo- ride. Another 5’00 ml. of distilled water was added through the dropping funnel at the same rate at which it was being removed by distillation. This procedure was necessary to remove unchanged benzyl chloride and henzyl alcohol. When the steam dis cillation was conplete ed, the aqueous solution of l-(3'~heptyl)-11--benzyl-S-iminotetrazoline hydro- ! o q a o . chloride was cooled in an ice bath, 20 g. (0.5 mole) of 32 sodium hydroxide was added and the reaction 111ixture stirred for two hours. At the end of this time, 150 ml. of ether was added to dissolve the brow, gut-Ly fiee l-(3'-heptyl)- 1+-benzyl-Suit-“tinetotrazsoline x-Jhicl'i had separated from the aqueous reaction mixture. The mixture .-as stirred for one half hour and the other layer was separated. The aqueous layer was extracted with three 570 ml. portions of ether; the ethereal layers combined and dried over anhydrous potas- sium carbonate. The ethereal solution was decanted from the potassium carbonate and evaporated to dryness on the steam bath with the aid of an air jet. The oily, crude tetrazoline was taken up in 100 ml. of 95% ethanol and its hydrochloride precipitated with the addition of 20 ml. of concentrated hydrochloric acid. The impure 1-(3'-hcptyl)J+-benZyl-5- iminotetrazoline hydrochloride was redissolved in hot 70% ethanol and decolorized with charcoal, after which crystal- lization was allowed to occur. The reaction gave 12 g. (71.L+% of theory) of material melting at 150-1510 c. Analysis. Calculeted for 035ng0le C, 58.1; H, 7.8; Cl, 11.1%; N, 22.6. Found: C, 58.1; H, 7.9; Cl, 11.3; N, 223.". 1 Identification of the gaseous product of the benzzlation 0f 1- ertiar but 1- -aminotetrazole. The cold trap containing the clear, colorless product 33 from the benzylation of 1-tertiary butyl-S-aminotetrazole was removed from the dry ice-acetone bath and connected to a nitrogen cylinder. A stream of nitrogen x-ras used to sweep the volatile material into a solution of bromine in other, which was partially decolorized. The excess bromine was removed with a solution of sodium bisulfite and the organic layer was separated, washed with three 20 ml. portions of t-rater and dried over anhydrous sodium sulfate. The ether was evaporated and the boiling point, density, index of refraction and infrared spectrum of the residual material were determined. An authentic sample of isobutylene dibromide was pre- pared by dehydrating tertiary butyl alcohol with sulfuric acid and passing the isobutylene into a bromine-ether solu- tion. The isobutylene dibronide was purified as in the above case, and the same physical properties were determinea. Table I Isobutylene dibromide (22) Unknown material b.p. 1%9-151° c. b.p. 1h9-1500 C. DE0 1.7287 9&0 1.728% n50 1. 51186 n2DO 1. 5118 The infrared spectra of isobutylene dibromide and the unknown material showed the same bcnds at approximately equal intensities lgcntification of the gaseous pr ct f om the all: a ion sglfionate. The volatile material from the above alkylation was passed into a solution of bromine in ether, and after puri- fication, the brominated product was shown to be isobutylene dibromide. A 0"idat e . d« ‘on. The oxidation was done according to procedure B. as recommended by Shriner and Fuson (17). One gram of the volatile material was added to 80 ml. of water which contained four grams of potassium perran- ganace. One milliliter of 10% sodiuw hydror ide was added and the reaction mixture was refluxed for 30 minutes. At -eating peLiod, the prarrtus was recificd for distillation and the reaction mixture was distilled Very slowly into a test tube which contained a 5% solution 35 of 2,H-dinitrophenylhyarazine in 20% perchloric acid. A precipitate formed, which after recrystallization from 35% ethanol, melted at 125-1260 C. This melting point corres- ponded to the melting point of acetone 2,M-dinitrophenyl- hydrazone and indicated the volatile material contained a grouping which could be converted to acetone 0n oxidation. B, Degree of ungaturation and Bromine Number. The volatile material decolorized a solution of bromine in carbon tetrachloride, so this technique was used to de- termine the molecular weight of the compound. A modifica- tion of MbIlhiney's technique (18) was used. The results are as follows: Table II % Bromine Bromine Molecular Determination Uptake Number 'Weight I 102.9 1%6.7 108.9 II 100.3 1u3.1 111.7 III 99. 1H1.9 112.6 IV 101. IHH.S 110.6 Average 101.0 lhh.l 111.0 Theoretica1* 100.0 142.6 112.1 3: Based on the assumption of molecular formula of 08Hl6 36 The infrared spectrum of the olefin was conpared with the known spectra of 2,%,4-trimethyl-l-pentene and 2,%,H- trimothyl-B—pentcne (23). In addition, the spectrum of diisobutylene, a commercially available mixture of the two isomeric hydrocarbons, was deternined and compared with the infrared spectrum of the olefin. Similar bands, both in intensity and position, were found in all spectra. it. Jill . .oaouwuumaonwsenm unahudnahzuoemupmul.m..m..H..Hvua scum coomammmm camoao mo Eshuoemm nonwhmcH .H mssmflm mucu0fizwm NH OH m 0 .F 1 q ‘ ll 1 a. —& d’ ission C % Transm O \O OH .mcoahusnowwwm HewosoSEou mo fissuoemm woumumcH .HH muamflm 1 iii. 1' 1‘: 1lldgktuv up": . )ul 5 -\u H .‘C'I‘!J“ll n'!‘.l...|. 4'31 I: I‘ll-1.1 J1; ,I‘IQII. mcouoflZ‘HH -am n O 3 .1 m 8 n a r T % I60 Low b it; .r . cod DISCUSS ION PART TWO Discussion Lhny'different methods have been employed in the prepa- ration of S-hydroxytetrazoles (2%). These methods, however, alnmst without exception, have used a tetrazole which has ‘been substituted by a sulfur containing group in the S-posi- tion with the sulfur atom attached directly to the tetrazole :ring. The purpose of this part of the investigation was 'twofold: to explore the possibility of preparing a group of Ilpsubstituted-5-hydroxytetrazoles and to determine the effect (3f an alkoxyalkyl or aryloxyalkyl group on the reactions of El l-substituted-S-aminotetrazole. A group of l-alkoxyalkyl-S-aminotetrazoles and l-aryl- cxxyalkyl-S-aminotetrazoles was prepared from the correspond- illg alkoxyalkylamines or aryloxyalkylamines by interaction ivtith.cyanogen bromide-and hydrazoic acid in aqueous ethanolic S R-N— fi-NH2 N N \N/ CH3-O-CH2-CH2-, CH3-07CH2-CH2-CH2- CéHg-O-CHZ-CHg-q C6H5-O-CH2-CH2-CH2- RH: cH.3\ . ‘ICHFO-CH2-CH2-CHZ- C“H3 Dnee'to the nature of the compounds, some changes had to be made'in.the separation techniques. l-(3'-ISOpropoxypropy1)~5-aminotetrazole was prepared frOD?tl-isopropoxypropylamine by interaction with cyanogen bI‘Omide in aqueous ethanolic solution. The reaction was I'Hl. The reaction mixture was heated on the steam bath at a teamerature of 50° C. for one hour, cooled to 00 C., and filtered with suction. The precipitate of phthalhydraside 51 was washed with distilled water until the washings were no longer acidic to litmus and the washings were combined with the original filtrate. The combined washings and filtrate were then evaporated to dryness, first by means of a reduced pressure distillation and then on a steam bath by means of an air jet. The colorless amine hydrochloride was washed with anhydrous ether and dried. The yield of 3-phenoxypro- pylamine hydrochloride was 37.5 g. (89% of theory) of mate- rial melting at 165-1660 C. (27). SYNTHESIS OF l-ALKOXIALKYL—5-AKIHCTETRAZOLES These compounds were prepared by methods only slightly different than those used by Garbrecht and Herbst (10). Preparat'on of 1-(3'-i§opropoxypropylz-fi-aminotetrazole. A one liter three necked flask fitted with a mechanical stirrer, dropping funnel, reflux condenser and alcohol ther- mometer was charged with a solution of 23.4 g. (0.2 mole) of 3-iscpropoxypropylamine in 160 m1. of 95% ethanol and the Solution was cooled to 00 C. A solution of 21.2 g. (0.2 mole) of c'anogen bromide in #0 ml. of distilled water and 1+0 mla of 95% ethanol was added with stirring at such a rate that the temperature did not exceed 100 C. After all the Cyanogen bromide solution had been added, a solution of 8 g. (0.2 mole) of sodium hydroxide in 20 ml. of distilled water 52 was added dropwise with stirring, keeping the temperature below 100 C. After the couplete addition of the sodium hydroxide solution, the reaction mixture was stirred for one and one half hours with the temperature held below 100 C. A solution of 15.6 g. (0.2% mole) of sodium azide in 50 ml. of distilled water was adaee with stirring over a period of five minutes, followe‘ by 20 ml. (0.2% mole) of concentrated hydrochloric acid diluted with 20 ml. of dis- tilled water. The diluted acid was added at such a rate that the temperature did not exceed 100 C. After the addi- tion of the hydrochloric acid, the reaction mixture was stirred for three hours, during which time it was allowed to warm to room temperature. At the end of that time, the reaction mixture was heated under reflux on the steam bath ier an additional three hours, still with constant stirring, and then allowed to stand overnight. The ethanol and part of the water were removed by dis- tillation. The tetrazole precipitated on cooling the solu- tion. The solid product was separated by filtration and the filtrate was further concentrated to obtain a second crop of the crude tetrazole. The crude l-(3'-isopropoxypropy1)-5- amflaotetrazole was recrystallized from distilled water. The yield.was 2% g. (65% of theory) of material melting at 128- 1290 C. Analysis. Calculated for C7H15N50: C, M5.M; H, 8.2; N, 37.8. Found: c, 15.1; H, 7.9; :1, 37.8. Preparation of 1-(3'-methoxypropylL-i:a_m_inotetrazole. A solution of 89 g. (1 mole) of 3-n.ethexypropylamine in 800 ml. of 95",}? ethanol was placed in L three liter three necked flask which was fitted with a dropping funnel, reflux condenser, mechanical stirrer and alcohol thermometer. The solution was cooled to 0° C. and a solution of 106 g. (1 mole) of cyanogen bromide in 200 ml. of distilled water and 200 ml. of 957% ethanol was added dropwise, with stirring, at such a rate that the temperature of the reaction mixture did not exceed 100 C. A solution of 110 g. (1 mole) of sodium hydrox- ide in 100 ml. of distilled water wes then added dropwise, with stirring, while holding the temperature below 10° C. After the addition of the sodium hydroxide, the solution was Stirred for one and one half hours while holding the tempera- ture below 10° C. A solution of 78 g. (1.2 moles) of sodium azide in 2h0 ml. of distilled water was added over a period of approxi- mately five minutes and then a mixture of 100 ml. (1.2 moles) of concentrated hydrochloric acid and 100 ml. of dis- tilled water was added to the reaction mixture at such a 1'31 te that the temperature did not exceed 10° C. After the hYdtrochloric acid solution had been added, the reaction mix- tuI‘e was boiled under reflux on the steam bath, with stir- ring, for six hours and then allowed to stand overnight. The solution was evaporated to dryness and the residue, a. paste of mineral salts suspended in the oily, crude tetra- 51;. zole, was treated with three 100 ml. portions of ice-cold anhydrous methanol to remove the tetrazole from the inor- ganic salts. The methanol solution l-ras decolorized with charcoal and the methanol was removed under diminished pressure. The tetrazole remained as an oil, and was in- duced to crystallize by treating with hot benzene and cool- ing the benzene solution. The yield was 6’+ g. (63.‘+% of theory) of material melting at a temperature of 92-930 C. Analysis. CalcuLted for C5H11N50: C, 38.2; H, 7.1; N, was. Found: c, 38.2; H, 7.0; N, who. Pr separation of l- (2 ' -methO‘-:ye th1'1)-5-a_minote trazole . A two liter three necked flask was fitted with a mecha- nical stirrer, dropping furmel, alcohol thermometer and re- flux condenser. In the flask was placed a solution of 58 g. (approximately 0.5 mole) of an aqueous solution of 2-meth— OXYethylamine (65-70%) in 500 ml. of 95% ethanol and the resulting mixture was cooled to 0° C. in an ice bath. A SOlution if 53 g. (0.5 mole) of cyanogen bromide in 100 ml. of 95% ethanol and 100 ml. of distilled water was added dropwise with stirring, keeping the temperature below 10° C. dur ing the course of the addition. Following the addition of “the cyanogen bromide solution, 20 g. (0.57 mole) Of sodium hydra-Lido dissolved in 50 ml. of distilled water was added with stirring, keeping the temperature of the reaction below 0 . ,. . . . . 10 C. After complete »L-::_(ll'ClCJll o: the sodium hydroxide I 55 solution, the rea tion mixture was stirred for one and one half hours, maintaining the low temperature. A solution of 39 g. (0.6 mole) of sodium azide in 150 ml. of distilled water was added over a period of five mir- utes, followed by the addition of 50 ml. (0.6 mole) of con- centrated h"(erCthTjC acid dilute d with an eeue.l volure of 1 distilled water. The hydrochloric acid solution was aade £4 at such a rate that the temperature of the reaction mixture did not exceed 10° C. Following the addition of the hydro- chloric acid, the re action mixture was stirred for three J hours, during which tine it was allowed to warm to room temperature, after which it was boiled und er reflux for four hours. The apparatus was modilie d fo or distillation and the ethanol was removed by distillation under diminished pres- sure. The reaction n xture WiiS cooled in an ice bath, but no product precipitated. The remainder of the solvent was rerwved by distillation under reduced pressure; the residue was transferr e1 to a Soxhlet apparatus and continuously extracted with anhydrous ether for twelve hours. The crude l-(2'-net.o ”"etnrl)---arlno etrazole whic:1 was only very sparingly soluble in other was recrystallized from an atso ute ethan l-ether mixture to yield 22.5 g. (31.5% of theory) of product melting at 112-1130 Anaiyci . Calculated for CHH9HSO: C, 33.6; H, 6.3; 17:193.9. Found: C, 33.5; H, 6.3; N, 48.9. Preparation of 1112'-phenoxvet 1v1)- -aminotetrazole. A one liter three necked flask fitted with a dropping funnel, mechanical stirrer, low temperature alcohol ther- mometer and reflux condenser was charged with a solution of #3.5 g. (0.25 mole) of 2-phenoxyethylamine hydrochloride in 200 m1. of 05% ethanol. The solution was cooled to 0° C. and a solution of 26.5 g. (0.25 mole) of cyanogen bromide in 50 ml. of 95% ethanol old 50 m1. of distilled water was added at such a rate that the temperature did not exceed 100 C. After t1e cyanogen bromide had been added, a solu- tion of 20 5. (0.5 mole) of sodium hydroxide in 50 m1. of distilled water was added at such a rate that the reaction temperature did not exceed 10° C. Following the addition of t' no so o.iium hydroxide solution, the reaction mixture was stirred for an additional one and one half hours, keepil 1g the temperature below 100 C. A solution of 19.5 g. (0.3 mole) of sodium aZ“i do in 60 31. of distill water was added, followed by 25 L1. (0.3 mole) of concentrated hydrochloric acid diluted with an mi ual voline of distillecl water. The two solutions were added at such a rate that t”e temperature of the mixture did not exceed 10° C. The re1cifl on mixture was then stirred overnight at roou terperature. In the morning, a crude yel- low product had crystallized from the solution. The so id was removed by filtration and the mother liquor was concen- trated to obtain a second crop of crude product. 57 The crude 1-(23-p -1nem: et11yl)-5-an:i trazole we 3 recrystallized from absolute ethanol to give 28 g. (57% <1)" ae"""1*'°*v'1‘°l’+lr'o of theOIy ol material we tlnb at 7 - 7) Analysis. Calculated for 09H11N50: C, 52.7; H, E.M; N, 3h.1. Found: C, 52.8; H, 5.5; N, 3#.2. arat on o” ~(3'~phenoxyprepy1J-51aninotetrazole. A solution of #7 g. (0.25 mole) of 3-phenoxypropylamine hydrochloride in 200 ml. of 95% ethanol was placed in a ene litel th‘ee necked flask fitted with an alcohol thermometer, 1 St 11"."01", and droppjjlg fUJlflGl. 5.0: eflux condenser, Lechanice The contents of the flask were cooled to 00 C. and a solu- tion of 26.5 g. (0.25 mole) of cyanogen bromide in 50 m1. Of Orfl ethanol and 50 ml. of distilled water was added at :nlch a rate that the temperature did not exceed 100 C. A soZLution of 20 g. (0.5 mole) of sodium hydroxide in 50 m1. Of distilled water was then added, keeping the temperature Exilow 100 C., and the reaction mixture was stirred for one andl one half hours at the low temperature. Next, a solution of 19.5 g. (0.3 mole) of sodium azide in 330 ml. of distilled water was added, keeping the tempera- ture below 100 c. I‘txrenty-i‘ive milliliters (o. 3 mole) of concuentrated hydrecl loric acid diluted with n1. of dis- til]x:d.water was then added, Blaintaini 1g the lowered tempera- hum}, and the reaction mixture was stirred for three hours, whicll time it was allow ecl to reach room temperature. durin ~ to After the warm-up period, the-reaction mixture was heated to reflux temperature and this temperature was maintained for twelve hours. At the end of the reflux period, the ethanol was re- moved by distillation and the solution was cooled until the crude l-(3'-phenoxypropyl)-S-aminctetrazole precipitated. The precipitate was removed by filtration and the aqueous mother liquor was concentrated and a second crop of material was obtained. The crude tetrazole was recrystallized from absolute ethanol to yield 29 g. (53% of theory) of material which melted at 168-1690 C. Analysis. Calculated for ClOH13N50: C, 5h.8; H, 6.0; N, 32.0. Found: c, 51+.9; H, 6.2; N, 31.7. SYNTHESIS OF 1,l+-DISUBSTITUTaD- 5- II-IBJOTETRAZOLINES The l,h-disubstituted-S-iminotetrazolines were pre- pared by procedures only slight y modified from those of Herbst, Roberts and Harvill (8). tetrazoline. A mixture of 18.5 g. (0.1 mole) of l-(3'-isopropcxy- prople-Séaminotetrazole and 15.2 g. (0.12 mole) of benzyl chloride was placed in a urea tube and heated in an oil bath to a temperature of IMO-145° C. for a period of four hours. 59 The material first turned to a clear melt which solidified during the later stages of heating. At the end of the heat- ing period, the crude reaction mixture was washed out of the reaction tube with hot 95% ethanol and transferred to a one liter three necked flask fitted with a mechanical stirrer, dropping funnel and distillation apparatus. The ethanol solution was diluted with 500 ml. of distilled water and the ethanol was removed by distillation. Following the re- moval of the ethanol, approximately 500 ml. of water was steam distilled to remove any excess benzyl chloride. The reaction mixture was cooled and 10 g. (0.25 mole) of sodium hydroxide was added to convert the crude lo(3'-isgpropoxy- propy1)-h-benzyl-S—ininotetrazoline hydrochloride to the free tetrazoline base. The reaction mixture was stirred for one half hour following the addition of the sodium hydroxide. One hundred milliliters of ether was added to the flask and the mixture was stirred for one half hour, after which the ethereal layer was separated and the aqueous layer was ex- tracted further with two 50 ml. portions of ether. The ethereal extracts were combined and dried over anhydrous potassium carbonate. The dry ether solution was decanted fronzthe potassium carbonate and evaporated to dryness on the steam bath with the aid of an air jet. The oily, residual l-(3'-isopropoxypropyl)-h-benzyl-f- imhiotetrazoline was taken up in 50 ml. of 95% ethanol and Precipitated as the hydrochloride by the addition of 20 ml. 60 of concentra ted hydrochloric acid. The light tin solid was redissolved in hot ethanol and the resulting soluti cn was decolorized with charcoal. After recrystallization from ethanol, the. ieldo1-(3'-isopropoxypropyl)-+-benzyl-;- k: 11.notetrazollhe hydl ochlor ide was 21.3 3. 68.¥£ of theory) of material me ting at 163-16h0 Analysis. Calculated for 014H2201n5c: C, 53.9; H, 7.1; Cl, ll.h; N, 22.5. Found: c, 53.9, 53.9; a, 7.1, 7.0 Cl, 11.6, 11.6; N, 22.u, 22.6. Preparationol-(?'-reL.Lnfill-4.be1zy1.§.ih;w,otgtra- zoline. A urea tube was c‘1arged with 1%.3 g. (0.1 e le) of k 3. (0.12 mole) l” () ('1 O r J C.) N O H O g.) {L H o I ’1 l-(2'-1‘.1L, 1: '1c: :ye ' 1.371)-f7-:.1.1- of benzyl chloride. A necnan cal stil rer was introduced and the re tion n .ix ture was heated to a t«m1perlture of lHO- h-'0 C. for a period of four hours. The mixture first turned to At the end of F! F‘I p. a clear melt and later partially sol'L reaction mix- (:4 U) H F: H: F4) F1. (J Cu the heating period, the par tial--;, A ture was washed from the tube with hot Ch; ethanol and trans- ferred to a one liter three necked flasc fitted .I Iith a dis- tillation apparatus, mechanical stirrer and dropping funnel. Five hundred milliliters of distilled water was add d and he alconol Jas removed by distillation. Following the re- moval of the alcohol, 500 ml. of water was steam distilled to remove any unreacted benzyl chloride; the “ace tion mix- 61 ture was coclef ahfi treats; with 10 g. (0.25 mole) of sodium hydroxide to 11 earste the free te trazol 1e base. ipter stir- ring for one ha t hour, 100 ml. of ether was added and stir- r11g was continued for an additional one half hour. The U.) (‘1' hereal layer was separated and the aqueous layer was ex- tracted with three 50 K1. portions of ether. The ethereal extracts were combined and dried over anhyd ous potassium carbonate. he other was rolloV3d by evaporation on the stean bath with the aid of a jet of air; the residual l-(2'- methoxyethyl)-h-benzyl-§-irinotetrazoline was dissolved in 20 L1. of 95p etllnol and do color ized with charcoal. The alcoholic solution was treated wi'h 10 ml. of con- centrated hydrochloric acid and the precipitated l-(2'-meth- oxyethyl)-h-benzyl-S-ininotetrazoline hydrochloride was re- crystallized froa ethanol to yield 17.2 g. (64% of theory) of material nelting at 161-1620 C. H, 0.0; v.1) \l O m113'8i5. calCUlEItGC‘L fOI‘ CllH16CUI5‘O: C’ 11“?! Cl, 1301; N" 26.0. Foulld C,1TL).L2; H, 6.1; Cl, 13.1{.; 0 N’, 250D. .EVI -h-benzrl- ~im otetra- zoline. A.rixture of 10.4 g. 05 mole) of l-(2'-phenox3ethyl)- fieaminot3trazole eull 7.0 g. (0.06 mole) of benzyl chloride was placed in a urea. tut-:6 a:L; heated :11: an oil bath at 1110- lh5° C. for five hours. The reaction mixture was cooled, 62 and the crufe benzyla ion product was wished from the tube with 100 al. of hot alcohol. The crude material was placed in a one liter three necked flask fitted with a mecharical stirrer, dropping funnel and distillation apparatus. Two hundred milliliters of distilled water was added and the ethanol was removed by distillation. After the renoval of the ethanol, 300 ml. of water was steam distilled to re: ove unreacted benzyl chloride. Tiie reaction miizture was cooled and 10 g. (0.25 mole) of sodium hydroxide was added to liber- te the l-(2'-phenoryetnyl)-k-cenzyl-5-irinotetrazoli.e from 3;: ts hydrochloride. The a xture was stirred for one half H- hour, followed by extraction of the free base with three 50 ml. portions of ether. The ethereal extracts were combined and dried over anhydrous potassium arbonate. The dry ether olution was decanted from the potassium carbonate and satu- rated wit‘z1 dry hydrogen chlorile. The desired compound, l-(2'-phenoxyethyl) -h-benzyl-5 -im actetrazoline hydrochlor- ide, precipitated from solution and was recrystallized from ethanol. The yield was 15 g. (88.2% of theory) of material melting at 17%...175O 0. Analysis. Calculated for cléaln01ngo: C, 57.9; H, f.5; Cl, 10.7; N, 21.1. Found: c, 57. ; H, 5.3; Cl, 10.6; N, 21.1. Preparafi on of l-(3'~Daenor"propyl)-4-oenzrl- -ir.inote1c.- zo 1 . A mixture of 7.2 a. (0.033 mole) of l-(3‘-phenoxy- propyl)-E-aninotetrasole and H.§ g. (0.035 mole) of benzyl chlroide was placed in a urea tube and heated to a tempera- ture of 1110-11150 c. in an oil bath for five hours. The mixture first liquified to a clear melt which solidified during the later stages f heating. At the end of the heating period, he re7ction Ixixtur was washed out of the urea tube with 10 0 *al. of hot 95% ethanol and placed in a one liter three necked flask fitted with a dropping funnel, mechanical stirrer and distillation apparatus. Two hundred milliliter of dis till lea water wasw1 do 3d and the ethanol was retoved by distillation. Approximately l£131.01? water was added drepwise at the same rate it was removed by distil- lation. Any unreacted benzyl chloride was removed by this procedure. The reaction uixture was then cooled and 10 g. dad to liberate t:- {34 (D F '3 H (D (D H I A UL) I of potassium hydroxide was a phen03, on, oi s e e ting pe:i a, a1, TQICLlCn uixture was wasced from the urea tube by neans of 100 nl. of hot 95% ethanol and the ethanol solution was transferred to a 500 mi. f_1sk and diluted with 200 ml. of distilled water. The ethanol was TCIOVCd by distzllrrtion; the con- tents of the flas: were cooled and extracted with two 50 ml. portions of other to remove any unreacted 2-phenoxyethyl 65 bromide. The ethereal extracts were discarded and the aqueous portion was treated with 10 g. (0.25 mole) of sodium hyiroxide in order to free l-(3'-1Wet ioxypropyl)-h-(2"-phen- ”"ethyl)-5-1”nnotetrszoline frozu its hy ”Obr011fl7 The free tetrazcline base wcs ex,racted from its as ueous sus- V - .‘_‘ '. , “T“. a: '1 . 9 cN', . H . . layers were CCLulflOd and urie; cxer anhydrous potaSsiun potassiur carbonate and saturated with gaseous hydrogen chloride. The precipitate of l-(3'-1:et oxyprcnvl)-~-(2" p e o"y‘to"l)-)-imieoterr zoline hydrochloride was recrys ta lli zed from etfanol to yield 17.6 g. ( 56% of theory) of material melting at 1457-11960 0 J- ..'1 .0 - -' o ‘ : O o 1 O Afl'll‘rSlS . CQlCUlE. UCLL .L \Jr CIBEIZOCL. 5’02 0 C, “PT. “1‘, H, 6. F, oz— - 'A'” "'0 ‘ ‘1 0. if ‘ o , Cl, 11.3; h, 22.3. Found. C, +E.o, H, o. , CI, 11.2; PEEL :l'LTHICLRgA DERIVALIV“ '3 CF 1, r-DIDL~flmI~11 145D- S-ILIECTSIJAZCLBIES ‘- --~1r -‘.~ -., -, . r53“ 3 \~ Phen,ltiiouroa usi«vativ ti l-(i' iscpron'rroropwl)-—- he gram of l-(3‘- ise reporypropyl)-#-benzyl-S-iriho- tetrazoliae ydrecelr" .e was oi ssolved in 10 ml. of dis- tilled water and reared with approximately two grams of potassiul . hy ‘rroxide. The aqueous suspension of the oily 66 iminotetrazoline base was extracted with three 10 ml. por- tions of ether and the ethereal extracts were combined and dried over potassium carbonate. The ethereal solution of the free base was evaporated to dryness on the steam bath with the aid of a stream of air and the residual oil was treated with 0.5 ml. of phenyl isothiocyanate and warmed on the steam bath for ten minutes. The crude product was cooled and washed successively with two 5 ml. portions of petroleum ether and two 5 ml. portions of Sofl’isopropyl alcohol. The crude product, a viscous oil, was chilled in a.dry ice-isopropyl alcohol bath and stirred until crystal- lization took place. The crude phenylthiourea derivative was recrystallized from isopropyl alcohol and melted at 121-1220 0. Analysis. Calculated for 021H26N503: C, 6l.k; H, 6.h; N, 20.5; S, 7.8. Found: C, 6l.#; H, 6.2; N, 20.7; S, 7.8. Phenzlthiourea derivatiye of - 2'-me ho et 1 -h-ben 5-iminotetragoligg. A.solution of one gram of l-(2'~methoxyethyl)-h-benzyl- Seiminotetrazoline hydrochloride in 10 ml. of distilled water was treated with two grams of potassium hydroxide.and the resulting suspension of the free iminotetrazoline base was extracted with three 10 m1. portions of ether. The ethereal extracts were combined, dried over anhydrous potas- sium carbonate and the ether removed on a steam bath with 67 the aid of a current of air. The residual l-(2'-methoxy- ethyl)-H-benzyl-5Qiminotetrazoline was treated with 0.5 ml. of phenyl isothiocyanate and the resulting reaction mixture was warmed on the steam bath for ten minutes. The material was allowed to cool and then was washed with two 5 ml. por- tions of petroleum ether and two 5 m1. portions of 50% iso- propyl alcohol. The crude phenylthiourea derivative was chilled in a.dry ice-isopropyl alcohol bath to induce crys- tallization. Recrystallization from 75% isopropyl alcohol gave a material melting at 99.5-100.5° C. Analysis. Calculated for C18H20N603‘ C, 58.7; H, 5.5; N, 22.8; S, 8.7. Found: C, 58.9; H, 5.6; N, 22.9; S, 8.5. P rivat v of - 2'- enox t -H-b - WW. TWO grams of potassium hydroxide was used to liberate the free base from a solution of one gram of 1-(2'-phenoxy- ethyl)-#-benzyl-5;iminotetrazoline hydrochloride in 10 ml. of distilled water. The free base was extracted with three 10 ml. portions of ether and the combined ethereal extracts were.dried over anhydrous potassium carbonate. The ether was removed on a steam bath with the aid of a-current of air and the residual free tetrazoline base was treated with 0.5 ml. of phenyl isothiocyanate. The reaction mixture was warmed for ten minutes on the steam bath, cooled and washed with two 5 m1. portions of petroleum ether and two 5 ml. 68 portions of 50% isopropyl alcohol. The crude phenylthiourea derivative was chilled in a dry ice-isopropyl alcohol bath to promote crystallization and the solid was recrystallized from 75% isopropyl alcohol to give a substance melting at 118-119° 0. Analysis. Calculated for 023H22N6OS: C, 6%.2; H, 5.2; N, 19.5; s, 7.5. Found: c, 6#.l; H, 5.5; N, 18.9; s, 7.3. Ph lt ioure~ rivat v o l- '- h nox ro ~k-b nz l- E-iminotetrazoline. .A solution of one gram of l-(3'-phenoxypropyl)-H-benzyl- 5-iminotetrazoline hydrochloride in 10 ml. of distilled water was treated with two grams of potassium hydroxide and the resulting aqueous suspension of the tetrazoline base-was extracted with three 10 ml. portions of ether. The ethereal extracts were combined, dried over anhydrous potassium car- bonate and the ether removed by heating on a steam bath 'with the aid of an air jet. The residual l-(3‘-phenoxy- jpropyl)-h-benzyl-5-iminotetrazoline was treated with 0.5 ml. «of phenyl isothiocyanate.and warmed on the steam bath for‘ 'ten minutes. The reaction mixture was cooled, washed with ‘two 5 ml. portions of petroleum ether and two 5 ml. portions cxf 50% iSOpropyl alcohol and then chilled in a dry ice- isopropyl alcohol bath to induce crystallization. The crude Phenylthiourea derivative was recrystallized from 75% iso- FPOpyl alcohol to give a material melting at 89-900 C. 69 \ Analysis. Calculated for nghésNéos: C, 68.8; H, ;.+; N, 18.9; S, 7.2. Found: C, 68.9; H, 5.5; N, 18.9; s, 7.2. Phenylthiourea derivative of l-g3'-m§thoxypropylz-h-§2"- One gram of l-(3'-methoxypropyl)-h-(2"-phenoxyethyl)- 5-iminotetrazoline hydrochloride was dissolved in 10 ml. of distilled water and treated with two grams of potassium hydroxide. The aqueous suspension of the free tetrazoliner base was extracted with three 10 ml. portions of ether and the ethereal extracts were combined and dried over anhydrous potassium carbonate. The ether was removed with the aid of an air jet by warming on the steam bath and the residual free base was treated with 0.5 ml. of phenyl isothiocyanate. The reaction mixture was heated on the steam bath for ten minutes, cooled and then washed with two 5 ml. portions of petroleum ether and two 5 ml. portions of 50% isopropyl alcohol. The crude phenylthiourea was chilled in a dry ice- isopropyl alcohol bath to aid crystallization and the solid was recrystallized from 75% isopropyl alcohol to yield a material melting at 92.5-93.5o C. Analysis. Calculated for C20H2MN60233 C, 58.2; H, 5.9; N, 203+; s, 7.8. Found: c, 583+; H, 5.9; N, 20.2; s, 7.6. 7O SYNTHESIS OF l,H-DISUBSTITUTED-SQKETOTETRAZOLINES These compounds were prepared by a slight modification of the procedure of Percival (l5). Pr aration of 1- '-iso ro o ro l -h-ben 1- -k 0- tetrazoline. One gram of l-(3'-isopropoxypropyl)-%-benzyl-5-imino- tetrazoline was obtained from its hydrochloride by dissolu- tion of the hydrochloride in 10 ml. of distilled water and treatment of the water solution with two grams of potassium hydroxide. The aqueous suspension of the free iminotetra- zoline base was extracted with three 10 ml. portions of ether and the ethereal solution was dried over anhydrous potassium carbonate. The ethereal solution of the free base was evaporated to dryness on the steam bath with the aid of a current of air and the residual oil was boiled under reflux for one half hour with 10 ml. of acetic anhy- dride, after which the acetic anhydride was removed by evap- oration on the steam bath. The oily residue was treated ‘with 10 m1. of glacial acetic acid and the mixture was boiled under reflux for thirty minutes, at which time the acetic acid was removed by evaporation on the steam bath with the aid of an air Jet. The process was repeated with another 10 ml. portion of glacial acetic acid and, after evaporation of the acid, the residue was washed with two 71 5 ml. portions of distilled water to remove acetamide. The l-(3'-isopropoxypropyl)-h-benzyl-5-ketotetrazoline was subjected to molecular distillation at a temperature of 130-1350 C./ 1 mm. pressure. The compound solidified on the cold finger, which was chilled with dry ice-isopropyl alcohol, but liquified on warming to room temperature. Analysis. Calculated for Cth20NHO2‘ C, 60.8; H, 7.3; N, 203. Found: c, 60.8; H, 7.1; N, 20.5. Ezeparatign of l-§2'-m§thoxy§thyll-H-bgnzzl-fi-ketotetra- zolin‘ e. An amount of l-(2‘-methoxyethyl)-%-benzyl-5-iminotetra- zoline hydrochloride sufficient to prepare one gram of the free iminotetrazoline base was dissolved in 10 ml. of dis. tilled water and treated with two grams of potassium hydrox- ide. The aqueous suspension of the free base was extracted with three 10 ml. portions of ether; the ethereal extracts were combined and dried over anhydrous potassium carbonate. The dried solution was warmed on the steam bath in a current of air to remove the ether and the residual iminotetrazoline was boiled under reflux for thirty minutes with 10 ml. of acetic anhydride. The reaction mixture was evaporated to dryness on the steam bath with the aid of an air jet and the residual oil was heated under reflux with 10 ml. of glacial acetic acid for one half hour, after which the solution was taken to dryness on the steam bath. The process was 72 repeated with another 10 ml. portion of glacial acetic acid and taken to dryness as before. The crude l-(2'-methoxy- ethyl)-h-benzyl-5letotetrazoline was washed with two 5 ml. portions of cold distilled water to remove acetamide and subjected to molecular distillation at a temperature of 130-1350 C. The ketotetrazoline solidified on the cold finger, which was cooled with dry ice-isopropyl alcohol, but melted on warming to room temperature. Analysis. Calculated for Cllfithko2: C, 56.4; H, 6.0; N, 23.9. Found: C, 56.2; H, 6.1; N, 23.8. Pre aration of l- 2‘- heno eth l -4-benzyl:52ketote§ga- zoline. A.water solution of 11 g. (0.033 mole) of l-(2'-phen- oxyethyl)-H-benzyl-5-iminotetrazoline hydrochloride was treated with potassium hydroxide to liberate the free iminotetrazoline base and the aqueous suspension was ex- tracted with three 50 m1. portions of ether. The ethereal solution was dried over anhydrous potassium carbonate, de- canted from the potassium carbonate and the ether removed by warming on the steam bath. Fifteen milliliters of acetic anhydride was added and the mixture was boiled under reflux for one hour, at which time 25 ml. of isopropyl alcohol was added and the mixture was distilled until approximately one half of the volume was removed. The reaction mixture was transferred to a steam bath and the remainder of the liquid 73 was removed with the aid of an air jet. The residual oil was treated with glacial acetic acid and warmed on the steam bath for one hour, after which the acetic acid was removed with the aid of an air jet. The residual oil was washed with cold distilled water to remove acetamide, and the non-aqueous portion was taken up in cyclohexane and chilled. The crude l-(2'-phenoxy- ethyl)QH-benzyl-5%ketotetrazoline was recrystallized from cyclohexane to yield 7 g. (71% of theory) of material melt- ing at 81+-850 0. Analysis. Calculated for C16316NH02‘ C, 68.8; H, 5.h; N, 18.9. Fbund: C, 65.0; H, 5.5; N, 18.9. Preparation of l-S3‘-phenoxypropyl)-H-benzyl=§§§gtgtg§g§- zoline. Enough l-(3'-phenoxypropyl)-h-benzyl-5;iminotetrazoline hydrochloride to prepare one gram of the free tetrazoline base was dissolved in 10 ml. of distilled water and treated with two grams of potassium hydroxide. The aqueous suspen- sion of the free base was extracted with three 10 ml. por- tions of ether; the ethereal extracts were combined and dried over anhydrous potassium carbonate. The ethereal solution of l-(3'-phenoxypropyl)-4-benzyl-5-iminotetrazoline was evaporated to dryness and the residue was boiled with 20 ml. of acetic anhydride for one hour, then the reaction mixture was evaporated to dryness on the steam bath. The 7% residual oil was mixed with 10 ml. of glacial acetic acid and evaporated to dryness on the steam bath. The procedure was repeated with an additional 10 ml. of glacial acetic acid; the residual oil was washed with 10 ml. of ice-cold distilled water to remove acetamide and the oil was finally subjected to molecular distillation at a temperature of 130- 1350 C./ 1 mm. pressure. The l-(3'-phenoxypropy1)-#-benzyl- 5-ketotetrazoline solidified on the cold finger, but liqui- fied on coming to room temperature. Analysis. Calculated for 017318Nh°2= C, 65.8; H, 5.8; N, 18.5. Found: c, 63.5, 63.8; H, 6.0, 6.0; N, 18.3. The anomalous values for the percentage of carbon in this determination may be accounted for by the presence of acetamide in the amount of 5e10%. This quantity of acetamide could lower the value of carbon without raising the value of hydrogen and nitrogen percentages out of the bounds indicated by the above values. ketotetrazolige. An amount of l-(3'-methoxypropyl)-h-(2"-phenoxyethyl)- 5Aiminotetrazoline hydrochloride sufficient to prepare one gram of the free tetrazoline base was dissolved in 10 ml. of distilled water and treated with two grams of potassium hydroxide to liberate the free base. The aqueous suspension of the iminotetrazoline was extracted with three 10 ml. por- 75 tions of ether; the ethereal extracts were combined and dried over anhydrous potassium carbonate. The dried ethe- real solution was heated on the steam bath in a current of air to remove the ether and the residual l—(3'-methoxy- propyl)-h-(2“-phenoxyethyl)-5-iminotetrazoline was boiled under reflux for thirty minutes with 10 ml. of acetic anhy- dride. The reaction mixture was evaporated to dryness on the steam bath with the aid of an air jet; the residual oil was warmed with 10 ml. of glacial acetic acid for thirty minutes and the acetic acid was removed by evaporation on the steam bath with the aid of a current of air. The pro- cess was repeated with another 10 ml. portion of glacial acetic acid and the l-(3'-methoxypropyl)-H-(2"-phenoxy- ethyl)-5-ketotetrazoline was washed with two 5 ml. portions of distilled water to remove acetamide. The ketotetrazoline was subjected to molecular distil- lation at a temperature of 130-1350 C./ 1 mm. pressure. The compound solidified on the cold finger, which was chilled with dry ice-isopropyl alcohol, but liquified on warming to room temperature. Analysis. Calculated for C13H18Nu03: C, 56.1; H, 6.5; N, 20.1. Found: C, 56.0; H, 6.6; N, 20.0. 76 ATTEMPTED SYNTHESIS OF l-(2'-PHENOXYETHYL)-5. HYDROXYTETRAZOLE The procedure used was only slightly modified from that of Herbst and Percival (3). .A solution of 2.96 g. (0.01 mole) of l-(2‘-phenoxy- ethyl)-h-benzyl-5—ketotetrazoline in 100 m1. of absolute ethanol was Shaken with 0.1 g. of palladium oxide at a hydrogen pressure of 50 p.s.i. in a Burgess-Parr low pres- sure hydrogenation apparatus. After shaking for twelve hours, the catalyst was filtered off, washed with hot ethanol and the ethanol solution was evaporated to dryness. The residue was recrystallized from cyclohexane to give a material which melted at 84-850 C. No depression of the melting point was observed on admixture with an authentic sample of l-(2‘-phenoxyethyl)-h-benzyl-5-ketotetrazoline. The hydrogenolysis was attempted under the same exper- imental conditions with platinum oxide and palladium black as catalysts. No hydrogenolysis was observed. SUMMARY Summary 1. The alkylation of l-(l‘,l',3',3'-tetramethylbutyl)- S-aminotetrazole with p-chlorobenzyl chloride resulted in the displacement of the l,l,3,3-tetramethylbutyl group and the formation of l,H-di-(p-chlorobenzyl)-5;iminotetrazoline. 2. l-Tertiary butyl-S-aminotetrazole was prepared and alkylated with benzyl chloride. Products of the reaction were l,H-dibenzyl-S-iminotetrazoline and isobutylene. 3. Alkylation of l-tertiary butyl-5-aminotetrazole with ethyl p-toluenesulfonate also displaced the tertiary alkyl group to give l,#-diethyl-S-iminotetrazoline and iso- butylene as products. 1+. Alkylation of l-(l',l',3',3'-tetramethylbutyl)-5- aninotetrazole with benzyl chloride gave l,H-dibenzyl-5- iminotetrazoline and an olefin which was shown to be a mix- ture of 2,h,H—trimethyl-l-pentene and 2,H,#-trimethyl-2- pentene. 5. Preparation and alkylation of l-(3'—heptyl)-5- aminotetrazole with benzyl chloride gave no displacement of the secondary alkyl group. The normal alkylation pro- duct, l-(3'-heptyl)-4-benzyl-Seiminotetrazoline was formed. 78 6. A group of l-alkoxyalkyl-E-aminotetrazoles and l-aryloxyalkyl-S-aminotetrazoles were prepared by inter- action of the corresponding alkoxy- or aryloxyalkylamines with cyanogen bromide and treatment of the resulting cyan- amide with hydrazoic acid. 7. Alkylation of the l-alkoxya kyl-S-aminotetrazoles with either benzyl chloride or 2-phenoxyethyl bromide pro- duced the desired l,H-disubstituted-Seiminotetrazolines. The iminotetrazolines were characterized as their hydro- chlorides and phenylthiourea derivatives. 8. Acetolysis of the iminotetrazolines produced the corresponding ketotetraaolines. Attempted hydrogenolysis of l-(2‘~phenoxyethyl)-h-benzyl-5-ketotetrazoline failed to remove the benzyl group and produce the desired 5- hydroxytetrazole. LITERATURE CITED 1. 2. 3. 5. 6. 7. 9. 10. 11. 12. 13. 11+. 15. 16. 17. Literature Cited J. Thiele and H.Ing1e, Ann., gal, 232 (1895). R. Herbst and D. Percival, J. Org. Chem., 12, #39 (19%»). A. Hantzsch and A. Vagt, Ann.,,3fli,.339 (1901). R. Stolle, Ber., 92, 1118 (1929). R. Stolle, J. prakt. Chem.,. 132, 282 (1932). J. Von Braun and W. Keller, Ber.,,§£, 1677 (1932). R . Herbst, C. Roberts, and E. Harvill, J. Org. Chem., 16, 139 (1951). K. Schmidt, Ber., 57,, 70% (1921+). w. Garbrecht and R. Herbst, J. Org. Chem. IQ, 101% (1953)- R. Herbst and C. Froberger, J. Org. Chem., 22, 1050 (1957). bk Freund and T. Paradies, Ber., 33, 3115 (1901). M. Freund and H. Hempel, Ber., gg, 78 (1895).. R. Stolle and Fr. Henke-Stark, J. prakt. Chem., 123:, 261 (1930). D. Percival and R. Herbst, J. Org. Chem., 2;, 925 (1957). L. Birkofer, Ber., ZS, ’+29 (1942). R. Shriner and R. Fuson, The Systemic Identification of Organic Compounds, Third Edition, John Wiley and Sons, Inc., New York, N. Y., l9h8, p. 198. Organic Analysis, Vol. III, Interscience Publishers Inc., New York, N. Y., 1956, p. 237. M. Tiffeneau, Bull. Soc. Chim., (H) 33, 186 (1923). 80 20, H. Raper, J. Chem. Soc., 21, 1837 (1907). 21. Organic Reactions, Vol. III, Jenn Wiley and Sons, Inc., New York, N. Y., 19%, p. 283. 22. ‘w. Keretinsky, Ber., 55, 2757 (1922). 23. Catalog of Infrared Spectral Data of the American Petroleum Institute Research Project HM, Spectrum Serial Numbers H0 and ##9. 2%. F. Benson, Chem. Rev., ’11, 1 (1947). 25. J. Sheehan and W. Bolhofer, J. Am. Chem. Soc., 2;, 2786 (1950). 26. Co SChmidt, Ber., 13-, 3255 (1889). 27. J. Lohman, Ber., 23, 2631+ (1891).