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W'f- THE SYNTHESIS OF SOME ‘G*N)H-DIALKYLAMINO) ALKYL- 3-THIENYL SULFIDE HYDROCHLORIDES By A THESIS Submitted to the School of Graduate Studies of Michiga1 State College of Agriculture and Applied Science in partial tulfileent of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry ‘Year 1952 l 5/1 ‘7 x" 5 2* a J ACE N OWLEDG EMI-JNT The author wishes to eXpress hie sincere appreciation to Dr. Robert D. Schuetx for his friendly counsel throughout the course of this work. ‘5 '—\ ' M I .v at) TABLE OF CCNTLKTS IHTHOEUCTION e e e e e e o e e e e e e e e e e HISTORICAL e e e e e e . e e e e e o e e e e 0 DISCUSSION......,............ CHEMICAL REAGEKTS. e e e e e e o e e c e e e e EXPERIMEETAL e o e e e e e e e e e e e e e e e ¢(N,N-Die.lky1amino)alky1 Alcohol'e . . . . . o(N,N-Dialkylamino)alkyl Chloride HFfiTOGthPidGBe e e e e e e e e e e e e e “JN}H-Dialkylamino)alkyl-Bathionyl Sulfide HYdPOOthPidOIe e e e e e e e e e e e e e d—Hydroxyalkyl-B-thienyl Sulfide: e . e e e cJ-Chloroalkyl-B-thienyl Sulfides. . . . . . Tetramethylene Chlorohydrin. . . . . e . . . ANALYSIS . . e e e e e e e . e . . e . . . e . SUMMARY. . . . . . . . . . . . . . . . . . . . BIBLIOGRAPHY..o.............. VITA C O O O O I O O O C . O O I O O O O O O O Page 11 25 25 30 ‘é‘fif‘ai 52 55 57 LIST OF TABLES Table Page 1 a)~(N,N-Dialkylamino)~alky1 Chloride Hydrochloride: e e e e e e e e e e e e e e e e 13 2‘0l,H-Dielky1amino ulkyl-B-thienyl Sulfide Hydrochloride: . e . e e e e e e e . . . . . e 15 3 «Dnaydroxyalkyl-3-thienyl Sulfidele e e e e e e e 19 h. aé-Chloroalkyl-B-thineyl Sulfidel e e e e e e e.e 19 S p-Phenyl-uzobenzoetee of the -Hydroxyelkyl- BOtBIODYI I“1fidOI e e e e e e e e e e e e e e 20 INTRODUCTION Extensive chemical research has had as its object the elucidation of the structural relationship of compounds to their physiological activity. Numerous investigations have been directed toward the preparation of compounds structur- ally related to naturally occurring active substances, with the aim of finding some relationship between chemical structure and biological activity. Such studies have, in a few cases, led to the synthesis of important new drugs. Compounds which embody the following features in their structures, A-M-(c)n-N= where A represents an aryl group, and H is a heteroatom or heterogroup, have been the keen object of these investi- gations since Einhorn's1 historic synthesis of 'chocain'. Based on the results of many investigations, an im- portant prediction was made by Pyman2 , who generalised the relationship for compounds of this general structure with respect to their physiological actions. Following this, Lofgren3 gave the detailed structural requirements of a compound which should possess local anesthetic preperties. Because of the similarity in chemical structure of the organic sulfides to the ethers, the pharmaceutical usefulness of certain aryl ethers which contain a tertiary amino group, and the reported lower toxicity of the thicphene nucleus compared to that of benzeneu's, the investigation herein reported.was undertaken to synthesise a series of *mixed tertiary amino thienyl alkyl sulfides. These compounds can be represented by the general formula: R q- C"1 - I In the present study, a systematic attempt was made to vary the length of the polymethylene chain, attached between the thienyl group and the amino nitrogen, from two to five carbon atoms. The terminal amino groups in the compounds prepared were piperidine and morpholine. Compounds of this type can be regarded as potential local anesthetics. However, only laboratory and clinical tests, which have not been conducted, as a part of the present work, will determine the usefulness of such compounds. HISTORICAL Part I Local anesthetics, according to Chen and Scotté, are drugs which block pain impulses at the periphery, while general anesthetics produce anesthesia by blocking pain sensation in the brain accompanied by loss of consciousness. Attempts to produce local anesthesia have been known for a great many years. The earliest of these employed the use of manual pressure. A serious objection to this practice is that it often resulted in permanent paralysis or anemia. A later deve10pment depended on spraying the area to be anesthesized with easily volatilized organic liquids which freeze the skin by rapid evaporation. However, a painful period of initiation usually proceeds complete anesthesia and serious damage to the frozen area was often objectionable in this procedure. The use of local anesthetics in.medicine began in lBBh, with.Karl Kcller's7 use of cocaine in cpthamological practice and surgery. Serious objections to the alkaloid are its toxicity and habit forming prOperties. Also it is unstable to the action of microorganisms and purification by heat results in chemical decomposition. Following Willstatter's8 characterisation of cocaine h at the beginning of the twentieth century, a large number of compounds structurally related to cocaine were prepared and studied to determine-what structural features of the cocaine molecule are responsible for its activity. These investigations led the way for Einhorn's1 discovery of novocaine, an excellent local anesthetic of much lower toxicity than cocaine. Until recently most compounds possessing local anes- thetic activity were structurally related to cocaine or novocaine. A thorough review of the field, up to 1930, is given by Hirschfelder and Bieter.9 Recently, however, compounds related only slightly or not at all to Pyman's basic structure have been reported as local anesthetics. These include certain sterols, amino alcohols, n-hexyl amine and phenylethyl alcohol. This indicates a need for a revision of Pyman's hypothesis. Lofgren1° preposed a scheme which accounted for the local anesthetic prOperty of a larger number of compounds. According to this scheme the structures of local anes- thetics should contain the following three units: LipOphillio center-olntermediate chaina-Hydrophillic center Lofgren believes that the following are desirable factors in active compounds: First, the lipOphillic center should be aromatic. Secondly, the intermediate chain should consist of a hydrocarbon residue joined to the aromatic group through an ester, amide, ether oxygen, amino nitrogen, or ketonic carbonyl linkage. Next, the hydrOphillic end should consist of a tertiary or secondary amino group. Finally, it is important to achieve a balance between the lipOphillio and hydrophillic centers. There is given no definition as to the meaning of the term "balance" nor are the factors governing this "balance" explained. Part II it the present time no information is available on the physiological and pharmacological effects of tertiary amine derivatives of mixed Bathienyl alkyl sulfides. However, some work has been done regarding the same effects in the phenyl analogs and a good deal more information has been reported on the other analogs of the phenyl compounds. A review of the feasible methods available for the synthesis of tertiary’amine derivatives of mixed thienyi alkyl sulfides as well as the intermediates used in their- preparation will be discussed to indicate why the methods used in the present investigation were chosen. There were available two methods or variations of these by which the molecule could be constructed. These are shown in the two sequences of reactions: I | SNI 3(CH2)nOH U + Cl(CHz)n0H -—+ [‘5 ll aysna US(CH2)nC1 . J . 44 .,1!I‘, 1' r 3 C Cl [:f:IB CH NR 5 5‘ RZNH'HGI 1121111 4» «(origami—9 Rzn(cnz)noa jig-hazmcnzhcl BC]. anon c1 311 s1ca)nn 2‘ 2):: * U ‘ ———’ U 2n 2 S‘ . 3 Coneiderably more information was available describing the former or these methods. Marveln reported that the reactions between sodium phenoxide and 1.2-diohloroethane or 1,3-dibromopropane gave 55-56 percent and Bil-85 percent yields reapeotively or the tJ-ohloroalkyl phenyl ethers, but there was no evidence that the reaction would be applicable to the more reactive sodium salt or 3-thiophenethiol. A better yield of the (5-ohloroethyl phenyl other is obtained by the use of fi-ohloroethyl-p-toluene sulfonate as a chloroalkylating agent for eodium phenoxide as initially employed by Clemo end Perkin 12.. (111930261 4» ClCHgCfigOh;——’ . 31130200112011201 + 1101 @011 + 033©80200H26H201 K/ > 00112011201 «1» CH3© 303112 V u~ ‘13 I 0 e _e . m ' ”‘ouwo .' \ ‘ L - V. ‘. ins!" 3 - w ,1 ‘ I"- U The (suchloroethyl phenyl ether was obtained in e 76 percent yield by Steinkopf13 on passing gaseous hydrogen chloride into e heated mixture of phenol, sodium hydroxide and ethylene chlorohydrin in alcoholic solution. EtOH ' «1- Real Leder and Stocklinu" reported the production or poohloroethyl phenyl sulfide in good yield by passing ethylene gas into an anhydrous carbon tetrachloride solution of phenyleulfenyl chloride. ,‘ @5111; ”2.032 ..__.. -3032sz - .tu‘ -‘ The condensation of ethylene oxide with thicphenol in the presence or activated charcoal is reported to yield d-hydroxycthyl phenyl sulfide .15 ©1334‘3E302932 301120112011 Fuson and Koohnekelé prepared acmethyl- (3-hydroxy— ,i " ethyl phenyl sulfide by the Meerwein, Ponndorf, Verly reduction of thiOphenyl acetone, obtained by the reaction of sodium thiophenolate with chloroscetoneo o ' o .. Anon), . ,. n 3 ‘ Q 3N9. y alcazccaz-fi -303200113 ——¢ on / o < \> 3011ch . 033 They also obtained the isomeric (methyl. (Sc-hydroxyw ethyl phenyl sulfide by treating thiophenol with allyl alcohol in the presence of sulfur as a catalyst. . CH ' / \ 1 3 SH 4- Chg-CH-CHBOH —e N SOB-($203 Renshov and co-workers17 prepared dialkyleminomethyl alkyl sulfides in good yields by the reaction of meroaptane and secondary amines with formaldehyde, but this method has not been applied to aromatic or heterocyclic mercaptans. 833 s 33H 4» RENE —e~ RSCHZNRZ + H20 Bennett and Berryle, in a method similar to Stein- kopf' s1; successfully prepared fi-hydroxyethyl phenyl sulfide by the addition of ethylene ohlorohydrin to a sodium thic- phenolate solution. They further reported that distillation of the product resulted in an unsaturated compound. 19 However, Kirner of fichydroxyethyl phenyl sulfide. Bennett2° reported was unable to confirm this instability the reaction of the acetates of the longer chained chloroo hydrins with sodium thiOphenolate to yield d-aeetoxy alkyl phenyl sulfides which were hydrolysed and easily converted to the é-chloro compounds by means of thionyl chloride. One method emplOyed in the present investigation was analogous to that suggested by Powellaa and developed by Kimerz3; for the preparation of fl-hydroxylethyl and (.hydroxy-nepmpyl phenyl sulfides. It involved the reaction of the sodium salt of the mercaptan with a chloro- hydrin at reflux temperature and gave excellent yields of the intermediates, (Dc-hydroxyalkyl-B-thienyl sulfides, used in this work. Brookszh reported the preparation of a number of derivatives of 3-thiOphenethiol and among these was the synthesis of p-hydroxyethyl 3-thienyl sulfide which was prepared by the interaction of 3-thiophenethicl with ethylene chlorohydrin in the presence of aqueous potassium hydroxide. No information was given concerning the experimental conditions of this preparation. A second general method of synthesis was based on the preparation of the dialkylamino alcohols. their conversion to the corresponding chlorocompound and then treatment of the latter with the sodium salt of the mercaptan. Bram _e_t_ 5135 reported a satisfactory method for the synthesis of the dialkylamino alcohols by the reaction of piperidine with ethylene chlorohydrin in acetone. 0 : 011360113 Clinton 32 2.1.26 employed a similar method, obtaining 95 percent yields, using ethyl alcohol as a solvent and a small quantity of sodium iodide. The latter reagent served the purpose of shortening the reaction time by exchange of iodine for the chlorine atom in the chlorohydrin. A successful conversion of (l-hydroxyethyl morpholine 10 into the corresponding chloro compound was accomplished by Mason and Block27 who used thionyl chloride in anhydrous chloroform. By careful control of the temperature (3-ohloro- ethyl morpholine hydrochloride is obtained in a good yield. ,-\ CHCl —-\ o H 1103 OH OH + $001 —1—. 61111032021261 + so \ , 2 2 2 \ L. 2 am An elegant synthesis of Y-chloroprOpyl morpholine is reported by Adams and Clarkza, which involved the inter- action of morpholine and trimethylene chlorobromide in absolute benzene, yielding the desired product and the hydrobromide of morpholine in stoichiometrio quantities. C H 2‘3“ '0' BP(CH£)301 ii, ‘ H H(CHz)3°1 '0‘ (ENH'HBP DISCUSSION After consideration of the several methods available for the synthesis of N,N-dialkylaminoalkyl J-thienyl Inlfide hydrochlorides the procedure, used initially in the present investigation, is shown in the following sequence of reactions. No.1 2 321m + Cl(CI{2)nOH 37:63 R2N(CH2)nOH 4. RZNH‘HOl 11 Manager. + some $11. R2N(Cfiz)nCl . 502 1101 ' N303 .. Rzié:H2)nCI «b.3131 ——-—> US(an)nNR2 4- 113101 This method had the advantages of ready.availability of reagents, excellent yields. few side-reactions and easy purification of the product. The preparation of the N(a>-hydroxyalkyl).morpholines and piperidines was carried out by refluxing a stirred mixture of the secondary amine and ohlorohydrin in absolute ethanol to which a small quantity of sodium iodide had been added. The latter accelerated the reaction by replacing the organic chlorine with iodine. The molar ratio of reactlnts employed was two of amine to one of chlorchydrin. and the reaction time was 23 to 2h.hours. The precipitate 12 of secondary amine hydrochloride, proportional to the amount of product. separated during the reaction. In general, piperidine, due to its greater basicity, reacted somewhat more rapidly than did morpholine. The yields obtained varied between 63 and 86 percent. The dhydroxy compounds were obtained as colorless liquids by vacuwm distillation. The N(d>-chloroalkyl) piperidines and morpholines were obtained from the corresponding 40-hydroxy compounds by means of the Darzens reaction using dry chlorofcrm.as a solvent. Yields ranging from 50 to 95 percent were obtained by treating the N(c3-hydroxyalky1) amines with a 25 percent excess of thionyl chloride under conditions which prevented any sudden reaction temperature rise during the addition of thionyl chloride. The reaction was completed by re- fluxing at the boiling point of chloroform for an additional hour. during which the reaction mixture generally became dark red in color and the hydrochloride salt of the product crystallised from the reaction.medium. It was found that yields were considerably improved by sweeping a current of dry air across the reaction surface to remove sulfur dioxide which seemed to cause greater coloration in the reaction mdxture. Five of the ca(dialkylamino)alkyl chlorides have not been previously reported and some of their physical preperties are recorded in Table l. The tertiary amine derivatives of the mixed 3-thienyl 13 ea.e m an a \ om.e na.e :ma-m.mme some m o Hassucuocaflonneoaam. He.e m .H me.e dm.e ”NH- om“ honor emu Hapcn-n-ocnaoceno:uq. mH.~ m we a . . ac.e om.e m.Hmaa om” fleece m o Hanceoceaohnaesmenfihnsexwv. nm.e N am A Hm.e oa.e o:a.m.ema Hoz mo 0 assa1c10ceeesoaea- w 00.0 N N. o mo.e No.5 oom-m.~om Hue am e . Hasaoosaeneoancmiunannoxnv. Wagon Hm .oaso 330300.32“ cw «no.3»... wmwfiodfin hunched oo :78 «Hanson “egoasoo E meaHaonmooaewm anemones qwsqeaxozuaenwsq15 mm 032 032 4- Hal \\ l o The possible side reactions which could be ascribed to the low yields have been reported.31 CHEMICAL REAGENTS V .3Th10phonJE:I(App. 50%) Courtesy of SoconyvVacuum, purified by extraction with sodium hydroxide solution, neutral- ization of the aqueous portion with h drochloric acid and vacuum distillation, b.p., 6MP C 7 mm. Piperidine - Practical grade, Eastman.Kodak Co. Morpholine . Technical grade, Matheson Co. Ethylene chlorohydrin . White label, Eastman.Kodak Co. Prepylene chlorohydrin - White label, Eastman.Kodak Co. Trimethylene chlorohydrin . Practical grade, Matheson Co. Ethylene chlorobromide . Practical grade, Hatheson Co. .Trimethylene chlorobromide - Practical grade, Matheson Co. Pentamethylene chlorohydrin - Obtained as student preparation. Tetrahydrofuran . Courtesy of E. I. DuPont de Nemours Co. Thionyl chloride . C. P. grade, purified by distillation from quinoline followed by distillation from boiled linseed oil. Ethanol - C. P. grade, absolute, dried by distillation from magnesium powder. Chlorofom - C. P. grado, lbflOlth, I‘iOPOk & 0°. Benzene . C. P. grade, dried by distillation from sodium. Ether . C. P. grade, absolute, dried in contact with sodimm. Z—Morpholino-ethanol . Courtesy of Carbide and Carbon Chemicals Co. IlOprOpyl alcohol - C. P. grade, absolute. HydrOgen chloride - Anhydrous gas, obtained in a pressure cylinder from Matheson Co. EXPERIMENTAL a)(N,N-Dialkylamino}alkzl Alcohols 9-Piperidinoethyl alcohol .CHZ‘c§@ C32 /NCHZCH20H \ In a 500 ml three-necked fhask fitted.with a stirrer and reflux condenser was placed 80 g (1.0 mole) of ethylene chlorohydrin, 166 g (2.0 moles) of piperidine and 7.5 g of sodium iodide dissolved in 225 ml of absolute ethanol. The stirred mixture was heated moderately with an electric mantel. Within an hour, precipitation of piperidine hydrochloride commenced. Reaction was continued for 2h hours, at the end of which time there was no further precipitation, indicating completeness of reaction. After allowing the reaction mixture to cool to room temperature, it was treated with a solution containing 200 ml of absolute ethanol and 22 g of dissolved sodium.mota1. The precipitate of inorganic salts was filtered and washed with three 50 m1 portions of dry ethyl ether. The combined filtrate and washings were distilled until a temperature of 110° C was reached in the column head to remove other, alcohol, and unreaoted piperidine. At this point the remaining inorganic salts were removed.by filtration and washed with other which was combined with the filtrate. Following removal of the 26 ether on a steam bath, the residue was vacuum distilled in a colum1 30 cm in height, 12 mm in diameter packed with 1/8" glass helices, to yield 109 s (0.81.15 moles, 814.5% yield) of a clear oily liquid having: an unpleasant odor and boiling at 90-92° c/16-17 mm. A small amount of unreacted chlorohydrin was obtained in the forerun. The reported boiling point of the product is 89-910 0/20 m.32 4-Methyl- fi-piperidinoethyl alcohol (Gaz'céz CH2 N-CHZ-CHCH \ / 1 Using the apparatus and procedure descrioed above, 9“ 8 {1.0 mole) of prOpylene chlorohydrin and 166 g (2.0 moles) of piperidine were dissolved in 225 ml of absolute ethanol containing 7.5 g of sodium iodide. The stirred mixture was heated under reflux for 2h.hours and then cooled. After neutralization, filtration, and distillation as pre- viously described, the crude oil was fractioned giving 112 g (0.785 moles, 78.5% yield) of a clear product boiling at 63-650 C/h-S mm. The reported boiling point is l9h° 0.33 y-Piperidino-n-pro'pyl alcohol (032-032 F, _ CHg-CHZ 27 The apparatus and procedure employed here were the same as in the previous preparations. This compound was prepared by refluxing for 2h.hours a stirred.mixture of 166 g (2.0 moles) of piperidine, 9h 3 (1.0 mole) of tri- methylene chlorohydrin and 7.5 g of sodium iodide in 200 ml of absolute ethanol as a solvent. Following the separation procedure used in the former preparations, the crude product was fractioned, yielding 117 g (0.82 moles, 82% yield) of a pure produce which boiled in the range 83-860 0/8-9 mm. Its reported boiling point is 93.5-95° q/9 mm.36 3-Piperidino~n-butyl alcohol ,cfia-az ‘ as? Incszcszcszcaaos 032.032 Using the same general procedure discussed above, 70 g (0.65 mole) of tetramethylene chlorohydrin, 108 g (1.3 moles) of piperidine and 6 g of sodium iodide dissolved in 150 ml of absolute ethanol were heated under reflux with stirring for 22 hours. Fractionation of the crude product yielded 78 g (0.h95 moles, 76% yield) of the pure product which distilled at lit-116° c/e mm. The reported boiling point for this compound is th-lhh° C/lSmmfih 28 E ~Piperidino-n-amyl alcohol ,032‘052 Griz [scazcaacsacaacnzos Chg-CH2 Following the same technique as that used in the foregoing esperiments, the interaction of 25 g (0.205 mole) of pentamethylene chlorohydrin, 33.8 g (0.1m mole) of piperidine, and 3 g of sodium iodide dissolved in 100 ml of absolute ethanol, gave, after purification and fraction- ation, 22.5 8 (0.128 moles, 61$ yield) of a clear colorless liquid product. The boiling point at a pressure of 10 mm was 131.435" 0. The literature value for the boiling point of the compound is l63-l65° 0/15 mm.» .( methyl- a morpholinoethyl alcohol CH ~CH / 2 .\2 O HCHZCHOH \ / By reacting 57 g (0.5 mole) of prepylene chlorohydrin, 87 g (1.0 mole)- of morpholine and h. g of sodium iodide in 125 ml of absolute ethyl alcohol, there was obtained, according to the previously described procedure, 62 g (0.1).) moles, 86% yield) of a colorless liquid which dis- tilled at 96-97° 0/12 mm. The reported boiling point of this substance is 81-82° 0/5 rtIrri.35 29 Q-Morpholinom-butyl alcohol H - ‘ [C 2 egg 0 HCH CH CH CH CH ‘ I 2 2 2 2 CHZ-CHZ The same procedure and apparatus was used as in the preparations described earlier. By stirring and maintaining at reflux temperature, a mixture of 70 g (0.65 mole) of tetramethylene chlorohydrin, 111 g (1.3 moles) of morpholine and 6 g of sodium iodide in 150 m1 of dry ethanol, there resulted, after purification and fractionation, 82 g (0.511. moles, 79% yield) of a pure liquid product distilling at 131.1330 0/? mm. The boiling point given in the literature is 116-ll7° 0/5 mm.35 6 -Horpholino-n-amyl alcohol IQHZ-CEZ 0‘ [NCHZCHZCHZCHZGHZOH CHz-CHZ By a similar procedure, involving the interaction of 25 g (0.205 mole) of pentamethylene chlorohydrin, 3h 3 (0.1). mole) of morpholine, and 3 g of sodium iodide in 100 ml of absolute ethanol, there was obtained after purification and fractionation 22 g (0.126 moles, 63% yield) of a liquid product boiling at lib-451.5o 0/11 use. The reported boiling point is 133M311,o 0/5 mus; 30 a)-N,N-Dialkylamino)slkylgChloride Hydrochloride: @nPiperidinoethyl chloride hydrochloride CHZ-CH / \2 , e qu INCHchZCI HUI In a 500 ml three-necked flask fitted with a stirrer, reflux condenser, and drapping funnel were placed 65 g (0.5 mole) of dupiperidinoethyl alcohol. Provision was made to draw a slow stream of dry air through the reaction , flask. To the reaction flask was added a solution of 72 g (0.6 mole) of purified thionyl chloride dissolved in 100 ml of dry chloroform at a rate sufficient to maintain the reaction temperature between 50 and 55° 0. Following the addition of the thionyl chloride solution, which required two hours, the reaction.mixture was heated on a steam.bath at reflux temperature for a half hour. Upon cooling to room temperature, a crystalline solid separated from the reaction.mixture. This was collected on a filter and washed with dry ether. The combined ether washings and filtrate was evaporated to one-third of its original volume and on cooling a second crap of crystals was obtained. The two quantities of crystalline material were combined and recrystallized from.250 ml of absolute ethanol, using 5 g of Norit A. to remove colored.material. The crystals, after washing with ether and drying, weighed 60 g (0.33 moles, 66% yield) and had a melting point of 206.5-208o 0. 31 The reported melting point of this material is 208° 0.36 («ethylop piperidinoethyl chloride hydrochloride /csz-c1\i2 ca mosa- ~ci-HCIL \2 The reaction of 71 g (0.5 mole) of x-methyl—(J-pipere idinoethyl alcohol with 89 g (0.75 mole) of thionyl chloride dissolved in 100 ml of dry chloroform, following the pre- viously described procedure, resulted in the formation of a slightly yellow crystalline product. After recrystall- isation from 150 ml of absolute ethanol, there was obtained 52 g (0.265 moles, 53:1 yield) of colorless crystals which melted at 207.5-209° 0. Analysis of the compound for nitrogen gave the following results: came. for casunazz N, 7.07. Found: n, 6.95; 6.99. J-Piperidinc-n-prOpyl chloride hydrochloride ”Kraft?! as, /NGHZCH20H201-Hcl csZ-csz Following the procedure employed in previous prepar- ation, 70 g (0.5 mole) of X-piperidino-n-prOpyl alcohol were treated with a solution of 75 g (0.65 mole) of thionyl chloride dissolved in 75 ml of dry chloroform. The slightly brown crude product was treated as in the foregoing 131‘.th atione, and after recrystallisation from 180 ml of dry 32 ethanol, 60 g (0.305 moles, 61% yield) of a white cry- stalline product melting at 218-219.5° 0 W88. obtained. Its reported melting point is 220° 0.37 ‘Q-Piperidino-n-butyl chloride hydrochloride x°Ha‘°§2 CH2 HCH20320H203201-HCI \CHZ-Cfiz The same general procedure as previously described ‘was employed, using 15.7 8 (0.10 mole) of Aupiperidino- n-butyl alcohol and 15 g (0.125 mole) of thionyl chloride dissolved in 50 ml of dry chloroform. Recrystallization of the crude product from a mixture of equal parts of ethanol andether resulted in 16 g (0.091;. moles. 93.5% yield) of a white crystalline product. The melting point was 160.5-161.5° c, and the reported literature value is 1629 0.33 £§~Piperidino~n~amyl chloride hydrochloride [CHZ.C?2 CHZ-CHZ Adding, during a one hour period, 13.1 g (0.11 mole) of thionyl chloride dissolved in 25 ml of dry chloroform to 15 g (0.088 mole) of 65-piperidino-n-amyl alcohol in 25 ml of the same solvent and.heating this reaction mixture at reflux for an additional half hour resulted in 17.5 g 33 of a crude yellow crystalline product, After recrystallo isation from a mixture of equal volumes of benzene and ethanol, there was obtained 16 g (0.071 moles, 80.h% yield) of a pure crystalline material melting at 138.5- lh0° 0. Analysis of the compound for nitrOgen gave the following data: Calo'd. for 010H21N012x H, 6.19. Found: N, 6.21; 6.33. G-Morpholinoethyl chloride hydrochloride /CHZ-c§2 O‘CH2.C§:032032010301 The reaction of 6h 3 (0.5 mole) of pdmcrpholinoethyl alcohol with 72 g (0.605 mole) of thicnyl chloride using 100 ml of dry chloroform as a solvent over a one hour period resulted in the precipitation of the product as the hydro- chloride. By means of the previously described separation procedure and recrystallization from isOprOpyl alcohol, there was obtained 67.5 g (0.395 moles, 79% yield) of a white crystalline product which melted at 186.187.s° c. The melting point given in the literature for this sub- stance is 182—18250 (3.27 d u-Methyl- a amorpholinoe thyl chlori do hydrochlori do 1032-032. 0 N-C’HzeCH-010H01 \ I ’ 0 Treatment of 35 g (0.21.; mole) of q-methyl-(l-mcrpho. 31L linoethyl alcohol with 36 g (0.3 mole) of thionyl chloride in 100 ml of dry chloroform according to the previously discussed procedure resulted in the formation of the crude yellow product. Recrystallization from dry ethanol gave 36 g (0.19 moles, 79% yield) of a white crystalline solid melting at 180-181.5° C. A nitrOgen analysis of the com- pound resulted in the following data: Calc'd. for C7H15R0012: N, 6.99. Found: N, 6.91: 7.18. J-Morpholino-n-butyl chloride hydrochloride CHa‘CHa ’ \ 0‘ ’ NChchaChZCHZCl .HCI Gila-CH2 Addition from a drOpping funnel of 31 g (0.26 mole) of thionyl chloride dissolved in 25 ml of dry chloroform to ho g (0.226 mole) of 79-mcrpholino-nubutyl alcohol dissolved in 25 ml of the same solvent during a period of one hour followed by 30 minutes of heating at reflux thperature gave a slightly colored reaction.mixture. After the usual isolation procedure and recrystallisation from a mixture of equal parts of benzene and ethanol, there resulted.h7 g (0.22 moles, 97% yield) of a white crystalline solid whose melting point 1. 120-1241" 0. Analysis of the compound for nitrogen resulted in the following information: Calc'd. for CBHI-INOClz! Np 6.52.... Fomd: Np 6063’ 6.61. 35 éfauorpholino-nnamyl chloride hydrochloride [032-932 0‘ lNCHgCHgCHgCHgCHgClOHCl 032-032 The reaction of 15 g (0.087 mole) of €omcrpholino- naamyl alcohol with 13.1 g (0.11 mole) of thionyl chloride dissolved in 50 ml of absolute chloroform resulted in a practically colorless reaction mixture. After separation of the crude product and purification by recrystallization from an isOprOpyl alcohol-benzene mixture of equal parts, there was obtained 19 g (0.083 moles. 95.5% yield) of the pure crystalline product which melted at 1225-1217." 0. A nitrogen analysis gave the following information: Calc'd. for cgnl9uoc12: N, 6.13. Found: N, 6.30; 6.19. J ~1—Iorpholino-n-pr0pyl chloride hydrochloride [CHZ-ng 0 NCH20H20H201'H01 ‘CHZ-cfiz Into a dry three-necked 500 ml flask fitted with a reflux condenser, dropping funnel and stirrer was placed 60 g (0.38 mole) of trimethylene chlorobromide dissolved in 150 ml or dry. benzene. To this solution 50 g (0.6 mole) of morpholine was added with stirring. After the addition of the morpholine was completed the reaction mixture was heated gently until an exothermic reaction took place which caused the solution to reflux for about a half hour without the application of heat. Morpholine hydrobromide had begIm 36 to precipitate almost immediately and after a further half hour of heating at reflux temperature the reaction appeared to be complete as indicated by no further salt formation. The crystalline morpholine hydrobromide was removed by filtration and washed thoroughly with dry ether. The ether washings were combined with the benzene solution and then were extracted with 3N hydrochloric acid. The aqueous acid extract was made basic with lON sodium hydroxide and tho oil layer which separated was removed in a separatory funnel. The aqueous layer was extracted once with other. The combined ether extract and oil were dried over anhydrous sodium sulfate. Gaseous hydrogen chloride was passed slowly into the chilled other solution to form the insoluble amine hydrochloride which was filtered and washed with dry ether. After recrystallization from isoprOpyl alcohol h5 g (0.22 moles, 73% yield) of a whdte crystalline material was obtained which melted at 162.5—16u° c. The free base, obtained by making basic an aqueous solution of the amine salt and extraction with ether, boiled at 101-102° 0/20 mm. The reported boiling point is 113-1150 C/25'mm.28 drcchlorides fi-Piperidinoethyl-B-thienyl sulfide hydrochloride PHZ‘CHa - 30333321“ :csaoHCJ. fl if ~ one-ca; Into a dry threeunecked 500 ml flask equipped with 37 stirrer, reflux condenser and drOpping fUnnel was poured 33 g (0.25 mole) of 3-th10phenethiol dissolved in a solution containing 30 g of sodium hydroxide in 100 ml of water. To this was added from a drOpping funnel 28 g (0.15 mole) of upiperidinoethyl chloride hydrochloride dissolved in 100 ml of water. The stirred.reaction mixture was maintained at reflux temperature during the addition of the salt solution which required an hour. Reaction was continued for an additional hour and a half, at the end of which a yellowish oil had separated. This was removed and the aqueous layer was extracted three times with 100 ml portions of other. The combined ether extracts and oil was washed with a 5 percent sodium hydroxide solution and then.with water to remove any unreacted 3~th10phenethiol. After drying with anhydrous sodium sulfate, the other solution, while being kept cold, was treated with a gentle stream of dry hydrogen chloride until there was no further precipitation of amine hydrochloride. Difficulties were frequently encountered in filtering the stick white hydrochloride. These were best overcome by using just sufficieit hydrOgen chloride for completing the precipitation. The bulky precipitate was collected on a Buchner funnel and the filtrate tested with hydroEen chloride gas for complete removal of cmine. The crude hydrochloride was dissolved in 100 ml of hot, dry iBOprOpyl alcohol and decolorized with Horit. Two recry- stallizations from isOprOpyl alcohol and a final washing with dry other followed by drying gave 29 g (0.12h moles, 38 83% yield) of a white crystalline product which melted at lh9.S-lSO.S° 0. Analysis of the compound for nitrogen - and sulfide sulfur gave the following results: Calo'd. for 01131333201' R. 5.31; 3, 12.15. Found: N. 5.33: 5.27. 8. 12.26; 12.h1. OL-Hethyl-(S opiperidinoethyloJ-thienyl sulfide hydrochloride 4632.032 Following the same procedure as described above, 33 g (0.25 mole) of 3-thiophenethiol dissolved in a solution containing 30 g or sodium hydroxide in 100 ml or water . were treated with 20 g (0.10 mole) of d-methyl-fl-piper- idinoethyl chloride hydrochloride dissolved in 100 ml or water. The addition or the latter reactant required an hour and was followed by a half hour of heating, with good stirring, at reflux temperature. The product was purified in the previously described manner. The hydrochloride was recrystallised from dry isOprOpyl alcohol giving 20 g (0.083 moles, 83% yield) of a crystalline salt which melted at l'I2--l?3.50 O. The analysis of the compound for nitrogen and sulfide sulfur gave the following results: Calo'd. for 012320N3301x N. 5.0u; s, 11.5u. Found: N, 5.01: 5.16. 3. 11.763 11.81. 39 X-?iperidinoen-prOpyl-Bathienyl sulfide hydrochloride 082-032 \ Uscuzwzcnzsfcfi £32.30; -CH 5 2 2 The procedure was the same as that employed in the previous preparations. A quantity of to g (0.2 mole) of ¢ydpiperidino-n-pmpyl chloride hydrochloride in 100 ml of water was added to a wellcstirred solution, at its reflux temperature, of 66 g (0.50 mole) of 3-thiophenethiol dis- solved in 100 ml of water containing to g of sodium.hy. droxide. Two hours were required for the reaction to be completed. After the usual operations. the crude‘hydrou chloride was recrystallized frmm absolute ethanol. The pure crystalline product weighed hS g (0.162 moles, 81% yield) and had a melting point of 120-121“ a. The analysis of the compound for nitrogen and sulfide sulfur resulted in the following data: . Calo'd. for 0128201382018 x. 5.th c. 11.51.. Found: I. 5e09, 5e17e S. 11e36’ 11e67e ‘9oPiperidinoon-butyl-B-thienyl sulfide‘hydrochloride ,mz'cfigfl I. (SCHZCHZCHZCHZR‘GH , 2-301 . 2"“2 5 Interaction of 13.2 g (0.10 mole) of BathiOphenethiol dissolved in a solution of 10 g of sodium hydroxide in 30 ml of water with 19 g (0.05 mole) of ‘)-piperidino-n-butyl chloride hydrochloride in 30 ml of water resulted in the to separation of an oily product after heating for an hour and a half at reflux temperature. After the usual puri- fication procedure the hydrochloride salt of the product was recrystallized twice from a mixture of equal parts of ethanol and'benzene to yield 13 g (0.0hS moles, 89% yield) of a pure crystalline product melting at 131-1330 0. Analysis of the compound for nitrOgen and sulfide sulfur gave the following data: Calo'd. for 013322N82013 N. n.89: 8, 10.98. Found: N. b.723 b.68. 3. 10.61: 10.72. é“-Piperidino-nuamyl-B-thienyl sulfide hydrochloride /GHa-Cflz \ ‘ 0H20H20H26h2032N\ /°Hz‘H°1 ! ' ca ~03 S 2 2 Employing 12 g (0.053 mole) of é?-piperidino-n-amyl chloride hydrochloride in 50 m1 of water and 7 g (0.06 mole) of 3-thiophenethiol dissolved in a solution con» taining 6 g of sodium.hydroxide in 50:ml of water and following the previous procedure, there was obtained. after recrystallisation from an isoprOpyl alcohol and benzene mixture of equal parts, 15 g (0.0h8 moles. 93% yield) of a crystalline product. The observed.melting point was 69.5-91.5° 0. Analysis for nitrOgen and sulfide sulfur gave the following data: Calc'd. for clhhzhhszcl: N, n.58; s. 10.h8. Found: N, h.§2: n.68. 3, 10.5h3 10.67. 3—Morpholinoethyl-3-thienyl sulfide hydrochlorlds 032.0112 scaacn ' 20-ch ' ' ‘03 -GH 2 2 5 Using 11 g (0.083 mole) of 3-thiOphenethiol dissolved in a solution of 10 g of sodium.hydroxide in 50 ml of water and treating it with 10.5 g (0.056 mole) of 9-morpholinoo ethyl chloride hydrochloride in 25 ml of water, there was obtained an insoluble oil after two hours of heating at reflux temperature. After separation and conversion to its hydrochloride salt, it was recrystallized from isoprOpyl alcohol. The crystalline product weighed 11.5 8 (0.0h3 moles. 77.5% yield) and gave an observed.me1ting point of 109-110.5o C. The following data was obtained by analysis for nitrOgen and sulfide sulfur: Calc'd. for 010H16N320013 N, 5.27; 3, 12.06. Found: X. 5e20, 5e31e 3. 11e96‘ 11.81. d-Methyl-flwmorpholinoethyl-B-thienyl sulfide hydrochloride 032*an \ 'O'HCI 632.032 I ' s-cazacnz-x “3 The addition of 18 g (0.15 mole) of 3-th10phenethiol dissolved in a solution containing 10 g of sodiumfihydroxide and 25 ml of water, to 121 g (0.070 mole) of «methyl-.0- morpholinoethyl chloride hydrochloride dissolved in 25 ml of water resulted in the formation of an insoluble oily layer after an hour and a half of heating and stirring at h2 reflux temperature. Using the same isolation procedure and recrystallizing from a one to one isOpropyl alcohol. benzene mixture containing a small amount of other gave 15 g (0.051;. moles, 77% Field) of a pure product melting at 95-96" 0. Analysis for nitrogen and sulfide sulfur gave the following results: Calc'd. for 01111131132001: N. 5.00; 3, 11.06. Found: N, 11.91; 5.18. 8, 11.621 11.70. 'Yahorpholino-n-prOpy1-3-thienyl sulfide hydrochloride /CH2'C{12 I . scngmzcszm ’coacn To 111 g (0.07 mole) of I-morpholino-n-prcpyl chloride hydrochloride dissolved in 25 ml of water was added 18 g (0.15 mole) of 3-thiophenethiol in 25 ml of lON sodium hydroxide. After the reaction was carried out as described above. a yellow oil separated. This, after separation, purification and recrystallization from iscprOpyl alcohol, gave 16.5 g (0.060 moles, 85% yield) of the hydrochloride salt which melted at 157-15850 0. Analysis for nitrogen and sulfide sulfur gave the following results: Calc'd. for 011H13N32001: H, 5.00; s, 11.u6. Found: x. 11.92; 5.09. 3. 11.65: 11.79. 2-Mcrpholino-n-butylo3-thienyl sulfide hydrochloride ”32"ng The quantity. 7 g (0.06 mole) of 3-thi0phenethiol was #3 dissolved in a solution containing 6 g of sodium hydroxide dissolved in 50 ml of water. To this, by means of a drOpping funnel, was added a solution of 8 g (0.037 mole) of )v-mor- pholino-n-butyl chloride hydrochloride in 50 ml of water. Purification and recrystallization from isoprOpyl alcohol gave 9.5 g (0.03h.moles, 92% yield) of crystalline hydro- chloride having a melting point of 1118-11190 0. Analysis for nitrOgen and sulfide sulfur resulted in the following analytical data: Calc'd. for 0123201132001: N, 1.77; 3. 10.98. Found: N, h.883 n.92. 8, 11.193 11.16. a?oMorpholino-n-amyl-B-thienyl sulfide hydrochloride 9324332 SCHzCHaCHzCH 201121! /0 'HCl x ‘ ‘5 " The interdc'tion of 12 g (0.052 mole) of earnerpho- linOon-amyl chloride hydrochloride in 50 ml of water and 7 g (0.06 mole) of 3-th10phcnethiol dissolved in a solution of 6 g.cf sodium.hydroxide and 50 ml of water, produced an insoluble oil in a reaction period of one hour. Following the usual separation procedure and recrystallization of the product from a benzene-iscprOpyl alcohol mixture of equal parts, gave 1h.g (0.0h5 moles. 87.5% yield) of a crystalline hydrochloride which melted at 135-1365o 0. Analysis for nitrogen and sulfide sulfur gave the following data: Gale'd. for 01311221132001: x. 21.55; 3. 10.01. Found: a. 11.51: 11.69. 3. 10.28; 10.61.. .34Horpholino-n-butyl-3-thienyl sulfide hydrochloride CHZ-CH2 ’ \ 3-CH CH CH CH O'HCI I. ‘l 2 2 2 2R\CH2.Cfi2 In order to test the second general method of syn* thesis, 7 g (0.03h mole) of .9-chloro-n-butyl¢3~thienyl sulfide and 6 g (0.070 mole) of morpholine were added to 50 ml of dry benzene and allowed to stand with occasional shaking for a one-half hour period. Following this the solution was heated at its reflux temperature for four hours, at the end of which no additional formation of morpholine hydrochloride was observed. After cooling to room temperature, the reaction was made basic and steam distilled until the Simon's test for secondary amines indicated the complete removal of excess morpholine. The solution remaining in the distillation flask was made acidic with us hydrochloric acid and extracted twice with ether to remove unreacted. )~chloro-n-buty1-3-thienyl sulfide. 0n neutralization with hN sodium hydroxide a brownish oil separated which was extracted twice with ether and dried over anhydrous sodium sulfate. Dry hydrogen chloride was slowly passed into the chilled ether solution to form the hydrochloride, which separated as a clear oil. Consider- able difficulty was experienced in crystallizing the pro- duct and‘was accomplished only by seeding the oil with a crystal of the compound prepared previously by the first general method. After recrystallization from isoprOpyl ’45 alcohol, there was obtained 1.0 g (0.0035 moles, 10.5% yield) of a crystalline product melting at 11.16.541.180 0. There was no depression in melting point when a sample of this product was mixed with a sample of the substance prepared in the previously described manner. Analysis for nitrOgen gave the following data: Calc'd. fOI' clzszonszom: N, 11.77. Found: N, 11.56; 11.51. 9-Piperidinoethyl-3-thieny1 sulfide hydrochloride ”332-0132 -scs on s as .1101 ' ‘ 2 2 ‘03 -cfi 2 [5) 2 2 According to the method employed in the previous preparation. 11:. g (0.079 mole) of 6-chloroethylc3-thienyl sulfide and 12 g (0.11). mole) of piperidine were added to 100 ml of dry benzene and allowed to stand for a half hour followed by heating at the reflux temperature of the solution for five hours at the end of which there was no further separation of piperidine hydrochloride. After the usual separation procedure the hydrochloride was obtained as a clear oil which could be crystallized only by seeding with a crystal of the coupound prepared by the first method. The solid product was recrystallised once from dry isopropyl alcohol by seeding the hot solution with a few crystals of the material. The yield of crystalline material obtained was h g (0.015 moles. 19% yield). The substance melted at 1118450" 0 and gave no depression in melting point when mixed with a sample of the same compound prepared previously. h6 Analysis for nitrOgen gave the following results: Calc'd. for 011s18s3201: s. 5.31. Found: a, 5.21: 5.19. 69oflydroxyalkzlogothienyl Sulfide; «9nfiydroxy-n-butyl-B-thienyl sulfide In a 500 ml three-neckod flask fitted with a stirrer and reflux condenser was placed 87 g (0.75 mole) of 3-thioo phenothiol dissolved in a solution prepared from 35 g of sodium hydroxide and 150 ml of water. To this stirred solution was added dropwise, over a half hour period, 65 g (0.60 mole) of tetramethylene chlorohydrin. Immediately after the addition of the chlorohydrin was completed the reaction.mixture was heated to its reflux temperature for an hour and then.allowed to cool to room temperature, at which point a yellow oil separated. The oily layer was separated in a separatcry funnel and the aqueous fraction extracted twice with ether. The combined other extracts and oil were washed twice with water and dried over anhydrous sodium sulfate follOwed by removal of the other by dis- tillation. The oil was vacuum distilled using the column previously described and resulted in 96 g (0.51 moles, 85% yield) of a clear slightly yellow liquid product. A few ml of unreacted chlorohydrin were obtained in the 1+7 fore-run. The product boiled at 131.1«435o 0/1.5 m. Analysis for sulfide sulfur gave the following results: Calc'd. for 085123208 3. 16eh9e Found: 3. 16e023 16ell-2e Methyl. p -hydroxye thyl —3-thi enyl sulfide S-CHz-CH-OH [a -" ' 53 :5: 3 Employing the previously described procedure, 58 g (0.50 mole) of 3-thiOphenethiol dissolved in 30 g of sodium hydroxide and 150 ml of water was reacted with 57 g (0.60 mole) of propylene chlorohydrin. After the afore mentioned separation the liquid product was distilled in vacuo to yield 70 3 (0.1.85 moles. 97% 11.1.1) of clear yellowish oil boiling at 116° 0/5 m. Analysis for sulfide sulfur gave the following results: Calc'd. for 07810320: 3, 18.110. Found: 3. 18.26; 18.81. A second preparation gave a yield which was 85 pereent of the theoretical and the product distilled at 111° c/l. mm. (Sofiydroxye thyl-3-thienyl sulfide 030112011203 By the interaction of 35 g (0.30 mole) of 3-thiophene- thiol dissolved in a solution of 15 g of sodium hydroxide and 150 ml of water with 28 g (0.35 mole) of ethylene chlorohydrin a yellow oily layer was obtained after a reaction period of one hour. Separation and vacuum dis- 118 tillation gave h0.5 g (0.25 moles, 8h% yield) distilling at 1145.117" c/z mm. Only on. boiling point. 125° 0/1 an. is given in some unpublished work.2h [Analysis of the compound for sulfide sulfur gave the following results: Calc'd. for 0638820: 3. 20.02. Found: 3. 19.76; 20.23. 44- o ,alk lo othien l Sulfide; 9-Chloro-n-butyl—3-thienyl sulfide The quantity. 5h g (0.h5 mole) of thionyl chloride was added dropwise to a solution of 68 g (0.36 mole) of 3-hydroxy-n-butyl-3-thienyl sulfide dissolved in 35 g of pyridine. The reaction was carried out in an apparatus consisting of a three-necked flask fitted with a stirrer. dropping funnel. and reflux condenser. Provision was made ”to allow a stream of dry air to be drawn across the surface of the reaction.mixture. Stirring was maintained during the addition of the thionyl chloride and at various time intervals the reaction flask was immersed.in an ice bath to control the exothermic reaction. Addition of the thicnyl chloride required an hour after which the reaction mixture was allowed to cool to room.temperature. The I crude. brown. oily product was washed twice with water, dissolved in 200 ml of other and dried over anhydrous 119 sodium sulfate. After removal of the other by distillation, the oil was distilled under vacuum to give 17 g (0.086 moles. 221% yield) of greenish yellow oil boiling at 131° 0/1.5 mm. Analysis of the product for sulfide sulfur gave the following results: Calc'd. roi- 033113201: 3. 15.51. round: 5. 15.78; 15.92. A second preparation employing reversed addition of the reagents resulted in a 29 percent yield of product which distilled .1: 135° c/2.5 mm. A ~0hlcroethyl-3-thienyl sulfide USCH 203 201 The quantity. 50 g (0.113 mole) of 3—th10phenethicl was dissolved in a solution of 18 g of sodium hydroxide and 200 ml of water. The resulting solution was poured into a 1000 m1 flask fitted with a reflux condenser. stirrer and dropping funnel. The stirred mixture was heated to reflux temperature and 73 g (0.50 mole) of ethylene chlorobromide was added slowly over a period of a half hour. The reaction was allowed to continue an .. additional hour after the addition of ethylene chloroa bromide was complete. Upon cooling to room temperature, a heavy yellow oil separated and this was collected with the aid of a separatory funnel. The aqueous layer was extracted with a 100 m1 portion of other which was added 50 to the oil. The resulting other solution was washed with water followed by drying over anhydrous sodium sulfate. The ether was removed by distillation and the yellow oil remaining was fractionated under vacuum using the previously described column. There was a few ml of forerun followed by 55 g (0.31 moles. 72% rind) of a slightly yellow, clear oil which boiled at 123° c/a mm. Analysis for sulfide sulfur gave the following data: Calc'd. for C6H732011 3, 17.93. Found: 3, 18.38; 17.71. Tetramethzlene Chlordhzdrin A 1000 ml flask was equipped with a reflux condenser, thermometer, and gas diffusion tube extending to the bottom of the flask. The quantity. hOO g (6.h5 moles) of tetra- hydrofuran were added to the flask and heated to its reflux temperature (6h° C) using an electric mantel. The introduction of gaseous hydrogen.chloride being commenced at this point. The reaction was continued for 18 hours in which time the reaction temperature had risen to 103° 0. Excess hydrogen chloride was removed from the reaction mixture with a water aspirator and the product was dried by the addition of anhydrous sodium.sulfide. A small quantity, 5 g, of capper powder was added to the solution to prevent peroxide formation. The reaction mixture was distilled under vacuum producing 195 g of unreacted tetra- hydrofuran as a forerun, followed by 158 g (3.29 moles, 51 51% yield) which distilled at “Io-71° (3/? mm. Starr and Hixson30 reported a Eli-S7 percent yield of product boiling at 87° C/lO mm. ANALYSIS Determination of Nitrogen The analytical method used.was that of Redsmann39 which employed the KJeldahl method on a semimicro scale. Using a'microdKjeldahl distilling apparatus, a mixture containing 20-60 mg of sample, 0.1 g quantity of equal parts of mercuric oxide and potassium sulfate in the ratio of 8 to 100, and S’ml of concentrated sulfuric acid, was digested until a clear, colorless solution resulted. After cooling the digested mixture was diluted with 15 ml of 50 percent aqueous sodium hydroxide. The receiving flask consisted of a 200 ml conical flask containing a known amount of standard hydrochloric acid. After hO—SO ml of distillate was collected, a few drOps of methylene blueemethyl red indicator were added and the solution was titrated with standard sodium hydroxide. Determination of Sulfide Following the procedure of Siggia and Edsbergho. a sample containing about 0.002 mole of alkyl sulfide was weighed directly into a 250 ml conical flask and dissolved in no ml of acetic acid. To this solution was added about 10 ml of distilled water followed by 3 ml of concentrated 53 hydrochloric acid. The solution was titrated with 0.1K bromate-bromide solution until the first yellow color due to excess bromine was visible. A blank was run on the solvents to correct for the amount of excess bromine needed to detect the endpoint. l. 2. 3. 11. SUMMARY Two s>~piperidinoalkyl chloride hydrochlorides and three a amorpholinoalkyl chloride hydrochlorides were prepared for the first time and some of their physical properties are reported. Two £3dhydroxyalkyle3-thienyl sulfides with two and four carbon atoms in the alkyl chain were prepared for the first time and some of their physical preperties were determined. The p-phenyl asobensoate derivatives of these were synthesized and their melting points are reported. Two fi’ochloroalkyl-B-thienyl sulfides having two and four carbons in the alkyl chain were prepared for the first time and some of their physical preperties were determined. Ten .s(N,N-dialkylamino)alkyl-Bcthienyl sulfide hydro- chlorides were synthesised for the first time and some of their properties were investigated. 1. 2. 3. LL. 5. 6. 7. 8. 9. 10. 11. 12. 13. 11+. 15. 16. 17. 18. 19. 20. 21. 22. BIBLIOGRAPHY Einhorn and Uhlfelder. Ann” 121.. 131 (1908). Pyman, J. Chem. Soc.. 91. 1793 (1908). Erdtman and Lofgren, Svensk. Kem. Tid., 11.9.! 163 (1937). Campaign and LeSeur, J. Am. Chem. 300.. 13‘. 333 (1911?). Campaign, J. Am. Chem. 300.. IE. 31198 (19118). Chen and Scott. First Nat. Med. Chem. Syrup... p. 15. Ann Arbor. Michigan (19118). Keller, Wien Med. Wochenschr., 21", 1271, 1310 (18611). Willstater, Wolfes, and Mader, Ann., 1.1111! 111 (1923). Hirschfelder and Bieter, Physiol. Rev.. .13. 190 (1932). Erdtman and Lofgren, Svensk. Kem. Tid" 12, 323 (19116). Marvel and Tanenbaum, ”Org. Syn.“ Col. VoI. John kiley and SURE, 1:10.. NOW York, Ne Ye; 19%! P. h35e Clemo and Perkin, J. Chem. 300.. 12$. 6142 (1922). Steinkopr. Herold, and Stohr, Ber... 53, 1012, (1920). Leder and Stocklin, Ber” 26;. 1111. (1925). Nenitaesen and Scarlatescu, Ber.. 2813,. 589 (1935). Fuson and Koehneke, J. Org. Chem. 13, 706 (19119). Renshow and Searle. J. Am. Chem. 800.. 52. 2057 (1937). Bennett and Berry, J. Chem. 800.. 129, 1676 (1927). Kirner and Richter. J. Am. Chem. Soc.. 2. 31109 (1929). 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Knorr, Horlein and Roth, Ber., 38, 3138 (1930). Gabriel and Coleman, Ber.. 32, 2886 (I90‘). Albert, Ber..‘§g, 550 (1909). Redemann, Ind. Eng. Chem.. Anal. Ed..';l, 635 (1939). Siggia and Edsberg, Ind. Eng. Chem.. Anal. Ed.. 23. VITA Name: William Harper Houff Born: April 27, 1928, in New HOpe, Virginia Academic Career: September 19h5 . June l9h6 September l9h6 - June 1950 September 1950 . June 1952 Degrees Held: Bachelor of Science a 1950 Augusta Military.Academy Fort Defiance, Virginia College of William & Mary Department of Chemistry Williamsburg, Virginia Michigan State College Department of Chemistry hast Lansing, Michigan College of‘william.& Mary Williamsburg, Virginia THE SYNTHESIS OF SOME aJ6N,N-DIALKYLAMINO§ALK‘e- 3-THIENYL SULFIDE HYDROCHLORIDES 5! William.H. Houff AN ABSTRACT Submitted to the School of Graduate Studies of Michigan State College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of MASTER or SCIENCE Department of Chemistry Year 1952 Approved\\\ William H. Houff As a study of sulfur containing compounds of pharma- cological interest, some <0(MN-dialkylanino)alky1-3-thienyl sulfide hydrochlorides were prepared because of the :interesting activity as local anesthetics possessed by the corresponding phenyl analogs and because of the reported flower toxicity of the thicphene nucleus when incorporated into such compounds as compared with that of benzene. These compounds may be represented by the general formula, 'S(CHZ)nN:: 'HC1 where -H:§ is a morpholino or piperidine group and "n” varies from two to five. The first general method of synthesis involved the following sequence of reactions: EtOH 2.921111 4- c1(csz)noa ——. R2N(CH2)nOH + R 1111-1101 2 CHCl , R2N(CH2)n0H .- 30012—47 3211(632)n01 HCl 4- 30 NaOH USE + Cl(CHz)nNR2‘HCl ——e U8(CHZ)nNR2 4» Etc}. The first intermediates, 4W(N,N-dialkylamino) alcohols, were prepared by refluxing the preper secondary amine and chlorohydrin in absolute ethanol. The synthesis of the 9(N,N-dialkylamino)alkyl chloride hydrochlorides involved the careful addition of thionyl William H. Houff chloride to a chloroform solution of the eMNJ-dialkyl- amino) alcohol. Five compounds which had not been pre- viously reported were prepared and some of their physical preperties were determined. The (Jéfl,N-dialkylwmino)alky1-3-thienyl sulfide hydro- chlorides were prepared by the interaction of the preper 4)(N,N-dialkylamino)alky1 chloride with 3-thiOphenethiol in aqueous sodium hydroxide solution. The products were isolated and characterized as the hydrochloride salts. Altogether, ten (OGN,N-dia1ky1amino)alkyl-3-thienyl sulfide hydrochlorides were prepared and some of their physical preperties are reported. In an effort to improve the yields of the final product and to shorten the time required for their preparation a second general method of synthesis was studied, and is indicated in the following series of reactions: 11’ OH USE 4- C1(Cfiz)nOH -—d-—-) US(CH2)nOH 4* NBC]. 4' H20 0 N(CH ) .S(CHQ)nOH 0 SOC12 635 3 g“? U3(CH2)DCI + 302 + C6H5N(CH3)2°HCI William H . 210qu As represented by the first equation, 3-thiophenethiol was reacted with the appropriate chlorohydrin in aqueous sodium hydroxide to yield the U-hydroxyalkyl-B-thienyl sulfide. Three o-hydroxyalkyl-B-thienyl sulfides were prepared which had not been previously reported and some of their physical prOperties were determined. The 9-hydroxyalky1-3-thienyl sulfides were converted to the aJ-chloroalkyl-B-thienyl sulfides by the addition of thionyl chloride employing dimethyl aniline as solvent. Two d-chloroalkyl-d-thienyl sulfides which were not pre- viously reported in the literature were synthesised and some of their prOperties were investigated. By reacting the J-chlorcalkyl-3-thienyl sulfide with the appropriate secondary amine, the “(mm-dialkyl- aminoealkyl-B-thienyl sulfide was obtained and isolated as the hydrochloride. Two such compounds were prepared in this manner and were found to be identical with those pre- pared by the first general method. A study of the methods of preparation employed revealed that the first general method was most applicable to the synthesis of the desired series of compounds. The yields were, in general, better, isolation was simpler, the purity of the products was more satisfactory and fewer side- reactions were involved in the synthesis. . No information concerning the pharmacological properties of the «MN,N-dialkylsmino}alkyl-3-thienyl sulfide hydro- chlorides is given since this work deals only with the synthesis of these compounds. ‘ CH 25.1.1151!!! Win mm 1‘0 33;? JUL 1 4 56‘s / '3' Rev“ '61 t3“ ’4. —--.-y TA "'TITI'I‘EIQIHILIIJIQILHWLit’fliujfymflififlfyfimfi“