THE FREPARATION OF SOME 3,6: AND ‘3.4-DlSUBSTiTUTE§> THQANAPHTHENES - Thesis Far {+29 Degm cf :Ph. D. V MECHIGAN STATE UNIVERSITY Richard Lee Titus U964 THESIS mm 3m: UNIVERSITY I 056mm ABSTRACT THE PRFTARATION OF SOUR 3,6- AND 3,u-DISUBSTITUTED THIANATHTUENES by Richard Lee Titus The original goal of the investigation was to prepare the alkaloid reserpine with a thianaphthene ring in place of the indole ring. One of the compounds essential to this synthesis was f5(6-methoxythianaphthyl-3)ethylamine. Attempts to prepare this intermediate were not successful. One method involved an attempted substitution on the number three carbon of the b-methoxythianaphthene ring. Subsequent work showed that the presence of tho é-methoxy group directs the substitution away from the number three carbon. A second attempt involved the preparation of 6-bromothiananhthene. It was found that 6-bromothianaphthene could not be prepared by the method used in a desirable state of purity. Large amounts of h-bromo- thianaphthene were also formed. The third attempt involved the preparation of 6-methoxythianaphthyl-3-acetamide. This compound was prepared in a pure state but the reduction of it to 5(b-methoxythianarhthyl-3)ethylamine was unsuccessful. I Since the preparation of the desired amine was unsuc- cessful to this point it was decided to prepare a model compound having some of the gross structure of reserpine so that its physiological properties could be investicatad. Richard Lee Titus This was done by reacting piperidine with 6-methoxythia- naphthyl-3-acetyl chloride which was prepared from 6-meth- oxythianaphthyl-3-acetic acid which in turn was obtained by the hydrolysis of the above amide. The tertiary amide obtained was reduced usinr lithium aluminum hydride to an ’ I , 7 amine, §__§(6-methoxythianaphthyl-3)ethylipiperidine, which L-‘ was isolated and purified as its hydrochloride. This compound was submitted for testing regarding its physio- logical properties. Several other compounds were prepared as a result of this investigation, viz, ethyl (6-methoxythianaphthyl-3)- acetate, h-methoxythianaphthyl-3-acetamide, h-methoxythia- naphthyl-3—acetic acid, and gin-methoxvthianaphthyl-3)- I ethanol. THE PREPARATION OF SOME 3,6- AND 3,u-DISUBSTITUTED THIANAPHTHENES By Richard Lee Titus A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry lQéh ACKNOWLEDGMENTS My deepest thanks go to Professor R. D. Schuetz for the encouragement he has given me throughout my graduate studies and to Professors R. Herbst, G. Goerner, and L. Lo Quill for the valuable advice and encouragement they have given me in my chosen field as a chemist. To Dr. John Bonner and Mr. Robert McComb go thanks for the helpful suggestions and assistance they gave regarding this problem. I would also like to thank my wife Carolyn for her assistance in preparing this thesis. The plant growth assays for h-methoxythianaphthyl-3- acetic acid and 6-methoxythianaphthyl-3-acetic acid were performed by her and Mr. Roger Ritzert. VITAE Richard Lee Titus Candidate for the Degree of Doctor of Philosophy Major Subject: Organic Chemistry Minor Subject: Analytical Chemistry Biographical Data: Date of Birth: August 6, 193A; Dayton, Ohio Father: Anthony W Titus Mother: Agnes B. Titus Education: Fairmont High School 19u8-1952 DePauw University 1952u1956, B.A° Chemistry Michigan State University 1956~196h Experience: Graduate Assistant, Michigan State University, September 1956 through June 1962 Instructor, University of Toledo, September 1962 through June 196u Professional Affiliations: American Chemical Society Society of the Sigma Xi American Association for the Advancement of Science The Ohio Academy of Science iii TABLE OF CONTENTS Introduction and Historical. . . . . . . . . . . . . . Experimental Preparation of sodium metawhydroxybenzenesulfonate. . . 6 Preparation of sodium meta-methoxybenzenesulfonate. . . 6 Preparation of meta-methoxybenzenesulfonyl chloride . . . . . . . . . . . . . . . . . . . . . 7 Preparation of meta-methoxythiOphenol . . . . . . . . . Preparation of meta-methoxyphenyl (3-diethoxyethyl sulfide. . . . . . . . . . . . . . . . . . . . . . 9 Preparation of 6-methoxythianaphthene . . . . . . . . .10 Attempted preparation of 3-chloromethyl-6-methoxy- thianaphthene. . . . . . . . . . . . . . . . . . .ll Attempted preparation of 3-cyanomethyl-6-methoxy- thianaphthene. . . . . . . . . . . . . . . . . . .12 Attempted preparation of 3-bromo-6-methoxythia- naphthene. . . . . . . . . . . . . . . . . . . . .13 Attempted preparation of 3-carboxy—6-methoxy- thianaphthene. . . . . . . . . . . . . . . . . . .13 Preparation of a bromo-6-methoxythianaphthene . . . . .15 Desulfurization of the carboxy-o-methoxythia- naphthene. . . . . . . . . . . . . . . . . . . . .15 Preparation of sodium meta-brOmobenzenesulfonate. . . .16 Preparation of meta-bromobenzenesulfonyl chloride . . .17 Preparation of metaubromothiophenol . . . . . . . . . .17 iv Preparation of metawbromophenyl (nudiethoxyethyl sulfide. . . . . . . . . . . . . . . . . . . . Ring closure of metaubromophenyl cn-diethoxyethyl sulfide. . . . . . . . . . . . . . . . . . . . Conversion of the bromothianaphthenes to carboxylic acids. . . . . . . . . . . . . . . . . . . . . Desulfurization of the thianaphthene carboxylic acids. . . . . . . . . . . . . . . . . . . . . Preparation of ethyl chhloroacetoacetate. . . . . Preparation of ethyl u-(meta—methoxyphenylmercapto)- 3-OXObutyI’ate o o o o o o o o o o o e o o o o 0 Preparation of ethyl (6-methoxythianaphthyl-3)acetate and ethyl (h-methoxythianaphthyl—B)acetate . . Preparation of 6-methoxythianaphthyl-3-acetamide. . Preparation of h~methoxythianaphthy1-3—acetamide. . Preparation of 6-methoxythianaphthyl-3-acetic acid. Preparation of u-methoxythianaphthyl-3-acetic acid. Structure determination of 6-methoxythianaphthyl- 3~acetic acid. . . . . . . . . . . . . . . . . Preparation of (6—methoxythianaphthyl-3)acetyl chloride . . . . . . . . . . . . . . . . . . . Preparation of ethyl (6-methoxythianaphthyl-3)- acetate. . . . . . . . . . . . . . . . . . . . Preparation of lg(6-methoxythianaphthyl-3)ethanol and l8(h-methoxythianaphthyl-3)ethanol . . . . O °18 .2O .21 .22 .22 .23 .2h .25 .25 .26 .27 027 .28 .28 .29 Attempted preparation of /9(6-metnomythianaphthyl— 3)ethylamine . . . . . . . . . . . . . . . . Preparation of E(6-methoxythianaththvl-34acetyl)- piperidine . . . . . . . . . . . . . . . . . Preparation of E;Lfl(6-methoxythianaphthyl-3)ethyi] piperidine hydrochloride . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . . Bibliography . . . . . . . . . . . . . . . . . . . . vi INTRODUCTION AND HISTORICAL The total synthesis of reserpine (l)(2)(3) and yohimbane (u) suggested simple direct synthetic routes to their sulfur analogs wherein a thianaphthene nucleus would replace the indole ring in these naturally occurring alka- loids. The aim of the present study was to investigate the physiological properties of such a molecule, $.3. of "thioreserpine" I. The total synthesis of reserpine involved the pre- paration of three large fragments of the molecule and combination of them to form the desired structure. The three fragments employed in the total synthesis of reserpine were 6-methoxytryptamine II, 3,u,S-trimethoxybenzoyl chloride III, and finally, ring E of the reserpine molecule in a form suitable for further reaction IV. OCH HZCHZNHZ 9 3 I ClC OCH3 CH 0 N 3 H OCH II III IV The synthesis of "thioreserpine" then required the development of synthetic routes to the unknown sulfur analog of the bwmethoxytryptamine or [8(6-methoxythia- naphthyl-3)ethylamine V. JCHZCHZNHZ JCHZCHZNHZ CH S S 30 V VI Similar thianaphthene derivatives have been described, 3.5. Werner Herz (5) prepared VI, VII, and VIII, while VII VIII P. Cagniant gt 3;. (6) prepared II. The latter contains IX u a ring system similar to that of reserpine even though structurally it is quite dissimilar. A literature search revealed no description of a suitable 3,6~disubstituted thianaphthene from which the f3(6-methoxythianaphthylo3)ethylamine might be synthe- Sized. Further, the literature examination showed only a few 3,6wdisubstituted thianaphthenes had ever been prepared and the majority of these had only been investigated as intermediates in the synthesis of dyes. The 6-methoxy- thianaphthenes described had been prepared by the ring closure of an appropriately substituted sulfide (7), g.g. X to XI. 0 “f / / \ CH Ho 3/ 3 X XI Such a ring closure would seem to depend upon the steric hinderance of the meta substituent on the benzene ring to prevent formation of a large amount of the h~sub~ stituted thianaphthene, 1.3. XII. OH / \ Other owsubstituted thianaphthenes prepared by this procedure are 6-methoxythianaphthene (8), 6-chlorothia- naphthene (9), and 6-methylthianaphthene (9)(lO). Another widely used synthesis of 3,6-disubstituted thianaphthenes has the advantage that the ring closure can occur one way as in XIII to XIV (ll), employing an aromatic dicarboxylic sulfide. O 9 H O COH COH , u I ———. —_._. OCCH3 /..2 J XIII XIV However, a disadvantage of the latter method is the gen— eral difficulty of obtaining the appropriately substituted benzene. Another ring closure procedure to obtain 6—substituted thianaphthenes starts with an ortho mercapto alkyl benzene ‘which is pyrolyzed at hhSo in the presence of a copper oxidewchromium oxide catalyst supported on charcoal, g.g. XV to XVI (12). 'H2 SH Cr203 HZN‘\\ s uu5° EXPERIMENTAL Preparation of Sodium meta~Hydroxybenzenesulfonate A solution containing 97.6 g. (0.5 mole) of sodium meta- aminobenzenesulfonate (metanilic acid, sodium salt; Eastman Practical) and 37 g. (0.536 mole) of NaNO2 dissolved in 600 ml. of water was cooled to 50 and poured into a stirred mixture of 100 ml. of cone. HCl and 500 g. of ice. The chilled solution was then diluted with 500 ml. of water and heated slowly with stirring on a steam bath to 600. When nitrogen evolution had ceased, the solution was heated to 70-800 for an hour and then made alkaline with 20% NaOH solution to a pH of approximately 8. The resulting dark red solution was heated on a steam bath under a stream of air until a crust of NaCl began to form. The mixture was then cooled and an equal volume of absolute alcohol added to precipitate the NaCl. This was removed by vacuum filtration and the filtrate evap- orated to dryness under a stream of air on a steam bath. The residue was dried at l30O in an oven, and ground to pass a hO mesh screen. The product was used without further puri~ fication. Preparation of Sodium meta-Methoxybenzenesulfonate A 150 g. (0.76 mole) quantity of sodium meta~hydroxy~ benzenesulfonate and ISO g. of a 20% NaOH solution were stirred in a two~liter three-necked round bottom flask fitted with a reflux condenser while being heated on a steam hath under a stream of air to obtain a syrupy consistency. The mix- ture was cooled to room temperature and 72 ml. (0.76 mole) of dimethyl sulfate added with vigorous stirring. Stirring was continued until the mixture hardened, shortly after which it swelled quickly to several times its original volume. It was reheated on a steam bath for two hours. A 190 ml. volume of water was added and the solution was heated on a steam bath to dissolve the product. The hot solution was transferred to an Erlenmeyer flask and sufficient absolute alcohol added to make the solution turbid. The mixture was set aside in a refrigerator to allow crystallization of the product. The light yellow solid was removed by vacuum filtration, dried in an oven at 1300, and ground to pass a ho mesh screen. The product was used without further purification. Preparation of meta»Methoxybenzenesulfonyl Chloride A 200 g. (0.95 mole) quantity of sodium meta methoxy« benzenesulfonate, previously dried overnight at 1350 in an oven, was placed in a round bottom flask fitted with a reflux condenser. A 70 ml. (0.76 mole) volume of P001 was then added and the mixture shaken well. The mixture was placed in an oil bath and heated at 1650 for 3st hours. At the end of this time an additional hO ml. (O.h0 mole) of POCl3 was added and the mixture shaken thoroughly to break up the caked solids. The reaction mixture was held at 1650 for a day with occasional shaking. It was then cooled in an ice bath and pieces of ice were added to decompose excess P0C13. Sufficient water was added to dissolve inorganic salts. The dark organic layer was separated and the aqueous layer extracted with three lOO—ml. portions of benzene. The combined product and benzene extracts were washed with 100 ml. of water and dried over anhydrous MgSO The drying 14-0 agent was removed by filtration and the benzene was removed under reduced pressure. The dark oily residue was distilled in vacuo, with the majority of the material (light yellow) distilling at 1550/1.2 mm. Hg; yield 70% of theory. Preparation of meta—Methoxythiophenol A 160 ml. volume of absolute alcohol and 80 g. (1.22 gr. at.) of zinc dust were placed in a two-liter threennecked round bottom flask fitted with condenser, stirrer, and droppinv funnel. The mixture was heated to boiling on a steam bath, and 78 g. (0.38 mole) of meta-methoxybenzenesulfonyl chloride were added dropwise at a rate sufficient to maintain the mixture at its reflux temperature. Following addition of the acid chloride the mixture was stirred a half hour and 50 ml. of cone. HCl was added to the reaction mixture. Following a modest induction period a vigorous reaction ensued and the stirrer was started. An additional 190 ml. of the acid (HCl) was added at a rate to maintain reflux tempera- ture. When all the acid had been added the stirred reaction mixture was heated on a steam bath for 3-h hours. The mixture was cooled to room temperature and 1.2 l. of water was added. The reaction mixture was transferred to a two-liter separatory funnel and the organic layer separated. The aqueous layer was extracted with three lOO-ml. portions of ether. The product and combined ether extracts were washed with three 50—m1. portions of water. The ether solution was dried over anhydrous MgSOu, filtered, and the ether re- moved by distillation. The light yellow oily product was vacuum distilled; b.p. 95°/9 mm. Hg - 1100/9 mm. Hg; :yield 83% of theory. Preparation of meta-Methoxyphenyl (D-Diethoxyethyl Sulfide A 19.8 g. (0.86 gr. at.) quantity of sodium was added in portions to hOO ml. of absolute alcohol in a liter three- necked round bottom flask fitted with a reflux condenser and dropping funnel. When all the sodium had reacted, 120 g. (0.86 mole) of meta-methoxythiophenol was added, in portions, to the sodium alkoxide solution with shaking to insure thorough mixing. After the addition of the methoxythio- phenol was complete the reaction mixture was heated on the steam bath for a half hour and then 12.9 g. (0.096 mole) of NaI was added with shaking, followed by the addition, in 10 small portions with intermittent shaking, of a solution of 170 g. (0.86 mole) of bromoacetaldehyde diethy acetal dis- solved in 30 ml. of absolute alcohol. Heat was evolved after an induction period of several minutes and a white precipitate of NaBr formed. Following complete addition of the acetal the reaction mixture was heated on the steam bath for 16 hours. The alcohol was removed under reduced pressure and 600 ml. of water was added to the residue to dissolve the inorganic salts. The mixture was transferred to a sepa- ratory funnel and the layers separated, the aqueous layer being extracted with three 100-ml. portions of ether. The product and ether extracts were combined and washed with two 50-ml. portions of water. The ether solution was dried over anhydrous MgSOu, filtered, and the ether removed by distillation. The light orange residue was distilled lg zgggg_using a Fenske column. The pure product collected boiled at th~ll9°/<:l mm. Hg; yield 153.h g. which was 70% of theory. The 2,hedinitrophenylhydrazone of the product was pre- pared; m.p. 122-12h0; literature value (8) 123-12h°. Preparation of 6—Methoxythianaphthene A as ml. volume of 85% H3P0u and 80 g. (0.56 mole) of P205 were placed in a 500 ml. three-necked round bottom flask fitted with a thermometer extending below the surface of the flask contents and a dropping funnel, the tip of 11 which was drawn out to a fine capillary extending below the surface of the polyphosphoric acid. The reaction flask was connected to a receiver using a short path connection and the entire system was evacuated to a pressure of 2.2 mm. Hg. The reaction flask was heated to 1600 in an oil bath and 16.5 g. (0.6h mole) of meta-methoxyphenyl ca-diethoxyethyl sulfide was placed in the dropping funnel, and added in small amounts to the reaction mixture. The sulfide on contact with the acid mixture initiated a very vigorous reaction resulting in the simultaneous direct distillation of the product, 6~methoxythianaphthene, into the receiver. When the reaction had subsided another portion of sulfide was added, and so on until all of the sulfide had been added. At this point the pressure in the reaction flask was reduced to 0.07 mm. Hg for 15 minutes to collect the final quantity of product. The crude 6-methoxythianaphthene was redistilled; b.p. 60°/0.07 mm. Hg - 6h°/0.03 mm. Hg; yield 60% of theory. The picrate of the product melted from th.h-105.80; literature value (8) 105-1060. Attempted Preparation of 3-Chloromethyl-6-methoxythianaphthene A mixture containing 8.2 g. (0.05 mole) of 6~methoxy- thianaphthene, h.8 ml. of cone. HCl, u.2 g. of 37% formalin, and 10 ml. of 95% ethanol was placed in a 50 m1. round bottom flask fitted with a two-hole stopper containing a gas inlet tube reaching to the bottom of the flask and an outlet tube 12 leading to a water trap to absorb excess HCl. The reaction mixture, stirred with a magnetic stirrer, was cooled to 00 and dry HCl gas was bubbled through it for 15 minutes. At this point the stirred mixture was allowed to warm up to room temperature while passing a gentle stream of HCl through it. The reaction mixture was then set aside for three hours, at which time it had become a solid dark blue mass. Methylene chloride was added to dissolve the dark blue mass and the layers were separated. The methylene chloride solution was washed first with water, then with sodium bicarbonate solu— tion, and finally again with water. The light yellow solu- tion was dried for three hours over anhydrous MgSO , filtered, and poured slowly into a large excess of ice cold alcohol. The almost white precipitate, weighing 5.2 g., was recovered by filtration and dried. Attempted Preparation of 3~Cyanomethyl-6-methoxythianaphthene A 5.2 g. (0.024 mole) quantity of what was assumed to be 3-chloromethyl-6-methoxythianaphthene, 2.h g. (0.0h9 mole) of NaCN, 0.5 g. (0.0033 mole) of NaI, and 17 ml. (0.23 mole) of anhydrous acetone were placed in a 50 ml. round bottom flask. The mixture was heated to 55C and stirred vigorously for 36 hours with a magnetic stirrer, in which time it darkened somewhat. The solid salts were removed by filtra- tion and the acetone was removed from the filtrate by evap- oration. An orange solid remained which, however, failed 13 to give a positive test for nitrogen or chlorine after being fused with sodium. Attempted Preparation of 3-Bromo-6-methoxythianaphthene A 10.0 g. (0.061 mole) quantity of 6-methoxythianaphthene, 10 g. (0.12 mole) of sodium acetate, and 80 ml. (l.u mole) of glacial acetic acid were placed in a 250 ml. round bottom flask fitted with an addition tube, having a dropping funnel on top and a second tube connected from it to a sodium hydr- oxide trap at the side. A solution of 9.6 g. (0.06 mole) of bromine dissolved in 50 ml. of glacial acetic acid was placed in the dropping funnel. The contents of the flask were maintained at 200 and stirred magnetically while the bromine solution was added dropwise. Following the addition of the bromine, the reaction mixture was poured onto crushed ice and dilute NaHSO3 solution to destroy excess bromine. About 50 ml. of methylene chloride was added to dissolve the product and the mixture was transferred to a separatory funnel and the layers were separated. The methylene chloride was removed under reduced pressure at room temperature. The residue was quickly distilled lnggggg_and the fraction collected which boiled at 900/0.oo mm. Hg - 1030/0.07 mm. Hg. This material was used immediately in the next step of the synthetic reaction sequence to prepare the acid. 11+ Attempted Preparation of 3-Carboxy-6—methoxythianaphthene A 2.u3 g. (0.10 gr. at.) quantity of magnesium turnincs was placed in a 300 ml. three-necked round bottom flask fitted with dropping funnel, stirrer, and a condenser with attached drying tube. A solution containing 2.57 ml. (0.03h mole) of ethyl bromide, 70 ml. of absolute ether, and the entire yield of the 6~methoxybromothianaphthene obtained from the previous bromination was placed in the separatory funnel. A solution of 2 ml. (0.026 mole) of ethyl bromide and 10 ml. of absolute ether was added to the flask. After initiating the reaction, the alkyl bromide ether solution in the separatory funnel was added at~a rate to maintain the mixture at its reflux temperature. After adding the alkyl halide the reaction mixture was set aside for 20 minutes, followed by heating it under reflux on a steam bath for 30 minutes. It was then cooled to room temperature, and poured quickly with stirring over 150 g. of crushed dry ice. After the excess carbon dioxide evolved, 100 g. of ice was added to the mixture followed by 150 ml. of water and 35 ml. of cone. HCl. The mixture was transferred to a separatory funnel and repeatedly extracted with ether. The combined ether extracts were extracted with four lOO-ml. portions of saturated NaHC03 solution. The combined bicarbonate extracts were decolorized with Norite and acidified to Congo red. The faintly pink precipitate was recovered by filtration 15 dried, and weighed (3.h3 g.). The melting point of the crude acid was 221-22h0, softening at 2180. After repeated recrys- tallizations from 95% alcohol a small quantity of material (approx. 0.1 g.) was obtained which melted at 279-280.5o (decomp.). An equivalent weight determination gave a value of 207. Calculated equivalent weight for a carboxymethoxy- thianaphthene is 208. 523:! Calcd. for C H O S: 'C, 56.90; H, 3.93; S, lh.7o 10 8 3 Found: C, 57.7; H, 3.87; s, ls.h. Preparation of a Bromo-6-methoxythianaphthene A 10 g. (0.061 mole) quantity of 6-methoxythianaphthene, 10.8 g. (0.061 mole) of Efbromosuccinimide, and 100 ml. of carbon tetrachloride were placed in a 250 m1. round bottom flask fitted with condenser and drying tube. The reaction mixture was heated at its reflux temperature for 2h hours, cooled, filtered, and the solvent removed under reduced pres- sure. The dark orange residue was distilled l§_ygggg. The product distilling at 88«90°/0.07 mm. Hg was collected. The yield was 11.3 g. (0.0h7 mole), 77% of theory. Desulfurization of the Carboxy-6-methoxythianaphthene An 8.20 g. (0.039 mole) quantity of the carboxy-6- methoxythianaphthene was refluxed with 20 g. of Haney nickel and 250 ml. of ethyl alcohol in a 500 m1. round bottom flask for 20 hours. The mixture was filtered and the alcohol 16 removed by distillation. The melting point of the crude product was 201-2330 (decomp.). The crude product was de- sulfurized again as described until no further depression in melting point (88u920) of the product was observed. Preparation of Sodium meta-Bromobenzenesulfonate An 83 g. (0.h8 mole) quantity of sodium metanilate and 3h.5 g. (0.50 mole) of NaNO were dissolved in 850 ml. of 2 distilled water. The solution was cooled to 100 and filtered into a stirred mixture of 250 ml. of cone. HCl and 100 g. of ice contained in a four-liter beaker. Ice was added, as needed, to maintain a temperature of 0-50. This solution was added slowly to a stirred suspension of 160 g. (0.56 mole) of Cu2Br2 in 200 ml. of water and 75 ml. of h8% HBr. After adding the diazonium salt solution the reaction mixture was stirred at room temperature for 2 hours, heated to 750 on a steam bath for an hour, and then cooled and the Cu2Br2 removed by vacuum filtration. The filtrate was adjusted to pH 9-10 with 20% NaOH solution. Norite, 5 g., and Celite, 6 g., were added to the alkaline filtrate and the mixture was filtered through a Bachner funnel. The filtrate was then concentrated by heating it on a steam bath under a stream of air, until a crust of solid material had formed on the inner surface of the container. The mixture was heated to its reflux temperature to dissolve solid material then cooled to room temperature to crystallize the product, 17 which was recovered by vacuum filtration. Yield, 93.3 g. (0.36 mole), 75% of theory. Preparation of meta-Bromobenzenesulfonyl Chloride Sodium.metaebromobenzenesulfonate, 93.3 g. (0.36 mole), and 26 ml. (0.28 mole) of POCI3 were placed in a 500 ml. round bottom flask fitted with a reflux condenser and heated to 175° for a half hour. An additional 15 ml. (0.18 mole) of P0013 was then added; the mixture was shaken thoroughly and again heated for another 1h hours. The reaction mixture was cooled by immersion in an ice water bath and excess POCl3 destroyed by adding pieces of ice to the mixture. The semisolid material was transferred to a liter sep- aratory funnel and sufficient water was added to dissolve the inorganic salts. The dark oil was separated and the aqueous layer extracted with two lOO-ml. portions of benzene. The benzene extracts and dark oily product were combined and the benzene was removed under reduced pressure. The residual oil was distilled lp'zgggg. The light yellow colored pro- duct distilling at 82.5—910/0.o mm. Hg was collected. The yield was 58.0 g. (0.23 mole), 63% of theory. The meta-bromobenzenesulfonamide after two recrystallizations from water melted at 153—l5h.50. Preparation of meta—Bromothioohenol A 50.0 g. (0.76 gr. at.) quantity of zinc dust and 18 100 ml. of absolute alcohol were placed in a two-liter three~ necked flask fitted with a dropping funnel, stirrer, and condenser. The stirred mixture was initially brought to its reflux temperature on a steam bath and 55 g. (0.23 mole) of meta-bromobenzenesulfonyl chloride was added at a rate to maintain reflux. After addition of the acid chloride the gray mixture was stirred an additional 15 minutes and 150 m1. of conc. HCl was added dropwise. There was an induction period before a vigorous reaction with HCl was initiated. Following the acidification the reaction mixture was heated for h hours on a steam bath, cooled to room temperature and transferred to a 500 m1. separatory funnel and the layers were separated. The aqueous layer was diluted with 500 ml. of water and ex- tracted with three 100-m1. portions of methylene chloride. The combined product and methylene chloride extracts were washed with three 100-m1. portions of water and dried over anhydrous MgSO The drying agent was removed by filtration u!) and the solvent by distillation. The oily residue was dis- tilled under reduced pressure, collecting the product boiling from 92-1000/10 mm. Hg. The yield was 32.0 g. (0.17 mole), 7h% of theory. Preparation of meta-Bromophenyl GJ-Diethoxyethyl Sulfide Metallic sodium, 13.1 g. (0.57 gr. at.), was added in portions to 285 ml. of absolute alcohol contained in a liter l9 three-necked round bottom flask fitted with a reflux condenser, a drying tube and a dropping funnel. When the sodium had dissolved, 106.8 g. (0.56 mole) of meta-bromothiophenol was added, with shaking, in portions to the sodium alkoxide solution. Then 0.85 g. (0.057 mole) of NaI was added and the mixture thoroughly shaken. Following the addition of the iodide, 112 g. (0.57 mole) of bromoacetal was added, with vigorous shaking, in 10-15 m1. portions. External cooling was necessary to control the reaction. The mixture was set aside for a half hour then heated on a steam bath for eight hours. The alcohol was removed by distillation and 300 m1. of water was added. The mixture was transferred to a sepa- ratory funnel and the aqueous layer was separated and ex- tracted with three 100-m1. portions of ether. The crude product and combined ether extracts were washed with 100 m1. of water, and dried over anhydrous MgSOu. The drying agent was removed by filtration and the ether by distillation. The residual yellow colored oil was distilled lg £2222 using a Fenske column. The product distilling in the range 10h- 116.5°/0.08 mm. Hg was collected. The yield was 87.6 g. (0.29 mole), 51% of theory. The 2,h-dinitrophenylhydrazone of the product was pre- pared and purified by recrystallizing from 95% alcohol. It melted from 9L1.8-95.5O then immediately recrystallized and again melted from ll3-llh.20. 20 Ring Closure of metaeBromophenyl cnuDiethoxyethyi Sulfide The procedure used was identical to that described for the ring closure of meta«methoxyphenyl (pediethoxyethyl sulfide. 56.2 ml. / A mixture of 23.2 g. (0.076 mole) of the sulfide, of 85% H3P0u and 9h g. (0.66 mole) of P205 was used to effect the ring closure at a reaction temperature of 1650 and a system pressure of 2.6 mm. Hg. The yield of crude product was 12.2 g. (0.056) mole, 7h% of theory. The crude product, 31 g., was fractionated, using a 16-inch tantalum spiral col- umn, into two fractions. The first was collected in the range h2—500/0.07 mm. Hg, Q55 1.6kh0, 5.2 g. The second fraction was collected from 50157050/0007 mm. Hg, ESE 1.6688, lh.9 g. By setting fraction I inside a refrigerator for several days a white solid which melted from 38-h3° was obtained. This was purified by sublimination at reduced pressure to a white solid melting from hh.8wh50. By cooling fraction II in a refrigerator for several days a white solid which melted from 53~56.5O was obtained. After sublimation at SOC/0.06 mm. Hg a pure white solid melting from 511..8«-55.8n was obtainedo A 1.98 g. (0.0092 mole) quantity of the bromothianaph- thene, melting at 550, was converted to its Grignard reagent by placing the halide, magnesium metal, and dry tetrahydrofuran in a round bottom flask, and after adding several drops of ethyl bromide to initiate the reaction, refluxing the reaction 21 mixture for 5 hours. The solution was then cooled to room temperature and poured over crushed dry ice, hydrolyzed and the product isolated in the usual manner. The melting point of the crude product was 185-1960. After several recrystal- lizations from alcohol-water the acid melted from 2OO~203O. A Grignard reagent was prepared from the noncrystalline residue of fraction I of the bromothianaphthene distillation by refluxing the halide and magnesium turnings in tetrahydro- furan for 5 hours, after initiating the reaction with a few drops of ethyl bromide. The reaction mixture was then cooled to room temperature and poured over crushed dry ice, hydrolyzed and the product isolated in the usual manner. Melting range of the crude material was 131-1500. This material was dissolved in base and precipitated by acidifying to Congo red. After drying, the precipitate was sublimed at reduced pressure to yield a product which melted from 139-1550. Fractional recrystallization failed to further purify the material. A Grignard reagent was prepared from the noncrystalline material of fraction II of the bromothianaphthene distilla- tion by refluxing it with magnesium turnings in tetrahydro- furan for 5 hours after initiating the reaction with a few drops of ethyl bromide. The reaction mixture was cooled to room temperature, poured over crushed dry ice, hydrolyzed and the product isolated in the usual way. The melting range of the crude product was 155wl600. Sublimation of the crude acid 22 at l3OO/O.03 mm. Hg changed its melting point to lh2u1570. Extensive fractional recrystallization failed to purify this crude acid appreciably. The majority of the fraction had a melting range of 155~162O. However, a few milligrams of an acid melting from 188~1890 were also obtained. The equivalent weight of this acid was determined to be 185; the calculated equivalent weight for a thianaphthylcarboxylic acid is 178. Anal. Calcd. for C ————— 9 c, 60.28. H, 3.65. H6023: C, 60.65; H, 3.39. Found: A gram of the acid fractions melting from approximately lSomlSSO was desulfurized by refluxing it with Raney nickel for several hours. The catalyst was removed by filtration and the alcohol by distillation. The melting point of the acid residue was determined and the acid was again desulfur« ized as described. This process was repeated until no fur- ther depression of the melting point of the product recurred. The acid finally obtained was a semi-solid which melted from 60-700. Preparation of Ethyl K-Chloroacetoacetate A gram of HgClP (0.003? mole) and 2u.0 g. (1.0 gr. at.) of magnesium were placed in a two liter threeenecked flask fit- ted with stirrer, condenser, and dropping funnel. A solution of 2h5.2 g. (2.0 mole) of ethyl chloroacetate dissolved in ) 173 ml. of dry ether was placed in the dropping funnel. A 23 small amount of the ester solution was added to the magnesium which was broken with a stirring rod to initiate the reaction. The remainder of the ester solution was added at a rate to maintain reflux temperature in the reaction mixture. A precipitate soon formed and the reaction became a pale green in color. After adding the haloester the reaction mixture was refluxed with stirring on a steam bath for four hours, and hydrolyzed by pouring it onto crushed ice. Sufficient dilute HZSOM was then added to dissolve the magnesium salts. The ether layer was separated and the aqueous layer extracted with three 100-m1. portions of ether. The combined ether extracts were washed with 50 m1. of dilute H2SOu, then with two 100-m1. portions of water. The ether solution was dried over anhy- drous MgSOu and filtered. The ether was removed by distilla— tion. The oily residue was distilled under reduced pressure. Unreacted ethyl chloroacetate was obtained in the fraction distilling at 25~79°/9 mm. Hg and the product was collected in the boiling range from 75-1000/9 mm. Hg. The yield was h8% of theory. Preparation of Ethyl hm(metawMethoxyphenylmercapto)~leovobutyrate A 60.0 g. (0.h3 mole) quantity of meta-methoxythiouhenol was dissolved in 300 ml. of pyridine in a liter three-necked round bottom flask fitted with a stirrer, thermometer sup- ported in a slotted cork, and a dropping funnel. To this 2h stirred solution was added dropwise 70.0 g. (O.h3 mole) of ethyl ‘x-chloroacetoacetate while holding the reaction temp- erature between 25-300 by means of an ice bath. When the haloester had been added the mixture was set aside for 15 minutes, then heated to 70-800 for 15 minutes on a steam bath, and cooled to room temperature. The pyridine was dissolved by slowly adding 600 ml. of 8 g HCl. The layers were separated and the aqueous layer extracted with two 100-m1. portions of ether. The product and ether extracts were combined and washed with two SO-ml. portions of water. The ether solution was dried over anhydrous MgSOu, filtered, and the ether removed by distillation. The residue was dis- tilled lg 13939. Decomposition occurred during distillation as evidenced by the continually rising pressure in the dis— tillation system. The product boiling from lOOO/O.2 mm. Hg to 170°/O.5 mm. Hg was collected. The yield was 88.6 g. (0.33 mole), 77% of theory. Preparation of Ethyl 6—Methoxythianaphthyl-3-acetate and Ethyl u-Methoxythianaphthyl-3—aCetate A ha ml. volume of 85% H3P0u, 96 g. (0.68 mole) of P205, and a solution containing 28.8 g. (0.107 mole) of ethyl u-(meta- methoxyphenylmercapto)-3~oxobutyrate dissolved in 200 m1. of chlorobenzene were placed in a liter round bottom flask fitted with a condenser. The reaction mixture was heated at its reflux temperature for three hours. The chlorobenzene solution was 25 then decanted from the semisolid reaction mass and 200 ml. of benzene was added and the mixture was again heated at its reflux temperature for three hours. The benzene layer was then de- canted and combined with the chlorobenzene solution. The com- bined aromatic solutions were washed with 50 m1. of dilute NaHCOB, followed by two 50-ml. portions of saturated NaCl solu- tion. The benzene and chlorobenzene were removed under reduced pressure and the residue was distilled. The crude product was collected distilling from 90_155°/o.l mm. Hg; yield 22.u g. (0.090 mole); 83% of theory. The crude product was fraction- ated using a small heated Vigreaux column, and a small fore- run boiling from 50-1200/0.07 mm. Hg was discarded. The combined h- and 6-methoxy esters were collected in the temp- erature range from l20-l6hO/O.O7 mm. Hg. Preparation of 6—Methoxythianaphthy1-3-acetamide A 10.0 g. mixture of the crude ethyl u- and 6-methoxy- thianaphthyl-3-acetate and 200 m1. of cone. NHuOH were placed in a 500 cc. Paar bottle and shaken at room temperature for a week. At the end of this time the solid product was re- covered by filtration. The yield of the crude amide after drying was 6.6 g. (0.030 mole), 75% of theory. Pure 6-meth- oxythianaphthyl~3-acetamide was obtained by crystallizing the crude amide from 95% alcohol and it melted at l92.8—193.3O. Pure h-methoxythianaphthyl-3~acetamide was obtained by chromatographing the residue obtained by removing the alcohol 26 from the filtrates obtained from the purification of 6-meth- oxythianaphthyl~3-acetamide. A 0.h g. quantity of the above residue was dissolved in the minimum quantity of chloroform and then placed on a l" x 16" alumina column. The eluent used was chloroform. The first band obtained contained the 6-methoxy isomer and the second band contained the hemethoxy isomer. After removal of the eluent the separated amides were purified by recrystallization from 95% alcohol. The pure h—methoxythianaphthylc3-acetamide melted at 200.0»200.50. Approximately 1 g. of the h-methoxy isomer was obtained from 20 g. of the crude amide which had been obtained from the ammonolysis of the ester mixture. £231. Calcd. for CllHllOZNS: C, 59.72; H, 5.01; N, 6.36; S, 1h.u7. Found: 6~Methoxy amide: C, 60.21; H, 5.1h; N, 6.22; S, 1h.37. h-Methoxy amide: C, 59.83; H, 5.08; N, 6.h7; s, 1h.h2. Preparation of 6-Methoxythianaphthy1-3-acetic Acid A mixture containing 0.5 g. (0.0023 mole) of 6-methoxy- thianaphthyl-3-acetamide, 13 m1. of 10% NaOH, and 5 m1. of 95% alcohol was heated at its reflux temperature for two hours. The reaction mixture was cooled, filtered, and acidi- fied with HCl to Congo red. The white precipitate which formed on acidification was recovered by filtration and dried. After several recrystallizations from alcohol-water the acid melted at 1hl-lh2o. Its equivalent weight was found to be 27 228; calculated 222. Anal. Calcd. for 011H1003S: c, 59.u3; H, n.5u; s, 1h.39. Found: c, 59.37; H, n.7o; s, lu.33. Preparation of h-Methoxythianaphthyl-3~acetic Acid A mixture containing 0.5 g. (0.0023 mole) of hemethoxyw thianaphthyl~3~acetamide, 13 m1. of 10% NaOH, and 5 ml. of 95% ethanol was heated at its reflux temperature for two hours. The reaction mixture was cooled, filtered, and acidi- fied with HCl to Congo red. The white precipitate which formed on acidification was recovered by filtration and dried. After several recrystallizations from alcoholuwater the acid melted at 159.5-160.50. Aggl. Calcd. for c H o s: c, 59.u3; H, n.5h; s, 11 10 3 1h.39. Found: C, 59.11; H, h.71; S, 1h.33. Structure Determination of 6-Methoxythianaph~ thyl-3-acetic Acid Approximately 1.5 g. (0.0068 mole) of 6—methoxythiaw naphthyl-3wacetic acid was desulfurized by heating an abso- lute alcohol solution of it overnight under reflux with 10-15 g. of Raney nickel. The spent catalyst was removed by filtration and the alcohol by evaporation under a stream of air. To the greenish oily residue was added he ml. of water, 2 g. of KMnO and 8 drops of 20% NaOH solution. The oxi— 1+9 dizing mixture was heated at its reflux temperature until 28 the permanganate color had disappeared. The insoluble Mn02 was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in 20 ml. of water and the solution acidified with HCl to Congo red. The small quantity of precipitate was recovered by filtration and dried. After recrystallization from water, the material melted at 181-l8h0. A mixed melting point, with an authentic sample of anisic acid, showed no depression in the melting point of anisic acid. Preparation of 6~Methoxythianaphthyl-3~acety1 Chloride A 2.25 g. (0.01 mole) quantity of 6wmethoxythianaphthylw 3macetic acid, 22 ml. of absolute ether, and two drops of pyridine were placed in a 50 ml. round bottom flask and cooled to 0°. A 2 m1. (0.028 mole) volume of freshly distilled thionyl chloride was added to the reaction mixture which was set aside, at room temperature, for five hours, and then heated to its reflux temperature for 15 minutes on a steam bath. The ether was removed under vacuum and, to insure the complete removal of thionyl chloride, 20 ml. of dry benzene was added to the mixture to dissolve the product and then removed under reduced pressure. The red residue was used in subsequent reactions without further purification. Preparation of Ethyl 6~Methoxythianaphthy1-3-acetate To the acid chloride obtained from 2.25 g. (0.01 mole) 29 of 6-methoxythianaphthy1-3~acetic acid was added 25 m1. of absolute ethanol. The esterification mixture was set aside for a few minutes and then warmed gently on the steam bath, cooled, and the excess alcohol removed under reduced pressure. The residue was distilled twice to obtain an oil boiling at 25 D 1.5811. 1h0--1Li5°/0.07 mm. Hg; _I_1 Preparation of ffl6~Methoxythianaphthylw3)ethanol and l8(h—Methoxythianaphthylm3)ethanol A 5.28 g. (0.1h mole) quantity of the reducing agent LiAlHu and 100 m1. of anhydrous ether were placed in a 300 m1. three-necked round bottom flask fitted with a condenser, dropping funnel, and stirrer. A solution containing 30 g. (0.12 mole) of crude ethyl (h~ and (6-methoxythianaphthyl- 3)acetate dissolved in 30 ml. of anhydrous ether was added dropwise to the stirred reaction mixture at a rate which maintained it at its reflux temperature. When the ester had been added the mixture was stirred at room temperature for two hours and a dilute solution of H280“ (15 ml. of cone. H2SOM in 90 ml. of water) was added dropwise to hydrolyze the reaction mixture. It was then transferred to a separa- tory funnel where the aqueous layer was separated and extr- acted with two 50~ml. portions of ether. The ether solutions and product were combined and washed with 50 ml. of dilute NaHCOB solution and then with 50 ml. of water. The ether was removed and the oily residue was fractionated with difficulty and did not give a good separation. The fractions obtained were set aside for several weeks in which time some crystallization had started in the lower boiling fractions. The crystals were isolated and purified by crystallizing from benzene. The melting point of this solid material was 97.8» 98.50. It was concluded after comparison of the infrared spectrum of this solid alcohol with those of the corresponding acids and amides that this compound was [8(h-methoxythianaph- thy1-3)ethanol. The melting point of its 3,5-dinitrobenzoyl derivative was 19h.5-l99.50. Aggl. Calcd. for cllHleoas: c, e3.u3; H, 5.81; s, 15.no. Found: c, 83.59; H, 5.98; 3, 15.12. The other isomer, /3(6—methoxythianaphthylo3)ethanol, was not obtained in a very pure condition, and was obtained as an oil in spite of many attempts to crystallize it. The melting point of its 3,5wdinitrobenzoyl derivative was 167 05-1680 0 Attempted Preparation of /8(6~Methoxythia— naphthylw3)ethylamine A small amount, 2.7 g. (0.012 mole), of (6 methoxythia- naphthyl-3)acetamide was placed in a Sohxlet extractor attached to a 500 ml. threeenecked round bottom flask which in turn had been fitted with a stirrer and dropping funnel. A 1.39 g. (0.037 mole) quantity of LiAlHu and 200 ml. of dry ether were placed in the reaction flask and the reaction 31 mixture was heated at its reflux temperature for a day and a half. Then, 1.4 ml. of water was added dropwise to the stirred reduction solution followed by l.h m1. of 15% NaOH, and finally by h.2 m1. of water. The alkaline mixture was stirred vigorously for a half hour. The white precipitate was removed by filtration and washed with two 100wml. portions of ether. The combined ether extracts were dried over anhydrous MgSOu, filtered, and dry hydrogen chloride gas was passed into the ether solution. Only a very small white precipitate was observed to form. After filtering the ether solution, the ether was removed and the oily residue distilled, collecting the material boiling in the range 150~202O/0.07 mm. Hg. The product was a light yellow, viscous oil, insoluble in hydrochloric acid. Preparation of N(6-Methoxythianaphthylm3-acetyl)piperidine The acid chloride prepared from 2.5 g. (0.011 mole) of 6-methoxythianaphthyl-3wacetic acid as described above was dissolved in 10 ml. of dry benzene. To the acid chloride solution was added a second solution containing 2 ml. (0.02 mole) of piperidine dissolved in 20 m1. of dry benzene. Addition of the base solution to the acid chloride solution gave a color change of the reaction mixture to straw yellow and the formation of a gelatinous precipitate of piperidine hydrochloride. The contents of the flask were transferred to a separatory funnel and the benzene reaction solution was " ‘1 ‘ I._ . 8" q ’ x 4 . - ‘. A -‘ ‘. ‘- . —‘ -~ , ‘ .l .. o . .s,‘ '3 .,., ‘ I C) Ll'OLKYC/‘Cl Llj Lila!" 1“ L 0 (’1 ':’(;1Ll\l£ a ted J.p J,LU(\,)-2 8011.1 L 1 1L g (1".1'~:, t ,1 . - . . ‘ir - 1 -. .. ~ .- ,. —. . ' ~ m . .- , 1... . altn two 40~n1. p,.,: as of watei. ine benZenw c 1.2. ‘ ~ - -. A . ‘ ' g ‘ 1 ,‘ I ’. ~ “ . No A ' . - , ' \A ~ J‘ - - ‘r‘ ' ‘, ‘ then dried oVer arnylrous Macon. filtered. ail ime urn, . . ~ -. -. -. ‘- . .. a... ' ,.. [111”. v, : ,_,.- ' , ,‘ was removed tv eVFPbiatlan. inc Pes due of awlte Mm. 1‘“, _’ iv? L ’ : ‘~ -v: -a‘ . ,3 ‘ _‘ ‘. _ 0“... ._‘ I’.‘ il.%:.tiy to tile E‘llhu r iLhCfllL itn’tnei'}le31:13atl.ln. ‘ " I» r a 7‘ ‘ \ 7 ’\ ') \7: / T. “ v—v . . -. - ... ,~ - ,.. ‘1 v I” 1‘91”: :1, :1. '- 1. L111 (41 H l: B (0‘128 {11101131 thlariapt: of"! 1 r J 2,1 gnu—1.-.. Wis-.23; “we: 1 c,nyi presilline ,uPOLh orlle r‘."‘ ’- i- ‘. I. . ~ .. u. . ‘7! 1‘1 ‘ -. 1 1r- ‘ v- ‘ ’ 'V ‘ u ‘ ~ 0 i . 11’,.2- .‘(i i“Lin:Uimarliirhyi,_-‘_.-Ritci.y1)pl}.r;{'1 .._I?*.~ in in ,. . r r" r ‘ ._ , i ,. ‘- ,g ,1 ‘- . .' ' , -..‘ ‘t w i l'OTTl c? o :2 7.9 . (“J 0.1.] Joli) 1 C) 01 .) -1Ilc: L110 zit/1.1118118. (111111;; 1* l *- 0 a v 0 A I ’-" y’a‘ ‘ ."n ‘- ,1 acid as deceilpsz .icve n1: ilssolde in 50 ml. oi an: 'i i ,-‘ L'AV ., .l, V“ ,. ., ,. Stilt) . 1.1 .Llai'.,.,.«1Ll'~--1~.211 1%.“. {10(1th dl’OV.'1‘318€J t0 :1 .7 suspended in 3H m‘. ‘— - ‘ k e l I r‘ \ \/ ’5 V H r—-: L). > g“! ._.. . —‘w o . - a . o o - _ M ‘ - 7‘ __ ,‘ stirred anhvcr up sitar contained in a ChPUb‘HGCKGJ ro' . _ ‘. ‘3 7‘ I ' W . g 1 1‘, _ . g _ ~ _ r _ o ’ u" ‘ bellman f1 Ugh I .ciw- v-1Ln (KMIJQHSCH‘, stlIW%rr, ,nld o f‘ - -‘ . A. o I . , - ' a . ' ~,.-. -,. . -. -. -' . ‘- A r] 3 . , ‘ —.‘ ~ . .7 Tunnel. Ursh .ia c:?.q uh agent had been auccd the 1- &. Inl.XtJJI“3 2:923 :ft‘ ~.» 5 VV- arid'ltl.orn11.'héilf‘ lipiir, LilFfl ih?a - - .. :r'i . .,. W. .‘i-.‘ . . . . ' .1 ,V,- its re. -t- rm.‘-~J l-: l :3 hell :nl hoary (HQOLSd ix» W1 {Spirit-111,1 .7 ‘~ 0 A - e ’ E. 753:1 23115 14331:: (‘2 (Jule 41.0 iv ‘.1. 1- 1, o. ° ~ -. , - ' . -" i. ‘ 1, , . - . "\ ‘. H t ‘ ’ fl my -\ 7:. >7 ,. 1 S 1- l 11 T -f \-l s," ) . x L :_ .‘ i L n .l. i. . ‘ i 1!. y) ‘ ‘1 ~ .1 \J t} :7, U . '\ I. (‘1 n1 1 . O f .1 5 7;! i J (. . \_4" ’ I -: 1‘ ’ 1 - 7' W * " ' " " V " ,.- .. -‘ ‘ ' ' .3. ' ~ 1 1 {mid fiifiilfi ~I ..w‘1 :::. 01 initufw .Aitcf‘5311P1-fi~ v after two crystallizations from absolute alcohol, melted at 22h.5_225.50. £231. Calcd. for 016H220N801: C, 61.61; H, 7.11; N, u.u9; 3, 10.28; 01, 11.37. Found: 0, 81.77; H, 7.26; N, n.23; 3, 10.30; 01, 11.10. DISCUSSION The initial objective of this investigation was to pre— pare an appropriately substituted thianaphthene which could then be attached to the D and E ring system of the reserpine molecule. The thianaphthene needed was /fl(6-methoxythia- naphthy1-3)ethy1amine V. The starting material for this synthesis was sodium meta- aminobenzenesulfonate XVII (sodium metanilate). This was diazotized and the solution of the diazonium salt was warmed to produce sodium meta~hydr0xybenzenesulfonate XVIII. The hydroxy compound was methylated using dimethyl sulfate to obtain sodium meta-methoxybenzenesulfonate XIX (13). 1) HNO2 ) \ 2 ’//803Na ' H0 ’//803Na 2) heat XVII XVIII t CH 0 s0 Na NaOH 3 3 XIX 3M . K24 i, _. , i The meta-methoxybenzenesulfonyl chloride XX was prepared by treating the sodium metaamethoxybenzenesulfonate with an excess of phosphorus oxychloride at 1650 (1h). Reduction of meta~ methoxybenzenesulfonyl chloride using zinc dust and hydro- chloric acid produced meta-methoxythiophenol XXI. 1 P00 3 1 I \\ // CH3O 803Na heat CH30 $0201 XIX XX Zn HCl CH 0 SH XXI The meta-methoxythioohenol was then alkylated (8) using bromoacetaldehyde diethyl acetal (bromoacetal) (15) in the presence of sodium ethoxide to produce meta-methoxyphenyl co-diethoxyethyl sulfide XXII. The sulfide was converted to 6-methoxythianaphthene XXIII by the procedure of Sunthankar and Tilak (8). BrCH CH(0CH CH ) 2 2 3 2 k HC(OCH20H3)2 NaOCH CH H CH3O SH 2 3 CH 0 s/C 2 3 XXI XXII P205 Ll HBPOA CH3 XXIII The proposed synthesis of V from 6-methoxythianaphthene was based on the following sequence of reactions. HCl //’ I /U .11 /UCH201 CH 0‘\~ 3 H200 CH3O s ——————* XXIII XXIV l) LililHLL /”CH2C N g, [:::]::—:DCHZCH2NH2 CH3O s 2) H20 CH30 s XXV V 37 Chloromethylation of 6-methoxythianaphthene was attempted using the procedure of Avakian, Moss, and Martin (16). The off-white powder obtained gave only a weak test for chloride after fusion with sodium. However, an attempt was made to convert it to the nitrile XXV. Upon working up the reaction mixtdgh after removal of the sodium cyanide by filtration only starting material was recovered. Characterization of the product obtained from the Chloromethylation of 6-methoxy- thianaphthene was not undertaken. Instead, an alternate method of synthesizing V starting with 6-methoxythianaphthene was initiated, based on the following sequence of reactions. Br // 2 Br i'ji ———» J CH 0‘\\ \\s CH 0 s 3 3 XXIII XXVI 1) Mg 2) CH CH 7 ‘5 ‘ —_'_‘CH CH CH PBr .\g/ 2 [\¢;D /U 2 2 3 9 CH30‘\s \\s H 3) 20 XXVIII ‘—’:1FH20H2Br NH3 -—-:UCH20H2NH2 ————9 CH30 \\s CH30 s XXIX V 38 Bromination of 6-methoxythianaphthene yielded material which turned out to be largely 2sbromoe6smethoxythianaphthene. Two experimental procedures were used; bromination with elemental bromine in glacial acetic acid in the presence of anhydrous sodium acetate, and free radical bromination with Nfbromosuccinimide. Both procedures gave excellent results; however, the product was quite unstable and had to be used before it decomposed. The freshly distilled 2=bromoa6-methm oxythianaphthene was a light yellow solid which, when set aside, soon turned to a dark green or black intractable material with the evolution of hydrogen bromide. To deter: mine the structure of this material it was converted into the corresponding Grignard reagent by entrainment, using ethyl bromide as the other halide, followed by carbonation with dry ice. Isolation of the product yielded a crude acid which had a melting point range of 221-221;0 with softening at 2180. Several recrystallizations failed to give a purer product. However, several milligrams of a product melting at 279m 280.50, which had an equivalent weight of 207, were obtained from the recrystallizations. The equivalent weight of a carboxymethoxythianaphthene is 208. For determination of structure, the crude product ob- tained from the Grignard reaction was desulfurized by repeated treatment with Raney nickel in boiling alcohol until no fur« ther depression was noted in the melting point of the desul~ furized product. The crude material from.the desulfurization LA ‘ \D f. ) -) \ inelte d;h2 the Itnwme 88~9 {\ 3-Ca1t,xv-o IBLhOth ”his 32“ heme XXXI would desulfurizg to produce 2~(hmmethoxyphenyl)propionic acid XXXII which melt" “TCOH Ni \- -C —CCH J ———. I s. CH3 0\ \s CH 0 / 3 XXXI XXXII iile 2-carboxymethoxythianaphthene XXXIII would 0. ll Ni \ CHZCHsCOH L CH 0\ L1 0 CH 0 / 3 CU: C) )—L-( XXXIII XXXIV desulfurize to produce 3e(h-metnoxyphenyl)propionic acid XXXIV melting at th—SO (18). Since the crude product from the desulfurization melted from 88-920 it was evident that a large portion of the acid obtained was not the desired isomer XXXI. From the work 0. Campaigne (19) on the substitULion of c-ethoxythi can-)hthene it eems reasonable to assume that the 0) bromination did occur predominantly in the 2-positicn. The reason for this would seem to be the strong electron release of the methoxy group upon demand of an attacking electrophile. In this case then the active sites on C-methoxythianaphtheze d as: could be depict (D 40 Based on this it was assumed that if a thianaphthene could be prepared possessing a group less activating than methoxy in the 6-position the normally enhanced reactivity of the 3 position might again predominate over any activa- tion the Eurosition might receive“ Accordingly, it was decided to prepare 6~bromothianaphthene XXXIX in the anticm ipation that further substitution would occur in the 3epositiono The method of synthesis of o-bromothianaphthene was by a sequence similar to that used to prepare 6-methoxythianaph» theneo Sodium metanilate was diazotized and converted 123 the Sandmeyer reaction to sodium meta~bromobenzenesulfonate XXXVo The meta~bromobenzenesulfonyl chloride was prepared by heating XXXV to 1650 with an excess of phosphorus oxy- chloride” The meta-bromothiophenol XXXVII was prepared by reduction of XXXVI with zinc and hydrochloric acido The bromothiophenol XXXVII was then alkylated with bromoacetal to produce meta-bromophenyl cowdiethoxyethyl sulfide XXXVIIIC The method of ring closure of the sulfide was identical to that utilized for the preparation of o-methoxythianapnthenea Ml l) HNC2 H2N SO3Na 2) Cu2Br2 Br SOBNa XVIII xxxv Zn dust Pool3 // g // ———i> Br\\~ 30201 HCl Br\\\ SH XXXVI XXXVII BrCHZCH(OCHZCH3)2 HC(0CH2CH3)2 HBPOu 9 *~/CH2 '—___———9 NaOCHZCH3 Br s P205 XXXVIII Br /|l l/l[| Br\\~ S/J \\‘ S/J XXXIX XL The sulfide was introduced below the surface of a mixture of phosphorus pentoxide and phosphoric acid at a temperature of 165° under a system pressure of 2.6 mm. Hgo The bromothia- naphthene was collected by distillation into a receiver as it formed. 1,2 ‘t was necessary to prove the structure of the ring closure product since it had been shown by Hansch (12) that metawchlorOphenyl condiethoxyethyl sulfide closes to give prew dominantly h~chlorothianaphthene and not 6~chlorothianaphthene as Sunthankar and Tilak (9) had assumed. Since there are two alternate paths by which ring closure may occur, either h~bromothianaphthene XL, énbromothianaphthene XXXIX, or both could be obtainedo The crude bromothianaphthene product was fractionated using a 3O~cm° tantalum spiral columno Two fractions were obtained° The first, 25% of the material, was collected from h2»500/0007 mm. Hg; Egg approximately 1.6hh. The second was collected from SO~S7.SO/O°O7 mm° Hg; n35 approximately 10669o After being set aside for several days in a refrigerator the first fraction crystallized to a white solid which, after sublimation, melted at hhod MSG, When the second fraction was also set aside for several days in a refrigerator a white solid was obtained which, after sublimation, melted at Sh.8~55.800 A melting point of 560 has been reported for o-bromothianaphthene (257‘)° The reliability of this melting point is in question, however, since these workers converted the bromothianaphthene to what they considered ovcarboxythianaphthene and report its melting point as l62oo Hansch (l2) has also prepared a 6~carboxythianaphthene by a seemingly unambiguous route and gives a melting point of 215~2160. The identities of the bromothianaphthenes were not determined since at this juncture the objective was to establish Whether enough M3 cobromothianaphthene was present in the ring closure product to make continuing the synthetic reaction sequence feasible° A portion of each of the two noncrystalline bromothia- naphthene fractions was converted to the carboxylic acid gig its Grignard reagento In each case an acid mixture was ob- tained which had a broad melting range of about thwlCOO indicating that the bromothianaphthene fractions were not pureo An unsuccessful attempt was made to purify these mix- tures by fractional recrystallization from alcohol/watero However, a few milligrams of an acid melting from 188~1890 was obtained which had an equivalent weight of 185° The equivalent weight of a thianaphthenecarboxylic acid is 1780 The acid mixtures were then desulfurized using Raney nickelo The melting range of the desulfurized acid was 60- 7000 b-Bromothianaphthene would give o-carboxythianaphthene which upon desulfurization would yield para-ethylbenzoic acid having a melting point of llO-lllo° h-Bromothianaphthene would give h-carboxythianaphthene which upon desulfurization would give ortho-ethylbenzoic acid with a melting point of 680° The melting point of the product from the desulfur- ization indicates that it was predominantly the ortho isomer, thus showing that the starting bromothianaphthene was pre» dominantly the h~bromo isomero This conclusion was further substantiated by the determ mination and examination of the substitution pattern of the infrared spectrum of the desulfurized product. uh As a further confirmation, 2 g. of the bromothianaphthene o ‘J C melting at Sh.8~Sb.SJ was converted to its corresponding acid. After several recrystallizations a pure sample of acid which melted at 200-2030 was obtained. This melting point agrees with neither of the values cited above for o-carboxva thianaphthene. Since the mixture of isomeric bromothianaphthenes ob- tained from the ring closure did not contain enough of the desired 6misomer a new synthetic reaction sequence was started at this juncture using an approach similar to that used by Tilak gt El" (21) to ootain a suitable 3,6-disubstituted thianaphthene. Meta-methoxythiophenol was alkylated with ethyl ‘K-chloroacetoacetate, prepared by the procedure of Harm} (23), in pyridine (21) to obtain ethyl hu(meta-meth» oxyphenylmercapto)w3-oxobutyrate XLI. The latter compound (XLI) was then cyclized to a thianaphthene derivative by heat- ing it with phosphorus pentoxide and 85% phosphoric acid using chlorobenzene (21) as a reaction solvent. The ring closure produced both ethyl (ovmethoxythianaphthyl-3)acetate XLII and ethyl (h methoxythianaphthyl-3)acetate XLIIT. However fractional distillation using a Fenske column failed to separate the mixture of the esters XLII and XLIII. The ester mixture of XLII and XLIII was shaken with concentrated aqueous ammonia for a week to produce 6-meth- oxythianaphthyle3wacetamide XLIV and u-methoxythianaphthyl~j 3~acetamide XLV. The isomeric amides were easily separated AS 0 O §CCH EOCH CH // I 2 2 3 | CH CH3CQ§: s/ 2 XLI n 9 /UCHZCOCH2CH3 /flCH2COCH2CH3 CH 30 S S XLII XLIII CCH3 o / II I /lfH20NH2 \ S ' XLIV XLV by crystallization and chromatography. The reaction mixture containing the amides was first crystallized from alcohol. The solid obtained was o-methoxythianaphthyl-3-acetamide. The filtrate from the crystallization, containing both the 6-methoxy and humethoxy isomers, was evaporated to dryness and the residue chromatographed on alumina using chloroform as the eluent. The é-methoxythianaphthyl-3-acetamide was removed from the column first followed by the h-methoxy- thianaphthyl-B-acetamide° H6 The next step in the reaction sequence was reduction of 6-methoxythianaphthyli3-acetamide to the amine (V) using lithium aluminum hydride. This reduction was tried several times in diethyl ether and in tetrahydrofuran as reaction solvents and in each case only a trace of an amine was ob~ tained. At this point in the study it was apparent that the original goal of synthesizing "thioreserpine" could not be realized in a reasonable period of time. Thus, it was decided to prepare structurally simpler thioreserpine type compounds which could be tested for potential physiological activity. While not giving a definite answer regarding the physiological activity of thioreserpine, these simpler thia- naphthenes having the basic ring structure of reserpine would give some indication of the physiological properties of the basic ring system devoid of the functional groups present in reserpine. These compounds would be similar to those prepared by Werner Herz (S) and P. Cagniant (6). The simplest and most direct route to this alternate objective was to obtain more easily reducible amides and convert these to their corresponding amines. .The structures of the amides had to be proven first. Each amide was hydrolyzed to the corresponding acid, 1.3. XLIV was hydrolyzed to é-methoxythianaphthyl-3-acetic acid XLNI and XLV was hydrolyzed to give h-methoxythiananhthyl- 3-acetic acid XLVII. XLVI was shown to be the 6-methoxy L ' \1 isomer by desulfurization using Haney nickel followed by “A. -. oxidation of the oily desulfurization product with pi-a sium permanganate to obtain para~anisic acid 312. .CHgaOH I I" Ni A CHqO S/’ V ) XLVI 9 I Kl’anLL 'fll COH The para-anisic acid obtained did not depress the melting point of an authentic sample of para-anisic acid. The brmethoxythianaphthyl~3-acetic acid was then cone verted to its acid chloride using thionyl chloride. The acid chloride was not isolated but was immediately treated with an excess of piperidine to obtain the amide §(o«ncthm oxythianaphthylw3-acetyl)piperidine XLIX which, without further purification, was reduced to the amine L. This was isolated as the hydrochloride LI, 5 L8(o-methoxythia- naphthyl-3)ethyl]piperidine hydrochloride. The amine salt (LI) after purification by several recrystallizations was submitted for physiological evaluation. Ha V? II II /UCH2COH /UCH2CC1 CH O S CH O S XLVI XLVIII V O :11 N 020 0 W CH O S 3 _____ : > <3: . : ‘ JCHZCH2N (‘ECHZCHZNH C) CH3O S CH3O S Cl L LI A sample of pure ethyl (6-methoxythianaphthyl-3)acetate was prepared by treating the acid chloride XLVIII with absolute ethyl alcohol. Some of the ester mixture of XLII and XLIII obtained from the ring closure reaction described was reduced using lithium aluminum hydride to a mixture of the alcohols /9(6-methoxythianaphthy1e3)ethanol LII and /6(h-methoxythiaw naphthyl~3)ethanol LIII. These could not be separated satis- H9 factorily by distillation. After being set aside several weeks in the laboratory, however, some of the fractions from the distillation did crystallize partially. When these crystals were separated and recrystallized a solid alcohol was obtained which melted from 97.8-98.50. By comparing the substitution bands in the infrared spectrum with those in the spectra of the other 3,h- and 3,6—disubstituted thia- naphthenes it was established that this alcohol was /5(h-meth- oxythianaphthyl-3)ethanol. The other isomer, [8(éamethoxy- thianaphthyl-3)ethanol, did not crystallize. Several dism tillations of alcohol gave an oil which did not give the infrared pattern of the h-methoxy alcohol. The oil was not purified further. OCH3 O JOHg CH2 OH JCHZCHZ OH CH3O s s LII LIII SUMMARY While the original objectives, $.3. the total synthesis of "thioreserpine" or the preparation of /6(6-methoxythianaphe thyl~3)ethylamine V, were not realized, it is felt that the preparation of the amine V from o-methoxythianaphthyl‘3w acetamide is entirely possible. This can be accomplished either by using a different reducing medium, g.g. sodium in alcohol, or by carrying out repeated reductions with lithium aluminum hydride since the initial aluminum complex formed might be too sterically hindered for complete reduction. While somewhat short of its original aims this inves- tigation gained several important goals. First, a compound of a structure grossly similar to rings A, B, C, and D of reserpine was obtained which was submitted for testing for its physiological activity; secondly, a sound synthetic route for the preparation of 6-substituted thianaphthyl-3w acetic acids was developed using a procedure similar to Sunthankar and Tilak; thirdly, several 3,6~ and 3,hwdisubn stituted thianaphthenes previously undescribed were pre» pared and characterized. Somewhat as an aside from.the main theme of the study the é-methoxythianaphthyl-3~acetic acid and hamethoxythia- naphthyl-3wacetic acid were submitted for testing as plant growth regulators using £1333 coleoptile sections. Quali- tatively the hamethoxy isomer was only slightly less active 50 51 than indole-3-acetic acid while the 6-methoxy isomer was inhibitory at concentrations up to 10-5 molar, at which con» centration it was then slightly active as a growth promoter. There are several facets of the present problem which require further investigation. The identities of the isomeric bromothianaphthenes were not established due to limitations of time and the very conflicting literature reports on the preparation of Cucarboxythianaphthene. Several additional pure compounds should also be prem pared to complete the series reported in the present work, g.g. ethyl (h-methoxythianaphthyl-3)acetate and lfl(o-meth~ oxythianaphthyl-3)ethanol were not prepared in a pure state. The preparation of /B(6—methoxythianaphthyl-3)ethanol would give an alternate route to the preparation of the amine V. The alcohol could be converted to 6-methoxy~3«”Bwbromoethyl)e thianaphthene using phosphorus tribromide. The bromide could then be interacted with a large excess of ammonia to produce the amine V following neutralization. An additional ob- jective of value would be the preparation of either a o-nitro- or cmaminothianaphthyl~3macetic acid since both groups could readily be converted to other functional groups gig diazo- tization of the amine, thus enabling a wide variety of 3,6-disubstituted products to be synthesized. Finally, the complete Synthesis of "thioreserpine" or of "thioyohimbane" would be of value in determining to what S2 extent the difference between the nitrogen and sulfur heteroatom affects the physiological activities of a specific alkaloid. 11° 12. 130 150 BIBLIOGRAPHY Woodward, R, Bo, Bader, Fo E0, Bickel, Ho, Frey, A, Jo, and Kierstead, Ru W0, Journal of the American Chemical Society lg, 2023 (1956)° ' Woodward, Bo Bo, Bader, Fo Eu, Bickel, Ho, Frey, A, Jo, and Kierstead, a, we, Tetrahedron 2, 1-57 (1958), Woodward, R, Bo, Bader, F° Ea, Bickel, Ho, Frey, A, Jo, and Kierstead, R, Wu, Journal of the American Chemical Society IQ, 2657 (1956)o van Tamelen, E0, and Shamma, M., Journal of the American Chemical Society Zé, 95C (195u). Herz, Werner, Journal of the American Chemical Society 12; M999 (1950)o Cagniant, Po, and Caignant, Mrso P., Bulletin de la Société Chimique de France, 3&0 (1952). 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