June, 1946 ARYLPROPYLAMINESFROM ALLYLCHLORIDE 1009

[CONTRIBUTION FROM THE DEPARTMENTOF CHEMISTRY, PURDUE UNIVERSITY] Synthesis of Arylpropylanrines. I. From My1 '

BY T. M. PATRICK,JR.,:: E. T. MCBEEAND H. B. HAS The isolation and proof of structure of the hor- thesis of atylpropylamines by ammonolysis with mone epinephrine (generally attributed to Abela) ammonia or amines. The aminations were car- has led in succeeding years to the synthesis of ried out in an autoclave at 125-160' for reaction many similar compounds which have the common times of four to nine hours. In some cases aqueous property of increasing the blood pressure, but solutions of ammonia or methylamine were used, may also exhibit other varied and interesting but alcoholic solutions resulted in somewhat physiological effects. Inasmuch as benzedrine, better yields and mixtures containing fewer by- l-phenyl-2-propylamine2 and its derivatives wi?re products. The principal advantage of alcoholic found to be among the most important of the solutions is complete homogeneity of the reaction pressor amines,4 this group was selected for the mixture. present study of new compounds possessing 110- By-products in the reaction' are the alcohol tential pressor activity. and ethyl ether corresponding to the halide un- In 1933 Nenitzescu and Isacescus synthesized dergoing reaction, in addition to higher amines. 2-chloro-1-phenylpropane from , allyl The formation of higher amines is suppressed by chloride, and ferric chloride using a large excess of the aminating agent and by avoiding excessively long reaction times. FeCh The amines were readily separated from the n+ CH2=CHCH1CI L_f non-basic by-products by extraction of a benzene solution of all organic matter with dilute hydro- chloric acid. The desired amine boiled sufficiently lower than the higher amines to allow separation in fairly pure form by careful distillation of a basic extraction mixture. Further purification was readily accomplished by recrystallization of A by-product of the reaction was 1 ,a-diphenyl- the hydrochlorides. 1,n the present work a large propane, evidently formed by further reaction of excess of ammonia (or methylamine) was em- 2-chloro-1-phenylpropane with benzene. We ployed and only small amounts of the higher have applied successfully the technique of Neriit- amines were formed. zescu and Isacescu to other aromatic compounds. Primary generally gave better yields Both chlorobenzene and bromobenzene gave than did secondary chlorides. This is in accord ortho and para halogenated arylchloropropanes with the observations of Cheronisz who studied with allyl chloride, but fluorobenzene and anisole the reaction rates of the four bromobutanes with gave only the para isomers in detectable amounts. alcoholic ammonia, and evaluated the yields Truffault6found that aromatic compounds add therefrom.

Downloaded by CKRN CNSLP MASTER on August 9, 2009 to allyl chloride in the presence of sulfuric acid or The highest yields of amines were obtained oleum to form 2-aryl-1-chloropropanes. Truf- from compounds having no substituent on the fault's experiments were repeated in this Labora-

Published on May 1, 2002 http://pubs.acs.org | doi: 10.1021/ja01210a032 benzene ring. Moreover, the more labile the sub- tory using benzene and chlorobenzene, respec- stituent, the lower was the yield. Thus fluor0 tively, as the aromatic reactants. In the. case derivatives gave better yields than did chloro of chlorobenzene, an isomer was formed as well derivatives, which in turn were more productive as 2-(p-chlorophenyl)-l-chloropropane which than bromo compounds. Yields were markedly Truffault reported. The ethers, anisole and vera- lower in the amination of ortho substituted aryl- trole, failed to add to allyl chloride by this chloropropanes than in the case of para isomers. method. It was possible to prepare a number of aryl- Experimental chloropropanes, many of them new, from allyl l-Aryl-2-chloropropanes.-The procedure for prepara- chloride by these techniques. These compounds tion of 2-chloro-1-(o-chloropheny1)-propane and Zchloro-1- (Table I) are suitable as intermediates in the syn- (p-chloropheny1)-propaneis given as typical for this class of compounds. A mixture of 450 g. (4.0 moles) of chloro- (1) Based upon a thesis submitted by T. Xi. Patrick! Jr.. to the benzene and 32.4 g. (0.2 mole) of anhydrous ferric chloride Faculty of Purdue University in partial' fulfillment of the require- was cooled to -21' by an icesalt-bath. Allyl&loride ments for the Degree of Doctor of Philosophy, April, 1943. (76.5 g., 1.0 mde) was then added dropwise with stirring (2) Abbott Laboratories Fellow, 1941-1942. Present address over a two-hour period. Stirring was continued for three Monsanto Chemical Co.. Dayton 7, Ohio. hours longer. Meanwhile the temperature had risen to (3) Abel, 2. ghysiol. Chcm., 48, 318 (1899); Chcm. Zentr., 60, 11, -16'. chloride was evolved weakly through- 382 (1889). out the entire reaction period. The mixture was shaken (4) Barger and Dale, J. Physiol., 41, 19 (1910). (5) Nenitzescu and Isacescu, Be., 66, 1100 (1933). (7) Clark, Olin and Deibel, U. S. Patent 2,183,499 (Dec. 12, 1939). (6) Truffault, Bull. soc. chim., 8, 726 (1939): Comfit. rend., POP, (8) Cheronis, Trans. Illinois Stak Acad. Sci.. 81, 126 (1938); 1286 (1936); 1307, 676 (1938). c. A., aa, 6792 (1939). 1010 T. M.PATRICK, JR., E. T. MCBEEAND H. B. HASS Vol. 68

TABLEI ARYLCHLOROPROPANES FROM ALLYLCHLORIDE Yield, ec.B. P., --Analyaes. %- Compound % Mm. d% lmD Calcd. Found 2-Chloro-1-(P-chlorophenyl) -propane 2 1 111-112 10 1.1678 1.5360 C137.5 37.0 2-Chloro- 1 - (o-chlorophenyl)-propane 32 103 10 1.1706 1.5351 C137.5 37.5 l-(p-Bromophenyl)-2-chloropropane 13 124-126 10 1.4100 1.5582 C 46.3 46.4 H 4.3 4.1 l-(o-Bromophenyl)-2-chloropropane 311 115-117 10 1.4159 1.5568 C 46.3 46.2 H 4.3 4.d 2-Chloro-l-(p-fluorophenyl)-propane 24 81 10 1.1186 1.4971 C120.5 20.7 F 11.0 11.0 2-Chloro-1-(p-methoxyphenyl) - propane 14 107 5 1.0891 1.5270 C119.2 19.4 2-Chloro-1-phenylpropane 32 80-814 10 1-Chloro-2-phcnylpropntle 20 82-83b 10 l-Chloro-2-(p-chlorophenyl)-propane 6 94" R * Nenitzescu and Isacescd reported 79' at 10 mm. * Truffault' reported 8:5' at 13 mm. Truffault' reported 117' at 16 mm. with about 1 kg. of crushed ice and 100 ml. of concentrated tion. From the rectification curve and density data the . The organic layer was separated and yields were calculated to be 32% of 2-chloro-l-(o-chloro- washed with dilute hydrochloric acid, and finally with phenyl)-propane and 21% of 2-chloro-l-(p-chlorophenyl~- distilled . It was then filtered to remove a small propane, or a total yield of 53% of products. amount of solid condensation product, and dried over an- No allyl chloride was recovered from the reaction; how- hydrous calcium sulfate. ever, rectification of the lower boiling fraction from the first The dried reaction mixture was distilled from a Claisen distillation yielded, in addition to chlorobenzene, two flask to effect a rough separation of unreacted materials, compounds whose boiling points corresponded to 1,2di- product, and tar. The fraction containing the products chloropropane (9 9.) and 1,3-dichloropropane (12 g.). No was carefully rectified at 10 mm. pressure, using a 5-foot, attempt was made to prove their identity conclusively. glass-helices-packed column. A reflux ratio of 25:l was Further distillation of the tarry residue from the reaction maintained. Two products, boiling at 103" at 10 mm. produced a viscous, slightly fluorescent oil (b. p. 133-135' and 111-112' at 10 mm., respectively, were obtained from at 2 mm.), consisting of bis-(chloropheny1)-propanes (10- the rectification. They yielded o-chlorobenzoic acid and 12% yield). The remainder of the material was non- P-chlorobenzoic acid, respectively, on permanganate oxida- distillable tar. TABLEI1 AMINESBY AMMONOLYSISOF CHLORIDES M. p. of Yield, B. P.. derivative, ----Analyses, %- Compound, propylamine % "C. Mm. *C. dmta nmD Calcd. Found 2- (p-Chlorophenyl) -1- 40 99-101 5 205" 0.9639 1.5398 C 45.2" 45.2 H 3.8" 4.0 l-(p-Chlorophenyl)-2- 44 93-94 5 164-165b 1.0762 1.5343 C 63.7" 63.8

Downloaded by CKRN CNSLP MASTER on August 9, 2009 H 7.1" 7.3 1-(p-Bromophenyl) -2- 35 123-124 10 204-206b 1.3080 1.5569 Ion. C1 14.9 14.2 l-(o-Bromophenyl)-2- 26 118 10 200-201' 1.2984 C1 14.9 14.3 Published on May 1, 2002 http://pubs.acs.org | doi: 10.1021/ja01210a032 1.5582 Ion. l-Phenyl-2- 51 80-82d 11 147-14@*' 2-Phenyl-l- 51 81-83' 10 145' 1- (p-Fluorophen yl) -2- 43 w 15 152-154"* 1-(&hlorophenyl)-2- 25 103-105' 10 l@J l-(p-Methoxyphenyl)-2- 20 10?5-106k 5 207-208''' N-Methyl-2-phenyl-l- 62 95-96 15 155" 0.9178 1.5102 C 50.8" 51.0 H 4.8" 4.8 N-Methyl-1-(o-Chloro- 24 110 10 156" 1.0536 1.5288 C 46.6" 46.5 phayl)-2- H 4.2" 4.4 N-Methyl-1-(p-chlaro- 35 114-115 10 103" 1.0442 1.5259 C 46.6" 44.4 phenyl)-2- H 4.2" 4.6 N-Methyl-l-(p-fluoro- 41 87-89 10 125" 0.9984 1.4922 C 48.5" 48.7 phenyl)-2- H 4.3" 4.3 N-Methyl-l-phenyl-2- 44 98-100" 20 133'-" Picrate. Hydrochloride. e Free amine. Woodruff and Conger, THISJOURNAL, 60,465 (1938), reported 102-104' at 22 mm. ' Woodruff and Conger, ibid.,reported 152'. v. Braun, Grabowski and Kirschbaum, Ber., 46, 1280 (1913), reported 104' at 21 mm. Suter and Weston, THISJOURNAL, 63, 602 (1941), reported 95-96' at 17 mm. h Suter and Weston, ibid., reported 156-157'. Johns and Burch, THISJOURNAL, 60,919 (1938), reported 75-80" at 8 mm. i Johns and Burch, ibid., reported 175-176". Mannich and Jacobsohn, Bcr., 43,189 (1910). reported 158" at 25 mm. Man- nich and Jacobsohn, ibid., reported 210'. ,,, Woodruff, Lambooy and Burt, THISJOURNAL, 62,922 (1940), reported 78- 80" at 6 mm. * Woodruff, Lambooy and Burt, ibid.. reported 135-136'. June, 1946 POLYMER PRODUCT OF 'rYROSINE AND FORMALDEHYDE 1011

Other I-aryl-2-chloropropanes, listed in Table I, were with 15-ml. portions of 6 M hydrochloric acid to secure prepared similarly using bromobenzene, fluorobenzcne, the amine as a solution of its hydrochloride. The aqueous and anisole in place of chlorobenzene. acid solution was made basic with sodium hydroxide aod l-Chloro-Z-( pchloropheny1)-propane.-The method was extracted several times with benzene. The latter benzene adapted from Truffault.6 To a mixture of 380 g. (ca. 4.0 solution was dried over anhydrous potassium carbonate. moles) of fuming sulfuric acid (10% oleum) and 337.!5 g. This benzene solution was distilled from a Claisen flask (3.0 moles) of chlorobenzene there was added over a two- giviiig 11.1 g. of benzedrine boiling at 80-82" at 11 mm. hour period with stirring and cooling, 153.0 g. (2.0 moles) The yield was 51"/b. of allyl chloride. The mixture was stirred overnight at Ammonolysis of Chloro Compounds to Secondary Methyl- room temperature. The reaction mixture was shaken with amines.-The technique for preparing the N-methylamines several times its volume of crushed ice, washed with water listed in Table I I was identical to that used for synthesis of and dried over anhydrous calcium sulfate. The dried the primary amines, except that an alcoholic solution of product was rectified to strip off lower boiling components. methylamine (204 g. per liter) was used as the aminating A higher fraction, boiling at 91-99' at 6 mm., was re- agent. fractionated at 5 mm. pressure. Two distinct materials, Acknowledgment.-The authors wish to ex- boiling at 90.5-92.0° at 5 mm. and 94.0' at 5 mm., re- spectively, were obtained. The latter compound gave a press their appreciation to the Abbott Labora- negative test for active with alcoholic silver nitrate tories for a grant which made this research in the cold. Permanganate oxidation yielded p-chltxo- possible. benzoic acid, proving that it was 1-chloro-2-(p-chloro- phenyl)-propane (reported by Truffault). The yield was summary 6y0. The former compound, evidently an isomer (~*O:O 1.1801, n*% 1.5404, calculated for GHloCln, 3i.5% C1, The reaction of allyl chloride and benzene in the found, 37.4% Cl), was not identified conclustvcly. It gave presence of ferric chloride to produce 2-cllloro-1- a positive test for active chlorine with alcoholic silver phenylpropane, described by Nenitzescu and nitrate, but failed to yield a solid acid derivative on trcat- Isacescu, has been extended to four other aro- ment with permanganate, dichromate, or nitric acid- silver nitrate. It was obtained in 7.5% virld. matic compounds. Total yields of arylchloro- Ammonolysis of Chloro Compounds to Primary Amines. propanes were 14 to 53%. -The preparation of benzedrine is typical of the method Truff ault's method of adding aromatic com- used for synthesis of the primary amines listed in Table 11. pounds to allyl chloride in the presence of sulfuric Twenty-five grams (0.16 mole) of 2-chloro-1-phenyl- propane was dissolved in 450 ml. of saturated alcoholic acid was utilized for the preparation of 2-aryl-l- ammonia solution (125 g./l.) and sealed in an iron-pipe chloropropanes. autoclave. The autoclave was mechanicatly rocked and Nine arylchloropropanes have been treated was heated by an electric resistance winding. The charge with alcoholic ammonia to give 20-51% yields of was heated at about 160' for nine hours. It was then allowed to cool and filtered. The alcohol and excess am- the corresponding arylpropylamines. Five of the monia were distilled, and the residue was made strongly arylchloropropanes yielded 24432% of the N- basic with 6 M sodium hydroxide. The basic mixture methylarylpropylamines on treatment with alco- was extracted four to five times with 20-mi. portions of holic methylamine. benzene, and the aqueous residue was discarded. The benzene solution was next extracted three to four times LAFAYETTE,INDIANA RECEIVEDDECEMBER 1, 1945

[CONTRIBUTION FROM THE EAS~TERNREGIONAL RESEARCH LABORATORY1]

Downloaded by CKRN CNSLP MASTER on August 9, 2009 A Polymer Reaction Prodiict of Tyrosine and Formaldehyde

Published on May 1, 2002 http://pubs.acs.org | doi: 10.1021/ja01210a032 BY ALFREDE. BROWN^ In a study of modified proteinsa it was foiund the 1(-)-tyrosines side chain is involved in bind- that when the free amino groups of the protein ing formaldehyde has been mentioned.' We were were apparently completely acylated, the deriva- interested, therefore, in investigating the manner tives still had an appreciable formaldehyde-csm- in which the hydroxyphenyl group of tyrosine bining capacity as determined by a modification might react with formaIdehyde as well as in the of the method of Nitschmann, et al.,' which in- stability to acid hydrolysis of any linkages which volves acid hydrolysis of the formaldehyde- might thus be formed. The reaction with tyro- treated products, and distillation and titration sine itself was first studied, with the expectation of the formaldehyde. In addition to the acid- of subsequently using N-acylated tyrosine deriva- labile formaldehyde, it may well be that linkages tives and peptides of tyrosine. It will be evident stable to acid hydrolysis can be formed by pro- that the experimental conditions employed in the teins and formaldehyde.6 The possibility that present work were different from those ordinarily (1) One of the laboratories of the Bureau of Agricultural and In- used to harden proteins with formaldehyde. duatrial Chemistry, Agricultural Research Administration, United Ullmann and Brittner* were able to prepare States Department of Agriculture. Article not copyrighted. (2) Present address: Milton Harris Associates, Washington, D. C. (6) I(-)-tyrosine was used throughout the investigation so the (8) Gordon, Brown and McGrory, Ind. Eng. Chem.. 88,90 (1946). prefix I(-) will be odtted henceforth. (4) Nitschnunn, Hadorn and Lauena, RJu. Chim. Acta, 16, 1069 (7) Carpenter and Lovelace, Ind. Enr. Chcm., 86, 680 (1944); (1943); Wood, Swain and Kokes, to be published. Nitschmann and Hadorn, Hclo. Chim. Acta, 17, 290 (1044). (6) Baudouy, Compl. rend., 314, 692 (1942). (8) Ullmann and Brittner, &r., 42, 2539 (1009).