A New Synthesis of Mescaline

5495

NOTES

ru'ov., 19.51 Per oxi de f 1sochroman.-The viscosity f isochroman increas increased ed markedly when when i t was allowed allowed to st and t room temperature in glass vessel for several days. white crystalline material formed slowly and it was purified by recrystallization from ethyl ether in which it is moderately soluble. soluble. Th e solid is only slightly soluble soluble in alcohol. alcohol. The compound melts sharply with decomposition 147' and vacuo. Isachroman is probably decomposes decomposes slowly a t 78 oxidized at the 1-position. Calcd. for C18 C18H1 H18O 8Oa: a:C, 72.41; , 6.08. Fou nd Anal. C, 72.32; 72.32; , 6.15. 6.15. 3-Phenylisochr 3-Phenylisochroman oman is also sensitive to air an d is consequent ly troublesome o purify. However, 1,3-diphen 1,3-diphenylisoylisochroman is appar ently unreact ive. A sample f this compound was unaltered after storage for two years in screw cap vial. OF CHEMISTRY DEPARTMENT

OF T E C H N O L O G Y ILLINOIS INSTITUTE TECHNOLOGY CENTER

CHICAGO 16, ILL.

RECEIVED JUNE 11 1951

New Synthesis of Mescaline BY MAKEPEACE TSAO

The cactus alkaloid, mescaline, p-(3,4,5-trimethoxypheny1)-ethylamine, has been studied for years , because f its it s most interesting effects effects some years, on the psychic states human subjects. Since Since th e elucidation elucidation of of the th e chemical chemical str ucture uct ure th alkaloid through the synthesis by Spath,' a few other methods met hods of of prepar p reparation ation have been been published. simple synthesis utilizing lithium aluminum hydride is presented in this report. The synthesis may be outlined as follows: gallic acid 3,4,5-trimethoxybenzoic 3,4,5-trimethoxybenzoicacid acid -- methyl ester 3,4,5-trimethoxybenzoicacid 3,4,5-trimethoxybenzoic acid 3,4,5-trimethoxybenzyl alcohol alcohol -- 3,4,5-trimethoxybenzyl chloride 3,4,5-trimethoxyphenylacetonitrile -+ mescaline. ---f

--f

Experimental Methyl Ester of 3,4,S-Trimethoxybenzoic Acid.-To soluti on prepared from 100 g. of 3,4,&-tr imetho xybenzo ic acid* (0.47 mole), 20 of sodium hydroxide, 55 g. of sodium carbonate carbonate an 30 ml. water is added, with stirring, 94 ml. f methyl sulfate (0.94 (0.94 mole) mole) during the c e of of 20 minutes, Th e reaction mixt ure is refluxed refluxed for one-half one-half hour. The crude ester (69 g., 61%) preeipitates preeipitates from the cold mixture. mixture. From filtrate 38 g. of of s tar tin g mater ial is recovered recovered upon acidification acidification with dilute d hydrochloric hydrochloric acid. Th e ester is furthe r purifie purified d by solution solution in th e minimum minimum amount f methanol and treatment with norite. norite. Usually Usually it is necessa necessary ry to repeat this treatment t o obtain colorless colorless crystalline product that melts at 80-82". Semmler: who employed different process, reported m.p. 83-84'. 3,4,~-TrimetlaoxybeazylAlcohol.-To suspensioa sf 4.6 g. (Q.12 mole) mole) of of lith ium aluminum hy dride in 200 ml , of an soluhydrous ether is added, in th course 30 minutes, tion 22.6 g. (0.1 mole) of the methyl ester of 3,4,5-trimethoxybenzoic methoxybenzoic acid in 300 300 ml. of of eth er. Th e solid which forms is carefully decomposed decomposed first with 50 ml. ice-water. After deca ntat ion of of t he e the r, 250 ml. of ice-col ice-col 10% sulfuric acid is added . Th e produ ct is extracted with 150 ml. f ether. Th e combined combined extract s, afte r dryin g over sodium sulfate, are freed freed of of ether and t he residue residue distilled; distilled; b,p 135-137' (0.25 mm.) ; yield 14.7 (73%). This com129 (1919). (1) E. Spnth, M o # a l s h . , fjlotta and H. Heller, Bcr., (2) K. , 3029 (193 (1930) 0) Frissh and E. Waldmann, German Patent 545,853, J u l y 3, (3) 1930; 35211 (1932). Kiadler ond W. Peschke, Arch. P h a r m . . $ 7 0 , 41 0 (1932). (4 (1932). Slotta and G. Sayzka, p r o k l . Chcm., 137,33 9 (1933) (5) (1934). (6 G. Hahn and H. Wassmuth, Bcr., 67 (7 G. Hahn and F. Rnmpf, i h i d . , TlB, 2141 214 1 (1938) Blatt, "Organic Syntheses," Coll. Vol. 1, 2nd ed.. J o h n (8 A. 1946, p. 537. Wiley and Sons, Sons, Inc., N ew York, N. Y., Semmlcr, B c r . , 41, 1774 (1908) (9) F.

pound was obtained by a different method by MarxlO; b.p. 228' (25 mm.). 3,s-Dinitrobenzoate of ,S-Trimethoxybenzyl Alcohol This deri vativ e was was prepared wit h 3,5-dinitrobe 3,5-dinitrobenzoyl nzoyl chloride an d recrystallized from ethanol. Th e yellow diamondshaped shaped crystals melt at 143-144'.11 A n a l . Calcd. fo C~rHlsoS": c, 52.04; H, 4.11. Found: C, 52.3 52.31; 1; , 4.21. 4.21. 3,4,5-Trimethoxybenzyl Chloride.Chloride.-A A mixt ure f 25 g. f 3,4 ,5-tri methox ybenzyl alcohol and 125 ml. of of ice-cold concentrated hydrochloric acid is shaken vigorously until homogeneous solution is obtained. In few minutes turbidit y develops, develops, followed followed by heavy precipitation f gummy produ ct. After 4 hours and dilution with 100 ml. of of icewater, the aqueous layer is decanted and extracted with three M)-ml. portions of benzene benzene.. Then the gummy gummy organic residue dissolved in the combined benzene extracts. The benzene solution is washed with water and dried over sodium sulfate. Th e benzene benzene solution is transferred to a distilling flask flask and The the benzene is removed under diminished pressure. red semisolid residue is suspended in small amount icecold cold ether and filtered filtered through chilled funnel. Th e crystalline produ ct, a fter washing with small portions of of cold ether , weighs weighs 9.7 g. Th e combined filtrates on standing in refrigerator yield more crys tals. Th e tot al yield is 13.0 g. (48%). After four re cr ys ta ll iz at ip from from benzen benzene, e, colorles colorles needles are obtain ed; m.p . 60-6 60-6 Anal. Calcd. Cal cd. for f or C10H C10H18 1803 03Cl Cl:: , 55.42; 55. 42; 6.05. Found: C, 55.55; 6.13. This compound is extremely soluble in ether, alcohol and acetone, but slightly soluble in petroleum ether. Stand ing at room temperature for few weeks causes causes th e crystals to turn into a red semi-solid. An alcoholic soluti on of p ure material gives an instantaneous precipitation with alcoholic silver silver nitrat e. 3,4,5-Trimethoxyphenylacetonitrile.-A mix tur e of 9 g. o potassium cyanide in 35 ml. of water and 60 ml. of of met hanol an g. f 3,4,5;trimethoxybenzyl chloride is hea ted for 10 minutes at 90 The solvents are partially removed g dimin diminishe ished d pressure. pressure. The residue residue is then extracte with 90 ml. of of ether in three portions. Th e combined extract s are washed washed with water an d dried over over sodium sulfate. After the removal of of t he dryi ng agent the et her solution solution is warmed on steam-bath and the ether is removed with stream of air. On chilling, the residue yields scale-like crystals. Recrystallization from ether gives gives rectangular prism; yield 2.5 g. (27% ); m .p . 76-7 76-77'. 7'. Baker and Robinson's reported meltin g poi nt of 77' for thi s compoun d. 15 ml. of anhy drous eth er is suspended Mescaline.-In suspended 0.85 g. f lithium aluminum hydride powder. powder. With stirring, 2.0 g. 3,4,5-trimethoxyphenylacetonitrilein 150 ml. of anhyd rous ether was added duri ng th e course f 15 minutes. A f t e r 15 minutes' st irri ng, 10 ml. of of ice-water ice-water is dropped in carefully. Then mixt ure o 10 g. sulfuric acid in 40 ml. f wa ter is added at moderate rate. The aqueous aqueous layer is separated and t reated with concentrated concentrated sodium sodium hydroxide. hydroxide. Th e brown brown oil is extr acted wit h thre e portions of of 30 ml. each f ether . Th e combined extracts are washed washed once with water and dried over stick potassium hydroxide. To decanted ether solution is added a mixture of g. of sulfuric acid and 25 ml. ether. Th e white precipitate is washed washed several times with ether; yield 1. g. (40%). After two recrystallizations from 95% ethanol, the colorless long thin plates soften 172' 172' a nd melt at 183'. A sample of of mescaline mescaline acid sulfa te prepared from t he natu ral source and kindly furnished by Dr . Seevers f t he Depa rtme nt of of Pharmacology softens at 170' and melts at 180: 180:.. Th e mixed melti ng point of of abov e tw o sample s is 181 The picrate, prepared from th e acid acid sulfate, melts at 217' (dec.), aft er three recrystallizations from ethanol. Theochloroplatinate Theochloroplatinate prepared from free base melts a 184185 Spa thl gave the followin following g melting points: points: sulfate, 183-186 picra te, 21&-2 21&-218 18 chloroplatinate, 187-188 '.

Acknowledgment.-The author is indebted to Dr P. S. Smith for generously making available the facilities of his laboratory in carrying (10) M. Marx, A n n , 463, 25 (1891) (11) All m.ps. are uncorrected. (12) Raker an R. Robinson, Chcm

So

160 ( l S 2 0 )

out a part of this investigation. Th e reading the manuscript by Dr. F. F. Blicke is deeply appreciated. DEPARTMENT OF PEDIATRICS UNIVERSITY OF MICHIGAN ASK ARBOR,M I C H I G A N

CHO

IlCOH

COMMUNICABLE DISEASES H O L H R E C E I V EJULY D 5, 1951

IICO HC

>C

CHsL

HOCH

HCOH ---f

Prep Pr epar arat atio ion n

f

l-C1-'-D-Xyl l-C1-'-D-Xylose ose from fr om Glucose

1-Ci4-0D-Glucose

J O H NC. SOWDEN

Diacetonen-glucose I1

Th e development of of methods for th e isotopic isotopic labeling of of sugars sugar s in th e aldehydic carbon ha supplied valuable means elucidating certain chemical and biochemical reactions that involve fragmentation of of the sugar sugar carbon chain. Either Eit her th e nitromethane synthesis using CI4-nitrometha ne1 HC or the cyanohydrin synthesis using C14-cyanide, which were first used to prepare l-C14-~-glucose HCOH CHO and l-C14-~-mannose from D-arabinose, are generCH~OH ally applicable to the synthesis aldehyde-labeled 5-L41do-rnonohlonoacetonealdose sugars. the pentose series, Rappoport acetone-D-xylose D-glUCOX and Hassid have described the preparation of 111 IV C14-~-arabinoseby by application of of the t he C'*-nitromethane synthesis to L-erythrose.$ L-erythrose.$ Recently, l-C'4-~-xylosehas has been employed in a stud st ud y f the t he mechanism of of ferment fer mentation ation of this aldopentose by Lactobacillus p e n t o ~ u s . ~The prep FIOCH HOCH aration of aldehyde-labeled D-xylose by one of the two chain-lengthening chain-lengthening synt hetic het ic methods would HC HCOH require as a starting material the tetrose sugar, CHSOH CHSOH D-threose. D-threose. An alte al tern rnat atee method, described herein, MonoacetoneD-XylOV starts from from l-C14-~-g lucose and utilizes a sequence n-xylose f reactions reactions tha t eliminates eliminates car bo n4 from from th glucose glucose molecu molecule le and transforms t he grouping a carbon-5 to a primary alcohol. The substituted dialdehyde, is f inter in terest est The Th e well-known acetona tion of D-glucose D-glucose (I)6 th at its asymm etry is maintained maintained only by virtue to 1,2;5,6-diisopropylidene(di- the 1,2-ketal substituent. (Hydrolysis 1,2;5,6-diisopropylidene-~-glucofurano ~-glucofuranose se (Hydrolysis of t he acetoneglucose) (11) and the controlled hydrolysis blocking acetone group would produce the mesa of the latter to 1,2-isopropylidene-~-glucofuranose,~ compound, xylaric dialdehyde.) dialdehyde. ) Similar preserva(monoacetoneglucose) (111) have been improved tion asymmetry by substitution is familiar recently' to provide excellent yields o in solu- an intrinsic fea ture tur e of of asymmetric glycero tion.8 The oxidative glycol cleavage of mono- chemistry." acetoneglucose leads to the substituted dialdehyde, Experimental 5-aldo-1,2-isopropylidene 5-aldo-1,2-isopropylidene-~-xylofurano -~-xylofuranose se (IV) .9 The reduction the latter with hydrogen in th

presence Raney nickel produced the previously known lo ,2-isopropylidene-~-xylofuranose(V Finally, mild acid hydrolysis of removed the acetone substituent give D-xylose (VI). Th n-glucose to

D-XY~OS~

reaction sequence has been accomplished, without th e isolation of of intermed inte rmediate iates, s, in 55-6070 yield. (1

J. C. Sowden, S c i o r c c . 109, 229 (1949);

(1949).

J.

Bioi. C h c m . , 180, 55

(2) D. E. Roshland, Jr., and F. H. Westheimer, TEIIS JOURNAL, J OURNAL, 71, 1139 (1949); i b i d . , 72, 3383 (1960). (3 D. A. Rappoport and W. Z. Hassid. Abstracts 119th Meeting, America American n Chemical Society, Boston, Mass., April 1-5, 1961. (4 J. 0. Lampen, H. G e s t and J. C. Sowden, J. B a c t . , 61, 97 (1931). (3 E. Fischer, Be?., 28, 1145 (1896). (6 E. Fischer, i b i d . , 28, 2496 ( 1 8 9 3 . (7) C. L. Mehltretter, R. L. Mellies, J. C. Rankin and C. Rist, J O U R N A L , 75 2424 (1951). 18) The author is indebted to Dr. C. L. Mehltretter for making t h e s e directions directions availab le to him prior to their publication. (9 K. Iwadare, Bull. C h c m . SOL.J a p a n , 16, 40 (1941). ($0) S j i j l w r g , B a r . , 66, 80 (1923). Swrnberg . L n i i

20 ct./min./mg.), was acetonl-Cl%-gIucose,* (630 ated b y th e method method of Bell" Bell" an d the resulting diaceton diacetoneeglucose hydrolyzed according to the directions Coles, Goodhue and Hixon*ato monoacetoneglucos. The lat ter after recrgstallization, was oxidized oxidized with aqueous sodium metaperiodate and the resulting 5-aldo-monoacetonexylose was reduced to monoacetonexylose as described below. Th e acetonate d pentose pentose was purified purified by distillation in high vacuum and then hydrolyzed with dilute sulfuric acid 18.8' equil. in water I-C'h-xylose, m.p. 145-146', [cY]*~D 1.2). Th e isolation isolation of of th e intermediates, especially especially monoacetoneglucose, leads to considerable losses and conse uent ly the over-all yield of l-C 14-~-xylosewas 14-~-xylosewas only only abo ut 20%. Subsequent to the radioactive radioactive preparation, experiments with non-radioactive D-glucose have led to the improved procedure described described below. below. Th e directions Mehltretter et al. ,7 for the production monoacetoneglucose solution were employed and the isolation of of all int erm edi ate products was eliminated with a consequent increase in yield to 55 60 D-xylo D-xylose se from D-glu D-glucos cose. e. Th e main loss in th folL. Fischer and E. Baer, C h e m . R t v s . , 29, 287 (1941). (12) D. J. Bell, 1874 (1935). C h e m . SOL.,1874 (13) IT. I l i x o n ' h r q .IOIIHS*I Colr- 1;. D. C o o c l h u ~i l n d

(11) Cf,H.

61

51

(1RL"II