[CONTRIBUTION FROM O F THE
ORGANICCHEMISTRYLABORATORIES UNIVERSITY OF FLORIDA]
THE
DERIVATIVES OF PIPERAZINE. XX. MONOALKYLATION OF PIPERAZINE WITH ALKENE OXIDES' LELAND J. KITCHEN* AND C. B. POLLARD Received May 17,1942
Both monosubstituted and disubstituted piperazines have been obtained by the alkylation of piperazine with alkene oxides. Fourneau and Barrelet (1) obtained the mono- and di-alkylated piperazines from the reaction of piperazine with the oxides of 2-methylbutene-l , 3-butoxypropene-l ,3-phenylpropene-1, and 3-phenoxypropene-1. A French patent (2) has been granted on this series of amino alcohols, some of which appeared useful as local anesthetics. In a further search for compounds with local anesthetic properties Fourneau and Samdahl (3)prepared two series of disubstituted piperazines, utilizing alkene oxides as alkylating agents. For one series there were utilized oxides of the type RC(CH,)CH20, with R extending from propyl through heptyl; the other series was derived from 3-alkoxypropene-1 oxides, ROCH2CHCH20, the alkoxy groups ranging from propoxy through heptoxy. Mousseron (4) has synthesized the series of mono- and disubstituted piperazines derived from the oxides of cyclopentene, cyclohexene, cycloheptene, cyclooctene, and indene. The initial investigators of piperazine-alkene oxide reactions, Krasuskii and Kosenko ( 5 ) , carried out reactions of piperazine with the oxides of 2-methylpropene and trimethylethylene. Failing to isolate a monosubstituted product, they concluded that the reaction proceeds with simultaneous addition of two molecules of alkene oxide to one molecule of piperazine, thereby yielding only disubstituted product. The work of Fourneau and Barrelet (1) disproved this hypothesis in part. Likewise Krasuskii and Pilyugin (6) obtained only the disubstituted product 1,4-bis-(/3-hydroxypropyl)piperazine from the reaction of piperazine with propene oxide. 1,4-Bis-(P-hydroxyethyl)piperazinehas been synthesized by the piperazineethylene oxide reaction (7), but the intermediate 1-@-hydroxyethy1)piperazine has been obtained only by tedious indirect methods (8,9). It was not obtained in sufficient quantity for its physical properties to be described. I n this investigation it was desired to prepare 1-(6-hydroxyethy1)piperazinein amount sufficient for characterization and for use as an intermediate for further syntheses. The reaction of piperazine with ethylene oxide proved to be a convenient method for the synthesis in good yield of this monosubstituted piperazine. Similarly, propene oxide and 2-methylpropene oxide yielded 1-(B-hydroxypropyl) The material in this paper is abstracted from part of a dissertation submitted by L. J. Kitchen to the Graduate Council of the University of Florida in partial fulfillment of the requirements for the Ph.D. degree, February, 1943. Present address: Firestone Tire and Rubber Co., Akron, Ohio. 338
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ALKYLATION OF PIPERAZINE
piperazine and 1-(P-hydroxy-P-methylpropyl)piperazine,respectively, in good yield, The reactions were carried out by addition of the alkene oxide to a methanol solution of piperazine, the solution being kept a t a temperature of about 80". Rapid reaction took place a t this temperature. The sealed-tube technique of Krasuskii, et al. ( 5 , 6) was found to be unnecessary. In every case some disubstituted product was obtained; the combined yields of monosubstituted and disubstituted piperazines were essentially 100%. In general it appears that the amount of disubstitution was minimized by presence of excess piperazine (Table I). Thus, in reaction of one mole of ethylene oxide with 2.8 moles of piperazine, eighty-six per cent of the piperazine used was obtained in the yield of monoalkylation product. However, when piperazine was treated with the molecular amount of propene oxide, only sixty-two per cent of the piperazine used was present as monoalkylated piperazine when the reaction was complete. TABLE I EFFECTOF EXCESSOF PIPERAZINE IN PIPERAZINE-ALKENE OXIDE REACTIONS MOLAR RATIO OF PIPERAZINE TO ALKENE OXIDE
ALKENE OXIDE USED
Ethylene oxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propene oxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-Methylpropene oxide. . . . . . . . . . . . . . . . . . . . . . . . . . .
MOLAR RATIO OF MONOSUB. TO DISUB. PRODUCT
6.3:l 1.6:l 2.7:1
EXPERIMENTAL
The dihydrochlorides were prepared by adding excess dilute hydrochloric acid (bromo phenol blue indicator) to the amine, evaporating to a syrup on the water-bath, cooling, and precipitating by addition of absolute alcohol. The granular crystalline solids were filtered, washed on the filter with 95% alcohol, and recrystallized from aqueous alcohol. The products were dried in a vacuum over phosphorus pentoxide. The picrates, prepared by mixing alcohol solutions of picric acid and of the amino alcohol, were recrystallized from aqueous alcohol. All melting points are corrected capillary melting points. Preparation of l-(8-hydrosyethyZ)piperazine. The reaction was carried out by allowing the ethylene oxide (220 g., 5 moles) t o distill into a solution of 1200 grams (14 moles) of piperazine dissolved in 1 liter of warm methanol. The solution was kept a t 80" and was agitated during the reaction. The bottle of ethylene oxide was placed in a beaker of warm water, and the ethylene oxide was allowed to distill into the piperazine solution at a regulated rate. The ethylene oxide addition required ninety minutes. The reaction mixture was separated by fractional distillation. After separation of the methanol approximately 544 g. (6.3 moles) of piperazine was recovered. The yield of 1-(8-hydroxyethy1)piperazine obtained by fractionation a t reduced pressure was 499 grams (3.8 moles), a yield of 76%. The product, a light yellow viscous liquid with a mild amine odor, had b.p. 119.2"/10 mm.; d: 1.0595, d: 1.0541; n: 1.5069, nfd 1.5052, n z i s 1.5028. Molecular refraction: Calc'd for CeHlrNzO: 36.77. Found : 36.64. Dihydrochloride: m.p. 188.6-189.6" [lit., m.p. 182-183" (911. Anal. Calc'd for CeH16Cl&gO: C1, 34.91. Found: C1, 34.98.
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L. J. KITCHEN AND C. B. POLLARD
Picrate: m.p. ca. 245' (dec.); at temperatures down to about 240', i t slowly decomposed without melting; [lit. m.p. 247-248' (9)l. Phenylthiourea of I-(6-hydr0xyethyE)piperazine. Thirteen grams of the amino alcohol was mixed with 13 g. of phenylisothiocyanate, forming a homogeneous yellow oil; heat was evolved. After being heated for several minutes, the material cooled to an amorphous mass. It was rrystallized from absolute alcohol and recrystallized from 95% alcohol, m.p. 114.9-115.3'. 1 ,.&Bis-(j+hydroxyethyZ)piperazine. The 104 g. of residue from the above distillation was 1,4-bis-@-hydroxyethyl)piperazine. The melting point after recrystallization from absolute ethanol was 134.3-135.0";that given in the literature is 134-135" (10). Preparation of 1 -@-hydroxypropyZ)piperazine. The reaction was carried out in a manner analogous to the preparation of the hydroxyethyl derivative, 232.4 g. (4.1moles) of propene oxide being added by means of a dropping-funnel to the piperazine (352.5 g., 4.1 moles) dissolved in 2 liters of methanol. Approximately one hour was required for the addition of the propene oxide. Eighty-six grams (1 mole) of piperazine was recovered from the reaction mixture by distillation. The yield of 1-(8-hydroxypropyl)piperazine, b.p. 108.5"/10mm., was 260 g. (1.8moles), a yield of 44%. The amino alcohol, a light yellow viscous liquid with a mild amine odor, had d r 1.0103;nz 1.4911,ng 1.4877. Molecular refraction: Calc'd for C,HleNPO: 41.39. Found: 41.42. Dihydrochloride: m.p. ca. 237.3" (dec.). Anal. Calc'd for C,Hl&12N20: GI, 32.66. Found: C1, 32.68. Picrate: m.p. 174.5-177.5". Phenylthiourea: m.p. 144.0-144.5'. 1,4-Bis-(8-hydroxypropyl)piperazine. The distillation residue, 226 g. of crude 1,4bis- (8-hydroxypropyl)piperazine,after recrystallization from hexane-absolute alcohol had the m.p. 116.7-117.9'; the melting point given in the literature (6) is 115-116". Dihydrochloride of 1,4-bis-(B-hydroxypropyl)piperazine,m.p. 223.7-224.7' (dec.). 1-(8-hydroxy-B-methyZprop$)piperazine. Four hundred thirty grams (4 moles) of piperazine was heated with 500 ml. of methanol until i t was completely dissolved. To the hot solution (70-80") was slowly added 216 g. (3 moles) of 2-methylpropene oxide with frequent shaking during a thirty minute period. The methanol was distilled off, and the piperazine and the two products were separated by distillation and redistillation through a fractionating column. Approximately 190 g. of piperazine was recovered. The monoalkylation product was 302 g. of white crystalline solid (needles), m.p. 71-77', which was collected a t 105-110" a t a pressure of approximately 10 mm. The distillation residue, 111 g., had the m.p. 97-102";mixed m.p. of distillate and residue was 61-75'. A sample of the distillate, 1-(6-hydroxy-6-methyIpropyl)piperazine,had the m.p. 80.2-80.5' after two recrystallizations from hexane. The product, a white hygroscopic solid with a slight odor, needles or prisms, had the b.p. 89.3"/3 mm., 106.0"/10mm. Dihydrochloride : dec. ca. 215" without melting; dec. slowly at temperatures below 215'. Picrate: m.p. 257' (dec.). Phenylthiourea: m.p. 129.3-129.5' (from absol. alcohol). 1,4-Bis-(~-hydroxy-~-rnethyZpropyZ)piperazine. The 111 g. of residue from the above distillation after recrystallization from hexane-absolute alcohol had the melting point 1015-102.5". The melting point of 1,4-bis-(p-hydroxy-~-methylpropyl)piperazine given by Krasuskii and Iiosenko (5) is 102-102.5'. SUMMARY
The reaction of piperazine with the oxides of ethylene, propene, and 2-methylpropene has been shown to yield monoalkylation products as well as the previously described disubstituted piperazines. 1-(8-Hydroxyethyl)piperazine, 1-(8-hydroxypropy1)piperazine and 1-(&hydroxy-0-methy1propyl)piperazine are described and characterized. The latter two have not been prepared previously. GAINESVILLE, FLA.
ALKYLATION OF PIPERAZINE
REFERENCES (1) FOURNEAU AND BARRELET, Bull. soc. chim., 46, 1172 (1929). (2) SOC.DES USINESCHIM. RHONE-POULENC, French Patent 698,687, Oct. 7,1929. (3) FOURNEAU AND SAMDAHL, Bull. S O C . chim., 47, 1003 (1930). (4) MOUSSERON, Bull. SOC. chim., 61, 782 (1932) (5) KRASUSKII AND KOSENKO, Ukrain.Khem. Zhur., 4, 38 (1929). (6) KRASUSKII AND PILYUGIN, Ukrain.Khem. Zhur., 6, Sci. Pt., 349 (1930). (7) ADELSON, MACDOWELL, AND POLLARD, J . Am. ChPm. Soc., 67,1988 (1935). ( 8 ) MOORE, BOYLE,AND THORN, J. Chem. SOC., 39 (1929). AND USTRICEV, Ann., 636, 37 (1938). (9) PRELOG, CERKONIKOV, (10) PYMAN, J . Chem. Soc., 93, 1802 (1908).
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