[CONTRIBUTION FROM THE DEPARTMENT OF CHEMISTRY AND CHEMICAL ENGINEERING OF TEE UNIVERSITY OF PENNSYLVANIA]
THE PREPARATION OF 2-ALKYLAMINOBENZIMIDAZOLES ALBERT BLOOM
ALLAN R. DAY
AND
Received November 18, 1958
The imidazole ring structure is of considerable interest because of its presence in histidine and histamine. The latter has been isolated from ergot. It exhibits pressor action and, like the ergot alkaloids, has the property of producing marked uterine contraction. In spite of the importance of these properties no extended effort appears to have been made t o synthesize and study compounds of similar structure. Similar derivatives of dihydroimidazole have likewise been neglected, although recently F. A. Jones and C. Wilson' have reported that trimethoxybenzyldihydroimidazole shows pressor activity. This statement is of interest, as it might indicate that the physiological activity may be inherent in the ring structure itself and thus not be dependent on the presence of an ethylamino side-chain. A survey of the literature shows that other compounds containing the imidazole ring, such as benzimidazole and 9 ,10-phenanthrimidazole derivatives, show promise of possessing interesting physiological properties. Various benzimidazole derivatives have been reported as showing anesthetic, antipyretic, or hypnotic action. N-Methyl-9,lO-phenanthrimidazole has been reported as having morphine-like properties.2 The above statements appear to warrant a more comprehensive study of compounds which contain the imidazole grouping. The present paper deals entirely with benzimidazole derivatives. The work is being continued, and is also being extended to the phenanthrimidazoles and the imidazoles. Only a few benzimidazole derivatives showing physiological activity have been reported, and in those few cases, no series of one type of derivative has been investigated. The nomenclature used, for the discussion of benzimidazole derivatives in this paper, is based upon the following formula for benzimidazole.
H
H
C
N
/'\/I\
HC6
C
HCs
C-N '
I
II
CH
I/
H 1
JONESAND WILSON,Lancet, 1, 195, (1938). VAHLEN,Arch. e x p . Pathol. Pharmak., 47, 368, (1932). 14
PREPARATION OF 2-ALKYLAMINOBENZIMIDAZOLES
15
The following compounds, which were prepared by earlier workers, have specific pharmacological properties. %Diethylaminopropyl-5-phenoxy-3 benzimidazole was reported to be a local anesthetics 2-Ethoxymethylben~imidariole~ 5-ethoxy-2-ethoxymethylbenz~dazole, 2-phenoxymethylbenzimidazole,and 5-ethoxy-Zphenoxymethylbenzimidazole have antipyretic a ~ t i o n . 8-Benzimidazolylethylamine, ~ benzimidazole-%propionic acid, 5-ethoxybenzimidazole-%propionic acid and 8-5-ethoxybenzimidazolylethylaminehave been prepared for possible use as antimalarial^.^ It is interesting to note that even though a close structural resemblance exists between 8-benzimidazolylethylamine and histamine, the former is stated to have no pressor action even in large doses. A few other benzimidazole derivatives have been reported as having therapeutic value or simply as pharmaceutical preparations witha out mention of any specific K. Miescherlg in his studies on local anesthetics, attributed the anesthetic action to basic substituents or those containing oxygen combined with higher aliphatic or hydroaromatic as well as negative groups. He further concluded that heterocyclic groups are effective and that the accumulation of the heterocyclic rings increases local anesthetic activity. It is interesting to compare the structures of the compounds that have just been described and those prepared in this investigation with his conclusions. The compounds prepared in the course of the present work are substituted in the 2 positions and have the following structures. '9
"y' 'c-cH~.
N
/
A few of the benzimidazole derivatives previously mentioned have structures similar to those described by Miescher and show local anesthetic action while others have antipyretic activity. If one considers the compounds prepared by the author, it is seen that the carbon atom adjacent to the number two carbon atom has a heterocyclic ring on one side and a substituted amine on the other. The morpholiino- and piperidino- derivatives have two heterocyclic rings around this carbon atom. Local anesthetics containing the morpholine ring have already been r e p ~ r t e d , ~ I. G. FARBENIND. A.-G., D.R.P. 550, 317. Co., Brit. Pat. 243, 766. 5 CHATTERJEE, J . Chem. SOC.,1929, 2965. 8 ANDERSAG AND JUNQ,D.R.P. 578, 488. 7 I. G. FARBENIND.A.-G., Brit. Pat. 388, 374. 8 MARON,D.R.P. 282, 375. 9 MIESCHER, Helv. Chim.Acta., 16, 163, (1932). a
* F. BAYERAND
16
ALBERT BLOOM AND ALLAN R. DAY
and certain nitrogen-substituted amines, as well as the imines of highmolecular-weight polymethylenes, have local anesthetic properties.10, 11 Miescher makes no mention of the imidazole ring, the only heterocyclic rings considered being picoline, pyrrole, thiophene, and furan. The well known local anesthetic "Holocaine" contains a grouping
N * Cd.f,OCoHs
\
NH * CJ&OCzHa
found in the imidazole ring. Since it contains no higher aliphatic or hydroaromatic groups attached through oxygen but does contain the
/N-
, found in the imidazole ring, it would seem that \NHits local anesthetic properties might be due essentially to that structure.12 The 2-alkylaminobenzimidazoles were obtained by condensing 2chloromethylbenzimidazole with a suitable amine. Some difficulties were encountered in the preparation of 2-chloromethylbenzimidazole. In both Sika'sE3and Poole'sl* methods, o-phenylenediamine and a fatty acid are heated at the boiling point of the mixture or at 150" in an oil bath. No chloromethylbenzimidazole could be obtained by these methods, and it was later found that the compound decomposed at the temperatures used by Sika and Poole. The chloromethyl derivative was finally prepared in good yields by the method of Phillip~.'~ structure -C
EXPERIMENTAL
2-Chloromethylbenzimidazo1e.-o-Phenylenediamine (10.8 g.), chloroacetic acid (14.2 g.) and 4 N hydrochloric acid (100 cc.) were heated under reflux for 45 minutes. The mixture was allowed to stand overnight, filtered, diluted with 200 cc. of water, cooled and carefully neutralized with 6 N ammonium hydroxide solution. The solution must be kept cold during the neutralization and stirred vigorously to prevent the formation of gums. Solid sodium bicarbonate may also be used. The product was filtered, washed well with cold water, and pressed between porous plates for a few hours. It was then placed in a vacuum desiccator until dry. The yields obtained varied from 80 to 85 per cent. This product was pure enough for the subsequent condensations. Samples for analysis were obtained as colorless prisms by recrystallization from dioxan; m.p. 165". Care must be taken in handling GARDNER AND HAMMEL, J . Am. Chem. SOC., 68, 1360, (1932). OOATA,J . Pharm. SOC.Japan, 466, 81, (1920). l2 RUZICKA, SALOMON, AND MEYER, Helv. Chim. Acta., 20, 127, (1937). 1s SIKAAND MULLER, Monatsh., 67, 97, (1931). P PO OLE, J . Am. Chem. SOC.,69, 178, (1937). l6 PHILLIPS, J . Chem. Soc., 1928, 2393. lo 11
PREPARATION OF 2-ALKYLAMINOBENZIMIDAZOLES
17
2-chloromethylbenrimidazole since it is a powerful skin and mucous membrane irritant. Anal. Calc'd for CsH&lNl: N, 16.83. Found: N, 16.76. G. Hughes and L. LionsI6 recently reported the preparation of this compound. They obtained very low yields by the direct action of chloroacetic acid on o-phenylenediamine. Yields of 71 per cent. were obtained by the action of thionyl chloride on 2-hydroxymethylbenzimidazole. The low yield obtained by Hughes and Lions by the first method can be explained by their not allowing the reaction mixture t o stand a considerable time after refluxing. It has been noted, during the course of this investigation, that yields as low as 20 per cent. were obtained when that procedure was not followed. When the reaction mixture was allowed to standovernight at room temperature the yield was always good. Hughes reported a melting point of 161". When the melting point was taken in a capillary tube the compound became yellow and softened a t this temperature but did not melt. Furthermore, the melting point by this method varied with the rate of heating, slow heating raising the melting point and rapid heating lowering it. For these reasons the melting point reported here was taken on a Fisher-Johns melting-point apparatus. Reaction of 2-chloromethylbenzimidazole with amines.-The reaction in many cases did not proceed smoothly. In preliminaty trials, gums and other side-reaction products were frequently encountered in large quantities. After the time, temperature, and solvent giving the best yields were found, further difficulty was met when the hydrochloride of the condensation product was being precipitated. In most cases oils separated, and variations in solvent were without effect. The gradual addition of a solvent saturated with hydrogen chloride to the chilled solution of the condensation product, or rapid stirring while passing the gas into or over the solution gave no better results. It was finally found that if, after saturation of the solution with hydrogen chloride, the supernatant solvent was removed from the oil, fresh solvent added, and the mixture allowed t o stand in the ice box, the oil would solidify and could be recrystallized. This procedure was followed throughout the investigation wherever such conditions occurred. 2-(Methylaminomethyl) benzimidazole.-Five grams of methylamine was dissolved in 100 cc. of ether containing 5 cc. of alcohol, and 13.4 g. of 2-chloromethylbenzimidazole was added in small portions, keeping the temperature below 15'. After the reaction subsided the temperature was slowly raised t o 30" and kept there for three hours. The reaction mixture was then allowed to stand overnight at room temperature. Two hundred cubic centimeters of ether was added, the reaction flask placed in an ice bath for a few hours, and the precipitated methylamine hydrochloride was removed. The filtrate was saturated with hydrogen chloride, the precipitate was collected, washed with cold ether, and dried; yield 15.1 g. Recrystallization from alcohol by means of ether gave colorless needless; m.p. 207-209", dec. Anal. Calc'd for C ~ H I ~ N S . ~ hH',C17.95. ~: Found: N, 17.78. 8-(Ethylaminomethyl)benzimidazolewas prepared in the same way as the methyl derivative, using 5.4 g. of ethylamine and 10 g. of 2-chloromethylbenzimidazole; yield 14 g. Recrystallization from alcohol and ether gave colorless prisms; m.p. 223-225", dec. Anal. Calc'd for CloHI8Ns.2HC1:N, 16.94. Found: N, 16.79. 2-(Butylaminomethyl) benzimidazole.-n-Butylamine (8.8 9.) was dissolved in 75 cc. of alcohol; 10 g. of 2-chloromethylbenzimidazole was added, and the mixture was heated under reflux at 50" for three hours. After standing overnight a t room 16
HUQHESAND LIONS,J . Proc. Roy. SOC.,N. IS.Wales, 71, 209, (1938).
18
ALBERT BLOOM AND ALLAN R. DAY
temperature, most of the alcohol was removed under reduced pressure a t 30", and 300 cc. of ether was added. The mixture was allowed to stand in the ice box for a few hours, and the precipitated n-butylamine hydrochloride was removed. The filtrate was washed with a few small portions of water, dried, and saturated with dry hydrogen chloride. The precipitate was collected, washed with ether, and dried; yield 8.8 g. Recrystallization from alcohol and ether gave colorless prisms; m.p. 203-204", dec. Anal. Calc'd for C I ~ H I ~ N I ~ ~N,H 15.22. C ~ : Found: N, 15.20. %-(n-Amylarninomethyl)benzim.drlasolewas prepared in the same way as the nbutyl derivative, using 11.6 g. of n-amylamine and 11 g. of 2-chloromethylbenzimidazole; yield 8.1 g. Recrystallization from alcohol and ether gave needles; m.p. 19019l0, dec. Anal. Calc'd for ClrH1&Ta.2HC1:N, 14.48. Found: N, 14.29. 8-(Benzylaminomethyl)benzimidazole.-The procedure used was somewhat similar to that used for the methylamino derivative, using 12.3 g. of benzylamine, 10 g. 2-chloromethylbenzimidazole, and 25 cc. alcohol plus 50 cc. ether as the solvent. The reaction mixture was heated a t 35" for three hours, allowed t o stand overnight a t room temperature; then ether was added, and the condensation product was isolated as in the case of the methylamine derivative; yield 16.5 g. Recrystallization, as before, gave colorless plates; m.p. 211-213', dec. Anal. Calc'd for ClsHlrN~.2HC1:N, 13.55. Found: N, 13.45. 8-(CyclohexylaminomethyZ)benzimidazole was prepared in the same way as the methylamine derivative, using 12 g. of cyclohexylamine and 10 g. of 2-chloromethylbenzimidazole; yield 14.3 g. The crude derivative was purified by recrystallization from acetone, followed by washing with a few cubic centimeters of cold acetone. The product was then dissolved in a small quantity of hot alcohol, cooled, saturated with hydrogen chloride gas, and then precipitated with ether. I t was obtained as colorless needles by recrystallization from boiling dioxan; m.p. 213-214", dec. Anal. Calc'd for ClrH~sN8.2HC1:N, 13.9. Found: N, 13.89. &(Phenethylaminomethyl)benzimidazole was prepared in the same way as the butylamino derivative, using 8 g. of phenethylamine and 11.7 g. of L-chloromethylbenzimidazole; yield 6.5 g. On recrystallization, i t was obtained as colorless plates; m.p. 23&239", dec. Anal. Calc'd for ClsH17N~.2HC1:N, 12.96. Found: N, 12.98. Condensation with secondary amines.-With the secondary amines it was not possible to obtain a pure product by the methods described. The precipitate obtained from the hydrogen chloride treatment was usually a gum or a n oil which could not be purified. In the methods to be described the pure bases were isolated except in the case of the piperidino and morpholino compounds. Attempts t o prepare the hydrochlorides from these bases were unsuccessful. The bases, however, form stable solutions in dilute hydrochloric acid and therefore may be tested physiologically with the same ease as the hydrochlorides prepared. d-(Diethylaminomethyl)benzimidazole.-Diethylamine (8.8 g.) was dissolved in a mixture of 30 cc. of ether and 5 cc. of alcohol, 10 g. of 2-chloromethylbenzimidazole was then added in small portions, keeping the temperature below 15". After the reaction had subsided the mixture was heated under reflux for three hours. After standing overnight a t room temperature, 100 cc. of ether was added, the mixture was chilled, and the precipitated diethylamine hydrochloride was removed. The filtrate was washed with water and then evaporated to dryness a t 35". The product was collected and pressed on a porous plate. Recrystallization from hot acetone, by the careful addition of water, gave yellow needles; m.p. 170". The yield after the first recrystallization was 11.7 g.
PREPARATION OF
ZALKYLAMINOBENZIMIDAZOLES 19
Anal. Calc'd for CI,H17Ns: N, 20.68. Found: N, 20.51. This compound was recently reported by Ahmed, Narang and Ray" with a m.p. of 169". I-(Di-n-butyluminomethyl)benzimidazole.-Di-n-butylamine (15.6 g.) was dissolved in 20 cc. of alcohol, cooled, and 10 g. of 2-chloromethylbenzimidazole was added in small portions. When the reaction had subsided, the temperature was slowly raised to 50" and kept there for three hours. After standing overnight a t room temperature, 100 cc. of ether was added, the mixture was cooled, and the precipitate was removed. The filtrate was treated as in the case of the diethylamino derivative. Colorless needles were obtained by recrystallization from acetone and water; m.p. 132"; yield 14.2 g. A n d . Calc'd for CtsHtsNs: N, 16.21. Found: N, 16.18. I-(Dibenzy1aminomethyl)benzimidazole.-The procedure was similar to that for the dibutylamino derivative, using 23.7 g. of dibenzylamine dissolved in 50 cc. of alcohol and 10 g. of 2-chloromethylbenzimidazole. The mixture was finally refluxed for 3 hours. Colorless plates were obtained by recrystallization from acetone and water; m.p. 169"; yield 14.6 g. Anal. Calc'd for CtzHzlNa: N, 12.84. Found: N, 12.68. 8-(Piperidinomethy1)benzimidazole.-The method of preparation was similar to that for the methylamino derivative, using 10.2 g. of piperidine and 10 g. of 2-chloromethylbenzimidazole in 50 cc. of ether plus 10 cc. of alcohol. Colorless needles were obtained by recrystallization from alcohol and ether; m.p. 204-5", dec.; yield 15.7 g. Anal. Calc'd for ClrHl,Na*2HCl: N, 14.58. Found: N, 14.41. 2-(Morpholinomethy1)benzimidazole.-The method of preparation was similar to that for the methylamino derivative, using 10.5 g. of morpholine dissolved in 75 cc. of alcohol and 10 g. of 2-chloromethylbenzimidazole. The reaction mixture was refluxed for three hours. After removal of the morpholine hydrochloride, the filtrate was washed, dried, and saturated with hydrogen chloride. Colorless prisms were obtained by recrystallization from alcohol and ether; m.p. 194-5", dec.; yield 16.3 g. Anal. Calc'd for C12HIbNa.2HCI: N, 14.48. Found: N, 14.36. The piperidino and morpholino derivatives have been recently reported by Hughes,le who gave 193-194" and 211" respectively for the melting points of the free bases. The semi-micro Kjeldahl method was used for the determination of nitrogen, and the titrations were carried out in boric acid solution as recommended by Meeker and Wagner.]* All melting points recorded were taken on the Fisher-Johns meltingpoint apparatus. SUMMARY
1. Certain !&alkylaminomethylbenzimidazoles have been prepared to see whether they are physiologically useful. 2. An explanation for a previously-noted low yield in the preparation of Zchloromethylbenzimidazole is given. 17
I*
AEMED,NARANQ, AND RAY,J. Indian Chem.Soc., 16, 152, (1938). MEEKERAND WAQNER, Ind.Eng. Chem.,Anal. Ed., I,396 (1933).
