“fi— -; - _"' ‘W— w _ THE SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLES A25 POTENTIAL SERQTONIN ANTAGONISTS TImsIs ,Im III. Doqm OI DII. D. MICHIGAN STATE UNIVERSITY Homer Albert Burch 1960 MCHI GAN STATE UNIVERSI 1;; III I IIlII’lIlIaIIIlIIIIIIIIIIIII )1 -2 IV:IIL;I1 I.NSTAI§n1$IVI—R3m LIII.II.':I':;ity A #1 This is to certify that the thesis entitled THE SYNTHESIS OF SUBSTITUTED BENZDIIIDAZOLES AS POTENTIAL SEROTONIN ANTAGONISTS presented by I Homer Albert Burch has been accepted towards fulfillment I of the requirements for Ph . D .~ degree in Cheml stry RIM/44 MIL/1% Major professor Date March I, 1960 0-169 " Hfl¥_._____ ._ MICHIGAN STATE ‘ , I, l, 1/ fl}; ' . THE SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLES AS POTENTIAL SEROTONIN ANTAGONISTS By Homer Albert Burch AN ABSTRACT Submitted to the School for Advanced Graduate Studies of Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry Year 1960 KIMM Mf— ABSTRACT The potential value of a series of substituted benzimidazoles as potential antagonists toward serotonin (or S—hydroxytryptamine), prompted the investigation in this laboratory of various modes for their synthesis. The first part of this investigation was concerned with the syn- thesis of l-(p~dialkylaminoethyl)-S-methoxy-2-methyl- and]:(B-dialkyl- aminoethyl)-S-methoxybenzimidazoles in which the dialkylamino groups consisted of the following: dimethylamino, pyrrolidino, morpholino, diethylamino, and piperidino. Using commercially available b-methoxy-Z-nitroaniline as the starting material and using synthetic procedures recorded in the liter- ature (1,2), various h-B—dialkylaminoethylamino—3-nitroanisoles were prepared as intermediates. h-Methoxy-Z—nitroaniline was converted to 3-nitro-h—p-toluenesulfonamidoanisole. Alkylation of this compound with various dialkylaminoethylchlorides followed by removal of the p- toluenesulfonyl group by hydrolysis gave the desired intermediates. Reduction of the h-fi—dialelaminoethylamino—3-nitroanisoles gave the 3-amino-h-B-dialkylaminoethylaminoanisoles which, in turn, were converted into the desired 2-H- and 2~methylbenzimidazoles by heating with formic acid or acetic acid, respectively. The second part of this investigation was concerned with the prep- aration of l-(B-dialkylaminoethyl)—6-methoxy-2-methyl— and l—(B—dialkyl- aminoethyl)-6-methoxybenzimidazoles. Aqylation of h-methoxy-Z—nitro— aniline followed by reduction of the nitro group gave h-acylamido-B- aminoanisoles. Subsequent alkylation with various dialkylaminoethyl- chlorides followed by ring closure gave the desired benzimidazoles. The benzimidazoles were characterized as dipicrates, dihydrochlor- ides, and, in some cases, dimethiodides. Infrared and ultraviolet ab- sorption spectra were also obtained. For evaluation of physiological and pharmacological actions, the benzimidazoles were converted into dihydrochlorides. LITERATURE CITED 1. A. M. Simonov, J. Gen. Chem. (U.S.S.R.) lg, 1588(l9bO); C.A. 2E, 2870(19II1) . 2. F. E. King, R. J. 8. Beer, and S. G. Waley, J. Chem. Soc., l9b6, 92. THE SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLES AS POTENTIAL SEROTONIN ANTAGONISTS BY Homer Albert Burch A THESIS Submitted to the School for Advanced.Graduate Studies of Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1960 ACKNOWLEDGMENT Sincere appreciation is expressed to Doctor Robert M. Herbst under whose direction this investigation was accomplished. His continued guidance, patience, and inspiration made this thesis possible. Appreciation is also extended to Michigan State University for their financial assistance in the form of Graduate Teaching Assistant- ships, and to Parke, Davis and Company for their fellowship during the academic year 1958-1959. To my wife Janice TABLE OF CONTENTS Page INTRODUCTION......................... 1 HISTORICAL.......................... 1; PART I. A. 1- (B- DIALKYLAMINOETHYL)- 5- METHOXY— 2- METHYIBENZ- IMIDAZOLES . . . . . . . . . . . . . . . 9 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . 9 EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . lb N-B-Hydroxyethyldimethylamine . . . . . . . . . . . . . 1h N-B-Hydroxyethylpyrrolidine . . . . . . . . . . . . . . 1b N- B- Hydroxyethylmorpholine . ...... . . . . . . . 15 N- -B- Hydroxyethyldiethylamine . . . . . . . . . . . . . 16 N- B- Hydroxyethylpiperidine ........... . . . 16 N— B— Chloroethyldimethyl amine hydrochloride . ..... 16 N- -B- Chloroethylpyrrolidine hydrochloride . . . . . . . 16 N- B- Chloroethylmorpholine hydrochloride . . . . . . . . 16 N— -B- Chloroethyldiethylamine hydrochloride . . . . . . . 17 N- -B- Chloroethylpiperidine hydrochloride . . . . . . . . 17 3-Nitro-h~p- toluenesulfonamidoanisole . . . . . . . l7 3—Nitro- h— —p— toluenesulfon-(B- dimethylaminoethyl)- amidoanisole . . . . . . . . 18 h- B- Dimethylaminoethylamino- 3- nitroanisole . . . . . . l9 1- (B- Dimethylaminoethyl) -S-methoxy- 2- -methyl— benzimidazole . ..... . . . . . . . . . . . . 2O 3-Nitro-h-p-toluenesu1fon-(B-pyrrolidinoethyl)— amidoanisole . . . . . . . . . . . . . . . . . . . . 21 3-Nitro-h-B—pyrrolidinoethylaminoanisole ..... . . 23 5- -Methoxy- 2-methy1-l-(B-pyrrolidinoethyl)- benzimidazole . . . . . . . 2h 3—Nitro- h—p- toluenesulfon— (B- morpholinoethyl)- amidoanisole . . . . . . . . . . . . . 25 h- B- Morpholinoethylamino- -3- nitroanisole . . . 26 5— —Methoxy- -2- -methyl- -1- (B- morpholinoethyl) -benzimidazole. 27 3-Nitro- h-p- toluenesulfon-(B- diethylaminoethyl) amidoanisole . . . . . . . . . . . . 29 h— B— Diethylaminoethylamino— 3 nitroanisole . . . . . . . 3O 1— (B- Diethylaminoethyl)- S— -methoxy- 2- -methyl- benzimidazole . . . ...... . . . . 31 3-Nitro— h- -p-toluenesulfon-(B- piperidinoethyl)- amidoanisole . . . . . . . . . . . 32 3-Nitro- h- B- piperidinoethylaminoanisole . . . . . 33 5-Methoxy-2-methyl-1- (B-—piperidinoethyl) -benzimidazole. 3h TABLE OF CONTENTS - continued Page PART I. B. l-(B-DIAIKYLAMINOETHYL)-S-METHOXYBENZIMIDAZOLE. . . 36 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . 36 EXPERIMENTAL . . . . . . . . . . . . ...... . . . . . 38 l—(B-Dimethylaminoethyl)~5-methoxybenzimidazole . . . . 38 S-Methoxy-l—(B-pyrrolidinoethyl)benzimidazole . . . . . 39 S-Methoxy—l—(B-morpholinoethyl)benzimidazole ..... bl 1-(B-Diethylaminoethyl)-S-methoxybenzimidazole .. . . . b3 S—Methoxy—l-(B—piperidinoethyl)benzimidazole . . . . . bu PART II. A. 1--(Is -DIA1KY1AMINOBTHYL)- 6- METHOXY- 2-METHYL BENZIMIDAZOIES... .. .. .....IIT DISCUSSION........................117 EXPERIMENTAL.......................52 h- -Methoxy— —2- nitroacetanilide ..... . . . . . . . . 52 h- Acetamido- 3- aminoanisole . . . . . . . . S2 2-Acetamido- h-methoxy- N- (B- piperidinoethyl)aniline . . S2 1— (B- Dimethylaminoethyl)— 6- ~methoxy- 2- -methylbenzimidazole Sh 6—Methoxy-2-methyl-l-(B-pyrrolidinoethyl)benzimidazole. S6 6-Methoxy-2—methyl-l-(B-morpholinoethyl)benzimidazole . S7 l-(B-Diethylaminoethyl)-6-methoxy-2-methylbenzimidazole 59 6—Methoxy-2-methyl-l-(B-piperidinoethyl)benzimidazole . 61 PART II. B. l—(B-DIAIKYLAMINOETHYL)~6-METHOXYBENZIMIDAZOLE . . 6h DISCUSSION........................6A EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . 65 h- Formamido- 3-nitroanisole . . . ...... . . . . . 65 3- Amino h- formamidoanisole . . . . . . . . . . . . 65 l- (B- Dimethylaminoethyl)— 6-methoxybenzimidazole . . . . 66 6-Methoxy- l- (B- pyrrolidinoethyl)benzimidazole . . . . . 68 6-Methoxy-l-(B-morpholinoethyl)benzimidazole. . . . . . 7O l—(B-Diethylaminoethyl)-6-methoxybenzimidazole . . . . 71 6-Methoxy-l-(B-piperidinoethyl)benzimidazole. . . . . . 73 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 LITERATURE CITED . . . . . . . . . . . . . . . . . . . . . . . 77 APPENDIX TABLE II III LIST OF TABLES Page Some previously prepared benzimidazoles . . . . . . . 8 Ultraviolet absorption Spectra of 1,5-disubstituted and 1,2,S-trisubstituted benzimidazoles . . . . . . . 83 Ultraviolet absorption spectra of 1,6—disubstituted and 1,2,6-trisubstituted benzimidazoles . . . . . . . 8b INTRODUCTION During the past few years antimetabolites have been the subject of considerable investigation. Such compounds have two distinguishing features (1): (a) they resemble in chemical structure some naturally occurring compound which is essential in living processes, and (b) they specifically antagonize the biological action of such an essential compound. The net result of the interference by the antimetabolite with the utilization of the essential metabolite is to bring about a deficiency of the essential metabolite. Such results may be either detrimental or beneficial to the organism. An example of such an "es- sential metabolite" is serotonin (or S-hydroxytryptamine). HO ZCHZNHZ Since the isolation of serotonin from blood serum and its charac- terization by Page, gt 31., in l9h7, the pharmacological effects of serotonin have been found to be most extensive, so much so that it is difficult to assess its true place in physiology (2,3,h). Of its many effects, vasoconstriction is, perhaps, the most noteworthy. A wide variety of antagonists for serotonin have been found in the past few years. Most of them are competitive but there are also non- competitive antagonists that block one or more of the actions of sero- tonin. Such antagonists are of interest because they make possible the demonstration of the participation of serotonin in a variety of mechanisms. Numerous examples of naturally occurring serotonin antagonists Eire described in the literature, all of which ellicit a variety of responses, such as, behavioral changes and mental disturbances. The following compounds are examples of this class: HO HZCH2N(CH3)2 R N N N H Bufotenin H3COOC R" OR' R' = R" = H Yohimbine: R Reserpine: R = OCHS, R' = CH3, R" -OOC(C6H2)(OCH3)3 The above examples bear certain structural similarities to serotonin, for example, they have the B-aminoethyl group in the 3-position of the indole ring. A great number of synthetic serotonin antagonists have been pre— pared. Again the following compounds serve as examples of this class: C2H5 CH30 CHZCHZNH2 CH3.> , \ CH3 EHZC6H5 (Medmain) (BAS) In 1957 Wheatley and Stiner (5) recorded the first example of a jpotential serotonin antagonist in the isosteric benzimidazole ring system. However, their synthesis of l-(B-aminoethyl)—5(or 6)—methoxy- laenzimidazole was not unequivocal. 7 ' l 6 NCHZCHZNHZ CH3 / 2 5 N h 3 No mention was made of an attempt to separate the two isomers prepared in their investigation. This part of the problem.was completed in 1957 when Ing, EE.§I°’ (6) reported an unequivocal synthesis for l-(B- aminoethyl)-6-methoxybenzimidazole. These latter investigations prompted the synthesis in this lab— oratory of the following benzimidazole derivatives as potential sero- tonin antagonists: >< I “ N(CH3)2: N /7 CH3 NH2 “”20 CH3 N NHz ,/J CH 3 N III IB H As shown in the above formulas, the benzimidazole ring may be written in two tautomeric forms (IA and IB) when a hydrogen atom is attached to the nitrogen atom. Substitution of a group other than hydrogen on the nitrogen atom destroys the tautomerism and allows two isomeric structures to be written and synthesized when there is a sub- stituent on the benzene portion of the molecule. The synthetic schemes employed in this investigation for the prep- aration of 1,5- and 1,6-disubstituted and 1,2,5- and 1,2,6—trisubsti- tuted benzimidazoles made use of the above methods of ring closure, and were modeled after the investigations of Simonov (ll) (Schemes A and B), and of King, E£.§$': (12)(Scheme B). SCHEME A CH30/ N02 Fe CH3O// NH2 NaCl > \ NHCOCH; H20 \ NHCOCH3 V I v RC1 110-1150c. V / c1130 / I NR 135-1I00c. GISOONHR < -H o NHOOCH §§§ NeeJCHs 2 \\\ 3 v1 R = -CHZCH2CH2N(C2H;)2 SCHEME B /// SOZC5H4CH3(p) NHSOZC6H4CH3(P) base _ N-(CH2IXNIC2HSI2 CH 0 No ’ 3 \VII 2 (C2H5)2N(CH2)XCI CH3O N02 VIII 90% H2804 OOC. V N f ./ —-—-—- H\CH2)XN\C2H5)2 < Redn. /// NH(CH2)XN(C2H5)2 CH O NH 3 2 CHso \ N02 IX RCOOH Simonov: x = 3, R = CH3 V King:x=2,R=H N(CH2)XN(C2H5)2 CHSO N R X Benzimidazoles of the general structure shown in Schemes A and B have been tested for possible antimalarial properties but were found to be inactive. Benzimidazoles l-h in Table I were prepared by Clemo and Swan (13), in 19MB, and were found to be without action on avian malaria. In l9h6, McKee, et a1., (1h) prepared the compounds 5 and 6 in Table I and reported them also to be devoid of any antimalarial activity. Wright (15), in l9h9, prepared the benzimidazoles 7-9 shown in Table I, which were reported to possess only slight antihistamine activity. Finally, Ing, SE 31., (6) in 1957, investigated the benz- imidazoles 10-17 shown in Table I as potential serotonin antagonists, but no results of physiological testing were reported. No. R; 1 OCH3 2 OCH3 3 H h H 5 H 6 H 7 H 8 H 9 H 10 H 11 H 12 H 13 OCH3 1h OCH3 15 OH 16 NH2 17 NHCH3 TABLE I SUBSTITUTED BENZIMIDAZOLES R3 C6H4OCH3(p) SCH3 H CH(CH;3)2 C6H5 CH3 CH3 CH3 CH3 R -CH(CH3)(CH2)3N(C2H5)2 -CH(CH3)(CH2)3N(C2H5)2 -CH(CH3)(CH2)3NICH2>3N<62H5>2 -CH(CH3)(CH2)3N(C2H5)2 -mZCH2N(CH3)2 -CHZCHzN(CH;5)2 -CH2CH2N(CH3)2 -CH2CH2N(CO)2C6H4 -CH2CHzNH2 -CH2CH2NH2 —CH2CH2N(CO)2C6H4 -GQGQMQ ~CHZCH2NH2 'Csz PART I. A. 1—(B-DIALKYLAMINOETHYL)-5-METHOXY-2-METHYLBENZIMIDAZOLES Although the methods of synthesis used in this work have been reported previously in the literature, several useful modifications have been employed to circumvent the problems involved in adapting such procedures to larger scale preparations. For convenience, the problem will be discussed in two major parts, first, the preparation of 1,5- disubstituted and 1,2,5-trisubstituted benzimidazoles, and, second, 1,6-disubstituted and 1,2,6-trisubstituted benzimidazoles. DISCUSSION The procedures used for preparing this series of Compounds are shown schematically in Scheme B on page 6. In order to obtain only monoalkylation of the primary amino group in h-methoxy-2-nitroaniline, the amino group was first protected by sulfonamide formation, thus making di- and trialkylation impossible. Following the alkylation of the sulfonamide, the protecting sulfonyl group was removed by hydrolysis. Two satisfactory procedures for the preparation of 3-nitro- h-p-toluenesulfonamidCIanisole have been reported in the literature. Barber, gt a1., (16) prepared this compound by sulfonating h-methoxy-2- nitroaniline with p-toluenesulfonyl chloride in pyridine solution, while Simonov (11) obtained the same compound by nitrating h-(p-toluenesulfon- amido)anisole. Because of the commercial availability of h-methoxy-2- nitroaniline the method of Barber, et 21., was chosen. To prevent difficulties at later stages in the synthesis, it was necessary to 10 separate the monosulfonamide from the small amount of impurity, pre- sumably the disulfonamide, produced during sulfonamide formation by taking advantage of the alkali solubility of the former compound. Alkylation of the sulfonamide can also be achieved in a number of ways. Both Simonov (11) and King, et al., (12) used absolute ethanol as the solvent and sodium ethoxide as the base in the formation of the sodium salt of the sulfonamide. This method was satisfactory when 50 grams or less of the sulfonamide was alkylated. However, attempts to scale this reaction up to 100 grams caused a marked decrease in the yield and an increased recovery of apparently unalkylated sulfonamide. It was suSpected, though not established, that salt formation was in- complete and that the sodium ethoxide was reacting instead with the di- alkylaminoethylchloride in a Williamson type reaction to form the ether, l-dialkylamino-2—ethoxyethane. Only a trace of material identifiable as an aliphatic ether by means of infrared analysis could be obtained. The small amount of ether that was isolated, however, did not account for the large decrease in the yield of alkylated sulfonamide that was observed. Consistently good yields (85 per cent of the theoretical or better) could be obtained when the sodium salt of the sulfonamide was prepared in dry benzene using freshly prepared sodium sand. The sodium salt of the sulfonamide was obtained as a bright red solid. Interaction of the sodium salt in benzene suSpension with various dialkylaminoethylchlorides ‘was effected with ease. Alkylation of the sulfonamide was accompanied by a change in color from red to yellow. Hydrolysis of the resulting h-[N-(B-dialkylaminoethyl)-p-toluene- sulfonamido]-3-nitroanisoles was effected easily in cold 90 per cent ll sulfuric acid. The temperature of the reaction mixture during the addi- tion of the sulfonamide to the acid was most critical; it was usually kept below 10°C. Once the sulfonamide had dissolved, the reaction could be hastened by gentle warming of the reaction mixture on a steam- bath. All of the h-B-dialkylaminoethylamino-3-nitroanisoles prepared by this method were solids except the dimethylamino derivative. All were characterized as monopicrates. Reduction of the nitro group leading to 3-amino-h—$~dialkylamino— ethylaminoanisoles could be brought about by either chemical or cata- Lytic methods. For convenience, the latter method was chosen using Raney nickel as the catalyst. Platinum oxide was also an effective catalyst. The choice of solvent was important at this point. Although ethanol was the solvent used by King, et al., (12) it was found to be inadequate in this work when the reduction was scaled up from 0.007 mole to approximately 0.2 mole. Glacial acetic acid was the solvent of choice for two reasons. First, as an acid, it helped reduce the ease with which oxidation occurred during the subsequent exposure of the reaction mixture to air. Second, since the reaction of o-phenyl- enediamine derivatives with acetic acid produces 2—methylbenzimidazole derivatives the actual isolation of the unstable o-phenylenediamine derivatives was unnecessary. Substituted o-phenylenediamine deriva- tives of the type prepared here, have been isolated as red oils by distillation and have been characterized as dihydrochlorides. For example, Simonov (11) has reported that 3-amino-h-(Z’-diethylamino- propylamino)anisole boils at 196-1980C./h mm. L0tt:.§£.§l" (17) have also reported in a patent that 3-amino-h—B—diethylaminoethylamino)- anisole dihydrochloride has a melting point of loo-162°C. However, because of their apparent unstability, the author did not attempt to l2 purify and to characterize the o¥phenylenediamine derivatives as such. The characteristic behavior of the o—phenylenediamines during reduction and their subsequent conversion to benzimidazoles by interaction with carboxylic acids was considered sufficient proof of their formation. The 2-methylbenzimidazoles prepared in this investigation were high boiling, goldenfiyellow, viscous oils which crystallized in some cases. The over all yields for the reduction and for the ring closure reactions ranged from 60 to 80 per cent of the theoretical. The benzimidazoles were characterized as dipicrates and as dihydro— chlorides. In addition, infrared and ultraviolet absorption spectra of the benzimidazoles were obtained. A brief discussion of these spectra appears in the appendix. For evaluation of physiological and pharmacological actions the benzimidazoles were converted into dihydrochlorides, not, however, without some difficulties. The dinydrochlorides were found to be quite hygroscopic. They were best purified by using absolute ethanol and anhydrous diethyl ether as the solVent system. Normally, purification was effected by dissolving the dihydrochloride in the minimum amount of boiling ethanol, treating the solution with decolorizing charcoal, filtering, and then diluting the solution with anhydrous ether until turbid. When the solution was chilled, colorless needles precipitated in some cases. However, in the cases of l-(fi—morpholinoethyl)-, l-(fi- piperidinoethyl)-, and, to some extent, l-(B—pyrrolidinoethyl)—S—methoxy- 2~methylbenzimidazole dihydrochlorides, this treatment caused the material to turn pink or red. This happened frequently to all of the 2—methylbenzimidazole dihydrochlorides prepared in this investigation. Such coloring could be avoided, or at least minimized, by dissolving 13 the sample in ethanol at room temperature, filtering the solution, and diluting it with anhydrous ether. EPERIMEN ”PAL-x. ’ ”3* Nsfijflydroxyethyldimethylamine This compound was commercially available from Eastman Kodak Com- pany. NMfi-Hydroxyethylpyrrolidine A solution of 500 g. (7.03 moles) of pyrrolidine (Eastman Practical Grade) and 368 g. (b.58 moles) of ethylene chlorohydrin (Eastman Practical Grade) in 1.5 l. of dry benzene was allowed to stand at room temperature with slow stirring for two hours. By means of a steam-bath the temperature was gradually raised until refluxing began, after which the bath was removed. A vigorous, exothermic reaction continued for about one hour. After the initial reaction had subsided, external heating and refluxing with stirring were continued for ten hours. Upon cooling the solution two phases appeared. The lower layer which con- tained the product was separated, and the upper benzene layer was ex- tracted repeatedly with 3N hydrochloric acid in small portions totaling 1 l. The combined product layer and acid extracts were made distinctly alkaline by the addition of 500 ml. of lON sodium hydroxide solution causing two phases to appear again. The upper layer containing the product was separated, and the lower aqueous layer was extracted with diethyl ether in several portions totaling 1.5 1. After drying the *All analyses were done by Micro—Tech Laboratories, Skokie, 111. ”*All melting points were taken in open capillaries and are uncorrected. 15 extracts over anhydrous sodium sulfate, the ether was removed by dis- tillation over a temperature range of 35-500C. at atmospheric pressure. The next fraction, consisting of recovered pyrrolidine, distilled over the range 50-900C. at atmospheric pressure. The product was obtained as a colorless oil boiling at 77-830C./15 mm. in a yield of 301.3 g. (7h.h% of the theoretical based on pyrrolidine). A boiling point of 78—810C./15 mm. has been reported for this compound (18). Nefieflydroxyethylmorpholine A solution of 308 g. (3.53 moles) of morpholine (Eastman Practical Grade) and 190 g. (2.30 moles) of ethylene chlorohydrin (Eastman Prac— tical Grade) in 900 m1. of dry benzene was allowed to stand at room temperature for one hour with slow stirring. The resulting solution was then refluxed gently for eight hours with stirring on a steam-bath. .After chilling the solution morpholine hydrochloride was filtered with suction and washed with 250 ml. of anhydrous diethyl ether in several portions. The combined filtrate and washings were then extracted with cold 3N hydrochloric acid in several portions totaling 1 1. The acid extracts were made distinctly alkaline by the addition of 1 1. of 10M sodium hydroxide solution. The product was obtained hy extracting the alkaline solution with diethyl ether in several portions until the aqueous solution was colorless. The extracts were dried over Drierite, and the ether was removed.in vagug on a warm.water-bath. Distillation of the residue in a vacuum gave the product as a colorless oil boiling over the range 106-1150c./1u mm. in a yield of 12u.8 g. (53.8% of the theoretical based on morpholine). A boiling point of 118—1200C/Pb mm. Ihas been reported for this compound (19). N-§:Hydroxyethyldiethylamine This compound was commercially available from Eastman Kodak Company. Nap-Hydroxyethylpiperidine This compound.was prepared by the method used to prepare N-fi-hy— droxyethylmorpholine. The product was obtained as a clear, pale yellow oil boiling at 92-10h0C./23 mm. in a yield of 87.2% of the theoretical based on piperidine. A boiling point of 196-1990C. at atmospheric pressure has been reported for this compound (20). N-B-Chloroethyldimethylamine(hydrochloride This compound, prepared according to the procedure of Tilford, et a1., (18) was obtained as long, colorless needles melting at 202-203.5°C. with decomposition in a yield of 80 per cent of the theoretical. Melt— ing points of 19h~196°C. (18) and of 201°C. (21) have been reported for unscmmmmd Nip-Chloroethylpyrrolidine hydrochloride This compound, prepared according to the procedure of Tilford, et 31., (18) was obtained as long, colorless needles melting at 171-1720C. with decomposition in a yield of 83.6 per cent of the theoretical. A melting point of 171-1720C. has been reported for this compound (18). N-fi-Chloroethylmorpholine hydrochloride This compound, prepared according to the procedure of Tilford, et 31., (18) was obtained as long, colorless needles melting at 180.5- 182°C. with decomposition in a yield of 91.3 per cent of the theoretical. A melting point of l82-18h0C. has been reported for this compound (18). 1? N:fi-Chloroethyldiethylamine hydrochloride This compound, prepared according to the procedure of Gough and King (22), was obtained as long, colorless needles melting at 209-. 2100C. with decomposition in a yield of 81 per cent of the theoretical. A melting point of 210-2110C. has been reported for this compound (22). Nip-Chloroethylpiperidine hydrochloride This compound, prepared according to the procedure of Tilford, gt gt., (18), was obtained as colorless needles melting at 228.5—229.5°C. with decomposition in a yield of 85.3 per cent of the theoretical. Melting points of 231-2320C. (l8) and 229-2310C. (20) have been re- ported for this compound. 3-Nitro—h-p-toluenesulfonamidoanisole The procedure of Barber, EE.§1': (16) was followed on a smaller scale. A mixture of 100 g. (0.60 mole) of h-methoxy-2-nitroaniline (East- man Practical Grade), 125 g. (0.72 mole) of p-toluenesulfonyl chloride, and 350 ml. of redistilled pyridine was gently heated on a steam-bath with stirring for 2h hours. The crude product was isolated by pouring the reaction mixture into 2.h 1. of ice-water and stirring vigorously with scratching until the gummy material crystallized. After filtering the mixture with suction and'washingthe filter cake with water to re- move the pyridine, the product was purified by adding it to 300 ml. of warm 2N sodium hydroxide solution forming a red slurry. This was di— luted with 2.7 1. of water and filtered.with suction to remove any di— sulfonamide formed. Acidification of the filtrate with 6N hydrochloric acid.precipitated the product. The product was obtained as yellow 18 crystals melting at 100—1030C. in an average yield of 168 g. (87.5% of the theoretical). Barber, gt gt., report a melting point of 102-1030C. 3—Nitro-h—p-toluenesulfon-(fi-dimethylaminoethyl)amidoanisole One hundred grams (0.31 mole) of 3-nitro-h-p-toluenesulfonamido— anisole was dissolved in 2 1. of warm, dry benzene. After solution was complete, 7.2 g. (0.31 gram-atom) of freshly prepared sodium sand was added. This mixture was refluxed with stirring on a steam-bath for two hours. Meanwhile, 57.6 g.(0.h mole) of N—B-chloroethyldimethyl- amine hydrochloride was dissolved in a solution of 30 g. of sodium hydroxide in 300 m1. of water. After eXtracting the N-B-chloroethyl- dimethylamine with benzene, drying the extracts over anhydrous sodium sulfate and filtering, the solution was added to the above salt sus- pension. This reaction mixture was then refluxed with stirring on a steam-bath for b8 hours. The chilled solution was filtered with suction to remove sodium chloride, and the benzene removed.tg XEEEQ on a steam- bath. The residue was treated with h00 m1. of 2N sodium hydroxide solution, and the product extracted with diethyl ether in several por- tions until the extracts were colorless. Dhying of the extracts over anhydrous sodium sulfate followed by evaporation of the ether gave 105.6 g. (86.5 % of the theoretical) of crude product as an orange-yellow solid. The melting point of the crude product was 92—950C. Three re- crystallizations of a sample from 50 per cent aqueous ethanol (Norite) gave the product as yellow needles melting at 98.5-99.50C. AnaLysis: Calculated for C13H23N3058: C, 5h.95; H, 5.89; N, 10.68; s, 8.15. Found: c, 55.06; H, 5.95; N, 10.73; s, 8.01. l9 3—Nitro-b-p—toluenesulfon-(p—dimethytaminoethyl)amidoanisolepicrate The picrate was formed by dissolving 0.5 g. of the sulfonamide in 50 ml. of hot absolute ethanol and adding 50 m1. of a saturated alcoholic solution of picric acid. The precipitate which formed was filtered with suction and recrystallized three times from 95 per cent aqueous ethanol (Norite) to give the picrate as a pale yellow powder melting at 183-l8h0C. with decomposition. Analysis: Calculated for C24H26N60128: N, 13.50; S, 5.15. Found: N, 13.31; S, 5.03. h-fi—Dimethylaminoethylamino-3—nitroanisole To 250 ml. of 90 per cent aqueous sulfuric acid chilled to 0-50C. was added, in small portions as it dissolved, 101.3 g. (0.26 mole) of 3-nitroJrqrtoluenesulfon-(fi-dimethylaminoethyl)amidoanisole. The mix— ture was allowed to stand overnight at 0-50C. and then was heated on a steam—bath for 30 minutes to complete the hydrolysis. After pouring the reaction mixture over 500 g. of ice and making it basic by the careful addition of cold concentrated aqueous ammonia, the product was obtained by extracting the basic solution with diethyl ether in several portions until the extracts were colorless. The ether extracts were dried over anhydrous sodium sulfate. Evaporation of the solvent left the product as a bright red oil which failed to chystallize on chilling. The average yield was 58.5 g. (9h.8% of the theoretical). hefi:Dimethylaminoethylamino-3-nitroanisoleApicrate The picrate was prepared in hot absolute ethanol and was recrys— tallized three times from glacial acetic acid (Darco) from which it 20 separated as long orange needles melting at 191.5-193OC. with decompo- sition. Analysis: Calculated for C17H20N6010: C, h3.59; H, b.30; N, 17.95. Found: C, h3.75; H, h.hb; N, 17.8h. 1-(fi-Dimethylaminoethyl)-5-methoxy-2—methylbenzimidazole Thirty and eight—tenths grams (0.13 mole) of b-B-dimethylamino— ethylamino-3-nitroanisole was dissolved in 200 ml. of glacial acetic acid, Raney nickel catalyst was added, and the mixture subjected to hydrogenation at room temperature at an initial hydrogen pressure of 50 p.s.i. After the theoretical amount of hydrogen had been taken up, the catalyst was removed by filtration with suction. The light green filtrate was then refluxed with stirring in an oil-bath at 125°C. for 17 hours. After cooling the reaction mixture, it was diluted with 100 m1. of water and was made distinctly basic with EN sodium hydroxide solution. The product was obtained by extracting the basic mixture with benzene in several portions totaling 900 ml. After drying the extracts over Drierite, the benzene was evaporated lg zgggg on a steam-bath. The solid residue was mixed intimately with Norite and was subjected to an extraction with n-hexane in a Soxhlet apparatus. Evaporation of the n- hexane yielded 2b.5 g. (81.8% of the theoretical) of product as pale yellow needles melting at 69-71°C. Recrystallization of a small sample from n-hexane raised the melting point to 70—7l.5°C. This compound was not analyzed as the free base but was character- ized by the following derivatives. 1-(fi-Dimethylaminoethyl)—5-methoxy-2-methylbenzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was 21 recrystallized three times from glacial acetic acid (Darco). The di- picrate separated as short, yellow needles melting at 22l.5-2230C. with decomposition. Analysis: Calculated for C25H25N9015: C, h3.h2; H, 3.6h; N, 18.23. Found: C, h3.h7; H, 3.59; N, 18.12. l-(fi—Dimethylaminoethyl)—5-methoxy-2-methylbenzimidazo1e dihydrochloride Twenty-three and nine—tenths grams (0.1 mole) of the free base was dissolved in 500 ml. of anhydrous diethyl ether, and the cold ethereal solu- tion was saturated with dhy hydrogen chloride. The precipitate which formed.was purified twice by dissolving it in the minimum amount of hot absolute methanol (Norite), diluting the solution with anhydrous di- ethyl ether until turbid and then chilling. The dihydrochloride was obtained as a pale pink powder melting at 2h5.5-2h7°C. with decomposi- tion in a yield of 13.5 g. (h3.l% of the theoretical). An analytical sample was purified again in the same manner. The melting point rose to 2h6.5-2h8°C. with decomposition. Analysis: Calculated for C13H21C12N30: C, 50.98; H, 6.91; Cl, 23.16; N, 13.72. Found: c, 50.71; H, 7.08; c1, 22.95; N, 13.62. 3-Nitro-brpatoluenesulfon-(B-pyrrolidinoethyl)amidoanisole One hundred grams (0.31 mole) of 3-nitro-h-p-toluenesulfonamido- anisole was dissolved, with warming, in 1.5 1. of dry benzene. After solution was complete, 7.2 g. (0.31 gram-atom) of freshly prepared sodium sand was added, and the resulting mixture was refluxed with stirring on a steam-bath for two hours to complete salt formation. Meanwhile, N-B-chloroethylpyrrolidine was prepared by dissolving 68.0 g. (0.h0 mole) of N-B-chloroethylpyrrolidine hydrochloride in a solution 22 of NO g. of sodium hydroxide in h00 m1. of water. The free base was obtained by extracting the alkaline solution with benzene in eight 50 ml. portions. After drying the extracts over anhydrous sodium sul— fate and filtering the solution, the benzene solution was added to the above salt suspension. Refluxing and stirring were then continued for h8 hours. After chilling and filtering the mixture with suction to remove sodium chloride, the benzene solution was extracted with hN sodium hydroxide solution in several portions totaling 1 1. .After washing the benzene solution with several portions of water to remove any base and any unchanged sulfonamide salt, the yellow benzene solution was dried over anhydrous sodium sulfate. About 1 1. of benzene was then recovered by distillation; the remaining solution was evaporated to dryness on a steam-bath. The yield of crude product as a yellow solid was 125.0 g. (97.3% of the theoretical). This material was used without further purification. A small sample was rechystallized three times from 70 per cent aqueous ethanol (Norite) from which it separ- ated as a pale yellow powder melting at 82-83.5°C. Analysis: Calculated for C20H25N3OSS: C, 57.26; H, 6.01; N, 10.02; S, 7.6b. Found: C, 57.16; H, 5.98; N, 9.87; S, 7.h2. 3-Nitro-h-p-toluenesulfon-(fi-pyrrolidinoethyl)amidoanisole picrate The picrate was formed in hot absolute ethanol and was recrystal- lized three times from 95 per cent aqueous ethanol (Norite). The picrate separated as yellow needles melting at l93.5-19h.5°C. with decomposition. Analysis: Calculated for C25H28N60128: C, h8.1h; H, b.35; N, 12.96; S, b.9b. Found: C, b8.28; H, b.52; N, 13.01; S, b.92. 23 3-Nitro-h-fiepyrrolidinoethylaminoanisole One hundred and eighty grams (0.h3 mole) of powdered 3-nitro—h-p- toluenesulfon-(B-pyrrolidinoethyl)amidoanisole was added in small por— tions as it dissolved to 600 ml. of 90 per cent aqueous sulfuric acid at 0-10°C. The reaction mixture was allowed to stand in an ice-box at 0-100C. for h8 hours with occasional swirling. The mixture was then warmed on a steam-bath for 20 minutes to complete the hydrolysis, after which it was poured over 1 kg. of ice and.was made distinctly basic by the careful addition of cold concentrated aqueous ammonia. External cooling in an ice-bath was necessary. The product was obtained by ex- tracting the basic solution with 2 l. of diethyl ether in several por- tions. After drying the solution over anhydrous sodium sulfate, and filtering, the ether was evaporated. The yield of crude product was 99.1 g. (87.1% of the theoretical). This material was used without further purification. A small sample was recrystallized three times from 70 per cent aqueous ethanol (Norite) from which the free base separated as long, bright red needles melting at 51-51.5°C. Analysis: Calculated for C13H19N303: C, 58.85; H, 7.22; N, 15.8h. Found: C, 59.12; H, 6.96; N, 15.76. 3-Nitro-befijpyrrolidinoethylaminoanisole,picrate The picrate was formed in hot absolute ethanol and was recrystal- lized three times from 95 Per cent aqueous ethanol (Norite) from.which it separated as orange needles melting at 18h-18h.5°C. with decomposi- tion. - Analysis: Calculated for C19H22N5010: C, h6.17; H, h.h93 N,l7.00. Found: C, h5.9h; H, b.63; N, 16.71. 2b 5-Methoxy-2-methyl-1-(fi-pyrrolidinoethyl)benzimidazole Thirty and six-tenths grams (0.12 mole) of 3-nitro-h-fi-pyrrolidino- ethylaminoanisole was dissolved in 200 ml. of glacial acetic acid, 0.2 g. of platinum oxide catalyst was added, and the mixture was sub- jected to hydrogenation at an initial pressure of 50 p.s.i. at room temperature. After the theoretical amount of hydrogen had been taken up, the catalyst was recovered by filtration with suction. The result- ing solution was then heated under reflux with stirring in an oil—bath at lbOOC. for ten hours. The reaction mixture was chilled and was made distinctly alkaline by the addition of hN sodium hydroxide solution. The product was obtained by extracting the basic solution with benzene in portions totaling 800 ml. After dhying the extracts over anhydrous magnesium sulfate, the benzene was removed 12 XEEEE on a steam-bath. Distillation of the residue in a vacuum gave the product as a golden- yellow, viscous oil boiling at 180-190°c./0.5 mm. in a yield of 22.1; g. (7h.6% of the theoretical). 0n long standing in the cold the oil solidified partially to a pale yellow, waxy material. This compound was characterized by the following derivatives. The free benzimidazole was not analyzed. 5-Methoxy-2-methy1-l-(fi-pyrrolidinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized five times from glacial acetic acid (Norite) from which it separ- ated as bright yellow needles melting at 2hl-2h2°C. with decomposition. Analysis: Calculated for C27H27N9015: C, h5.l9; H, 3.79; N, 17.57. Found: C, h5.19; H, 3.85; N, 17.53. 25 5—Methoxy—2-methy1-l-(pryrrolidinoethyl)benzimidazole dihydrochloride Twenty-two grams (0.09 mole) of the free base was dissolved in 500 ml. of anhydrous diethyl ether. The chilled ethereal solution was saturated with dry hydrogen chloride. The colorless precipitate which formed was filtered with suction and was purified by dissolving it in the minimum amount of absolute ethanol at room temperature. After di- luting the alcoholic solution with anhydrous diethyl ether until turbid and chilling the solution, the dihydrochloride separated as short, colorless needles melting at 2h2-2hboc. with decomposition in a yield of 20.5 g. (72.7% of the theoretical). Six additional purifications of a small sample raised the melting point to 2bh-2h5°C. with decomposition. Analysis: Calculated for C15H23C12N30: C, 5h.22; H, 6.98; Cl, 21.3u; N, 12.65. Found: c, Sh.00; H, 6.99; Cl, 21.02; N, 12.68. 3-Nitro-h-p-toluenesulfon—(§:mo§pholinoethyl)amidoanisole One hundred grams (0.31 mole) of 3-nitro-h-p-toluenesulfonamido- anisole was dissolved with warming in 1.5 l. of dry benzene. After solution was complete, 7.2 g. (0.31 gram-atom) of freshly prepared sodium sand was added, and the resulting mixture was refluxed with stirring on a steam-bath for two hours to complete salt formation. Mean- while, N-B-chloroethylmorpholine was prepared by dissolving 75.8 g. (0.h mole) of N-B-chloroethylmorpholine hydrochloride in a solution of to g. of sodium hydroxide in NOD ml. of water. The free base was ex— tracted with benzene in eight 50 m1. portions. After dhying the extracts briefly over anhydrous sodium sulfate and filtering the mixture, the benzene solution was added to the above salt suSpension. Refluxing and stirring were then continued for N8 hours. After chilling and 26 filtering the reaction mixture with suction to remove sodium chloride, the benzene solution was extracted with EN sodium hydroxide solution in several portions totaling 1 1. After washing the benzene solution with several portions of water to remove any alkali and unchanged sul- fonamide salt, the yellow solution was dried over anhydrous sodium sulfate. Approximately 1 1. of benzene was then recovered by distilla— tion and the remaining solution evaporated to dnyness on a steam-bath. The yield of crude product as a tan solid was 128.3 g. (95% of the theoretical). This material was used without further purification. A small sample was recrystallized three times from 50 per cent aqueous ethanol (Norite) from which the product separated as a pale yellow powder melting at ll6-117°C. Analysis: Calculated for C20H25N3058: C, 55.16; H, 5.79; N, 9.65; s, 7.36. Found: C, 55.12; H, 5.89; N, 9.56; s, 7.68. 3-Nitro-hjp-toluenesulfon—(p-morpholinoethy1)amidoanisole picrate The picrate was formed in hot absolute ethanol and was recrystal- lized three times from 70 per cent aqueous acetic acid from which it separated as yellow needles melting at 189.5-191°C. with decomposition. Analysis: Calculated for C26H28N6013S: C, h6.98; H, b.25; N, 12.65; S, b.82. Found: C, h6.96; H, b.22; N, 12.83; S, b.68. hag-Morpholinoethylamino-3-nitroanisole Sixty-six and five-tenths grams (0.15 mole) of powdered 3-nitro- b-p-toluenesulfon-(B—morpholinoethyl)amidoanisole was added in small portions as it dissolved to 300 ml. of 90 per cent aqueous sulfuric acid at 0-10°C. The reaction mixture was allowed to stand in an ice- box at 0—10°C. for A8 hours with occasional swirling. After warming on 27 a steam—bath for 20 minutes to complete the hydrolysis, the reaction mixture was poured over 500 g. of ice. The aqueous mixture was made distinctly basic by the careful addition of excess cold, concentrated aqueous ammonia. External cooling in an ice-bath was necessany. The product was obtained by extracting the basic suspension with 1.5 1. of diethyl ether in several portions. After drying the extracts over anhydrous sodium sulfate and filtering the solution, the ether was evaporated. The yield of solid, crude product was b0.0 g. (93.5% of the theoretical). This material was used without further purification. A small sample was recrystallized three times from 50 per cent aqueous ethanol (Norite) giving the product as long, bright red needles melt- ing at 86-86.5°C. Analysis: Calculated for C13H19N304: C, 55.50; H, 6.81; N, lh.9h. Found: C, 55.8h; H, 6.82; N, 1h.80. h-fl-Morpholinoethylamino-3-nitroanisolepicrate The picrate was formed in hot absolute ethanol and was recnystal- lized three times from water (Darco) from which it separated as short, red-orange needles melting at 218.5-219.5°C. with decomposition. Analysis: Calculated for 019H22N5011: C, bb.7l; H, b.3h; N, l6.h8. Found: C, hb.61; H, b.03; N, 16.55. 5-Methoxy-2-methyl-l-(B-morpholinoethyl)benzimidazole Thirty grams (0.11 mole) of h-B-morpholinoethylamino-3-nitroanisole was dissolved in 200 m1. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at room tem- perature at an initial hydrogen pressure of 60 p.s.i. After the uptake of the theoretical amount of hydrogen, the catalyst was removed.by 28 filtration with suction. The filtrate was then heated under reflux with stirring in an oil—bath at 1h0°C. for eight hours. The cooled reaction mixture was diluted.with 200 m1. of hot water and was made distinctly alkaline by the addition of AN sodium hydroxide solution. The product was obtained by extracting the alkaline solution with 800 ml. of benzene in several portions. After drying the extracts over anhydrous sodium sulfate, the benzene was removed tg'zgggg on a steam- bath, and the residue was distilled in a vacuum. The yield of product as a pale yellow, viscous oil boiling over the range 183-203°C./0.05 mm. was 18.9 g. (6h.3% of the theoretical). 0n standing the material crystallized to a pale yellow solid melting at 111-113°C. This compound was characterized by the following derivatives; it was not analyzed as the free base. 5—Methoxy-2—methy1-l-(fi-morpholinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized four times from glacial acetic acid.(Norite). The dipicrate separated as short, yellow needles melting at 222.5—223°C. with de- composition. Analysis: Calculated for C27H27N9016: C, hh.21; H, 3.71; N, 17.19. F0und; C, hb.50; H, 3.87; N, 17.07. 5-Methoxy-2-methy1-1-(fi-morpholinoethyl)benzimidazole dihydrochloride Sixteen and nine-tenths grams (0.06 mole) of free base was dis- solved in 500 ml. of anhydrous diethyl ether. After saturating the cold ethereal solution with dry hydrogen chloride, the colorless pre— cipitate which formed was filtered with suction and purified by dis- solving it in the minimum amount of hot absolute ethanol, treating the 29 solution with Norite and filtering. The solution was diluted with an- hydrous diethyl ether until turbid and then chilled. The product sep- arated as long, slightly pink needles melting at 21175-211800 with de— composition. The yield.was 18.7 g. (87.8% of the theoretical). Analysis: Calculated for C15H23C12N302: C, 51.73; H, 6.66; Cl, 20.36; N, 12.07. Found: C, 51.56; H, 6.8h; C1, 20.19; N, 12.00. 3-Nitro4£p7toluenesu1fon-(fi:diethylaminoethy1)amidoanisole The proCedure of King, gt gl., (12) for the preparation of this compound was modified as follows: One hundred grams (0.31 mole) of 3—nitro-h-p-toluenesulfonamido- anisole was dissolved with warming in 1.5 1. of dry benzene. After solution was complete, 7.2 g. (0.31 gram-atom) of freshly prepared sodium sand was added, and the resulting mixture stirred under reflux on a steam-bath for two hours. The N-B-chloroethy1diethylamine was prepared by dissolving 77.5 g. (O.b5 mole) of N—B-chloroethyldiethyl- amine hydrochloride in a solution of 30 g. of sodium hydroxide in 300 ml. of water. After extracting the alkaline solution with benzene in five 50 m1. portions, drying the extracts over anhydrous sodium sulfate and filtering, the N-B-chloroethyldiethylamine solution was added to the above salt suspension. Refluxing and stirring were con- tinued for h8 hours. The chilled solution was filtered with suction to remove sodium chloride, and the benzene was removed.lg‘tgggg on a steam—bath. The residue was treated with hOO ml. of 2N sodium hydrox- ide solution, and the product extracted.with 1 1.of diethyl ether in several portions. Drying of the extracts over anhydrous sodium sulfate followed by evaporation of the ether gave an average yield of 12h g. 3O (95% of the theoretical) of product as a dark yellow, viscous oil which failed to chystallize. 3—Nitro-h-p-toluenesulfon-(fi-diethylaminoethyl)amidoanisolepicrate The picrate was formed in hot absolute ethanol and.was recnystal- lized twice from 95 per cent aqueous ethanol (Norite) from which it separated as yellow needles melting at 153-155°C. with decomposition. King, gt 31., (12) report a melting point of 15h°C. for this compound. hjfirDiethylaminoethylamino-3-nitroanisole Thirty grams (0.07 mole) of 3-nitro-h-p-toluenesulfon-(B-diethyl- aminoethyl)amidoanisole was added in small portions as it dissolved to 150 ml. of 90 per cent aqueous sulfuric acid at 0-5°C. The mixture was allowed to stand over night at 0-5°C. and then was heated on a steam— bath for 20 minutes to complete the hydrolysis. After pouring the re— action mixture over 300 g. of ice and carefully making the aqueous solution alkaline with cold concentrated aqueous ammonia, the product was obtained.by extracting the alkaline solution with diethyl ether in several portions until the extracts were colorless. The extracts were dried over anhydrous sodium sulfate followed by evaporation of the ether. The average yield of product as bright red needles was 17.2 g. (90.5% of the theoretical). The melting point of the crude product was 38-h1°C. King, 32.31:: (12) report a melting point of h2°C. b-fi-Diethylaminoethylamino-3-nitroanisolepicrate The picrate was formed in hot absolute ethanol and.was recnysta1~ lized once from 95 per cent aqueous ethanol (Darco) from which it sep- arated as orange-red needles melting at 179-181°C. with decomposition. 31 King, gt gt., (12) report a melting point of 181°C. with decomposition. 1-(B-Diethylaminoethyl)-5—methoxy—2—methylbenzimidazole Twenty-five grams (0.09 mole) of h-B—diethylaminoethylamino-3- nitroanisole was dissolved in 2&0 m1. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydrogen- ation at room temperature at an initial hydrogen pressure of 50 p.s.i. After the theoretical amount of hydrogen had been taken up, the light green mixture was filtered with suction to remove the catalyst. The filtrate was then refluxed.with stirring in an oil-bath at 135°C. for eight hours. After cooling the solution, it was made distinctly alka- line by the addition of LN sodium hydroxide solution, and.was extracted with 1 1. of benzene in several portions. After drying the extracts over Drierite, the benzene was removed 12 zgggg on a steamrbath. Distillation of the residue in a vacuum gave the product as a golden- yellow oil boiling over the range 161-181°C./0.05 mm. in a yield of 16.9 g. (69.3% of the theoretical). This compound was characterized by the following derivatives; it was not analyzed as the free benzimidazole. 11(QeDiethy1aminoethyl)-5-methoxye2-methy1benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized three times from glacial acetic acid (Darco) from which it sep- arated as yellow needles melting at 227-228°C. with decomposition. Analysis: Calculated for C27H29N9015: C, h5.07; H, b.06; N, 17.52. Found: C, h5.07; H, b.18; N, 17.38. 32 1-(fi-Diethylaminoethyl)-5-methoxy-2-methylbenzimidazole dihydrochloride Sixteen and one-tenth grams (0.06 mole) of the free base was dis- solved in 500 m1. of cold anhydrous diethyl ether and the solution saturated with dry hydrogen chloride. The colorless precipitate which formed was filtered.with suction, dissolved in the minimum amount of hot absolute ethanol, treated with Norite, and again filtered. The filtrate was diluted.with anhydrous diethyl ether until turbid and.was then chilled thoroughly. The product separated as colorless needles melting at 233.5-2350C. with decomposition in a yield of 17.2 g. (83.5% of the theoretical). Analysis: Calculated for C15H25C12N30: c, 53.89; H, 7.5h; Cl, 21.21; N, 12.57. Found: C, 53.65; H, 7.7h; C1, 21.08; N, l2.hh. 3-Nitro-hep-toluenesulfon-(fifpiperidinoethyl)amidoanisole One hundred grams (0.31 mole) of 3-nitro-h-p-toluenesulfonamido- anisole was dissolved with warming in 2 1. of anhydrous benzene. After solution was complete, 7.2 g. (0.31 gram-atom) of freshly prepared sodium sand.was added, and the resulting mixture stirred under reflux (x1 a steamebath for two hours. The N-B-chloroethylpiperidine was prepared.by dissolving 7h.0 g. (O.h mole) of N-B—chloroethylpiperidine hydrochloride in a solution of 30 g. of sodium hydroxide in 300 m1. of water. After extracting the free base with five 50 m1. portions of benzene, dnying the benzene solution over anhydrous sodium sulfate and filtering, the N-B-chloroethylpiperidine solution was added to the above salt suspension. Refluxing and stirring were continued for h8 hours. 'HFB chilled mixture was filtered with suction to remove sodium chloride, éfiki the benzene was removed 12 vacuo on a steam-bath. The residue was 33 treated with too ml. of 2N sodium hydroxide solution, and the product extracted with a 3:1 solution of diethyl ether and.benzene. Drying of the extracts over anhydrous sodium sulfate followed by evaporation of the solvent gave 131.6 g. (98% of the theoretical) of crude product melting at 87-91°C. After three recrystallizations of a small portion from 70 per cent aqueous ethanol (Norite), the product was obtained as pale yellow needles melting at 89.5-91°C. Analysis: Calculated for C21H27N305S: N, 9.69; S, 7.h0. Found: N, 9.71; S, 7.36. 3-Nitro-h:p-toluenesu1fon-(B:piperidinoethy1)amidoanisolepicrate The picrate was formed in hot absolute ethanol and was recrysta1~ 1ized three times from 95 per cent aqueous ethanol from which it sep- arated as yellow needles melting at 150-152°C. with decomposition. Analysis: Calculated for C27H30N601ZS: N, 12.68; S, b.8b. Found: N, 12.91; 5, 11.91. 3-Nitro-h-fispiperidinoethylaminoanisole Fifty grams (0.12 mole) of 3-nitro-h-p—toluenesulfon-(B-piperidino- ethyl)amidoanisole was dissolved in 250 m1. of 90 per cent aqueous sul- furic acid at 0-10°C. and allowed to stand at this temperature overnight. After warming the solution for 20 minutes on a steam-bath to complete the hydrolysis, the solution was poured over 500 g. of ice and made distinctly alkaline by the addition of cold concentrated aqueous ammonia. The product was obtained by extracting the alkaline solution with di- ethyl ether in several portions until the extracts were nearly color- less. After dbying the extracts over anhydrous potassium carbonate, the ether was evaporated. The average yield of product as a bright orange 3h solid was 28.1 g. (87% of the theoretical). Two recrystallizations of a small sample from 70 per cent aqueous ethanol gave the product as long orange needles melting at 73.5-750C. . Analysis: Calculated for C14H21N303: C, 60.19; H, 7.58; N, 15.0h. Found: C, 60.23; H, 7.h6; N, 15.1h. 3-Nitro-h-fi-piperidinoethylaminoanisole picrate The picrate was formed in hot absolute ethanol and was recrystal- lized three times from 95 per cent aqueous ethanol from which the pic- rate separated as long, orange needles melting at 193.5-19h0C. with decomposition. Analysis: Calculated for CZOHMNGOIO: N, 16.53. Found: N, 16.68. 5-Methoxy-2-methy1-1-(fiapjperidinoethy1)benzimidazole Thirty grams (0.11 mole) of 3-nitro-b-B-piperidinoethylaminoanisole was dissolved in 200 ml. of glacial acetic acid, Raney nickel catalyst was added, and the mixture subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. After the theoret- ical amount of hydrogen had been taken up, the pale green solution was filtered rapidly with suction to remove the catalyst. The filtrate 'was heated in an oil-bath with stirring under reflux at 1hO°C. for 16 Inours. Upon cooling, the solution was made distinctly alkaline by the addition of 2N sodium hydroxide solution. The product was obtained by extracting the alkaline solution with 700 m1. of benzene in several portions. After drying the extracts over anhydrous sodium sulfate, the benzene was removed.lg‘tgggg on a steam-bath. Distillation of the residue in a vacuum gave the product as a light yellow, viscous oil boiling at 182-192°C./0.01 mm. Upon cooling and standing, the yellow 35 oil crystallized as colorless needles which melted at llO-ll2°C. The yield was 23.9 g. (81.3% of the theoretical). This compound was characterized by the following derivatives; it was not analyzed as the free benzimidazole. 5-Methoxy-2-methyl-l-(Biplperidinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized three times from glacial acetic acid (Darco) from which it sep- arated as yellow needles melting at 227-228°C. with decomposition. Analysis: Calculated for C28H29N9015: C, h5.973 H, 3.99; N, 17.23. Found: C, h5.99; H, b.03; N, 17.h1. 5-Methoxy-2—methy1-1-(B-piperidinoethyl)benzimidazole dihydrochloride The dihydrochloride was prepared by dissolving 23.0 g. (0.08 mole) of the free base in 500 m1. of anhydrous diethyl ether. Saturation of the cold ethereal solution with dby hydrogen chloride gave a gummy pre- cipitate which was filtered rapidly with suction and dissolved in the minimum amount of hot absolute ethanol. After treating the solution with Darco, filtering, and diluting with anhydrous diethyl ether until turbid, the solution was chilled thoroughly. Two similar purifications gave the dihydrochloride as a light pink powder melting at 2h5-2h6.5°C. with decomposition in a yield of 22.b g. (76.8% of the theoretical). Analysis: Calculated for C16H25C12N30: C, 55.h9; H, 7.28; C1, 20.h8; N, 12.13. Found: c, 55.27; H, 7.37; Cl, 20.58; N, 12.07. PART I. B. 1-(8-DIALKYLAMINOETHYL)-5-METHOXYBENZIMIDAZOLES DISCUSSION Several attempts to hydrogenate the h-(B—dialkylaminoethylamino)- 3-nitroanisoles at low pressure over Raney nickel catalyst using formic acid as the solvent failed. .Attempts to use the procedure of Ing, gt gt., (6) for the reduction and the ring closure also failed. By this latter method, reduction was brought about by adding a dilute aqueous solution of formic acid and hydrochloric acid to a hot aqueous mixture of iron powder and the nitro compound. Prolonged heating of the mix- ture after completion of the reduction brought about ring closure. Since reduction of the nitro group occurred with ease in glacial acetic acid over Raney nickel catalyst, this method.was chosen for this series of compounds. It then became necessary, however, to isolate the inter— mediate o-phenylenediamines by making the acidic reduction mixture alkaline and separating the product by repeated ether extractions. After removal of the ether, ring closure was brought about by refluxing the o-phenylenediamines with formic acid. The average yields for the combined reduction and ring closure reactions ranged from AD to 60 per cent of the theoretical. King, gt gt., (12) have reported l-(B-di-~ ethylaminoethyl)-5-methoxybenzimidazole to be a red oil. Careful dis- tillation, however, gave the compound as a golden-yellow oil. The red color was possibly due to residual material in the distillation pot which bumped over thus discoloring the distillate. Distillation of the other compounds in this series also resulted in yellow oils, some of which, namely, l-(B-morpholinoethyl)- and l-(B-piperidinoethy1)-5- methoxybenzimidazole, crystallized. 37 No difficulties were encountered in this series during either the preparation or the purification of these substituted benzimidazole dihydrochlorides. The benzimidazoles were further characterized as dipicrates. For a discussion of the infrared and of the ultraviolet absorption spectra of the benzimidazoles see the appendix. EXPERIMENTAL l-(fi3Dimethylaminoethy1)—5-methoxybenzimidazole Thirty-six and four-tenths grams (0.15 mole) of h-B-dimethylamino- ethylamino-3-nitroanisole was dissolved in 190 m1. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at room temperature at an initial hydrogen pressure of 50 p.s.i. After the theoretical amount of hydrogen had been taken up, the catalyst was removed by filtration with suction; the chilled filtrate was diluted with 250 m1. of water and was made distinctly alkaline by the addition of concentrated aqueous ammonia. The diamine was obtained by extracting the alkaline solution with hOO ml. of diethyl ether in several portions. The extracts were dried over Drierite, and the ether evaporated tg,zgggg. To the red, syrupy residue was added 150 ml. of 90 per cent formic acid. This solution was refluxed with stirring in an oil-bath at 120°C. for eleven hours. After cooling and dissolving the reaction mixture in 250 m1. of warm water, it was made distinctly alkaline by the addition of bN sodium hydroxide solution. The product was obtained by extracting the alkaline solution with benzene in several portions totaling 500 ml. After dtying the extracts over Drierite, the benzene was evaporated.tg ygggg on a Steam.bath, and the residue was distilled in a vacuum. The yield of product as a pale yellow, viscous oil boiling over the range lh0-153°C./0.03 mm. was 15.6 g. (h7.6% of the theoretical). Some decomposition occurred dur- ing the distillation. The material crystallized partially as colorless needles on standing in the cold. 39 This compound was characterized by the following derivatives. The free base was not analyzed. 1-(B-Dimethylaminoethyl)—5-methoxybenzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized three times from 50 per cent aqueous acetic acid from which it separated as short, light yellow needles melting at 20h-205.5°C. with decomposition. Analysis: Calculated for C24H23N9015: C, h2.5h; H, 3.h2; N, 18.62. Found: C, h2.78; H, 3.63; N, 18.60. 1—(fi-Dimethy1aminoethyl)-5-methoxybenzimidazole dihydrochloride Eighteen and eight-tenths grams (0.09 mole) of the free base was dissolved in 500 m1. of anhydrous diethyl ether. After saturating the cold ethereal solution with dry hydrogen chloride, the colorless precip— itate was filtered.with suction and purified twice by dissolving it in the minimum amount of hot absolute methanol (Norite), filtering the solution, diluting the filtrate with anhydrous diethyl ether until tur- bid, and thoroughly chilling. The yield of product as a colorless powder melting at 236-2370C. with decomposition was l7.h g. (69.h% of theoretical). A third purification of a small sample raised the melting point to 237- 238°C. with decomposition. Analysis: Calculated for C12H19012N30: c, N9.32; H, 6.55; C1, 28.27; N, 18.38. Found: C, 89.20; H, 6.uS; Cl, 2h.hl; N, 1h.39. 5-Methoxy-1-(papyrrolidinoethyl)benzimidazole A solution of 26.5 g. (0.1 mole) of 3-nitro-h-B-pyrrolidinoethyl- aminoanisole in 150 ml. of glacial acetic acid containing Raney nickel hO catalyst was subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. After the uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration with suction. After diluting the solution with 500 m1. of cold.water, it was made distinctly alkaline by the addition of cold concentrated aqueous ammonia. The diamine was obtained by extracting the alkaline solution with 600 m1. of diethyl ether in several portions. The extracts were dried over anhydrous sodium sulfate, and the ether was removed.tg ygggg. To the residue was added 100 ml. of 90 per cent formic acid. The re- sulting solution was refluzed with stirring in an oil-bath at 120°C. for 12 hours. Upon cooling, the reaction mixture was diluted with 100 m1. of water and was made distinctly alkaline with AN sodium hydroxide solution. The product was obtained by extracting the alkaline solution with benzene in several portions totaling hOO ml. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed 12 33222 on a steam‘bath. Distillation of the residue in a vacuum gave 17.0 g. (69.h%fof the theoretical) of product as a light yellow, vis- cous oil boiling at 165-180°C./0.15 mm. This Compound was characterized by the following derivatives. It was not analyzed as the free base. 5~Methoxy-1-(fi-pyrrolidinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and was recrystal- lized three times from glacial acetic acid (Darco) from which it separ- ated as short, yellow needles melting at 206-207.5°C. with decomposition. Analysis: Calculated for CZ6H25N9015: C, hb.38; H, 3.58; N, 17.92. Found: c, uh.2l; H, 3.82; N, 17.71. bl 5—Methoxy-1-(B-pyrrolidinoethyl)benzimidazole dihydrochloride A cold solution of 25.3 g. (0.1 mole) of the free base in 800 m1. of anhydrous diethyl ether was saturated.with dny hydrogen chloride. The colorless precipitate was purified by dissolving it in the minimum amount of hot absolute ethanol (Darco), and filtering the solution. Dilution of the filtrate with anhydrous diethyl ether followed by chilling gave the dihydrochloride as a colorless powder melting at 226-228OC. with decomposition in a yield of 28.3 g. (86.2% of the theoretical). Three additional similar purifications of a small sample gave the dihydrochloride as fine, colorless needles melting at 227- 228.5°c. with decomposition. Analysis: Calculated for C14H21C12N30: C, 52.83; H, 6.65; C1, 22.28; N, 13.20. Found: c, 52.85; H, 6.63; c1, 22.18; N, 13.39. 5-Methoxy-1-(fl-mogpholinoethyl)benzimidazole Twenty-five grams (0.09 mole) of h-B-morpholinoethylamino-3-nitro- anisole was dissolved in 150 ml. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. The reduced solution was filtered with suction to remove the catalyst, and the green filtrate was diluted with 500 m1. of cold water. After mak- ing this solution distinctly alkaline by adding cold.bN sodium hydroxide solution, the diamine was extracted with 1 l. of diethyl ether in sev- eral portions. The extracts were dried over anhydrous sodium sulfate, and the ether was removed tg‘zgggg. To the residue was added 100 m1. of 90 per cent formic acid, and the resulting solution was refluxed with stirring in an oil-bath at 135°C. for eight hours. After cooling 112 the solution, it was made distinctly alkaline by the addition of AN sodium hydroxide solution. The product was obtained by extracting the alkaline solution with benzene in several portions totaling hOO ml. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed lg zgggg on a steammbath. Distillation of the residue in a vacuum gave the product as a light yellow, viscous oil boiling at 190~208°c./0.05 mm. The yield of product was 8.0 g. (311.5% of the theoretical). 0n standing in the cold the product crystallized as a pale yellow solid melting at 73-75°C. This compound was characterized by the following derivatives; the free base was not analyzed. 5-Methoxy-1-(B-morpholinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized three times from 50 per cent aqueous acetic acid (Darco) from which it separated as a yellow powder melting at 230-231.5°C. with decomposition. Analysis: Calculated for C25H25N9016: C, h3.h0; H, 3.50; N, 17.52. Found: C, h3.55; H, 3.56; N, l7.h2. 5-Methoxy-1-(fi-morpho1in0ethy1)benzimidazole dihydrochloride The dihydrochloride was formed by dissolving 17.8 g. (0.07 mole) of the free base in 500 ml. of anhydrous diethyl ether, and saturating the cold ethereal solution with dry hydrogen chloride. The colorless product was purified.by dissolving it in the minimum amount of warm absolute ethanol, diluting the solution with anhydrous diethyl ether until turbid, and finally chilling the suspension. The dihydrochloride separated as slightly pink needles melting at 2hh-2h6°C. with decomposition E3 in a yield of 13.7 g. (60% of the theoretical). Three additional puri— fications of a small sample gave the dihydrochloride as colorless needles melting at 2E5-2E60C. with decomposition. Analysis: Calculated for C14H21C12N302: C, 50.31; H, 6.333 Cl, 21.22; N, 12.57. Found: c, 50.12; H, 6.11; Cl, 21.22; N, 12.76. 1-(fi-Diethylaminoethyl)-5-methoxybenzimidazole Thirty-three grams (0.12 mole) of E-B-diethylaminoethylamino-3- nitroanisole was dissolved in 200 ml. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydrogena— tion at room temperature at an initial hydrogen pressure of 50 p.s.i. After the uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration with suction, and the colorless filtrate was made alkaline by adding an excess of EN sodium hydroxide solution. The diamine was obtained by extracting the alkaline solution with diethyl ether in several portions totaling 1 1. After dbying the ether solution over anhydrous sodium sulfate, the ether was removed.12,tgggg. To the dark red, oily residue was added 100 ml. of 88 per cent formic acid. The resulting solution was refluxed.with stirring in an oil-bath at 120°C. for 18 hours. The reaction mixture was cooled and diluted with 250 ml. of water. After making the solution distinctly alkaline by the addi— tion of concentrated aqueous ammonia, the product was obtained by ex- tracting the alkaline solution with E00 ml. of benzene in several por- tions. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed.ig‘zgggg on a steam—bath. Distillation of the residue in a vacuum gave the product as a light yellow oil boiling at 160—165°C./0.15 mm. in a yield of 19.5 g. (63.8% of the theoretical). Eb This compound was Characterized by the following derivatives; the free base was not analyzed. 1-(B-Diethy1amdnoethyl)-5-methoxybenzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and was recrystal— lized three times from glacial acetic acid (Darco) from which it separ- ated.as yellow needles melting at 215-216.5°C. with decomposition. Analysis: Calculated for C25H27N9015: C, EE.26; H, 3.86; N, 17.87. Found: c, lupin; H, E.01; N, 17.90. 1-(fi-Diethylaminoethyl)-5-methoxybenzimidazole dihydrochloride Eighteen and five-tenths grams (0.08 mole) of the free base was dissolved in 500 m1. of anhydrous diethyl ether. After saturating the cold ethereal solution with dby hydrogen chloride, the colorless precip- itate was filtered with suction and.was purified by dissolving it in hot absolute ethanol, treating the solution with.Norite and filtering. The filtrate was diluted with anhydrous diethyl ether until turbid and then thoroughly chilled. The yield of dihydrochloride as short, colorless needles melting at 200-202°C. with decomposition was 18.6 g. (77.5% of the theoretical). Three additional purifications of a small sample raised the melting point to 202-203°C. with decomposition. King gt gt., (12) report a melting point of 203°C. for the dihydrochloride. 5-Methoxy—1-(fi-piperidinoethy1)benzimidazole Twenty-six and two-tenths grams (0.09 mole) of 3-nitro-E-B-piper- idinoethylaminoanisole was dissolved in 200 ml. of glacial acetic acid, Raney nickel catalyst was added, and the mixture was subjected to hydro- genation at room temperature at an initial hydrogen pressure of 50 p.s.i. b5 After the uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration with suction. The chilled solution was then made distinctly alkaline by the addition of cold, dilute aqueous ammonia. The red, oily diamine was obtained by extracting the alkaline solution with diethyl ether in several portions until the extracts were colorless. The extracts were dried over anhydrous sodium sulfate, and the ether removed.tg‘tgggg. To the red, solid residue was added 150 ml. of 98 per cent formic acid. The resulting solution was refluxed.with stir- ring in an oil-bath at 120°C. for ten hours. The cooled reaction mix- ture was diluted.with 100 m1. of water, and.was then made distinctly alkaline with concentrated aqueous ammonia. The product was obtained by extracting the basic solution with 600 m1. of benzene in several portions. After drying the extracts over anhydrous sodium sulfate, the benzene was removed 12 ygggg on a steamrbath. Distillation of the residue in a vacuum gave 13.E g. (55.2% of the theoretical) of product as a pale yellow, slightly viscous oil boiling at 170-187°C./0.05 mm. On standing in the cold this material crystallized as a pale yellow solid melting at 68-70°C. This compound was characterized by the following derivatives; the free base was not analyzed. 5-Methoxy—l-(fi-piperidinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized three times from acetone (Norite) from which it separated as a yellow powder melting at 212-212.5°C. with decomposition. Analysis: Calculated for C27H27N9015: C, E5.19: H, 3.79; N, 17.57. Found: C, E5.25; H, 3.90; N, 17.35. E6 5-Methoxy-1-(fi-piperidinoethy1)benzimidazole dihydrochloride Twelve grams (0.05 mole) of free base was dissolved in 500 m1. of anhydrous diethyl ether. Saturation of the cold ethereal solution with dry hydrogen chloride caused a colorless precipitate to separate which, after filtration with suction, was purified by dissolving it in the minimum amount of warm absolute ethanol. Dilution of the alcoholic solution with anhydrous diethyl ether until turbid followed by chilling gave 13.7 g. (81.5% of the theoretical) of dihydrochloride as a white powder melting at 237.5—239°C. with decomposition. Analysis: Calculated for C15H23C12N30: C, 5E.22; H, 6.98; C1, 21.31:; N, 12.65. Found: c, 53.98; H, 7.16; c1, 21.21:; N, 12.38. PART II. A. 1-(B-DIALKYLAMINOETHYL)-6—MBTHOXY-2—METHYLBENZIMIDAZOLES DISCUSSION The synthetic sequence used by Simonov (11), as shown in Scheme A on page 5, for the preparation of 1,6-disubstituted and 1,2,6-trisub- stitutedbenzimidazoles was modified to some extent as described.below. The starting material for this series, E—acetamido—3-nitroanisole, was prepared by different methods. Acetylation of E-methoxy-2-nitroaniline with acetic anhydride gave a product which was extremely difficult to separate from unacetylated starting material. In all attempts, this reaction failed to go to completion. Separation of the product from the starting material was best achieved.by repeated recrystallizations from dilute aqueous ethanol. However, this procedure caused a marked decrease in the yield of the amide due to the solubility of the amide in the solvent system chosen. The use of acetyl chloride as the acylating agent in dry pyridine solu- tion failed to give better results. Since E—methoxy-2-nitroaniline was prepared commercially by acetyla— tion and nitration of p-anisidine, followed by hydrolysis of the amide, the first step in this synthesis was utilized, with excellent results, to prepare the desired amide. The procedure for the acetylation of p- anisidine followed by nitration of the p-acetanisidide recommended by Fanta and Tarbell (23) was used without modification. This method gave A-acetamido-3-nitroanisole in high yield and in high purity as long, yellow needles. The reduction of the nitro group to form E-acetamido-3-aminoaniso1e E8 was not achieved without some difficulties. Using the method of Simonov (ll), reduCtion was brought about by means of iron filings in hot water as the reducing agent. Since this o-phenylenediamine deriv- ative was slightly soluble in cold water and readily soluble in hot water, it was necessary to salt out the amine from solution with sodium chloride. The yield of product was only fair, possibly due to decompo- sition on exposure to air and to light. Subsequent alkylation of the primary amino group of E-acetamide-3- aminoanisole with various dialkylaminoethylchlorides resulted in at least two other products in addition to the desired E-acetamido-3-(fi— dialkylaminoethylamino)anisoles. Dialkylation of the 3-amino group followed by quaternary salt formation could account for some of these by-products. The temperature of the oil-bath during the alkylation reaction was most important. Normally this reaction was carried out at an oil- bath temperature of loo—115°C. If the oil-bath temperature was much above 120°C., ring closure would have taken place prior to alkylation with the formation of 5-methoxy-Z-methylbenzimidazo1e. Subsequent alkylation of this compound could result in a mixture of 1—(E-dialky1- aminoethyl)-6-methoxy-2-methyl- and 1—(fi-dialkylaminoethyl)-5-methoxy- 2-methy1benzimidazole. Thus, it was necessary to maintain a lower temperature until alkylation had taken place, before the temperature was raised to bring about ring closure. This reaction was further complicated.by the formation of quaternary salts resulting from the reaction of the 1-fi-dia1kylaminoethylbenzimidazoles with any dialkyl- aminoethylchloride still present. E9 One final complication, which must be taken into consideration, involved the reaction of the hydrogen chloride, produced during the alkylation step, with any or all of the above mentioned amino deriva- tives forming salts. Thus, one might expect some of the starting mater— ial, E-acetamido-3-aminoanisole, to undergo hydrochloride formation. Alkylation of this salt would then be unlikely to occur, but, upon raising the temperature of the oil-bath, ring closure would take place resulting in the formation of some 5-methoxy-2-methylbenzimidazole. This, in turn, could then undergo alkylation and salt formation as dis— cussed above. Though a complicated mixture of products could and, undoubtedly, did occur in the above two-step reaction, the isolation of the desired 1,2,6-trisubstituted benzimidazoles was accomplished with ease. An ether extraction of an aqueous solution of the reaction mixture removed any excess dialkylaminoethylchloride. After making the aqueous solution distinctly alkaline, the product was obtained by extraction with benzene. A considerable amount of intractable tar remained which was soluble in ethanol, and.was assumed to be a mixture of quaternaby salts. Evapora- tion of the benzene from the extract followed by distillation of the residue in a vacuum gave the desired benzimidazole. Yields were seldom above 35 per cent of the theoretical based on E-acetamido-3—aminoanisole. In an attempt to establish the course of the above alkylation and ring closure reactions, the following experiments were performed. E~ Acetamido-3—aminoanisole was alkylated with N-E-chloroethylpiperidine at an oil-bath temperature of 110—115°C. 2~Acetamido-5-methoxy-N-(p- piperidinoethyl)ani1ine was obtained as a colorless powder melting at 125-125.50C. in a yield of 51 per cent of the theoretical. Subsequently 50 this material was heated under reflux in xylene solution at an oil—bath temperature of l35-1E00C. to produce 6-methoxy-2-methy1-l-(B—piperidino- ethyl)benzimidazole, identical with the product obtained by the com- bined alkylation and ring Closure reactions. Since the course of this reaction sequence was known, these benz- imidazoles were normally prepared without purification of intermediates in the three-step sequence of reactions in an attempt to obtain as high a yield as possible. The reduction of the nitro group in E-acetamido- 3-nitroanisole was carried out by hydrogenation over Raney nickel. When ethanol was used as the solvent, it was not necessary to isolate the E— acetamido-3-aminoanisole prior to alkylation. The reduced reaction mix- ture was immediately subjected to alkylation and ring closure procedures. Ethanol, however, was not a good solvent for the reduction because of the low solubility of both the starting material and the product in it. Glacial acetic acid.was an excellent solvent for the reduction, but, when it was used, it was necessary to isolate the E-acetamido-3-amino- anisole prior to alkylation. This was accomplished by first concentrat- ing the acid solution, then making it distinctly alkaline, and, finally, extracting the alkaline solution with diethyl ether. After evaporation of the solvent, the o-phenylenediamine derivative was alkylated in ethanol as described previously. The yield of benzimidazole from this procedure, however, was quite poor. During the later stages of this investigation it was observed that dioxane was a better solvent for the reduction than either ethanol or glacial acetic acid. After com- pletion of the reduction the E-acetamido-3-aminoanisole could be isolated by removing the dioxane 12.23222: or the reduction mixture could be subjected directly to the alkylation and ring closure reactions. Satis- factory yields of benzimidazoles were obtained when dioxane was used. The benzimidazoles prepared in this series were found to be yellow 51 viscous oils boiling at higher temperatures than the corresponding 1,2,5-trisubstituted isomers. On standing in the cold crystallization could be induced in some cases. These benzimidazoles were characterized as dimethiodides and as dihydrochlorides. While the dipicrates could be prepared, no suitable solvent could be found for purifying them. All of the dihydrochlorides in this series developed deep colors when dissolved in hot ethanol. By using cold ethanol to dissolve the sample and then diluting the cold solution with diethyl ether, the di- hydrochlorides were usually obtained as colorless needles. EXPERIMENTAL E—Methoxy—2-nitroacetanilide The preparation of this compound according to the procedure of Fanta and Tarbell (23) resulted in a yield of 67 per cent of the theor- etical of product as long, yellow needles melting at 115—ll6°C. Fanta and Tarbell report a melting point of 116.5—117°C. E-Acetamido-3-aminoanisole The procedure of Simonov (11) was followed on a larger scale. Two hundred and thirty-seven grams (1.12 mole) of E-acetamido—3- nitroanisole was added in small portions over a period of one hour to a well stirred mixture of 600 g. of E0 mesh iron filings and 50 g. of sodium chloride in 2.1 1. of water maintained at a temperature of 90°C. for two hours. The hot reaction mixture was filtered rapidly with suction through a preheated 21 cm. Bfichner funnel. The filter cake was washed.with two 300 m1. portions of boiling water. The hot filtrate was saturated with sodium chloride and chilled. The precipitate was filtered with suction and dried in a vacuum desiccator over Drierite. The yield of crude product as colorless needles melting at 1E2-1E6°C. was 1EO.E g. (69.5% of the theoretical). Repeated recnys- tallizations of a small sample from hot water raised the melting point to lE8-1E9.5°C. Simonov has reported the melting point of this com- pound as 150-150.5°C. 2-Acetamido-5-methoxy—N:(B-piperidinoethyl)aniline Twenty and two-tenths grams (0.11 mole) of‘N-B-chloroethylpiper- idine hydrochloride was dissolved in 50 m1. of EN sodium hydroxide 53 solution. The N-B-chloroethylpiperidine was extracted with four 50 m1. portions of diethyl ether. After drying the extracts over anhydrous sodium sulfate, the ether was evaporated £2 XEEEE‘ To the residue was added 18.0 g. (0.10 mole) of E-acetamido-3-aminoanisole and 5 m1. of absolute ethanol. This mixture was refluxed in an oil-bath at 110—112°C. for E0 hours with vigorous stirring. The cooled reaction mixture was dissolved in 60 m1. of hot water, and extracted with two 50 m1. p0r- tions of diethyl ether to remove any unchanged.N-B-chloroethylpiperidine. The aqueous layer was added to 150 g. of 50 per cent aqueous sodium hydroxide solution. The product was obtained by extracting this alka- line solution with EOO m1. of benzene in several portions. The extracts were washed once with 150 ml. of water and dried over anhydrous sodium sulfate. Evaporation of the benzene left 1E.O g. (51% of the theoreti- cal) of crude product as a brown solid melting at 117-118°C. Three recrystallizations of a small sample from 50 per cent aqueous ethanol raised the melting point to 125-125.50c. Analysis: Calculated for C16H25N302: C, 65.95; H, 8.65; N, 1E.E2. Found: C, 65.78; H, 8.7E; N, 1E.28. 6-Methoxy-2-methyl-1-(fi-piperidinoethy1)benzimidazole dimethiodide One and four-tenths grams of 2—acetamido-5-methoxy-N-(B-piperidino- ethyl)aniline was heated under reflux in 50 ml. of xylene for seven days. Evaporation of the xylene left a small amount of residue con- sisting of a dark yellow oil. This oil was dissolved in 15 ml. of methyl iodide, and the solution was heated on a steam-bath until the excess methyl iodide had evaporated. The gray, ctystalline residue ‘was recrystallized twice from absolute ethanol (Norite). The SE dimethiodide separated as colorless needles melting at 2E7-2E9°C. with decomposition. A mixture melting point of this material and a sample of the same compound prepared for analysis by a different method showed no depression. 1-(B-Dimethylaminoethyl)—6-methoxye2-methylbenzimidazole Fifty grams (0.2E mole) of E-acetamido-3-nitroanisole was dissolved in 250 ml. of warm dioxane, Raney nickel catalyst was added,and the mix- ture was subjected to hydrogenation at an initial hydrogen pressure of 55 p.s.i. at room temperature. Meanwhile, 5.5 g. (0.2E gram-atom) of sodium was dissolved in 150 m1. of absolute ethanol. To this solution was added 3E.3 g. (0.2E mole) of N—B-Chloroethyldimethylamine hydrochlor- ide. The sodium chloride which formed was removed by filtering the so- lution with suction. The filter cake was washed with 20 ml. of ethanol. To the dioxane suspension of E-acetamido-3—aminoanisole was added the ethanolic solution of N-B-chloroethyldimethylamine. The resulting mix- ture was concentrated by distillation to a volume of about 250 ml. This mixture was then refluxed.with stirring in an oil-bath at 105-1lO°C. for ten hours. While the temperature of the oil-bath was raised to 135- lEO°C., all but about 50 m1. of the solvent was removed by distillation. Refluxing with stirring was then continued at this temperature for eight hours. The hot reaction mixture was dissolved in 250 m1. of warm water and then cooled. The Raney nickel catalyst was removed by filtering the solution with suction. The aqueous solution was extracted with diethyl ether in two 100 m1. portions to remove any unchanged.N—B-chloroethyldi- methylamine. The aqueous solution was then made distinctly alkaline by the addition of 10N potassium hydroxide solution. The product was obtain- ed by extracting the alkaline solutinn with E50 m1. of benzene in several portions. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed 12 vacuo on a steamebath. Distillation of the residue in a vacuum gave the product as a yellow, viscous oil boiling at 170- 1800c./0.06 mm. in a yield of 19.7 g. (35.5% of the theoretical). 55 Since this compound was characterized by the following derivatives, it was not analyzed as the free base. 1-(B-Dimethylaminoethyl)-6-methoxy-2-methy1benzimidazole dimethiodide Five-tenths gram of the free base was dissolved in 10 m1. of methyl iodide. The solution was warmed on a steam-bath until the excess methyl iodide had evaporated. The colorless residue was dissolved in the min- imum amount of boiling absolute ethanol (Norite). The filtered solution was diluted.with anhydrous diethyl ether until turbid and then chilled thoroughly. A second purification gave the dimethiodide as colorless needles melting at 238.5-2EO°C. with decomposition. Analysis: Calculated for C15H25IZN30: C, 3E.83; H, E.87; I, E9.08; N, 8.13. Found: C, 311.65; H, 5.07; I, 18.91; N, 8.26. 1-(B-Dimethylamdnoethyl)-6-methoxy-2-methylbenzimidazole dihydrochloride Twenty-two grams (0.09 mole) of the free base was dissolved in 700 m1. of anhydrous diethyl ether. The cold ethereal solution was saturated with dry hydrogen chloride. The colorless precipitate was filtered rapidly with suction, and was dissolved in about 1 l. of warm absolute isopropyl alcohol. Dilution of the alcoholic solution with anhydrous diethyl ether until turbid followed.by chilling gave the dihydrochloride as short, faintly pink needles melting at 225—227°C. with decomposition in a yield of 16.5 g. (57.1% of the theor- etical). Two additional purifications of a small sample gave the product as short, pink needles melting at 226-227°C. with decomposition. Analysis: Calculated for C13H21C12N30: C, 50.98; H, 6.91; C1, 23.16; N, 13.72. Found: c, 51.00; H, 7.17; c1, 23.01;; N, 13.6E. 56 6—Methoxy-2-methyl-la(fijpyrrolidinoethy1)benzimidazole Forty grams (0.19 mole) of E-acetamido-3-nitroanisole was dissolved in 250 m1. of dioxane, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. After the theoretical amount of hydrogen had.been taken up, the catalyst was removed by filtration with suction. Meanwhile, E.E g. (0.19 gram-atom) of sodium was dissolved in 150 m1. of absolute ethanol. To this solution was added 32.3 g. (0.19 mole) of N-B-chloroethylpyrrolidine hydrochloride. The sodium chloride which formed was removed by filtration with suction, and the filter cake was washed with 20 m1. of ethanol. The N-B—chloroethylpyrrolidine solution was added to the above dioxane solution of E—acetamido-3—amino- anisole. The resulting solution was refluxed with stirring in an oil- bath at 105-110°C. for ten hours. While the temperature of the oil- bath was being raised to l35-1E0°C., all but about 50 m1. of the sol- vent was removed by distillation. The resulting solution was refluxed with stirring at this temperature for ten hours. The solution was then diluted with 150 m1. of hot water and cooled. Extraction of the aqueous solution with diethyl ether in two 50 ml. portions removed any un- changed.N—B—chloroethylpyrrolidine. After making the aqueous solution distinctly alkaline with EN sodium hydroxide solution, the product was obtained by extracting the alkaline solution with E00 ml. of benzene in several portions. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed 12.23222 on a steamebath. Dis— tillation of the residue in a vacuum gave the product as a pale yellow, viscous oil boiling at l90-195°C./0.08 mm. in a yield of 20.2 9. (E1% of the theoretical). 0n standing in the cbld this material ctystallized.partia1ly. 57 Since this compound was characterized by the following derivatives, it was not analyzed as the free base. 6-Methoxy-2vmethyl-l-(figpyrrolidinoethyl)benzimidazole dimethiodide The dimethiodide, which was prepared and purified as described on page 55, was obtained as colorless needles melting at 2E6-2E7°C. with decomposition. Analysis: Calculated for C17H27IZN30: I, E6.72; N, 7.73. Found: 1, E6.73; N, 7.86. 6-Methoxy-2-methyl—l-(B-pyrrolidinoethyl)benzimidazole dihydrochloride Twenty and two-tenths grams (0.08 mole) of the free base was dis- solved in 500 m1. of anhydrous diethyl ether. The cold ethereal solu- tion was saturated with dry hydrogen chloride. The colorless precipi- tate was filtered rapidly with suction and was dissolved in the minimum amount of isopropyl alcohol. The alcoholic solution was diluted with anhydrous diethyl ether until turbid and then was chilled thoroughly. The dihydrochloride separated as a faintly tan powder melting at 238- 239°C. with decomposition in a yield of 1E.8 g. (57% of the theoretical). Two additional purifications of a small sample gave the dihydrochloride as short, colorless needles melting at 2E0.5-2E1°C. with decomposition. Analysis: Calculated for C15H23C12N30: C, 5E.22; H, 6.98; C1, 21.311; N, 12.65. Found: C, 51:02; H, 7.13; Cl, 21.13; N, 12.59. 6-Me thoxy-2-me thLl- 1—(g-morpho1inoe thyl )benzimidazole Sixty-three and one-tenth grams (0.30 mole) of E-acetamido—3- nitroanisole was partially dissolved in 250 m1. of absolute ethanol, Raney nickel catalyst was added, and the mixture was subjected to 58 hydrogenation at an initial hydrogen pressure of 60 p.s.i. at 60°C. After the uptake of the theoretical amount of hydrogen, the E—acetamido— 3-aminoanisole was dissolved in l l. of hot absolute ethanol, and the solution was filtered to remove the catalyst. The ethanol solution was then concentrated.tg 23229 on a warm water bath to a volume of about 100 m1. Meanwhile, 7.E g. (0.32 gram-atom) of sodium was dissolved in 200 m1. of absolute ethanol. To this solution was added 58.9 g. (0.32 mole) of N-B-chloroethylmorpholine hydrochloride. The mixture was filtered with suction to remove sodium chloride, and the filter cake was washed with 50 ml. of ethanol. The combined filtrate and washing containing N-B-chloroethylmorpholine was added to the E-acetamido-3— aminoanisole, and the resulting mixture refluxed with stirring in an oil-bath at 100°C. for 15 hours. All but about 50 ml. of the ethanol was then removed by distillation, and the remaining mixture was heated under reflux with stirring for eight hours at an oil-bath temperature of 135-1E0°C. After cooling the mixture, it was dissolved in 200 m1. of warm water, and extracted with two 50 ml. portions of diethyl ether to remove any unchanged.N-B-chloroethylmorpholine. The aqueous solu- tion was then made distinctly alkaline with 10N sodium hydroxide solu- tion. The product was obtained by extracting the alkaline solution with benzene in several portions totaling 900 ml. .After drying the extracts over anhydrous sodium sulfate, the benzene was removed it ygggg on a steam-bath. Distillation of the residue in a vacuum gave the product as a viscous, yellow oil boiling at 185-2100C./0.O7mm. in a yield of 20.8 g. (25.2% of the theoretical). 0n standing in the cold this material solidified to a pale yellow, waxy solid. 59 Since this compound.was characterized by the following derivatives, it was not analyzed as the free base. 6-Methoxy—2—methy1-l-(B-morpholinoethyl)benzimidazole dimethiodide The dimethiodide, which was prepared and purified according to the procedure described on page 55, was obtained as colorless needles melt- ing at 215-216°C. with decomposition. Analysis: Calculated for C17H27IZN302: C, 36.51; H, E.87; 1, 15.39: N, 7.51. Found: C, 36.31; H, 5.16; 1, 15.31; N, 7.39. 6-Methoxy-2-methy1-l—(B-morpholinoethyl)benzimidazole dihydrochloride Fourteen and five-tenths grams (0.05 mole) of the free base was dissolved in 700 m1. of anhydrous diethyl ether. The cold ethereal solution was saturated with dby hydrogen chloride. The colorless pre— cipitate which formed was filtered rapidly with suction and.was dis- solved in the minimum amount of absolute ethanol at room temperature. The alcoholic solution was diluted with anhydrous diethyl ether until turbid and then chilled thoroughly. The dihydrochloride separated as pink needles melting at 232~23E°C. with decomposition in a yield of 12.1 g. (65.7% of the theoretical). Three additional purifications of a small sample raised the melting point to 236.5-237.5°C. with decompo- sition. Analysis: Calculated for C15H23C12N302: C, 51.73; H, 6.66; C1, 20.36; N, 12.07. Found: C, 51.53; H, 6.95; C1, 20.05; N, 12.18. 1-(B-Diethy1aminoethyl)-6-methoxy-2-methy1benzimidazole Sixty—three and one-tenth grams (0.30 mole) of E-acetamido—3-nitro- anisole was partially dissolved in 250 m1. of absolute ethanol, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation 60 at an initial hydrogen pressure of 60 p.s.i. at 60°C. After the theor- etical amount of hydrogen had been taken up, the reaction mixture was diluted to l 1. with boiling absolute ethanol and filtered to remove the catalyst. The alcoholic solution of E-acetamido—3-aminoanisole was then concentrated.ig'!gggg on a warm water bath to a volume of about 100 m1. Meanwhile, 7.6 g. (0.33 gram-atom) of sodium was dissolved in 250 m1. of absolute ethanol. To this solution was added E7.5 g. (0.33 mole) of N-B-chloroethyldiethylamine hydrochloride. The sodium chloride that formed.was removed by filtration with suction and the filter cake washed with 50 m1. of cold ethanol. The alcoholic filtrate and washing containing Nffi~chloroethyldiethylamine were added to the alcoholic suspension of E-acetamido-3—aminoanisole. The resulting mixture was heated under reflux with stirring in an oil—bath at 100°C. for 15 hours. All but about 50 m1. of the solvent was removed by distillation after which heating under reflux with stirring was continued for ten hours at an oil-bath temperature of 1E0-1E50C. The cooled reaction mixture was diluted with 250 m1. of warm water. Extraction of the aqueous solution with diethyl ether in two 100 m1. portions removed the unchanged.N-B— chloroethyldiethylamine. The aqueous solution was made distinctly alkaline by the addition of 10N sodium hydroxide solution. The product was separated by extracting the alkaline solution with 700 ml. of hen- zene in several portions. After dnying the extracts over anhydrous sodium sulfate, the benzene was removed 12 22232 on a steam-bath. Dis- tillation of the residue in a vacuum gave the product as a viscous, golden oil boiling at 185—2000c./0.07 mm. in a yield of 22.6 g. (28.9% of the theoretical). Since this compound.was characterized by the following derivatives, it was not analyzed as the free base. 61 l-(fi-Diethylaminoethyl)-6-methoxy:2-methylbenzimidazole dimethiodide The dimethiodide, which was prepared according to the procedure described on page 55, was obtained as short, colorless needles melting at 236.5-2370C. with decomposition. Analysis: Calculated for C17H2912N30: C, 37.b5; H, 5.36; 1, E6.55; N, 7 71. Found: C, 37.E9; H, 5.65; 1, E6.23; N, 7.93. l-(fi-Diethylaminoethyl)-6-methoxy-2-methylbenzimidazole dihydrochloride Twenty-one and five-tenths grams (0.08 mole) of the free base was dissolved in 500 m1. of anhydrous diethyl ether. The cold ethereal so- lution was saturated with dry hydrogen chloride. The colorless precip— itate was isolated by filtering the mixture rapidly with suction. The filter cake was dissolved in the minimum amount of absolute ethanol at room temperature. The alcoholic solution was diluted with anhydrous diethyl ether until turbid, and then Chilled thoroughly. The dihydro- chloride separated as colorless needles melting at 225-227°C. with de- composition in a yield of 1E.0 g. (51% of the theoretical). Three additional purifications of a small sample in a similar manner gave the dihydrochloride as short, pink needles melting at 227-228°C. with de- composition. Analysis: Calculated for C15H25C12N30: C, 53.89; H, 7.5E; Cl, 21.21; N, 12.57. Found: C, 53.66; H, 7.63; Cl, 21.00; N, 12.51. 6-Methoxy-2-methy1-1-(B-piperidinoethyl)benzimidazole Thirty-two and two-tenths grams (0.18 mole) of N-B-chloroethyl- piperidine hydrochloride was added to 9.5 g. (0.18 gram-atom) of sodium methylate in 200 ml. of absolute ethanol. The mixture was filtered with suction to remove sodium chloride and the filter cake was washed 62 with 50 ml. of ethanol. To the combined filtrate and washing was added 30.0 g. (0.17 mole) of E—acetamido-3-aminoanisole. The resulting mix- ture was refluxed.with stirring in an oil-bath at 110-115°C. for ten hours. All but approximately 50 m1. of the solvent was then removed by distillation while the temperature of the oil-bath was raised to 135-1E0°C. Refluxing with stirring was continued at this temperature for eight hours. After cooling the reaction mixture and diluting with 250 m1. of hot water to dissolve all solids, the unchanged.N-B-chloro— ethylpiperidine was removed by extraction with two 50 m1. portions of diethyl ether. After making the aqueous solution distinctly alkaline with EN sodium hydroxide solution, the product was obtained by extract- ing the alkaline solution with benzene in several portions totaling 800 ml. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed.tg'ygggg on a steam-bath. Distillation of the residue in a vacuum gave the product as a viscous, yellow oil boiling at 196-216°C./0.E mm. in a yield of 8.0 g. (17.5% of the theor- etical). On standing in the cold this material crystallized partially. This compound was characterized by the following derivatives; it was not analyzed as the free base. 6-Methoxy-2-methyl—l-(fi-piperidinoethyl)benzimidazole dimethiodide The dimethiodide, which was prepared according to the procedure described on page 55, was obtained.as Colorless needles melting at 2E8.5-250°C. with decomposition after three recrystallizations from absolute ethanol. Analysis: Calculated for CIBHZQIZNSO: C, 38.80; H, 5.2E; I, E5.55; N, 7.5E. Found: C, 38.51; H, 5.36; I, E5.27; N, 7.3E. 63 6—Methoxy-2~methy1-l-(fi-piperidinoethyl)benzimidazole dihydrochloride Nineteen grams (0.07 mole) of the free base was dissolved in 500 m1. of anhydrous diether ether and the chilled solution saturated with dry hydrogen chloride. The colorless precipitate was purified three times by dissolving in the minimum amount of hot absolute ethanol (Norite). After filtering, the solution was diluted with anhydrous diethyl ether until turbid and then chilled thoroughly. The yield of dihydrochloride as short, pink needles melting at 235.5-236.5°C. with decomposition was 13.9 g. (57.5% of the theoretical). Analysis: Calculated for C16H25C12N30: C, 55.b9; H, 7.28; C1, 20.E8; N, 12.13. Found: C, 53.7E, 53.E8; H, 7.02, 7.09; C1, 20.6E; N, 11.91. The analysis of two additional samples failed to improve the carbon value although the chlorine and nitrogen values were in agreement with the calculated values. PART II. B. 1—(fi-DIALKYLAMINOETHYL)—6-METHOXYBENZIMIDAZOLES DISCUSSION The preparation of E—formamide-3-nitroanisole, required as an intermediate for the synthesis of this group of benzimidazoles, was best achieved by direct formylation of E-methoxy-2-nitroaniline with anhydrous formic acid. The yields obtained by this method.were 80 per cent of the theoretical or better. All attempts to obtain the desired amide from p-anisidine by successive formylation and nitration were unsuccessful. Subsequent reactions of E-formamido-3-nitroanisole leading to the preparation of the benzimidazoles in this series were achieved in much the same manner as described in the previous section for the prepara- tion of 1-(B-dialkylaminoethyl)-6-methoxy-2—methylbenzimidazoles. The l-(B-dialkylaminoethyl)-6-methoxybenzimidazoles were obtained by distillation in a vacuum as golden—yellow, viscous oils boiling at slightly higher temperatures than the corresponding 1,5-disubstituted isomers. The benzimidazoles were characterized as dipicrates and as dihydro- chlorides. The dihydrochlorides were prepared for evaluation of physiological and pharmacological actions of the compounds. Little difficulty was en- countered during their preparation and purification. A brief discus— sion of their infrared and of their ultraviolet absorption Spectra is given in the appendix. EXPERIMENTAL E-Formamido-3-nitroanisole Seventy-five grams (O.E5 mole) of E-amino-3-nitroanisole was dis~ solved in 300 m1. of anhydrous formic acid (boiling point 101-103°C.). The resulting solution was boiled under reflux with stirring for 2E hours. The mixture was poured over 300 g. of ice, diluted to approxi- mately 1.5 1. with water, and allowed to stand in an ice-bath for three hours to complete the precipitation of the amide. The product was filtered with suction and washed with 300 ml. of cold water to remove traces of formic acid. After air drying, an average yield of 85.8 g. of crude product was obtained as a light tan powder. This material was recrystallized from 2 1. of boiling 70 per cent aqueous ethanol (Norite) giving an average of 69.9 g. (80% of the theoretical) of product as golden-yellow platelets melting at 1E5-1E8°C. Repeated recrystallizations of a small sample raised the melting point to 1E9- 150°C. Knunyants and Benevelenskaya (2E) report this compound to melt at 150-1510C. 3-Amino-E—formamidoanisole Thirty-six grams (0.18 mole) of E-formamido—3-nitroanisole was added in small portions, over a period of one-half hour, to a vigor- ously stirred mixture of 110 g. of E0 mesh iron filings, 15 g. of sodium Chloride, and 300 m1. of water at 90°C. After completing the addition, the mixture was stirred for an additional two hours at 90°C. The hot reaction mixture was filtered rapidly with suction through a preheated 21 cm. BEChner funnel, and the filter cake was washed with 150 m1. of boiling water. 0n chilling the solution to 0°C. and filtering with 66 suction, an average yield of 18.2 g. (60% of the theoretical) of product was obtained as a gray solid melting at 136-138°C. Two recrystalliza- tions of a small sample from hot water (Norite) gave the product as colorless needles melting at 139.5—1E0.5°C. Analysis: Calculated for CeHloNZOZ‘ C, 57.82; H, 6.06; N, 16.86. Found: C, 57.81; H, 6.20; N, 16.61. 1-(fi-Dimethylaminoethyl)-6-methqubenzimidazole Fifteen grams of E-formamido-3-nitroanisole was dissolved in 250 m1. of dioxane, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. After the theoretical amount of hydrogen had been taken up, the catalyst was removed by filtration with suction. The resulting solution was evaporated to dryness £2.XEEES on a warm water-bath. A total of E5.0 g. (0.23 mole) of E-formamido-3-nitro- anisole was reduced in this manner. Meanwhile, 5.5 g. (0.2E gram—atom) of sodium was dissolved in 150 m1. of absolute ethanol. After adding 3E.3 g. (0.2E mole) of N-p-chloroethyldimethylamine hydrochloride, the sodium chloride which formed was removed by filtration with suction and 'washed with 50 m1. of ethanol. The alcoholic solution of’N-fi-chloro- ethyldimethylamine was added to the combined 3-amino-E-formamidoanisole solution, and the resulting mixture was refluxed.with stirring in an oil-bath at 105-110°C. for ten hours. After removing all but about 50 m1. of the solvent by distillation, the mixture was refluxed with stirring in an oil-bath at l35-1E0°C. for eleven hours. The reaction mixture was dissolved in 250 ml. of warm water and cooled. Extraction with two 100 ml. portions of diethyl ether removed any unchanged 6? N-fi-chloroethyldimethylamine. After making the solution distinctly alkaline by the addition of 10N sodium hydroxide solution, the product was obtained by extracting the alkaline solution with benzene in several protions totaling 700 ml. The extracts were dried over anhydrous sodium sulfate, and the benzene was removed.ig'tgggg on a steam-bath. Distil- lation of the residue in a vacuum gave the product as a yellow, viscous oil boiling over the range 1E0—1600c./0.05 mm. in a yield of 17.2 g. (33.2% of the theoretical). Since this compound was characterized by the following derivatives, it was not analyzed as the free base. 1-(B-Dimethylaminoethyl)-6—methoxybenzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and was recrystal- lized three times from glacial acetic acid.(Norite) from which it separated as long, yellow needles melting at 217-219°C. with decomposi- tion. Analysis: Calculated for C24H23N9015: C, E2.5E; H, 3.E2; N, 18.62. Found: C, E2.7S; H, 3.68; N, 18.38. 1-(B-Dimethylaminoethyl)-6-methoxybenzimidazole dihydrochloride Twenty-one and seven-tenths grams (0.1 mole) of the free base was dissolved in 500 m1. of anhydrous diethyl ether. The cold ethereal solution was saturated with dry hydrogen chloride. The colorless pre- cipitate was filtered rapidly with suction and dissolved in the minimum amount of warm absolute ethanol. The alcoholic solution was diluted with anhydrous diethyl ether until turbid and then chilled thoroughly. The dihydrochloride separated as a colorless powder melting at 221-223°C. with decomposition in a yield of 13.5 g. (E6.7% of the theoretical). 68 Two similar additional purifications of a small sample raised the melt- ing point to 222-2230C. with decomposition. Analysis: Calculated for C12H19C12N30: C, E9.32; H, 6.55; Cl, 2E.27; N, 1E.38. Found: C, E9.l6; H, 6.81; Cl, 2E.32; N, 1E.18. 6—Methoxy;1-( -pyrrolidinoethyl)benzimidazole Twenty-nine and four-tenths grams (0.15 mole) of E-formamido-3- nitroanisole was dissolved in 200 m1. of hot absolute ethanol, Raney nickel catalyst was added and the mixture subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at 60°C. After the theor- etical uptake of hydrogen, the hot reaction mixture was filtered with suction to remove the catalyst, and the filter cake was washed with 100 m1. of boiling absolute ethanol. To this filtrate was added an alcoholic solution of N—B-chloroethylpyrrolidine, which was prepared by adding 30.6 g. (0.18 mole) of N-B-chloroethylpyrrolidine hydrochloride to a solution of E.1 g. (0.18 gram-atom) of sodium in 100 ml. of abso- lute ethanol and filtering to remove the precipitated sodium chloride. The reaction mixture was then refluxed with stirring in an oil-bath at 100°C. for 12 hours. After distilling all but 50 m1. of the ethanol, the temperature of the oil—bath was raised to 135-1EO°C. and maintained at this point for eight hours. The cooled reaction mixture was dissolved in 250 m1. of hot water and extracted with two 100 ml. portions of diethyl ether to remove any unchanged.N-B-chloroethylpyrrolidine. The aqueous solution was made alkaline by the addition of 200 m1. of EN sodium hydroxide solution, and the product was obtained by extracting the alkaline solution with E00 m1. of benzene in several portions. The extracts were dried over Drierite, and the benzene removed lg vacuo 69 on a steam-bath. Distillation of the residue in a vacuum gave 1E.1 g. (38.3% of the theoretical) of product as a pale yellow, slightly vis- cous oil boiling over the range 171-1900C./O.05 mm. This compound was characterized by the following derivatives; it was not analyzed as the free base. 6-Hethoxy-lfikpyrrolidinoethyl ) benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and.was recrystal- lized five times from glacial acetic acid (Darco) from.which it separ- ated as bright yellow platelets melting at 216—217°C. with decomposi- tion. Analysis: Calculated for C26H25N9015: C, EE.38; H, 3.58; N, 17.92. Found: C, EE.55; H, 3.8E; N, 17.91. 6-Methoxy—l-(fi—pyrrolidinoethyl)benzimidazole dihydrochloride Fourteen and five-tenths grams (0.06 mole) of the free base was dissolved in 600 m1. of anhydrous diethyl ether. Saturation of the cold ethereal solution with dry hydrogen chloride precipitated the colorless product which was purified twice by dissolving in the minimum amount of hot absolute ethanol (Darco), filtering the solution, and diluting the filtrate with anhydrous diethyl ether until turbid. After thoroughly chilling the suSpension, the product was obtained as a colorless pow— der melting at 22E-225.5°C. with decomposition in a yield of 11.3 g. (60% of the theoretical). Analysis: Calculated for C14H21C12N30: c, 52.53; H, 6.65; c1, 22.28; N, 13.20. Found: C, 52.6E; H, 6.61; c1, 22.N0; N, 13.22. 70 6-Methoxy-1-(fi-morpholinoethyl)benzimidazole To 26.8 g. (0.16 mole) of 3—amino-E-formamidoanisole was added 26.0 g. (0.17 mole) of N-B-chloroethylmorpholine, the latter obtained by liberation of the free base from its hydrochloride, and 5 m1. of absolute ethanol. The mixture was heated under reflux with stirring in an oil-bath at 112—115°C. for four hours, and for 17.5 hours at l35-1EO°C. After cooling, 100 m1. of hot water was added, and the solution extracted with three 100 ml. portions of diethyl ether to re- move any unchanged.N-B-chloroethylmorpholine. After making the aqueous solution alkaline by the addition of 200 m1. of EN sodium hydroxide solution, the product was obtained by extracting the alkaline solution with benzene in several portions totaling 600 ml. Drying of the ex- tracts over Drierite followed by removal of the benzene $2 X2222 on a steam-bath left a residue which was distilled in a vacuum. The product was obtained as a light yellow, viscous oil, which solidified partially, boiling over the range 215-230°C./O.3 mm. in a yield of 21.0 g. (50.3% of the theoretical). This compound was characterized by the following derivatives; it was not analyzed as the free base. 6-Methoxy-1-(fl-morpholinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and was recrystal- lized three times from glacial acetic acid (Norite) from which it sep— arated as a yellow powder melting at 203.5-205°C. with decomposition. Analysis: Calculated for C25H25N9016: C, E3.E0; H, 3.50; N, 17.52. Found: C, E3.62; H, 3.62; N, 17.E8. 71 6-Methoxy-1—(B—morpholinoethyl)benzimidazole dihydrochloride The dihydrochloride was prepared by dissolving 20.0 g. (0.08 mole) of the free base in cold anhydrous diethyl ether and saturating the ethereal solution with dry hydrogen chloride. The colorless precipi- tate was purified by dissolving in the minimum amount of hot absolute ethanol (Norite), filtering the solution, and diluting the filtrate with anhydrous diethyl ether until turbid followed by thorough chilling. Two similar purifications gave 1E.8 g. (57.8% of the theoretical) of product as colorless needles melting at 256.5-257.5°C. with decomposi- tion. Analysis: Calculated for C14H21C12N302: C, 50.30; H, 6.333 C1, 21.22; N, 12.57. Found: C, 50.11; H, 6.51; Cl, 21.06; N, 12.63. l-(fi-Diethylaminoethyl)-6—methoxybenzimidazole Fifteen grams of E-formamido-3-nitroanisole was dissolved in 250 ml. of dioxane, Raney nickel catalyst was added, and the mixture was subjected to hydrogenation at an initial hydrogen pressure of 50 p.s.i. at room temperature. After the uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration with suction. The dioxane was removed.tg 23222 on a warm water bath. A total of E5 9. (0.30 mole) of E-formamido-3-nitroanisole was reduced in this manner. Meanwhile, 7.E g. (0.32 gram—atom) of sodium was dissolved in 200 ml. of absolute ethanol. To this solution was added 55.0 g. (0.32 mole) of N-B-chloroethyldiethylamine hydrochloride. This mixture was filtered with suction to remove sodium chloride, and the filter cake was washed with 50 m1. of cold absolute ethanol. The alcoholic solution of N-B- chloroethyldiethylamine was added to the above 3-amino-E-formamidoanisole. The resulting mixture was refluxed with stirring in an oil-bath at 72 105-110°C. for ten hours. All but about 50 m1. of the solvent was removed by distillation. Refluxing with stirring of the residual mater— ial was then continued for ten hours at an oil-bath temperature of 130-135°C. The cooled reaction mixture was diluted with 250 ml. of warm water. Extraction with two 50 ml. portions of diethyl ether re- moved the unchanged.N-B-chloroethyldiethylamine. The aqueous solution was made distinctly alkaline by the addition of EN potassium hydroxide solution. The product was obtained by extracting the alkaline solution with benzene in several portions totaling 600 ml. After drying the ex- tracts over anhydrous sodium sulfate, the benzene was removed £2.X§EEE on a steam-bath. Distillation of the residue in a vacuum gave the product as a golden-yellow oil boiling at 150-170°C./0.05 mm. in a yield of 13.6 g. (2E.l% of the theoretical). Since this compound was characterized by the following derivatives, it was not analyzed as the free base. l-(fi-Diethylaminoethyl)-6-methoxybenzimidazole dlpicrate The dipicrate was formed in hot absolute ethanol and was recrystal- lized three times from 70 per cent aqueous acetone (Norite) from.which it separated as a yellow powder melting at 200-201.5°C. with decomposi- tion. Analysis: Calculated for C25H27N9015: C, EE.26; H, 3.86; N, 17.87. Found: c, EE.30; H, E.05; N, 17.67. 15(fi—Diethylaminoethyl)~6-methoxybenzimidazole dihydrochloride Thirteennand six-tenths grams (0.06 mole) of the free base was dissolved in 500 ml. of anhydrous diethyl ether. The cold ethereal solution was saturated.with dry hydrogen chloride. The colorless 73 precipitate which formed was removed by a rapid filtration with suction, and dissolved in the minimum amount of hot absolute ethanol. Dilution of the alcoholic solution with anhydrous diethyl ether until turbid, followed.by thorough chilling, gave the dihydrochloride as pale pink needles melting at 217.5-219°C. with decomposition in a yield of 16.1 g. (91.5% of the theoretical). Three similar additional purifica— tions of a small sample gave the dihydrochloride as long, colorless needles melting at 218.5-220°C. with decomposition. Analysis: Calculated for Cl4H23C12N30: C, 52.50; H, 7.2E; C1, 22.11;; N, 13.12. Found: c, 52.52; H, 7.16; c1, 22.22; N, 13.17. 6-Methoxy-l-(B-piperidinoethyl)benzimidazole Fifty grams (0.26 mole) of E—formamido-B-nitroanisole was partially dissolved in 250 m1. of absolute ethanol, Raney nickel catalyst was added, and the mixture was hydrogenated at an initial hydrogen pressure of 50 p.s.i. at 60°C. After the uptake of the theoretical amount of hydrogen, the reaction mixture was concentrated 32.33222 to about 100 m1. Meanwhile, to a solution of 6.9 g. (0.30 gram-atom) of sodium in 150 m1. of absolute ethanol was added 55.2 g. (0.30 mole) of N-B-chloroethyl- piperidine hydrochloride. The sodium chloride which formed was filtered with suction and.washed with 50 m1. of cold absolute ethanol. The alcoholic solution of N-B-ChloroethylJaiperidine was then added to the 3~amino-E-formamidoanisole mixture. The resulting mixture was refluxed with stirring in an oil—bath at 100-105°C. for 12 hours. All but about 50 m1. of the solvent was removed by distillation and the residual mixture heated under reflux with stirring for seven hours at an oil- bath temperature of lEO-1E5OC. After cooling, the reaction mixture was 7E dissolved in 250 m1. of hot water and filtered with suction to remove the nickel catalyst. Extraction of the aqueous solution with two 50 ml. portions of diethyl ether removed any unchanged'N-E-chloroethylpiper- idine. The aqueous solution was then made distinctly alkaline by the addition of EN sodium hydroxide solution, and extracted with 1.2 1. of benzene in several portions. A large amount of black tar which was insoluble in water and in benzene but soluble in ethanol was discarded. The extracts were dried over anhydrous sodium sulfate and the benzene removed.i§ X2222 on a steamrbath. Distillation of the residue in a vacuum gave 19.5 g. (29.6% of the theoretical) of product as a golden- yellow, viscous oil boiling over the range 168-18E°C./0.03 mm. 0n standing in the cold partial crystallization of the product occurred. This compound was characterized by the following derivatives; it was not analyzed as the free base. 6-Methoxy-l-(fi-piperidinoethyl)benzimidazole dipicrate The dipicrate was formed in hot absolute ethanol and was recrystal- lized three times from acetone (Norite) from which it separated as a yellow powder melting at ZOO-201°C. with decomposition. Analysis: Calculated for C27H27N9015: c, 15.19; H, 3.79; N, 17.57. Found: C, E5.E6; H, 3.98; N, 17.6E. 6-Methoxy-l-(B-piperidinoethyl)benzimidazole dihydrochloride Nineteen and five-tenths grams (0.08 mole) of the free base was dissolved in 500 ml. of anhydrous diethyl ether. Saturation of the cold ethereal solution with dry hydrogen chloride produced a colorless pre- cipitate-which was.fi1tered rapidly with suction and dissolved in 1.5 1. of absolute ethanol at room temperature. Dilution of the alcoholic 75 solution with anhydrous diethyl ether until turbid followed by thorough chilling gave the dihydrochloride as short, colorless needles melting at 2E2.5-2E3.5°c. with decomposition in a yield of 20.2 g. (81.5% of the theoretical). Analysis: Calculated for C15H23C12N30: C, 5E.22; H, 6.98; C1, 21.3u; N, 12.65. Found: C, 5E.19; H, 6.9E; Cl, 21.E3; N, 12.75. SUMMARY ' 1. By means of a four step sequence of reactions the following benz— imidazoles have been prepared from E-methoxy-2-nitroaniline: l-(E-di— methylaminoethyl)-5-methoxy-, 1-(B-dimethylaminoethyl)-5-methoxy-2—methy1-, 5~methoxy-l-(B-pyrrolidinoethyl)—, 5-methoxy-2-methy1-1f(B-pyrrolidino— ethy1)-, 5-methoxy-1—(E-morpholinoethy1)-, 5-methoxy-2-methy1-1-(B- morpholinoethy1)-, 1-(Bediethy1aminoethy1)-5-methoxy-, 1—(B-diethylamino— ethyl)-5-methoxy—2~methyl-, 5-methoxy-l~(E-piperidinoethyl)-, and 5~ methoxy-2-methyl-l-(E-piperidinoethy1)benzimidazole. 2. In addition, the corresponding 6-methoxy- isomers of the above benzimidazoles have been prepared by means of a four or five step se~ quence of reactions starting with E—methoxy-2—nitroaniline or p-anisi- dine, respectively. 3. All the benzimidazoles were characterized as dipicrates and as di- hydrochlorides. In each case sufficient dihydrochloride was prepared to permit evaluation of the physiological and pharmacological actions of these compounds. C" O\\J'L 10. 11. 12. 13. 1E. 15. 16. 17. 18. 19. 20. 21. 22. LITERATURE CITED D. N. Woolley, Science $22, 615(1959). I. H. Page, Physiol. Rev. 3t, 563(195E). I. H. Page, Physiol. Rev. 3t, 277(1958). G. P. Lewis (ed.), "5—Hydroxytryptamine", Pergamon Press, New York, 1958. W. B. Wheatley and G. F. Stiner, J. Org. Chem. g3, 923(1957). R. Foster, H. R. Ing, and E. F. Rogers, J. Chem. Soc. 3251, 1671. F. Hobrecker, Ber. 5, 920(1872). J. B. Wright, Chem. Rev. té, 397(1951). K. Hofmann, "Imidazole and Its Derivatives, Part I", Interscience, New York, 1953. A.Ladenburg, Ber. 8, 677(1875). A. M. Simonov, J. Gen. Chem.(U.S.S.R.)tO, 1588(19EO); C.A. 35, 2870(19E1). F. E. King, R. J. S. Beer, and S. G. Naley, J. Chem. Soc. 19E6, 92. G. R. Clemo and G. A. Swan, J. Chem. Soc. 19EE, 27E. R. L. McKee, M. K. McKee, and R. w. Bost, J. Am. Chem. Soc. é8, 19oh(19A6). J. B. Wright, J. Am. Chem. Soc. 1;, 2035(l9E9). H. J. Barber, F. N. Major, and W. R. Wragg, J. Chem. Soc. 19E6, 613. W. A. Lott, F. H. Bergeim, and K. A. Losee, U. S. Patent 2,E07,309, Sept. 10, 19E6; C. A. ti, PE8E(19E7). C. H. Tilford, R. S. Shelton, and M. G. vanCampen, Jr., J. Am. Chem. Soc. 19, E001(19E8). J. H. Gardner and E. 0. Haenni, J. Am. Chem. Soc. 53, 2763(1931). F. F. Blicke and c. E. Maxwell, J. Am. Chem. Soc. 95, E29(19E2). K. H. Slotta and R. Behnisch, Ber. égg, 75h(1935). G. A. C. Gough and H. King, J. Chem. Soc. 1928, 2E37. 78 23. P. E. Fanta and D. S. Tarbell, "Organic Synthesis", Coll. Vol. III, John Wiley and Sons, Inc., New York, 1955, p. 661. 2E. I. L. Knunyants and Z. V. Benevelenskaya, J. Gen. Chem. (U.S.S.R.) Z: 2E71(1937)3 C- A- £2: 2119(1938). 25. L. J. Bellamy, "The Infra-red Spectra of Complex Molecules", John Wiley and Sons, Inc., New York, 1959. APPEN DIX PART I. INFRARED ABSORPTION SPECTRA An examination of the infrared absorption spectra of the twenty benzimidazoles prepared in this investigation showed them to be quite similar as would be expected. Because of their similarities, the spectra have not been reproduced in this thesis. They were used primarily as an indication that ring closure had taken place prior to the analysis' of the benzimidazole dipicrates, dimethiodides, and dihydrochlorides. All of the spectra were determined in carbon tetrachloride solution on a Perkin—Elmer Recording Spectrophotometer, Model 21. The presence of two bands in the spectra in the range 6.05—6.12 microns and 6.5E—6.66 microns was taken as evidence for ring closure. According to Bellamy (25), a band falling in the range 6.02-6.13 microns may be attributed to the stretching vibrations of a structure containing an aromatic ring in conjugation with C=N. Such a structural unit ap- pears in the benzimidazole ring. Bellamy further states that benzothia- zoles usually give two bands in the range 6.07-6.61 microns and 6.5E- 6.79 microns. Because of structural similarities between benzothiazoles and 1-substituted benzimidazoles, one could expect them to show similar characteristic absorption bands. Since no discussion of the infrared absorption Spectra of benzimidazoles was found in the literature, two previously characterized compounds of simple structure were prepared for comparative purposes, namely, l-methyl— and 1,2-dimethy1benzimidazole. In both cases two bands were present in the ranges 6.05 microns and 6.55- 6.65 microns, reSpectively. Several other bands of interest were noted. Of the benzimidazoles 81 examined only the 2-methylbenzimidazoles contain the structural unit C—CH3 for which a band in the range 7.03-7.10 microns was present. This band was absent in the Spectra of the 2~H~benzimidazoles. The location of bands which could be ascribed to the ether func- tion was quite difficult. Bellamy states that a strong band is usually found in the range 8.70—9.E3 microns for alkyl ethers. The benzimid- azoles containing the morpholine ring showed a strong band at 8.95 microns which was absent in the spectra of the other benzimidazoles. Assignment of bands to the aromatic methoxy group was more difficult. In all of the spectra a sharp band in the range 9.57-9.70 microns was present. Bellamy states that a band of medium intensity in the range 9.35-10.0 microns could possible be connected.with vibration of the CHZ—O— residue of the molecule. Such a band was not present in the model compounds, but was present in E-methoxy-2-nitroaniline at 9.57 microns. Bellamy further assigns a strong band in the range 7.87—8.13 microns to the CH3-0-Ar group. In all of the spectra strong bands were present in the range 7.83~8.35 microns, but it was not possible to as- sign a band to this functional group. Both of the model compounds had strong bands in this range, and E-methoxy-2—nitroaniline had a strong doublet in the range 7.95-8.05 microns. PART II. ULTRAVIOLET ABSORPTION SPECTRA The ultraviolet absorption spectra of the benzimidazole dihydro- chlorides were determined in 0.01N hydrochloric acid solution using the Beckman DK—2 Recording Spectrophotometer to locate the approximate wave— length at which maximum absorption occurred. By means of the Beckman DU Spectrophotometer, the molar extinction coefficients (£5) at maximum wavelengths were determined. For convenience log 5i, along with other pertinent data, have been summarized in Tables II and III. The molar extinction coefficients were calculated according to the following equation: 5 a HIE A=Absorbance; M = molecular weight; b = cell thickness in cm., and c = concentration in g./1. A comparison of these spectra with the spectrum of benzimidazole showed two interesting features. Benzimidazole has two characteristic sharp bands, one at 267031 (c = 0.0272 g./1., log &= 3.55) and 2735101 (log 6 = 3.5E). Substitution of a methoxy group in position 5 or 6 of the benzimidazole ring causes a characteristic bathochromic shift to about 2880K, and a loss of fine structure. Only one broad band was present. TABLE II ULTRAVIOLET ABSORPTION MAXIMA OF SUBSTITUTED BENZIMIDAZOLES NCHZCHZX R '2HC1 N//’ X R cz g.(1. Anex, A _l29JEL N(CH3)2 H 0.025E 2890 3.82 N(CH3)2 CH3 0.0271 2880 3.90 NC4H8 H 0.0329 2890 3.82 NC4H8 CH3 0.02E8 2880 3.88 NCQHBO H 0.0289 2880 3.83 NC4H80 CH3 0.0239 2880 3.89 N(C2H5)2 H 0.02E3 2900 3.83 N(C2H5)2 CH3 0.02E2 2890 3.86 NC5H10 H 0.02E2 2890 3.81 NC,Hlo CH3 0.0272 2875 3.90 TABLE III 8E ULTRAVIOLET ABSORPTION MAXIMA OF SUBSTITUTED BENZIMIDAZOLES CH3 ’/// \\\ X _i_ N(CH3)2 H N(CH3)2 CH3 NC4HB H Ncha CH3 NC4H80 H NC4H80 CH3 N