A series of Schiff's bases and secondary amine derivatives from

Transcription

1 A series of Schiff's bases and secondary amine derivatives from W. KREMERS AND J. W. STEELE School of Pharmacy, University of Manitoba, Winnipeg, Manitoba Received November 8, 1966 Can. J. Chem. Downloaded from by on 04/10/18 The various recorded methods of synthesizing 10-methylphenothiazine were reviewed, and an improved process is suggested which gives consistent yields of 50-60% purified product. A series of bis-schiff's bases was prepared by condensation of 3-formyl-10-methylphenothiazine with a number of diamines, and reduction of this series yielded a corresponding series of bis-secondary amines. The secondary amines did not show an NH absorption band in the infrared spectra unless considerably higher than normal concentrations were used, but nuclear magnetic resonance studies in deuteriochloroform confirmed the existence of the -CH2NHgroup. A model compound of the same type (namely, 3-phenyliminomethylene-10-methylphenothiazine) was synthesized, and it was found to exhibit exactly the same effects in the infrared spectra and in the nuclear magnetic resonance spectra in deuteriochloroform. In dimethyl sulfoxide-ds, the model compound showed clear evidence of coupling between the NH and the adjacent methylene group, an effect which is rarely seen. Quaternization of the secondary amines was unsuccessful in all but a few cases. Canadian Journal of Chemistry. Volume 45, 745 (1967) 10-IIethylphenothiazine was required in large quantities for this study, and a number of reported syntheses were attempted and the results compared. The sodamide condensation- method (1-3) gave excellent results ( yield) provided that high-quality sodamide was used. Treatment of phenothiazine with methanol and hydrogen chloride (4) required a long reaction time and gave low yields. A consistent yield of 30-40y0 was obtainable by heating phenothiazine with dimethyl oxalate (5), but the method is again lengthy. The method of Gilman and Nelson (6) involves heating phenothiazine in dioxane with dimethyl sulfate and anhydrous sodium carbonate. The reported yield of 10-methylphenothiazine is 58770, but it was found that apparently identical experiments gave erratic yields, ranging from 0 to 80%. This latter method has been adapted as part of this work, and repeated experiments consistently gave 50-6OyO purified product. 10-Methylphenothiazine was formylated (7), and the resulting 3-formyl-10-methylphenothiazine mas condensed with a number of aliphatic and aromatic diamines to form a series of his-schiff's bases I (Table I). Of 13 diamines used, only 2,G-diaminopyridine and 3,3'-diaminodipropylamine failed to yield a characterizable product. The product from 2,2'-dimethoxy-4,4'-di- aminobiphenyl did not give satisfactory carbon analysis results and appeared to slowly decompose during recrystallization. The Schiff's bases are yellow or golden crystalline solids, with the single exception of the compound obtained from 2,2'-diaminodiethyl sulfide, which is a yellow oil. Hydrazine reacts readily with 3-formyl-10- methylphenothiazine in the ratio 1:2, to give an azine (I, R =zero). All attempts to isolate a mono-schiff's base (or hydrazone in this case) by mixing hydrazine and 3- formyl-10-methylphenothiazine in a 1:1 ratio were unsuccessful, and the only identifiable product was lo-methylphenothiazine. The elimination of the carbonyl group in these attempts is unexpected, although not unknown under similar circumstances in Wolff-Kisher reductions (8). Reduction of the his-schiff's base series with lithium aluminium hydride yielded a corresponding series of bis-secondary arnines 11, usually only slightly paler in color than the Schiff's bases. The same experimental conditions were used in all the reductions, except for variations in the reaction time (see Table 11). Compound 1 (Table I) did not give a characterizable reduction product, and cornpound 7 gave inconsistent results, low yields, and a poorly characterizable product. The bis-secondary amines I1 are crystalline solids, except for compounds

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3 Compound TABLE I1 3,3'-(Substituted-bis(iminomethylene))bis(l0-methylphenothiazines) m Calculated (%) Found (%).. Crystallization Yield Refluxing Melting point - Formula solvent* (%) time (h) ("0 C H C 2 *I. benzene; 2. dioxane. tthis compound is a straw-colored oil. The bis-acid maleate was rt.crystallized from 95y0 ethanol, m.p OC. Anal. Calcd. for C~gHaoNaO&h.: C : H Found: C : $This compound is a yellow oil. Tire dihydrochloride was recry&tallized fro'm 95% ethanol, m.p. 232 "C. Anal. Calcd. for C~ZH~ECIZN~S~.H~O: C ; H, Found: C, 58.10; 13, H 0

4 748 CANADIAN JOURNAL OF CHEMISTRY. VOL. 45, and 18 (11, R= -CH2CHnCH2- and -CH2CH~SCH2CH2-), which are liquids (characterized as the bis-acid maleate and dihydrochloride, respectively). The bis-secondary amines are not readily soluble in acid solution, but they do form salts such as hydrochloride, acetate, or maleate. The infrared spectra in solution (c, 1-2) showed no evidence of the NH group, but when much higher concentrations were used, the spectra did show a weak absorption band at p. This agrees with reports that secondary amines are sensitive to surrounding structures and may give rise to very low intensity peaks (9). lliicroanalyses and equivalent weight determinations were in good agreement with the theoretical values, and nuclear magnetic resonance spectra established that the iminomethylene grouping was definitely present. As a final check, a relatively simple model compound (111, S-phenyliminomethylene-10-methylphenothiazine) was synthesized. This model compound does not show the expected NH absorption band at p in solution spectra at normal concentrations. The nuclear magnetic resonance spectrum in deuteriochloroform sho~~~s only three peaks at higher field: a threeproton singlet at 3.26 p.p.m. (CH3) ; a oneproton broad band centered at approximately 3.67 p.p.m. (NH), which is removed by the addition of deuterium oxide; and a two-proton singlet at 4.13 p.p.m. (CH2). In dimethyl sulfoxide-ds, I11 shows peaks at 3.30 (three-proton singlet, CH,), 4.18 (twoproton doublet, J = 6 c.p.s., CH2), and 6.15 p.p.m. (one-proton triplet, J = 6 c.p.s., NH). The doublet at 4.18 and the triplet at 6.15 p.p.m. are evidence of coupling between the proton attached to the nitrogen atom and the adjacent methylene group. This coupling is only seen in dimethyl sulfoxide because this solvent slovs the exchange rate, and it is not normally seen in other solvents except in the presence of strong acids or bases (10). 'The addition of deuterium oxide in this case eliminated the NH peak and collapsed the methylene doublet signal to the expected singlet. Attempts were then made to prepare a series of bis-quaternary compounds of struc- ture IV. When R is a simple aliphatic chain, quaternization with methyl iodide works very well, but attempts to prepare the corresponding derivatives of compounds were unsuccessful. When ethyl iodide was used, even the straight-chain secondary amines did not undergo complete quaternization and only partially quaternized products were obtained. The bis-secondary amines I1 and the quaternary products were screened for pharmacological activity, but no significant effects were noted. EXPERIMESTAL Infrared spectra were determined on a Beckman IR-8 instrument. Nuclear magnetic resonance spectra were obtained on a Perkin-Elmer model R-10 or on a Varian DA-60 spectrometer, in the stated solvents. Tetramethylsilane and sodium 2,2-dimethyl-2-silapentane-5-sulfonate were used as internal reference material in deuteriochloroform and dimethyl sulfoxide solutions, respectively. 10-Methylphenothiazine Finely powdered phenothiazine (200 g, 1 mole) was heated with 132 g of dimethyl sulfate (1.05 moles) until the phenothiazine dissolved (20-30 min). After the mixture was cooled, a slight excess of 20% sodium hydroxide solution was added and the mixture was heated for a further 15 min. The aqueous layer was run off, the residue was exhaustively extracted with benzene, and the combined benzene extracts were dried (anhydrous sodium sulfate). Benzene-insoluble matter was discarded. Chromatography of the coilcentrated benzene solution on an alumina column (2.5 X 20 cm), followed by recrystallization from ethanol (95%), gave 10-methylphenothiazine, m.p ". The yield was consistently between 50 and 60% for a number of experiments. Bis-Schiff's Bases The diailline (0.1 mole) was refluxed with 10- methyl-3-formylphenothiazine (0.2 mole) in 125 rnl of ethanol (9570) for 2 h. The precipitated Schiff's bases were filtered off, washed with ethanol, and

5 KREMERS AND STEELE: 3-FORMYL-10-METHYLPHEXOTHIAZINE DERIVATIVES 749 Can. J. Chem. Downloaded from by on 04/10/18 recrystallized. See Table I: compound 1, 3,3'- (bis(nitrilomethylidyne)) bis (lo-methylphenothiazine) ; compound 2, 3,3'-(ethylenebis(nitri10- methylidyne))bis(lo-methylphenothiazine) ; compound 3, 3,3'-(trimethylenebis(nitrilomethy1idyne))- bis(l0-inethylphenothiazine) ; compound 4, 3,3'- (hexalnethylenebis (nitrilomethylidyne)) bis (10- methylphenothiazine) ; compound 5, 3,3'- (decamethylenebis(nitrilomethylidyne))bis(lo-methylphenothiazine) ; compound 6, 3,3'-(p-phenylenebis(nitrilomethylidyne))bis(lO-methylphenothiazine) ; compound 7, 3,3'-(m-phenylenebis(nitrilomethylidyne))bis(lO-methylphenothiazi) ; compound 8, 3,3'-(4,4'-biphenylenebis(nitrilomethy1idyne))bis(lO-methylphenothiazine) ; compound 9, 3,3'- (methylenebis(p-phenylenenitrilomethylidyne))bis(lo-methylphenothiazine) ; and compound 10, 3,3'-(thiabis(ethylenenitrilomethylidyne))bis(lOmethylphenothiazine). Bis-Secondary Amines The Schiff's bases (0.1 mole) were added to lithium aluminium hvdride (0.05 mole) in anhvdrous dioxane (500 ml) and refluxed for the timesstated in Table 11. After the addition of a few milliliters of water, the reaction mixture was filtered and the solvent was removed from the combined filtrate and washings. The residue was crystallized from the stated solvent. See Table 11: compound 11, 3,3'- (ethylenebis (iminomethylene)) bis (10-methylphenothiazine) ; compound 12, 3,3'-(trimethylenebis (iminomethylene)) bis(l0-methylphenothiazine) ; compound 13, 3,3'-(hexamethylenebis(imin0- methylene))bis(lo-methylphenothiazine); compound 14, 3,3'-(decainethyknebis(iminomethylene))bis(lOmethylphenothiazine) ; compound 15,3,3'-(p-phenylenebis (iminomethylene)) bis(l0-methylphenothiazine) ; compound 16, 3,3'-(4,4'-biphenylenebis- (iminornethylene)) bis (10- methylphenothiazine) ; compound 17,3,3'-(methylenebis(p-phenyleneiminomethylene))bis(lO-methylphenothiazine) ; and compound 18, 3,3'-(thiabis(ethyleneiminomethy1ene))- bis(l0-methylphenothiazine). Bis-Quaternary Products The amine was dissolved in anhydrous benzene, mixed with an excess of alkyl iodide, and left overnight. The precipitated solid was then filtered off and recrystallized from aqueous dimethylformamide. Trimethylenebis (dimethyl((10- methylphenothiazin - 3-y1)methyl)ammonium iodide) (IV, R = -(CHz)a-, R' = CH3).-'4 buff solid, m.p. 199' (decomp.). Anal. Calcd. for C~SH~ZN~S~I~: C, 50.24; H, Found: C, 50.63; H, Hexanzethylenebis (dimethyl ((10-methylphenothiazin-3-y1)methyl)ammoniunz iodide) (IV, R = -(CH2)6-, R' = CH3).-A buff solid, m.p. 202' (decomp.). Anal. Calcd. for C ~~H~~N~SZIZ: C, 51.93; H, Found: C, 51.78; H, Decamethylenebis(dimethyl((l0-methylphenothiazin-3-yl)nzethyl)ammoniunz iodide) (IV, R = -(CH2)1o-, R' = CHa).-A buff solid, m.p. 179' (decomp.). Anal. Calcd. for C ~~HS~N~SZI~: C, 53.95; H, Found: C, 53.57; H, Phenylnitrilomethylidyne-10-methylphenothiazine Aniline (9.3 g) was refluxed with 3-formyl-10- methylphenothiazine (24.1 g) in 150 ml of 95y0 ethanol for 2 h. The solvent was evaporated and the resulting yellow oil (87% yield) was not purified further. 3-Phenylinzinomethylene-10-methylphenothiazine Lithium aluminium hydride (0.1 g) was refluxed with 3.2 g of 3-phenylnitrilomethylidyne-10-methylphenothiazine in dry ether (75 ml) for 13 h. The reaction mixture was then worked up in the usual manner to yield colorless crystals (8lY0), m.p , after recrystallization from ethanol. Anal. Calcd. for CZOHI~~\T~S: C, 75.43; H, 5.70; N,8.80.Found: C,75.27;H,5.87;N,8.83. ACKNOWLEDGMENTS The authors are grateful to the Chemistry Department, University of Manitoba, and to Mr. G. McDonough, School of Pharmacy, Chelsea College of Science and Technology, London, England, for the nuclear magnetic resonance spectra. J. W. S. is also grateful for financial support from the National Research Council of Canada and for grants to support this project from the Canadian Foundation for the Advancement of Pharmacy. REFERENCES 1. A. BURGER and A. C. SCHIXUZ. J. Org. Chem. 19, 1841 (1954). 2. W. A. SCHULER and H. KLEBE. Ger. Patent No. 1,014,544 (August 1957); Chem. Abstr. 53, (1959). 3. W. A. SCHULER and H. KLEBE. Ger. Patent No. 1,001,684 (January 1947); Chem. Abstr. 54, 1566 (1960). 4. H. I. BERNSTEIN and L. R. ROTHSTEIN. J. Am. Chem. Soc. 66,1886 (1944). 5. C. LESPAGNOL. Bull. Soc. Chim. France, 112 (1960); Chem. Abstr. 55,2651 (1961). 6. H. GILMAN and R. D. NELSOS. J. Am. Chem. SOC (1953). N. P. BUU-HOI aid N. HOAN. J. Chem. Soc (1951). D. TODD. Org. Reactions, 4, 381 (1948). L. J. BELLAMY. The infra-red spectra of complex molecules. 2nd ed. Methuen & Co., Ltd., London p R. H. BIBLE. Inter~retation of NMR s~ectra. Plenum Press, New korlr Chap. 3.'