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Some intermediates for the synthesis of [beta](3-methoxy-4-hydroxy-phenyl)-[beta]-hydroxy-ethylamine,… Attree, Richard Willoughby Alec 1947

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.SOME INTERMEDIATES FOR THE SYNTHESIS OF £ - (3-METKOXY- 4-HYDROXY-PHENYL) -A - HYDROXY-ETHYLAMINE. Part II A Thesis submitted by RICHARD WILLOUGHBY ALEC ATTREE in partial fulfilment of the requirements for the degree of MASTER OF ARTS in the DEPARTMENT OF CHEMISTRY UNIVERSITY OF BRITISH COLUMBIA. May, 1947. ABSTRACT The synthesis of ^-(3-methoxy-4-hydroxy phenyl- )-ft -hydroxy ethylamine was attempted, as the i n i t i a l step i n the investigation of i t s pharmacological properties. Attempted reduction of 3-niethoxy-4-nydro2y-M»-nitrostyrene gave no iso-lated products. Bromination of the side chain of the nitro-styrene, followed by treatment with potassium acetate and potassium hydroxide i n methanol gave an amorphous material and not the expected y0-(3-methoxy-4-hydroxy phenyl-) -dimethoxy-nitroethane. Vanillin was then converted into benzoyl v a n i l l y l chloride which on treatment with diazomethane, gave the sub-stituted *o -diazoacetophenone which i n turn was converted through the a) -chloro derivative to the u3 -iodoacetophenone. This was condensed with hexamethylene tetramine. Further work on the problem i s under way. ACKNOWLEDGEMENTS. I would like to thank Dr. R. H. Clark, under whom the work described in this thesis was carried out, for guidance and criticism throughout. I would also like to thank Dr. R. F. Patterson of the Powell River Co. Ltd., for certain suggestions, and also for supplying a complete survey of the literature of Vanillin; Mr. J. K. Hamilton, my associate in this research, for assistance and dis-cussion; also to Mr. R. F. Robertson and Mr. R. Stewart for suggestions. A l l these mentioned have been very helpful in c r i t i c i s i n g the work undertaken, and much benefit has been derived from the many discussions and consultations in which they have taken an active part. V PREFACE. The description of the research found in this thesis represents only a portion of the entire research carried out in these laboratories on this subject. The thesis "Some intermediates in the Synthesis of f$ -(3-methoxy-4-hydroxy-phenyl)-/& -hydroxy-ethylamine, Part I t t by Mr. J. K. Hamilton, my associate in this re-search, should also be consulted i f a complete picture of the problem is desired. 1. Some Intermediates for the Synthesis of^-(3-methoxy- 4-hydroxy-phenyl)-/3 - hydroxy Ethylamine. Part II,  Introduction. Since adrenaline was f i r s t synthesised in 1906, numer-ous compounds have been synthesised to test their pharmaco-logical properties. Using the mass of data obtained by the various workers in this f i e l d , i t is possible to co-relate the structure of a compound with i t s sympathomimetic action, and thus predict more or less accurately the most promising lines of reaearch. Prom a study of the relation-ship between structure and activity, certain facts appear, which may be summarised in the statement that the more important sympathomimetic agents posses a phenethylamihe skeleten, with one or more hydroxyl groups attached to the benzene ring, and usually a hydroxyl group attached to the beta carbon atom in the side chain. It is found that meth-ylation of the phenolic hydroxyl groups lowers both the potency and the toxicity of the drug. Adrenaline (I) s t i l l remains the most important of the existing sympathomimetics, but i t i s not without toxic effects,. It seems reasonable, in view of the known facts as outlined above, to suppose that/?-(3-methoxy-4-hydroxy-phenyl)-/3 - hydroxy ethylamine (II) would possess pharma-cological properties similar to adrenaline, but would perhaps be less toxic. It was therefore decided to under-take the synthesis of this compound. Because of certain obligations, as holder of the Powell River Company Limited Scholarship, i t was necessary for the author to use v a n i l l i n as the starting material in such a synthesis. This would not appear to present great d i f f i -culties, as many methods are described in the literature for the conversion of aromatic aldehydes into phenethanol-amines. The principal of these w i l l be described below. The most direct method would appear to be the reduction of the cyanohydrin of the aldehyde (III). This method has olamines ( 2 ) . Another worker, Mr. J. K. Hamilton, is at present investigating this method. A second method which suggests i t s e l f i s the reduction of v a n i l l y l cyanide (IV). The cyanide could be prepared from the aldehyde by oxidising the latter to the acid, con-verting to the chloride, thence to the desired cyanide by the usual method. Mr. Hamilton is also investigating this method. I been used to produce both phenethylaminea (l) and phenethan-3. C M , 0 O H C H - C N C H j O C H s C H N O t III IV v £ third possible method is via the nitrostyrene (V). This intermediate may be prepared in excellent yield by condensing the aldehyde with nitromethane in the presence of a suitable catalyst. Several methods are available for the conversion of this nitrostyrene to the corresponding phene thano1amine• Apparently some nitrostyrenes add water to the double bond in the side chain in the presende of suitable hydrating agents, notably acetic acid. The resulting compound may be reduced* to the phene thano lamine. (3). A slightly more complicated method i s that of Reichert and Koch (4) following the earlier work of Thiele and Haekel ( 5 ) . These workers brominated the Souble bond of the nitro-styrene, then s p l i t off hydrogen bromide to yield the (O -bromo-*> -nitrostyrene (VI) which was then treated with alcoholic potassium hydroxide to give an acetal (VII). This intermediate could be hydrolyaed to the to -nitro-acetophenone which could be reduced to the desired phenethanolamine. The synthesis is represented diagramatically below. A slight modification of this synthesis was used by Neber, Burgard and Thier (7). 4 R i s substituted phenyl group. HO Ac _ K O M ?*H* f#* C M . O M ' * Two methods have been described for conversion of <t>-nitro-styrenes into H-methy1 phenethan©laminea (8, 9). The corresponding acetophenone or i t s derivatives can be used as intermediates in a number of different syntheses ofuiphenethanolamines. The synthesis of theu>-nitroacetophe-none and i t s subsequent reduction has already been mentioned above. The acetophenone i t s e l f , which may be,readily obtained from the aldehyde by a modification of Grignard'a reaction (10) may be converted to the isonitroaoacetophenone ( Y i i i ) by means of isamyl n i t r i t e and sodium ethylate (ll)» or by the action of sodium nitroprusside. (12). This compound may then be reduced to the phenethanolamine with sodium and ethanol. (13). 0 "R. C - C H « N O H V I M Neber, Burgard and Thier found that p-toluene aulfonyl 5. chloride reacted with acetopiperone oxime in pyridine to give a compound which could be rearragned to give aminoacetopiperone, which could then be reduced(7). **> -haloacetophenones may be converted to the corres-ponding amines by one of three methods: the Gabriel synthesis using potassium phthalimide: by reaction with aqueous ammonia (14), or by condensing with hexamethylene tetramine to give a product which may be hydrolysed to the amine. The desired haloacetophenone may be obtained in the case of the chloro or bromo compound, by diredt halogenation of the acetophenone prepared from the aldehyde as autlined .above (15), or from the aldehyde, by means of the following series of reactions.# ° r _ i O O T l - C H *- J. P -RCOH » - ^ C C I Once the chloroacetophenone has been obtained, i t may be converted into the bromo or iodo derivative by treatment with sodium, potassium or ammonium bromide or iodide in absolute acetone. (16). The iodoacetophenone can be convert-ed into the nitro derivative by treatment with silver nitrate # see below for references 6 . (17), and this may be reduced as described above, but this method does not seem to offer any improvement over those described. Of the methods outlined in the introduction, four have been chosen for investigation in this synthesis. These are the methods involving the eyanohydrin, the cyanide, the nitrostyrene, and the chloroacetophenone. Of these the f i r s t two are being investigated by Mr. Hamilton, and a report of the results w i l l be found elsewhere(18). A c r i t i c a l discussion of the methods used in the research reported in this thesis with a statement of results obtained, and a comparison of the conditions and methods employed in this laboratory with those reported in the literature w i l l be found in the next chapter. II. DISCUSSION 03? THE METHODS USED. Methods involving the nitrostyrene. Synthesis of 3-methoxy-4-hydroxy-w-nitrostyrene offered l i t t l e d i f f i c u l t y . It was effected by condensation of va n i l l i n with nitromethane. Various catalysts and solvents have been used for this and similar condensations, e.g., sodium hydroxide (19), ammonium acetate in glacial acetic acid (20), potassium hydroxide in alcohol (7, 21) sodium 7. methylate (23), and methylamine (21, 24). Of these, methyl-amine appears* to give the highest yields (97-100^). It may best be added to the reaction mixture in the form of methylamine hydrochloride. An equivalent amount of sodium carbonate is then added, which liberates the methylamine. It is recommended that the nitromethane be purified by repeated d i s t i l l a t i o n before use, otherwise resinous polymers ' appear. Since some workers (25) we of the opinion that para-hydroxy groups interfered with this type of condensation, acetyl v a n i l l i n was f i r s t used. However, this product gave only the unacetylated to -nitrostyrene, and only in low yield. Further investigation disclosed than v a n i l l i n i t s e l f readily undergoes this condensation, and hence the intermed-iate acetylation was dispensed with. Rosenmund (26) states that when benzoyl v a n i l l i n is condensed with nitromethane, and the reaction mixture acidi-fied with acetic, boric or oxalic acid, the corresponding nitroethanol (IX) is formed. A similar reaction was tried using acetyl v a n i l l i n , but, as mentioned above, only the nitrostyrene formed. (IX) 8. It was then decided to follow the method of Reichert and Koch (4). As stated no d i f f i c u l t y was encountered in synthesising the nitrostyrene, using commercial v a n i l l i n , t r i p l y d i s t i l l e d nitromethane, methylamine hydrochloride and sodium carbonate in absolute ethano1. The yields are almost quantitative, and the product could usually be used without further purification. If further purification was desired the product was recrystallised from 98%UJBIthano 1. Great d i f f i c u l t y was encountered in the attempted preparation of the dibromo derivative of the nitrostyrene. The nitrostyrene was found to be only slightly soluble in inert solvents suitable for bromination, such as chloroform or carbon tetrachloride. The method f i n a l l y used was to in chloroform, which is a better solvent than carbon- tetra-chloride and a solution of bromine in chloroform was added dropwise un t i l a slight excess was present. More of the nitrostyrene was added and the process repeated u n t i l the desired quantity of nitrostyrene had been brominated. After the reaction mixture had stood for a short time, the chloro-form and any unreacted bromine was removed under reduced pressure, leaving a crystalline and a liquid residue. The yellow crystalline product could be recrystallised from dissolve a small portion of the nitro-styrene to be brominated, 9. chloroform to give a pure white compound, unstable in the ai r and decomposing from 125 - 150° with the evolution of brown fumes. It was assumed for a time that this was the desired dibromo derivative. The asxt step in the synthesis was the elimination of hydrogen bromide with potassium acetate in alcohol to give (VI) VI When this procedure was carried out, using the method of Reichert and Koch, a light brown, amorphous precipitate was formed, soluble in dioxane, alcohol and benzene, slightly soluble in water, and insoluble in petroleum ether. It did not melt below 300°, and showed none of the expected properties of the desired compound. Since a l l analogous derivatives described in the l i t e r -ature melt in the neighbourhood of 100°, i t was assumed that the product formed by this reaction was not the expected to -bromo-<*> -nitrostyrene (VI). No satisfactory explanat-ion of this fact has been found. It ia possible that the dibromo derivative was not formed in the i n i t i a l halogenat-ion, but rather brominated in the ring (see 29). Another possible explanation is that theu> -bromo-*«> -nitrostyrene formed i n i t i a l l y but polymerised under the influence of the elevated temperature at which reaction was carried out, or 10. of the basic solution. Cyclisation i s also a possible explanation. Because of these unsatisfactory results, i t was decided to abandon this method of synthesis, and concentrate on the reduction of the nitrostyrene under conditions which would favour addition of water to the double bond. Zinc and acetic acid, with or without the addition of formaldehyde (see 27); and aluminum with acetic acid were tried as re-ducing agents under a wide variety of conditions. N© pro-ducts of interest were isolated from the reaction mixture, so this method, too, was abandoned. The next method which came under consideration was that mentioned briefly in the outline under the reactions involving acetophenones. The complete synthesis which was f i n a l l y arrived at is diagrammed below. c-ci I 11. o H q ^ CH*°/ \ f> rHi CHgOt—y OH H O / V c CHXNHZ Ho( Y c H - C H , NHZ There are several points worthy of notice in connection with t h i 3 synthesis. Since v a n i l l i n possesses a para hydroxy 1 group, i t w i l l not undergo the reaction which is perhaps the most convenient method for obtaining the acid from an aromatic aldehyde.# #. A number of explanations have been proposed for this apparent anomaly. The one most generally accepted today i s as follows: Although v a n i l l i n and other aromatic aldehydes with a hydroxyl group either ortho or para to the aldehyde group do not enoliae in the usual sense of the word, the 12. Further, any attempt to use oxidising agents on v a n i l l i n either has no effect, forms dehydrovanillin (30a) or else results in the complete destruction of the aromatic nucleus. Low yields of v a n i l l i n acid have been obtained by the oxida-tion of v a n i l l i n with peracetic acid (30b), nitrobenzene(6) or ozone (31), but i t was not u n t i l Pearl proposed the use of silver oxide that the osidation of v a n i l l i n became a. # Contd.) anion formed in basic solution is capable of undergoing a mesomeric shift to give structures such as (X) X The mechanism of the Canizzaro reaction is not definite-ly known, but i t seems probable that i t takes place as follows;(28) - OK* , 0 WHO ?« ° ^ XI o or _ _ _ ^ » " K « C H a O * £ ' "R • O H " • " R C H r O . C . ' R OH *R' C H 4 O H • col From this i t w i l l be seen that i f the aldehyde were present as the meaomer (X) the Canizzaro reaction would be unable to take place, since the postulated intermediate(XI) would not be able to form. 13. practical method of synthesising v a n i l l i c acid. By this method (32a), v a n i l l i n is treated with sodium hydroxide and either silver oxide, or silver nitrate. When the reaction mixture is warmed, a modified Canizzaro reaction takes place probably catalysed by traces of metallic silver (32b). The v a n i l l y l alcohol formed is immediately oxidised by the silver oxide to v a n i l l i c acid. Hydrogen is evolved, and f l u f f y silver metal is deposited. The silver i s removed by f i l t r a t i o n , and the solution is treated with sulfur d i -oxide. If a mineral acid is used, i t is found that consider-able 5-nitrovanillic acid is formed. Va n i l l i c acid may be obtained in two crystalline forma by this method. If the basic solution obtained as above is saturated with sulfur dioxide while i t is s t i l l hot, the precipitate of v a n i l l i c acid which forms is dense, and slightly yellow. The crystals are compact and the whole has a granular appearance. If, however, the alkaline solut-ion is allowed to cool before saturation with the acid, the va n i l l i c acid is precipitated in a flocculent, pure white form, in which the crystals are exceedingly long and felted together. These forms have not been noted previously. Either form may be used for the following procedures without further purification. Pearl states that the silver metal may be recovered most conveniently by oxidising i t to the oxide with potass-ium permanganate. However,' as the second method listed by 14. Pearl uses silver nitrate rather than silver oxide, the method i s of no use. It was found that the silver metal resulting from the oxidation of the v a n i l l i n was readily soluble in n i t r i c acid. The impurities, presumably principally 5-nitro v a n i l l i c acid, could be removed by f i l t r a t i o n and by treating the solution with decolourising charcoal. Usually three treatments with charcoal were sufficient to give a substantially colourless solution of silver nitrate. The water was removed by evaporation in a current of air, and the silver nitrate erystala resulting were used for subsequent syntheses. However, i t was found desirable to f i l t e r the solution of the silver nitrate before addition to the v a n i l l i n solution, to remove traces of silver chloride and 5-nitro v a n i l l i c acid. ¥o decrease in yields on purity of product were noted using this recov-ered silver nitrate. Because of the great reactivity of the phenolic hydroxyl group, i t was decided to protect i t either by acetylation or by benzoylation. It was decided to attempt the prepar-ation of the acetyl derivative, but after numerous attempts, including a Schotten-Baumann reaction, and refluxing v a n i l l -ic acid with acetic anhydride, or acetyl chloride, either with or without pyridine or ether as solvents, oa£y minute yields of the O-acetyl v a n i l l i c acid were obtained. That some reaction had taken place was confirmed by examining, under the microscope, portions of the reaction product after 15. recrystallising. A. change of crystal form was noted. The synthesis of bonzoyl v a n i l l i c acid was next attempted. Hb product eould be isolated from a refluxed mixture of ether, benzoyl, chloride, and v a n i l l i c acid, although some reaction had taken place, as evidenced by the heat of reaction which was sufficient to boil the ether.# Va n i l l i c acid was recovered unchanged. However, benzoyl v a n i l l i c acid could readily be prepar-ed by the Schotten-Baumann reaction, in about 65-70^ yield, which is higher than that reported in the literature(4). It was found, by this worker, that much higher yields could be obtained i f a large excess of benzoyl chloride were em-ployed, than i f the usual quantities were used. The benzoyl chloride hydrolyses on standing in contact with the solution forming benzoic acid as well as the benzoyl v a n i l l i c acid, Since benzoic acid is a stronger acid than benzoyl v a n i l l i c acid, the latter is. liberated from the salt, and precipit-ates out of solution. It may be f i l t e r e d off, and freed from any benzoic acid which may have been precipitated at the same time by boiling with water and f i l t e r i n g while hot. If i t is not deemed advisable to add such a large excess of benzoyl chloride, the benzoyl v a n i l l i c acid may be precip-itated from the reaction mixture with hydrochloric acid. # This may have been due to reaction between the thionyl chloride and the ether. 16. It is recommended that in this case the acid be added slowly with much sti r r i n g , as the benzoyl v a n i l l i c acid exhibits a tendency to form an o i l , which sinks to the bottom and then suddenly crystallises to form a hard mass, which i s very d i f f i c u l t to free from occluded benzoic acid. The next step in the synthesis is conversion of the benzoyl v a n i l l i c acid to the chloride. The two reagents usually used for this type of reaction are phosphorousm pentachloride and thionyl chloride . Use of the former has been reported in the literature(33), but. these results could not be duplicated in this laboratory (see 18). Fortunately thionyl chloride gave the desired product in nearly quanitative yi e l d . It is desirable to purify the thionyl chloride before use by d i s t i l l i n g from linseed o i l and quinoline(34). However i t was found that the commercial product could be used without detrimental effects i f i t were not too highly coloured. After refluxing the benzoyl v a n i l l i c acid with twice i t s weight of thionyl chloride u n t i l a clear solution resulted, l i g r o i n was added, and the whole refluxed once more un t i l clear. If the resulting solution were too highly coloured, i t was refluxed for a few moments with Darco decolourising charcoal, and f i l t e r e d through scintered glass. Upon cooling in a freezing mixture of dry ice and alcohol, the benzoyl v a n l l l y l chloride precipitated out in small crystals. Small quantities of a 17. brown o i l , of unknown composition, formed the principal impurity, but this could be easily removed by washing the precipitate on the f i l t e r with cold l i g r o i n . The product was used without further purification. The diazo compound, (CgRgCOO) (CK30)CgH3.C0.CBJr2» which has not been reported previously, was obtained in excellent yield by treating a solution of benzoyl v a n i l l y l chloride in benzene-ether with diazomethane. The latter was prepar-ed by a method suggested by Dr. R. F. Patteraon(35), from ^-nitrosomethyl urea, which in turn was prepared from methylamine ^hydrochloride, sodium n i t r i t e , and potassium cyanate (36). If i t is desired te isolate the diazo acetophenone, the solution of benzoyl v a n i l l y l chloride must be added dropwise to a cooled solution of excess diazomethane in ether. In this manner formation of the tt> -chlor-acetophenone as a side product i s reduced to a minimum, since the excess diazo methane, rather than the diazo acetophenone, reacts with the hydrogen chloride pro-duced. The diazo-acetophenone may be obtained by evapor-ating the solvent in a current of dry a i r , and may be recrystalliaed from l i g r o i n . A solution of this material evolves nitrogen on boiling with water, or upon the addition of acid. It takes the form of short, lemon yellow crystals. The diazo-aeetophenone was. not usually isolated, but instead dry hydrogen chloride was bubbled through the etherial solution obtained as above. In this case, i t ia 18. not necessary to add the benzoyl v a n i l l y l chorlide solution to the diazo methane solution slowly, as the "by-product11' resulting from too rapid addition i s actually the product desired. The chloracetophenone may be obtained by evapor-ating the solvent in a current of dry a i r , and may be re-crystallised from aqueous alcohol. (50$). It i s a greyish, micro-crystalline material. It has not been reported in the literature. There are several methods for converting chloroaeeteo-phenones to the amine. The two classical methods, the Gabriel synthesis and treatment with an aqueous solution of ammonia, have both been used.(vide supra). A more mod-ern method, which seems to be suprior to the others, i s based on certain observations of Mannich and Hahn(37). These workers discovered that when hal-acetophenone i s treated with a chloroform solution of hexamethylene tetra-mine, a complex addition product of undetermined structure precipitated out of solution. This material proved to be soluble in water, and the halogen present was completely ionised by this aqueous solution. This complex addition compound could be hydrolysed to the corresponding amino acetophenone by allowing i t to react with alcoholic hydro-chloric acid for several days. Recently Baltzly and Buck (15), have proposed that this hydrolysis be carried out by refluxing the addition product with alcoholic hydrochloric acid, thus increasing the rate of reaction. Inasmuch aa 19. the amino acetophenones are as a general rule, unstable in alkaline solution, and since this method is carried out only in acid or neutral solutions, higher yields of purer products are obtained than with the classical methods. It has been found (37) that relatively low yields of the addition product are formed i f the halogen in the acetophenone is chlorine. Higher yields are reported i f i t i s bromine, while i f i t is iodine, the yield is almost quantitative. For this reason i t would appear advantageous to convert the acloroacetophenone obtained as outlined above into either bromo or the iodo compound. This may be accomplished by allowing an acetone solut-ion of the chloroacetephenone to react with an absolute acetone solution of sodium, ammonium or potassium bromide or iodld (16). After a few days, the sodium, ammonium, or potassium chloride which is insoluble in absolute acetone, may be fi l t e r e d off, and the bromo- or iodo-acetophenone may be obtained by evaporation of the solvent. The yields are reported to be almost quantitative. In this investigation, ammonium iodide was used, be-cause i t is far more soluble in acetone than the sodium or potassium salt. A disadvantage, however, is that the ammon-ium chloride reacts slwoly with the acetone, thus introduc-ing impurities in the f i n a l product. Hexamethylene tettamine was prepared by the usual method of evaporating a mixture of Z0% formaldehyde and concentrated ammonium hydroxide. The product so obtained 2 0 . i s practically 100$ pure. The condensation of the iodo acetophenone and the hexa-methylene tetramine takes place in chloroform. It i s com-plete in about 48 hours at room temperature. The product may be filtered off, since the addition compound is insol-uble in chloroform. Hydrolysis to the aminoacetophenone should take place as described by Batlzly and Buck (B). The material is refluxed for up to eight hours with alcohol and concentrat-ed hydrochloric acid, and the amine recovered by evaporation of the solvent. Once the amino acetophenone is obtained, i t may be reduced to the desired phenethanolamine. Catalytic hydro-genation is parobably the best method, although a number of reducing agents have been used for similar reductions. Zinc and acetie acid, or sodium and acetic acid are those reported most frequently. 21 EXPERIMENTAL Part I. Method of Reichert and Koch.  Synthesis of Acetyl V a n i l l i n . 51 g. of acetic anhydride was added dropwise with rapid o s t i r r i n g to a solution of 67 g. of commercial v a n i l l i n in l.H. potassium hydroxide. Depending on conditions, either a thick o i l which crystallised almost at once, or fine white crystals were obtained. The product was f i l t e r e d off from the mother liquors, washed twice with cold water, and recrystallised twice from 50$ alcohol. Yields 65.7 g. or 76$ of the theoretical. Melting point 78°. Attempted synthesis of (5-methoxy-4-acetoxy-phenyl)--hydroxy ethylaminei 6 g. of the acetyl v a n i l l i n prepared as above were dissolved in 400 Ml. of absolute ethano1. The solution was cooled to 40° and 2.8 g. of tr i p l y dis-t i l l e d nitromethane was added. Sodium ethoxide solution, prepared by adding 1.07 g. of sodium metal to an excess of absolute ethano1, was added dropwise. When reaction had ceased, usually after 24 hours, the solution was diluted with an equal volume of water, and made slightly acid with 3 N. acetic acid, neutralising the excess with sodium b i -carbonate solution. Upon standing, a yellow precipitate separated out. This product, when recrystallised twice from 50$ ethanol, melted indistinctly in the neighbourhood of 156°. It gave a l l the reaetiona of 3-methoxy-4-hydroxy-22. o>-nitrostyrene (M.P. 168°) Synthesis of 3-methoxy-4-hydroxy- ***-nitro styrene 60 g. of commercial v a n i l l i n and 30 ml. of t r i p l y d i s t i l l e d nitromethane were dissolved in 150 ml. of absolute alcohol, and 2 g. of methylamine hydrochloride and 2 g. of sodium carbonate added. The reaction mixture was allowed to stand at room temperature overnight, after which the product was fi l t e r e d from the mother liquor, using suction and washed with 0.753SF. HC1. After recryatallising twice from 95% alcohol, the product melted sharply at 170-172.°. (this value is slightly higher than those previously reported in the literature.) Yield 80-90$^ Attempted synthesis of 2(3'-methoxy-4'-methoxy-phenyl-)-- 1, 2-dibromo nitroethane. 10 g. of 3-methoxy-4-hydroxy-a> -nitro-styrane, prepared as above, were shaken with 100 ml. of chloroform, and the solvent decanted. 11 g. of bromine in 25 ml. of chloroform was added dropwise to the solution of nitrostyrene in chloroform, adding the remaining nitro-styrene from time to time. At the end of hr., the chloro-form and a slight excess of bromine which remained were removed by d i s t i l l a t i o n under vacuum, giving a yellow cryst-a l l i n e mass. This product was recrystallised twice from chloroform, to give pure white crystals, with no melting point, but which decomposed with the evolution of a brown gas at temperatures abo«e 125°. The product turned yellow when exposed to the air for several hours. The product i s 22.a very soluble in ether, soluble in petroleum ether-ether, but insoluble in petroleum ether. Attempted synthesis of 3-methoxy-4-hydroxy-«»bromo- u> -nitrostyrene, 5 g. of 2-(3'methoxy-4'hydroxy-phenyl)-l, 2, -dibromo-^ni tree thane were dissolved in 20 ml. of absolute alcohol and heated to boiling. 2 g. of potassium acetate dissolved in absolute alcohol were added to the boiling mixture. The resulting solution was filtered while hot, and the f i l t r a t e , after cooling, was diluted with 70 ml. of water. A fine light brown precipitate settled out, which was f i l t e r e d off. The material appears to be micro-crystalline. It i s soluble in 50-50 dioxane-petroleum ether, in benzene, in alcohol, but only slightly soluble in water. With alkaline solutions i t gives a rose colour. Yields 3 grams. The compound did not melt below 300°. In view of the high melting points and chemical re-actions of these two compounds, this method of synthesis was abandoned. Attempted Reduction of 3-methoxy-4-hydroxy u>-nitro- styrene. The following table summarises the quantities of reagents used, the naute of the solvent, and the conditions employed. The only products isolated and characterised were zinc acetate, aluminum hydroxide, and benzoic acid. In each case a number of fractions of other products were obtained, none of which could be purified or characterised 23. further, and in general gave the appearance of high molec-ular weight polymers and byproducts. No material contain-ing an amino group could be isolated, although in several cases the reaction mixture gave a positive test with nitrous acid. , 24. Table showing the  methods of reduction of 5-methoxy-4-hydrpxy -4>-nitroatyrene Tt. of nitro- • Reducing styrene Agent Solvent Conditions Remarks. 2 g. 2 g. 2 g. 2 g. 2 g. 4 g. ditto 2 g.Al excess Zn dust ditto ditto ditto ditto ditto 100ml 6N.HAC 80 ml. 3IT.HC1. ditto plus 5ml. Z0% formaldehyde 40 ml. 6U. acetic acid ditto plus 5 ml. 30# formaldehyde Heated under reflux £ hr. Reflux for £ hour. ditto ditto ditto 1 150 ml.alcohol Reflux until 20 ml. glacial colourless acetic acid & 20 ml. Z0% formaldehyde. ditto ditto Product sol. in HH40H, FaOH,glacial HAc, insol. concHCI no product isolated. ditto ditto ditto , Zn. precipitated as far as possible with HgS. Three fractions, isolated each containing zinc. Mother liquor when treated with acetic an-hydride gave small quantity red brown o i l . Evaporated to dryness under vacuum after pptx of Zn. Residue benzoyl-ated using K0H and ben-zoyl Chloride. Product consisted of a viscous brown o i l containing benzoic acid. 25. Synthesis of Van i l l i c Acid;(32) X 30.4 g. of va n i l l i n were dissolved in 400xml. of water to which 48 g. of sodium hydroxide had been added. The mixture was heated to 55°, and a solution of 34 g. of silver nitrate in 150 ml. of water was added. Silver oxide immed-iately precipitated out. The mixture was heated with mechanical sti r r i n g u n t i l the temperature of the reaction mixture rose rapidly, indicating that the reaction was proceeding. The source of heat was removed, u n t i l the maximum temperature was reached, usually about 10-15° higher than the i n i t i a l temperature. After this point had been reached, the mixture was heated for a further period of five minutes to assist in the coagulation of the silver, which in some cases showed a tendency to pass through the f i l t e r . T£e solution was f i l t e r e d while hot, and the pre-cipitate of finely divided silver was thoroughly washed with water, the washings being added to the f i l t r a t e . The f i l t r a t e was usually pale yellow at this point, but was occasionally deep brown. It was found that the more dilute the a l k a l i , the higher the temperature necessary for the reaction, and the deeper the colour of the solution. In general, the lighter coloured solutions gave better yields of purer products, but thisnwas not always the case. The f i l t r a t e from the above treatment was neutralised with sulfur dioxide, prepared from sodium b i s u l f i t e and concentrated sulfuric acid. The v a n i l l i c acid which precip-itated out was separated by f i l t r a t i o n , wash and dried. 26. Yield: 22.4 or 66$ of the theoretical. Melting point 211-212°. Conversion of Silver to Silver Nitrate: The silver obtained from the synthesis of V a n i l l i c acid was stirred to a pasty mass with a small quantity of water, and concentrated n i t r i c acid was added, with vigourous stirring, u n t i l no further reaction took place. Any lumps of silver must be broken up by hand. The mix-ture was then f i l t e r e d to remove the precipitate of 5-nitrovanillic acid (?) which formed, and.the deep yellow solution was boiled with decolourising charcoal u n t i l pale straw colour. The silver nitrate was obtained by evaporating the solution to dryness. Synthesis of Benzoyl V a n i l l i c Acid: Method 1. 25 g. of v a n i l l i c acid were dissolved in 400 ml. of water containing 24 g. of sodium hydroxide, and the solu-tion treated with 32 g. of benzoyl chloride. The reaction mixture was kept in an ice bath, and stirred mechanically for 30 minutes. At the end of this time, the solution was acidified with three portions of hydrochloric acid. The f i r s t fraction, which was gray, consisted principally of benzoyl v a n i l l i c acid and benzoic acid, and the third, which was pure white, consisted of benzoic acid, fhe f i r s t two fractions were extracted five times with 200 ml. of boiling water, leaving a residue of substantially pure benzoyl v a n i l l i c acid. Yield 25.4 g. of 61^ of the 27. theoretical. Melting point, 160-163°. Method 2. 25 g. of v a n i l l i c acid were dissolved in 400 ml. of water containing 24 g. of sodium hydroxide, and the solution treated with 50 ml. of benzoyl chloride. The reaction mixture was cooled in an ice bath and mechanically stirred for i hour. At the endof this time the precipit-ate of benzoyl van i l l i c acid was f i l t e r e d off, and extract-ed three times with boiling water. Acidification of the f i l t r a t e with hydrochloric acid yielded only benzoic acid. Yield of Benzoyl v a n i l l i c acid, 28.5 g. or 70$ of the theoretical. Synthesis of benzoyl vanilloyl chloridet 15 g. of benzoyl v a n i l l i c acid prepared as above were refluxed with 30 g. of purified thionyl chloride u n t i l the acid had gone into solution, and for 15 minutes more. 30 ml. of l i g r o i n were then added, and the mixture refluxed u n t i l clear. If necessary, decolourising charcoal was added and after refluxing for a short time, was f i l t e r e d off from the hot solution through scintered glass. The solution was then cooled in a mixture of solid carbon dioxide and ethanol and the benzoyl vanilloyl chloride fultered from the cold solution, and washed with a l i t t l e cold l i g r o i n . Yield 15.2 g. or 95$ of the theoretical. Melting point 95-97^5°. Synthesis of ff-nitroao methyl urea. (36). 20 g. methylamine hydrochloride and 30 g. of potassium cyanate were dissolved in 120 ml. water, and the solution 28. o heated to 80 for fifteen minutes, then boiled for a short time. The solution was then f i l t e r e d , cooled to 0°, and a cold solution of 20 g-. sodium n i t r i t e in 40 ml. water was added, followed by the dropwise addition with strong cooling of 100 ml. 25# sulfuric acid. After stand-ing a short time, the cream coloured product which separ-ated out was removed by f i l t r a t i o n , washed with cold water and stored in an ice box over calcium chloride. The addit-ion of a l i t t l e acetic acid to the product helps to prevent decomposition. (35). Synthesis of u)-diazo acetovanillone: Diazo methane was prepared from the IT-nitrosomethyl urea by treatment with potassium hydroxide, and was purified by c o d i s t i l l -ation from the reacting mixture with ether(35). Details of the method used are to be published elsewhere and hence may not be given here. 10.g. of benzoyl vanilloyl chloride in sufficient ether-benzene to effect solution was added dropwise to the ethereal solution of diazo methane prepared from 12 g. of M-nitr© methyl urea, with vigorous shaking. A brisk evolution of nitrogen was observed. The reaction mixture was allowed to stand at room temperature overnight, and the solvents evaporated in a current of dry a i r . Yield* 8.7 g. of crude material, or 85$ of the theoretical. Melting point 114-118°. 29, Synthesis of <»?-chloroacetovanillonet The residue of crudek>-diazo acetovanillone obtained as above, was dissolved in 200 cc. of ether and dry hydrogen chloride was bubbled through the solution for 1 hr. At the end of that time, the ether was evaporated in a current of dry a i r , leaving the *>-chloroacetovanillone. This appeared as pale cream coloured granules, melting point 121-123°. Yield* 8.6 g. or practically the theoretical. Synthesis of«»-iodo aeetovanillonet 0.60 g. of w-chloro-acetovanillone was dissolved in 25 ml. absolute acetone, and 15 ml. of a solution of 2 g. of ammonium iodide in 100 ml. absolute acetone were added, and the mix-ture f i l t e r e d immediately through seintered glass. React-ion appeared to be complete after 16 hours. The precipit-ate of ammonium chloride was fil t e r e d off, and the acetone ' removed by evaporation. The material remaining was not purified, nor were melting points taken. The whole mater-i a l was reserved for the following procedure. Condensation of <u-iod6acetovanillone:. with hexa- methylene tetracaine; The material obtained above was dissolved in 10 cc. of chloroform, and 0.2 g. of hexameth-ylene tetramine in 25 ml. chloroform added. After standing 48 hours a brown precipitate was obtained. Melting point 192-7°. The yield was high. Condensation of <^-ehloro aceto vanillane with hexa- methylene tetraminet An experiment similar to the condens-30. ation of the 0 -iodo derivative was conducted. &t the end of three weeks, only a very small portion of a white condensation product had formed. Work on remaining synthesis i s progressing. Summary of Results Obtained. It has not been found possible to synthesise the compound -(3-methoxy-4-hydroxy-phenyl-)- (i -hydroxy-ethylamine. However, a number of new compounds have been synthesised as intermediates in unsuccesful attempts at this synthesis. These are list e d below with any physical data which is known. Compound. Colour Melting Point Solubility (3-methoxy-4-benzoyloxy)-O-diazoacteophenone lemon yellow 114-118° sol. hot 80$ alcohol (3^me thoxy-4-benzoyloxy)-&>-ehloroacetophenone pale yel-low white 121-128° v.s.s. in 50-50 li g r o i n ether inso. li g r o i n . (3-me thoxy-4-benzoyloxy)-to? <»iod.o)ac e tophenone orange Sol. chloroform acetone (3-methoxy-4-benzoyloxy)-V-iodoacetophenone addit-ion product with hexameth-ylene tetracaine. 192-7° Sol. water, ins. chloroform brown 1 - (3 'me thoxy-4 * hydroxy-phenyl- )-1,2-dibromo-2-nitroethane.(#) white no m.p. below 300° (#) There i s doubt as to whether this was the compound actually obtained. REFERENCES. 1. Rupe and Engel, Helv. Chim. Acta. 18, 1190-1203 (1935). 2. (a) Kindler, Peschke and Brandt, Ber. 68B, 2241-5, (1935). (b) D.R.O. 157, 300; 193, 634; and 195, 814. 3. Friedlander, Ann., 229, 217, 225 4. Reichert and Koch, Ber. 68B, 445, (1935). 5. Thiele and Haekel, Ann. 325, 1 (1902). 6. Ciamician and Silber, Ber. 38, 3821 (1905). 7. Neber, Burgard and Thier, Ann. 526, 277-94 (1036). 8. Mannich, Chem. Z. 1909, I, 923. 9. Posdick et a l . , J. A. CS. 68, 840 (1946) 10. Finnemore, J. Chem. Soc. 93, 1517. 11. Claissen and Manasse, Ber. 20, 2194 (1887) 12. Cambi, R. A. L. (5) 22 I, S80. 13. Kolshorn, Ber. 37, 2482 (1904) 14. Gabriel, Ber. 41, 1144 (1908) Goedeckemeyer, Ber. 21, 1280 (1888) 15. Baltzly and Buck, J.A.C.S. 62, 164, (1940). 16. Collet, Compt. Rendu.128, 312. Paal and Stern, Ber. 32, 532 (1899) 17. Lucas, Ber. 32, 601 (1899) 18. Hamilton, J.K. Thesis, "Some intermediates for the Synthesis of -(3-methoxy-4-hydroxy-phenyl-)-/3 -hydroxy eaihylamine. Part I* University of Bri t i s h Columbia, May 1947. 19. Worall, Organic Syntheses, 9, 66 (1929). Hahn and Rumpf, Ber. 71B, 2141, (1938) 20. Raiford and Fox, Proc. Iowa Acad. S c i . 40, 111, (1933) J. Org. Chem, 9, 170-4, (1944) 21. (a) Koboyoshi and SJaozo, Sci.Papers.Inst. Phys. Chem. Research (Tokyo), 6, 149-65(1927). 22. Lange and Hambourger, J.A.C.iS. 53, 3865-71, (1931). 23. Rosenmund, Ber. 46, 1034 (1913) 24. Tomita and Watahabe, J.Pharm.Soc. Japan,58, 783 (1938) 25. Rosenmund Ber. 46, 1036, (1913) 26. Rosenmund, D.R.P. 247, 817. 27. Kanao, J. Pharm. Soc. Japan, 49, 238(1929) 28. Adams, Organic Reactions, Vol. II, p. 96 29. Raiford and Pox, J. Org. Chem. £, 170 (1944) 30. (a) Tiemann, Ber. 18, 3493 (1885). Elba and Lerch, J. Prakt. Chem 93, 1-9, (1916) (b) Dorland and Hibbert, Can. J. Research. 18B, 30 (1940) 32. (a) Pearl, J.A.C.S. 67, 1628(1945), 68, 429,1100 (1946) 33. Heap and Robinson, J. Chem. Soc, 1926, 2336-44 34. G-ilman and Blatt, Organic Syntheses, Co. Vol.11 p. 570 35. Dr. R. P. Patterson, Private communication. 36. GattermanrWielands, Laboratory Methods of Organic Chemistry. MacMillan, p. 271. 37. Mannich and Kahn, Ber. 44, 1542 (1911) 38. Pisovschi, Ber. 43, 2137 (1910). 


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