THE PREPARATION OF SOME DERIVATIVES OF RETENOXAZOLE

[CONTRIBUTION FROM

THE DEPARTMENT OF CHEMISTRY AND

OF THE

CHEMICAL ENGINEERING UNIVERSITY OF PENNSYLVANIA]

T H E PREPARATION OF SOME DERIVATIVES OF RETENOXAZOLE AND RETENIMIDAZOLE AND A STUDY OF THE REACTION MECHANISM' SAUL I. KREPS

AND

ALLAN R. DAY

Received September 80, 19.10

The reaction of phenanthraquinone with benzaldehyde and aqueous ammonia to form 2-phenylphenanthroxazole was first noted by Japp and Wilcock (1). The mechanism of this reaction has not been clearly established. Hence it was thought advisable to extend the earlier work, and by making a more thorough study of the intermediates, to establish the reaction mechanism. Since some of the previous work had a direct bearing on the work done in this investigation, a brief review is included. Japp and Wilcock suggested that the reaction involved as the first step the formation of phenanthraquinoneimine.

A hydrolytic oxidation between the imine and benzaldehyde with the formation of 10-amino-9-phenanthrol was next postulated. The latter compound then underwent the Ladenburg ring-closure with benzoic acid to form the oxazole.

An abstract of a thesis submitted by Saul I. Kreps in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry. 140

RETENOXAZOLES AND RETENIMIDAZOLES

141

2H20

Later Japp and Wilcock (2) noted that other aromatic aldehydes reacted, under the same conditions, as readily as benzaldehyde. Furfuraldehyde also condensed, but the corresponding phenanthroxazole was obtained in poor yields. In attempting to extend this condensation to acetaldehyde they had no success. They further noted that salicylaldehyde condensed with phenanthraquinone and ammonia to form 2-(2'-hydroxypheny1)phenanthrimidazole and not the expected phenanthroxazole. Japp and Streatfeild (3) investigated the anomalous action of salicylaldehyde and found that the hydroxyaryl aldehydes condensed with phenanthraquinone and ammonia to yield 2-aryl phenanthrimidazoles, while the corresponding methoxyaryl aldehydes formed both oxazole and imidazole. Sircar and Sircar (4) modified the method of Japp by dissolving the phenanthraquinone and aromatic aldehyde in the minimum of hot amyl alcohol and passing ammonia through the solution. They observed that certain nitroaryl and bromohydroxyaryl aldehydes also formed 2-aryl phenanthrimidazoles. Sircar and Ray ( 5 ) showed that at high temperatures the hydroxyaryl, bromohydroxyaryl, and nitroaryl aldehydes formed imidazoles; while oxazoles were formed a t lower temperatures. They assumed two distinct reaction trends depending upon the temperature employed for the condensation.

n

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SAUL I. KREPS AND ALLAN R. DAY

With benzaldehyde a t both low and high temperatures only the oxazole was formed. They stated however that the course of the reaction was not dependent upon the character of the aldehyde, intimating that a t high enough temperatures all aromatic aldehydes would form imidazoles. Sircar and Sen (6) reported more conclusive evidence that the course of the reaction was affected by the temperature used. Working with acenaphthoquinone, aromatic aldehydes, and ammonia, they were able to distinguish four groups of aldehydes, each showing a different reactivity. The first group form only oxazoles at temperatures near Oo, while at higher temperatures only imidazoles were formed. The second group formed mixtures of the corresponding oxazoles and imidazoles at 0" and only imidazoles at higher temperatures. The third group formed only imidazoles even at 0". The fourth group gave no reaction cold, and when heated yielded only imidazoles. The formation of both oxazoles and imidazoles in some cases led Sircar and Sen to assume that in those reactions the acenaphthoxazoles were formed first, and by subsequent replacement of the oxygen atom by the amino group yielded the corresponding imidazole. They attempted the conversion of 2-(2'-nitrophenyl)acenaphthoxazole to the corresponding imidazole by heating the oxazole with aqueous ammonia a t 130" in a sealed tube. After thirty hours, an increase in nitrogen content of 1.5% was found. However they were not able to isolate any of the imidazole. Such a conversion would probably involve hydrolysis of the oxazole ring, followed by replacement of OH by NH2 and a subsequent ring-closure with the elimination of water. Apparently, no study has been made on the ease of hydrolysis of any of the acenaphthoxazoles. However, Japp and Wilcock attempted the hydrolysis of 2-phenylphenanthroxazole by heating with concentrated hydrochloric acid at 200",but no hydrolysis was noted. The postulate that phenanthroxazoles were necessary intermediates in the formation of the corresponding imidazoles is untenable for two reasons: (a) the extreme difficulty of splitting the phenanthroxazole ring; and (b) the rapid formation of phenanthrimidazoles from phenanthraquinone, certain aromatic aldehydes, and ammonia at moderate and even low temperatures. The only other synthesis of a 2-aryl phenanthrimidazole has been reported by De and Ghosh (7). They obtained 2-phenylphenanthrimidazole by the reaction of benzamidine with the hydrochloride of 9-amino-10phenanthrol a t 190-200". It did not seem possible to draw any definite conclusions from the reported work concerning the mechanism of the formation of oxazoles and

143


imidazoles from ortho quinones. The mechanisms suggested have not been tested and no independent evidence has been brought forward to confirm or dispute them. Previous workers have stressed the action of ammonia with the quinone, and have assumed this to be the essential reaction in the formation of oxazoles. They have neglected the possibility that the action of ammonia on the aldehyde to form a hydrobenzamide might also be an important step in the reaction. It was decided therefore to make a thorough study of this type of reaction, using retene quinone, aromatic aldehydes, and ammonia. The study consisted of six parts: (A) the reaction of ammonia with retenequinone; (B) the reaction of retenequinoneimine with aromatic aldehydes; (C) the reaction of retenequinone with hydrobenzamide ; (D) the reaction of retenequinoneimine with hydrobenzamide; (E) the action of ammonia on 2-aryl retenoxazoles; and (F) the preparation of a series of 2-aryl retenoxazoles. ACTIONOF TIYD

60 min.. ........................ 60 min.. ........................ 45 min.. ........................ 30 rnin.. ........................

TABLE I AMMONIA ON RETENEQUINONE PBODUCT8

I1 I1 Mixture I and I1

I

Y.P.

'c.

123 120 111-113 107-108

% N FOUND

3.80 3.92 4.72 5.10

Retenequinoneimine (I) was prepared by treating a chloroform solution of the quinone with an alcoholic solution of ammonia (8). When the reaction was carried out by passing ammonia through a suspension of the quinone in alcohol, other products were also obtained. From one run of this type, carried out a t 5', a product was isolated that melted sharply at 125' and contained 3.62y0 of nitrogen. The most reasonable structure assignable to this product was a hydrobenzamide type of structure 11. Another compound was isolated when this reaction was carried out in hot alcoholic solution. Melting points were indefinite but analyses indicated a molecular complex of one mole of the quinoneimine and one mole of the quinone. It was found that as the time of addition of ammonia to alcoholic quinone solutions increased, the nitrogen content of the resulting product decreased. Thus for a series of reactions carried out a t room temperature, the results shown in Table I were obtained. This might be explained on the basis of the following reactions:

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To test the mechanism of Japp and Wilcock, benzaldehyde and p-hydroxybenzaldehyde were treated with retenequinoneimine under various conditions. No reaction occurred between benzaldehyde and the quinoneimine in the absence of a solvent, even on warming the mixture. In dry toluene, after refluxing for three hours, only a 1.4% yield of 2-phenylretenoxazole was obtained. A small amount of ammonia was given off during the refluxing. No reaction was observed between the quinoneimine and p-hydroxybenzaldehyde in absolute alcohol after three days. After standing for thirty days, a small amount of product (6% yield) was obtained which was found to be a mixture of 2-(4'-hydroxypheny1)retenoxazole and 2-(4'-hydroxypheny1)retenimidazole. In hot absolute alcohol ammonia was liberated, and after three hours a sixteen per cent yield of the oxazole and imidazole was obtained. In dry toluene, after refluxing for forty-five


145

minutes, only a trace of product could be found. The aldehyde was recovered almost quantitatively and only a trace of ammonia was liberated during the reaction. It was noted that reaction-products were isolated only in those cases were ammonia was liberated. This indicated partial hydrolysis of the quinoneimine by slight traces of water present in the solvents, or partial alcoholysis of the quinoneimine. The presence of the quinone, aldehyde, and free ammonia then established the conditions for the formation of the oxazole and the imidazole. These results pointed to the fact that the quinoneimine was not the only necessary intermediate for the reaction. The possibility that hydrobenzamide might be formed in the reactionmixture led to a study of the reaction of hydrobenzamide with retenequinone in various solvents. Oxazole formation was noted only in those cases where ammonia and benzaldehyde were liberated, indicating that the hydrobenzamide first underwent hydrolysis or alcoholysis, and then oxazole formation resulted. When hydrobenzamide and retenequinone were refluxed for three hours in isoamyl alcohol, a sixty per cent yield of 2-phenylretenoxazole was obtained. Ammonia was liberated steadily during the reaction. When the reaction was carried out in dry toluene, no product was isolated, and the quinone was recovered nearly quantitatively. After refluxing retenequinone and hydrobenzamide in dry toluene for three hours, a 2.1% yield of the oxazole was obtained. Ammonia was evolved in both cases. Hydrobenzamide alone in dry toluene liberated only slight traces of ammonia. In one run, 0.019 moles of hydrobenzamide liberated 0.0002 moles of ammonia after refluxing for three hours, indicating the extent of hydrolysis to be 0.5% within that period. The observed increase in the amount of ammonia liberated in the quinone-hydrobenzamide mixture is accountable by the reaction of these traces of ammonia liberated from hydrobenzamide with the quinone, water and retenequinoneimine being formed. The traces of moisture thus formed cause increased hydrolysis of hydrobenzamide. Concurrent with this increased liberation of ammonia is an increase in the yields of oxazole. The low yields of oxazole observed can be correlated with the slight extent of hydrolysis within the period of the reaction. It would appear that any proposed mechanism which limited itself to the formation of only one necessary intermediate, quinoneimine or hydrobenzamide, would fail to meet the requirements imposed by experimental results. To test the possibility that both might be necessary intermediates, the interaction of retenequinoneimine and hydrobenzamide was studied. The reactions were carried out in dry toluene to avoid such complicating side reactions as hydrolysis and alcoholysis. When retenequinoneimine and hydrobenz-

146


amide were refluxed in dry toluene, the solution turned dark green in about six minutes but no ammonia was liberated. After another four minutes the solution became light yellow and ammonia was given off. One run, stopped after ten minutes, gave a seventy-eight per cent yield of oxazole. In another run, 0.010 moles of retenequinoneimine and 0.010 moles of hydrobenzamide were refluxed for three hours in dry toluene. The oxazole was isolated in a yield of ninety-six per cent (0.0096 mole) and 0.0057 moles of ammonia was evolved during the run. These results indicated the following mechanism.

xNH + CaH&H=N> CsH&H=N

CHCsHs

+

+ CsHsCH=NH

3

The benzaldimine formed would then be converted into hydrobenzamide and ammonia.

3 CeH,CH=NH

+

+ ( C O H ~ C H ) ~NH3 ~'~


147

In this series of reactions it will be noted that for each mole of oxazole formed, 0.66 moles of ammonia would be liberated. The ratio of ammonia to oxazole would be 0.66. The ratio actually determined was 0.60. The rapidity of the reaction and the nearly quantitative yields obtained offered further confirmation of the proposed mechanism. The syntheses of oxazoles by the methods of Japp and Wilcock and Sircar and Sircar are best explained by the formation of the quinoneimine and the hydrobenzamide of the aromatic aldehyde used, followed by their further reaction according to the scheme shown above. To test the assumption of Sircar and Sen that the oxazole was formed first and imidazole then resulted by the replacement of the oxygen by the imino group, 2-phenylretenoxazole was heated with aqueous ammonia at 170-180"and 500 lbs. pressure for forty-nine hours. The starting material was recovered almost quantitatively. Melting points, mixed melting points, and analyses all indicated that no conversion had occurred. Similar treatment of 2-(2'-hydroxyphenyl)retenoxazole likewise resulted in no conversion. When a sample of the latter was heated a t 240-250" for fifty hours under 1100-1300 lbs. pressure, almost complete decomposition resulted but no trace of the imidazole was found. This failure to convert oxazole to imidazole, even with the salicylaldehyde product, whose imidazole was formed in the cold, indicated that the oxazole cannot be the necessary intermediate for imidazole formation. These compounds must be formed independently and through different mechanisms. The remaining part of this study was devoted to the preparation of a series of 2-aryl retenoxazoles and several of the corresponding imidazoles. The compounds which for convenience were called 2-arylretenoxazoles, may also be called 2-aryl-5-isopropyl-1l-methylphenanthroxazoles.

The method of Sircar and Sircar was modified in certain respects. Isolation of the products was simpler when the condensations were carried out in absolute ethyl alcohol rather than in isoamyl alcohol and the yields were higher in many cases. The condensations were also carried out in boiling toluene. The best results were obtained when equivalent amounts

148


of the retenequinone and aldehyde were dissolved in the boiling solvent and a rapid stream of dry ammonia was passed through the refluxing solutions for a short time, usually no longer than thirty minutes. The condensations were also carried out a t room temperature as well as cold, using either ethyl or isoamyl alcohol as the solvent. Ammonia was passed through the suspension of retenequinone in the solvent containing the aldehyde until the quinone was entirely dissolved, or until the product precipitated to a solid mass. The yields were lower than those obtained from hot solutions. In no case did a change in temperature alter the nature of the products obtained. Heated, benzaldehyde, p-tolualdehyde, o-chlorubenzaldehyde, m-nitrobenzaldehyde, p-dimethylaminobenzaldehyde, p-diethylaminobenzaldehyde] vanillin, anisaldehyde, veratraldehyde, piperonal, and furfuraldehyde formed only oxazoles. Salicylaldehyde and p-hydroxybenzaldehyde gave, both hot and cold, mixtures of the corresponding oxazoles and imidazoles. When such mixtures were obtained from hot reactions, the oxazoles were usually found in greater quantities than the imidazoles. In cold reactions this also held true except with the salicylaldehyde condensation carried out in cold isoamyl alcohol. Some condensations were also carried out by the method of Japp and Wilcock. Retenequinone, the aldehyde, and an excess of aqueous ammonia were heated together in an autoclave. Using benzaldehyde a t temperatures up to 230" and pressures of 1000 lbs., only the oxazole was obtained. The yields were high but not quantitative. With salicylaldehyde a t temperatures up to 200" and 580 lbs. pressure, a mixture of oxazole and imidazole was obtained. A larger relative percentage of imidazole was obtained than in runs in boiling ethyl or isoamyl alcohol, but the overall yield was low due to decomposition of the products a t the temperatures used. With m-nitrobenzaldehyde, only the oxazole was obtained a t 200" and 670 lbs. pressure. These results are a t variance with those reported by Sircar and Ray, and Sircar and Sen. This may be due to a difference in the chemical behavior of retenequinone and phenanthraquinone and acenaphthoquinone. Sircar used the last two compounds in his work. It will be noted that the retenoxazoles are formulated in an arbitrary manner in this paper, with the nitrogen atom of the heterocyclic ring always attached to the 9-position of the retene structure. The reactions leading to the formation of this ring are also indicated as taking place a t this position. All attempts to establish the absolute structure of these compounds were unsuccessful. It was planned to convert the retenoxazoles to either 9- or 10-retenol, the final product depending upon the relative positions of the nitrogen and oxygen atoms of the oxazole ring.


149

However these compounds resisted hydrolysis even under the most rigorous conditions. The arbitrary formulas assigned were considered the most probable after an examination of the work of Lux (9), who found 3-methyl-4'isopropylbiphenyl-2-carboxylic acid among the decomposition products of retene. This acid was esterified only with difficulty, due

to the steric hindrance offered by the methyl and isopropylphenyl groups which occupied the positions adjacent to the carboxyl group. Such steric hindrance might also be a factor in inhibiting reactions with the quinoid oxygen in the 10-position and reaction would then occur preferentially a t the 9-position. The fact that only one oxazole was obtained in each case can be explained only on the basis of such an assumption. This work is being continued and extended to the mechanism of irnidazole formation by Day and co-workers. EXPERIMENTAL

AmEysis. The semi-micro Kjeldahl method was used for the nitrogen deterr minations. The distillate was absorbed in 4% boric acid solution, and titrated to a methyl red end-point, according to the method of Meeker and Wagner (10). Molecular Weights. The Rast method of determining molecular weights by the depression of the melting point of d-camphor was used, according to the directions of Shriner and Fuson (11). Retenequinone. Fifty grams (0.21 moles) of retene (Eastman practical grade) was suspended in 2 1. of glacial acetic acid. Ninety-two grams (0.92 moles) of chromic anhydride was dissolved in the minimum of cold water. This solution was diluted with an equal quantity of glacial acetic acid and added dropwise, over a period of two hours, to the well stirred retene suspension. The reaction-mixture was cooled when necessary to keep the temperature below 40'. After the addition was completed, the reaction-mixture was stirred for two hours. It was then diluted with 4 1. of distilled water and allowed to stand for one-half hour. The precipitated retenequinone was removed by filtration and washed with cold water until the waahings were colorless. The crude product was dried in air and then recrystallized twice from chloroform; m.p. 197.5' (corr.). This method gave an excellent product and purification through the bisulfite addition-product waa not necessary. The yield was 50% of the theoretical, based on the quantity of retene used. Preparation of retenequinoneimine. [After Bamberger and Hooker (S).] Ten grams of retenequinone was dissolved in 400 cc. of chloroform and 400 cc. of a saturated solution of ammonia gas in absolute alcohol was added. This was allowed to stand, tightly stoppered, a t room temperature for five days. The solution was evaporated as rapidly as possible a t room temperature and the crystalline product obtained was separated from the small amount of gums formed. Slow evaporation, particularly in moist air, produced poor results. The product was recrystallized

150


from absolute alcohol saturated with dry ammonia gas and was obtained as yellow needles. Prolonged heating was avoided. M.p. 108-110" (corr.) ; yield, 60%. Anal. Calc'd for CiJIirNO: N, 5.32. Found: N, 5.25. The reaction ojretenequinone with ammonia. (a) Ten grams of retenequinone W M suspended in 250 cc. of absolute alcohol and anhydrous ammonia gas was passed through the solution for thirty minutes. The temperature rose during the addition from 18' to 40" and then fell to 13". The red solution was filtered from unreacted retenequinone and was diluted with an equal volume of water. The resulting yellow precipitate was filtered from the colloidal suspension. All attempts to break the colloidal suspension which invariably resulted a t this stage were futile. The crude product was recrystallized from ethyl alcohol (max. temp. 40') and wm obtained as yellow needles, m.p. 104-105° (corr.). Anal. Calc'd for CicHirNO: N, 5.32. Found: N, 5.28. (b) Five grams of retenequinone was suspended in 200 cc. of absolute alcohol and the suspension WBB cooled to 5". Anhydrous ammonia was added for seven and one-half hours; the temperature rose to 16" and then fell to 11". The dark red solution was filtered and was then diluted with an equal volume of distilled water. The precipitated product was recrystallized from ethyl alcohol and was obtained as yellow plates, with a greenish-gold tinge, m.p. 125' (corr.), (Compound 11). Anal. Calc'd for CUHUNIO~:N, 3.63. Found: N, 3.62. (c) Ten grams of retenequinone was dissolved in 250 cc. of boiling absolute alcohol and ammonia gas was passed through the refluxing solution for forty-seven minutes. The dark red solution was poured into 500 cc. of cold distilled water and the precipitated yellow product was isolated by filtration. After recrystallization from ethyl alcohol, it was obtained as shining golden plates, m.p. 159-169" (corr.), (Compound 111). Anal. Calc'd for C J L N O s : pu', 2.66. Found: N, 2.55. (d) Other runs were carried out in the same manner. The results shown in Table I were obtained by suspending 10 g. of retenequinone in 250 cc. of absolute alcohol and adding ammonia for the desired period. The solutions were filtered, diluted with an equal volume of distilled water, and the resulting product recrystallized from ethyl alcohol. The reaction of retenequinoneimine mathbenzaldehyde. Five grams (0.019 moles) of retenequinoneimine and 2.0 cc. (0.019 moles) of benzaldehyde were dissolved in 60 cc. of dry toluene and refluxed for three hours. Ammonia was evolved slowly over the entire period, The solution was chilled and the precipitated product was filtered from the liquid. By fractional crystallization from ethyl alcohol, a small amount of 2-phenylretenoxazole was separated from retenequinone. Evaporation of the toluene liquor yielded no further oxazole but only benzaldehyde and retenequinone. Recovered retenequinone, 76%; yield of oxazole, 1.4%; m.p. of the 2-phenylretenoxazole, 171-173" (corr.). The reaction of retenequinoneimine with p-hydrozybenzaldehyde. (a) One gram of retenequinoneimine and 0.6 gram of p-hydroxybenzaldehyde were dissolved in 100 cc. of absolute alcohol. After forty-eight hours standing a t room temperature, a slight positive test for ammonia was obtained. After eight days, a very slight precipitate was observed in the flask. After thirty days the precipitate was filtered from the solution, extracted with 50 cc. of hot alcohol, and then recrystallized from dioxane. The product was obtained as tan plates, m.p. above 300', yield, 6%. Anal. Calc'd for C%sH,1NO%: N, 3.81, for CZ&LNSO: N, 7.65. Found: N, 7.13.


151

(b) Two grams of retenequinoneimine and 1.1g. of p-hydroxybenzaldehyde were dissolved in 100 cc. of absolute alcohol and the mixture was refluxed for three hours. Ammonia was given off. The reaction-mixture was chilled and the precipitated product was removed. It was extracted with ethyl alcohol and then recrystallized from dioxane. M.p. above 3W0, yield, 16%. Analysis showed that the product consisted mostly of the corresponding imidazole. Evaporation of the mother liquor under reduced pressure yielded retenequinone and p-hydroxybenzaldehyde but no further product was found. (c) One gram of retenequinoneimine and 0.6 g. of p-hydroxybenzaldehyde were dissolved in 100 cc. of dry toluene and the mixture was refluxed for forty-five minutes. A small amount of ammonia was liberated. On chilling, an orange product was obtained which was entirely soluble in ethyl alcohol. It was identified as retenequinone. Evaporation of the mother liquor yielded more retenequinone and p-hydroxybenzaldehyde. The reaction of retenequinone with hydrobenzamide. (a) Five grams (0.019 moles) of retenequinone and 5.46 g. (0.019 moles) of hydrobenzamide were dissolved in isoamyl alcohol and the mixture waa refluxed for two hours. Ammonia was evolved during this period. After standing overnight, the precipitated solid was removed by filtration and recrystallized from ethyl alcohol. It was identified aa 2-phenylretenoxazole, m.p. 170" (corr.), mixed m.p. with 2-phenylretenoxazole, 170" (corr.) ; yield, 60%. (b) The reaction was repeated in 150 cc. of dry toluene and after refluxing for one hour, the solution was cooled. A small amount of ammonia was given off during the refluxing period. Chilling the solution yielded unchanged quinone. The solution was evaporated and retenequinone and hydrobenzamide were recovered. In the last residues, lophine was isolated and identified by its melting point, 275" (corr.), mixed m.p. with an authentic sample of lophine, 275" (corr.). Recovery of retenequinone waa 90% complete. (c) The reaction was repeated in 100 cc. of dry toluene. After refluxing for three hours, during which period ammonia was given off, the reaction-mixture was chilled and precipitated retenequinone waa removed. By evaporation of the mother liquor under reduced pressure and fractional crystallization from ethyl alcohol, 2-phenylretenoxazole was isolated, m.p. 172" (corr.) ; yield, 2.1%. The reaction of retenequinoneimine with hydrobenzamide. (a) Two and one-half grams (0.010 moles) of retenequinoneimine and 2.82 g. (0.010 moles) of hydrobenzamide were dissolved in 50 cc. of dry toluene and the mixture refluxed for exactly three hours. As ammonia formed it was collected in 50 cc. of 4% boric acid solution; and after the refluxing period the system was swept out for thirty minutes by a stream of dry air to complete the collection of ammonia. The trapped ammonia was titrated to a methyl red end-point with standard hydrochloric acid, after the method of Meeker and Wagner. During the refluxing period, color changes were observed in the reaction-mixture. After six minutes of refluxing, the solution turned a very dark green. During this period no ammonia was evolved. After another four minutes the solution became a light yellow and ammonia was evolved. After refluxing for three hours and sweeping out for thirty minutes, the reactionmixture was made slightly acid with hydrochloric acid, chilled for twelve hours and filtered. By repeated evaporation and chilling, more product was obtained. After recrystallization from dioxane, i t was identified as 2-phenylretenoxazole, m.p. 172" (corr.); yield, 96%; 0.0096 moles. Titration of the ammonia as described above indicated a yield of 0.0057 moles.

152

SAUL I. KREPS .4ND ALLAN R. DAY

(b) The reaction WM repeated with the same quantities of reactants. The color changes were observed to occur exactly as described above. The reaction-mixture was chilled after refluxing for ten minutes and acidified with hydrochloric acid. 2-Phenylretenoxazole was obtained as the product. After recrystallization from dioxane, i t melted a t 172" (corr.), yield, 78%. The hydrolysis o j hydrobenzamide. Hydrobenzamide (5.64 g. ; 0.019 moles) was dissolved in 100 cc. of dry toluene and refluxed for three hours. The quantitative procedure described in the foregoing section for the determination of ammonia was followed. Titration of the ammonia given off with standard hydrochloric acid t o a methyl red end-point indicated that 0.0002 moles of ammonia were liberated. Attempted conversion o j 2-aryl retenoxazoles to $-aryl retenimidazoles. (a) Five grams of pure 2-phenylretenoxazole was mixed with 250 cc. of aqueous ammonia (28%) and heated in the autoclave for forty-nine hours a t 170-180" and400-500 pounds pressure. The solid product was then separated from the ammoniacal liquor. Evaporation of the liquor left no organic residue. The solid was recrystallized from acetone. Yield, 4.8 g., 96% recovery of 2-phenylretenoxazole, m.p. 173" (corr.), mixed m.p. with a sample of 2-phenylretenoxazole, 172" (corr.). Anal. Calc'd for CzsHllNO: N, 3.99. Found: N, 4.04. (b) Five grams of pure 2-(2'-hydroxyphenyl)retenoxazole was mixed with 250 cc. of aqueous ammonia and heated for fifty hours at 170-180° and 900-1150 lbs. pressure. Ninety-four per cent of the original material was recovered. Bfter recrystallization from dioxane, the melting point was 242' (corr.). Anal. Calc'd for C z ~ H * l N ON, ~ : 3.81. Found: N, 3.87. (c) Five grams of pure 2-(2'-hydroxyphenyl)retenoxazole was mixed with 250 cc. of aqueous ammonia and heated for fifty hours at 240-250" and 1100-1300 lbs. pressure. The compound was completely destroyed under these conditions. Attempts to hydrolyze 2-aryl retelzoxazoles. (a) Two grams of 2-phenylretenoxazole and 40 cc. of concentrated hydrochloric acid were heated i n pressure flasks for 100 hours at 130-140". At the end of this period, the compound was removed from the mixture and washed with water until free of acid. Recovery was 100%. The compound was slightly yellow, m.p. 171-172" (corr.). After recrystallization from ethyl alcohol, the compound melted a t 172" (corr.). Anal. Calc'd for C26H21NO:N, 3.99. Found: N, 4.03. (b) Hydrolysis of 2 g. of 2-phenylretenoxazole by 40 cc. of 95% acetic acid, at 140-150" for 100 hours waa attempted. The same technique described in part (a) was used. The compound was appreciably soluble in acetic acid. Recovery on cooling, 90%. Careful addition of water to the filtrate yielded more of the product. Total recovery, 98%, m.p. 172" (corr.), mixed m.p. with 2-phenylretenoxazole, 172" (corr.), (c) Hydrolysis of 1 g. of 2-(3'-nitrophenyl)retenoxaeole (m.p. 238") by 20 cc. of concentrated hydrochloric acid at 130-140' was also attempted. The recovered solid showed some evidence of decomposition; m.p. 220-237", with slight decomposition. After recrystallization from ethyl alcohol, the melting point was 238.5' (corr.). Recovery, 98%. No further product could be found, Preparation of I-aryl retenoxazoles and %aryl retenimidazoles. The method of Sircar and Sircar was used, modified in certain respects. Ten grams (0.038 moles) of retenequinone and 0.038 moles of the appropriate aldehyde were dissolved in 100-150 CC. of the solvent. This mixture was heated to boiling and anhydrous ammonia gas was passed through the refluxing mixture for thirty minutes, except in those cases where the product precipitated from the reaction-mixture in a shorter


153

time. The solution was cooled and filtered and the crude product was washed with cold ethyl alcohol t o remove colored impurities. By evaporation of the mother liquor under reduced pressure more of the product was usually obtained. The reaction waa also carried out cold, by suspending the retenequinone in a solution of the aldehyde in the solvent. Anhydrous ammonia gas was passed through the solution for thirty minutes or until the product precipitated from the reactionmixture. The general procedure was then followed as outlined above. The method of Japp and Wilcock was also employed in some cases. The retenequinone and aldehyde were mixed with an excess of aqueous ammonia and heated in a stainless steel autoclave a t high temperatures. At the end of this period the product was removed, ground up into a fine powder, and purified. I-Phenylretenorazole(IV). This compound was prepared by the method of Sircar and Sircar, using hot isoamyl alcohol as the solvent. It was recrystallized from dry alcohol, yield, 24%. The compound was also prepared by the method of Sircar and Sircar from cold ethyl alcohol, yield, 16%. The method of Japp and Wilcock was also used. The mixture was heated for six hours at 230" and 1000 lbs. pressure, yield, 90%. 8-(3'-Methylphenyl)retenoxazole (V). The compound was prepared by the method of Sircar and Sircar, from retenequinone and m-tolualdehyde dissolved in 100 cc. of boiling absolute ethyl alcohol. A solid precipitated before the reaction was completed. The product was recrystallized from dioxane and obtained as needles with a pink tinge, yield, 43%. 8-(I'-ChZorophenyl)retenoxazole (VI). The compound was prepared from retenequinone and o-chlorobenzaldehyde dissolved in 100 cc. of boiling isoamyl alcohol. It was recrystallized from dioxane, yield, 33%. I-(3'-NitrophenyZ)retenosazoZe (VII). This compound was prepared from retenequinone and m-nitrobenzaldehyde dissolved in 100 cc. of boiling absolute ethyl alcohol. The yellow product precipitated from the reaction-mixture after twenty minutes. It was recrystallized from dioxane, yield, 56%. This compound was also prepared by the method of Japp and Wilcock. The mixture was heated for six hours a t 200" and 670 lbs. pressure, yield, 96%. 2-(4'-DimethyEaminophenyl)retenoxazoZe (VIII). This compound was prepared from retenequinone and p-dimethylaminobenzaldehyde dissolved i n 100 cc. of boiling absolute ethyl alcohol. It was obtained as lemon yellow prisms, showing a slight green fluorescence, after recrystallization from dioxane, yield, 52%. 8-(4'-Diethylarninophenyl)retenoxazole (IX). This compound was prepared from retenequinone and p-diethylaminobenzaldehyde dissolved in 100 cc. of boiling isoamyl alcohol. It was recrystallized from dioxane, yield, 30%. I-(2'-Hydroxyphenyl)~etenoxazoZe (X) and I-(2'-hydroxypheny2)retenimidazole (XI). These compounds were prepared from retenequinone and salicylaldehyde dissolved in 100 cc. of boiling absolute alcohol. The products began to separate out of the reaction-mixture a t the end of ten minutes, although the addition of ammonia was continued for the full thirty minute period. The products were separated by fractional crystallization from dioxane. By cooling the dioxane slowly to room temperature, the oxazole was obtained; i t was recrystallized from dioxane, yield, 63%. By evaporating the dioxane mother liquor to a small volume and chilling, the imidazole was obtained. This was recrystallized from ethyl alcohol, yield, 7%. The compounds were also prepared from retenequinone and salicylaldehyde i n cold isoamyl alcohol. The general procedure was followed. By chilling the reac-

154


tion-mixture overnight, the crude product was obtained. The components were separated by fractional crystallization from ethyl alcohol. Yield of oxazole, 2%; of imidazole, 30%. The preparation waa also carried out in hot isoamyl alcohol. Separation was effected by fractional crystallization from dioxane. Yield of oxazole, 20%; of imidazole, 1%. The method of Japp and Wilcock was also used. It was noted that the salicylaldehyde and aqueous ammonia reacted immediately upon mixing to form a gummy yellow precipitate. After heating the mixture for five hours at 200" and 580 lbs. pressure, the products were separated by fractional crystallization from dioxane and were at the same time separated from gums and carbon caused by extensive decomposition at the temperature of the reaction. Yield of the oxazole, 32%; of the imidazole, 12%. 8-(4'-Hydroxyphenyl)retenozazole (XII) and 8-(4'-hydroxyphenyl)retenimidazole (XIII). The compounds were prepared from retenequinone and p-hydroxybenzaldehyde, dissolved i n 100 cc. of boiling absolute ethyl alcohol. The general procedure was followed. After ten minutes, the mixture had set into a solid mass. The product was removed from the cool mixture by filtration and was waahed with cold alcohol. Evaporation of the mother liquor produced no further product. The crude product was recrystallized from dioxane and was obtained as small tan plates, m.p. above 300". The color persisted through further recrystallization and could not be removed by treatment with decolorizing charcoal. Nitrogen analysis indicated that a mixture of the oxazole and imidazole was present. Attempts a t fractional crystallization and fractional extraction with a variety of solvents including dioxane, benzene, toluene, chloroform, acetone, and alcohol were ineffectual due t o the similar solubilities of XI1 and XIII. Separation was finally effected by dissolving the mixture in a large volume of hot dioxane and passing dry hydrogen chloride into this hot solution. The hydrochloride of the imidazole was precipitated and filtered from the hot solution. Further addition of hydrogen chloride to the clear hot filtrate did not produce further precipitation. On cooling this solution, the pure oxazole was obtained, yield, 16%. The imidazole hydrochloride was boiled with dioxane to remove any contaminating oxazole. It was obtained as buff colored plates, m.p. above 300". Anal. Calc'd for C&z*N20*HC1: N, 6.95. Found: N, 6.81. The base was obtained by boiling the hydrochloride in 5% aqueous sodium hydroxide for two hours. The solid was separated by filtration, washed with water and alcohol and then recrystallized from dioxane. It was obtained as small, shining, tan plates, yield, 19%. These compounds were also prepared cold by the method of Sircar and Sircar, using 100 cc. of chloroform as the solvent. Evaporation of the solution to dryness was necessary to recover the product. It was extracted with a mixture of alcohol and acetone, under reflux for one hour, and then recrystallized from dioxane. Analysis for nitrogen indicated that the product was a mixture of the oxazole and imidazole, of approximately the same composition as the mixture obtained from hot alcohol. Total yield, 26%. 8-(~'-Hydroxy-d'-methoxyphenyl)retenoxazole(XIV). This compound was prepared from retenequinone and vanillin, dissolved in 100 cc. of boiling absolute ethyl alcohol. The product was obtained after chilling the reaction-mixture in the ice box for two days. It was recrystallized from dioxane, yield, 71%. 8-(4'-Methoxypheny1)retenozazole (XV). This compound was prepared from


. . . . . . . . . . . . . . .. .. .. .. .. .. .. .. . . . . .. .. . .

155

156


retenequinone and anisaldehyde dissolved in 100 cc. of boiling absolute ethyl alcohol. The same procedure waa used as for the vanillin condensation. The product waa recrystallized from dioxane, yield, 55%. ~-(S‘,~’-Dimethozyphenyl)retemzazoZe (XVI). This compound was prepared from retenequinone and veratraldehyde dissolved in 100 cc. of boiling absolute ethyl alcohol. The same procedure was followed as for the vanillin condensation. It was recrystallized from dioxane, yield, 60%. b-(S’, 4‘-MethyZenediozypheny2)retemmzole (XVII). This compound was prepared from retenequinone and piperonal dissolved in 100 oc. of boiling absolute ethyl alcohol. The same procedure was used aa for the vanillin condensation. The product was crystallized from dioxane, yield, 62%. B-(a-FurfuryZ)rete~zazoZe(XVIII). This compound waa prepared from retenequinone and furfuraldehyde dissolved in 100 cc. of boiling absolute ethyl alcohol. A t the end of thirty minutes, the reaction-mixture had set into a solid mass. After recrystallization from dioxane and then from alcohol, the compound ww obtained as small, white needles, yield, 40%.

PHILADELPHIA, PA. SUMMARY

1. The reaction of retenequinone and ammonia has been studied. 2. A critical study has been made of the mechanisms previouslyassigned to the reaction of o-quinones and aromatic aldehydes in the presenceof ammonia to form oxazoles and imidazoles. 3. A new mechanism, in agreement with experimental findings, has been developed to explain the formation of 2-aryl retenoxazoles from retenequinone, aromatic aldehydes, and ammonia. 4. A series of 2-aryl retenoxazoles and 2-aryl retenimidazoles has been prepared. REFERENCES

(1) JAPPAND WILCOCK,J . Chem. SOC.,37, 661 (1880). (2) JAPPAND WILCOCK,J . Chem. SOC.,39, 225 (1881). (3) JAPPAND STREATFEILD, J . Chem. Soc., 41, 146 (1882). (4) SIRCAR AND SIRCAR, J . Chem. Soc., 123, 1559 (1923). (5) SIRCAR AND RAY,J . Chem. SOC.,127, 1048 (1925). AND SEN,J . Indian Chem. SOC.,8, 605 (1931). (6) SIRCAR (7) DE AND GHOSH,J . Indian Chem. SOC.,7 , 357 (1930). (8) BAMBERGER AND HOOKER, Ann., 229, 102 (1885). (9) Lux, Monatsh., 29, 763 (1908). (10)MEEKERAND WAGNER,Ind. Eng. Chem., Anal. Ed., 6, 396 (1933). (11) SHRINER AND FUSON, “The Systematic Identification of Organic Compounds”, p. 67, John Wiley, New York, 1935.

THE PREPARATION OF SOME DERIVATIVES OF RETENOXAZOLE

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