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methyl ketone and 2-phenyl quinoline-4-methyl ketone, the preparation of the ... of p,p'-diacetyldiphenyl (4),. 20.5 g. .... Four hundred twenty grams...
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THE CHEMICAL

RESEARCH LABORATORY OF SCHERINQ

CORPORATION]

PREPARATION OF ARYL ALIPHATIC ACIDS BY THE MODIFIED WILLG-ERODT REACTION ERWIN SCHWENK

AND

DOMENICK PAPA

Received July 9 , 1946

Recently there has been described from these laboratories (1) a simplified procedure for carrying out the Willgerodt rearrangement of aryl methyl ketones to the aryl acetic acids using morpholine and sulfur in place of the conventional ammonium polysulfide. In the course of other investigations we have had the opportunity to apply this modification of the Willgerodt reaction to a number of ketones not previously studied. In the meantime, the reaction has been used successfully by other investigators (2) with slight modification. We have now established that the reaction is much more general than previously reported. Under the proper conditions amino and hydroxy substituted aryl-aliphatic ketones can be converted into the corresponding aryl-aliphatic acids in yields ranging from 40-6070. Halogenated aryl ketones give the corresponding acetic acids in yields of 50%. In addition, ketones such as phenyl n-propyl and phenyl n-butyl ketones react to give the w-phenyl aliphatic acids in yields of 36Y0 and 14% respectively. With carboxy or carbalkoxy substituted ketones, an interesting series of reactions takes place. When such ketones are heated with sulfur and an excess of morpholine, the keto group undergoes the normal Willgerodt rearrangement to the thioacetmorpholide with the simultaneous aminolysis of the carboxy or carbalkoxy group to the morpholide. For example, o-acetyl benzoic acid and its ethyl ester gave under such conditions the dimorpholide of o-carboxy phenylthioacetic acid. With the isomeric m- and p-acetylphenylacetic acids and their esters, amide formation, although observed, is not complete. In addition, it was established that with excesses of sulfur, the morpholide could be further converted into the morpholide of the corresponding thioacid. However, in spite of the apparent diversity of reactions which occur, the conversion of carboxy or carbalkoxy aryl ketones into the corresponding acids proceeds in good yields. Several heterocyclic ketones were also studied. In the case of 3-pyridyl methyl ketone and 2-phenyl quinoline-4-methyl ketone, the preparation of the thioacetmorpholide proceeded normally. However, a-thienyl meth-yl ketone on treatment with sulfur and morpholine gave a black tarry mass from which none of the thiomorpholide could be isolated, and on saponification none of the expected 2-thienyl acetic acid was obtained. From the readily accessible mono- and di-acetyldiphenyls, p-xenylacetic acid and the p ,p'-diphenyldiacetic acid have been obtained in over-all yields of 80-85%. These two acids hare previously been prepared by the chloromethylation of diphenyl and conversion of the chloride to the nitrile followed by hydrolysis. Such reactions give, a t best, exceedingly poor over-all yields. 798

PREPARATION OF ARYL ALIPHATIC ACIDS

799

In general, the morpholine-sulfur modification of the Willgerodt reaction is applicable to any aromatic-aliphatic ketone except those ketones substituted by groups which are attacked under the conditions of this reaction. EXPERIMENTAL

p-Xenylacetic acid. A mixture of 78.4 g. (0.4 m.) of p-phenylacetophenone, 20.5 g. (0.64 m.) of sulfur, and 125 cc. of morpholine was refluxed for 6-8 hours. A large excess of morpholine was used in this and subsequent preparations since i t was found desirable t o have the reaction mixture fluid during the reflux period. Toluene and xylene were unsatisfactory solvents. While the mixture was still hot, i t was poured into 500 cc. of methyl alcohol, cooled, filtered, and washed with a small volume of cold methyl alcohol, yield 112 g. (94oJ,), m.p. 137-139".'* This material was sufficiently pure for hydrolysis t o p-xenylacetic acid. Recrystallized for anaylsis from ethyl alcohol, m.p. 142-143". Anal. Calc'd for Cl&IloNOS: N , 4.71. Found: N , 4.72. One hundred twelve grams of the crude thioacetmorpholide was refluxed for eight hours with 750 cc. of 70% ethyl alcohol and 150 cc. of 50% NaOH. The alcohol was then removed by evaporation, water added to the residue, and after neutralizing with HC1 and treating with charcoal, the solution was filtered. The filtrate, on acidification, gave 76 g. (95%) of p-xenylacetic acid, m.p. 155-159". Recrystallized from acetic acid, m.p. 16&165", literature m.p. 153" (3). Anal. Calc'd for C14H120z: C, 79.21; H , 5.66. Found: C, 79.12; H , 5.94. Replacing morpholine by piperidine in the above reaction gives rise to the piperidide of p-xenylthioacetic acid,lb m.p. 131-132' after recrystallization from alcohol. Anal. Calc'd for CloHllNS: N , 4.74. Found: K,4.86. p, p'-Diphenyldiacetic acid. A mixture of 47.6 g. (0.2 m.) of p,p'-diacetyldiphenyl (4), 20.5 g. (0.64 m.) of sulfur, and 150 cc. of morpholine was refluxed for 8-10 hours. The bisthioacetmorpholidelCwaa isolated by pouring the reaction mixture into alcohol, yield 78 g. (88.5%), m.p. 225-227". Recrystallized from benzene and petroleum ether, m.p. 228-229". Anal. Calc'd for C2&,Nz0~S2: C, 65.47; H, 6.41. Found: C , 64.96; H , 6.50. Seventy-two grams of the crude bis-thioacetmorpholide was refluxed with 750 cc. of 70% alcohol and 100 cc. of 50% NaOH for approximately 12 hours. The reaction mixture was worked up as described for p-xenylacetic acid, the crude p, p'-diphenyldiacetic acid being recrystallized from acetic acid, yield 38 g. (86%), m.p. 280-282", literature m.p. 270-273' (5). Recrystallized from acetic acid for analysis, m.p. 282-284". Anal. Calc'd for ClsHl,OI: C, 71.08; H, 5.22. Found: C , 70.82; H , 5.54. p-Phenylenediacetic acid. A mixture of 82.4 g. (0.4 m.) of ethyl p-acetylphenylacetatez (6), 20.5 g. (0.64m.) of sulfur, and 150 cc. morpholine was refluxed for six hours, then poured into 500 cc. of ethyl alcohol. The reaction product could not be crystallized and was hydrolyzed by refluxing with alcoholic alkali for six hours. The alcohol was then evaporated and the p-phenylenediacetic acid isolated using the procedure described for p-xenylacetic acid, yield 60 g., m.p. 220-230". Recrystallized from dilute ethanol, yield 53.5 g. (70%), m.p. 253-254'; literature m.p. 236", 240-241", and 244". A n d . Calc'd for CloHlo04:C, 61.85; H, 5.19; N.E., 97. Found: C, 61.77; H, 5.37; N.E., 98. The Survey Number, designated SN, identifies a drug in the files of the Survey of Antimalarial Drugs. The activities of these drugs will be given in a forthcoming monograph; la, SN-13,097; l b , SN-13,098; IC, SN-13,096; Id, SN-13,099; l e , SN-13,095; If, SN-13,656. 2 The free acid can be used in this preparat,ion and gives approximately the same yield.

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ERWIN SCHWENK A N D DOMENICK PAPA

m-Phenylenediacetic acid. A mixture of 197 g. of crude ethyl m-acetylphenylacetates

(6), 50 g. of sulfur, and 250 cc. of morpholine was refluxed for eight hours. The thioacetmorpholide did not crystallize from alcohol and was directly hydrolyzed by refluxing for 8-10 hrs. with lo00 cc. of 70% alcohol and 200 cc. of 50% sodium hydroxide. Thereaction product was worked up and 120 g. of m-phenylenediacetic acid was obtained, m.p. 166167'. The ethyl ester was prepared in the usual manner and distilled, yield 145 g., b.p. 145-150"/1 mm. The distillate partially solidified, and the liquid and solid fractions were separated by filtration. The solid fraction, amounting to 25 g., was saponified and identified as p phenylenediacetic acid, m.p. and mixed m.p. 253-254". The liquid fraction was saponified yielding m-phenylenediacetic acid, m.p. 171.5-172", literature 170'. Anal. Calc'd for CIOHIOO~: C, 61.85; H, 5.19; N.E., 97. Found: C, 61.74; H, 5.26; N.E., 97.8. Homophthalic acid. Refluxed for five hours 16.4 g. (0.1 m.) of o-acetylbenzoic acid (7), 4.8 g. (0.16 m.) of sulfur, and 20 cc. of morpholine. After cooling, the somewhat viscous solution was slowly poured into a mixture of ice and sulfuric acid. The solid product, SO obtained was filtered and recrystallized from dilute alcohol, yield 5 g. (15.5%): m.p. 160Recrystallized for analysis from dilute alcohol, m.p. 163.5-164'. The compound SO 164'. obtained is the dimorpholide of o-carboxyphenylthioaceticacid.ld Anal. Calc'd for C Z ~ H X N ~ OC,~ 61.06; S: H, 6.64; N , 8.38. Found: C, 61.16; H, 6.76; N, 8.51. The above described dimorpholide was also obtained from ethyl o-acetylbenzoate by refluxingfor six hours 23 g. of ester, 5 g. of sulfur, and 40 cc. of morpholine. The reaction mixture, while still warm, was diluted with ethyl alcohol, and after the addition of ice, the dimorpholide crystallized out, yield 26 g., m.p. 163.5-164.5'. Mixed melting point with product obtained from the free acid showed no depression. Ten grams of the dimorpholide was saponified with SO cc. of 10% alcoholic sodium hydroxide. The alcoholic solution was then diluted with an equal volume of water, the alcohol evaporated and the aqueous solution acidified. The crude homophthalic acid was filtered and then recrystallized from water, yield 3.5 g. (65%), m.p. 176-177", literature 175-177'. Hydrocinnamic acid. A mixture of 28.8 g. (0.2 m.) of propiophenone, 10.2 g. (0.32 m.) Bulfur, and 23 g. (0.26 m.) of morpholine was refluxed for six hours. The reaction product was poured into 200 cc. of 10% alcoholic sodium hydroxide and refluxed for 6-8 hrs. After removing the alcohol, the alkaline solution was diluted with water, acidified with hydrochloric acid to Congo Red paper and extracted twice with ether. The ether extracts were washed with water, dried, and after removing the ether, the residue was distilled, yield 19.5 g. (65%) ; b.p. 125-129'/6 mm.; m.p. 46-47", 7-Phenylbutyric acid. A mixture of 74 g. (0.5 m.) of phenyl n-propyl ketone, 25.6 g. (0.8m.) of sulfur, and 75 cc.of morpholine was refluxed for 15 hours. The oily reaction product was saponified and worked up by ether extraction. The ether residue was recrystallized from water, yield 30 g. (36%), m.p. 47-49". Recrystallized again from water, 1n.p. 50-51', literature 51". Keutral equivalent 164; found 164.6. A-Phenylvaleric acid. A mixture of 81 g. (0.5m.) of phenyl n-butyl ketone, 25.6 g. (0.8m.) of sulfur, and 75 cc. morpholine was treated as described for the phenyl n-propyl ketooe. The ether residue was recrystallized from water, yield 12 g. (14%), mop. 58-59', literature 57-58'. Keutral equivalent 178; found 179. p-Methozyphenylacetic acid. Four hundred twenty grams (2.8 m.) of p-methoxyacetophenone, 135 g. (4.2 m.) of sulfur, and 298 g. (3.5 m.) of morpholine were refluxed for five hours. The reaction mixture was slowly poured into water, allowing the first addition t o crystallize before the bulk of the mixture was added. The crude yellow solid was filtered, thoroughly ground up with water, filtered, and air-dried, yield 676 g. (96%), map.64-67.5". Recrystallized for analysis from dilute methanol, m.p. 71-72". 3 This represents the yield obtained when the theoretical amount of morpholine is used. In an experiment using 50 cc. of morpholine, the yield was 65%.

PREPARATION OF ARYL ALIPHATIC ACIDS

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Anal. Calc'd for ClSHI7NO2S:N , 5.58; S, 12.75. Found: N,5.65;S, 12.45. T o 4 liters of 10% alcoholic sodium hydroxide, 502 g. (2m.) of the crude thioacetmorpholide was added and the mixture refluxed for 10 hours. After removing most of the alcohol, one liter of water was added to the distillation residue and the alkaline solution strongly acidified with HCI. The resulting solution was cooled and then thoroughly extracted with ether. The ether extracts were combined, evaporated, and the residue recrystallized from water, yield 260 g. (78%), m.p. 83-85', literature 85'. The aqueous filtrates should be extracted with ether since p-methoxyphenylacetic acid is quite soluble in water. p-Methoxyhydrocinnamic acid. Eighty-two grams (0.5m.) of p-methoxypropiophenone, 25.6 g. (0.8 m.) of sulfur, and 75 cc. of morpholine were refluxed for 8 hours. The oily thioacetmorpholide was added to 500 cc. of 10% alcoholic sodium hydroxide and the mixture refluxed six hours. The alcoholic solution was diluted with 250 cc. of water, the alcohol evaporated, and the resulting solution acidified and extracted with ether. After removing the ether, the residue was recrystallized from benzene-petroleum ether, yield 56 g. (62%); m.p. 98-100". Recrystallized again, m.p. 101-102", in agreement with the literature. p-Hydroxyphenylacetic acid. A mixture of 27.8 g. (0.2m.) of p-hydroxyacetophenone, 10.2 g. (0.32m.) of sulfur, and 35 cc. of morpholine was refluxed for six hours. The reaction product was poured into 200 cc. of 10% alcoholic sodium hydroxide and refluxed for six hours. The resulting alcoholic solution was diluted with an equal volume of water and the alcohol evaporated. The aqueous solution was acidified, cooled, and thoroughly extracted with ether. The ether was evaporated and the residue recrystallized from benzene, yield 12.6 g . (42%), m.p. 144-147". A second recrystallization raised the m.p. to 147-149",literature 148'. p-Hydroxyhydrocinnamic acid. Thirty grams (0.2 m.) of p-hydroxypropiophenone, 10.2 g. sulfur, and 35 cc. of morpholine were refluxedfor eight hours. The crude reaction product was saponified with 200 cc. of 10% alcoholic sodium hydroxide and worked up as described for the p-hydroxyacetophenenone. The ether residue wxs recrystallized from benzene-petroleum ether, yield 8.8 g. (26.801,),m.p. 126-127", literature 128'. p-Chlorophenylacetic acid. A mixture of 38.5 g. (0.25m.) of p-chloroacetophenone, 12.8 g. (0.4m.)of sulfur, and 30 cc. of morpholine was refluxed for eight hours. The crude product was saponified and poured into water. After evaporating the alcohol, the residue was acidified, cooled, and filtered, yield 28 g., m.p. !40-94". Recrystallized from water, yield 20 g. (47%), m.p. 100-101". A second recrystallization gave 18..6 g. of pure p-chlorophenylacetic acid melting at 102-104";literature 104'; 105-106'. p-Bromophenylacetic acid. The procedure as described for the chloro compound, was employed 50 g. (0.25m.) of p-bromoacetophenone, yield 25 g. (51%), m.p. 106-109" after recrystallization from water; recrystallized again, m.p. 112-113", literature 114-115'. p-Aminophenylacetic acid. Thirty-three grams (0.25m.) of p-aminoacetophenone, 12.8 g. (0.4m.) of sulfur, and 35 cc. of morpholine was refluxed for eight hours. The oily reaction product was saponified, poured into water, and the alcohol removed. The aqueous solution was then acidified with acetic acid, cooled thoroughly and filtered, yield 30 g., m.p. 170-186' dec. It, was recrystallized twice from water, yield 16.5 g. (43.8%), m.p. 194-196" dec., literature 199-200". Methyl 3-pyridylacetate. One hundred twenty-one grams (1.0m.) of 3-pyridyl methyl ketone (8),52 g. (1.6m.) of sulfur, and 150 g. of morpholine were refluxed for six hours. The reaction mixture was then poured into ice, and after standing overnight the crude solid was filtered, yield 141 g. (65.5%), m.p. 72-76'. It was recrystallized from benzene and petroleum ether, m.p. 78.5-79.5'. Anal. Calc'd for ClIHI,N20S: C, 59.44;H, 6.35. Found: C, 59.30;H, 6.40. Twenty-two and two-tenths grams (0.1m.) of the thioacetmorpholidd" was refluxed with 100 cc. of 50y0alcohol and 20 cc. of 50yosodium hydroxide. The reaction mixture was evaporated t o dryness under reduced pressure. The residue was taken up in 150 cc. of methyl

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ERWIN SCHWENK AND DOMENICK P h p A

alcohol, and, after saturating the alcoholic solution with dry HCl, it was concentrated to drynew. The residue was then extracted in a Soxhlet with methyl alcohol, and after removing the methyl alcohol the methyl 3-pyridylacetate was distilled, yield 8 g., b.p. 85"/2 111111. ~-Phenylqtlinoli7ae-~-thioocelmospholide.~f~ To 4.5 g. of sodium dust was added 100 cc. of anhydrous ether and 12 cc. of absolute ethyl alcohol. After the formation of the sodium ethoxide was complete, 17.5 g. of absolute ethyl acetate and 34 g. of ethyl P-phenylcinchoninate was added dropwise. The mixture was refluxed for 20 hours, poured into water and extracted with ether t o remove unreacted esters. The alkaline solution was acidified with HCl, the mixture refluxed for two hours and then made alkaline and extracted with ether. The ether was evaporated and the crude 2-phenylquinoline 4-methyl ketone was recrystallized from aqueous alcohol, yield 12.5 g., m.p. 76-78". Recrystallized for analysis, m.p.

n-780. Anal. Calc'd for ClTHlaNO: N, 5.67. Found: N, 5.93. A mixture of 9.5 g. of the ketone, 2 g. of sulfur, and 10 cc. of morpholine was refluxed for five hours. The cooled reaction mixture was poured into methyl alcohol and the crude solid product was recrystallized from alcohol, yield 8.6 g., m.p. 191-192'. Recrystallized for analysis, m.p. 193-194". Anal. Calc'd for CIIH~oN~OS: N, 8.04. Found: N, 8.27. ACKNOWLEDGMENT

h

The authors wish to express their appreciation to Miss Hilda Hankin, Mrs. a Klingsberg, and Mr. Peter Hirschler for their technical assistance. SUMMARY

1. The morphohe-sulfur modification of the Willgerodt reaction has been applied to the synthesis of halogen, hydroxy, and amino substituted aryl acetic acids. 2. C a r b o y and carbalkoxy methyl ketones react normally t o give carboxy arylacetic acids, 3. Several heterocyclic ketones were studied; the pyridyl and quinolyl methyl ketones reacting normally, whereas a-thienyl methyl ketone yielded only tarry products. B L O O ~ I PN. LD J. , REFERENCES

(1) SCHWENX AND BLOCK, J . Am. Chem. SOC.,84, 3051 (1942). J. Org. Chem., 9, 518 (1944); ARNOLD AND RONDESVEDT, J . Am. Chem. SOC., (2) NEWMAN, 67, 1265 (1945). (3) WILLQERODT AND SCHOLTZ,J. prakt. Chem., (2), 81,393 (1933). (4) SILVER AND LOWY, J. Am. Chem. SOC., 68, 2429 (1937). (5) v. BRAUN,IRXISCH, AND NELLES,Ber., 88, 1475 (1933). (6) PAPA, SCHWIENX,AND STRAUSS, J. Am. Chem. SOC.,In press. (7) GABRIEL,Ber., 26,952 (1893). ( 8 ) HURDAND WEBB,J . Am. Chem. Soc., 49,551 (1927); STBONG AND MCELVAIN, J. Am. Chem. SOC.,66, 818 (1933).