Scott P. Runyon, Srinivas Peddi, Jason E. Savage, Bryan L. Roth, Richard A. Glennon, and Richard B. Westkaemper. Journal of Medicinal Chemistry 2002 4...
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In the course of an investigation, reported elsewhere,' on the addition reaction between diphenylketene and styrene, the synthesis of the following acids was undertaken for comparison with an acid of formula C22H2002 derived from the addition product by hydrolytic fission : (0-ethylpheny1)diphenylacetic acid (I) ; benzohydrylbenzylacetic acid (11) ; [o-(a-phenylethy1)phenyllphenylacetic acid (111) ; [o-(8-phenylethyl)phenyl]phenylacetic acid (IV) ; o-benzyl-a-phenylhydrocinnamic acid (V) ; o-benzyl-p-phenylhydrocinnamic acid (VI). As the methods used and the substances newly prepared may be of some interest, the results are recorded in the present paper.

















KcH2cas \\




(0-Ethylpheny1)diphenylaceticacid (I) was prepared by carbonation of (o-ethylphenyl)diphenylmethylsodium, which in turn was obtained from (o-ethylphenyl)diphenylcarbinol via the chloride. In the preparation of the carbinol from o-ethylbenzophenone and phenylmagnesium bromide, part of the ketone was reduced to the corresponding pinacol. Similar observations have been made before by Barnett, Cook, and Nixon,2 1 2

BERQMANN AND BLUM-BEROMANN, J . Chem. Soc., 1938, 727. BARNETT, COOK,and NIXON,ibid., 1937, 509. 1



and by Hatt.a Benzohydrylbenzylacetic acid (11) was easily available through the condensation of diphenylbromomethane with ethyl sodiobenzylmalonate in the absence of alcohol. In the synthesis of [o-(aphenylethyl)phenyl]phenylacetic acid (111), the last steps were similar to those in the preparation of (I), namely carbonation of the sodium compound, corresponding to (111), which in turn was obtained from o-(a-phenylethy1)benzohydrol (VII) via its methyl ether. The carbinol (VII) was prepared by reducing o-(a-phenylethy1)benzophenone by means of aluminum amalgam and alcohol or by addition of sodium and subsequent hydrolysis of the disodium compound. For the synthesis of o-(a-phenylethyl)benzophenone, it was necessary to make o-(a-phenylethy1)benzoic acid (VIII) easily available. By interaction of ethyl (0-benzoy1)benzoate and methylmagnesium iodide, Ostersetzerl had obtained methylphenylphthalide (IX) which could be reduced by zinc and ammonia to yield the desired acid (VIII). We have observed that besides IX, o-(a-methylenebenzyl) benzoic acid (X) is formed in the above reaction; catalytic hydrogenation converted it into VIII. The two substances represent tautomeric forms and therefore are interconvertible (ring-chain tautomerism); on drying a t looo, the acid (X) was occasionally converted into methylphenylphthalide (IX). 0


VI1 0





*HATT,ibid., 1929, 1623. 4 OSTERSETZER, Monatcrh., 54, 796 (1913). For similar observations compare, inter alia, FIESBR AND NEWMAN, J . Am. Chem. Soc., 68,2376 (1936); 69, 1004 (1937); COOK,ROBINSON, AND GOULDEN, J . Chem. SOC.,1957,393.




Treatment of the acid chloride of VI11 with benzene in the presence of aluminum chloride did not lead to o-(a-phenylethyl)benzophenone, but rather to intramolecular condensation products, viz. anthraquinone and a substance which, according to analyses and behavior, most probably is 9 , g’-dimethyl-lO ,lO’-diketo-9,9’ , 10,lO’-tetrahydro-9,9’-bianthryl (XI). Hence another method had to be applied to the conversion of VI11 into the corresponding substituted benzophenone: the nitrile, which is accessible by heating the acid with lead thiocyanate,s was treated with phenylmagnesium bromide. The synthesis of [o-($phenylethyl)phenyl]phenylacetic acid (IV), which has recently been prepared by Natelson and Gottfried6 by a different method, was accomplished in exactly the same way as in the case of the alpha compound (111), starting with o-(j3-phenylethy1)benzoic acid. For the reduction of o-(8-phenylethyl)benzophenone, aluminum isopropylate proved most satisfactory, since amalgamated aluminum partly finished its action with the production of the corresponding pinacol. For the synthesis of o-benzyl-a-phenylhydrocinnamic acid (V), the suitable starting material proved to be o-benzylbenzaldehyde (XII), which on heating with sodium phenylacetate and acetic anhydride gave obenzyl-a-phenylcinnamic acid. For the preparation of the aldehyde (XII), ethyl orthoformate was treated with the magnesium derivative of o-bromodiphenylmethane,’ and the acetal so obtained was hydrolyzed by boiling hydrochloric acid. In this latter reaction, a certain amount of anthracene was formed, most probably according to the following scheme:


/ \

H 6


Compare HOUBEN-WEYL, “Die Methoden der organischen Chemie,” Leipzig,

1930, Vol. 111, p. 945.


GOTTFRIED, J . Am. Chem. Soc., 68, 1432 (1936). Compare CLARKSONAND GOMBERG, ibid., 62, 2887 (1930).



This, apparently, is a modification of the Elbs synthesis of anthracene derivatives, especially interesting as it takes place at remarkably low temperatures (120" as compared with the normal 400450' of the Elbs reaction). As pointed out by Cook,s a transanellar migration of hydrogen would most satisfactorily explain the course of the Elbs r e a ~ t i o nin ; ~ the present instance, too, the above-formulated intermediary enolic form would meet the requirements of a reasonable explanation. The synthesis of o-benzyl-p-phenylhydrocinnamic acid (VI) was accomplished through o-benzylbenzonitrile, prepared from the corresponding acid by interaction with lead thiocyanate; reaction of the nitrile with phenylmagnesium bromide led to o-benzylbenzophenone (XIII).lo When this ketone was treated with zinc and ethyl bromoacetate, the two forms of o-benzyl-p-phenylcinnamic acid were obtained, which were subsequently hydrogenated. In the course of these synthetic experiments, we attempted to prepare a seventh isomeric acid, (0-benzylpheny1)benzylacetic acid (XIV), but without success. From o-benzylcyclohexanone with zinc and methyl bromoacetate we obtained methyl l-benzylcyclohexene-(l)-acetate-(2) (XV) (or the corresponding a ,p-unsaturated ester), but dehydrogenation of this compound to o-benzylphenylacetic acid (which was ultimately t o be condensed with benzaldehyde) was not achieved, palladium giving anthracene, and bromine giving a crystalline acid, which according to the analysis was x-bromo-2-benzylphenylacetic acid.






(0-Ethy1phenyl)diphenylacetic acid (I) o-Ethy1benzophenone.-From o-ethylbenzoic acid" (26 g.) and thionyl chloride (80 cc.), the chloride (26 g.), b. p. 105-106"/14 mm., was obtained by heating the mixture for three hours. The chloride was heated with anhydrous aluminum chlo8 COOK,J. Chem. SOC., 1931, 487; compare FIESER,"Chemistry of Natural Products Related to Phenanthrene,'' New York, 1936, 1st Ed., pp. 99-108. 9 Compare, also for references, BERGMANN, Ber., 63, 1037 (1930). 10 Compare BLICKE AND SWISHER, J . Am. Chem. SOC.,66, 923 (1934). 11 GABRIEL AND MICHAEL, Ber., 10, 2206 (1877).





ride (20.5 g.) in benzene (130 cc.) for three hours, the mixture decomposed by ice and hydrochloric acid and the o-ethylbenzophenone purified by distillation; b. p. 165"/18 mm. ; yield, 23 g. (0-EthyZphenyZ)diphenylacetic acid (I).-o-Ethylbenzophenone (21 g.) was introduced into a phenylmagnesium bromide solution (from 2.7 g. of magnesium and 11.5 cc. of bromobenzene). The reaction gave a transitory violet color, and was completed by boiling for three hours. The product, isolated by acid decomposition, gave, on trituration with alcohol, beautiful crystals (2.5 g.), which, after recrystallization from propyl and amyl alcohols, melted a t 151-152" and were, according to the analysis, the pinacol of o-ethylbenzophenone. Anal. Calc'd for C ~ O H ~ OC,O85.3; ~ : H, 7.1. Found: C, 85.0; H, 7.3. (0-Ethylpheny1)diphenyZcarbinoZitself could not be obtained in a crystalline state; the mother liquor of the above-described crystals, therefore, was evaporated, and the residue (22 9.) was dissolved in benzene and, after addition of acetyl chloride (10 cc.), was saturated with gaseous hydrogen chloride. The solution was evaporated, finally in a desiccator over potassium hydroxide. The oily (0-ethyZpheny1)diphenylchloromethane (4.5 g . ) was shaken with 1% sodium amalgam (150 9.) in a Schlenk tube. The reaction started a t once and gave the dark-brown (0-ethylpheny1)diphenyZmethyZsodium. It was decomposed with carbon dioxide; the precipitated sodium salt was extracted with water, and the solution was acidified. The acid was dried and recrystallized twice from a mixture of benzene and ligroin (2:3); m. p. 204-205" (slight decomp.). Anal. Calc'd for C22H2~Ol:C, 83.5; H, 6.3. Found: C, 83.2; H, 6.3. Benzohydrylbenzylacetic acid (ZZ) Ethyl benzohydryZbenzylmalonate.-To a suspension of sodium powder (3.4 g.) in benzene (100 cc.), ethyl benzylmalonate (35 g.) was added slowly, a t a temperature of about 15-20". Within twelve hours' standing, the mixture was converted into a crystalline magma, to which diphenylbromomethane (34 9.) was added. The spontaneous reaction was completed by three hours' boiling, then water and ether was added, and the ethereal layer was distilled. After a head fraction (b. p. 118-128"/0.1 mm.), the reaction product went over a t 185-195"/0.02 mm., and after repeated distillation a t 190"/0.02 mm., consisted of a viscous, colorless oil; yield, 33 g. Anal. Calc'd for C28H20O4:C, 77.9; H, 6.7. Found: C, 77.8; H, 6.3. Benzohydrylbenzylacetic acid (11).-The foregoing ester (10 g.) was boiled for seven hours with potassium hydroxide (4.1 g.; 3 moles) in amyl alcohol (25 cc.). The solid cake obtained on cooling was filtered, washed with ether, dissolved in water, and after treatment with charcoal, was filtered and acidified. The precipitate was triturated with a mixture of 500/, acetic acid in acetone, and was recrystallized, first from 70% acetic acid, and then from light petroleum (b. p. 80-100"); needles, m. p. 175-177". Analysis showed that the procedure applied had incidentally caused spontaneous decarboxylation. Anal. Calc'd for C22HIIp~02: C, 83.6; H, 6.3. Found: C, 83.1; H, 6.6. [o-(a-PhenyZethyZ)phenyl]acetic acid (ZZZ) Ethyl (0-6enzoyZ)benzoate was prepared from the acid (46 9.) by boiling with alcohol (125 cc.) and concentrated sulfuric acid (10 g.) for four hours. The alcohol was distilled off on a water bath; the residue was poured out into water, extracted with ether, washed with soda solution and then evaporated. The ester crystallized



easily, and was recrystallized from light petroleum, containing some benzene; m. p. 59-61.5"; yield, 40 g . Reaction un'th methylmupmsium iodide.-A Grignard solution (from 5.42 g. of magnesium and 14.3 cc. of methyl iodide) was added to a solution of ethyl (0-benzoyl)benzoate (52 8.) in ether (250cc.); during the vigorous reaction a yellow precipitate separated. After thirty minuted boiling the mass was decomposed with ice and sulfuric acid. The ethereal layer was washed with sodium thiosulfate solution and then extracted with sodium hydroxide. On acidification, o-(a-methylenebenzy1)benzoic acid (X) waa obtained (average yield, 11g., the amount varying from 11t o 15g.); from EO% acetic acid, needles, m. p. 136-136.5'. Anal. Calc'd for C I B I ~ O , :C, 80.4; H, 5.4. Found: C, 80.1,80.2; H, 5.6,5.2. The neutral residue obtained after evaporation of the ethereal layer was purified by distillation in a vacuum; b. p. 162"/1.2 mm. The solidified distillate was triturated with light petroleum and some alcohol, and was finally recrystallized from benzine; leaflets, m. p. 78-81"; yield varying from 7 to 15 g. Occasionally, the methylphenylphthalide (M) crystallized without previous distillation. Anal. Calc'd for ClJ3120~:C, 80.4; H,5.4. Found: C, 80.4; H, 5.4. Both isomers are reduced easily to form o-(a-phenylethy1)benzoic acid. o-(a-Phenylethyl)benzoicacid (VIIZ).-(a) Tbe foregoing unsaturated acid (14 g.) was hydrogenated for six hours in boiling propyl alcohol (75 cc.) in the presence of palladized barium sulfate (4 g.). The solvent was evaporated in a vacuum and the residue after solidification recrystallized from 50% acetic acid or benzine; m. p. 104-106", yield, 13 g. Anal. Calc'd for C1J31~On: C, 79.7; H, 6.2. Found: C, 79.9; H, 6.1. (b) Phenylmethylphthalide (26.5 g.) was dissolved in alcohol (130 cc.); 15% ammonia solution (700 cc.), zinc dust (93 g.) and copper sulfate solution (37 cc.) were added and the whole mass was heated on a water bath for twenty hours, filtered and acidified; yield, 26 g. The phthalide may also be reduced by red phosphorus and hydriodic acid, but the yields are rather poor. In order t o obtain the desired o-(a-phenylethyl)benzophenone,application of the Friedel and Crafts reaction to the corresponding crude acid chloride was first tried, but this, on reaction with benzene and aluminum chloride, gave only autocondensation products, namely anthraquinone and a substance crystallizing from butyl acetate containing some benzene, in glistening brownish crystals, melting to a greenish liquid a t !280-283"in a sealed tube, after discoloration as low as 258". The aubstance, exhibiting a beautiful red color with concentrated sulfuric acid, is 9,9'dimethyl-lO,lO'-diketo-g,9', lO,lO'-tetrahydro-g, g'bianthryl (XI). Anal. Calc'd for C&*rOn: C, 87.0; H, 5.3. Found: C, 87.4, 87.3;H, 4.8, 5.0. o-(a-PhenyZethyZ)benzonitm'le.-The foregoing acid (16 g.) and lead thiocyanate (24 g.) were mixed and heated in a stream of hydrogen to 205-210", until the evolution of carbon dioxide ceased. The mass was extracted with ether and the solution washed with soda; b. p. 166-168"/6.5 mm.; 151"/1.8 mm.; yield 7.8 g. Surprisingly, the substance exploded during the combustion analysis, but its constitution was ascertained by hydrolysis with 50% sulfuric acid, which resulted in the above acid. Anal. Calc'd for Cl&IlaN: C, 87.0; H, 6.3; N, 6.8. Found: C, 86.3; H, 6.2; N, 6.7.




o-(a-PhenyZethy1)bcnzophenone.-The above nitrile (18 g.) was added t o a phenylmagnesium bromide solution (prepared from 3.2 g. of magnesium and 11.2 cc. of bromobenzene), and the mixture heated for six hours. After about two hours, the reaction product separated suddenly as a yellowish crystalline powder. It was decomposed by ice and ammonium chloride, and the residue from the ethereal layer was heated with acetone (18 cc.), concentrated hydrochloric acid (12 cc.), and water (37.5 cc.) for five hours, poured out into cold water, extracted with ether, and washed with alkali. The ketone is a colorless oil, exhibiting a blue fluorescence; b. p. 184186'/0.8 mm.; yield, 21.1 g. AnaZ. Calc'd for C21H180:C, 88.1; H, 6.3. Found: C, 87.8; H , 6.5. o-(or-PhenyZethyZ)benzohydroZ (VZZ).-Since the compound contains two asymmetric carbon atoms, two isomerides were t o be expected and were actually found. One of them is a crystalline substance, the other a viscous oil, which, although having a constant boiling point, may still contain some of the crystalline isomer, and therefore is not definitely sterically homogeneous. ( a ) An ethereal solution of the ketone was shaken with sodium powder (Schlenk's method) for several days, decanted from the excess of sodium and decomposed with water. The product was isolated by distillation in a vacuum; greenish-yellow oil, exhibiting a blue fluorescence; b. p. 186-189'/1.3 mm. On standing, the oil deposited crystals (half its weight) which were triturated with light petroleum and crystallized from the same solvent; stout crystals, m. p. 91-93". Anal. Calc'd for CelHzoO: C, 87.5; H, 7.0. Found: C, 87.1; H, 7.0. The liquid portion of the product was distilled again; b. p. 178-181'/0.9 mm.; n: = 1.6140. Anal. Found: C, 87.3; H, 7.2. (b) The ketone (10 g.) was dissolved in a hot mixture of alcohol (62 cc.) and water (8 cc.); then amalgamated aluminum (25 g.) was introduced. After three hours' boiling the liquid was sucked off still hot, the solid was washed with boiling alcohol, and the solvent was evaporated. From the residue the solid isomer crystallized (3.2g.) spontaneously on trituration with light petroleum. The oily residue was twice fractionated in a vacuum; the liquid isomer (4.4 9.) had the b. p. 178180°/0.5 mm. o-(or-Phenylethy1)benzohydryZ methyl ether.-The different isomeric hydrols were methylated separately. It cannot be decided whether and t o what extent the configuration of the hydrols is preserved; in any case the interaction of the methylated products and sodium powder gave identical results, which can be accounted for by the alternative assumptions, that configurational change takes place during methylation, or during the formation of the alkali-organic compound. The solid hydrol (2.7 g.) was heated for two hours with methyl alcohol (12 cc.) and concentrated hydrochloric acid (1 cc.); after some minutes the methyl ether started t o separate. It was isolated by treatment with ether and water; b. p. 168-172'/0.8 mm.; 164"/0.6 mm.; n t = 1.5910. AnaZ. Calc'd for C22Hz20: C, 87.4; H, 7.3; OCHs, 10.3. Found: C, 87.5; H, 8.0; OCHa, 11.3, 11.4. From the liquid hydrol the methyl ether was prepared in the same way; b. p. 171-173'/0.9 mm.; n: = 1.6029. [o-(or-PhenyZethyZ)phenyZ]phenyZaceticacid (ZZZ).-Each of the above methyl ether preparations was shaken with sodium powder for six days, and the dark-brown solution was decomposed with dry carbon dioxide. The reaction product was decanted



from the excess of sodium and taken up with water. On acidification, a thick oil separated, which was isolated by extraction with ether. The residue was triturated with a mixture of light petroleum and some acetone. The first crystalline crop (0.25 g. from 5 g. of methyl ether) was recrystallized several times from 50% acetic acid. The analysis of the diamond-shaped crystals, m. p. 261-263" (decomp.), pointed to the formula CzsH2oO4 of the following acid: /CI" f)(CH\COOH

'COOH which has been formed by successive splitting of the C-0 bond and substitution of the tertiary hydrogen atom. Anal. Calc'd for CZ3H1001:C, 76.7; H, 5.5; mol. wt. 360. Found: C, 76.5, 76.2; H, 5.5, 5.4; mol. wt. 367 (camphor). A second crystalline fraction (0.55 g.) still contained the above dicarboxylic acid, which could be separated through its insolubility in boiling benzine. From the benzine solution, leaflets of the desired acid C 2 z H 2 ~separated 02 on cooling; they were purified by subsequent recrystallization from dilute acetic acid and benzine; m. p. 14C141". Anal. Calc'd for C22H2~02: C, 83.5; H, 6.3. Found: C, 83.2, 83.5; H, 7.0, 6.8. [o-@-PhenylethyZ)phen~Z]phenylaceticacid (ZV) o-@-Phenylethy1)benzonitrile.-According to the method already described, lead thiocyanate reacted with o-(8-phenylethy1)benzoic acidfi at 195". The reaction was accomplished within six hours. The product, isolated by means of ether, was an oil, which on standing a t 0" with light petroleum and acetone deposited small quantities of o-(19-phenylethy1)benzamide; from propyl alcohol, needles, m. p. 128". Anal. Calc'd for ClsHlsNO: C, 80.0; H, 6.7; N, 6.2. Found: C, 79.8; H, 7.1; N, 6.0. The nitrile, after separation oflpthe above crystals, was purified by distillation; b. p. 168"/4 mm., 150'/1.3 mm.; nD = 1.5762. Anal. Calc'd for ClsH13N:N, 6.7. Found: N, 6.7. The amide usually amounted to 10% of the nitrile. Its appearance is noteworthy, as according to the literature (Zoc. c i t . ) this method gives amides along with the nitriles only in the case of aliphatic acids. o-(8-PhenyZethyZ)benzophenone.-The nitrile (18 9.) was heated with phenylmagnesium bromide (3.2 g. of magnesium, 14.2 cc. of bromobenzene) for three hours, and the whole mass was decomposed with ice and ammonium chloride, and boiled with a mixture of acetone (18 cc.), water (37.5 cc.) and concentrated hydrochloric acid (12 cc.) for five hours. The ketone had the b. p. 199-200"/3 mm.; yield, 24 g. Anal. Calc'd for Ct1H1sO: C, 88.1; H, 6.3. Found: C, 88.0; H, 6.6. GABRIEL, Ber., 18, 2444, 3479 (1885); SCELEINK AND BERGMANN, Ann., 468, 266 (1928).





o-@-Phenylethy1)benzohydrol.-Forty grams of the above-mentioned ketone was heated with 30 g. of aluminum isopropylate and 300 cc. of isopropyl alcohol for five hours. The solvent was then evaporated, the residue was dissolved in isopropyl alcohol, concentrated again and so on, until the distillate gave no positive test for acetone. Then the mass was treated with dilute potassium hydroxide solution and ether; b. p. 195-196"/0.6 mm.; yield, 33 g.; n! = 1.6055. After some time the colorless oil solidified spontaneously; from light petroleum, prisms, m. p. 57". Anal. Calc'd for C21H*00:C, 87.5; HI 7.0. Found: C, 87.1; H, 7.0. The reduction of the above ketone with amalgamated aluminum turnings in moist ether gave unsatisfactory results; besides the hydrol, 30% of the ketone was found in the form of the corresponding pinacol. This separated on concentration of the solution of the obtained product, and was recrystallized from a mixture of benzene and benzine. Quartz-like crystals, m. p. 141". The pinacol character of the substance is demonstrated by the fact that the benzene solution develops a deep-blue color on addition of sodium ethoxide solution. Anal. Calc'd for C42HJsO2: C, 87.8; HI 6.6. Found: C, 87.3; HI 7.1. o-(8-Phenylethy2)benzohydrylethyl ether.-The hydrol (20 g.), alcohol (85 cc.) and concentrated hydrochloric acid (8 cc.), were heated for three hours;ether and water were added, and the ethereal solution was washed with sodium carbonate solution; b. p. 200"/2.5 mm.; n! = 1.3797; yield 21 g. Anal. Calc'd for CtsHt40: C, 87.3; HI 7.6. Found: C, 87.3; H, 7.8. The preparation of the methyl ether proceeded less satisfactorily, due to the slight solubility of the hydrol in methyl alcohol. It was a nearly colorless oil, b. p. 177- 178'/0.7 mm . Anal. Calc'd for CZ~HZZO: C, 87.4; HI 7.3. Found: C, 87.5; HI 7.5. [o-(8-PhenylethyZ)phenyl]phenylacetic acid (ZV).-The above-mentioned ethyl ether was shaken in ethereal solution with sodium powder for three days, and the brown solution was treated with dry, gaseous carbon dioxide. The sodium salt formed was extracted with water and precipitated with acid. From light petroleum (b. p. 80-lOO0)or cyclohexane, clusters of needles, m. p. 117.5-118.5". Anal. Calc'd for C~ZHZOOZ: C, 83.5; HI 6.3. Found: C, 83.4; H, 6.4. o-Benzyl-cr-phenylhydrocinnamicacid ( V ) o-Bromobenzophenone.-To a cooled mixture of o-bromobensoyl chloride (50 g.) (b. p. 135'/22 mm.) and benzene (250 cc.), powdered aluminum chloride (33 g.) was added. After some time, reaction set in, the temperature gradually rising t o room temperature. After twelve hours' standing, the mass was boiled for three hours, and then decomposed with ice and concentrated hydrochloric acid; b. p. 151-153" /0.05 mm. ;yield, 30 g.Ia o-Bromodipheny1methane.-According to Clarkson and Gomberg' the foregoing ketone (30 g.) was reduced with amalgamated zinc wool (30 g.) and concentrated hydrochloric acid. When all the zinc had disappeared, the oily product was separated by extraction with ether. On trituration with methyl alcohol and some acetone, a crystalline by-product (3 g,) separated; the liquid distilled at 175"/22mm. and was pure o-bromodiphenylmethane. The solid was separated by fractional CATHCART AND MEYER,Ber., 26, 1498 (1892).



crystallization from methyl ethyl ketone into the diamond-shaped crystals of tetraphenylethylene (m. p. and mixture m. p. with an authentic sample, 222'), and long needles of a second hydrocarbon, m. p. 236'. Its constitution could not be elucidated; in any case, i t is not identical with 9,lO-diphenyl-9,1O-dihydroanthracene,14 which could easily have been formed in the above reaction.16 Removal of halogen in similar cases has been observed by Montagne and van Charante;16 it may be due t o the transitory formation of a substance like

containing an allylic bromine atom. With regard t o the formation of tetraphenylethylene, attention may be drawn t o the experiments of Steinkopf and Wolfram." o-Benzylbenzaldehyde diethylacetal.-When ethyl orthoformate (23 9.) was added to the Grignard solution, prepared from magnesium (2.7 9.) and o-bromodiphenylmethane (27.5 g.), no reaction occurred. When the solvent was distilled off, reaction took place with great violence; after addition of some more (7 g.) ethyl orthoformate, the mixture was heated for five hours a t 120' (oil bath) and was decomposed with ice-cold ammonium chloride solution. Fractionation of the oily product gave ( a ) diphenylmethane, b. p. 86-117°/0.04 mm., then 84-86"/0.04 mm. ; yield 7.7 g. ; and ( b ) the desired acetal; b. p. 118'/0.04 mm.; yield, 15.5 g. Anal. Calc'd for C18Hn202: C, 80.0; H, 8.1. Found: C, 79.7; H, 8.4. o-Benzylbenza2dehyde.-The acetal (13 g.) was heated a t 120' for six hours with dilute hydrochloric acid (52 cc.), anthracene continuously subliming into the reflux condenser. After dilution with water, the reaction product was extracted with ether and isolated by distillation (b. p. 116-118"/0.03 mm.). As anthracene distilled over with the acetal, the distillate had to be diluted with light petroleum (b. p. 40-60') and alcohol and kept at 0' for twenty-four hours, whereupon the anthracene (0.27 g.) separated quantitatively; m. p. and mixture m. p. 213-214'. The aldehyde was distilled again (b. p. as above); yield, 7.5 g. Anal. Calc'd for C1iH120: C, 85.7; H, 6.1. Found: C, 85.3; H, 5.9. o-Benzyl-a-phenylcinnamicacid.-The foregoing aldehyde (7.5 9.) was heated a t 160' for eight hours with sodium phenylacetate (6.4g.) and acetic anhydride (14 cc.). The reaction mixture was poured out on ice; after some hours i t was taken up with ether, and the ethereal layer was extracted with soda. The sodium salt separated l4 SCHLENK AND BERGMANN, Ann., 463, 153 (1924); HAACK, Ber., 62, 1771 (1929). I t may be identical with a substance sometimes formed in reactions with benzoBer., 63, 1627 (1930); 66, 457 (1932). hydrylsodium; cf. BERQMANN, 16 According to unpublished results from this laboratory, o-bromobenzophenone is converted by calcium amalgam into 9,lO-diphenylanthracene. 16 Compare, inter alia, MONTAGNE AND VAN CHARANTE, Rec. trav. chim., 31, 315 (1912); SPEER AND HILL, J. ORQ.CHEM.,2, 139 (1937). 1' STEINKOPF AND WOLFRAM, Ann., 430, 113 (1923).





as a thick oil between the water and the ether layers; on acidification, it gave the crystalline acid, which was recrystallized from 70% acetic acid; brilliant needles, m. p. 161-162"; yield, 6.8 g. Anal. Calc'd for C22H1802:C, 84.1; H, 5.4. Found: C, 84.0; H, 5.8. o-Benzyl*-phenylhydrocinnamic acid (V).-The unsaturated acid (4.5 g.) was catalytically hydrogenated in boiling propyl alcohol (50 cc.) during six hours in the presence of palladized barium sulfate (2 g.). The filtered solution was evaporated, and the residue, after trituration with light petroleum (b. p. 4O-6Oo), recrystallized from light petroleum (80-100"); clusters of white, shiny needles, m. p. 96-98'; yield 3.9 g. Anal. Calc'd for Cz2H2002: C, 83.5; H, 6.3. Found: C, 83.5, 83.5; H, 6.5, 6.5. o-Benzyl-8-phenylhydrocinnamicacid (VZ) o-Benzylbenzonitrile and o-benzy1benzamide.-An intimate mixture of o-benzylbenzoic acid (16 9.) and lead thiocyanate (24 g.) was heated in a current of hydrogen a t 200-210" for four hours. The product was extracted with ether, and the ethereal layer was washed with sodium carbonate solution, dried, and evaporated. The residue was triturated with a mixture of benzene and light petroleum, whereupon o-benzylbenzamide (0.6-0.8 g.) separated; from glacial acetic acid, glistening prismatic needles, m. p. 164.5". Anal. Calc'd for Clr&NO: C, 79.6; H, 6.2. Found: C, 79.4, 79.3; H, 6.6, 6.5. The nitrile had the b. p. 130-133"/0.02 mm. Anal. Calc'd for C&IIN: C, 86.7; H, 6.0; N, 7.2. Found: C, 86.5; H, 6.4; N, 7.2.18 o-Benzylbenzophenone (XZIZ).-o-Benzylbenzonitrile (10 9.) was boiled for three hours with phenylmagnesium bromide solution (from 2 g. magnesium and 8.5 cc. bromobenzene) ; the reaction mass crystallized after thirty minutes' boiling. It was decomposed by means of ice and ammonium chloride, and the product was heated on a water bath for five hours with acetone (10 cc.), concentrated hydrochloric acid (7 cc.) and water (20 cc.). The ketone so obtained was distilled in vacuo, b. p. 163"/0.03 mm., and formed a viscous oil, which exhibited an intense green fluorescence and crystallized on standing; m. p. 50"; yield, 12.5 g.lg The stereoisomeric o-benzyl-8-phenylcinnamicacids.-The foregoing ketone (12 g.) was gently warmed with zinc (10 g.) and methyl bromoacetate (17 cc.) in benzene (75 cc.), until reaction set in, and when i t ceased, for three more hours on the boiling water bath. The crude product, isolated as usual, was heated with 85% formic acid20 a t 160"for three hours. Methyl o-benzyl-8-phenylcinnamate was so obtained as a thick oil, b. p. 170"/0.005 mm., which according to the analysis was not analytically pure, some disproportionation into o-benzylbenzophenone having taken place. Anal. Calc'd for C ~ ~ H Z OC,O86.1; ~ : H, 6.1. Found: C, 86.8; H, 6.0. 1 s Essentially the same procedure has been used by BLICKEAND SWISHER, J . Am. Chem. Soc., 66, 923 (1934). 19 The same synthesis has been briefly mentioned by BLICKEAND SWISHEB, loc. cit.; compare SEIDEL, Ber., 61, 2267 (1928). 20 RIJPE,Ann., 396, 141 (1913); SCHLENK AND BERGMANN, ibid., 483, 237 (1928).



The same process, apparently, occurred to some extent during the subsequent saponification;21when the ester (8 g.) was heated with potassium hydroxide (2.69.) in a mixture of methyl alcohol (35 cc.) and butanol (20 cc.) for twelve hours, a neutral and an acid fraction were obtained. The former fraction consisted of o-benzylbenzophenone, the latter, of the two isomeric forms of the desired acids. On acidification of its alkaline solution, it was obtained as an oil, which crystallized under the influence of a mixture of benzene and light petroleum. After recrystallization from cyclohexane, the two forms could be separated mechanically; cubes, m. p. 177' ( A ) , and droplets, m. p. 148" (B) respectively, after final recrystallization from the same solvent. The lower-melting form begins to decompose a t about 160". C, 84.0; H, 5.7. Anal. Calc'd for C22H~801: Found ( A ) : C, 83.7; H, 5.7. (B): C, 84.2;H, 6.0. When the crude product from the above Reformatsky reaction was hydrolyzed directly by means of boiling alcoholic potash solution (5.4g. potassium hydroxide), o-benzyl-p-phenyl-p-hydroxyhydrocinnamicacid was obtained; i t was insoluble in cyclohexane, but crystallized easily from toluene; m. p. 179-180" (decomp.). Anal. Calc'd for C22H2~01: C, 80.0; H, 6.0. Found: C, 79.7;H, 6.0. The hydroxy acid was dehydrated by heating a t 180' for one hour in the presence of twice its weight of potassium acid sulfate. The inorganic material was extracted with acid and acetone. On recrystallization from cyclohexane, the product proved to be the lower-melting o-benzyl-p-phenylcinnamicacid, by its melting point (148') and by the form of the crystals. o-Benzyl-8-phenylhydrocinnamicacid (VZ).-The mixture of the unsaturated acids (0.5 9 . ) was hydrogenated in boiling isopropyl alcohol (15 cc.) in the presence of palladized barium sulfate (0.59.) for three hours. The filtered solution, on evaporation, left a resin which so far could not be induced to crystallize, but gave the expected analytical figures. Anal. Calc'd for CnlH2002: C, 83.5;H, 6.3. Found: C, 83.4;H, 6.3. o-Benzylcyclohexanone.-o-Benzylcyclohexanol (19 9 . ) which is easily accessible according to the method of Weizmann, Bergmann, and Haskelberg,*2was dissolved in warm (80') glacial acetic acid (100 cc.) and a solution of chromic acid anhydride (7.3 g.; excess of 10% over the theoretical amount) in dilute acetic acid added. When the vigorous reaction had ceased, the mass was kept a t room temperature for two hours, boiled for the same period and poured out into water. The ketone boiled a t 119-121"/0.01 mm.; yield, 16 g. Anal. Calc'd for ClsHlsO: C, 83.0;H, 8.5. Found: C, 82.7;H, 8.8. The semicarbazone formed needles (from 50% methyl alcohol) and had the m. p. 168-169 ?*

** For

similar observation, see BERGMANN, HOFFMANN, AND MEYEB,J . prakt.

Chem.,[2],136, 245 (1932). I* WEIZMANN, BERGMANN, AND HASKELBERG, Chem. & Ind., 66, 587 (1937); compare COOKAND CO-WORKERS, J. Chem. SOC., 1938, 62, 71. ** Compare, also for references, COOK,HEWETT,AND LAWRENCE, J . Chem. SOC., 1996, 69.





Methyl f-benzyl-f-cycEohezene-~-acetate (XV).-o-Benzylcyclohexanone (22 8.) reacted with zinc (17 g.) and methyl bromoacetate (28 cc.) in benzene (125 cc.), on gently heating. When the reaction had ceased, the mass was boiled for three hours, and the crude product, isolated as usual, was heated in benzene solution (125 cc.) with phosphoric oxide (20 g.). The product was decomposed with ice water, and the ester was purified by vacuum distillation; colorless oil, b. p. 135-136"/0.02 mm., n t 1.5231;yield, 18 g. On standing, the ester crystallized spontaneously; m. p. 63-65". Anal. Calc'd for Cl~H200z:C, 78.7; H, 8.2. Found: C, 78.5; H, 8.3. When the ester (5 9.) was heated for twelve hours a t 300" with palladous hydroxide on barium sulfate,*' and the product, isolated by means of acetone, sublimed a t 0.01 mm., crystals were obtained, which, after recrystallization from propyl alcohol, could be identified as anthracene; m. p. and mixture m. p. 215". When the above ester (3 9.) was kept a t room temperature with bromine (1.3 cc.) in glacial acetic acid (10 cc.) for twelve hours and then heated for three more hours, a copious evolution of hydrobromic acid took place. The product was poured out into water and separated into a neutral fraction (viscous, ill-defined, brominecontaining oil, b. p. 185-190"/0.01 mm.) and an acid, which distilled a t 0.7 mm.. and crystallized on standing. After trituration with acetone, i t was recrystallized from high-boiling (130") light petroleum; clusters of needles, m. p. 152". Anal. Calc'd for CIJ&tO~Br:C, 59.0; H, 4.0. Found: C. 59.5: H. 4.3. SUMMARY

(o-Ethylpheny1)diphenylacetic acid, benzohydrylbenzylacetic acid, [o-(a-phenylethyl)phenyl]phenylacetic acid, [o-(8-pheny1ethyl)phenyllphenylacetic acid, o-benzyl-a-phenylhydrocinnamic acid, and o-benzyl8-phenylhydrocinnamic acid have been synthesized, and the methods involved have been fully discussed. The synthesis of (0-benzylpheny1)benzylacetic acid failed. 2'

KUHNA N D STROEBELE, Ber., 70, 785 (1937).