370
JOSEPH C O R S E AND
EWALD ROHRMANN
Vol. 70
[CONTRIBUTION FROM THELILLYRESEARCH LABORATORIES]
Preparation of Some Substituted @-PhenylisovalericAcids BY JOSEPH CORSE'AND EWALD ROHRMANN j3-Phenylisovaleric acid was prepared by Hoff- tion of the p-halobenzene and mesityl oxide in carbon man2 by the haloform oxidation of 4-methyl-4- disulfide solution, essentially as described by Hoffman' for benzene. The organic layer was separated, dried and phenyl-2-pentanone1 d substance readily pre- distill6d in vacuo. pared by the reaction of benzene and mesityl 4-p-Fluorophenyl4-methyl-2-pentanone .-B . p. 66 ' oxide with aluminum chloride as catalyst. The (0.1 mm.); n% 1.4911; yield.38.0g. (70%). acid has also been prepared by the carbonation of.. - Anal. Calcd. for ClzHllOF: 6, 74.19; H, 7.78. Pound: C, 74.33; H, 8.03. neophylmagnesium ~ h l o r i d e . ~ p. 169We have carried out the synthesis of a number 1714-~-Chlorophenyl4-methyl-2-pentanone.-B. (16 mm.); n*'e5~1.5228; yield, 102.5 g. (95%). of substituted j3-phenylisovaleric acids which were Anal. Calcd. for C12H160C1: C, 68.40; H , 7.17. desired in connection with some antibiotic stud- Found: C, 68.35; H, 7.58. ies. These were prepared either from the corre4-g-Bromophenyl4-methyl-2-pentanone.-B. p. 128sponding substituted ketones by haloform oxida- 130 (0.6 mm.); n% 1.5392; yield, 52 g. (41%). Anal. Calcd. for CllHlsOBr: C, 56.48; H, 5.92. tion or from the parent unsubstituted j3-phenylisoFound: C, 56.38; H, 5.85. valeric acid. Haloform Oxidation of 4(p-Halophenyl) -4-methyl-2A number of substituted benzenes were sub- pentanones.-The haloform reactions were run with jected to reaction with mesityl oxide and alumi- sodium hypochlorite according to the directions of Newnum chloride. The reaction was found to proceed man and Holmes' to yield the corresponding ,%substituted well with benzene and with fluoro-, chloro- and phenylisovaleric acids. The yields varied from 51 t o 74% theoretical. bromobenzenes. We were unable b effect reac- of j3-(p-Fluorophenyl)-isovaleric acid.-M. p. 60-62'. tion with anisole and mesitylene, while complex Anal. Calcd. for CIIHISO~F: C, 67.23; H, 6.67. mixtures resulted With toluene, o-xylene and tet- Found: C, 66.76; H, 6.45. ralin. Eijkman4 noted a similar failure of tolu8-(p-Chlorophenyl) -isovaleric acid.-M. p. 65-67 '. ene to add to B1j3-dimethylacrylic acid, in conAnal. Calcd. for C1IH130,Cl: C, 62.11; H, 6.16. trast to the behavior of benzene. Reaction of thio- Found: C, 62.24; H , 5.68. 8-(p-Bromopheny1)-isovaleric acid.-M. p. 60-61 '. phene with mesityl oxide could not be satisfactorAnal. Calcd. for CIIHISOIB;: C, 51.38; H, 5.09. ily effected with either aluminum chloride or stanFound: C. 51.66; H , 4.77. nic chloride. 8-(p-Iodophenyl) -isovaleric acid.-This acid was preBoth Eijkman4 and Hoffman2 reported the pared by the method of Plati, et al. (cf. ref. 5(b)). The preparation of the nitro derivative of j3-phenyliso- crude acid was purified by conversion to the ethyl ester valeric acid by direct nitration of the acid. We which was fractionally distilled. That portion boiling have reduced this nitro acid catalytically to 8- a t 145-146' (0.9 mm.) proved t o be the desired ester; (+-aminopheny1)-isovalericacid, which was diazo- yield, 34.6 g. (%%), nlsD 1.5501. Anal. Calcd. for ClaHlrOII: C, 46.99; H, 5.16. tized and treated in the usual ways to give the C, 46.51; H, 4.80. arsono, +-arsenoso, +-bromo and p-hydroxy sub- Found: The acid was prepare: by saponification with potassium stituted phenylisovaleric acids. The bromo acid hydroxide; m. p. 76-78 . prepared by the Sandmeyer reaction from the Anal. Calcd. for CllH13021: C, 43.43; H, 4.31. amine was identical with that derived from 4- Found: C, 43.32; H, 4.49. methyl-4-p-bromophenyl-2-pentanone and sodium ,9-(p-Nitrophenyl)-isovaleric Acid.-One hundred and hypochlorite. This indicates that the nitration forty grams of &phenylisovaleric acid was added with over a period of one hour, to 250 ml. of fuming of phenylisovaleric acid occurs largely in the para stirring, nitric acid cooled t o -30" in a Dry Ice-bath. The temposition, as one might expect. perature was then ,allowed to rise during another hour to j3-(+-Iodophenyl)-isovaleric acid was made by +5O, and stirring was maintained an additional two hours a t 0 to 5". The solution was poured onto cracked ice and the direct iodination of j3-phenylisovaleric acid.6 product was collected on a filter and washed well with We wish to thank Mr. W. L. Brown and Mr. H. the water. The product w$s recrystallized from alcoholL. Hunter of these Laboratories for the analyses. benzene; m. p. 172-175 .
+-
Anal. Calcd. for C1~HISO,N:N, 6.28. Found: N, 6.63. ,9-(p-Aminophenyl)-isovalericacid.-Catalytic reduc4-(p-Halophenyl) -4-methyl-Z-pentanones.*--These were prepared by the aluminum chloride catalyst condensa- tion of the above nitro acid in methanol solution on the Adams machine, using Raney nickel catalyst or platinum oxide a t 3 atmospheres pressure, gave the p-amino sub(1) Present address: University of California at Los Angeles, stituted acid in almost quantitative yield. After being California. twice recrystallized from methanol-ether the melting (2) Hoffman, THIS JOURNAL, 61, 2542 (1929). point was 135'. (3) Whitmore, e1 ol., ibid., 66, 1469 (1943). (4) Eijkman. Chem. Wcckblod., 6, 655 (1909); C. A . , 9, 779 Anal. Calcd. for C11Hla02N: N, 7.24. Found: N, (1909); Cham. Zcnfr., TO, 11, 1100 (1908). 7.31.
Experimental
(5) (a) Varma and Panickar, J . Indian Chcm. SOC.,7' , 503 (1930); C. A , , 44, 5740 (1930); (b) Plati. Strain and Warren, THIS JOURNAL, 68, 1273 (1943).
--
( 6 ) "Organic Syntheses," Collective Vol. 11, John Wilcy and Sond, New York, N. Y., 1943, p. 428.
Jan., 1948
%ACETOFURAN INTO HEXEN-%DION-4,5-ACETAL-lAND
p-(#-Arsonophenyl) -isovaleric acid.-This acid was prepared from P-(#-aminophenyl) -isovaleric acid by the diazonium salt replacement reaction with arsenic trioxide. The crude acid was purified by recrystallization from hot water; yield, 56 g. (75%). Anal. Calcd. for CIIHLSOEAS:As, 24.85. Found: As, 24.38,24.35. &(p-Arsenosophenyl) -isovaleric acid.-Forty grams of the above arson0 acid was dissolved in a solution of 100 ml. of concentrated hydrochloric acid and 100 ml. of water. A small crystal of potassium iodide was added, and sulfur dioxide was passed through the solution for four and one-half hours. The solid which formed was collected and dissolved in sodium bicarbonate solution. Careful acidification with 10% hydrochloric acid precipitated the acid, which was collected and washed several times with cold water; yield, 9.2 g. The material was hygroscopic and analyzed for the hydrate. Anal. Calcd. for C11H160,As: As, 26.14. Found: As, 26.83,26.81.
[CONTRIBUTION FROM
THE
37 1
PYROCATECHOL
@-(#-Hydroxyphenyl)-isovaleric Acid.-This acid was prepared from 0-(9-aminophenyl) -isovaleric acid by the diazonium salt replacement reaction. Purification was best done by esterifying the crude acid with ethanol and sulfuric acid and taking advantage of the alkali solubility of the ester. Subsequent saponification and recrystallization of the acid from ethanol-ether-petroleum ether gave a white crystalline product melting a t 146-148’. Anal. Calcd. for C11HI4OJ:C, 68.02;H , 7.26. Found: C,68.04:~.H , 7.08.
Summary The Friedel-Crafts addition of three halogenated benzenes to mesityl oxide to give 4-methyl-4halogen substituted phenyl-2-pentanones is described. A number of B-@-substituted phenyl)-isovaleric acids are described. INDIANAPOLIS, INDIANA
RECEIVED JULY 21,1947
ORGANIC CHEMICAL INSTITUTE OF THE HUNGARIAN UNIVERSITY “BOLYAI”]
Studies on Furan Compounds. I. Conversion of 2-Acetofuran to Hexen-2-dion4,s-acetal-1 and Pyrocatechol BY
L.VARGHA, J. RAMONCZAI AND P. BITE
Several workers have already tried to synthe- HC-CH 3Hz0 I1 ll size 2-aminofuran. However, hydrolysis experi+. ments on furan-2-ethylurethan’ and on 2-benzyl$JOSO~C~H,CH~ and 2-propionylaminof~ran~ have only resulted I in the formation of ammonia and tar-like prodHC-CH ucts, probably because 2-aminofuran decomposes II II very rapidly. We have thought that a milder C-NHp. HOsSCsH4CHs procedure, such as the reaction discovered by HC\o/ I1 CHsCOOH Neber and v. Friedolf~heim~ on the p-toluenesulgen. Although very sensitive to heat, the liquid fonyl derivatives of certain aromatic ketoximes (A) might lead to the desired goal. According to can be distilled in vacuo a t constant temperature without being decomposed. The analysis and dethis process a compound like (A) termination of molecular weight gave the elemenR-C-R’ tary formula Cl~Hle04 (111). Methanol, instead of I1 H20 N-OSOzCsH,CHs +CHaCaH4SOz0-C-R’ -+ ethanol, gave rise to a very similar substance with I1 the formula C8Hl204 (IV). These substances were (A) (B) N-R found to represent ~is-hexen-2-dion-4~5-diethylHz0 acetal-1 (III), and -dimethylacetal-1 (IV), reR-NHCD-R’*HOaSCsH,CHs +
HC\dC-f-CH3
+
(C) R-NHvHOoSCsH4CHs (D)
+ R’-COOH
CH,COCOCH=CH CH (OR) 2 111, R = -CzH6 IV, R = -CHs CHsCOCOCH2CH2CH(OR) 2 V, R = -C2H6 VI, R -CHa
when shaken with ethanol a t room temperature, undergoes first a Beckmann rearrangement, then the intermediate (B) suffers hydrolytic cleavage (C) under the influence of traces of water with the spectively, as the end-products of the over-all reaction eventual formation of an amine (D).a94 However, on shaking p-toluenesulfonyl2-aceto- C ~ H ~ O - N O S O I C ~ H ~ C HHzO ~ + 2ROH = furan oxime (I) with ethanol, not the expected CHIC~HSOS(NH~) + I11 or JV toluenesulfonic acidic salt of 2-aminofuran (11) (1) was obtained. Rather, we isolated, in addition to Proof of the structures of 111 and IV rests on the ammonium p-toluenesulfonate, a yellowish-green, following experimental facts. strongly reducing liquid, which was free of nitroWith maleic anhydride no adduct originatedl (1) Leimbach, J . #rekl. Chcm., [2], 68, 20 (1902). from 111; therefore, the latter could not possess (2) Singleton and Edwards, THIS JOURNAL, 60, 540 (1938). the furan nucleus. On catalytic hydrogenation (3) Neber and v. Friedolfsheim. Ann., 449, 109 (1926). E:
+
(4) Neber and Huh, ibid., 616, 292 (1925).
(6) Alder end Schmidt, Bcr., 76, 18 (1943).
