SYNTHESIS OF p-ALKYLPHENYLACETIC ACIDS

E. D. MORGAN* “Shell” Rasarcfi Ltd., Egbam, Surrey

(Jkcehxd 13 June 1964; occqtcdfbr/diczatkm 24 October I!%@

Abbact-The preparation of fatty acids is de&bed wkc the /karbon atom haa bcut t+xd by aparbutituti phenyl group. FrkddCrrhs qlation of pbcnylsmtic cst~s givea mixtures am&ting &i&y of m- Mdpacylpbatylracptn.

THE inhibition of p-oxidation in oivo of fatty acids can be brought about by modifying the acids in various ways, such as inserting a hctero-atom, side branches or a ring.’ The absence of @-oxidation, and therefore lack of toxicity, in pfluorophcnylacetic acid has been demonstrated, but no acids have been reported in which the @a&on atom of a straight chain fatty acid is replaced by a phenyl group, with the exception of the 6rst member of the series (I, R = Me).*

A number of variations of the Friedel-CraRs reaction are available as routes to these compounds, but in general more than one positional isomer is formed, and the mixtures can be very difficult to separate. For example, formylation of n-butylbenxene by the method given’ gave a low yield of a mixture which by GLC was separated into four major and several minor components. Aluminium chloride is known to cause rearrangement and migration of alkyl groupsM and dealkylation of alkylbenxenes under the conditions of the Gattermann-Koch reacti0n.l Other routes requiring the use of aluminium chloride on an alkylbenzene were rejected for the same reasons.

A chloromethyl group can be introduced into an alkylbenxene with catalysts having less isomerizing tendency than aluminium chloride, such as stannic chloride7 or zinc chloride,8*0 but the products of these reactions have later been shown to be mixtures of o- and palkylbenxyl chlorides.lO*ll

Acylation of a phenylacetic acid derivative provides a short and simple route to the required compounds. Acetylation of phenylacetonitrile gives a mixture of m- and pisomers” R eports of the acetylation of phenylacetic esters arc conflicting.uJ4 A

l Raart address, Dept. of Chanistry, The University. Kc&, StatTs

’ F. L. M. Pattison and B. C. Saunders, J. Ckm. Sot. 274s (1949). ‘Thebrurhsdfhrinrddprepubdhac(Ic)hurincsbeaamrdebyWillgaodt~onon~

isopsntanykcetophakone. but tbc mctbod of preparation of the latter was not dkkai. Bdg Pat. 621,255; 1963.

’ N. N. Croume, Org. Reoctbnr 5,290 (1949). ’ L. Gattemann, L&b&s Ann. M7.347 (1906). * Kwrr and Wckcnborn, U.S. Pat. 1,776,lU. ‘RM.Robats,A.A.~~RN.Graeoa,J.AmC~.~.~U)46(19612 ’ H. Sommdct, C. R. Acad. Sci., Purfs l57. 1443 (1913). ’ L. Bert. C. R. Acd Scl. Par& UK, 373 (1928). l H. Stepkma, W. F. Short and 0. Gladdings, 1. Gem. Sot. 117, SlO(1920).

I* P. Hill d W. F. Short, 1. Ckm. Sk 1123 (1939. II P. P. Sborygin and S. A. SkoMhakqq 1. Gen. Chum., CJS.S.R, 6, IS78 (1936). I’ K. Rorig, J. Am. Chm. Sue. 75.5381 (19S3). Ia D. Papa, E Scbwark and A. Klingrbcrg. 1. Am Chem. Sot. 68,2133 (1946). ” E D. - and J. Mum, 1. Org. Ckm. M, S49 (1999).

1735

1736 E D. MOllOAN

recent method” claimed methyl pacetylphenylacetate in 66% yield, apparently free of isomers. We have found that the liquid Me ester obtained by this method also, is a mixture of all three positional isomers, both by GLC and IR spectral examination; and by truns-csttrification to the ethyl esters, from which the pisomer Ila crystallizes on cooling.

RI\ 0

<H,COOH R4 / ~,“.,00K 0

2 4 I II

(a) R = Et (a) R = Me R’ = Er (b) R = n-Bu (b) R - n-R R’ - H (c) R - 3ethylbutyl (c) R = n-I4 R’ = Et (d) R - n-pentyl (d) R = i-Bu R’ - H (e) R = II-hexyl (e) R = n-Bu K-H (f) R-i-Bu (f) R = n-pcntyl K-H

A number of p-acylphenylacetic acids and esters have been prepared in this way. The Fried&Crafts reaction products were analysed by gas chromatography. The proportion of p-isomer was highest (58 %) in the acetylphenylacetatcs and this fell to 46% in the butyrylpheoylacetates and then fell slowly with increasing mol wt and decreasing total yield (Table 1). The bulky acylating complex is prevented from attacking the o-position to any large extent by steric hindrance.” When stannic chloride was used in place of aluminium chloride in an attempt to change the isomer ratio, 00 reaction occurred.

TABU 1

Pcrccn* composition of reaction products Estc.rs 0 m P

- -- _._---__ . _... -_-. _ _. ~ _ Acuylphcnylaaxatcs 4 38 58 Butyrylphenylacerata 5 49 46 Huanoylphulylacctafa 6 49 44

The ethyl esters of the higherpacylphenylacctates could not be obtained crystalline by cooling the oily mixtures, so they were hydrolysed to the fret acid and thepisomer crystalhzcd at low temperature (refrigerator) from a small quantity of carbon tetra- chloride or benzene.

The identity of the pbutyrylpheoylacetic acid (IIb) was proved by oxidizing a sample to terephthalic acid, and confirmed by NMR spectroscopy. The higher acids were identified both by NMR spectra and by relating their IR absorptions to those of IIa, IIb and 11~. The 650 lo 900 cm-’ region in the spectra of these compounds contains too many strong absorptioos to be of diagnostic use, but a characteristic band of medium intensity at 1580 cm-’ appears in all the pacylphenylacetic acids (1575 cm-l in the corresponding Et esters .(l) A similar band at 1590 cm-’ appears in the m-isomeric acids and ethyl esters). The NMR spectra of all thepacylpheoylacctic esters showed a typical psubstitution pattern of aromatic protons appearing as an AB pattern with small extra peaks at the base of the main peaks. The position of absorption of protons 1 and 2 (in II) is 2.2 T and protons 3 and 4 is 2.7 7 (JISB and

1’ 0. A. Olah. M. E. Moffatt, S. J. Kuhn and B. A. Hard&I. Am. Chrm. SOC. 86.2198 (1964).

SyntlKsb ofpa&ylphenylacctic acids 1737

J,,, = 8 c/s). The aromatic protons of the corresponding p-alkylphcnylacetates had a single absorption at 2.95 T integrating for 4 protons.

There was no evidence of isomeric impurities in the pacylpheaylacetates by NM R and the greatest impurity detectable by GLC was 1% of m-isomer in ethyl phexyI- phcnylacetate, the most difficult of the series to purify.

The acylphtnylacetic acids were readily red~ced~~ to the alkylphtnylacetic acids (I) in almost quantitative yield.

EXPERIMENTAL

GLC was car& out on a 12 ft by @25 in column of 5 % Silicone gum SE30 01) Chromosorb G treatal with dimethyldi&lorosilam~ using He as carrier gas (SO ml@in) and a flame ionization detactor. IR lrpoctra were recorded on a Perkin-Elmer Infracord 237 and NMR spear% were deter- mired by Miss P. M. Lewis on a Perkin-Elmer R10 spectrometer, using CC& as soiveat.

Ethyl puce/y/)Aenylace~ufc (II&. C&y powdered AICI, (Merck anhyd sublimed AICI, for synthesis) (120 g, @9 mole) was covered with CS, (2.50 ml) and ethyl phenylacetate (65 g, @4 mole) added at 0’ with stirring. Acctyf chloride (38 ml. 42 g. 053 mole) was added slowly and the tanp slowly raised. FinaIIy the mixture was heated at r&x tunp for 10 hr, cooled, poured into a mixture of ice (800 gI and cone HCI (400 ml). and the product extracted with 3 portiom benzene. The combined extracts were washed with dil HCI, water and Na,CO, aq. dried (MgSOJ and the solvent removed. The residue was dbtilkd under vacuum. After removal of a little unchanged material, ethyl aatyl- pbenylacetata were ortllactcd, b.p. 16%171”/13 mm, (63-S g. 77*&.

The esters (247 g) partly solidifiad in the refrigerator lo give the solid pisomer (13.2 g). After one uystallization from light petroleum (b.p. 80-100”) it had m.p. 64-W. not raised on further crysUization (lit.” m.p, 67-W).

The mixed isomeric Me ataa wzre prepared in the same way in 87% yield, b.p. 167-172’/14 mm. The pisomcr could not be crystalIizd out at 0” and so the mixture was rronsaterified to the Et csta~, when thcpisomcr separated out on cooling.

pElhy/pheny&xeric u&i (Ia). A mixture of ethyl pacetylphcnylaatata (11 g, @OS mole), KOH ( IS g) and hydrazine hydrate (7.5 ml) in dicthyknc glycol(75 ml) was refhuted for 14 hr. The condo was then removed and solvent allowed to distill off until the liquid tanp had risen to 190”. Tbe oon- daua was replaced and the soln refJuxcd at the higher temp for 4 hr. cooled, diluted with wata. acid&d with dil HCl and the solid acid filteral off, dried and crystallizd from light petroleum (b.p. SO-loo”) to give p-rthyt’pheny/aceric acld with a strong spioc-like odour, m.p. 92-94”.

The ethyl ester was obtained as a colourkss oil, b.p. 148”/14 mm, nnn 1.4952. by cstcrification with EtOH containing toluarc psulphonic acid.

The~MdestaspnpandinthisworkuclistedinTabke3and4. Themethodrbywhich they were prepared are the same as that detailal for the first members of the suica (Table 2). All the compounds arc new exoept what a reference to literature is given,

ProdUCt .- -1--._-

Mixed isomeric methyl ~ylph~yl~~t~ Mix& isomeric ethyl aatylphenyla&at*i Mixed isomcric methyl butyrylphenylacetata Mixed isomeric ethyl butyrylphenylacetate Mixed isomcric methyl isovaJerytphenylaoetata Mixed isomeric ethyl isovakrylptiylurtata Mixed isomeric methyl valcrylphenylaalatcs Mixed isorn& ethyl hcxanoylphmylacetata

* Old laboratory stock aluminium chloride used

a‘ D. Tdd. 0~. Reocrlonr 4,378 (1948).

b.p. Yield “C/nUll %

.- .-_ 16?-172”/14 87 169-171°[13 77 18@-lW/l4 78 195-200~~20 74 144-I SZ’/O~S 43. 124-131”/02 71 138-1500/@4 62 MO-lso’/@I 62

1738 E. D. MWOAN

TASLM 3. Aam PREPARPD

Analysis Found Required

Compound mP* Yidd C H C H -_. -.-._ ..-- .

PBuWphenY~ Ilb 83-84” 16. 70.19 7.30 69.90 6.85 pIsovaktylphenylacctic IId 9S-97” 18. 70&l 7.21 7087 7.32 pvalcrylphenylac& IIC 9G92” 18. 7@S3 7.19 7087 7.32 pHczanoylpknylac& IIf 93-95” 19. 71.77 7.78 71.79 7.74 pEthylphenylacetic Ia 92-94” 98 72.7 I 740 73.14 7.38 pButylphenylaatic Ib 79-81” 98 74.88 8.42 74.94 8.39 pwtylphenytr Ic =I’ - 75.77 8.89 75.70 8.81 pPcntylphcnylac& Id 92 76.07 9a 75.70 8.81 pHexylphalylacetic IO 83-85” 85 76.00 8.92 76.32 9.15

l Of puritkd acid based on crude mixed esters. t Lit.’ m.p. 62.S-63.5”.

TAIU 4. EsreRs PREPARF.D

Compound b.p.

“C/mm “D

MM Found RCC@?d

C H C H

Ethyl pbutyrylphcnylaatatc 19s200”/20 g1511s 72.11 8.15 71.75 7.75 Ethyl pisovalcrylpknylaatate 208-210”/14 $15075 72.99 8.28 72.s 8.12 Ethyl pvalcrylphcnylacztatc 130-132”/@2 $15075 72.84 8.10 7255 8.12 Ethyl phaanoylphcnylaatate 144O/@l tgl*506S 72.84 8.28 73,24 846 Ethyl +hylphenylacctate M0/14. $1.4952 75.27 8.45 7494 840 Ethyl pbutylphenylaaxate lS7-158”/16 el.4912 76.18 9.20 76.33 915 Ethyl pisopcntylphenylac&atc 182-184”/30 el.4870 7642 9.80 76.89 948 Ethyl ppentylphatylacetatc 174-175”/20 t#.4898 76.75 966 76.89 948 Ethyl plwxylphmyltIcaate 188-190“/20 $14880 77.27 9.92 77.36 9.74

l Lit” b.p. 1 W/4 mm. n; l-4970.

For the identi5cation ofpbutyrylphcnylecdk acid, a sample wan oxidizal with KMoO, in K&O, soln. Tbc acid obtained was ester&d with MeOH containing BF,, giving dimcthyl torephthalate, mp. 138-140” after one aystallization from aq. ethanol, mp. undeprcsud on mixing with an authentic spazimcn.

Acknow/e&mnr-I wish to thank Sir Robert Robinson for his wt and hdpful disamiom.

I’ I. P. Belctskaya, G. A. Artamkina, E. A. Shevlyagina and 0. A. Rcutov. Zh. Obsch. Huh. 31, 321 (1964).