BENZYL-3-METHYLPENTANOIC ACID

3-BENZYL-3-METHYLPENTANOIC ACID (p-Benzyl-p-methylvaleric acid) 

Ethyl sec-butylidenecyanoacetate. In a 1-1. round-bottomed flask fitted with a 24/40 joint are placed 0.45 g. of /3-alanine, 113 g. (106 ml., 1.0 mole) of ethyl cyanoacetate (Note 1), 87 g. (108 ml., 1.2 moles) of butanone, 20 ml. of glacial acetic acid, and 100 ml. of benzene. A Barrett-type water separator (Note 2) and a condenser are attached to the flask, and the mixture is heated briskly under reflux until water ceases to be collected in the trap (7-12 hours). 

The reaction mixture is decanted into a 500-ml. round-bottomed flask which is attached to a fractionating column (Note 3). The solvent is removed at atmospheric pressure while the oil bath is heated finally at 160°. The residue is distilled at reduced pressure to furnish four fractions (a) acetic acid and other materials boiling below 95°/16 mm. (6) ethyl cyanoacetate, b.p. 95-110°/16 mm. (c) intermediate, b.p. 110-124°/16 mm. and (d) ethyl sec-butylidenecyanoacetate, b.p. 124-126°/16 mm., 2l 1.4640-1.4648. Fraction d amounts to 117-122 g., and re-fracticfnation of fraction c yields an additional 18-24 g. total yield, 135-146 g. (81-87.5%) (Note 4). 

Ethyl 3-benzyl-2-cyano-3-methylpentanoate. A 2-1. threenecked round-bottomed flask, fitted with a tantalum wire Hersh-berg stirrer, a condenser, and a separatory funnel, is arranged for use of a nitrogen atmosphere.2 Magnesium (19.2 g., 0.79 g.-atom) and 100 ml. of dry ether 3 are placed in the flask, and a solution of 100 g. (91 ml., 0.79 mole) of benzyl chloride in 500 ml. of dry ether is added in a period of 1.5-2.0 hours, with stirring, while the mixture boils spontaneously. The mixture is koiled for 15 minutes after completion of the addition, then a solution of 110 g. (0.66 mole) of ethyl sec-butylidenecyanoacetate in 130 ml. of benzene is added over a 30-minute period with spontaneous reflux. The reaction mixture is stirred and heated under rellux for an additional hour. A precipitate separates after about 30 minutes. 

The reaction mixture is poured onto about 400 g. of cracked ice and is made acidic with 20% sulfuric acid. After two clear phases 

---

N,N,o-trimethyl-, 34, 61 N-Benzylaniline, 36, 22 Benzyl chloride, 34, 65 Benzyl cyanide, 31, 53 32, 64, 65, 92 N-Benzylidenemethylamine, 34, 65 Benzyl isocyanide, 31, 54 Benzylmagnesium chloride, 34, 65 3-Benzyl-3-methylpentanenitkile, 35, 8 3-BENZYL-3-METHYLPENTANOIC ACID, 35, 6 /S-Benzyl-/ -methylvaleric acid, 35, 6 Benzylthiosulfuric acid, 32, 103 Benzyltrimethylammonium hydroxide,... 

D. 3-Benzyl-3-methylpentanoic acid. A solution of 112 g. of potassium hydroxide in 400 ml. of ethylene glycol is added to 93.6 g. (0.5 mole) of 3-benzyl-3-methylpentanenitrile in a 1-1. round-bottomed copper or stainless-steel flask. A condenser with a rubber stopper is attached, and the solution is heated under brisk reflux for 6 hours (Note 12). The reaction mixture is cooled, diluted with 400 ml. of water, and extracted with three portions of ether (250 ml., 100 ml., 100 ml.). The ether... 

When the combined aqueous washes from three runs were acidified, extracted, and distilled, there was obtained 1.8 g. of 3-benzyl-3-methylpentanoic acid, 1.5158. 

The ethyl 3-benzyl-2-cyano-3-methylpentanoate, 3-benzyl-3-methylpentanenitrile, and 3-benzyl-3-methylpentanoic acid preparations follow the procedure given by Prout, Huang, Hartman, and Korpics.9... 

Benzyl cyanide is first reacted with 2-butylbromide in the presence of sodium amide to give 2-phenyl-3-methylvaleronitrile which is hydrolyzed by sulfuric acid to give 3-methyl-2-phenylpentanoic acid. 24 g of 2-phenyl-3-methylpentanoic acid are heated for one hour at 175° to 185°C with 30 g of 2-diethylaminoethanol and 0.5 g of sodium methylate. The excess diethylaminoethanol is removed in vacuo, the residue is dissolved in 300 cc of 2 N-acetic acid, the acid solution is shaken with ether and made alkaline with concentrated potassium carbonate solution and ice. The ether solution is washed with water, dried with sodium sulfate and evaporated. The residue is distilled under high vacuum, yielding 20 to 21 g of the basic ester (60% of the theoretical) is obtained, the ester boiling at 98° to 100°C at a pressure of 0.03 mm. The hydrochloride of the ester melts at 112°to 113°C and the methobromide at 100° to 101°C. 

C. Mevalonolactone-2-13C. In a 250-mL Paar hydrogenation bottle are placed 50 mL of 95% ethanol, 0.107 g (0.001 mol) of palladium black (Note 14), and 0.519 g (0.00217 mol) of 5-benzyl-oxy-3-hydroxy-3-methylpentanoic acid-2-13C. The bottle is attached to a Paar hydrogenation apparatus (Note 15), charged to 50 psig with hydrogen, and shaken at room temperature for 2 hr. The... 

Ester enolates undergo alkylation reactions. When ethyl 3-methylpentanoate (110) reacts with sodium ethoxide in ethanol and then with bromoethane, the product is 111. Alkylation of malonate derivatives leads to an interesting sequence of reactions that are useful in synthesis. The reaction of diethyl malonate (90) and NaOEt in ethanol, followed by reaction with benzyl bromide, gives 112. In a second reaction, 112 reacts with NaOEt in ethanol and then with iodomethane to give 113. Saponification of 113 (see Chapter 20, Section 20.2) gives the dicarboxylic acid, 114, and heating leads to decarboxylation (Section 22.8) and formation of acid 115. This overall sequence converted malonic acid via the diester to a substituted carboxylic acid, and it is known as the malonic ester synthesis. 

---