Chemistry

E. P. Kaplyan, Corresponding Member of the Academy of Sciences of the USSR, A. D. Petrov

On the Interaction of Acid Esters with Lithium Alkyls

In our previous investigations \((^{1-3})\), we studied chiefly the influence of temperature on the direction of reactions of lithium alkyls with acid esters. It was shown that at \(-35^\circ\) the reaction proceeds according to the normal scheme, with formation of tertiary alcohols. At \(+35^\circ\) and above, the reaction proceeds anomalously, with formation of a ketone bearing the radicals of the initial acid ester.

However, β-keto esters remained unisolated (the Claisen-condensation product of the initial ester), the decomposition of which is the most probable route for formation of ketones of the indicated type. A β-keto ester was isolated by Zook \((^4)\) in the interaction of tert-\(\mathrm{C_4H_9MgCl}\) with the ester of propionic acid; however, its hydrolysis was carried out with an alcoholic solution of KOH at \(95^\circ\) for three hours, i.e., under conditions absent in Grignard syntheses.

From the work of Gilman and co-workers \((^{5,6})\) it is known that organolithium compounds are thermally unstable and readily decompose to an olefin and lithium hydride \((^7)\). The latter, apparently, may bring about a Claisen condensation.

Since the stability of lithium alkyls decreases in the series:

\[ \text{iso-}\mathrm{C_3H_7Li} > \text{sec.-}\mathrm{C_4H_9Li} > \text{tert.-}\mathrm{C_4H_9Li} > \text{tert.-}\mathrm{C_5H_{11}Li}, \]

different temperature conditions are also required for the formation of the anomalous products—the β-keto ester and ketone. This is in good agreement with our experimental data \((^1)\), which showed that diethyl ketone is obtained in the reaction of tert-\(\mathrm{C_5H_{11}Li}\) with ethyl caprylate even at \(-30^\circ\), whereas with iso-\(\mathrm{C_3H_7Li}\) only at \(+35, +70^\circ\). The possibility of the anomalous reaction is also influenced by the nature of the acid ester. Thus, for example, we did not observe formation of the ketone \(\mathrm{R{-}CO{-}R}\) from the ester of phenylacetic acid, evidently because here the β-keto ester is formed at a temperature considerably higher than that at which lithium alkyls decompose. Indeed, from the ester of phenylacetic acid the keto ester is formed upon heating with sodium ethylate for 6 hours at \(95^\circ\) \((^8)\). In the case of esters of aromatic acids (benzoic, naphthoic), where Claisen condensation is impossible, the reaction proceeds according to the acyloin-condensation type, with formation of ketols \((^2)\).

In the present investigation, wishing to stop the reaction at the stage of the intermediate product, the β-keto ester, we slowed its course by replacing the polar solvents ether and tetrahydrofuran (THF) with \(n\)-hexane. This same replacement excluded the possibility of formation of lithium alkoxide, obtained in the interaction of alkyl lithium with ether and acting as a strong condensing agent. Under these conditions we obtained, in 30% yield, ethyl 2-\(n\)-hexyldecan-3-oate and a small amount of diheptyl ketone:

\[ \text{tert.-}\mathrm{C_4H_9Li} + 2\mathrm{C_7H_{15}{-}COOC_2H_5} \rightarrow \mathrm{C_7H_{15}{-}CO{-}CH{-}COOC_2H_5} + \]

\[ \begin{array}{c} \\[-1.2em] \mathrm{C_6H_{13}} \end{array} \]

\[ +\, \mathrm{C_7H_{15}{-}CO{-}C_7H_{15}} + \mathrm{C_2H_5OH} + \mathrm{C_4H_8}. \]

Unsaturated β-keto esters, as was shown by Nazarov and co-workers \((^9)\), are hydrolyzed to ketones even in an aqueous medium with 10% KOH content. In our case, hydrolysis in aqueous solution proceeded with 5% LiOH.

We observed for the first time the formation of anomalous products also in the interaction of the ester of caprylic acid with a primary normal lithium alkyl—butyllithium. The reaction proceeded in THF at \(40{-}50^\circ\) for 8 hours with a yield of 20%, whereas secondary and tertiary lithium alkyls under milder conditions gave a yield of diheptyl ketone of 60–70%.

Experimental Part

Reaction of tert-\(\mathrm{C_4H_9Li}\) with caprylic acid ester. The synthesis was carried out in a stream of nitrogen in a flask equipped with a reflux condenser, stirrer, dropping funnel, and thermometer. Into the flask were placed 7 g of finely cut lithium, 200 ml of hexane, and 46 g of tert-\(\mathrm{C_4H_9Cl}\) was added dropwise at room temperature. To accelerate the formation of tert-\(\mathrm{C_4H_9Li}\), 1 ml of THF was added. After 5 hr of stirring, the lithium that had not entered into the reaction was filtered off. To the tert-\(\mathrm{C_4H_9Li}\) was added a solution of 43 g of ethyl caprylate in 50 ml of hexane. The first portion of the ester was added at a temperature of 20°; then the reaction proceeded vigorously, and the temperature rose to 55–60°. After decomposition at a temperature of 10–15° and distillation of the product, the following fractions were obtained:

60–85°/4 mm — 4 g of the initial ethyl caprylate.
120–165°/4 mm — 6 g of liquid, which crystallized.
By recrystallization from alcohol, 3 g of diheptyl ketone with m.p. 39° was obtained.
171–175°/4 mm — 10 g of ethyl ester of 2-hexyldecan-3-oic acid, \(n_D^{20}\) 1.4460.

Found, %: C 73.01, 73.27; H 11.30, 11.51
\(\mathrm{C_{18}H_{34}O_3}\). Calculated, %: C 72.44; H 11.46

IR spectra were recorded: on an IKS-14 with a NaCl prism in the region 2000–1600 cm\(^{-1}\), in \(\mathrm{CCl_4}\) solution, \(d = 1\) mm, and on an IKS with a LiF prism in the region 3600–3000 cm\(^{-1}\), in \(\mathrm{CCl_4}\) solution, \(d = 1\) mm. Bands were found: an intense band at 1740 cm\(^{-1}\), assigned to \(\mathrm{C=O}\) in the ester group, and a weak band at 1730 cm\(^{-1}\), corresponding to \(\mathrm{C=O}\) in ketones.

Hydrolysis of the keto ester. A mixture of 7 g of ethyl ester of 2-hexyldecan-3-oic acid and 25 ml of a 5% aqueous solution of LiOH was stirred for 1 hr at a temperature of 5–10°. Then 10% hydrochloric acid was added. The product was extracted with ether, washed with water, and dried. After fractionation, two fractions were obtained. The first, 150–165° — 3 g, rapidly crystallized. From it was isolated diheptyl ketone with m.p. 39° (from alcohol); a mixed-melting-point test with diheptyl ketone gave no depression. The second, 170° — 2.5 g, was the initial keto ester.

Reaction of \(n\)-\(\mathrm{C_4H_9Li}\) with caprylic acid ester. \(n\)-Butyllithium was prepared from 7 g of lithium and 47 g of \(n\)-\(\mathrm{C_4H_9Cl}\) in 200 ml of THF. The lithium that had not entered into the reaction was filtered off. To the \(n\)-butyllithium, at room temperature, 41 g of ethyl caprylate was added. Then the reaction mixture was stirred for another 8 hr at 40–50°, after which it was hydrolyzed with 5% HCl at 5–10°. Obtained: 145–146°/3 mm — 8 g of dodecanone-5, \(n_D^{20}\) 1.4546.

3 g of diheptyl ketone, m.p. 40°. 160–161°/3 mm — 3 g of heptyl-di-\(n\)-butylcarbinol, \(n_D^{20}\) 1.4508.

Found, %: C 80.08, 80.07; H 14.12, 14.04
\(\mathrm{C_{16}H_{34}O}\). Calculated, %: C 79.40; H 14.20

N. D. Zelinskii Institute of Organic Chemistry
Academy of Sciences of the USSR

Received
26 XI 1963

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