Chemistry

P. B. Terent'ev, A. N. Kost, A. A. Shchegolev
and Corresponding Member of the Academy of Sciences of the USSR A. P. Terent'ev

Synthesis and Some Reactions of Pyridylethynylcarbinols

Heterocyclic bases having a triple bond in the side chain have been studied very little. Yet such compounds may serve as starting materials for the synthesis of a whole series of new systems.

In studying the properties of the acetylene group attached to the pyridine nucleus, we carried out the condensation of 2-methyl-5-ethynylpyridine (I) (¹) with aldehydes and ketones under the conditions of the Favorskii reaction. As in the case of other substituted acetylenes (²), the best yields of carbinols were achieved with the use of a 4–5-fold excess of alkali. Condensation of (I) with ketones proceeds readily and in good yields in anhydrous ether at 0°. At the same time, the reaction of I with aldehydes could be carried out only at −20, −40° and at high dilution, using tetrahydrofuran as the solvent.

\[ \mathrm{ \begin{array}{c} \text{2-methyl-5-ethynylpyridine (I)} \end{array} \quad +\quad \begin{array}{c} R\\[-2pt] R_1 \end{array}\mathrm{C{=}O} \ \xrightarrow{\mathrm{KOH}}\ \text{2-methyl-5-pyridyl-} \mathrm{C{\equiv}C{-}C(OH)(R)(R_1)} } \]

The Kucherov reaction with the tertiary carbinols obtained does not take place in 15–20% sulfuric acid. Only by using 25% sulfuric acid were we able to obtain from carbinol II \((R = R_1 = CH_3)\) the corresponding α-keto alcohol (III), the structure of which was proved by the infrared spectrum (the presence of a frequency at 1714 cm\(^{-1}\), characteristic of a C=O group not conjugated with an aromatic nucleus) and by isolation from the products of its periodate oxidation of acetone (as the 2,4-dinitrophenylhydrazone).

\[ \mathrm{ II \ \xrightarrow[\mathrm{H^+,\,Hg^{++}}]{\mathrm{H_2O}}\ III \ \xrightarrow{\mathrm{HIO_4}}\ \left[\text{2-methyl-5-pyridylacetic acid}\right] + (CH_3)_2C{=}O } \]

Oxyketone III was subjected to the Fischer reaction by heating its phenylhydrazone with catalytic amounts of anhydrous zinc chloride at 190–210°. As a result, the sole product isolated was 2-(1-methyl-1-hydroxyethyl)-3-(6-methylpyridyl-3)-indole (V). It was identified by its IR spectrum (there is a frequency of N—H and OH vibrations in the region of 3200 cm\(^{-1}\), and the vibration frequencies of an unsaturated bond in the region of 1640–1660 cm\(^{-1}\) are absent) and by its UV spectrum (a maximum in the region of 267 mµ, characteristic of β-phenylindoles).

When an analogous reaction was carried out with oxyketone IV, in addition to 2-(1-hydroxycyclohexyl-1)-3-(6-methylpyridyl-3)-indole (VI), there was also isolated the pro-

product of its dehydration, 2-(cyclohexenyl-1)-3-(6-methylpyridyl-3)-indole (VII), in the IR spectrum of which there are vibration frequencies in the region of 1644 cm\(^{-1}\).

\[ \begin{gathered} \text{(IV)}\quad R+R_1=-(CH_2)_5- \\ \xrightarrow[\ 200^\circ\ ]{ZnCl_2} \\ \text{(V)}\quad R=R_1=CH_3 \\ \text{(VI)}\quad R+R_1=-(CH_2)_5- \\ \text{(VII)} \end{gathered} \]

Experimental Part

Condensation of I with ketones. To a mixture of 0.1 mole of I and 0.4 mole of powdered KOH in 25 ml of abs. ether at 0° and with stirring, 0.1 mole of ketone was added, the mixture was left overnight, saturated with carbon dioxide gas, and the carbinol was isolated (see Table 1).

Condensation of I with aldehydes. To a mixture of 0.05 mole of I and 0.25 mole of powdered KOH in 25 ml of abs. tetrahydrofuran, with stirring and cooling (\(-25\), \(-40^\circ\)), a solution of 0.1 mole of aldehyde in 20 ml of abs. tetrahydrofuran was slowly (1.5–2 hours) added, and the mixture was stirred for another 2 hours. On the following day it was acidified, extracted with ether, the aqueous solution was neutralized, extracted with ether, and the residue after removal of the solvent was chromatographed on alumina, eluting I with petroleum ether, and the carbinol with a mixture of benzene and acetone (1 : 1).

2-Methyl-5-(3-methyl-3-oxobutyl)-pyridine (III). A solution of 8.7 g of 2-methyl-5-(3-methyl-3-hydroxybutyn-1-yl)-pyridine (II, \(R=R_1=CH_3\)) in 50 ml of 25% sulfuric acid was boiled in the presence of 0.1 g of mercuric oxide for 10 hours, neutralized with soda, extracted with chloroform, and after removal of the solvent the residue was distilled in vacuum. Yield 50.5%, b.p. 158–162°/7 mm, m.p. 52–54°.

\[ \begin{aligned} &\text{Found, \%: } N\ 6.95;\ 7.05\\ &C_{11}H_{15}O_2N.\ \text{Calculated, \%: } N\ 7.25 \end{aligned} \]

2-(1-Methyl-1-hydroxyethyl)-3-(6-methylpyridyl-3)-indole (V). 1.9 g of III and 1 g of phenylhydrazine were heated (150°) for 0.5 hour, 0.2 g of anhydrous zinc chloride was added, and heating was continued for another 1.5 hours at 200–220°. The mixture was cooled, and the reaction mass was reprecipitated twice from an acidic solution. Yield 0.5 g (19%), m.p. 150–152° (from benzene + petroleum ether 1 : 1). \(\lambda_{\max} 267\ \text{m}\mu\) (\(\lg \varepsilon\ 4.08\)) (from methanol).

\[ \begin{aligned} &\text{Found, \%: } N\ 10.92;\ 10.81\\ &C_{17}H_{19}ON_2.\ \text{Calculated, \%: } N\ 10.53 \end{aligned} \]

2-Methyl-5-(2-(1-hydroxycyclohexyl-1)-2′-oxoethyl)-pyridine (IV). A solution of 4.3 g of II (\(R+R_1=-(CH_2)_5\)) in 25 ml of 25% sulfuric acid with addition of 0.05 g of mercuric oxide was boiled for 7 hours, neutralized with soda, extracted with benzene, the extract was evaporated and chromatographed on alumina. 2.7 g (49%) of a substance with m.p. 64–65° was isolated.

\[ \begin{aligned} &\text{Found, \%: } N\ 6.51;\ 6.15\\ &C_{14}H_{19}O_2N.\ \text{Calculated, \%: } N\ 6.00 \end{aligned} \]

2-(1-Hydroxycyclohexyl-1)-3-(6-methylpyridyl-3)-indole (V). 5.8 g of IV and 2.7 g of phenylhydrazine were heated (150°) for 0.5 hour, add-

Table 1

\[ \ce{CH3-C5H3N-C#C-C(OH)(R)(R1)} \]

* Based on pyridylacetylene charged.
* Picrate.
** Phenylurethane.

0.2 g of anhydrous zinc chloride was added and the mixture was heated for another 2.5 hours at 175–190°. It was cooled, reprecipitated twice from an acidic solution, and the resulting oil was extracted with benzene. From the extract, 0.9 g (12%) of V was obtained, m.p. 152–154°, \(\lambda_{\max} 275\) mµ \((\lg \varepsilon 4.01)\) (from methanol).

Found, %: N 9.03; 8.98
\(\mathrm{C}_{20}\mathrm{H}_{22}\mathrm{ON}_2\). Calculated, %: N 9.11

The residue insoluble in benzene was chromatographed on alumina. 0.3 g of VI was obtained, m.p. 70–71°.

Found, %: N 9.46; 9.33
\(\mathrm{C}_{20}\mathrm{H}_{20}\mathrm{N}_2\). Calculated, %: N 9.72

Moscow State University
named after M. V. Lomonosov

Received
6 VII 1961

REFERENCES

1. A. N. Kost, P. B. Terent’ev, T. Zavada, DAN, 130, No. 2, 326 (1960).
2. A. I. Zakharova, ZhOKh, 11, 939 (1941).