Chemistry

G. N. Dorofeenko, V. I. Dulenko

Synthesis of 1,3-Disubstituted 5,6,7,8-Tetrahydroisochromylium Salts

(Presented by Academician M. I. Kabachnik on 29 I 1964)

Pyrylium salts constitute a very interesting, but as yet little-studied, class of heterocyclic compounds. The high reactivity of the pyroxonium nucleus has made it possible to develop methods for converting pyrylium salts into various heterocyclic and aromatic compounds (¹). Recently the number of works in this area of organic synthesis has increased. A significant achievement was the discovery, in 1959, of the bisacylation reaction of olefins (²). The mechanism of this reaction consists in the intermediate formation of β,γ-unsaturated ketones, whose further acylation gives unsaturated 1,5-diketones that cyclize, with elimination of water, to pyrylium salts (³,⁴,⁵).

We have found that, upon acylation of readily available products of the crotonic condensation of cyclohexanone with acetone and acetophenone—cyclohexenylacetone (⁶) (I, R = CH₃) and cyclohexenylacetophenone (⁷) (I, R = Ph), which are β,γ-unsaturated ketones—with acid anhydrides in the presence of hydrochloric acid, substituted 5,6,7,8-tetrahydroisochromylium salts are formed. Subsequently, the crotonic condensation of cyclohexanone with heterocyclic ketones—2-acetothienone and 2-methyl-5-acetylfuran—was studied, as a result of which cyclohexenylacetothienone was obtained

\[ \left(\mathrm{I},\ R = \begin{array}{c} \text{2-thienyl} \end{array} \right) \]

and 2-methyl-5-cyclohexenylacetylfuran

\[ \left(\mathrm{I},\ R = \text{2-methyl-5-furyl} \right). \]

These compounds

\[ \mathrm{I}:\quad \text{cyclohexenyl-}\mathrm{CH_2COR} \]

like other products of the crotonic condensation of cyclohexanone, are β,γ-unsaturated ketones; therefore, on acylation they readily and rapidly form substituted pyrylium salts, which, under the action of ammonia, are converted into the corresponding 1,3-disubstituted 5,6,7,8-tetrahydroisoquinolines:

\[ \begin{array}{c} \text{cyclohexenyl-}\mathrm{CH_2COR} \ \xrightarrow[\ ]{\mathrm{R'CO^+ClO_4^-}}\ \text{acylated intermediate} \ \xrightarrow{-\mathrm{H_2O}}\ \text{tetrahydroisochromylium perchlorate} \ \xrightarrow{\mathrm{NH_3}}\ \text{1,3-disubstituted 5,6,7,8-tetrahydroisoquinoline}. \end{array} \]

Study of the acylation of compounds I with acid anhydrides in the presence of hydrochloric acid showed that cyclohexenylacetone, cyclohexenylacetophenone, and cyclohexenylacetothienone form salts of 5,6,7,8-tetrahydro-

Table 1

* The yield of 5,6,7,8-tetrahydroisoquinoline is given (b.p. 301—303°), since the salt could not be isolated in the crystalline state.
** Phenylacetic acid chloride was used as the acylating agent.

...isochromylium in high yield (65—90%), whereas 2-methyl-5-cyclohexenylacetylfuran is partly resinified during the reaction, which is connected with the acidophobic character of the furan nucleus; therefore the yield of pyrylium salts is 40—55%.

The high reactivity of β,γ-unsaturated ketones can probably be explained by the ease of enolization of the carbonyl group, which contributes to an increase of electron density at the γ-carbon atom:

\[ \begin{array}{c} \text{cyclohexenyl-}CH_{2}-C(=O)R \;\rightleftharpoons\; \text{enol form with increased electron density at the }\gamma\text{-carbon, }C(OH)R \end{array} \]

In the acylation of cyclohexenylacetoacetic acid, only polymerization products were isolated.

All the 5,6,7,8-tetrahydroisochromylium salts obtained by us, except for one \((R = R' = CH_{3})\) (⁴), were previously unknown. They are colorless or slightly colored crystals, sparingly soluble in acetone, alcohol, and water. Solutions of salts containing thiophene and furan nuclei as substituents fluoresce blue and yellow-green. The 5,6,7,8-tetrahydroisoquinolines corresponding to the salts, identified as picrates, are currently being tested for physiological activity.

Experimental Part

Preparation of the starting substances. Cyclohexenylacetone and cyclohexenylacetoacetic acid were obtained by alkaline condensation of cyclohexanone with acetoacetic ester (⁶), and cyclohexenylaceto-

phenone was synthesized from cyclohexanone and acetophenone (7). In a similar manner, the condensation of cyclohexanone with 2-acetothienone and 2-methyl-5-acetylfuran was carried out for the first time. Cyclohexenylacetothienone (yield 30%), b.p. 150–152°/6 mm; $d_{20}^{20}$ 1.1286; $n_D^{20}$ 1.5773; $MR_D$ 60.5; $MR_{\text{calcd}} = 59.9$.

Found, %: C 69.91; H 6.72; S 15.47
$C_{12}H_{14}OS$. Calculated, %: C 69.56; H 6.84; S 15.54

2-Methyl-5-cyclohexenylacetylfuran (yield 10%), b.p. 180–182°/22 mm; $n_D^{20}$ 1.5445.

Found, %: C 75.91; H 7.81
$C_{13}H_{16}O_2$. Calculated, %: C 76.43; H 7.90

Semicarbazone, m.p. 166–168°.

Found, %: N 15.83
$C_{14}H_{19}N_3O$. Calculated, %: N 16.08

Carrying out the reaction. To 0.01 g-mole of I is added a freshly prepared mixture of 0.05 g-mole of the acid anhydride and 0.01 g-mole of 70% $HClO_4$; the mixture is stirred well and left at room temperature for 20–30 min. The reaction mixture is diluted with ether, the pyrylium salt is filtered off, washed well with ether, and dried. In the acylation of cyclohexenylacetone the salts obtained usually do not crystallize immediately; therefore they are reprecipitated with ether from n-propyl alcohol. Salts contaminated with resin are washed on the filter with a mixture of acetone and ether.

The conversion of the salts into 5,6,7,8-tetrahydroisoquinolines was carried out by passing gaseous ammonia through a suspension of the salt in ethyl alcohol. The picrates were recrystallized from alcohol. The experimental data are given in Table 1.

Rostov-on-Don State University

Received
26 I 1964

CITED LITERATURE

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