CHEMISTRY

R. E. VALTER, Academician of the Academy of Sciences of the Latvian SSR G. Ya. VANAG

IODOMETHYLATION OF 2-SUBSTITUTED INDANDIONES-1,3

2-Amino-2-arylindandiones-1,3 (I) are physiologically active substances possessing narcotic, anticonvulsant, and anesthetic action ($^1$). Two of these preparations are already undergoing clinical trials ($^2$). In order to clarify the relationship between chemical structure and physiological activity of aminoindandiones, the study of 2-aminomethyl-2-arylindandiones-1,3 (II) was of interest.

\[ \begin{array}{cc} \text{(I)} & \text{(II)}\\[2mm] \text{2-amino-2-arylindandione-1,3 structure: } NR'R'',\, Ar & \text{2-aminomethyl-2-arylindandione-1,3 structure: } CH_2NR'R'',\, Ar \end{array} \]

\[ \begin{array}{ccc} \text{(III)} & \longrightarrow & \text{(IV)}\\[2mm] \text{2-hydroxymethyl-2-phenylindandione-1,3: } CH_2OH,\, C_6H_5 & & \text{2-halomethyl-2-phenylindandione-1,3: } CH_2X,\, C_6H_5 \end{array} \]

Since $\beta$-diketones do not form Mannich bases ($^3$), and the dialkylaminomethylation method developed by Böhme ($^4$) can hardly find broader application because of the difficult accessibility of dialkylaminomethyl halides, 2-halomethyl-2-substituted indandiones-1,3 could serve as starting substances for the synthesis of 2-aminomethyl-2-arylindandiones-1,3. 2-Chloromethyl- and 2-bromomethyl-2-phenylindandiones-1,3 (IV, $X = \mathrm{Cl}, \mathrm{Br}$) were obtained by us* by the action of phosphorus pentachloride or phosphorus and bromine on 2-hydroxymethyl-2-phenylindandione-1,3 (III), which in turn is obtained by the action of formaldehyde on 2-phenylindandione-1,3 ($^5$). In view of the low mobility of the chlorine and bromine atoms in the above-mentioned compounds, we were most interested in 2-iodomethyl-2-phenylindandione-1,3 (IV, $X = \mathrm{J}$), which, however, could not be obtained by the described route. It was obtained by prolonged heating of 2-chloromethyl-, or better 2-bromomethyl-2-phenylindandione-1,3 with sodium iodide in glacial acetic acid. Thus, its preparation is a complex three-stage synthesis (starting from 2-phenylindandione-1,3).

Subsequently we studied the possibilities of direct iodomethylation of 2-phenylindandione-1,3 with methyl iodide. It turned out that, upon heating 2-phenylindandione-1,3 with an excess of methyl iodide in the presence of potassium carbonate, 2-iodomethyl-2-

* The work is being printed in the Scientific Notes of the Riga Polytechnic Institute.

phenylindandione-1,3. The method is general also for other 2-aryl-, as well as 2-aralkyl- and 2-alkylindandiones-1,3:

\[ \begin{gathered} \text{2-substituted indandione-1,3} \ \xrightarrow[\mathrm{K_2CO_3}]{\mathrm{CH_2I_2}}\ \text{2-iodomethyl-2-substituted indandione-1,3} \\[4pt] R = \mathrm{C_6H_5},\ p\text{-}\mathrm{C_6H_4OCH_3},\ o\text{-}\mathrm{C_6H_4OCH_3},\ \mathrm{OCH_2O\text{-}C_6H_3},\\ \alpha\text{-}\mathrm{C_{10}H_7},\ \mathrm{CH_2C_6H_5},\ \mathrm{CH_2C_6H_4OCH_3},\ \mathrm{CH_3}. \end{gathered} \]

It is interesting to note that by this method 2-iodomethyl-2-α-naphthylindandione-1,3 was also obtained; Slovak chemists \((^{6})\) had unsuccessfully attempted to obtain it by the action of methylene iodide on the sodium salt of 2-α-naphthylindandione-1,3 in butanol solution. The authors explain this by steric difficulties, but here, apparently, it is necessary to carry out the reaction at a higher temperature. We heated 2-α-naphthylindandione-1,3 with methylene iodide and potassium carbonate to 140–150°, but under these conditions side processes also occur, since the yield of 2-iodomethyl-2-α-naphthylindandione-1,3 is only 19.5%. By the action of methylene iodide on benzalphthalide in the presence of sodium butylate, the above-mentioned authors obtained 2-iodomethyl-2-phenylindandione-1,3 (identical with that obtained by us), but in only 45% of theory.

By heating with methylene iodide even to 180°, we were unable to obtain the iodomethyl derivatives of 2-xanthydryl- and 2-benzhydrylindandiones-1,3, probably owing to bulky substituents, nor of 2-p-nitrophenylindandione-1,3. In the latter case this may be explained by the equalized electronic structure of 2-p-nitrophenylindandione-1,3 \((^{7})\).

The infrared absorption spectra of 2-iodomethyl-2-substituted indandiones-1,3 in the range 1500–1800 cm\(^{-1}\) (recorded in paraffin oil) have two maxima in the region 1708–1745 cm\(^{-1}\), characterizing the diketone form, and a maximum at about 1595 cm\(^{-1}\), assigned to the aromatic system (Table 1).

Table 1

Note. In parentheses—the percent absorption.

Experimental Part

2-Iodomethyl-2-phenylindandione-1,3. 11.1 g (0.05 mole) of 2-phenylindandione-1,3, ground in a mortar with 6.9 g (0.05 mole) of potassium carbonate and 12.1 ml (0.15 mole) of methylene iodide, is heated with a reflux condenser on an oil bath for 1.5 hours at a bath temperature of 180–190°. The end of the reaction is readily determined by the change in the color of the reaction mass: at first it is red; upon completion of the reaction it is yellow or light orange. To the mixture cooled to ~50° about 30 ml of ether is added, and on the second day the precipitate is separated, washed with a small amount of ether, then with warm water, and finally with a small amount of methanol. The yield of 2-iodome-

tyl-2-phenylindandione-1,3: 14.9 g (82.4% of theory). Yellowish crystals with m.p. 189–193°. After recrystallization from acetone or acetic acid, white or light-yellow crystals with m.p. 193–194°.

Found, %: I 35.28, 35.28. C₁₆H₁₁O₂I. Calculated, %: I 35.03.

2-Iodomethyl derivatives of 2-anisyl-, 2-veratryl-, 2-piperonyl-, 2-benzyl-, and 2-p-methoxybenzylindandiones-1,3 were obtained analogously. The reaction conditions and constants of the compounds obtained are given in Table 2. In the case—

Table 2

\[ \begin{array}{c} \text{general structure: 2-iodomethyl-2-}R\text{-indandione-1,3} \end{array} \]

of 2-p-methoxybenzylindandione-1,3, it is expedient to evaporate the ether filtrate in vacuo, after which an additional amount of 2-iodomethyl-2-p-methoxybenzylindandione-1,3 is isolated.

2-Iodomethyl-2-methylindandione-1,3. 6.4 g (0.04 mole) of 2-methylindandione-1,3, dissolved with 5.6 g (0.04 mole) of potassium carbonate and 6.6 ml (0.08 mole) of methylene iodide, are heated for 1.5 h at an oil-bath temperature of 140–150°. To the warm mixture about 50 ml of ether is added, it is thoroughly stirred and immediately filtered. After distilling off the ether in vacuo and cooling the residue in a refrigerator, yellowish crystals of 2-iodomethyl-2-methylindandione-1,3 separate. They are separated and washed with a small amount of ether. Yield 5 g (41.6% of theory). M.p. 95–103°. After recrystallization from a methanol–water mixture (2:1), white crystals with m.p. 102–104° are obtained.

Found, %: I 42.22; 41.91. C₁₁H₉O₂I. Calculated, %: I 42.30.

2-Iodomethyl-2-α-naphthylindandione-1,3 was obtained analogously (see Table 2).

Riga Polytechnic Institute

Received
18 XII 1961

CITED LITERATURE

1. Cyclic β-Diketones, Riga, 1961, pp. 191 and 359.
2. Science for Production, vol. V, Riga, 1960, p. 72 and 86.
3. H. Heilmann, G. Opitz, Angew. Chem., 68, 265 (1956); Lieb. Ann., 604, 213 (1957).
4. H. Böhme, E. Mundlos, G. Keitzer, Ber., 91, 656 (1958).
5. G. Ya. Vanag, E. V. Vanag, Author’s Certificate No. 134264, 7 XII 1959.
6. M. Furdik, P. Hrnčiar, V. Vačoková, Acta Fac. rerum natur. Univ. Comenianae Chim., 3, No. 2–3, 117 (1959); RZhKhim, 96443 (1960).
7. A. K. Aren, O. Ya. Neilands, G. Ya. Vanag, DAN, 132, 115 (1960).
8. Ya. V. Freimanis, G. Ya. Vanag, ZhOKh, 30, 3369 (1960).