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STRUCTURE AND AHBIPHILIC REACTIVITY OF INDOLIZINES . '3 . SYNTHESIS AND ISOMERIZING RECYCLIZATION " .. OF 7-METHYL-6C8)-NITR0-2-PHEHYLIND0LIZINES *
S . I . B.obrovskii , an d Yu . G . Bunde l E . V . Babaev , Yu , 0 . Vasil'ev** , Khimiya , . . ' ·

Vestni k Moskovskog o Universiteta . Vol . 4 2 , No . 1 , pp . 82-35 , 198 7 UDC 547.759,4.0 7 '.

This paper describes 7-methyl-6- and -8-nitro-2-phenylindolizines as objects of isomerizing recyciization with the formation of nitroindoles, by analogy vrith the 6- and 8-nitro-2-phenilindolizines. The absence of a recyciization product in the case of 8-nitroindolizine and the successful preparation of 6-methyl-5-nitro-3-phenylindole from the 6-nitro isomer permit the limits of applicability of the Kost-Sagitullin reaction in the nitrolndoiizine series to be marked out. A relatively short route to obtaining the previously inaccessible 6-methyl-5-nitro-3-phenyiindole may be mentioned. It has been established previously that 6- and 8-nitro-2-phenyl(methyl)indolizines take part under the action of alkali in an isomerizing recyciization reaction with the formation of 5- and 7-nitro-3-phenyl(methyl) indoles. The wide use of this reaction for obtaining nitroindoies has been hindered by the poor accessibility of the initial 6- and 8-nitroindolizines, the synthesis of which requires several stages [3]. Continuing investigations devoted to the structure and ambiphilic reactivity of the indolizines [1,4] , we have synthesized 7-methyl-6- and -8-nitro-2-phenylindolizines as objects for isomerizing recyclization. The initial compounds were the readily accessible nitrolutidines (la, b ) which, unlike the 3- and 5nitro-2-picolines, can be obtained by the direct nitration of 2,4-lutidine [5]

1 The quaternization of the nitrolutidine (la) took place in methyl ethyl ketone solution at room temperature with the formation of the phenacylate (IIa);

*For communication 2, see [I] .
**Deceased· ' 93 · · ·


Table 1 Characteristics of the Compounds Obtained

the production of the isomer (IIb) required the boiling of the reaction mixture. The cyclocondensation of the salts (II) , taking place spontaneously even in the cold in 20% aqueous ethanolic solution, led to high yields of the nitroindolizines (Ila, b ) when the reaction mixture was treated with-sodium bicarbonate. Column chromatography was used to purify compounds (IIa, b) . The nitroindolizines obtained were colored substances comparatively sparingly soluble in nonpolar solvents and in chloroform. The characteristics of compounds III are given in Table 1. Spectral characteristics confirmed the structures of the nitroindolizines obtained. The electronic absorption spectra of indolisines (IIa, b ) were close to those of lower homologues. A short-wave band in the 250-253 nm region was observed both in the case of the 6- and the 8-nitro-2-phenylindolizines and in the spectrum of 2-phenylindolizine [1] . To distinguish isomers it is possible to use the second absorption band, which is located in the region of longer wavelengths for the 8-nitroindolizines than for the 6-nitro isomers [1,3]. The long-wave absorption band appears in the spectrum in the form of a broad shoulder. The mass spectra of compounds (III) were monotypical and, on the whole, similar to the spectra of their lower homologues [3,6] , An important new fragmentation pathway was the elimination of HO. as a consequence of the ortho : positioning of CH3 and NO2 groups (the "ortho effect" [7]). Here the ortho effect was more pronounced for indolizine (IIIa) (Table 1) than for the isomeric (IIIc). We found similar relationship in the case of the 2,7-dimethyl6- and -8-nitrolndolizines [4, 8] . · " · ' The nitroindolizines(IIIa, b) were subjected to the isomerizing recyclization reaction. In this reaction, (IIIa) was converted with a yield of 26% into the nitroindole (IV), which has not yet been described previously. Under the same conditions, the isomeric (IIIb) did not lead to the formation of the corresponding indole but the initial compound could not be regenerated:

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The structure of the indole obtained was confirmed by the totality of spectral characteristics. Thus, the UV spectrum of this compound practically reproduced the1 spectrum of a lower homologue - 5-nitro-3-phenylindole (V) In the mass spectrumo f indole (IV) which was , on the whole,' similar tO that (V7) [6] , the [M - OH] + peak due to the 'ortho effect' was1 also observed, as in
case of the nitroindolizines (IIIa, b).

its [9]. of the

In our opinion, one of the possible reasons for the different behaviors of the nitroindolizines (IIIa, b ) in the isomerizing recyclization reaction is the different acidities of the 7-CH3 groups in these compounds. Because of the sub- · stantially polyenic nature of the C5=C6=C7=C8 fragment of the nucleus of the nitroindolizines [10] , the-7-CH2 carbanion formedo n the deprotonation of (IIIb) must be stabilized by conjugation with the 8-NO2 group . Similar reactions with the participation of such an anion competing with the recyclization process may be the cause of the observed resinification of the reaction mixture. In the case of the indolizine (IIIa), the formation of the analogous 7-CH2 carbanion is less favorable because of the absence of conjugation with the 6-NO2 group. Experimental Part. Mass spectra were taken on a Varian MAT-212 instrument (E - 7O eV) ; UV spectra on a Specord M-40 instrument; and PMR spectra on a BS467 instrument (60 MHz ) with TMS as internal standard. The individuality of the compounds obtained was checked chromatographically on Silufol plate. The compounds were purified by column chromatography on silica gel L 4.0/100. 2,4-Dimethyl-5-nitro-l-phenacylpyridinium bromide (IIa) . A mixture of 4.95 g (3.25*10-2/mole) of (la) and 9.27 g (4.66*1O-2 mole ) of phenacyi bromide in 8 ml of methyl ethyle ketone was kept at room temperature for 4 days. The pre cipitate that had deposited was separated off and was washed wit h cold acetone, giving 6.52 g (1.36*10-2 -mole, 57%) of the salt (la) with mp 223-224°C (decomp. from methanol) . Found, %: C 50.46; H 4.68; N 7.86, C15H15BrN2O3. Calculated,
%. C 51.28 ; H 4.27 ; N 7.86 .

2 ,4-Dimethy]-3-nitro-1-phenacylpyriidinium bromide (IIb) . A mixture of 3.O8 g (2.03-10-2 mole ) of (Ib) and 8.32 g (4.18*10-2 mole) of phenacyl bromide was boiled in 8 ml of methyl ethyl ketone for l8 hr. The precipitate was separated off and was washed with cold acetone to give 2.30 g (6.55*10-3 mole, 32%) of the salt (lIb)m p 214° (decomp. from methanol) . Found, %: C 51.33; H 4.56. C15H15BrN 2 0 3 . Calculated, %: C 51.28; H 4.27. 7-Methyl-6-nitro-2-phenyl indolizine (IIIa). A solution of 2.15 g (6.12*10-3 mole) of the salt (IIa) was boiled in 200 ml of 25% aqueous ethahol for 30 min and was then neutralized with sodium bicarbonate to pH 8 and was boiled for another 1 hr. The solution, containing a precipitate, was cooled and extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent had been driven off , the residue was chromatographed on a column (benzene, SiO 2 ). ' This gave 15 1 mg (6.0*10-3 mole , 98%) of an orange powder of (IIIa) . *10-4 7-Methyl-8-nitro-2-pheny1indolizine (III b) . The salt (IIb) (0.35 g; 9.85* mole) was treated in a similar manner to (IIa) . After chromatography,

0.22 g (8.65*10-4 mole , 98%) of dark brown crystals of (IIb ) was isolated. 6-Methyl-5-nitro-3-phenyl indole (IV) . In a current of argon 0.336 g

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1.30*lO-3 mole) of (IIIa) was boiled in 30 ml of 85% ethanol containing 6 g of KOH for 3 hr. After cooling, the reaction mixture was poured onto ice and was neutralized with dilute HC1 to pH 7. The solution was extracted with chloroform and the extract was evaporated. The residue was chromatographed (benzene, Si0 2 ) and a fraction with Rf 0.35 was collected. This gave 0.073 g (3.10-10-4 mole , 26%) of orange crystals of the indole (IV) . PMR spectrum (DMS0-d6)} d, ppm: 11,7 (br.s), 1-H; 6.4 (s); 4-H; 7.43 (m) , 2-H, 7-H, 3-C6H5; 3.26 (s) , 6-CH3. Reaction of (III b) with an Aqueous Ethanolic Solution of KOH. In a current of argon, 0.09 g of (IIIb) was boiled with 2 g of KOH in 20 ml of 85% ethanol. After the beginning of heating, the reaction mixture darkened appreciably. It was found by the TLC method (benzene, Silufol) that after heating for 2 hr the reaction mixture contained neither the initial indolizine nor a compound of the indole series. After the mixture was worked up in manner similar to that used in the isolation of (VI) , it was impossible to detect an indole in the organic
phase.

REFERENCE S

1. S, I. Bobrovskii, E. V. Babaev, K. A. Paseshnichenko, and Yu. G. Bunde1,
KhGS, no. 2, 1987 .
" ····..

2.
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A. N. Kost, R. S, Sagitullin, and S. P. Gromov, DAN SSSR,vol . 230, A. N. Kost, R. S, Sagitullin, and S. P. Gromov, KhGS, p. 922, 1976. S. I. Bobrovskii, E. V . Babaev, and Yu. G. Bundel, KhGS, no . 2, 1987. L. Achremowich, Pr. Nauk. Instyt. Chem. Organ- i fiz., no. 23 S Wroclaw,

3. 4. 5.
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6. P. B. Terent'ev, 0. A. Solov'ev, R. A. Khmel'nitskii, S. P., Gromov, and R. S. Sagitullin,, KhGS, p. 765, 1982. 7. R. A. Khmel'nitskii and P. B. Terent'ev, Usp. Khim., vol. 48, p. 854,
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8. S. I. Bobrovskii, E. V. Babaev, and Yu. G. Bundel, Vestn. Mosk. Un-ta, Ser. 2, Khimiya [Moscow University Chemistry Journal], vol. 26, p. 222, 1985. 9. R. I. Fryer, J. V. Earleuy, and L. H. Sternbach, J. Org. Chem.,vol . 32 , p. 3798, 1 9 6 7 . · 10. V. A. Tafeenko, L. A. Aslanov, A. N. Kost, R. S. Sagitullin, and S. P. Gromov, DAN SSSR-, vol. 252, p. 126, 1980. 10 December 1985 , Department of Organic Chemistry