New Substituted Indolizines by 1,3-Dipolar Cycloaddition VI. 7-(4-Nitrobenzyl)indolizines

New indolizine derivatives 6 and 7 containing a 4-nitrobenzyl group attached to the pyridinic ring are obtained by the reaction of N-phenacylpyridinium bromides 3 with 3-butyn-2-one, methyl and ethyl propiolate in 1,2 epoxypropane medium. The compounds structure was assigned by elemental analysis, NMR and IR spectroscopy.

Indolizine derivatives are quite common in nature, mainly as alkaloids, and benefit from considerable attention due to their potential applications as pharmaceuticals.Moreover, the high degree of cojugation of their aromatic system generates intense optical properties, that make indolizine and azaindolizine systems [1][2][3][4] valuable spectral sensitizers or even dyes.By attaching different substituents on this relatively simple system the fluorescence quantum yield may be variated and, on the other side the bioavailability of the therapeutic agents based on such type of derivatives may be increased.
Furthermore, indolizines substituted at the 7 position may be used as highly selective chemosensors when attached to a cyclodextrin moiety [4].
The molecular construction of such substituted indolizines can be achieved by numerous synthetic routes.One of the simplest, yet most versatile method is the 1,3dipolar cycloaddition of pyridinium N-ylides to activated alkynes or alkenes [5].
The synthesis of new functionalized indolizines, containing a 4-nitrobenzyl group attached to the pyridine ring, hereby presented, is carried out by 1,3-dipolar cycloaddition reactions of pyridinium N-ylides to acetylenic non-symmetrical dipolarofiles: 3-butyn-2-one, methyl and ethyl propiolate.By introducing the 4-nitrobenzyl substituent on the pyridine ring and by varying the substituents on the pyrrole moiety, it may be possible to obtain a finer tuning of the optical properties of indolizine derivatives.

Experimental part
Melting points were determined on a Boëtius hot plate microscope and are uncorrected.The elemental analysis was carried out on a COSTECH Instruments EAS32 apparatus.The IR spectra were recorded on a Nicolet Impact 410 spectrometer, in KBr pellets.The NMR spectra were recorded on a Varian Gemini 300 BB instrument, operating at 300 MHz for 1 H and 75 MHz for 13 C. Supplementary evidence was given by HETCOR and COSY experiments.

Results and discussion
The indolizines 6 and 7 were obtained by 1,3-dipolar cycloaddition reactions between pyridinium N-ylides (generated in situ from the corresponding pyridinium salts) and electron deficient alkynes.The pyridinium bromides 3 were prepared by N-alkylation of 4 nitrobenzylpyridine 1 with the corresponding 2-bromoacetophenones 2 in methanol at reflux (scheme1).
The structure of the bromides 3 was confirmed by 1 H-NMR spectra, which present all the predictable signals.The methylene protons appear as a singlet, each of them being influenced by the neighboring groups as follows: the methylene linked to the benzyl moiety is more shielded (δ = 4.45-4.50ppm) than the methylene linked to the quaternary nitrogen atom and the carbonyl group (δ = 6.35-6.53ppm).The nitro group grafted on the benzyl moiety has no significant influence on the 1 H-NMR signals of the pyridinic protons as compared with previously presented 4-benzyl substituted pyridinium bromides (table 1).Some differences can be noted in comparison with 4-benzoyl and 4-cyano substituted pyridinium bromides described in previous literature data, where both benzoyl and cyano group, respectively, have a divergent influence on the 1 H-NMR signals.In these compounds the methylene group linked to the quaternary nitrogen atom is more deshielded (δ = 6.60-6.88ppm), and also the protons from the pyridinium ring are deshielded by about 0.5 ppm (table 1).
The protons from the nitrobenzyl moiety appear as two doublets with the coupling constant J = 8.8 Hz.The ortho protons with respect to the nitro group are deshielded (δ = 8.23 ppm) with approximately 0.7-0.8ppm due to influence of the nitro group as compared with the meta protons (δ= 7.45 ppm).
The 13 C-NMR spectrum was recorded for the bromide 3a, the representative compound in the series, and compared with similar compounds.The spectrum presents all the expected signals.Due to the influence of the quaternary nitrogen atom, the α and γ carbons from the pyridinic ring are more deshielded (δ = 145.7 ppm) than the beta carbons (δ = 128.0ppm).The effect of the 4nitrobenzyl group is similar to that of the 4-benzyl and the 4-tert-butyl group [6c], with the only significant difference at C-4, which appears with around 10 ppm more deshilded in the case of the tert-butyl substitution.(table 2).
The geminal (δ = 147.4ppm for C-4") and the para (δ = 142.8 for C-1") aromatic carbon atoms from the 4nitrobenzyl radical are strongly deshielded by the nitro group, while the carbon atoms from the benzoyl moieties present normal limits for the chemical shifts of such type of compounds.
The carbon atoms of the two methylene groups are assigned in respect of the influence of the neighbouring groups at δ = 41.0 ppm for the methylene group linked to the 4 nitrobenzyl moiety and the more deshielded methylene group appears at 66.1 ppm due to the influence of the quaternary nitrogen atom and the ketone group.
The product was recrystallized from methanol and light yellow crystals with mp 233-5 o C were obtained; Yield 98 %.Anal.Calcd.C 20 H 17 BrN 2 O 3 : N 6.78.

Table 1
REPRESENTATIVE 13 H-NMR DATA FOR BROMIDES OF TYPE 3

Table 2
REPRESENTATIVE 13 C-NMR DATA FOR BROMIDES OF TYPE 3