No abstract

A new route to poorly available 5-alkoxyindolizines has been developed by reaction of oxazolo[3,2-a]pyridinium salts with sodium alkoxides; the structures of three indolizines and one parent salt have been confirmed by X-ray diffraction analysis.The indolizine ring is isomeric and isostructural to indole, and substituted indolizines are frequently prepared as bioisosters of biologically active indole derivatives. A well-known class of psychotropic indole compounds (e.g., psillocine, psylocibine and pindolole) belongs to the family of 5-hydroxy(alkoxy)indoles. An isostructural class of indolizines bearing 5-OR group (A in Scheme 1) may serve as the biomimetics of such indoles. This class can be designed by a mental rearrangement of the indole ring nitrogen into bridgehead positions.The entire class of 5-alkoxy(hydroxyl)indolizines is poorly investigated since there is lack of synthetic methodologies leading to this scaffold. Rare examples of preparation of the members of class A include their synthesis from pyrrole derivatives 1-3 and by means of photolytic C-5 oxidation of the indolizine ring. 4 Structure B with the desired motif was prepared via 1,3-dipolar cycloaddition. 5 The most common strategy to indolizine ring (the Chichibabin cyclization) failed for the case of 6-methoxy-2-picoline. 6 It is, however, possible to annelate the pyrrole ring to pyridine by condensation of the Guresci pyridone with α-bromoketones 7,8 leading to 5-indolizinones C, which are stable tautomers of desired 5-hydroxyindolizines D. We found 9 that pyridone-like derivatives C can be converted into 5-chloroindolizines E, which react with MeONa leading to 5-methoxy-6-cyanoindolizines F. However, simple 5-alkoxyindolizines A (without other substituents in the pyridine ring) remain unknown.We reported an efficient strategy [10][11][12] to build the indolizine ring by a somewhat unusual conversion of oxazolo[3,2-a]-pyridinium salts G (route a in Scheme 2). This reaction allowed us to prepare 5-dialkylaminoindolizines H. Recently, 13 this methodology has attracted attention in industrial chemistry as a source of a library of 5-substituted indolizines with potential bioactivity. However, only secondary amines are suitable for such a transformation, and with primary amines (route b) salts I were formed instead of indolizines. Therefore, it is unclear which other nucleophiles are suitable for this new strategy of indolizine synthesis from oxazolopyridines. Furthermore, the ring system of salts G may undergo alternative modes of ring opening depending on the group R and the nature of the nucleophile. Thus, salts G with R = H react with secondary amines with pyridine ring opening (route c 11 ), whereas with alkoxide the C(2)-O bond cleavage was observed (route d 14 ). In this paper, we studied the direction of the reaction of salts G (R = Me) with alkoxides to test the synthesis of 5-alkoxyindolizines A.

Alkylation of 3-methyl-1-isoquinolone and 1-methyl-3-isoquinolone with phenacyl bromides proceeds regioselectively with the formation in the first case of only an N-phenacyl derivative and in the second only the O-derivative. The 5-methyl[1,3]oxazolo[3,2-a]isoquinolinium salt has been synthesized and itsreactions with ammonia, morpholine, and sodium methylate have been investigated.

Evolution of the theory of aromaticity has raised interest in the synthesis of pericondensed indolizines such as cyclazines 1 and their analogs. 1 Yet, chemistry of hetero counterparts of such structures, including antiaromatic ones, are still poorly understood. Figure 1 shows the currently known representatives of [3.3.2]cyclazine series 1a-i. 2 The synthesis of such cyclazines includes addition of a five-and/or six-membered ring, 2 in accordance with cylization schemes shown in Figure 2.Theoretically, indolizines 2 containing a heteroatom at position 5 could serve as precursors of [3.3.2]cyclazines, but these compounds are not readily available. Our research group has developed a new strategy for the synthesis of 5-substituted indolizines by recyclization of oxazolopyridinium salts 3 by the action of nucleophiles (amines and alkoxides). 3 The use of bifunctional reagents (Nu -a nucleophilic heteroatom, E -an electrophilic carbon atom) in such a reaction could lead to indolizines 2, potentially capable of cyclization into cyclazine 1 analogs via attack by an electrophilic atom on the π-excessive pyrrole moiety (Scheme 1).Amine derivatives having a carbonyl group at the chain end could serve as suitable reagents. Of course, such agents must be stable under recyclization conditions (high temperature and concentration of the reagents). Of secondary amines, N-methylaminoacetaldehyde (acetal 5-Methyloxazolo[3,2-a]pyridinium salts were shown to react with (methylamino)acetaldehyde dimethyl acetal leading to the formation of functionalized 5-aminoindolizines, which in turn are capable of closing the pyrimidine ring in acidic media forming aza[3.3.2] cyclazines.