Optimisation, scope and limitations of the synthesis of 5-aminoindolizines from oxazolo[3,2-a]pyridinium salts

Nevskaya

Dlynnikh

2015

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.

mentioning

confidence: 99%

Rearrangement of oxazolo[3,2-a]pyridines as an approach of synthesizing aza[3.3.2]cyclazines

Nevskaya

Dlynnikh

2015

“…Such a transformation proceeds successfully under the action of secondary amines [38][39][40][41][42][43] or alcoholates [42,44] and is accelerated by microwave irradiation [43]. The functions in the pyridine fragment vary extremely widely, and they include acceptor type substituents (A = CN, CONH 2 , CO 2 Et, NO 2 ), alkyl groups and/or alicycles where the number of additional methylene units n varies from 1 to 4 [42][43][44][45][46][47][48]. The preparative aspects of this reaction were described in the review [38], and in this context it is important to note the uniqueness of the structural type of this oxazoles to pyrroles conversion, which does not have analogs in the chemistry of monocyclic oxazolium salts.…”

mentioning

confidence: 99%

Pyrroles from oxazoles

2012

The review is devoted to the transformation of oxazoles (including those with cationoid and mesoionic structures) into compounds of the pyrrole series.The search for new methods for the synthesis of heterocyclic systems is always actual, and the development of new methods for the construction of the pyrrole ring is particularly significant: the pyrrole ring is the basis of life on Earth, as it is the major subunit of the vitally important biomolecules hemoglobin and chlorophyll. Like any other heterocycle, the pyrrole ring can either be assembled from acyclic precursors (one or several synthons) or another heterocycle can be used as its precursor, i.e., the pyrrole can be obtained by recyclization. Transformation of the oxazole ring can provide an interesting and unusual method for the production of pyrrole. Oxazoles are widely used as starting compounds in synthesis (e.g., of pyridines, imidazoles, and other heterocycles), but the diversity of the methods used for the transformation of oxazoles into pyrroles has not yet been duly reflected in the review literature.Preparation of this review was prompted by the discovery by author and his group of an entirely new family of oxazole transformations to pyrroles in a series of condensed heterocycles containing a bridging nitrogen atom. This transformation, which has already been included in the latest edition of the classic textbook [1] and in a recent monograph on the chemistry of oxazoles [2], deserves comparison with all other examples (both known and exotic) of the oxazole conversion to pyrroles. Such a comparison, with the emphasis on the structural type of the transformation and on comparison of monocycles with condensed systems, is the theme of the present review, which is of interest both to synthesis specialists and to a wide range of teachers and high school students.It is not necessary to duplicate the known examples of the pyrrole synthesis from oxazoles (presented in the books [2,3] in the form of detailed tables), and they will only be used in the general schemes in order to complete the picture. In view of classification it is convenient to divide the oxazoles from which pyrroles can be obtained into simple subfamilies -neutral oxazoles (mesoionic and "normal") and oxazolium salts. PYRROLES FROM "NORMAL" OXAZOLES WITH NEUTRAL STRUCTUREDuring Vilsmeier formylation of the oxazole 1 the pyrrole 2 was isolated [4].

“…The recyclization discovered by us of the oxazole nucleus into a pyrrole in 5-methyloxazolopyridinium salts (1, R = Me) leading to 5-substituted indolizines 2 is of the greatest interest [2][3][4][5] We have attempted to broaden the circle of substrates capable of an analogous conversion using the tricyclic systems 3 and 4. We previously succeeded in synthesizing oxazolopyridinium salt 3 (R = Me), in which the annelated ring A is cyclohexane.…”

mentioning

confidence: 99%

Heterocycles with a bridging nitrogen atom. 19. Development of routes for the synthesis of oxazoloisoquinolinium salts based on phenacylation of α-methyl-1(3)-isoquinolones

Nevskaya

Dlinnykh

et al. 2009