Computer-Assisted Search and Experimental Discovery of Novel Recyclizations

Babaev, Eugene V.;
Efimov, Andrey V.; Orlova, Irina A.; Maiboroda, Dmitriy A.; Pasichnichenko, Konstantin Yu.; Tsisevich Alexandr A.; Bush, Alexandr A.; Rybakov, Viktor B.; Bozhenko, Svetlana V.; Lushnikov, Dmitriy E.

Chemistry Department, Moscow State University, Moscow, 119899, RUSSIA


1. Introduction
2. Mathematical model
3. Computer program
4. Choice of the heterocycles and prediction of new recyclizations
5. Experimental confirmation
6. Acknowledgment
7. References

1. Introduction

An important class of organic reactions that play major part in the entire heterocyclic chemistry are the recyclizations of heterocycles. These elegant reactions (frequently discovered by a lucky chance) often lead to heterocycles with unusual disposition of heteroatoms and substituents, or products not available by any other synthetic methods.

Despite the enormous amount of factual material in this area and the profusion of reviews on this topic, one must conclude that there is no general rational classification of heterocyclic ring transformations in accordance with a structural principle. As a result, it is often difficult, for example, to establish the real degree of novelty of a recyclization or rearrangement declared as being "novel".

One important concept, that helps to classify chemical reactions from the structural viewpoint, is the concept of "reaction graphs". The reaction graph is a mental superimposition of the structures of the initial reagents and final products. It is a single diagram (that substitutes common chemical equation) which displays redistribution of bonds via chemical reaction. Reaction graphs, therefore, are convenient objects for storing information about reactions in computer databases. However, the reaction graphs are not very familiar to the audience of organic chemists. The structure of such graphs (even for common organic reactions) may be complex, and they are rarely used in practice of heterocyclic chemistry (see reviews [1,2]).

In early 1990s we have suggested [3-6] the simplified type of reaction graphs for the specific case of recyclizations of heterocycles. Simple structure of such graphs allows one to classify recyclizations, establish their structural similarity and dissimilarity and, furthermore, to use these combinatorial objects for predicting unprecedented examples of recyclizations. The goal of this communication is to overview how this methodology can be used in practical discovery of unknown recyclizations.

2. Mathematical model

In the series of papers [3-6] we suggested novel type of reaction graphs for description of heterocyclic rearrangements and ring transformations. These graphs -- the recyclization graphs (or graphs of cyclic bonds redistribution) -- have been utilized to classify recyclizations in the hierarchic system, to compare structural similarity of recyclizations, and to predict interesting examples of recyclization of previously unknown structural types. (For strict definition of the recyclization graph click here.)

Most important feature of recyclization graphs is the simplicity of their structures. For any simple ring transformation these graphs are labeled bicyclic graphs. Therefore, we may exhaustibly generate such bicyclic diagrams with the help of a computer program and compare abstract set of such diagrams with those that correspond to really observed processes.

Any abstract diagram, in turn, corresponds to a certain structural equation. Drawing a recyclization graph, therefore, is equivalent to drawing of the pair of initial and final heterocycles. Click here to visualize the idea of how to restore a structural equation from the recyclization graph.

3. Computer program

The suggested idea of the hierarchical classification seems very fruitful: all theoretically possible skeletal equations for recyclizations can be once and forever enumerated and classified by arranging their recyclization graphs into structural types, kinds, classes, and families. The classification, in turn, can be used as an organizational principle to create database on known recyclizations, to establish degree of structural similarity between such reactions (and real novelty of discovered examples), and to assist search of really new recyclizations in respect to the chosen hierarchical level. This ideal project has indeed been realized in practice [1] with the help of our computer programs GREH (Graphs of REcyclizations of Heterocycles) [3] and Heterocycland [2]. The programs are available to download from our homepage.

4. Choice of the heterocycles and prediction of new recyclizations

Our interest in the experimental chemistry of the bridgehead azoloazines stimulated our efforts in predicting novel examples of recyclizations in this class with the help of program GREH and to verify the predictions experimentally.

The bridgehead azoloazines (particularly the heteroaromatic cations) seemed to be attractive models for study new recyclizations, due to their ability to open either 5- or 6-membered ring (see our reviews [7,8]) and variety of modes for ring closure. After careful analysis of the literature data we have chosen for our studies poorly investigated aromatic cation -- oxazolo[3,2-a]pyridinium. This interesting cation could be equally considered as the initial heterocycle, as the target structure, and finally, as the intermediate of previously unknown recyclizations.

First, we have investigated experimentally the possibility of cleavage of various bonds in this cation. We found that, depending on the nature of nucleophile, three types of bonds can be broken in this bicycle, namely the bonds C8a-O [9], C2-O [10], and C5-N [11].

The GREH program has suggested for every cycle of the bicyclic oxazolopyridine the appropriate location of certain functions around the ring that are necessary for closure of new ring. In order to avoid „combinatorial explosionš, the strict limitations were used (like invariance of cycle size, minimal number of broken/formed bonds, etc.). The last requirement was the cleavage of only three most probable bonds in oxazolopyridine. After applying of such restrictions the predicted number of recyclizations decreased from few hundreds to few tens.

We have published sixteen selected examples of novel recyclizations as the forecast [12] and later successfully confirmed several of them experimentally.

5. Experimental confirmation

Example 1. First family of recyclizations previously unknown for oxazolo[3,2-a]pyridinium that we have found [9,13] were the simple "heteroatom exchange" reactions (click here to view examples). Under the action of simple N-, S-, and C-nucleophiles the oxazole fragment of bicycle was transformed to imidazole, thiazole, and pyrrole rings, respectively. These transformations are novel strategies to derivatives of imidazo[1,2-a]pyridines, thiazolo[3,2-a]pyridinium salts, and indolizines.

Example 2. In the previous example pyrrole ring was built from oxazole under the action of nitromethane. We found [14] that in reaction of oxazolopyridine with acetylacetone the same transformation (oxazole to pyrrole) occurs, however, the structural changes are quite different (click here to view recyclization graph and experimental result). This is another strategy to obtain indolizines from oxazolopyridines.

Example 3. An elegant transformation of the oxazole fragment to pyrrole was observed for 5-methyl homologues of oxazolo[3,2-a]pyridinium salts (click here to view the reaction). Recyclization readily occurs with secondary amines [15,16] (60-90%) and sodium alkoholates (30-50%) leading to previously unknown class of 5-substituted indolizines. With ammonia only the product of "heteroatom exchange" reaction -- imidazo[1,2-a]pyridine was formed.

Example 4. The highly reactive oxazolo[3,2-a]pyridinium cation may be in turn obtained as the result of recyclization of its mesoionic precursor [17]. Click here to view the discovered one-pot transformation of the mesoionic oxazolone (munchone) to this highly reactive cation. This reaction may be the rarest case in heterocyclic chemistry when the structure obtained by recyclization can be involved in the consequent recyclizations.

Example 5. Not only can oxazolopyridinium cation be the starting material (or even the product) of a recyclization. We found an example where such cation serves as intermediate. This was observed (and experimentally proved) for quite unusual transformation of pyridinium salts to oxazoles [18]; click here to view this transformation. The yields in the reaction with various secondary amines are usually quantitative [19], and the configuration (1E,3E or 1E,3Z) of isomeric 1-amino-4-(oxazolyl-2)butadienes depends on reaction temperature.

More examples may be found in our forthcoming publications. One direction, we consider the most intriguing, is an attempt to perform unprecedented "triple recyclization":
mesoionic oxazolopyridine - cationic oxazolopyridine - indolizine - indole.
(Click animated abstracts to estimate the beauty of such transformation). First two steps were discussed above, and the recyclization of indolizines to indoles is the topic of our long years interest [20-22].

6. Acknowledgement

E.V.B. thanks for generous support the following funding organizations: