TANDEM AMIDATION CATALYSIS IN THE SYNTHESIS OF DIAZAPHENOXAZINECARBOXAMIDES OF PHARMACEUTICAL INTEREST

ABSTRACT

Tandem amidation catalyzed synthesis of linear diazaphenoxazine carboxamide derivatives is reported. This was achieved by the reaction of 2-amino-3-hydroxypyridine and 2,3,5-trichloropyridine in aqueous basic medium which gave 3-chloro-1,9-diazaphenoxazine as white solid crystals. 3-Chloro-1,9-diazaphenoxazine was then subjected to Buchwald-Hartwig amidation coupling reaction with various amides namely formamide, phthalamide, 4- nitrobenzamide, benzamide and acetamide via water promoted catalyst preactivation protocol to afford the following, 3-amido derivatives of 1,9-diazaphenoxazine namely 3-formamido-1,9-diazaphenoxazine, 3- phthalamido-1,9-diazaphenoxazine, 3-(4-nitrobenamido)-1,9-diazaphenoxazine, 3-benzamido-1,9- diazaphenoxazine and 3-acetamido-1,9-diazaphenoxazine. The compounds were characterized using UV-visible, FTIR, 1HNMR and 13CNMR spectroscopy.

CHAPTER ONE

1.0 INTRODUCTION

1.1TANDEM CATALYSIS

The term tandem catalysis represents processes in which “sequential transformation of the substrate occurs via two (or more) mechanistically distinct processes”1 and there is no need to isolate the individual intermediates as the entire reaction takes place in one pot.

Types of tandem catalysis

There are three types of tandem catalysis

Orthogonal tandem catalysis: In this type of catalysis, there are two or more mechanistically distinct transformations, two or more functionally and ideally non-interfering catalysts with all catalysts present from the outset of the reaction, as shown in Scheme 1.

Scheme 1

Mechanism B        Product B

Auto-tandem catalysis: In this type of catalysis, there are two or more mechanistically distinct transformations which occur via a single catalyst precursor; both catalytic cycles occur

spontaneously and there is cooperative interaction of all species present at the outset of the reaction as shown on Scheme 2

Catalyst A (A)

Mechanism B         Product B

Assisted tandem catalysis: In this type, two or more mechanistically distinct transformations are promoted by a single catalytic species while the addition of a reagent is needed to trigger a change in catalyst function,2 as shown in Scheme 3.

Mechanism B         Product

1.2 TANDEM REACTIONS

In so far as one of the fundamental objectives of organic synthesis is the construction of complex molecules from simpler ones, the importance of synthetic efficiency becomes immediately apparent and has been well recognized. The increase in molecular complexity that necessarily accompanies the course of a synthesis provides a guide (and a measure) of synthetic efficiency. As

a goal, one would like to optimally match the change in molecular complexity at each step with reaction of comparable synthetic complexity.

Thus, the creation of many bond, rings and stereocenters in a single transformation is a necessary (although not sufficient) condition for high synthetic efficiency. The ultimate, perfect match would constitute a single-step synthesis. More realistically, especially In view of the desire for general synthetic methods, the combination of multiple reactions in single operations increase molecular complexity is a powerful means to enhance synthetic efficiency.

The concept for reactions in tandem as a strategy for the rapid construction of complex structures is well-known and has been reviewed1. In addition, a recent international attention, and books dedicated to tandem reaction3 and multi component cyclizations have now appeared. Within the universe of tandem reactions, the constellation of consecutive pericyclic reactions is still vast.

Consecutive pericyclic reactions involving at least one cycloaddition have enjoyed extensive application in synthesis as exemplified by tandem benzocyclobutene opening, Diels-Alder reactions4, Danheiser’s aromatic annulation5, electrocyclic opening of 1,3-dipolar cycloaddition and

endiandric acid cascade6.

1.3  DEFINITION OF TANDEM REACTIONS

The dictionary definition of tandem as “one behind the other” is in itself, insufficient since every reaction sequence would then be a tandem reaction. However, a rigorous and all encompassing definition of tandem or sequential reactions is very difficult to formulate because of the continuum of chemical reactivity. In other words we must decide what constitutes a reactive intermediate or a

stable, isolable entity which given the circumstances of reactant structure or reaction conditions, undergoes a secondary transformation .What is unique about the type of tandem process exemplified by tandem pericyclic reaction is the structural change that accompanies the initial reaction and the creation of an intermediate with the necessary functionality to perform the second reaction .Furthermore, if the process involves sequential addition of reagents the second reagent has to be included into the product. In addition, new bonds and stereocenters have to be created in the second reaction.

There is an all-encompassing definition of tandem as reactions that occur one after the other, and use the modifiers cascade (domino), consecutive, and sequential to specify how the two (or more) reactions follow. Thus, the family tandem cycloaddition reaction can be divided into three categories with the following definitions.

Tandem cascade cycloadditions: In this, the reactions are intrinsically coupled, that is, each subsequent stage can occur by virtue of the structural change brought about by the previous step under the same reaction conditions7.

In tandem cascade cycloadditions, both processes take place without the agency of additional components or reagents. Everything necessary for both reactions is incorporated in the starting materials .The product of the initial stage may be stable under the reaction conditions; however, the intermediate cannot be an isolable species but rather is converted to the tandem product upon workup. The classic examples of tandem cascade cycloadditions are “pincer”(path a)  and

“domino” (path b) modes of Diels-Alder reactions which have served as the corner stone in the

synthesis of the formidable pagodane and dodecahedrane8 structures respectively, as shown in

Tandem consecutive cycloaddtion, are reactions where the first cycloaddition is necessary but not sufficient for the tandem process, i.e external reagents or changes in reaction conditions are also required to facilitate propagation9.

Tandem consecutive reactions differ from cascade reactions in that the intermediate is an isolable entity. The intermediate contains the required functionally to perform the second reaction, but additional promotion10 in the form of energy (heat or light) is necessary to overcome the activation

barriers. Many examples of such consecutive cycloadditions have been documented10. A

particularly illustrative example is shown in Scheme 5.

The [4+2] cycloaddition produces a new olefin which is poised for an intramolecular [2+2] cycloaddition. Although, the first reaction is necessary, it is not sufficient for the tandem process, and a change in conditions (photochemical activation) is required.

Another example shown in Scheme 6 illustrates the problem of rigorous definition11 while the first [4+2] cycloaddition is not strictly necessary in that the second [4+2] process are already present in the precursor, the important structural consequences of intra molecularity is probably equally significant for the success of the tandem process as shown in scheme 6.

Tandem sequential cycloadditions are reactions wherein the second stage requires the addition of the cycloaddition partners or another reagent.

Tandem sequential cycloadditions require the addition of the second component for the tandem process to occur in a separate step. To qualify as a tandem reaction, the first stage must          create the functionality in the product to enable it to engage the second reaction. The intermediate may be isolable, though this is not a necessity. This class of reaction is not as well recognized as the previous ones, but it is nonetheless clearly illustrated in the synthesis of vernolepin and

Components of tandem [4+2]/[3+2] cycloaddition

The design of a tandem [4+2]/[3+2] cycloaddition process for nitroalkenes can be understood by recognizing the central role played by nitrates (Scheme 8). Early studies on the use of nitroalkenes as heterodienes (vide infra) led to the development of a general, high yielding, and stereoselective method for the synthesis of cyclic nitronates. These dipoles are well-known to undergo 1,3-dipolar cycloadditions (vide infra); however, synthetic applications of this process are rare. This is undoubtedly due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8, the potential for a powerful tandem process is formulated in the combination of an inverse electron demand [4+2] cycloaddition of a donor dienophile (D denotes electron withdrawing group). The resulting tandem process can construct four new bonds, up to four new rings, and up to six new stereogenic centers (three of which bear hetero atoms).

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