Amides synthon generation

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

Zaworotko has recently demonstrated the ability of the drug carbamazepine to form a crystalline homodimer.43 The structure was sustained by an amide dimer synthon (Fig. 23). The dimer possessed two pendant NH groups that participated in hydrogen bonds with solvent molecules (e.g. acetone). The solids were generated to develop new solid compositions of the drug. Such compositions are anticipated to lead to pharmaceutical materials that exhibit properties (e.g. bioavailability) not realized by previous crystalline forms of the drug molecule. 

Recently, Fmoc-N-protected (3-amino acid synthons have been prepared and used for the synthesis of (3-peptides on solid phase [103]. This methodology facilitates enormously the search for new bioactive compounds, above all through the generation of combinatorial (3-peptide libraries. In this context, (3-amino acids have been used as building blocks for RGD cyclic peptides and for the synthesis of an inhibitor of human cathepsin L, previously identified by screening and deconvolution of pentapeptide amide collections [104,105]. 

Despite their snccess, N-heterocyclic amides are not sufficiently versatile to make them ideal SRs. First, they can form self-complementary amide amide and amide- -pyridine hydrogen bonds, which makes it inherently difBcult to combine any of them with molecules that lack moieties that can compete successfully with such synthons. Second, if the two binding sites are attached to the same backbone (as is the case with isonicotinamide), it is not possible to tune the charges on individual atoms of the two sites independently, which reduces versatility. Thus, there is a need for second-generation SRs that can be refined such that they offer more opportunities for modular supramolecular synthesis through enhanced structural selectivity and specificity. 

Recently our group has developed concerted PCET-based methods for the activation of amide N-H bonds to form neutral amidyl radicals. Long recognized as valuable synthons for C-N bond formation [203, 208-213], these intermediates have not enjoyed widespread application in synthesis because of the inability to access these intermediates directly from native amide N-H bond precursors. The most common methods of amidyl generation typically require N-functionalized amides or the use of strong stoichiometric oxidants to effectively furnish the radical species. Few methods for catalytic amidyl generation have been reported [214]. We suspected that PCET could provide an amenable solution to producing neutral amidyls under mild catalytic conditions directly by activation of the amide N-H bond. 

Illustration of the concept of homo (amide-amide) (left) and hetero (amide-acid) (right) supramolecular synthons applied to the structural characterisation of co-crystal strnctures involving piracetam (left, cocrystal with mandelic acid (XOZSOV ) right, co-crystal with gentisic acid (DAVPAS" ). (Pictures generated with Mercury, CCDC)/ ... 

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