Synthesis of Diverse Nitrogen-Enriched Heterocyclic Scaffolds Using a Suite of Tunable One-Pot Multicomponent Reactions

Abstract

Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns.

The Groebke‐Blackburn‐Bienaymé Reaction

“…The use of hydrazines in the GBB‐3CR has not been explored until 2014. A variation in which 2‐hydrazinopyridine is used to obtain bicyclic pyridotriazines was introduced by Hulme et al The proposed mechanism is quite similar to that of the GBB‐3CR reaction, it involves a non‐concerted [5+1]‐cycloaddition of the Schiff base and isocyanide.…”

Assembly of New Heterocycles through an Effective Use of Bisaldehydes by Using a Sequential GBB/Ugi Reaction

“…To verify our new plan, the reaction between compounds 1a, 2a,a nd 3a was screened at 80 8Cu nder microwavei rradiationf or 10 min in various solvents, that is, THF, EtOH,w ater,a nd N,N-dimethylformamide (DMF);h owever, ac omplex reactionp rofile was obtainedi na ll cases ( Table 1, entries [1][2][3][4]. Next, the reactionw as screened withouta ny solvent at various operating temperatures (80, 100, 120,1 40, and 160 8C) under microwave irradiationf or 10 min and the desired product (4a)w as isolatedi n5 5%,6 0%,6 2%,7 5%,a nd 50 % yield, respectively ( Table 1, entries [5][6][7][8][9].…”

“…[3,4] Twon otable IMCRs are the Groebke-Blackburn-BienaymØ (GBB) reaction and the Ugi reaction. [5,6] The GBB reaction-typically an acid-catalyzed reaction between ah eterocyclic amidine, an aldehyde, and an isocyanide that proceeds through imine formation ands ubsequent [4+ +1] cycloaddition, provides access to fused bicyclic heterocycles, such as imidazo[2, 1-b]azines. [5] Imidazo[2, 1-b]azine scaffolds have been found to display aw ide range of biological activities,i ncluding antifungal,a ntiviral, anticancer,a nd anti-inflammatory activities, as wella sc alcium-channel antagonists, sedatives, andi nt he treatment of heart diseases.…”

“…[5,6] The GBB reaction-typically an acid-catalyzed reaction between ah eterocyclic amidine, an aldehyde, and an isocyanide that proceeds through imine formation ands ubsequent [4+ +1] cycloaddition, provides access to fused bicyclic heterocycles, such as imidazo[2, 1-b]azines. [5] Imidazo[2, 1-b]azine scaffolds have been found to display aw ide range of biological activities,i ncluding antifungal,a ntiviral, anticancer,a nd anti-inflammatory activities, as wella sc alcium-channel antagonists, sedatives, andi nt he treatment of heart diseases. [7] Similarly,t he Ugi reaction also delivers aestheticallye legant dipeptide architectures in at ruly "mix-andgo" mannert hrough the four-component reaction of an isocyanide, an acid, an amine, anda na ldehyde.…”

Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines

“…Another possibility consists in removing the carboxylic acid, allowing the nitrilium ion intermediate ( 4 ) to be intramolecularly intercepted by a passive nucleophile unable to interfere with the initial elementary steps of the Ugi reaction. This strategy is known as interrupted Ugi reaction and, despite its intrinsic potentiality, it has not been fully exploited by the scientific community [20,21,22,23,24,25,26,27,28]. The interrupted Ugi reaction could be a very powerful tool to create sets of multi-functionalized and drug-like heterocycles, as exemplified in Figure 1.…”