ABSTRACT
Substituted pyridines with diverse functional groups are important structural motifs found in numerous bioactive molecules. Several methodologies for the introduction of various bio-relevant functional groups to pyridine have been reported, but there is still a need for a single robust method allowing the selective introduction of multiple functional groups. This study reports a ring cleavage methodology reaction for the synthesis of 2-alkyl/aryl 3-electron-withdrawing groups (esters, sulfones, and phosphonates) 5-aminoaryl/phenol pyridines via the remodeling of 3-formyl (aza)indoles/benzofurans. Totally ninety-three 5-aminoaryl pyridines and thirty-three 5-phenol pyridines were synthesized showing the robustness of the developed methodology. The application of this methodology further provided a privileged pyridine scaffold containing biologically relevant molecules and direct drug/natural product conjugation with ethyl 2-methyl nicotinate.
ABSTRACT
Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann-Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C-N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.
Subject(s)
Amines/chemical synthesis , Biomimetics/methods , Chemistry Techniques, Synthetic/methods , Niacin/chemical synthesis , Niacinamide/chemical synthesis , Aza Compounds/chemical synthesis , Cyclization , Feasibility Studies , Indoles/chemical synthesis , Molecular Structure , Niacin/analogs & derivatives , Niacinamide/analogs & derivativesABSTRACT
In the interdisciplinary research field of chemical biology and drug discovery, diversity-oriented synthesis (DOS) has become indispensable in the construction of novel small-molecule libraries rich in skeletal and stereochemical diversity. DOS aims to populate the unexplored chemical space with new potential bioactive molecules via forward synthetic analysis. Since the introduction of this concept by Schreiber, DOS has evolved along with many significant breakthroughs. It is therefore important to understand the key DOS strategies to build molecular diversity with maximized biological relevancy. Due to the length limitations of this mini review, we briefly discuss the recent DOS plans using build/couple/pair (B/C/P) and ring-distortion strategies for the synthesis of major biologically relevant target molecules like natural products and their related compounds, macrocycles, and privileged structures.
ABSTRACT
A successful synthesis of α-fluoro-ß-ketosulfides using an electrophilic fluorination method has been reported for the first time. The reaction proceeds via an electrophilic fluorination of α-sulfenyl-ß-diketones followed by an unexpected tandem deacylation. The resulting products, α-fluoro-ß-ketosulfides, are easily oxidized to the corresponding α-fluoro-ß-ketosulfones, which can be used for further useful olefination reactions.
ABSTRACT
α-Sulfenyl ketones are potential precursors which find a variety of applications in organic synthesis. Their typical synthesis requires pre-functionalized starting materials and two to three step synthetic sequences. In addition, the selective pre-functionalization of unsymmetrical ketones is a challenge, which limits the synthesis of the desired sulfenylated ketones. To overcome these disadvantages, a metal-free, convenient one-step strategy for synthesizing α-sulfenyl ketones at ambient temperature via a cross-dehydrogenative coupling (CDC) strategy has been developed with a broad substrate scope. Therefore, this CDC strategy for C-S bond formation is attractive and may find wide applications in organic synthesis.
ABSTRACT
Sulfenylation of ß-diketones is challenging as ß-diketones undergo deacylation after sulfenylation in the reaction medium. The sulfenylation of ß-diketones without deacylation under metal-free conditions at ambient temperature via a cross dehydrogenative coupling (CDC) strategy is reported. The resultant products can be further manipulated to form α,α-disubstituted ß-diketones and pyrazoles.
Subject(s)
Ketones/chemistry , Pyrazoles/chemical synthesis , Sulfenic Acids/chemistry , Sulfhydryl Compounds/chemical synthesis , Molecular Structure , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistryABSTRACT
A facile transition-metal-free oxidative cross-dehydrogenative coupling reaction involving selective formation of a C-S bond leading to the synthesis of arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthiobenzothiazoles has been described. This highly regioselective C-H functionalization reaction with electron-rich aromatic systems including heteroaromatics is achieved by reversing the reactivity of sulfur in the presence of a suitable oxidant and strong acid.