Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines

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.

Fig. 1. Background for reaction development.

a Representative examples of commercially available bioactive nicotinates. b Representative examples of aniline-based pharmaceuticals. c Previously reported synthetic routes for substituted nicotinates with inevitable C₂ and C₆ substitutions. d Biosynthetic process of vitamin B₃ (a.k.a niacin or nicotinic acid) from l-tryptophan. e Reaction development with working hypothesis, which mimics the nature’s pathway for ortho-nicotinated anilines as the late-stage modification with vitamin B₃ without substituents at the C₂ and C₆ positions. f Regioselective direct C–H arylation of pyridines containing electron-withdrawing or directing groups. g Plausible synthetic route for the conjugating anilinic compounds with vitamin B₃ on the basis of the literature evidences. h This study: synthetic strategy for conjugating anilinic compounds with vitamin B₃ by mimicking nature’s biosynthetic pathway and its advantages.

Fig. 2. Substrate scope for N-substituted (aza)indole remodeling.

Reaction conditions: 1 (0.2 mmol), 2 (1.2 equiv.), NH₄OAc (4.0 equiv.) in an appropriate solvent (2 mL) at 100 °C for 8 h. Yields of isolated products (3 and 4) are given in parenthesis. nd = not detected. ^†Ethanol was used as the solvent for all of the reactions except for starting materials containing sulfonyl-protected indoles. ^‡Acetonitrile was used as the solvent in the case of sulfonyl-protected indoles as substrates. ^aReaction were performed at 0.5 mmol scale. ^b2.0 g scale reaction with respect to 1. ^c500 mg scale reaction with respect to 1. ^dReaction time 16 h.

Fig. 3. Substrate scopes for synthesis of nicotinated anilines/aminopyridines via (aza)indoles skeleton remodeling.

Reaction conditions: 5 (0.2 mmol), 2 (1.2 equiv.), NH₄OAc (5.0 equiv.), and Zn(OTf)₂ (10 mol%) at 120 °C. ^†Reactions were performed in EtOH (2.0 mL) for 6 h in the case of azaindole-based substrates (6a‒6e, 7a). ^‡Reactions were performed in CH₃CN (2.0 mL) for 16 h in the case of indole-based substrates (6 f‒6ac, 7b). Yields of the isolated products (6 and 7) are reported.

Fig. 4. Extending the scope of the reaction towards the synthesis of substituted bioactive niacinates and anilinic drugs.

a Scope of the reaction for the synthesis of meta-substituted bioactive nicotinates. b Scope of the reaction for the synthesis of ortho-substituted bioactive N-protected or free anilinic drugs. c A representative example of conjugates containing bioactive nicotinates and anilinic drugs via C–C bond. d, e Extension of the scope of our synthetic strategy for late-stage skeletal transformation of (aza)indole moiety in natural products and pharmaceuticals. See Supplementary Information for reaction condition and further details^(a–g).

Fig. 5. Plausible mechanisms of nature-inspired transformation of (aza)indole scaffolds into substituted meta-aminoaryl nicotinate scaffolds.

a Plausible mechanism A via imine formation and 6π electrocyclization followed by C–N bond cleavage and re-aromatization. Plausible mechanism B via Aldol-type addition, dehydration, and intramolecular cyclization followed by C–N bond cleavage and re-aromatization. Each proton in meta-aminoaryl nicotinates was color-coded to track its sources in starting materials. b Deuterium-labeling experiments revealed that our structural remodeling of (aza)indoles into substituted meta-aminoaryl nicotinate scaffolds occurs via plausible pathway B, as confirmed by NMR experiments.