Rational design of *N*-heterocyclic compound classes via regenerative cyclization of diamines

Reaction discovery is a central topic in chemistry, especially when it enables access to previously unsynthesized classes of compounds. Concepts that permit rational design of compound classes are rare. Iterative synthesis, in which the functional group originally modified is regenerated, can introduce chemical diversity. The authors propose regenerative cyclization, where ring closure of two functional groups regenerates a new pair of the same functional groups, enabling sequential ring closures to yield classes of (poly)cyclic compounds. Given the importance of N-heterocycles in pharmaceuticals, agrochemicals, dyes, and materials, the authors target systems in which amines are the regenerating functional groups. They introduce a catalytic consecutive three-component reaction: a diamine reacts with an amino alcohol via dehydrogenation, condensation, and cyclization to form an aminated intermediate that undergoes a second ring closure with an aldehyde, carbonyldiimidazole (CDI), or a dehydrogenated amino alcohol. Hydrogen is liberated in the first step, using an Earth-abundant manganese catalyst. The reaction proceeds diastereoselectively with broad scope and functional group tolerance (including hydrogenation-sensitive groups) under conditions that release H2 and use a hydrogenation-capable catalyst. The process is scalable and uses only catalytic base. None of the N-heterocyclic compounds synthesized were previously reported.

The work builds on iterative synthesis and ring-closure strategies for generating chemical diversity and novel cyclic frameworks. Classic synthesis of 2,3-dihydro-1H-perimidines from 1,8-diaminonaphthalene and aldehydes dates to 1964. Recent advances include catalytic in situ generation of aldehydes via dehydrogenation (e.g., phosphine-free manganese catalysts) and broader developments in borrowing hydrogen/acceptorless dehydrogenation catalysis with manganese and iron pincer complexes. Related sustainable syntheses include catalytic routes to pyrroles and pyridines via alcohol/amine dehydrogenative coupling. The authors contrast pincer ligand backbones, noting higher activity with a triazine-based PN5P manganese pincer versus pyridine-based variants in their system. The study positions itself within green catalysis using Earth-abundant metals, open-system H2 liberation, and multi-component one-pot reactions to access previously unknown N-heterocycles.

Reaction optimization began with coupling 1,8-diaminonaphthalene and 2-aminobenzyl alcohol to form 2-(2,3-dihydro-1H-perimidin-2-yl)aniline (A1). Various Mn, Fe, and Co pincer complexes were screened as dehydrogenation precatalysts. Manganese catalysts bearing a triazine-based PN5P pincer (Mn-I) were optimal, outperforming pyridine-based PNP variants. Optimized conditions for A1: 2 mmol 1,8-diaminonaphthalene and 2 mmol amino alcohol in 3 mL 2-MeTHF, 1 mol% Mn-I, 30 mol% KOtBu, 100 °C for 2 h in an open system equipped with a bubble counter to release H2. The first step dehydrogenates the amino alcohol in situ, minimizing self-condensation of the corresponding aldehyde. Consecutive one-pot synthesis of fertigines (second ring closure) was achieved by adding aldehyde after 2 h under the same conditions and continuing at 100 °C for 15 h. Substrate scope studies varied the amino alcohol (electron-donating/withdrawing, halogens, acetal, polycyclic, N-heteroaryl), aldehydes (aryl with EWG/EDG, heteroaryl, ferrocenyl, aliphatic), and diamines (substituted naphthalenediamines and acenaphthene analogs). Large-scale reactions gave similar yields. For aliphatic amino alcohols (e.g., L-alaninol, L-phenylalaninol), solvent was switched to 1,4-dioxane (12 mL) at 100 °C for 4 h to generate amino alkyl perimidines (A25–A27). Aldehyde-based second ring closure failed for these; instead, CDI-mediated cyclization was employed: perimidine (2 mmol), 30 mol% KOtBu, 1.15 equiv CDI in 1,4-dioxane (10 mL for batch), 130 °C, 2 h in a sealed pressure tube to give imidazo[1,5-a]perimidin-10-ones (C1–C3, termed kuenstlerines). Diastereomeric mixtures formed and were separable by chromatography. Amino fertigines (degree of modification 3) were prepared in a consecutive one-pot manner by adding 2-aminobenzyl alcohol instead of aldehyde after the first 2 h, continuing 15 h. Mechanistic studies: KOtBu activates Mn-I to form the active dehydrogenation catalyst. GC confirmed liberation of one equivalent of H2 during dehydrogenation of 2-aminobenzyl alcohol. Without diamine, self-condensation of in situ 2-aminobenzaldehyde occurs. Time-dependent 1H NMR supports initial imine formation and intramolecular cyclization to amino perimidines. No reaction occurs without base, indicating base-mediated cyclization. Evidence for a deprotonated amino perimidine intermediate (A1K) was obtained; A1K forms upon treating A1 with KOtBu, reverts to A1 on addition of water, and reacts with aldehyde to give fertigine even without added base, implicating A1K as a key intermediate in the second ring closure.

- A manganese-catalyzed, base-mediated consecutive three-component process enables regenerative cyclization of diamines with amino alcohols and electrophiles to form new classes of N-heterocycles. - Optimized conditions for the first ring closure (amino perimidines): 1 mol% Mn-I (triazine-based PN5P pincer), 30 mol% KOtBu, 2-MeTHF, 100 °C, 2 h, open system; H2 is released. - Amino perimidines A1–A21 synthesized using 21 aminobenzyl alcohols in isolated yields typically 71–97% (A1: 90%); broad tolerance of EDG/EWG including F, Cl, Br, methoxy, dimethoxy, OCF3, acetals, polycyclic aromatic, and N-heteroaryl groups. A1’s structure confirmed by single-crystal X-ray. - Second ring closure (fertigines) via addition of aldehydes afforded B1a–B1q in 70–93% isolated yields (e.g., B1a 93%) with minimal electronic/positional effects from substituents on the amino alcohol fragment; products include halogenated, acetal-bearing, polycyclic, and N-heteroaryl derivatives. B1a structure confirmed by X-ray. - Aldehyde scope: B2a–B2p and B3a–B3e obtained in 67–95% isolated yields using para/ortho-halogen benzaldehydes (up to 93%), methyl/methoxy (78–87%), alkenyl/acetoxy (68–69%), heteroaryl aldehydes (up to 79%), ortho-vanillin (70%), ferrocenaldehyde (72%), and aliphatic aldehydes (95% and 68%). Double-halogenated and fluorinated heterocycle/organometallic derivatives formed in 75–90% yields. No clear correlation between aldehyde electronics and yield. - Diamine variation: Substituted naphthalenediamines afforded A22–A24 in 76–91% yield; subsequent fertigines B4a–B4c (up to 78%, one case 56% due to solvation) and B5a–B5c (68–73%). - Amino alkyl perimidines A25–A27 (from aliphatic amino alcohols) formed in 91–94% yields (oily, air-sensitive). Their second ring closure required CDI to give kuenstlerines C1–C3 in 76–91% yields; diastereomeric mixtures obtained with dr 71:29 (C1), 88:12 (C2), and 61:19 (C3). - Amino fertigines B6a–B6c (degree of modification 3) formed in 38–79% yields. - Gram-scale upscaling delivered comparable yields for A1 and B1a. - Mechanistic evidence: H2 evolution confirmed; base essential for cyclization; a deprotonated amino perimidine (A1K) identified as an intermediate enabling the second ring closure in the absence of additional base.

The study addresses the challenge of rationally designing new compound classes by introducing regenerative cyclization: a ring closure that regenerates the same functional group pair (amines), enabling sequential cyclizations. Using a manganese PN5P-pincer catalyst for acceptorless dehydrogenation of amino alcohols, the authors generate imine intermediates in situ that undergo base-mediated cyclization to amino perimidines, then a second ring closure with aldehydes (or CDI/aminobenzyl alcohol) to afford novel N-heterocycles (fertigines, kuenstlerines, and amino fertigines). The approach demonstrates broad substrate scope, diastereoselectivity, and tolerance of hydrogenation-sensitive groups despite in situ H2 formation and the presence of a hydrogenation-capable catalyst. It leverages Earth-abundant manganese, catalytic base, and straightforward one-pot procedures, aligning with sustainable synthesis. Mechanistic experiments corroborate the proposed dehydrogenation and cyclization cascade, including the necessity of base and identification of a deprotonated amino perimidine intermediate for the second ring closure. Collectively, the results validate regenerative cyclization as a generalizable concept for accessing previously unknown N-heterocyclic scaffolds relevant to pharmaceuticals and materials.

Regenerative cyclization of diamines—where ring closure regenerates a pair of amines—enables the rational design and synthesis of new classes of N-heterocycles. Catalytic amino alcohol dehydrogenation with an Earth-abundant manganese pincer catalyst, followed by base-mediated cyclizations, affords amino perimidines and their further cyclized derivatives (fertigines, kuenstlerines, amino fertigines) with broad functional group tolerance, scalability, and diastereoselectivity. This strategy extends amino alcohol dehydrogenation-based heterocycle syntheses and suggests avenues for generalization to other systems. Future work may expand regenerative cyclization using alternative C1 donors such as methanol (as a formaldehyde surrogate) and explore additional diamine backbones, electrophiles, and iterative modification degrees to access diverse (poly)cyclic architectures.

- Certain substrates show reduced yields due to solubility/solvation issues (e.g., B4b 56%). - Amino alkyl perimidines (A25–A27) are not air-stable and did not undergo aldehyde-based second ring closure; CDI was required to achieve cyclization to kuenstlerines. - Amino fertigines (B6 series) exhibited lower to moderate yields (38–79%) and poor solubility in polar solvents. - Diastereomeric mixtures formed in CDI-mediated cyclizations (C1–C3), requiring chromatographic separation. - Reactions require strong base (KOtBu), elevated temperatures (100–130 °C), and manage H2 evolution (open or sealed systems), which may limit certain functional groups or scale-up environments. - No enantioselective variants were reported; stereochemical control beyond diastereoselection remains unaddressed.