Switchable synthesis of natural-product-like lawsones and indenopyrazoles through regioselective ring-expansion of indantrione

The study addresses the challenge of efficiently accessing natural-product-like lawsones (2-hydroxy-1,4-naphthoquinones) and indenopyrazolones, important scaffolds with notable bioactivities. While ring expansion of cyclic carbonyl compounds using diazo reagents is a classical homologation strategy, regioselectivity issues (competing 1,2-aryl vs 1,2-carbonyl migration) have hindered benzo-fused cyclic diones like indantrione. Prior examples mainly involve isatins or other cyclic ketones and often require metal catalysts. This work proposes and demonstrates a metal-free, solvent-controlled, regioselective ring expansion of indantrione with in situ generated α-aryldiazomethanes to access lawsones in acetonitrile and stereoselective indenopyrazolones in alcohols, thereby expanding scaffold generation for drug discovery.

Background methods include classical and modern use of diazo compounds for homologation and ring expansions of isatins and cyclic ketones, with catalytic enantioselective variants reported (Kingsbury, Maruoka, Feng groups). Despite the importance of lawsones and indenopyrazolones (antimalarial, antipneumocystic, CDK, HIF-1, tubulin-targeting activities), existing syntheses are generally multi-step, metal-catalyzed, and require pre-functionalized substrates. Solvent-controlled selectivity in related transformations has precedent in organometallic and radical chemistry. However, regioselective ring expansion of benzo-fused 1,2,3-triones (indantrione) had not been reported prior to this study.

Overall strategy: Generate α-aryldiazomethanes in situ from aldehydes and p-toluenesulfonyl hydrazide (N-tosylhydrazone formation and base-promoted diazo generation), then react with indantrione under base in different solvents to steer regioselectivity to lawsones (MeCN) or indenopyrazolones (alcohols). Optimization: Screening solvents and bases identified two optimal conditions: - For lawsones (4): Indantrione 1a (1.0 mmol) + Cs2CO3 (2.0 equiv) in MeCN at 80 °C for 3 h after in situ diazo formation; 4a obtained in up to 90% yield. Other solvents (1,4-dioxane, toluene, THF, DMSO, H2O, EtOAc) and bases (DBU, K2CO3, n-BuOK, Na2CO3, Et3N, NaOH) were less effective (Table 1). - For indenopyrazolones (5): Indantrione 1a (1.0 mmol) + Cs2CO3 (3.0 equiv) in EtOH at 80 °C for 10 h; 5a obtained in 83% yield, dr >95:5, with minor 4a (15%). Alcohol type modulated yields and provided corresponding ester variants; bases such as DBU, K2CO3, t-BuOK, Na2CO3, Et3N, NaOH were inferior (Table 1). General procedures: - Lawsons: Aldehyde (1.2 mmol) + p-toluenesulfonyl hydrazide (1.2 mmol) in MeCN (20 mL), rt 0.5 h, then add indantrione (1.0 mmol) and Cs2CO3 (2 equiv), 80 °C, 3 h; workup by solvent removal and silica gel chromatography (PE/EtOAc 8:1). - Indenopyrazolones: Aldehyde (2.1 mmol) + p-toluenesulfonyl hydrazide (2.1 mmol) in alcohol (30 mL), rt 0.5–1 h, then add indantrione (1.0 mmol) and Cs2CO3 (3 equiv), 80 °C, 10 h; workup by solvent removal and chromatography (PE/EtOAc 25:1). Control experiments: - Radical scavengers (2.0 equiv TEMPO or BHT) did not inhibit formation of 5a, and no coupling products were observed, indicating a non-radical pathway. - Deuterated MeOH labeling showed the ester group in 5 arises from bonding of indantrione C1 with CD3 (MeO-d3 incorporation). - Lawsone 4a did not convert to 5a under alcohol conditions with diazo present, indicating divergent pathways rather than sequential conversion. - Mixed solvent experiments (MeCN:EtOH) tuned selectivity: 100:0 yielded 4a 90%/5a 0%; 60:40 4a 53%/5a 43%; 50:50 4a 31%/5a 54%; 20:80 4a 22%/5a 73%; 0:100 4a 15%/5a 83%. - Ninhydrin hydrate (1a′) also furnished 5a in EtOH and 4a in MeCN under standard conditions. Computations (DFT): B3LYP-D3(BJ)-SMD with appropriate basis sets. In MeCN, α-aryldiazomethane adds to indantrione favoring C2 attack (pathway A) with lower barriers (TS-1 ~15.8 kcal/mol vs alternative initial step TS-3 higher; overall ~6.2 kcal/mol difference), leading to lawsones via 1,2-carbonyl migration and denitrogenation. In alcohols, alkoxide first attacks C1 to form INT-6 followed by 1,2-aryl migration (TS-5 20.1 kcal/mol), then diazo addition (TS-6 41.2 kcal/mol), Cs2HCO3+-assisted dehydration (TS-7, TS-8), conjugate addition (TS-9 −55.5 kcal/mol), and cyclocondensation to indenopyrazolones with high diastereoselectivity. Scale-up and derivatizations: Gram-scale reactions delivered 5a (76% in EtOH) and 5b (81% in MeOH) from 1a′/2a, and 4a (89% in MeCN) from 1a/2a. Downstream transformations included LAH reduction of 5a to 6a (selective carbonyl reduction), BBr3 demethylation of 5n to 6b, annulations from 4a to 6c/6d, acetylation of 4a to 6e, and conversion of 4w to carbazoloquinone 6f under metal catalysis.

- Developed a metal-free, solvent-controlled, regioselective ring-expansion of indantrione with in situ generated α-aryldiazomethanes to access two scaffold classes: • In MeCN: lawsones (2-hydroxy-1,4-naphthoquinones) in high yields (up to 96%). Example: 4a 90–92% under optimized conditions; diverse aryl aldehydes gave 4b (p-F) 96%, 4c (p-Cl) 94%, 4d (p-Br) 93%, 4j (p-CF3) 93%, 4t (B(pin)) 91%, heteroaryl 4ad 93%, 4ag 81%, sterically hindered 4af 85%, 4ah 80%; alkyl aldehydes also competent (4ai 74%, 4aj 71%, 4ak 50%). Substituted indantriones delivered 4al 88%, 4am 85%. • In alcohols: indenopyrazolones in high yields and high diastereoselectivity (dr ≥95:5). Examples: 5a 83% (Et), 5c (p-F) 91%, 5d (p-Cl) 88%, 5t (bulky aryl) 81%; across Me/Et/n-hexyl alcohols produced corresponding esterified products (e.g., 5o–5ab, 55–88% yields). Alkyl aldehydes were incompatible for 5 formation. - Solvent dictates selectivity; mixed-solvent experiments quantify tuning: MeCN:EtOH 100:0 → 4a 90%/5a 0%; 60:40 → 53%/43%; 50:50 → 31%/54%; 20:80 → 22%/73%; 0:100 → 15%/83%. - Mechanistic probes: Radical traps (TEMPO/BHT) did not impact yields; 4a is not a precursor to 5a; deuterium labeling in CD3OD confirmed incorporation of methoxy-d3 at C1-derived ester. - DFT rationalized regioselectivity: In MeCN, C2 attack (path A) lower barrier (TS-1 ~15.8 kcal/mol) than C1 attack (path B; initial step higher), favoring lawsones via 1,2-carbonyl migration; barrier difference ~6.2 kcal/mol. In alcohols, initial alkoxide addition at C1 (TS-5 20.1 kcal/mol) and subsequent steps (including TS-6 41.2 kcal/mol) lead to stereoselective indenopyrazolone formation; late steps highly exergonic (e.g., TS-9 −55.5 kcal/mol). - Structural confirmation: X-ray crystallography for representative products (lawsones: 4h, 4ae; indenopyrazolones: 5a, 5f, 5q, 5r). - Scalability and utility: Multigram syntheses achieved (5a 76%, 5b 81%, 4a 89%), with versatile downstream derivatizations to bioactive or synthetic intermediates (6a–6f).

The work demonstrates that solvent can switch the reaction pathway of indantrione with α-aryldiazomethanes, enabling selective access to either lawsones (in MeCN) or indenopyrazolones (in alcohols). Control experiments established non-radical mechanisms, divergence of pathways (4a does not convert to 5a), and solvent-dependent selectivity that can be continuously tuned by solvent mixtures. DFT analyses support that in MeCN, lower-energy nucleophilic addition at C2 followed by 1,2-carbonyl migration governs lawsone formation, while in alcohols, initial alkoxide addition at C1 and a subsequent rearrangement set up conditions for cascade addition and cyclization to indenopyrazolones with high diastereoselectivity. This addresses the longstanding regioselectivity challenge for benzo-fused 1,2,3-triones and provides a straightforward, metal-free approach to privileged scaffolds relevant to medicinal chemistry. The broad functional group tolerance, good to excellent yields, and successful gram-scale preparations underscore the method’s practicality and potential impact.

A solvent-controlled, metal-free, regioselective ring-expansion of indantrione with in situ generated α-aryldiazomethanes was developed. In MeCN, reactions provide lawsone derivatives via favored 1,2-carbonyl migration; in alcohols, stereoselective indenopyrazolones are formed. The protocol exhibits broad substrate scope (aryl and some alkyl aldehydes for lawsones; diverse aryl aldehydes for indenopyrazolones), high yields (up to 96%), and high diastereoselectivity (dr up to >95:5). Mechanistic experiments and DFT calculations elucidate the solvent-governed pathways. Gram-scale demonstrations and derivatizations highlight synthetic utility. Future work could explore enantioselective variants, extend scope (e.g., enabling alkyl aldehydes for indenopyrazolones), and further exploit the scaffolds in medicinal chemistry.

- For indenopyrazolone formation in alcohol solvents, alkyl-substituted aldehydes were incompatible and furnished no product. - Electron-donating aryl substituents generally gave slightly reduced yields compared to electron-withdrawing groups in both product classes. - High diastereoselectivity was achieved, but enantioselectivity was not investigated. - Reactions typically require elevated temperature (80 °C) and strong base (Cs2CO3), which may limit compatibility with very base/heat-sensitive functionalities.