Easy access to medium-sized lactones through metal carbene migratory insertion enabled 1,4-palladium shift

Selective C–H bond functionalization without preinstalled directing groups remains a central challenge because of the inherent inertness of C–H bonds and geometric constraints for forming palladacycles. Prior work on 1,4-transition-metal migration (notably Larock’s alkyne insertion-enabled 1,4-Pd shift) demonstrated remote activation after intermolecular reactions. The authors hypothesized that a modular one-carbon synthon (a palladium carbene from N-tosylhydrazones) could create a thermodynamically favorable five-membered palladacycle poised for a 1,4-palladium/hydride shift, enabling site-selective activation at an aldehyde C–H and facilitating ring closure to medium-sized lactones. This approach addresses limitations of traditional routes such as Baeyer–Villiger oxidation and macrolactonization, which suffer from low regioselectivity with unsymmetric ketones, multistep manipulations, and limited product diversity. The goal is to develop a general, intermolecular, feedstock-based method to access dibenzo-fused seven- and eight-membered lactones, including late-stage functionalizations of complex, bio-relevant molecules.

The study builds on extensive literature on 1,4-migration of palladium and rhodium in C–H activation (Ma, Gu; Larock; others) and ligand-directed Pd-catalyzed C–H functionalization. Previous inter- and intramolecular 1,4-Pd migrations typically required specific geometries within a single molecule. Larock’s seminal examples showed alkyne insertion creating vinylpalladium intermediates that undergo 1,4-Pd migration. Classic medium-ring lactone constructions via Baeyer–Villiger oxidation and macrolactonization face challenges in selectivity and step economy. N-Tosylhydrazones are established diazo precursors for Pd-catalyzed cross-couplings and carbene migratory insertions, suggesting feasibility for generating a Pd–carbene species to trigger migratory insertion and subsequent metal/hydride shift for C–H activation. The authors’ prior work on Pd-catalyzed acylation of aryl diazoesters with ortho-bromobenzaldehydes further supports the approach.

Reaction development: The coupling of 2-bromobenzaldehyde 1a with an o-hydroxy tethered N-tosylhydrazone 2a (as an in situ diazo source) in THF was screened. Using Pd2(dba)3·CHCl3 (2.5 mol%), dppm (7.5 mol%), and K3PO4 at 80 °C gave seven-membered lactone 3 in 5% NMR yield. Ligand optimization identified Xantphos as optimal with Pd2(dba)3·CHCl3, affording 77–80% NMR/isolated yields. Changing the Pd source to Pd(OAc)2 (5 mol%) with Xantphos and K2CO3 (3.0 equiv) provided 3 in 76% isolated yield in shorter time. o-Iodobenzaldehyde (1b) also worked with slightly lower yield. Substrate scope (seven-membered rings): With Pd(OAc)2 (5 mol%), Xantphos (7.5 mol%), K2CO3 (3 equiv) in THF at 80 °C (argon), a wide range of o-bromoaryl aldehydes delivered lactones 3–13 in 65–84% yields; 1-bromo-2-naphthaldehyde furnished 14 in 55% yield. Diverse o-hydroxy N-tosylhydrazones from salicylaldehyde analogs coupled with 1a to give 15–37, tolerating Me, OMe, Cl, F, Br substituents, alkynyl, and TMS groups. A hydroxylketone-derived N-tosylhydrazone also served as carbene precursor (product 30, moderate yield). Bio-relevant fragments (methylparaben, paracetamol, carvacrol, thymol, eugenol, estrone, methyl N-Phth-L-tyrosinate) provided e-lactones 31–37 in moderate to good yields. Electrophile variation and formal dimerization: Using o-pseudohalo benzaldehydes (e.g., 2-formylphenyl triflate 1c) under the standard conditions gave 3 in 53% GC yield; optimization identified [(η3-C3H5)PdCl]2 (2.5 mol%) as the best Pd source with Xantphos/K2CO3, delivering 3 in 80% isolated yield. Both coupling partners derived from 2-hydroxybenzaldehydes undergo formal homo- and cross-dimerization to seven-membered lactones (3, 38–42; 5, 9; 43–56), maintaining tolerance of bromo, alkynyl, and TMS groups. Eight-membered lactones: Applying seven-membered conditions gave eight-membered product 58 (n = 1) in 15% NMR yield. Optimization (ligands, Pd sources, bases) identified dppb (5 mol% Pd) as optimal, furnishing 58 in 76% isolated yield. A small amount of dihydroisobenzofuran side-product was observed (≈5%). The approach generalized to various substrates (57–63) with electron-donating and -withdrawing groups, delivering 51–70% yields and compatibility with TMS and alkynyl groups. Late-stage and fragment couplings: Triflates bearing pharmacophores (methylparaben, paracetamol, estrone, eugenol, thymol, methyl N-Phth-L-tyrosinate) reacted with salicylaldehyde-derived N-tosylhydrazones to furnish functionalized seven-membered lactones in 34–75% yields (64–69). The analogous hydrazones also coupled with 1c to give 31–37 (up to 81% yield). Eight-membered analogs incorporating paracetamol (70), estrone (71, 72), N-Phth-L-tyrosine (73), and methylparaben (74) were obtained in 54–78% yields. Cross-dimerizations between two pharmacophores afforded complex lactones (75–82) in 43–74% yields. Mechanistic studies: Isotopic labeling showed no D incorporation when D2O (10 equiv) was added, but [D]-1c yielded [D]-3, indicating intramolecular 1,4-Pd/hydride shift and negligible H–D exchange with solvent. A low kH/kD for aldehyde C–H cleavage suggested it is not rate-determining. A catalytic cycle is proposed: oxidative addition to o-pseudohalo benzaldehyde (I), carbene formation (II→III) via migratory insertion, 1,4-Pd/hydride shift to activate the aldehyde C–H (IV), and ring closure to lactone. DFT calculations (M06/def2-TZVP//B3LYP/6-31G(d)(LANL2DZ)) on la + 2a with Pd(OAc)2/dppb: weak precomplexation (ΔG 2.4 kcal/mol); oxidative addition barrier 12.1 kcal/mol (exergonic by 21.4 kcal/mol); partial ligand dissociation endothermic by 22.0 kcal/mol; bromide/K2CO3 exchange exergonic; dediazonation to Pd–carbene requires 27.2 kcal/mol (rate-determining, TS2); migratory insertion barrier 9.5 kcal/mol (TS3); C–H insertion to five-membered palladacycle barrier 20.6 kcal/mol (TS4); hydride transfer barrier 6.3 kcal/mol; ring closure via outer-sphere displacement barrier 12.5 kcal/mol. Alternative pathways are discussed in SI. Scale-up and derivatizations: On 4 mmol (≈1 g) scale of 1c, lactones 3 and 58 were isolated in 74% and 67% yields. LAH reduction of 3/58 gave diols 83/84 quantitatively. 83 cyclized to dibenzo-oxepine 85. 84 underwent DMP oxidation then TiCl4/Zn-mediated McMurry coupling to suberene 86, a versatile intermediate for medicinal scaffolds; cyproheptadine 87 was accessible in three steps by reported methods. General procedure: In an Ar-filled Schlenk tube: Pd(OAc)2 (5 mol%), Xantphos (7.5 mol%), K2CO3 (3.0 equiv), N-tosylhydrazone (0.4 mmol), then 1 (0.2 mmol) and anhydrous THF (2.0 mL). Stir at 80 °C; workup via celite filtration, concentration, and silica gel chromatography to isolate lactone.

- Developed a palladium-catalyzed intermolecular method to assemble dibenzo-fused seven- and eight-membered lactones via palladium–carbene migratory insertion followed by an intramolecular 1,4-palladium/hydride shift and ring closure. - Optimal seven-membered conditions: Pd(OAc)2 (5 mol%), Xantphos (7.5 mol%), K2CO3 (3 equiv), THF, 80 °C (Ar), giving target lactones in 65–84% yields across broad scopes; naphthaldehyde substrate gave 55% yield. - o-Pseudohalo aldehydes (triflates) are competent electrophiles; best with [(η3-C3H5)PdCl]2 (2.5 mol%) and Xantphos/K2CO3, affording up to 80% isolated yield. - Formal homo- and cross-dimerizations of salicylaldehyde derivatives proceed smoothly, tolerating halides (Cl, Br), alkynyl, and TMS groups. - Eight-membered lactones realized with optimized conditions (dppb, 5 mol% Pd), delivering up to 76% isolated yield; minor dihydroisobenzofuran side-product (~5%). Substrates bearing strong/weak EWG and EDG gave 51–70% yields. - Late-stage functionalizations of pharmacophores (methylparaben, paracetamol, estrone, eugenol, thymol, methyl N-Phth-L-tyrosinate) provided seven-membered lactones in 34–75% yields; eight-membered analogs in 54–78% yields. Cross-coupling of two pharmacophore fragments yielded complex dimers in 43–74% yields. - Mechanistic evidence: Deuterium labeling supports an intramolecular, irreversible 1,4-Pd/hydride shift; kH/kD indicates aldehyde C–H cleavage is not rate-determining. DFT reveals rate-determining dediazonation to form Pd–carbene (ΔG‡ ≈ 27.2 kcal/mol); key barriers: oxidative addition 12.1, migratory insertion 9.5, C–H insertion 20.6, hydride transfer 6.3, ring closure 12.5 kcal/mol. - Practicality: Gram-scale synthesis (1 g) delivers 74% (3) and 67% (58). Downstream transformations give diols quantitatively, dibenzo-oxepine 85, suberene 86, and access to drug-like scaffolds, including cyproheptadine 87.

The method validates the hypothesis that a Pd–carbene migratory insertion can position palladium to enable a selective, intramolecular 1,4-palladium/hydride shift for aldehyde C–H activation, circumventing the need for directing groups and overcoming geometric constraints typically impeding direct C–H palladation. The approach efficiently forges medium-sized lactones from readily available building blocks, including formal dimerization of salicylaldehyde derivatives, enhancing modularity and structural diversity compared to Baeyer–Villiger oxidation or macrolactonization. Functional group tolerance (halides, alkynes, TMS) and compatibility with complex pharmacophores highlight robustness and applicability to late-stage diversification and fragment-based drug discovery. Mechanistic experiments and DFT computations coherently support the proposed catalytic cycle and identify carbene formation (dediazonation) as the rate-limiting step, rationalizing condition sensitivity (ligand/base effects). The ability to favor eight-membered lactonization over competing five-membered pathways under optimized conditions underscores the controllable chemoselectivity of the platform.

This work introduces a general, modular strategy to synthesize dibenzo-fused seven- and eight-membered lactones via Pd–carbene migratory insertion-enabled 1,4-palladium/hydride shift and C–H activation. It achieves high efficiency and broad substrate scope from simple aldehyde feedstocks, enables formal homo- and cross-dimerizations, tolerates diverse functionalities and complex pharmacophores, and scales effectively. Mechanistic studies (isotopic labeling, DFT) substantiate the key 1,4-Pd shift and identify dediazonation to Pd–carbene as rate-determining. The methodology provides rapid access to bio-relevant scaffolds and downstream transformations to medicinally important frameworks. Future work may target catalytic asymmetric variants, expand migratory-insertion-enabled metal migrations to other C–H sites and functionalities, and integrate this platform into diversity-oriented synthesis for drug discovery.

- Some substrate combinations afford only moderate yields; initial conditions for eight-membered rings were low-yielding and required specific ligand (dppb) and catalyst optimization. - Formation of a small amount (~5%) of dihydroisobenzofuran side-product observed in eight-membered lactonizations. - Reaction requires inert atmosphere, elevated temperature (80–100 °C), and precise ligand/base selection; triflate electrophiles needed a different Pd source for optimal yields. - Asymmetric induction was not achieved in this study; establishing stereocenters remains for future development.