The efficient generation of privileged natural product scaffolds is a crucial strategy in drug discovery, emphasizing methodologies that produce structurally diverse and biologically active compounds. Ring expansion using diazo compounds is a classic homologation method for generating complex scaffolds. While ring expansion of isatins and other cyclic ketones has been reported, the regioselective ring expansion of benzo-fused cyclic dione substrates, such as indantrione, presents a challenge due to competing 1,2-aryl and 1,2-carbonyl migration pathways. Lawsones and indenopyrazoles are important polycyclic systems found in various bioactive compounds exhibiting antimalarial, antipneumocystic, and protease inhibitory activities. Current synthetic approaches are often multi-step, require high metal catalyst loadings, and utilize specialized starting materials. This research aims to develop a straightforward, metal-free, and solvent-controlled regioselective ring-expansion reaction of indantrione with α-aryldiazomethanes to efficiently synthesize lawsones and indenopyrazoles.

The literature reveals various methods for ring expansion reactions using diazo compounds, particularly with substrates like isatins and other cyclic ketones. Studies by Kingsbury, Maruoka, and Feng groups have demonstrated catalytic ring expansion reactions. However, the regioselective ring expansion of indantrione, a benzo-fused cyclic dione, remains largely unexplored due to the possibility of 1,2-aryl and 1,2-carbonyl migration. Existing methods for preparing lawsones and indenopyrazoles often involve multi-step reactions with limitations such as the need for high catalyst loadings and the use of less readily available starting materials. This study addresses the need for a more efficient and versatile synthetic approach.

The researchers optimized reaction conditions by screening various solvents and bases for the ring-expansion reaction of indantrione 1a, benzaldehyde 2a, and p-methylbenzenesulfonohydrazide 3. They found that acetonitrile favored the formation of lawsone derivatives (4a, 90% yield), while ethanol favored indenopyrazolone derivatives (5a, 83% yield with >95:5 diastereoselectivity). The substrate scope was investigated using different indantriones and aldehydes. For lawsones, a wide range of aryl and alkyl aldehydes with electron-donating or electron-withdrawing substituents reacted efficiently, affording the corresponding hydroxynaphthoquinones in good to excellent yields (up to 96%). Similarly, the synthesis of indenopyrazolones tolerated various aryl aldehydes with different substituents, providing high yields (up to 91%) and high diastereoselectivities (≥95:5 dr). Alkyl aldehydes proved incompatible with this transformation in alcohol solvent. X-ray crystallography confirmed the relative configurations of selected products. To elucidate the reaction mechanism, control experiments were performed, including radical trapping and isotopic labeling studies. Density Functional Theory (DFT) calculations were employed to explore the reaction pathways in both acetonitrile and ethanol solvents. Multigram-scale experiments demonstrated the scalability of the method. Finally, synthetic versatility was demonstrated through derivatization of the synthesized lawsones and indenopyrazoles into various other compounds, including those with potential biological activity.

The study successfully developed a metal-free, solvent-controlled regioselective ring-expansion reaction of indantrione with in situ generated diazomethanes. This method offers a highly efficient and versatile route to synthesize both lawsones and indenopyrazoles, valuable structural motifs in bioactive molecules. Acetonitrile selectively promoted the formation of lawsones through 1,2-carbonyl migration, while ethanol promoted the formation of indenopyrazoles with high diastereoselectivity. A wide range of substituted aryl and alkyl aldehydes (for lawsones) and various aryl aldehydes (for indenopyrazoles) were successfully incorporated into the reaction. Yields for lawsones reached up to 96%, while indenopyrazoles reached up to 91%, with diastereoselectivities up to 95:5 dr. Control experiments and DFT calculations provided mechanistic insights. The DFT calculations indicated that in acetonitrile, the reaction preferentially proceeds through pathway A (C2 attack), leading to lawsones; whereas in ethanol, the reaction proceeds through a pathway involving nucleophilic attack at C1 followed by rearrangements, leading to indenopyrazoles. Multigram-scale syntheses demonstrated the scalability of the method. Finally, derivatization examples showcased the versatility of the synthesized lawsones and indenopyrazoles as valuable synthons for accessing diverse structures with potential biological activities.

The findings directly address the challenge of efficiently synthesizing lawsones and indenopyrazoles, valuable building blocks in medicinal chemistry. The solvent-controlled regioselective ring-expansion reaction offers a significant improvement over existing methods, providing a more straightforward, metal-free, and efficient approach. The high yields, diastereoselectivity, and broad substrate scope make this method highly versatile and applicable to the synthesis of a wide range of structurally diverse lawsones and indenopyrazoles. The mechanistic studies, incorporating both experimental and computational approaches, provide a comprehensive understanding of the reaction pathway, explaining the solvent-dependent regioselectivity. The demonstrated scalability and synthetic versatility further enhance the practical value of this method for drug discovery and related fields.

This research successfully established a novel, efficient, and versatile method for synthesizing lawsones and indenopyrazoles using a metal-free, solvent-controlled regioselective ring-expansion reaction of indantrione with α-aryldiazomethanes. The method's high yields, diastereoselectivity, and broad substrate scope make it a significant advancement in the synthesis of these important bioactive scaffolds. Future research could explore the application of this methodology to other cyclic dione substrates and investigate the biological activities of the synthesized compounds.

While the method demonstrates high efficiency and versatility, limitations exist. The compatibility with alkyl aldehydes is limited, particularly in the synthesis of indenopyrazoles. Further optimization might be needed to expand the scope of suitable substrates. Additionally, the DFT calculations provide a theoretical framework for understanding the mechanism, but experimental verification of specific intermediates could further strengthen the mechanistic understanding.