Johnathan Board

The Directed ortho Metallation-Cross- Coupling Fusion: Development and Application in Synthesis

Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada *Email: victor.snieckus@chem.queensu.ca This review constitutes a detailed but non-exhaustive examination of the directed ortho metallation (DoM)– cross-coupling fusion in its many fl avours. Special attention is paid to the application of the concept of the linked reactions and the synthetic utility that it endows, particularly in the case of one-pot reactions that can greatly increase the ease and effi ciency of the process. Personal experience of particular issues that can arise from these reactions and examples of their solutions are given, as well as illustrations of the rapid access to complex molecules that the technique encourages.

Synthesis of Substituted Imidazo[1,5-a]pyrazines via Mono-, Di-, and Directed Remote Metalation Strategies

Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g (Table 1 ), and 4a-4d (Table 2 ). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising regioselective C5-deprotonation to afford, after electrophile quench, products 4b and 6a-6p (Table 3 ), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system.

Iodine-Mediated 1,3-Dipolar Cycloaddition to Benzo(f)isoindole-4,9-diones

14 H . M . H U A N G , J . R . GA O , L . F . H O U , J . H . J I A , L . H A N , Q . YE , Y. J . L I * ( Z H E J I A N G U N I V E R S I T Y O F TE C H N O L O G Y, H A N GZ HO U A N D Z H E N G Z H O U U N I V E R S I T Y, P. R . OF C H I N A ) The First Iodine Improved 1,3-Dipolar Cycloaddition: Facile and Novel Synthesis of 2-Substituted Benzo[f]isoindole-4,9-diones Tetrahedron 2013, 69, 9033–9037.

Biginelli Synthesis of Pyrimidones Using Terminal Alkenes as Precursors

Significance: Reported is the synthesis of pyrimidinones using a modified Biginelli reaction. In the traditional Biginelli reaction, the use of enolizable aldehydes (i.e., most aliphatic aldehydes) usually leads to low yield of the desired product due to side reactions of the aldehyde. The modification shown above circumvents this issue by ensuring that only a low concentration of aldehyde is present in the reaction at any given time. This is achieved through hydroformylation of a terminal alkene to produce the aldehyde which then undergoes a Biginelli reaction. Interestingly, the catalyst used for the hydroformylation reaction seems to promote the Biginelli reaction as well. Hence, although the term ‘tandem reaction’ is sometimes misused in the literature, in this case it is entirely accurate. Comment: Pyrimidines, and by extension pyrimidones, represent a very important class of heterocycles and are essential for all forms of life. Traditional methods for their synthesis usually involve condensation reactions, such as the Biginelli reaction (see Book below). The current work solves an important issue with the Biginelli reaction and allows the use of terminal alkenes as pro-aldehydes, thus avoiding side reactions. The reaction has been optimized with respect to time, temperature, stoichiometry, and pressure. Unfortunately, the optimum pressure for the reaction (necessary for the hydroformylation) is quite high and this may be a hindrance for its widespread adoption. The substrate scope was examined well with respect to the terminal alkene and demonstrated that the reaction conditions were sufficiently mild to tolerate esters, alcohol protecting groups, carbamates, amides, and phthalimides.

De Novo Synthesis of Pyridones From Enaminones and Alkynes

Significance: Reported is the copper-catalyzed synthesis of substituted pyridones from the reaction of dialkyl acetylenedicarboxylates with enaminones. Although simple dialkyl acetylenedicarboxylates (e.g. dimethyl acetylenedicarboxylate, DMAD) are commercially available, the enaminones must be synthesized. A method for their synthesis was not explicitly disclosed, but a quick search of the literature provides several different methods (e.g. a one-pot Sonogashira coupling of an acid chloride with ethynyltrimethylsilane followed by the addition of an amine and methanol; A. S. Karpov, T. J. J. Müller Org. Lett. 2003, 5, 3451). A mechanism for the reaction was proposed and studied through the isolation of intermediate A. This was re-subjected to the reaction conditions but did not generate product until more DMAD was added and the temperature was raised. This suggests that DMAD may be involved with the copper in generating a catalytically active species for the subsequent cyclization. Comment: Pyridones are important building blocks for the synthesis of substituted pyridines and other heterocycles and also represent pharmacologically relevant structures in their own right (e.g. M. A. Ciufolini, B. K. Chan Heterocycles 2007, 74, 101). Thus, the current method should be a useful addition to the plethora of established synthetic routes as it operates under mild conditions and uses inexpensive and easily synthesized starting materials. The reaction was optimized with respect to catalyst, catalyst stoichiometry and solvent. In addition, it was found that the reaction must be conducted under inert atmosphere to avoid the formation of pyrrole byproducts. The substrate scope was modestly examined and showed that the yields are generally good for enaminones with electron-donating groups and good to moderate for enaminones with electronwithdrawing groups. The reaction was relatively insensitive to the electronics of the enaminone carbonyl unit. N O R2 OR3 O O