Iridium-Catalyzed Borylation for the Syntheses of Novel Carbocyclic & Heterocyclic Compounds

Abstract

Arylboronic acids & esters are versatile synthetic intermediates used extensively in the synthesis of existing as well as new medicines, agrochemicals, conjugated polymers, and variety of other functional materials. One of the most common and well-known application of aryl boronic esters in organic syntheses is in the Suzuki cross coupling reaction (Chemistry Nobel Prize 2010). Due to large number of applications of aryl boronic esters, there is huge interest in the development of new & convenient routes for their syntheses. Traditionally aryl boronic esters have been prepared from aryl halides by generating organometallic species (organolithium or magnesium) followed by treatment with trialkyl borate. In 1995, Miyaura and co-workers reported a direct palladium catalyzed borylation of aryl halides which by-passed the need to prepare organolithium/magnesium compounds. More recently, groups of Smith-Maleczka and Hartwig- Miyaura have reported a new iridium-catalyzed route for the syntheses of aryl boronic esters directly from the hydrocarbon feed-stock. Chapter 1 describe the literature background about this methodology. While Chapter 2-4 summarize our efforts to synthesize fluorinated aryl & pyridylboronic esters using the newly developed iridium-catalyzed C–H borylation reaction. Fluorinated molecules are becoming increasingly popular in the pharmaceutical and agrochemical industries. This is due to the fact that strategically placed fluorine atoms often have a positive influence on the biological properties of active compounds. Fluorine atom as well as fluorine containing substituents such as triflouromethyl or flouroalkoxy groups are useful to tailor pKa values, help penetrating the cell membrane, and are stable to oxidative metabolism. About 20% of all pharmaceuticals and about 30% of agrochemicals under development or recently introduced on the market contain fluorine. Selected examples of fluorine containing drugs include Lipitor, Celebrex, Ciprofloxacin, Pantoprazole, and Fluoxetine etc. Consequently, synthetic methods for the selective preparation of specifically fluorinated intermediates and building blocks are of high importance. Chapter 2 describe our efforts to synthesize fluoroalkoxy substituted arylboronic esters by iridium-catalyzed aromatic C−H borylation. The fluoroalkoxy groups employed include trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, & 2,2-difluoro- 1,3-benzodioxole. Regioselectivities observed in iridium-catalyzed borylation of fluoroalkoxy arenes are complementary to those observed for electrophilic aromatic substitution and directed ortho metalation. 2,6-bis(trifluoromethyl) pyridine is a highly electron deficient heteroaromatic compound. Attempted functionalization of the C–H bonds of 2,6-bis(trifluoromethyl)pyridine using the traditional methodologies has not been successful. Electrophilic aromatic substitution is not possible due to the highly electron deficient nature of 2,6-bis(trifluoromethyl)pyridine. Literature search showed that attempted directed ortho metalation on this compound using butyllithium or tert-butyllithium has also not been successful. In Chapter 3, it has been shown that iridiumcatalyzed aromatic borylation can readily functionalize this substrate to yield 2,6- bis(trifluoromethyl)pyridine-4-boronic acid pinacol ester. The newly synthesized highly electrondeficient pyridine-4-boronic ester was employed in Suzuki coupling reaction using various (hetero)aryl bromides and the coupled products were obtained in good to excellent isolated yields. Double, and triple Suzuki coupling reactions of the pyridyl-4-boronic esters were also successful. These coupling reactions demonstrate that this new pyridine-4-boronic ester can be very useful for the incorporation of one of the strongest electron-withdrawing fluorinated aromatic group in organic materials. Chapter 4 describe our results on the borylation of unsymmetrical 2,6-di-substituted pyridines. Regioselective borylation on the 4-position of various 2,6-di-substituted pyridines was generally observed as expected based on steric effects. The only major exception being the 2,6-dimethoxypyridine in which significant amount of borylation ortho to the methoxy groups were also observed. Erosion in regioselectivity for this substrate was removed by lowering the reaction temperature. In conclusion, iridium-catalyzed aromatic C–H borylation is a convenient tool to functionalize fluoroalkoxy arenes and pyridines, allowing new regioselectivity patterns which are not available through the traditional routes. Synthetic utility of the newly synthesized pyridyl & arylboronic esters is demonstrated by using these in the Suzuki coupling reaction.