Heterocyclic Boronic Acids

Heterocyclic aromatic boronic acids, in particular pyridinyl, pyrrolyl, indolyl, thienyl, and furyl derivatives, are popular cross-coupling intermediates in natural product synthesis and medicinal chemistry. The synthesis of heterocyclic boronic acids has been reviewed recently [222], and will not be discussed in detail here. In general, these compounds can be synthesized using methods similar to those described in the above section for arylboronic acids. Of particular note, all three isomers of pyridineboronic acid have been described, including the pinacol ester of the unstable and hitherto elusive 2-substituted isomer, which is notorious for its tendency to pro-todeboronate [223]. Improvements and variants of the established methods for synthesizing heterocyclic boronic acids have been constantly reported [13, 182]. For example, a Hg-to-B transmetallation procedure was recently employed to synthesize a highly functionalized indolylboronic acid (entry 19, Table 1.3) [187]. 

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The interaction of PBA derivatives with molecular species having the above functional groups occurs optimally in the pH range of 8-9, but it is typically reversible at acid pH or in the presence of a high concentration of competing ligand. However, the heterocyclic boronic acid complex is relatively stable under optimal conditions of formation. 

For a recent review on heterocyclic boronic acids see Tyrrel, E. Brookes, P. Synthesis,... 

E. Tyrrell, P. Brookes, The Synthesis and Applications of Heterocyclic Boronic Acids, Synthesis 2003, 469 183. 

Syntheses and applications of heterocyclic boronic acids 03S469. 

In addition to the very important palladium-catalysed reactions, boronic acids undergo a number of useful reactions that do not require transition-metal catalysis, particularly those involving electrophilic ipso-substitutions by carbon electrophiles. The Petasis reaction involves ip,y(9-replacement of boron under Mannich-like conditions and is successful with electron-rich heterocyclic boronic acids. A variety of quinolines and isoquinolines, activated by ethyl pyrocarbonate, have been used as the Mannich reagent . A Petasis reaction on indole 3-boronic acids under standard conditions was an efficient route to very high de a-indolylglycines. " ... 

Boronic Acids , Ed. Hall, D. G., Wiley-VCH, 2005 The Synthesis and applications of heterocyclic boronic acids , Tyrrell, E. and Brookes, R,... 

An extensive review of arylboronic acid chemistry in older literature was written by Lappert [177], while an excellent and comprehensive review of heterocyclic boronic acids chemistry was summarized by Tyrrell and Brookes [178]. Since the arylboronic acids and esters became an important chemical intermediates, a number of these substances can be purchased. However, they are still quite expensive materials. 

Interestingly, in 2006, Fu and coworkers [127] reported a similar Suzuki-Miyaura reaction of heterocyclic boronic acids with chloroarenes, bromoarenes, and iodoarenes. This group used the simple, low-cost phosphane, PCyj, in their reactions, and they achieved spectacular results, for example, they could react 3-pyridineboronic acid with 4-butylchlorobenzene with Pd2(dba)j (1 mol%)/PCy3(4.2 mol%)/K3PO /dioxane/water at 100 °C to give the 3-(4-butylphenyl)pyridine in a yield of 92%. An array of nitrogen heterocycles was studied. 

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