Heterocyclic boronates

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,... 

For the last four decades, there has been an exponential increase in the synthesis and usage of a number of organic and inorganic boron compounds in industry and academia. Due to the explosive growth of heterocyclic boron-containing compounds, this topic is covered as a separate chapter here. Previously, the subject of this chapter was covered in a subsection of Chapter 4.24 in CHEC-II(1996) (Sections 4.24.1.3.6 and 4.24.1.3.7). This chapter covers as much literature as possible, but the space restraints did not permit a comprehensive coverage of all literature. 

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

Trimethylamine N-oxide, either anhydrous or as its readily available dihydrate, smoothly oxidizes a wide variety of alkyl, cycloalkyl, aryl and heterocyclic boron derivatives to the corresponding oiganyl-oxyboranes (equation 22) which, in Ae case of the dihydrate, are hydrolyzed in the reaction mixture. Anhydrous trimediylamine N-oxide is simply prepared and this reagent must be used for the oxidation of a enylboranes if prior hydrolysis is not to compete with oxidation. > Alkynylboranes are not oxidized by trimethylamine N-oxide. ... 

There are no publications concerning the reaction of nitroarenes with organoboranes. The only known reaction, is the electrolysis of trialkylboranes in nitro methane in the presence of Rj NX salts, which leads to higher nitroalkanes.12 The reaction of RjB with NO, which proceeds by a radical mechanism, has been used for the preparation of hydroxylamine derivatives (RaNOH), heterocyclic boron derivatives or alkylamines (see ref.1, p. 283.)... 

Boron-containing Heterocycles.—The enthalpies of adduct formation between pyridine, 2-picoline, 4-picoline, or 2,4,6-collidine and a number of heterocyclic boron derivatives (2-Br- or 2-organo-l,3,2-dihetero-borolans, -borinans, and -boroles) have been measured.282 The presence of Br greatly increases the Lewis acidity of the B atom. 

Syntheses and applications of heterocyclic boronic acids 03S469. 

Both enantiomeric (R)- and (S)-oxazaborolidines are available so it is possible to obtain at will either enantiomeric alcohol. The selectivity depends upon the geometry of the complex formed by coordination of the carbonyl oxygen to the Lewis acidic heterocyclic boron atom, complex 3.72 being favored. The catalytic cycle is shown in Figure 3.25. 

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. " ... 

A large number of heterocyclic boronates and, to a lesser degree, stannanes are available conunercially. Included in the suppliers lists are many compounds, the preparations and properties of which do not appear in the literature. They are often noted in papers just as reagents for syntheses of libraries for biological testing and, although this may be a practical approach, it is scientifically unsatisfactory because there is no trail of characterization, particularly as some of these compounds, for example azine a-boronates, are significant from a theoretical viewpoint. 

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

B n.m.r. spectra of heterocyclic boron compounds containing B—or B—O bonds are inconsistent with their having aromatic character. 

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. 

The Fu group [42a] has also successfiiUy extended their catalytic system to various heterocyclic boronic adds (Scheme 2.10). By applying a slightly modified procedure [42b], many pyridyl (63), pyrazolyl, pyrimidyl, indolyl, and pyrrolyl (64) boronic acids could be cross-coupled with aryl or heteroaryl chlorides to afford excellent yields of products. This method, however, is not suitable to 2-heterocyclic boronic adds due to the fadle protodeboronation associated with the latter class (see earlier discussion). In Organ s 2009 communication, two heteroaromatic boronic acids, 2-benzofuranyl and 3-furanyl boronic adds (leading to product 65), were shown to cross-couple effidently with heteroaromatic chlorides, indicating that the NHC catalyst can also be extended to the syntheses of various bisheterocycles [35b] (Scheme 2.10). 

The boron hydride-catalyzed exchange reaction is not limited to tri-organoboranes or boron heterocyclics. Boron trihalides readily exchange with organoboranes at low temperatures (12). Reaction of BCI3 with 1,4-... 

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. 

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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