Using pyridine boronic acids

Palladium-catalyzed processes are perhaps the most important developments in heterocyclic chemistry since CHEC-II and certainly since the original GHEG. The intermediates are never isolated, but, nonetheless, are essential to the transformations. Oxidative insertions of palladium (or less often, nickel, or iron), especially into bromo- or iodoazines, or triflates (prepared from -ols or - or -ones), or alternatively, the use of pyridine boronic acids, boronates, stannanes, silanes, and organmetallic species such as Grignard and zinc derivatives, form the basis of these methodologies. 

Where a heterocyclic organometallic reagent is required, Grignard and zinc derivatives are often satisfactory complications sometimes attend the use of lithio derivatives. The use of boronic acids has become very popular on account of their clean reactions, general stability to air and water, and their compatibility with practically any functional group furan, thiophene, indole and pyridine boronic acids have all been used. " ... 

To avoid the aforementioned instability issues associated with the pyridine-boronic acid derivatives, at least in the context of DMG-containing systems, a general one-pot DoM-Suzuki-Miyaura cross-coupling procedure has been developed for the production of various functionalized azabiaryls. It takes advantage of the use of triisopropylborate as an in situ boron electrophile for LDA-mediated DoM (Table 14.8). Except for the electron-rich aryl bromides (entries 3, 6, and 9), reasonable yields of cross-coupling products are obtained [25aj. 

Lam et al. [23a] have also investigated the use of alkylboronk acids. Cydohexylboron-ic acid cross-couples with t-butylaniline in low yields (16% for TEA and 6% for pyridine) under standard conditions for 2 days at 70 °C in dichloroethane (Scheme 5.29). However, no reaction with phenols or anilines was observed using cyclopropyl-boronic acid [23a, cj. 

The first synthesis of sorbic acid was from crotonaldehyde [4170-30-3] and malonic acid [141-82-2] in pyridine in 32% yield (2,17,18)- The yield can be improved with the use of malonic acid salts (19). One of the first commercial methods involved the reaction of ketene and crotonaldehyde in the presence of boron trifluoride in ether at 0°C (20,21). A P-lactone (4) forms and then reacts with acid, giving a 70% yield. 

In recent years, a variety of aryl boronic acids are commercially available, albeit in some cases they may be expensive for large scale purposes. During our work in the mid-1990 s boronic acid (II) was not commercially available and so two different protocols were used to prepare this acid. The first approach involved the transmetallation with n-butyl lithium of aryl bromide (I) and trapping the lithio species generated with trialkyl borate followed by an acid quench. Aryl bromide (I) is easily prepared by reaction of o-bromobenzenesulfonyl chloride with 2-propanol in the presence of pyridine as a base. The second approach was a directed metallation of isopropyl ester of benzene sulfonic acid (VII), to generate the same lithio species and reaction with trialkyl borate. The sulfonyl ester is prepared by reaction of 2-propanol with benzenesulfonyl chloride. From a long-term strategy the latter approach is... 

An interesting iridium-catalysed 5-CH boronation of 2,3-dimethylpyrazine was reported incidentally in a paper mainly devoted to the reaction of pyridines. The product 89 was used in a Suzuki coupling <06AG(I)489>. Selective mono coupling of 2,6-dichloropyrazine with boronic acids, followed by amine displacement of the second chlorine has been used to prepare potential anti-cancer compounds <06JMC407>. A full paper has been published on the chelation-driven selective Suzuki coupling of the pyridinium ylides 90 <06TL6457>. 

A potential way to avoid the formation of undesired side products, like in 7.2., is the use of such boron compounds that have only one transferable group. In most cases boronic acids are the compounds of choice, as they are easy to prepare, insensitive to moisture and air, and usually form crystalline solids. In certain cases, however the transmetalation of the heteroaryl group might be hindered by the formation of stable hydrogen bonded complexes. In such cases the use of a boronate ester, such as in equation 7.4., provides better yields. For example pyridine-2-boronic acid dimethylester coupled readily with a bromoquinoline derivative under conditions similar to 7.3. (potassium hydroxide was used as base and tetrabutylammonium bromide as phase transfer catalyst).6... 

Finally, the remarkably simple solution came from Evans et al. [21a] and researchers of DuPont [21b] simultaneously. Their method allows the coupling of structurally and electronically diverse phenols and aryl boronic acids in the presence of copper]11) acetate, trie-thylamine or pyridine, and molecular sieves at ambient temperature (Scheme 5). Even phenolic amino acid derivatives react smoothly without racemization. The only limitation has been observed when using orfho-heteroatom substituted boronic acids which resulted in lower product yields. The initial step in the proposed pathway (Scheme 6) is the trans-metallation of the boronic acid residue with the copper salt. 

Formaldehyde polymerizes by both anionic and cationic mechanisms. Strong acids are needed to initiate cationic polymerization and anionic polymerization is initiated by relatively weak bases (e.g., pyridine). Boron trifluoride (BF3) or other Lewis acids are used to promote polymerization where trioxane is the raw material. 

By analogy with pyridin-2-ylboronic acid, the azine boronic acids with the boron a to nitrogen would be expected to be relatively unstable. Pyrimidine-5-boronic acids have been quite widely used and pyridazine-... 

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