Pyridine-2-boronic acid

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... 

Pyridine 2-boronic acid is rather unstable (unlike the 3- and 4-isomers) and can only be isolated as esters, iV-substituted diethanolamine esters being the most stable. A possible rationale for this instability may be the parallel with the mechanism for the ready decarboxylation of pyridine 2-carboxylic acid via a transient ylide intermediate (8.11). 

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. 

Wide spectrum of fluorinated aromatic compounds has been synthesized by electrophilic fluorination of arylboronic acids. So 3-fluoropyridine (63) has been obtained from 3-pyridine boronic acids 86 and F-TEDA-BF4 in 72 % yield [76] (Scheme 32). 

Diethylboryl)pyridines and (3-Aminophenyl)boronic Acid Derivatives... 

Shinkai (65) exploited the boronic acid-diol motif mentioned above to self-assemble a polymer based on pyridine-magnesium porphyrin interactions. In this case, the evidence for polymerization comes from lightscattering experiments in dilute solution which yielded an average molecular weight of 109 g mol-1 for this system. 

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>. 

Pyridine-containing tricyclic compounds have been produced via a sequence consisting of a Suzuki reaction and a subsequent annulation. Gronowitz et al. coupled 2-formylthienyl-3-boronic acid with 3-amino-4-iodopyridine. The resulting adduct spontaneously condensed to yield thieno[2,3-c]-l,7-naphthyridine 59 [47]. They also synthesized thieno[3,4-c]-l,5-naphthyridine-9-oxide (60) in a similar fashion [48]. Neither the amino nor the N-oxide functional group was detrimental to the Suzuki reactions. 

A -Arylation of a wide range of NH substrates by reaction with boronic acid in the presence of cupric acetate and either triethylamine or pyridine at room temperature. The reaction works even for poorly nucleophilic substrates such as aryla-mide. 

Chloro-P-carboline (25) has served as a common intermediate in palladium-catalyzed cross-coupling reactions, offering easy access to several pyridine alkaloids. In Bracher s total synthesis of perlolyrine (27), a P-carboline alkaloid, the Suzuki reaction of 25 with 5-formylfuranyl-2-boronic acid (26) formed the C-C bond between the pyridine and the furan rings <92LA1315>. Reduction of the resulting Suzuki adduct with NaBIL subsequently... 

Pu reported the synthesis of axially chiral-conjugated polymer 82 bearing a chiral binaphthyl moiety in the main chain by the cross-coupling polymerization of chiral bifunctional boronic acid 80 with dibromide 81 (Equation (39)). The polymer is soluble in common organic solvents, such as THE, benzene, toluene, pyridine, chlorobenzene, dichloromethane, chloroform, and 1,2-dichloroethane. The polymer composed of racemic 80 was also synthesized, and the difference of characteristics was examined. Optically active polymer 82 was shown to enhance fluorescence quantum yield up to = 0.8 compared with the racemic 82 ( = 0.5). Morphologies of the optically active and racemic polymers were also compared with a systematic atomic-force microscopy (AEM). 

An alternate approach to the formation of pyridylboronic acids is the cross-coupling of a halopyridine with a diboronate ester (usually bis(pinacolato)diboron, 7.7.)9 The analogous reaction of 2-chloropyridine led to pyridine formation through protodeboronation. The product of the reaction, either after hydrolysis to the boronic acid or in the ester form, can be further reacted with another aryl halide to give a biaryl. In certain cases the reaction might also be carried out in a one-pot manner.10... 

Nguyen demonstrated the efficiency of the Suzuki coupling in a comparative study.21 The Suzuki coupling of pyridine 4-boronic acid with a... 

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