3- pyridyl boronic acid

The disclosure of a one-pot directed ortho metalation-boronation and Suzuki-Miyaura cross-coupling of derivatized pyridines 44 to give substituted azabiaryls 45 provided an excellent protocol for the in situ utilization of pyridyl boronic acids whose isolation is known to be difficult <07JOC1588>. The disclosed method relies on the in situ compatibility of LDA and B(Oz-Pr)3 and proceeds in good to excellent yields for the multi-step process. The report details a comprehensive survey of pyridyl boronates and is expected to be of considerable value in the synthesis of bioactive molecules. 

Coupling of 2-bromo-5-aminopyrazine (64) with 2-methoxy-4-pyridyl boronic acid... 

Pyridyl boronic acids (and pyrazines, pyridazines and pynimadines... 

Vinyl boronic acids were among the most reactive boronic acids used in the Petasis borono Man-nich reaction, but aryl boronic acids and heterocyclic derivatives (thienyl and pyridyl boronic acids, for instance) can also be used [54]. Mechanistically, this three-component reaction type is characterized by a complex equilibrium among all the three components involved, and several intermediates are formed, including a reactive imine (Scheme 6.39). 

One of the most reliable methods for the construction of an oligoheteroarene structure is the transition-metal-catalyzed cross-coupling reaction [26]. However, a problem to be overcome remains in the cross-coupling. The installation of a metal group into heteroaromatic compounds is often dififlcult because of problems with the stability of the resulting heteroaromatic metal reagent [27]. For example, 2-pyridyl boronic acid and its esters are easily decomposed by proton [28]. In addition to this problem with stability, the transmetallation of an electron-deficient heteroaromatic boron reagent to palladium is relatively slow [29]. 

FIGURE 8. Cobaloximes have been shown to form boronate esters with pyridyl boronic acids to produce (a) a dimeric molecular box, (b) a molecular parallelogram, and (c) trimeric assemblies... 

FIGURE 12. Coordinative linear polymers based on boronate ester formation result from (a) ditopic coordination of pyridyl boronic acids to bis-diol functionalized porphyrins and (b) through coordinative interactions between rhodoximes and 3-aminoboronic acid. 

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)quinoline (72) from 3-bromoquinoline (70) and 3-pyridylboronic acid (71) (91JOC6787) and 3-phenyl-quinoline 75 from substituted 3,7-dibromoquinoline 73 and (2-pivaloylaminophenyl)boronic acid 74 (95SC4011). Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the... 

A similar approach was taken for the synthesis of 45 by Miyaura. " Shaughnessy and Booth synthesized the water-soluble alkylphosphine 46, and found it to provide very active palladium catalysts for the reaction of aryl bromides or chlorides with boronic acids. The more sterically demanding ligand 47 was shown to promote the reactions of aryl chlorides with better results than 46. Najera and co-workers recently reported on the synthesis of di(2-pyridyl)-methylamine-palladium dichloride complexes 48a and 48b, and their use in the coupling of a variety of electrophiles (aryl bromides or chlorides, allyl chlorides, acetates or carbonates) with alkyl- or arylboronic acids very low catalyst loadings at Palladium-oxime catalysts 8a and 8b) have also been developed. In conjunction with... 

The unsubstituted pyrrole-2-boronic acid 93 was coupled with pyridyl bromide 94 on a Wang resin to afford nicotinic acid derivative 95 after cleavage [69]. 

Buchwald observed that using solubilizing functionality on the phosphine ligands allowed the Suzuki reaction to be executed under aqueous conditions [57]. This also obviated the need to protect free amino groups as no metal chelation was observed. Thus pyridyl derivative 164 was cross-coupled with boronic acid 165 using the modified ligand 166 to afford 167 in excellent yield. 

Chemistry conceptually similar to that described for tamoxifen analogs 218 has been applied to the synthesis of CDP840 222, a phosphodiesterase (PDE) IV inhibitor for the treatment of asthma [78]. In combination with the Liebeskind-variation of the Suzuki reaction, thiopyrimidine ether 220 was cross-coupled to pyridyl-4-boronic acid 210 to afford 221. Catalytic hydrogenation of the olefin gave rise to 222. 

Most of the mechanistic work on this reaction has been devoted to determining the role of the base. Its most obvious function would be to complex the Lewis-acidic boron reagent, rendering it nucleophilic and thus activating it toward transmetallation. However, Miyaura, Suzuki, and coworkers noted that an electron-rich tetracoordinate boronate complex was less reactive than a trivalent boronic ester.From this, they surmised that the role of the base was not to activate the boron toward transmetallation, but rather to transform the palladium halide intermediate to the hydroxide or alkoxide species, which would then be more reactive toward boron. However, in a mass spectrometry study of a reaction between a pyridyl halide substrate and an aryl boronic acid, Aliprantis and Canary saw no evidence of palladium hydroxide or alkoxide intermediates, despite observing signals in the mass spectra assignable to every other palladium intermediate of the proposed catalytic cycle. 

Ferrocene—1-(-4 pyridyl),l -boronic acid [Fe(7jTc5H4-4-C5H4N)(7jTC5H4-B(OH)2)] 55... 

The key step in the synthesis of CDP840 ( 108), a phosphodiesterase IV (PDE IV) inhibitor for the treatment of asthma included the Liebeskind variation of the Suzuki reaction i.e., the thiopyrimidine ether 106 was cross-coupled with pyridyl-4-boronic acid to afford 107. Catalytic hydrogenation of 107 then afforded racemic 108. 

Castanet and his team demonstrated a palladium-catalyzed carbonylative Suzuki reaction of pyridine halides in 2001. Under their conditions, pyridine halides reacted with aryl boronic acids to 2-pyridyl ketones in good yields (81-95 % Scheme 4.8). The proper choice of solvent, catalyst precursor, and CO pressure enabled the selective transformation of mono- and dihalopyridines. Later on, they... 

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). 

In 2007, Castanet reported an efficient carbonylative Suzuki reaction of pyridyl halides with different boronic acids using 50 bar of carbon monoxide. The catalyst used is a combination of Pd(OAc)2 and imidazolium salt precursors NHC-Cl. In all cases, carbonylated species 72 were obtained as the major products (Scheme 5.52). The best results were found with ligand precursor IMes-Cl, being also active in... 

B-Alkyl Suzuki coupling offers tremendous opportunities for one pot CTOSS-coupling between any alkene and aryl halides, as the intermediate alkylboranes are typically not isolated and can be used in situ for further cross-coupling. Some of the representative examples of this coupling include the synthesis of pyridyl alcohols 148 (Scheme 28.41), synthesis of alkyl arenes 149 (Scheme 28.42), and coupling of cyclopropyl boronic acid with aryl halides to obtain cyclopropyl arenes 153 (Scheme 28.43). ... 

Conceptually, this was first demonstrated using a metallated porphyrin that was functionalized with 2 diols (zinc dicatechol porphyrin) (Fig. 5). After addition of 3-pyridylboronic acid, absorption spectroscopy indicated that the pyridyl moiety was coordinated to the Zn-porphyrin. The observed affinity constant for this interaction, however, was more than 30 times what was expected for a simple pyridyl-Zn-porphyrin complex. It was, therefore, reasoned that the diols reacted with the boronic acids to afford the esters that would result in a cyclic structure (Fig. 5). Indeed, vapor phase osmometry (VPO) confirmed the 2 2 dimeric nature of the complex. Here the ester served as the key covalent linkage, though associated coordination was required between the metal and pyridine to create the cyclic structure. 

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