Pyrimidines 5-boronic acid

An alternative procedure using using 7-Pr2MgCl and /m-trimethylsilyborate was able to be performed at 0°C, and gave pyrimidine-5-boronic acid in 72% yield <2003SC795>. 

The synthesis of diazineboronic acids, for example pyrimidine 5-boronic acid (7.12.), is more challenging. Gronowitz succeeded in its preparation, by maintaining very low temperatures during the lithium-bromine exchange... 

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-... 

Mono- saccharide Phenyl- boronic acid 3-Carboxy- phenylboronic acid 3-Carboxy- benzoboroxole 3-Pyridinyl- boronic acid Pyrimidine- 5-boronic acid... 

An alternative synthesis of pyrimidine boronic acids, which avoids lithiation chemistry altogether, has been developed <2001SL266>. Thus, reaction of 2,4-dimethoxy-5-iodopyrimidine 352 with cedrane-8,9-diolborane 351 using catalytic amounts of Pd(PPh3)4 and Cul gave the intermediate boronate 353 which could be converted to the free boronic acid 354 in 83% yield by transesterification with diethanolamine, followed by treatment with acid (Scheme 3) <2001SL266>. 

Several pyrimidine boronic acid derivatives are now commercially available, and numerous other examples can be found in the literature, as their use in Suzuki and related cross-coupling chemistry is now well established . 

THF and then water to give the 2-methoxy-5-pyrimidine boronic acid 76 in 61% isolated... 

Quinazolines take part in the same types of reactions as pyrimidines, but because of their additional benzene ring, the products of these reactions may have the added feature of hindered rotation. An example of this is the synthesis of 2-phenyl-Quinazolinap by Guiry and co-workers <99TA2797>. Suzuki coupling of 4-chloro-2-phenylquinazoline (115) with boronic acids 116 led to 117 (R = OMe). These intermediates were parlayed into phosphinamines 117 (R = PPh2) and then subjected to chiral resolution to produce new chiral phosphinamine ligands for asymmetric catalysis. 

Cross-coupling reactions between organoboranes and heteroaryl halides are effectively catalyzed by Pd(0) in the presence of a base. Couplings in simple pyrimidines are illustrated by the reaction between 2-chloropyrimidine and 2- or 3-thiophene- and selenophene-boronic acids which give the corresponding 2-substituted pyrimidines (921) (Scheme 72). In 2,4-dichloro- or 2,4-dibromo-pyrimidine it is the 4-halo substituent which is the more reactive. 

Scheme 17 illustrates another fluorous sulfonate-based synthesis of library scaffolds. The tagged substrates were taken through aldol condensation and cycloaddition reactions to form the pyrimidine ring 18. The intermediates were then reacted with boronic acids for Suzuki reactions to form biaryl compounds 19 [31], reacted with HCO2H to give traceless detagged products 20 [34], or reacted with amine to form products 21 [33]. 

Boronic acids and boronate esters are usually prepared from lithium compounds, for example, from pyrimidines lithiated at the 5-position (Scheme 99). Boronates can also be obtained conveniently by Pd(0)-catalyzed couplings with, for example, pinacol diboron. 

Boronic acids and 9-BBN derivatives are often used as alkyl partners, but trifluoroborates may be more convenient and stable. Introduction of a protected aminoethyl chain, using a trifluoroborate, has substantial potential for bioactive molecules - the reaction shown below using 3-bromopyridine works equally well for pyrimidine (C-5), thiophene (C-2), and indole (C-5). ... 

Di-t-butoxy-pyrimidines are used as protected forms of uracil 5-boronic acids and 5-halides for Suzuki and Stille couplings, respectively, but suffer from the problem that an intermediate in their preparation (2,4-dichloro-5-bromopyrimidine) is highly allergenic. Unprotected 5-iodouracil will couple in some cases, but the Stille coupling of the 5-bromo-2,4-bis(trimethylsilyloxy) derivative is more consistently successful. ... 

As in the pyrimidine nucleosides discussed above, Pd-catalyzed coupling between a 2-iodo purine nucleoside and arylstannanes containing a boronic acid substituent in the aryl group proceeds chemoselectively at the C—Sn bond rather than at the C—B bond to give boron-containing nucleosides (177) (89JOC4734). 

The synthesis involved construction of a heteroaryl-aryl coupling, where the chloro-thiazole[5,4-i/]pyrimidine was coupled with p-fluorophenyl boronic acid in a Suzuki coupling. The reaction proceeded well even in the presence of a free amino group on the pyrimidine. 

Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethyl-amine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi-nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for NIO-vinylation. The boronic acids can be replaced with siloxanes or starmanes. The mild condition of this reaction is an advantage over Buchwald-Hartwig s Pd-catalyzed cross-coupling. The Chan-Lam C-X bond cross-coupling reaction is complementary to Suzuki-Miyaura s C-C bond cross-coupling reaction. 

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