Heterocyclic boronic acids, preparation

TBS and 1-TIPS indole-3-boronic acids, prepared in situ via halogen exchange, conple weU with a range of heterocyclic snbstrates. ... 

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

The Suzuki-Miyaura tactic carried out on solid support (Scheme 28) [52] provides routes to small libraries of condensed heterocycles. Thus, Merrifield resin with the LeznofF-linked bromobenzene derivative 78 undergoes cross-coupling under normal solution-phase conditions with boron pinacolate 79 or boronic acid 80, prepared by DoM, to afford phenan-thridines 81 or, via 82 and some manipulation, dibenzopyranones 83 in good yields and with high purities. The Stille solid-support reaction has also been successfully executed [53]. 

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. 

NMR experiments on the reactions of halophosphates esters with pyridine showed that equilibria involving the formation of pyridinium salts in these reactions are almost entirely shifted to the left for chloro- and bromo-phosphates and to the right for the corresponding iodophosphates. This explains dramatic differences in chemical reactivity between these compounds. Substituted medium-sized and large N-heterocycles (117) have been prepared via an extension of the Suzuki reaction involving the palladium-catalysed coupling of vinyl-phosphates (118) with aryl or heteroaryl boronic acids (Scheme 27). ... 

The use of trifluoroborate salts in couplings, which are very easily prepared from boronic acids by reaction with KHF2, is a useful variant of the Suzuki reaction. These salts have the advantage of enhanced (often considerably) stabihty compared to boronic acids and this is particularly notable for alkenyl compounds, which can be stored for a considerable time. The coupling conditions are very similar to those for boronates and are apphcable to a wide range of heterocyclic substrates, ... 

Lithio-benzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. ° Direct deprotonation of benzothiophenes follows the usual pattern for flve-membered heterocycles and takes place adjacent to the heteroatom,"" and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen the sequence below shows how this can be utilised to develop substituted benzothiophenes. 2-Lithiated reagents react with electrophiles for example with p-toluenesulfonyl cyanide, 2-cyano derivatives are produced and similarly, 2-trimethylstannylbenzofuran and -benzothiophene and benzofuran-2- and benzothiophene-2-boronic acids can be prepared. 

H-1,3,5-Oxathiazines. These new heterocycles have been prepared by the reaction of aliphatic aldehydes with thioamides in acetic acid containing 100% sulfuric acid. In one case boron trifluoride etherate in chloroform was used. ... 

The most general preparative method for silanes, stannanes, and boronic acids is the reaction of a heteroaryllithium with a chlorosilane, a chlorostannane, or with a borate ester,respectively. 3-Diethylborylpyridine can be similarly prepared by reaction of the lithiopyridine with triethylborane, followed by cleavage of an ethyl group with iodine this method does not work for electron-rich systems such as furan due to preferential cleavage of the heterocyclic group. Transmetallation reactions... 

These useful heterocycles were prepared originally by reaction of amino alcohols with BH3 THF or boronic acids, but these methods can require lengthy reaction times in the case of hindered pyrroiidines such as 1, (S)-2-(diphenylhydroxymcthyi)pyrrolidine. Reaction of 1 with a bis(trifluoroethyl)aikylboronate 2 at 110° for 30 minutes, generates the desired oxazaborolidine 3 in situ, which can be isoiated if desired in 95% yield. ... 

Numerous methods for the preparation of symmetrical and unsymmetrical diaryl- and hetaryliodo-nium organosulfonates have been developed. A common synthetic approach to unsymmetric diaryl-and hetaryl(aryl)iodonium tosylates (e.g 262, 264, 266 and 268) is based on the reactions of [hydroxy(tosyloxy)iodo]arenes with aryltrimethylsilanes 261 [198], aryltributylstannanes 263 [376], aryl-boronic acids 265 [377], or the appropriate heteroaromatic precursors 267 (Scheme 2.75) [378,379]. The reaction of HTIB with arylstannanes proceeds under milder conditions compared to arylsilanes and is applicable to a wide range of arenes with electron-withdrawing substituents. Arylboronic acids in general have some advantage over arylstannanes in the case of the electron-rich heterocyclic precursors [377]. 

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