Heteroaryl compounds

In this section, functionalized aryl and heteroaryl compounds prepared by arene-catalyzed lithiation will be considered. 

The imidoyl chloride moiety of 5-chloro-l-alkyl-1,4-benzodiazepin-2-ones participates in Pd-catalyzed, Suzuki crosscoupling reactions, reacting with a range of functionalized aromatic boronic acids to provide an efficient and versatile approach to 5-aryl and 5-heteroaryl compounds (Scheme 19) <2003JOC2844>. This chemistry readily extends to 3-amino-substituted compounds that are orally bioavailable inhibitors of the aspartyl protease 7-secretase <2003BML4143>. 

Likewise, 2-perfluoroalkyl-substituted pyrroles were obtained on reaction of perfluoroalkyl iodides and pyrroles in the presence of stoichiometric amounts of copper (87MI3). Polytrifluoromethylation can be achieved by the same methodology with polyiodinated aryl and heteroaryl compounds (92T189) (Scheme 16). 

Fig. 1. nC-NMR signals for some heteroaryl boranes. Numbers in parentheses refer to 13C chemical shifts relative to the parent heteroaryl compound. 

An interesting difference between the homoaryl and heteroaryl compounds is found in the reaction of 2-(tributylstannyl)-furan and -thiophene towards benzyhydryl cations.115 Whereas homoarylstannanes appear always to undergo ipso attack by electrophiles, the relative reactivities at the 2 (ipso) and 5 position in these two hetero-arenes are shown in Scheme 7-2 at both positions the reactivity is increased, but the effect is much larger at the 5-position. If C-Sn hyperconjugation is important in stabilising the Wheland intermediate, this unusual regioselectivity might be taken to imply that here there is an early transition state in which such an effect would be less important. 

The 5-bromo derivative 136 was the key starting material for the preparation of both classes of compounds. It was obtained from 135 (R = H) by addition of bromine to the C4-C5 double bond followed by ehmination of HBr, which can be spontaneous or induced by TEA. Stdle reaction on 136 (BusSnR, (Ph3P)2BnClPd) performed in toluene afforded the vinyl compoimd 137 (70%), the ethenyl derivative 138 (86%), and the aryl or heteroaryl compounds 139 (45-70%). Isothiazoles 140 fimctionahsed at C-5 with an isoxa-zoline ring were prepared by a regioselective cycloaddition reaction starting from the vinyl derivative 137 and nitrile oxides [46]. 

A number of ligand coupling reactions involving the treatment of an heteroaryllithium reagent with triphenylsulfonium salts leading to phenyl-heteroaryl compounds [(14) - (17) for example] have also... 

Direct coupling of aryl with heteroaryl compounds works well with o-CI and o-MeO groups on the phenylboronic acid in coupling with isoquinolines or coumarins. In the first case 271 it was... 

Optimization efforts with the goal of obtaining a minimum ten-fold improvement in both the virology and PK profiles over BMS-488043 (9) ultimately identified the C-7 position in the 6-azaindole series as the optimal position to achieve the intended goals. Certain C-7 amides and heteroaryl compounds provided enhanced potency and ultimately led to the development of coherent SAR [62, 63,... 

Phosphonation. Heteroaryl compounds (furans, pyrroles, thiazoles,...) undergo Mn(III)-mediated regioselective phosphonation with HP(0)(0Me)2. 

Schove, L. Ramnarayan, K. Yalamoori, V. Chan, M. F. Balaji, V. N. Aryl and heteroaryl compounds useful as fibroblast growth factor antagonists. PCT Int. Appl. WO 2000030632, 2000 Chem. Abstr. 2000,133, XlllC... 

A new method for direct phosphonylation of thiazoles, furans and pyrroles has been introduced. Thus heteroaryl compounds (138) reacted with dimethyl or diethyl phosphites and Mn(OAc)3 2H2O under mild conditions to give phosphonated products (139) in high yield and good regioselectivity (Scheme 49). ... 

Among the extensive studies for the preparation of heteroaryl compounds, organometallic reagents are frequently used and mainly prepared from metal-halogen exchange reactions or the metathesis of the corresponding organolithium... 

Burkholder C, Dolbier WR Jr, Medebielle M (1998) Tetrakis(dimethylamino)ethylene as a useful reductant of some bromodifluoromethyl heterocycles. Application to the synthesis of new gem-difluorinated heteroarylated compounds. J Org Chem 63 5385-5394... 

Scheme 41 Aryl-heteroaryl compounds via Suzuki coupling...

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