Heteroaryl bromides

Leadbeater described the use of Ni(CN)2 for the microwave-assisted cyanation of (hetero)aryl bromides [81]. The use of 0.6equiv of Ni(CN)2 was found to be optimal. Unfortunately, the heteroaryl bromides reported in the study gave relatively low yields due to significant decomposition (Scheme 70). 

Hence, microwave irradiation in DMA for 12 min at 120 °C or 30 min at 140 °C, depending on the substrate, resulted in 20 or 21 in 90-96% yields, compared to yields around 50% and a 24 h reaction time for conventional heating. As can be seen in Eq. 2 in Fig. 5, two possibilities exist to connect the heteroaryl bromide part with the five-membered heterocycle (indicated by a and fi. Table 2) that results in a six-membered 2-pyridone ring. Still, a very high selectivity was obtained yielding the 2-pyridones 21, in which the new bond had been introduced at Ca. It should be noted that the obtained structures 20 and 21 represent heterocyclic derivatives of 2-quinolones rather than true 2-quinolones. 

An Alternative Synthesis of Aryl and Heteroaryl Bromides from Activated Hydroxy Compounds," Katritzky. A.R. Li, J. Stevens, C.V. Ager, D.J. Org. Prep. Proceed. Int., 1994, 26, 439... 

Based on the use of di-l-adamantyl-n-butylphosphine (cataCXium A) 1 as ligand, a general and efficient palladium-catalyzed formylation of aryl and heteroaryl bromides has been developed by Degussa AG... 

Scheme 8. Palladium-catalyzed carboxylations of aryl and heteroaryl bromides...

Klaus S, Neumann H, Zapf A, Striibmg D, Hiibner S, Almena J, Riermeier T, GroB P, Sarich M, Krahnert W-R, Rossen K, Beller M (2006) A general and efficient method for the formylation of aryl and heteroaryl bromides. Angew Chem Int Ed 45 154—156... 

In addition, commercially available phenyltrimethoxysilane has been successfully cross-coupled with heteroaryl bromides including both bromopyridines and bromothiophenes [105], Both 2-bromopyridine and 3-bromopyridine were coupled with phenyltrimethoxysilane to give the corresponding phenylpyridines in 76% and 62% yield, respectively. Employing phenyl tris(trifluoroethoxy)silane, a siloxane with electron-withdrawing groups, did not improve the yields. 

Remarkably, halogen-magnesium exchange can also be extended to aryl and heteroaryl bromides [24, 25], Thus, the functionalized aryl bromides 28 and 29 (Scheme 2.7) were converted, at 0 °C and at —30 °C, respectively, into the corresponding Grignard reagents. After treatment with CuCN, the copper derivative 30 and 31 were obtained. Subsequent treatment with typical electrophiles such as benzoyl bromide or allyl bromide furnished the products 32 and 33, in 70 and 80% yields. 

Pd°-Cata) vsed Reactions of Trimethylalvtohynytzuic Chloride with Arvl and Heteroaryl Bromides... 

TABLE 10. Bromine-magnesium exchange of heteroaryl bromides with BuMe2MgLi... 

Aryl- or heteroarylzinc species have been successfully synthesized from the corresponding aryl or heteroaryl bromides or chlorides in high yields, on the laboratory scale (10 mmoles of substrate). The use of cobalt as catalyst allowed the synthesis of organozinc reagents using the sacrificial anode process with a wide variety of solvents. 

Polystyrene-bound secondary aliphatic amines and /V-alkyl amino acids can be ally-lated by treatment with a diene and an aryl iodide or bromide in the presence of palla-dium(II) acetate (Entry 14, Table 10.3). As the diene, 1,3-, 1,4-, and 1,5-dienes can be used, and, besides aryl halides, heteroaryl bromides have also been successfully used [63], This remarkable reaction is likely to proceed via the formation of an aryl palladium complex, with subsequent insertion of an alkene into the C-Pd bond. The resulting organopalladium compound does not undergo ( -elimination (as in the Heck reaction), but isomerizes to an allyl palladium complex, which reacts with the amine to give the observed allyl amines. 

Benzyloxymethyl-5-(tributylstannyl)tetrazole is a useful reagent for conversion of aryl and heteroaryl bromides and iodides to 5-aryl- and 5-hctcroaryl-l //-tetrazoles 24. The reaction involves a Stille palladium-catalyzed, copper(l) iodide cocatalyzed cross-coupling and an iV-benzyloxymethyl deprotection step. The coupling was possible with electron-neutral and electron-poor substrates in yields ranging from 35% to 93% (Scheme 33) <2000TL2805>. 

Scheme 17 Palladium-catalyzed cyanation of a heteroaryl bromide into a heteroaryl nitrile...

Klapars and Buchwald developed a method for the conversion of heteroaryl bromides into the correspondng iodides using a catalyst system comprising Cul and a 1,2- or 1,3-diamine ligand. In this manner, 5-bromo-2-aminopyridine was converted to the iodopyridine 124 (Equation 43) <2002JA14844>. 

Benzyloxymethyl-5-(tributylstannyl)tetrazole 782 can be used for coupling with aryl- and heteroaryl bromides and iodides (Scheme 164) <2000TL2805>. 

Imidazole-containing compounds have been utilized as reagents for various synthetic transformations. A convenient access to substituted allyl enol carbonates was established through the reaction of ketone enolates with the complex of allyl l//-imidazole-l-carboxylates 74 and boron trifluoride etherate <07JOC9372>. Relatively mild and highly efficient Cul-catalyzed /V-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of ligands 75 and cesium carbonate <07JOC2737>. a, -Unsaturated 2-acyl imidazoles 76 are an alternative and practical class of dienophiles for the DNA-based catalytic asymmetric Diels-Alder reaction in... 

Overman and co-workers [75] prepared alkenyltins via a vinyl triflate/ditin coupling. Mitchell and Kwetkat developed a simple route to acyltrimethylstannanes [187], whereas Hitchcock et al. [ 188] carried out a three-component tandem coupling reaction by reacting a 2-pyridyl triflate, aryl or heteroaryl bromides, and hexamethylditin with Pd(PPh3)4 the presence of LiCl to give azabiai yls (Scheme 4-48). 

The first Pd-catalyzed carboamination and carboetherification reactions of y-amino or y-hydroxy alkenes with aryl halides were described by Wolfe in 2004 [ 100]. As shown below, treatment of these substrates with aryl or heteroaryl bromides in the presence of NaOfBu and a palladium catalyst provides substituted tetrahydrofuran or pyrrolidine products. 

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