Heteroarenes oxidative cross-coupling

Scheme 58 Oxidative cross-coupling of N-protected indoles with N-heteroarenes.

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

Afterwards, Antonchick and coworkers [105] successfully extended this methodology to the oxidative cross coupling of heteroarenes and simple unfunctionalized alkanes (Scheme 40 (1)). The new C(sp )-C(sp ) bond formation occurred selectively at the electron-deficient site of the arene. The reaction was... 

The groups of Hu and You reported a remarkable palladium-catalyzed oxidative cross-coupling of Af-containing heteroarenes 62 with diversely substituted thiophenes 47 to afford products 63A-D (Scheme 10.19). The Af-containing heteroarenes included electron-rich heterocycles such as xanthines and azoles as weU as electron-poor heterocycles such as pyridine IV-oxides. In cases where heteroarenes demonstrated sluggish reactivity, CuBr was used as an additive to assist C—H bond activation. A computational study provided support for a two-fold C—H activation pathway via a CMD mechanism. 

C2-arylated thiazolopyrimidines can be synthesized via a Pd-catalyzed C-H oxidative cross-coupling with heteroarenes (eq 21). ... 

In 2011, Zhang and co-workers developed an efficient CuBr-catalyzed oxidative cross-coupling of iV//-dimethylanilines and heteroarenes to give N-containing heterocyclic compounds under mild conditions. In this transformation, they employed the environmentally benign molecular o g gen as the oxidant instead of tert-butyl hydroperoxide (TBHP) (Scheme 3.9). 

Scheme 17,46 Oxidative C-H/C-H cross-coupling of heteroarenes and arenes by Fagnou and DeBoef.

Cross-coupling. Heteroarenes, such as 1,3,4-oxadiazole and oxazole, efficiently undergo a copper(II) chloride-mediated oxidative coupling with terminal alkynes (eq 34). Electron-rich alkynes effectively coupled with 2-phenyl-1,3,4-oxadiazole, although electron-deficient substrates led to a decreased yield. The 1,3,4-oxadiazoles with various substituents at the 2-position were also suitable substrates, but the slow addition of terminal alkynes was essential to avoid undesired diyne formation. The desired 2-alkynyl-5-aryloxazoles were obtained in DMSO at 150 °C. 

Oxidative and Dehydrogenative C-H Cross-couplings. 2-Formylthiophene was used as a coupling partner with NMI in a Pd(II)-catalyzed, Cu-mediated oxidative C-H cross-coupling, forming the heteroarene in modest yield with some diarylated product (eq 71). ... 

Silver(I) carbonate functioned as an oxidant in combination with TBAI to provide optimal yields. Pivalic acid was superior to pyridine as an additive. Thiazole, pyrazole, thiophene, and pyrrole substrates could be cross-coupled however, heteroarenes bearing electron-donating substituents afforded better yields compared with electron-withdrawing groups. The reactions proceeded in high regioselectivity at the C2/C5 position. 

Dehydrogenative Cross-coupling of Heteroarenes. Phenan-throline derivatives can be directly arylated via an oxidative C-H/C-H cross-coupling process (eq 40)... 

A dehydrogenative cross-coupling between pyridines or five-membered heteroarenes with secondary phosphites has recently been developed (Schemes 4.251 and 4.252) [406]. The approach used silver nitrate as the promoter and K S Og as an oxidant. When the... 

The first cross-dehydrogenative intermolecular arylation of a heteroarene with an arene was reported by Fagnou in 2007. N-acetyl-lH-indoles were coupled with simple arenes and selective C3-arylation was obtained (88 89) in the presence of Pd(TFA)2 as catalyst in combination with superstoichiometric Cu(OAc)2 as terminal oxidant (Scheme 40) (2007SCI1172). The N-acetyl group proved to be crucial as no reaction product was achieved with IH-indoles, furthermore N-methyl-lH-indoles gave only self-dimerized products. 

Ruthenium- and rhodium-catalytic systems for the direct cross-dehydrogenative coupling (CDC) of acrylamides with electron-deficient alkenes forming (Z, )-dienamides using copper(II) acetate as the oxidant has been developed. Both methods exhibit wide functional group compatibility and substrate flexibility. It is proposed that the reaction is initiated by cyclometalation of acrylamide by amide-directing C-H bond activation. Coordination of the alkene to the metal centre, followed by insertion of the carbon-carbon double bond, forms a seven-membered ruthacycle or rhodacycle species. Subsequent -elimination occurs to afford the desired (Z, )-dienamide. A CDC between two heteroarenes is effected with copper(II) acetate in the absence... 

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