Dehydrogenative heteroarenes

Alkyl groups attached to aromatic rings are oxidized more readily than the ring in alkaline media. Complete oxidation to benzoic acids usually occurs with nonspecific oxidants such as KMnO, but activated tertiary carbon atoms can be oxidized to the corresponding alcohols (R. Stewart, 1965 D. Arndt, 1975). With mercury(ll) acetate, allyiic and benzylic oxidations are aJso possible. It is most widely used in the mild dehydrogenation of tertiary amines to give, enamines or heteroarenes (M. Shamma, 1970 H. Arzoumanian. 1971 A. Friedrich, 1975). 

Falck has recently reported dehydrogenative silylation of heteroarenes with triethylsilane (18) [97]. Coupling with the Si-H bond of triethylsilane, rather than the disilane Si-Si bond, in conjunction with the use of norbomene that presumably acts as a hydrogen acceptor, gives good yields with indoles, thiophenes, and furans, under relatively mild condition (80°C). Unlike the reaction shown in Scheme 7, silylation of indole did not require protection of the N-H group. 

More promising results were obtained for cross-dehydrogenative arylations with heteroarenes, since pronounced differences in reactivities gave improved chemos-electivity. In elegant studies it was shown that palladium-catalyzed oxidative arylations of indoles could be accomplished with unactivated arenes, which were used as solvents, in the presence of Cu(OAc)2 as terminal oxidant [130]. Notably, these reactions proceeded with high regioselectivities, leading predominantly to arylations at position C-3 (Scheme 9.51). 

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. 

Scheme 56 Rh- (a) and Cu-catalyzed (b) cross-dehydrogenative coupling of IH-indoles and 1 H-pyrroles with heteroarenes.

Scheme 60 Cu-mediated bidentate directed cross-dehydrogenative ortho-alkynylation of heteroarenes with terminal alkynes.

An interesting selectivity was uncovered in the direct cross-dehydrogenative coupUng between N-protected indoles and arenes (Scheme 11.40) [151]. Thus, whereas 2-arylated indoles 67a were preferentially obtained from N-acetyhndole in the presence of Cu(OAc)2, the reaction of N-pivalolyUndole with AgOAc led to 67b, with excellent selectivities. The reason for this C-2/C-3 selectivity is most likely due to the formation of higher-order palladium clusters or paUadium/copper clusters under the different reaction conditions. A related reaction between aryl-boronic acids and arenes or heteroarenes also proceeds under oxidative conditions with Pd(OAc)2 as catalyst [76]. A catalytic cycle initiated by an electrophihc attack of Pd(II) on the arene, followed by transmetallation with the aryl boronic acid and reductive elimination, was suggested. In this transformation, Cu(OAc)2 as stoichiometric oxidant could be replaced by O2, and for indoles, arylation at C-2 was observed. 

In parallel with the directed hydroarylation of olefins, a series of papers described the formation of ketones from heteroarenes, carbon monoxide, and an alkene. Moore first reported the reaction of CO and ethylene with pyridine at the position a to nitrogen to form a ketone (Equation 18.28). Related reactions at the less-hindered C-H bond in the 4-position of an A/-benzyl imidazole were also reported (Equation 18.29). - Reaction of CO and ethylene to form a ketone at the ortho C-H bond of a 2-arylpyridine or an N-Bu aromatic aldimine has also been reported (Equations 18.30 and 18.31). Reaction at an sp C-H bond of an N-2-pyridylpiperazine results in both alkylative carbonylation and dehydrogenation of the piperazine to form an a,p-unsaturated ketone (Equation 18.32). The proposed mechanism of the alkylative carbonylation reaction is shown in Scheme 18.6. This process is believed to occur by oxidative addition of the C-H bond, insertion of CO into the metal-heteroaryl linkage, insertion of olefin into the metal-acyl bond, and reductive elimination to form the new C-H bond in the product. 

The oxazoline-based double coordination strategy allows the otherwise difficult dehydrogenative C-N coupling of various heteroarenes and heteroarylamines to afford heteroatom-rich diarylamines of pharmaceutical importance (Eq. 32)... 

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). ... 

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

Pd-Catalyzed C-H Olefination of Heteroarenes Using Saturated Ketones. An oxidative dehydrogenation reaction between saturated ketones and heteroarenes was developed to provide... 

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... 

After the seminal work reported by Satoh and Miura in early 2011 on ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes [17], Ackermann demonstrated a ruthenium(ll)-catalyzed cross-dehydrogenative C-H bond alkenylations of benzoic acid derivatives with acrylonitrile or alkyl acrylates. Following the oxidative C—H bond alkenylation reaction, subsequent intramolecular oxa-Michael reaction occurred leading to phthalides in good yields (Eq. (7.12)) [18]. The reactions took place with water as an environmentally benign medium under mild conditions. 

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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