Cross-Dehydrogenative Arylations

The concentration of TFA impacts both the turnover number (TON) and the selectivity of these arylations. For example, the reaction of anisole with excess benzene affords a 1.3 1 ratio of the homo-coupled and cross-coupled products in the presence of 6.3 equivalents of TFA. Significantly higher selectivity for the cross-coupled product is observed with decreased amounts of TFA albeit with diminished efficiency (lower TON). The increased TON for B at higher [TFA] is in part due to the enhanced electrophilicity of the Pd species (presumably bearing a trifluoroacetate ligand) involved in the C—H activation of the limiting arene substrate. The formation of homo- and cross-coupled products is attributed to the similar reactivity of the two arenes (benzene and anisole) in the C—H activation step. 

SCHEME 24.19 General mechanism for CDC reactions using Strat y II. 

SCHEME 24.21 Site-selectivity of CDC between indoles and arenes. 

SCHEME 2A30 Effect of benzoquinone structure on CDC between 28 and 1,3-dimethoxybenzene. 

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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). 

Scheme 9.52 Palladium-catalyzed cross-dehydrogenative arylation of the indole 184 at position C-2.

Scheme 9.53 Palladium-catalyzed cross-dehydrogenative arylation.

Scheme 61 Pd-catalyzed cross-dehydrogenative arylation of 1-pivaloyl-1H-indoles via oxidant-controlled regioselectivity, AgOAc versus Cu(OAc)2 (Scheme 40).

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 40 Pd-catalyzed cross-dehydrogenative C3-arylation of W-acetyl-IH-indoles.

Scheme 45 Cu-mediated cross-dehydrogenative coupling of 2-aryl di)azines and (benz)-l,3-azoles.

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. 

The synthesis of a-acyloxy ethers (formation of C—O bonds) was achieved by the TBHP oxidation of a mixture of a carboxylic acid (R C02H, R =aryl, heteroaryl, alkyl) and an ether (R, R = alkyl, alkyl halide) in the presence of BU4NI as the catalyst. The transformation involved a cross-dehydrogenative coupling (CDC) reaction of the C-H bond. ... 

Zhao and Du s group [63] developed a metal-free cross-dehydrogenative coupling (CDC) of various 2-(A -arylamino)aldehydes 79 for direct aryl-aldehyde C (sp )-C(sp ) bond formation to provide a convenient approach for the synthesis of biologically important acridone derivatives 80 (Scheme 19). PIDA was used in combination with a substoichiometric amount of benzoyl peroxide as radical initiator for this oxidative intramolecular annulation reaction which presumably proceeds via the intermediacy of acyl radicals 81. 

Addition of vinyl and aryl groups Cope rearrangement Cross-dehydrogenative coupling Cycloaddition reaction... 

Prior to the concept of cross-dehydrogenative-coupling (CDC), Moritani and Fujiwara developed the oxidative formation of Heck-type reaction products directly from arenes and alkenes, instead of aryl halides and... 

The proposed iminium intermediate in the CDC-type allgmylation implies that other C-H based pronueleophiles, besides terminal allqmes, can also couple with an a-sp C-H bond of a nitrogen in amines via the same process. Thus, we examined eleetron-rieh arenes as one such nucleophile via a cross-dehydrogenative Friedel-Crafts type arylation. Indole derivatives were coupled with N-aryl-THIQs under the CuBr/TBHP system to produce the desired CDC reaction product in good-to-excellent yields (Scheme 1.9). It is worth noting that the reaction was not sensitive to moisture or air, and that the desired product was obtained in reasonable yield even when the reaction was... 

The groundbreaking work of Shue, de Vries and van Leeuwen others on oxidative olefinations and the contributions of Lu, Fagnou, DeBoef and others on direct arylations laid the foundation for the development of an impressive number of transition-metal-catalyzed selective cross-dehydrogenative sp C-H couplings. Notably, the Fujiwara-Moritani reaction is also commonly termed the oxidative Mizoroki-Heck reaction . Progress in this area has been extensively reviewed and will thus only be briefly mentioned here, notwithstanding their great importance. 

Efficient proeedures for the cross-dehydrogenative synthesis of aryl ketones have been introduced by complementing the radieal acylation with transition-metal-eatalyzed activation of aromatic C-H bonds. The first eross-dehydrogenative Pd-eatalyzed acylation of 2-phenylpyridines was developed independently by the groups of Chengf and Li. The latter demonstrated that various aliphatie, alicyclic and some aromatie aldehydes are smoothly converted in the presenee of 5 mol% of Pd(OAe)2 in combination with 1.5 equiv. of TBHP at 120 °C under an air atmosphere (Scheme 1.38). 

The ideal scenario would be to oxidatively couple two aryl C-H bonds and produce a new biaryl C-C bond. This coupling method, herein known as cross-dehydrogenative-coupling (CDC), requires no pre-functionalization steps and generates fewer by-products as waste (Scheme 6.1). 

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