Direct C-H arylation

The direct arylation, with substitution of hydrogen, mainly of electron-rich heterocycles, such as mono- and di-hetero 5-membered rings, by reaction with aryP or alkenyl halides, is a very useful supplement to cross coupling, eliminating the need for the preparation of an organometallic partner. 

Both palladium and rhodium are effective catalysts, but the rhodium reactions seem to be more subject to steric effects. The reaction proceeds via a catalytic cycle similar to cross coupling, except that the formation of the diorgano(palladium) is brought about by electrophilic attack by the arylpalladium halide, rather than a transmetallation reaction, hence the need for electron-rich systems. The equivalent alkynylation can also be carried out using haloalkynes.  

It is significant that these types of reaction may be easier than standard electrophilic substitutions in 

3-azoles, reflecting the different nature of electrophilic metal cations compared to simple electrophiles, such as bromine. 

Oxazoles can be arylated at either C-2 or C-5, the method shown being notable for the use of water as solvent. 2-Substitution of 5-aryl oxazoles, using palladium acetate, can be carried out without an added ligand.  

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Aryl or diaryl substituted 3,4-(ethylenedioxy)thiophenes have been prepared by palladium-catalyzed direct C-H arylation of 3,4-(ethylenedioxy)thiophene itself with ary 1/he ternary 1 iodides/bromides <07TL539, 07T10363>, and direct coupling of... 

Scheme 57 Trauner s application of direct C-H arylation in the synthesis of ( )-rhazinilam...

Trauner applied a C-H bond activation approach to the synthesis of rhazinilam [81]. The synthetic power of direct C-H arylation on nucleophilic heteroarenes was demonstrated through formation of the strained 9-membered ring using intramolecular coupling to an unactivated pyrrole (Scheme 57). 

Scheme 25 Rh-catalyzed decarbonylative directed C-H arylation of arenes by Zhao and Yu [118]...

Scheme 30 Rh-catalyzed tandem addition/directed C-H arylation with NaBPh4 by Ueura et al. [123]...

Scheme 35 Rh-catalyzed directed C-H arylation with boronic adds by Vogler and Studer [127]...

Yanagisawa S, Sudo T, Noyori R, Itami K (2006) Direct C-H arylation of (Hetero)arenes with aryl iodides via rhodium catalysis. J Am Chem Soc 128 11748-11749... 

Vogler T, Studer A (2008) Oxidative coupling of arylboronic acids with arenes via Rh-catalyzed direct C-H arylation. Org. Lett. 10 129-131... 

Larivee A, Mousseau JJ, Charette AB (2008) Palladium-catalyzed direct C-H arylation of iV-iminopyridinium ylides application to the synthesis of ( )-anabasine. 1 Am Chem Soc 130 52-54... 

Scheme 7 Chlorine-induced regioselectivity for direct C-H arylation of N-methylindoles.

Scheme 16 On water C2 direct C-H arylation of NH-free indoles.

The use of arylboron reagents for direct C-H arylation involves, conceptually, more s)mthetic steps for their preparation, usually from the correspond haloarene. Furthermore, in the absence of haloarene an additional stoichiometric oxidant is necessary. However, these methods tend to involve milder and lower temperature conditions. 

In 2009, Larrosa and co-workers developed the first decarboxylative direct C-H arylation methodology that allowed the intermolecular coupling of a variety of electron-poor benzoic acids with N-pivaloylindoles (090L5506). Remarkably, this process occurs with high chemo- and regioselectivity in both coupling partners and led to the formation of C3-arylated products exclusively, with good yields (Scheme 45). The authors proposed... 

Lu, W, Kuwabara, J., Kanbara, T., 2012. Synthesis of 4,4 -dinonyl-2,2 -bithiazole-based copolymers via Pd-catalyzed direct C—H arylation. Polym. Chem. 3, 3217-3219. 

Scheme 14.54 Ni-catalysed direct C-H arylation and alkenylation of heteroarenes with organosilanes. Starting material wC6Hi3CH=CHSi(OEt)3 EjZ — 13 87. 1.0 mmol of CsF was used.

A palladium-catalyzed direct C-H arylation of various imidazo[2,l-l)] thiazoles 73 with a range of aryl bromides under microwave irradiation has been reported (140BC5773). 6-Phenyl-substituted imidazo[2,l-l ]thiazoles can be arylated regioselectively at C-5 to provide various tri-substituted imidazo[2,l-lt]thiazoles 74. 

Benzoyliminopyridinium ylide couples with phenylboronic acids at C-2 and C-4 (Scheme 37).This direct C-H arylation occurs at room temperature with an inexpensive catalyst silver nitrate with potassium persulfate. An excess of the phenylboronic acid was necessary for a high conversion additionally, using phenylboronic acid pinacol ester decreased the yield. Coupling a quinoline ylide also resulted in a mixture of C-2 and C-4 arylation, with a slight preference for the C-2. Alkylated pyridine ylides also coupled with a mixture of C-2 and C-4 arylations when possible (14SL1413). 

In the process of testing the scope of a new, mild, and efficient photoredox-catalyzed direct C-H arylation of unsubstituted, electron-deficient... 

The photocatalyzed Meerwein arylation Classic reaction of aryl diazonium salts, in particular, direct C—H arylation ofheteroarenes 13AG(E)4734. Prebiotic chemistry in eutectic solutions at the water—ice matrix 12CSR5404. 

Direct C—H arylation of (hetero)arenes under microwave irradiation 13CEJ1158. 

Direct C—H arylation of heteroarenes catalyzed by palladium/nitrogen-based ligand complexes 13AJ0624. 

Direct C—H arylation of 1,3-azoles takes predominant place at C5-H (due to the TT-nucleophUicity of the C5-position) along with double arylation at C5/C2-H (C2-H is the most acidic proton) (Figure 6a). A reHable C2—H—C5—H—C4—H reactivity order for 1,3-azole functionaHzation, including thiazoles and 1 H-imidazoles, was developed by Fagnou in 2008 by transforming the 1,3-azoles into their N-oxides prior to C—H activation... 

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