Direct and selective functionalization of inert carbon-hydrogen (C−H) bonds is one of the most powerful approach for the construction of complex organic molecules.1,2 This approach, facilitated by various transition metals, has led to organic C−H bonds viewed as dormant synthetic equivalents of many reactive functional groups. The installation of new functionality otherwise none existed previously, has led to the construction of complex molecular architecture. While various transition metal catalysts have been employed for this purpose, palladium-catalyzed reactions are especially effective and thus have attracted much attention to construct diverse array of C−C or C−X (X = hetero atoms) bonds in the plethora of synthetic transformations.3 In this context Pd- catalyzed substrate-directed C−H functionalizations are privileged due to its preferential ortho directed chelation of Pd catalyst via the assiatance of various N or O donor atoms containing substrates,4 which assist the cyclometallation step and thus the regioselective functionalizations.
Various directing group containing substrates have been well explored toward palladium catalyzed oxidative C−−−−O bond formation, in particular o-acetoxylation, o- benzoxylation, o-alkoxylation and o-hydroxylation.5
IIA.2. Strategies for ortho C− − −O Bond Formation −
Representative examples pertaining to various forms of C−O bond formations are discussed below.
C–H Acetoxylation
Sanford group reported the first example of ligand-directed sp2 C−H bond oxygenation using PhI(OAc)2 as a stoichiometric oxidant in combination with catalytic Pd(OAc)2 (Scheme IIA.2.1).6a Other nitrogen-based directing groups, including imines, oxime ethers, azobenzene derivatives, and nitrogen heterocycles (e.g., pyrazoles and isoxazolines) and even amides were also effective. Other hypervalent iodine oxidants or peroxide oxidants have also been utilized towards acetoxylation reactions.6b-c
Scheme IIA.2.1. Pd-catalyzed sp2 C−H acetoxylation of 2-phenylpyridines
The same group also reported a Pd-catalyzed ligand-directed sp3 C−H bond oxygenation using PhI(OAc)2 as the terminal oxidant (Scheme IIA.2.2).6a,d Oxime ether and pyridine directing groups could be utilized for these transformations.6a,d
Scheme IIA.2.2. Pd-catalyzed sp3 C−H acetoxylation of ketoxime ethers
C–H Alkoxylation
Gooβen group demostrated a regiospecific Cu(II) catalyzed ortho-alkoxylation of aromatic carboxylates with concomitant decarboxylation (Scheme IIA.2.3).7 This protocol gives access to the important substrate class of aromatic ethers from widely available carboxylic acids.
Scheme IIA.2.3. Cu-catalyzed ortho-alkoxylation of arylcarboxylates
A number of Pd-catalyzed ortho sp2 C−H alkoxylation protocols are reported for various directing arenes viz. 2-arylpyridines, 2-aryloxypyridines, arylnitriles, arylamides, azoles, sulfoximines, O-methyl aryl oximes etc. (Scheme IIA.2.4).8 The
use of suitable oxidants (such as oxone, persulfate (S2O82-) or hypervalent iodine species) in combination with palladium catalyst and alcholoic solvent (ROH) are the crucial factors for the ortho selective C−H alkoxylation of various directing arenes.
Scheme IIA.2.4. Pd-catalyzed o-alkoxylation of directing arenes
Recently a number of Pd and Cu-catalyzed ortho sp2 and sp3 C−H alkoxylations by the assistance of bidentate chelating systems such as picolinamide9a, N-(1-methyl-1- (pyridin-2-yl)ethyl)amides9b, 8-aminoquinoline,9c pyridine-N-oxide9d and S-methyl-S- 2-pyridyl-sulfoximine (MPyS)9e (Scheme IIA.2.5) appeared in literature.
Scheme IIA.2.5. Ortho C−H alkoxylation using bidentate chelation
C–H Benzoxylation
Sanford et al. reported a palladium catalyzed o-benzoxylation of 2-phenylpyridines using benzoate iodonium salts as the ArCOO− surrogates. (Scheme IIA.2.6).10a Later, Shi group developed a similar palladium catalyzed o-benzoxylation of ketoxime ether via the in situ generation of benzoate iodonium salts.10b
Cheng group has demonstrated the use of aromatic carboxylic acids as the ArCOO− source for o-benzoxylation of 2-arylpyridines using rhodium catalyst.11a The same group has shown that acid derivatives in the form of carboxylic acid salt,11b anhydride11c and acid chloride11d could be used for the similar purpose (Scheme IIA.2.7). Zhong group has also achieved an oxidative o-benzoxylation of 2- phenylpyridines with aromatic carboxylic acids under ligand-free conditions using palladium catalyst along with copper and silver salts as additives.11e Aryl acylperoxides has also been found to be an effective benzoxy surrogate as illustrated by Yu group in a palladium catalyzed o-benzoxylation of 2-phenylpyridines.11f Pertinent to the o- benzoxylation in substrates possessing other directing groups, very recently Jeganmohan et. al. have reported a ruthenium catalyzed o-benzoxylation of acetanildes12a and benzamides12b using aryl carboxylic acids as coupling partners (Scheme IIA.2.7).
+
Scheme IIA.2.7. o-Benzoxylation of directing arenes using carboxylic acid derivatives Very recently our group13 has developed Cu(II)-catalyzed protocols for the o- benzoxylation of 2-phenylpyridine using terminal alkenes / alkynes and benzylamines as the benzoxy surrogates (Scheme IIA.2.8).
Scheme IIA.2.8. o-Benzoxylation of 2-phenylpyridines via sp2 C−H bond cleavage
C–H Hydroxylation
Yu group achieved a highly selective Pd-catalyzed ortho-hydroxylation of potassium benzoates via activation of dioxygen giving synthetically useful salicyclic acid derivatives (Scheme IIA.2.9).14a Apart from this; the same group has also
described a Cu-catalyzed ortho-hydroxylation of 2-arylpyridines which goes via acetoxylation/hydrolysis sequence.14b
Scheme IIA.2.9. Pd-catalyzed ortho-hydroxylation of arylcarboxylic acids In recent times tremendous progress has taken place in the substrate-directed hydroxylation of sp2 C−H bonds in arenes and heteroarenes using readily accessible ruthenium catalysts.15 Rao group has developed an ester directed o-hydroxylation using [RuCl2(p-cymene)]2 as the precatalyst and K2S2O8 or selectflour as the oxidant.15a Ackermann et al. have employed [RuCl2(p-cymene)]2, as well as other ruthenium complexes such as ruthenium(II)biscarboxylate complex [Ru(O2CMes)2(p- cymene)],15b-c or inexpensive [RuCl3, nH2O] as the catalyst in combination with (diacetoxyiodo)benzene [PhI(OAc)2] as the oxidant (Scheme IIA.2.10) for o- hydroxylation. For this chelation-assisted o-hydroxylation process the solvent mixture comprising of TFA and TFAA was found to be critical for the successful hydroxylation of various substrates.15
Scheme IIA.2.10. Ru(II)-catalyzed o-hydroxylation of weak directing arenes Jiao et al. recently developed a PdCl2 and N-hydroxyphthalimide co-catalyzed protocol for the sp2 C−H hydroxylation of 2-phenylpyridine using molecular oxygen (O2) as the sole oxidant source (Scheme IIA.2.11).16
Scheme IIA.2.11. o-Hydroxylation of 2-phenylpyridine using molecular oxygen