C HAPTER I
I.5.3.1. Representative examples of directed CDC reactions
Ortho-arylation via Csp2−−H / C−− sp2−−−−H
Sanford et al. reported a Pd(II) catalyzed highly chemo and regioselective sp2 C−H arylation of directing arene benzo[h]quinoline using Ag2CO3 and p-benzoquinone as terminal oxidants. This transformation is proposed to proceed via two discrete C−H activation steps following the idea of directed CDC reactions (Scheme I.5.3.1.1).72 A variety of directing arene such as 2-arylpyridine, 1-arylpyrazole, 2-arylpyrimidine and 8- methylquinoline derivatives were all effective under this reaction condition providing
similar cross-coupled products. Directed Csp2−H / Csp2−H coupling was also applied to directing arenes such as indolines, arylguanidines for similar ortho arylations.73
Scheme I.5.3.1.1. Pd(II)-mediated direct biaryl coupling of benzo[h]quinoline
Later on Miura group achieved a Pd-free, Cu-mediated intermolecular direct Csp2−H / Csp2−H coupling of arylazines and azoles (Scheme I.5.3.1.2).74
Scheme I.5.3.1.2. Copper(II)-mediated biaryl coupling of 2-arylpyridines and azoles
Ortho alkylation via Csp2−−H / C−− sp3−−H −−
Li group have demonstrated a lone strategy for the substrate directed arene−alkane coupling of 2-arylpyridine or analogous substrates with inert cycloalkanes as the coupling partner in presence of Ru(II) catalyst in combination of di-tert-butylperoxide (DTBP) as oxidant (Scheme I.5.3.1.3).75
Scheme I.5.3.1.3. Ruthenium(II)-catalyzed ortho cycloalkylation of 2-phenylpyridine
Ortho alkenylation via Csp2−−H / C−− sp2−−−−H
Yu group developed a protocol for aerobic Pd(II)-catalyzed C−H olefination of phenylacetic acid using a amino acid ligand, Ac-Val-OH. This interesting protocol demonstrates the use of suitable amino acid ligand to achieve o-alkenylaion involving double C−H’s (Scheme I.5.3.1.4).76
Scheme I.5.3.1.4. Palladium(II)-catalyzed C−H olefination of phenylacetic acid Alkenylation via Csp3−−−−H / Csp2−−−−H
In addition to the sp2 C−H olefination, Yu group also developed an amide group assisted Pd(II)-catalyzed reaction for the direct olefination of sp3 C−H bonds (Scheme I.5.3.1.5).77a The reaction conditions could also be applied to promote olefination of cyclopropyl methylene C−H bonds and substrates containing α-hydrogens. Later, the same group applied this method for the generation of β-quaternary carbon centers.27 Recently they have also demonstrated monoselective γ-C−H olefination of aliphatic acids using a combination of a quinoline-based ligand and a weakly coordinating amide directing group.77b
Scheme I.5.3.1.5. Pd-catalyzed amide directed sp3 C−H alkenylation Ortho alkynylation via Csp2−−−−H / Csp−−−−H
Yu group recently reported a Cu(II)-promoted ortho-alkynylation of arenes and heteroarenes with terminal alkynes to prepare aryl alkynes (Scheme I.5.3.1.6).78 A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.
Scheme I.5.3.1.6. Copper(II)-catalyzed auxillary assisted alkynylation of arenes
Ortho alkoxylation via Csp2−−H / O−− sp3−−H −−
Daugulis group developed a method for auxiliary-assisted alkoxylation and phenoxylation of β-sp2 C−H bonds of benzoic acid derivatives and γ-sp2 C−H bonds of amine derivatives using aromatic or aliphatic alcohol as coupling partners and (CuOH)2CO3 as the catalyst (Scheme I.5.3.1.7).79
Scheme I.5.3.1.7. Copper(II)-catalyzed auxillary assisted sp2 C−H phenoxylation Ortho benzoxylation via Csp3−−H / O−− sp3−−−−H
Cheng group described a chelation-assisted Pd(II)-catalyzed acyloxylation of the benzyl sp3 C–H bond with carboxylic acid employing PhI(OAc)2 as a stoichiometric oxidant (Scheme I.5.3.1.8).80 This procedure tolerates a series of functional groups, providing the acyloxylated products in moderate to good yields.
dry toluene, air 120oC Pd(OAc)2(10 mol %)
PhI(OAc)2(1 equiv) +
N H
N O C
NO2
O NO2
O H
Scheme I.5.3.1.8. Palladium(II)-catalyzed benzoxylation of benzylic sp3 C–H bond Ortho amination via Csp2−−−−H / Nsp3−−−−H
Using aminoquinoline as directing axillary Daugulis and co-workers reported the C−H / N−H coupling between morpholines and carboxylic acid derivatives (Scheme I.5.3.1.9).81 The reaction is catalyzed by a dual CuII–AgI catalytic system using N-methylmorpholine oxide (NMO) as the terminal oxidant.
Scheme I.5.3.1.9. CDC amination of benzamides with aliphatic amines
Recently Yu group demonstrated a Cu(II)-mediated C−H amination of arenes with a variety of anilines (Scheme I.5.3.1.10).82a The exceptional compatibility of this amination with multiple heteroatoms present in both reactants renders this reaction highly valuable.
Scheme I.5.3.1.10. Copper(II)-catalyzed amide directed amination of arenes
Amination via Csp3−−H / N−− sp3−−−−H
Gaunt and his coworkers developed a Pd-catalyzed Csp3–H activation of aliphatic amines that proceeds through an unusual four-membered ring cyclopalladation pathway.
This intramolecular sp3 C−H chemistry described here leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into a synthetically versatile nitrogen heterocycle (Scheme I.5.3.1.11).82b
Scheme I.5.3.1.11. Amine directed Pd(II)-catalyzed intramolecular sp3 C−H amination Ortho amidation via Csp2−−H / N−− sp3−−H −−
CDC protocol on intermolecular C−N bond formation demonstrated by Che group via a Pd-catalyzed pyridine and oxime ether directed C−H amidation (Scheme I.5.3.1.12).83 In this system, Pd(OAc)2 served as the catalyst and a combination of K2S2O8 and NH2R was used to introduce the nitrogen functionality.
Scheme I.5.3.1.12. Ketoxime ether directed palladium(II)-catalyzed amidation of arenes
In 2010 Li and co-workers published o-amidaion of arylpyridines using acetanilides as
combination.84 Thereafter in 2011, Liu and his team published the condensation of phenone derivatives with sulfonamides using Pd(II) catalyst. This process requires two equivalents of non atom economical electrophilic fluoro-oxidant (Scheme I.5.3.1.13).85a
Scheme I.5.3.1.13. Keone direced amidation of phenones with sulfonamides
Amidation via Csp3−−−−H / Nsp3−−H −−
Using picolinamide as directing auxillary, Daugulis group developed first Pd(II) catalyzed intramolecular amidation of unactivated sp3 carbons. (Scheme I.5.3.1.14).85b Later on similar auxillary directed intramolecular sp3 C−H amidation methods demonstrated by Chen, Ge and Kanai.85c-g
Scheme I.5.3.1.14. Pd(II) catalyzed intramolecular sp3 C−H amidation Ortho sp2 C–H sulfenylation via Csp2−−−−H / Ssp3−−−−H
In 2006 Yu group has accomplished a Cu(II)-catalyzed direct sulfenylation at sp2 C−H of 2-arylpyridine using benzene thiol as the coupling partner (Scheme I.5.3.1.15).32b
Scheme I.5.3.1.15. Copper(II)-catalyzed ortho-thiolation of arenes
Sulfenylation via Csp3−−H / S−− sp3−−−−H
Recently, Shi group demonstrated the nickel-catalyzed 8-aminoquinoline directed thiolation /sulfenylation of C(sp3)−H bonds to form thioethers (Scheme I.5.1.3.16).45d
Scheme I.5.3.1.16. Ni(II)-catalyzed sp3 C−H sulfenylation Ortho sp2 C–H phosphorylation via CDC
Yu group has reported the first Pd(II)-catalyzed C−H phosphorylation of 2- arylpyridines using both H-phosphonates and diaryl phosphine oxides as suitable coupling partners for this reaction (Scheme I.5.3.1.17).86a Later on Murakami group reported a similar o-phosphorylation using N-directed substrates such as 2-phenylpyridines, quinolines, isoquinolines, benzo[h]quinolines and pyrimidines.86b
Scheme I.5.3.1.17. Palladium(II)-catalyzed C−H phosphorylation of 2-phenylpyridine
I.5.4. An array of exceptions: Reactions which are not included in the above three classes