C HAPTER I
I. A Sketch of Transition Metal Catalyzed CH Functionalizations
I.5. Modern Era of CH Functionalization
I.5.3.1. Representative Examples of Directed CDC Reactions
Li group has demonstrated an efficient cross-dehydrogenative coupling (CDC) between sp3C–H adjacent to nitrogen atom and H–P bond of dialkyl phosphonate using copper(I) salt as the catalyst and molecular oxygen as an oxidant. This methodology provides an easy access to biologically important α-aminophosphonates (Scheme I.5.2.5.2).64
Scheme I.5.2.5.2. Cu(I)-catalyzed Csp3–P bond formation via CDC I.5.3. Directing Group Assisted Cross-dehydrogenative Coupling
The directing group assisted and cross-dehydrogenative coupling (CDC) strategies are the two most elegant approach to selectively functionalize ortho C–H bonds to form C–C or C–X (X = heteroatom) bonds. The combinations of both installed new functional group(s) at the o-site of directing arenes are discussed below.
Ortho Alkylation
A novel CC bond formation based on the direct oxidative Csp2H/Csp3H coupling involving directing arenes and cycloalkanes has been developed by Li group in the presence of Ru(II)-catalyst and di-tert-butyl peroxide (DTBP) as the oxidant (Scheme I.5.3.1.2).67
Scheme I.5.3.1.2. Ruthenium(II)-catalyzed ortho cycloalkylation of 2-phenylpyridine
Ortho Alkenylation via Csp2H/Csp2H Functionalization
Yu and co-workers reported a aerobic Pd(II)-catalyzed CH olefination protocol of phenylacetic acid using an amino acid ligand. In the presence of mono-N-protected amino acids ligand the reaction rate is dramatically accelerate, providing o-alkenylaion via double CH’s activation (Scheme I.5.3.1.3).68
Scheme I.5.3.1.3. Palladium(II)-catalyzed CH olefination of phenylacetic acid In addition to the sp2 CH olefination, Yu group also developed an amide group assisted Pd(II)-catalyzed direct olefination of sp3 CH bonds of cyclopropyl methylene.69a Recently, they have also demonstrated selective mono γ-C−H olefination for the synthesis of unnatural chiral α-amino acids using a combination of a quinoline-based ligand and a weakly coordinating amide directing group.69b
Ortho Alkynylation via Csp2H/CspH Functionalization
An alternative disconnection to Sonogashira coupling between directing arenes and terminal alkynes has been developed by Yu group to install an alkyne moiety at the ortho site of directing arenes using Cu(II) salt (Scheme I.5.3.1.4).70 A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction.
Scheme I.5.3.1.4. Copper(II)-catalyzed auxillary assisted alkynylation of arenes
Ortho Alkoxylation
An auxiliary-assisted alkoxylation and phenoxylation of β-sp2 C–H bonds of benzoic acid derivatives and γ-sp2 C–H bonds of amine derivatives has been reported by Daugulis et al. In the presence of (CuOH)2CO3 catalyst and air as an oxidant, phenol or alcohol coupled efficiently with directing arenes 8-aminoquinoline (Scheme I.5.3.1.5).71
Scheme I.5.3.1.5. Copper(II)-catalyzed auxillary assisted sp2 CH phenoxylation
Ortho Benzoxylation
A rhodium-catalyzed ortho-benzoxylation of the sp2 C−H bond by carboxylic acids has been described by Cheng group in the absence of external oxidant. The procedure tolerates carbomethoxy, formyl, bromo, chloro and nitro groups, providing the benzoxylated products in moderate to good yields (Scheme I.5.3.1.6).72
Scheme I.5.3.1.6. Rhodium-catalyzed benzoxylation of 2-arylpyridines
Ortho Amination
A method for direct amination of β-Csp2H bonds of benzoic acid derivatives and γ- Csp2H bonds of benzylamine derivatives has been developed by Daugulis and co-workers using aminoquinoline as the directing axillary (Scheme I.5.3.1.7).73a In the presence of Cu(OAc)2/Ag2CO3 catalytic combinations reaction shows high generality and functional-
group tolerance, as well as providing a straightforward means for the preparation of ortho- aminobenzoic acid derivatives.
Scheme I.5.3.1.7. Amination of benzamides with aliphatic amines via CDC Recently, Yu group developed a Cu(OAc)2-mediated C–H amidation and amination of arenes and heteroarenes using a readily removable directing group.73b A wide range of sulfonamides, amides and anilines function as the amine donors in this reaction.
Intramolecular Amination
A novel Pd-catalyzed Csp3–H amination that proceeds through an unusual four- membered-ring cyclopalladation pathway has been introduced by Gaunt group (Scheme I.5.3.1.8).74 This intramolecular cyclization leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into a synthetically versatile nitrogen heterocycle such as aziridines and β-lactams via carbonylation processes.
Scheme I.5.3.1.8. Amine directed Pd(II)-catalyzed intramolecular sp3 CH amination
Ortho Amidation
An intermolecular amidation of unactivated sp2 and sp3 CH bonds via Pd-catalyzed cascade CH activation protocol has been described by Che group (Scheme I.5.3.1.9).75 A variety of amides are directly installed at the ortho position of oxime ether using Pd(II)/K2S2O8 combination.
Scheme I.5.3.1.9. Ketoxime ether directed Pd(II)-catalyzed amidation of arenes
Later, similar intermolecular amidation strategy was extended to 2-arylpyridines and aromatic ketones using transition metal and suitable oxidant.76
Intramolecular Amidation
Using picolinamide as directing auxillary, Daugulis group developed a Pd(II)-catalyzed intramolecular amidation at unactivated sp3 carbons. (Scheme I.5.3.1.10).77a Later on a similar auxillary directed intramolecular sp3 CH amidation methods has been demonstrated by Chen, Ge and Kanai.77b-f
Scheme I.5.3.1.10. Pd(II)-catalyzed intramolecular sp3 CH amidation
Ortho Sulfenylation
Yu group has reported a Cu(II)-catalyzed direct thioetherification (sulfenylation) of aryl Csp2−H bonds of 2-arylpyridine using benzene thiol as the coupling partner and O2 as the stoichiometric oxidant (Scheme I.5.3.1.11).27b
Scheme I.5.3.1.11. Copper(II)-catalyzed ortho-thiolation of arenes
Recently, directed sulfenylation of both sp2 and sp3 C–H bonds was achieved by Shi group through a nickel catalyzed C–S bond formation.38d
Ortho C–H Phosphorylation via CDC
The first Pd(II)-catalyzed ortho C–H phosphorylation of 2-arylpyridines has been accomplished by Yu group using both H-phosphonates and diaryl phosphine oxides as suitable coupling partners (Scheme I.5.3.1.12).78a
Scheme I.5.3.1.12. Palladium(II)-catalyzed C−H phosphorylation of 2-phenylpyridine Later on Murakami group developed a similar o-phosphorylation of directing arenes such as 2-phenylpyridines, quinolines, isoquinolines, benzo[h]quinolines and pyrimidines using α-Hydroxyalkylphosphonate as the phosphonating reagent.78b
I.5.4. An Array of Exceptions: Reactions which are not included in the above three classes are discussed below.