C HAPTER I
I. A Sketch of Transition Metal Catalyzed CH Functionalizations
I.5. Modern Era of CH Functionalization
I.5.1.3. Representative Examples of CN Bond Formation
Transition metal catalyzed ligand-directed CH activation has also been utilized for the construction of CN bonds. Representative examples pertaining to various forms of CN bond formations are shown below.
Amination via sp2 C–H Bond Functionalization
A direct C–H amination of N-aryl benzamides has been achieved with o-benzoyl hydroxylamines using either Pd(II) or Pd(0) catalysts (Scheme I.5.1.3.1).31a Along with Pd- catalyst Rh has also been used for similar amination reaction using N-haloamines.31b-d
Scheme I.5.1.3.1. Pd-catalyzed intermolecular amination with alkylamines
Amidation via sp2 C–H Bond Functionalization
An efficient method for the synthesis of anthranilic acids using Pd-catalyzed ortho-C–H amidation of benzoic acids has been disclosed by Yu group (Scheme I.5.1.3.2).32a The amidation is proposed to proceed by carboxylate assisted ortho-C–H palladation to form an arylpalladium(II) complex, followed by a nitrene insertion into the Pd–C bond. Glorius reported a Rh(III)-catalyzed amidation of Csp2–H bonds using electron-deficient aroyloxycarbamates as the efficient electrophilic amidation partners.32b Along with N- mesitylsulfonates and N-carboxylates recently organic azides have been introduced as pre- activated aminating reagents in C–H activation protocols. Ru(II)-catalyzed amidation reactions using sulfonyl azides as precursors were illustrated notably by Ackermann,33a Sahoo33b-c and Jiao33d groups.
Scheme I.5.1.3.2. Pd-catalyzed ortho-amidation of benzoates with N-mesitylsulfonates
Ortho Nitration of sp2 CH Bond
Liu and co-workers described a Pd-catalyzed chelation assisted ortho nitration of aromatic CH bonds in the presence of K2S2O8 oxidant (Scheme I.5.1.3.3).34a A range of azaarenes, such as 2-arylquinoxalines, pyridines, pyrazoles and O-methyl oximes, were nitrated with excellent chemo- and regioselectivity. Later, Liu and Bi group reported a inexpensive Cu(II) mediated protocol for the ortho nitration of 2-arylpyridines using AgNO3 as the source of ‘NO2’ group.34b
Scheme I.5.1.3.3. Pd-catalyzed sp2 CH nitration of 2-arylquinoxalines I.5.1.4. Representative Examples of C–S Bond Formation
Transition metal catalyzed carbon-sulfur (C–S) bond formations are relatively fewer in numbers due to competing oxidation of sulfur compounds. Few examples pertaining to ligand directed CS bond formations are shown below.
Ortho C–H Sulfonylation
Dong group developed Pd(MeCN)2Cl2 catalyzed intermolecular ortho- arylsulfonylation of direcing arenes viz. arylpyridines, arylpyrazoles and aryloxime ethers using arylsulfonyl chlorides (ArSO2Cl) as the sulfonating reagent (Scheme I.5.1.4.1).35 Recently, Shi group introduced a Pd(II)-catalyzed sulfonylation of unactivated Csp3–H bonds with sodium arylsulfinates using 8-aminoquinoline auxiliary.36
Scheme I.5.1.4.1. Pd-catalyzed ortho-sulfonylation of 2-arylpyridine
Ortho C–H Sulfenylation
In 2012, an auxiliary assisted copper catalyzed or promoted sulfenylation protocol of benzoic acid derivative (β-sp2 C−H bonds) and benzylamine derivative (γ-sp2 C−H bonds) has been developed by Daugulis group using disulfide as the thiolating agent.37 Recently, disulfides38a-c and thiols38d have been used for nickel catalyzed auxiliary directed thiolation/sulfenylation of sp2 or sp3 C−H bonds (Scheme I.5.1.4.2).
Scheme I.5.1.4.2. Ni-catalyzed sp2 and sp3 CH sulfenylation I.5.1.5. Representative Examples of CarbonHalogen Bond Formation
Aryl halides are synthetic intermediates for organometalic reagent synthesis and cross- coupling reactions. Thus the installation of a CX (X = Cl, Br, I) bond via CH activation has got special synthetic importance in coupling chemistry for further functionalizations.
Ortho C–H Chlorination, Bromination and Iodination
Kodama and co-workers developed ortho-iodination of benzoic acids in the presence of Pd(OAc)2 and N-iodosuccinimide.39a Sanford group introduced directed chlorination, bromination and iodination of 2-arylpyridines using N-halosuccinimides (Scheme
I.5.1.5.1).39b Further, various group applied similar strategy for o-halogenation with a variety of directing arenes including pyridines, oxime ethers, isoquinolines, anilides, nitriles, O-arylcarbamates and isoxazolines.39c-i Apart from N-halosuccinimides, other halogenating agents such as CuX2 (X = Cl, Br),39j Suárez reagents (XOAc, X = Br, I)39k-m and CaX239n
were also used.
Scheme I.5.1.5.1. Pd-catalyzed ortho sp2 C–H halogenation of 2-arylpyridine
Bromination and Chlorination at sp3 CH Bond of Directing Substrates
A removable directing auxillary S-methyl-S-2-pyridyl-sulfoximine (MPyS) has been used for Pd(II)-catalyzed bromination and chlorination of β-sp3 CH bonds by employing N-halophthalimides as the halogen source (Scheme I.5.1.5.2).40 Yu group reported a Pd(II)- catalyzed sp3 CH iodination using a combination of PhI(OAc)2 and I2, that generates IOAc in situ.39e-f The same group also achieved ortho iodination protocol of various directing arenes with cheap molecular I2 as the sole oxidant.41
Scheme I.5.1.5.2. Pd-catalyzed sp3 CH halogenations (Br/Cl) of sulfoximine
Ortho C–H Fluorination
Sanford group described the development of a new Pd(II)-catalyzed method for the fluorination of C–H bond under an oxidative condition using electrophilic N-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate (Scheme I.5.1.5.3). Microwave irradiation in the presence of catalytic palladium acetate is the optimal condition for the fluorination of both sp2 and sp3 C−H bonds in a variety of substituted 2-arylpyridine and 8-methylquinoline derivatives.42a Further, a similar Pd(II)-catalyzed CF bond formation strategy was extended to triflamide-protected benzylamines-based substrates42b and benzamides42c using N-fluoro-2,4,6-trimethylpyridinium triflate as the “F+” source.
Scheme I.5.1.5.3. Pd-catalyzed ortho fluorination of 2-arylpyridines I.5.1.6. Representative Example of CB, CSi and CSe Bond Formations
Reactions pertaining to each of these categories viz. ligand directed ortho CB, CSi, and CSe bond formation reactions are exemplified below.
Ortho CH Borylation
Yu group reported a Pd-catalyzed ortho CH borylation of amides using diboron reagents (B2Pin2) as the coupling partner. The reaction proceeds in the presence of dibenzylideneacetone (dba) ligand, a weak base TsONa and an oxidant K2S2O8 (Scheme I.5.1.6.1).43
Scheme I.5.1.6.1. Pd-catalyzed sp2 CH borylation of benzamide
Ortho CH Silylation
Kanai and co-workers developed a Pd-catalyzed o-silylation protocol of bidentate 8- aminoquinoline directing group with hexamethyldisilane as silicon source in the presence of Ag(I) and calcium sulfate (Scheme I.5.1.6.2).44
Scheme I.5.1.6.2. Pd-catalyzed sp2 CH silylation of benzamide
Ortho CH Selenation
A direct o-selenation of directed substrates viz. benzamides, benzylamines, 2- arylpyridines and benzo[h]quinolines has been reported by Nishihara group in the presence of Pd(II) catalyst and diselenides (Scheme I.5.1.6.3).45
Scheme I.5.1.6.3. Pd-catalyzed sp2 CH selenation of benzamide I.5.2. Cross-dehydrogenative Coupling (CDC)
The formation of CC bonds directly from two different CH bonds via the formal removal of two hydrogen atoms is called “cross-dehydrogenative coupling” (CDC). Now- a-day, the CDC not only restricted to the coupling of two different CH bonds but also the coupling of CH and XH (X = heteroatoms) bonds.46 This strategy represents a new conceptual approach in atom economically planning synthesis. Generally a CDC reaction proceeds in the presence of a hydrogen acceptor viz. hydrogen peroxide, tert-butyl hydroperoxide (TBHP) or di-tert-butyl peroxide (DTBP) and N-halosuccinimides. A variety of metal catalysts such as Cu, Fe and Pd are employed for CDC reactions. There are also examples of CDC which proceed in the absence of metal catalysts.47
Advantages:
No need of any directing groups or pre-functionalization of starting materials.
Ambient reaction conditions and simple starting materials.
High degree of CH bond activation.
Limitations:
Regioselectivity issues (functionalization can occur at any of the CH’s).
Lacking of chemoselectivity due to over functionalization.