Representative Examples of Directed CC Bond Formation

C HAPTER I

I. A Sketch of Transition Metal Catalyzed CH Functionalizations

I.5. Modern Era of CH Functionalization

I.5.1.1. Representative Examples of Directed CC Bond Formation

Carboncarbon bond formation is the most fundamental transformation in synthetic organic chemistry. Now-a-days transition metal catalyzed ligand directed CC bond formation via CH activation is the most widely studied which affords ortho-aryl, alkyl,

alkenyl, alkynyl, carbonyl, trifluoromethyl and cyano products. Reactions relevant to each of these categories are exemplified below.

 Arylation via Csp2H and Csp3H Bond Functionalization

Daugulis and co-workers developed a Pd-catalyzed o-arylation protocol of directing arenes (2-arylpyridine, 2-ethylpyridine, 8-methylquinoline and benzo[h]quinoline) using aryl iodide as the aryl source and AgOAc as the oxidant.^11a Later a related ortho-arylation strategy has been applied to other directing arenes such as anilides,^11b benzoic acid derivatives,^11c 2-arylbenzoxazoles,^11d oxime ethers^11e and benzamide^11f derivatives (Scheme I.5.1.1.1). This Pd-catalyzed arylation strategy is not only limited to sp² CH bond functionalization but also applied to sp³ CH bonds.¹² Daugulis and co-workers reported a Pd-catalyzed arylation of unactivated 1° and 2° sp³ CH bonds with the assistance of a pre-existing bidentate directing group viz. aminoquinolines and picolinamides using a combination of ArI and AgOAc (Scheme I.5.1.1.1).^13a Arylation of weakly coordinating carboxylic acid derivatives has also been achieved using Pd(OAc)2 in combination with oxidant Ag2CO3, NaOAc and K2HPO4.^13b Apart from aryl iodides, a variety of other arylating agents such as diphenyliodonium salts,^12a-c aryl chlorides,^12d arylboronic acids,^12d-e arylsilyl ethers^12f-g and even aryl acyl peroxides^12h have also been employed for this purpose.

Scheme I.5.1.1.1. Pd-catalyzed arylation of directing arenes

 Alkylation via C_sp2H and C_sp3H Bond Functionalization

Daugulis group has demonstrated an auxiliary directed Pd(II)-catalyzed β-alkylation of sp³ and sp² C−H bonds in carboxylic acid derivatives (Scheme I.5.1.1.2).^14a In the presence of Pd-catalyst and inorganic base, 8-aminoquinoline amide substrates provided mono alkylation at the sp³ C−H sites where as di-alkylation occurs involving sp² C−H bonds. Similarly, directing group assisted alkylation has also been achieved using other alkyl sources such as tetra-alkyl tin reagents,^14b methylboroxines^14c and dicumylperoxide.^14d

Scheme I.5.1.1.2. Pd-catalyzed alkylation with alkyl iodides

 Alkenylation via Csp2H and Csp3H Bond Functionalization

In 2005, Daugulis group reported a PdCl2 catalyzed ortho-alkenylation using 3-halo acrylates as alkene substrates in the presence of AgOTf oxidant (Scheme I.5.1.1.3).^15a Recently, a direct ruthenium catalyzed regioselective alkenylation of aromatic C–H bonds of aryl and heteroarylpyridines or related compounds with alkenyl esters and ethers has been developed by Kakiuchi group. Besides this ortho alkenylation of aromatic sp² C–H bond a Pd(II)-catalyzed removable picolinamide auxiliary directed remote alkenylation of unactivated sp³ C−H bonds has also been achieved by Chen group using vinyl iodide as the alkenylating source.^15c

Scheme I.5.1.1.3. Pd-catalyzed coupling of halo-olefins with anilides

 Alkynylation via C_sp2H and Csp3H Bond Functionalization

Chatani group described a Pd(II)-catalyzed ortho-alkynylation protocol of anilides with a silyl-protected bromoalkyne in the presence of AgOTf oxidant and K₂CO₃ (Scheme I.5.1.1.4).¹⁶ Besides this Pd-catalyst, Ru, Rh and Ga have also been used for the

direct alkynylation of arenes and heterocycles with pre-activated alkynylating reagents such as alkynyl halides¹⁷ and benziodoxolone-based hypervalent iodine reagents.¹⁸ Chatani group also developed a Pd(II)-catalyzed direct ethynylation of sp³ C–H bonds in aliphatic carboxylic acid derivatives using bidentate 8-aminoquinoline auxillary.^19a Recently, the alkynylation of β-Csp3–H bonds in aliphatic amides with alkynyl halides has been enabled by Yu group using Pd(0)/N-heterocyclic carbene (NHC) and Pd(0)/phosphine (PR₃) catalysts.^19b

Scheme I.5.1.1.4. Pd-catalyzed ortho-alkynylation of anilides with haloalkynes

 Carbonylation via Csp2H and Csp3H Bond Functionalization

A Pd(II)-catalyzed direct aromatic carbonylation has been achieved in a phosphine free catalytic system using Pd(OAc)2 and Cu(OAc)2 in an atmosphere of CO (Scheme I.5.1.1.5).^20a The carbonylation of mono-protected benzylamines or N- alkylphenethylamines proceeded via ortho-palladation, inducing a remarkable site selectivity to afford a variety of five- or six-membered benzolactams. Further, a Pd(II)- catalyzed direct carbonylation has been applied to aniline, benzoic and phenylacetic acid derivatives to form esters^20b (cyclic or acyclic) and dicarboxylic acids^20c using CO as the carbonyl source. Diethyl azodicarboxylate (DEAD) has also been used as a substitute of toxic CO for Pd(OAc)2 catalyzed chemo- and regioselective ethoxycarbonylation reactions of 2-arylpyridines, pyrrolidinone, acetylindoline, quinoline and oximes.^20d

Scheme I.5.1.1.5. o-Carbonylation of benzylamines for the synthesis of benzolactams A Pd(II)-catalyzed β-Csp3−H carbonylation of N-arylamides under CO (1 atm) has been achieved by Yu and co-workers (Scheme I.5.1.1.6).²¹ This carbonylation protocol proceeds via intermolecular CO insertion to amide directed C_sp3−H bond followed by intramolecular C−N bond formation giving the corresponding succinimides, which could be readily converted to 1,4-dicarbonyl compounds. Recently, a mono selective γ-C–H

olefination and carbonylation of aliphatic acids has been accomplished by the same group using a combination of quinoline-based ligand and a weakly coordinating amide directing group.²²

Scheme I.5.1.1.6. Pd-catalyzed β-C_sp3H carbonylation of amides

 Ortho CH Trifluoromethylation

For the first time Yu group developed a Pd(II)-catalyzed ortho-trifluoromethylation of diverse heterocycle directing groups using electrophilic CF₃ reagent and trifluoro acetic acid (TFA) as a promoter (Scheme I.5.1.1.7).^23a Further, this strategy was extended to various directing arenes such as N-arylbenzamides,^23b benzylamines^23c and acetanilides^23d using similar type of electrophilic CF3 reagents.

Scheme I.5.1.1.7. Pd-catalyzed ortho-trifluoromethylation of directing arenes

 Ortho CH Cyanation

Chang group developed an Pd(II)-catalyzed ortho-cyanation of 2-arylpyridines using CuCN as the cyanide surrogate (Scheme I.5.1.1.8).^24a Further, similar o-cyanation of different directing groups have been achieved with N,N-dimethylformamide and ammonia combination,^24b potassium ferricyanide,^24c benzyl nitrile,^24d acetonitrile,^24e 2,2′- azobisisobutyronitrile (AIBN)^24f and tert-butyl isonitrile^24g as the cyanide source.

Scheme I.5.1.1.8. Pd-catalyzed ortho-cyanation of 2-phenylpyridine