C2-Functionalizations

As seen from Equations 1.73 and 1.74, the c/a, versus q or c1/a1 versus c2 functions are not linear because a composite amount containing the K s of both adsorbed components and the concentration of the other component is present, instead of the K constant, in Equation 1.64. 

Oestxeich found that the direct arylation of indolines could be accomplished without over oxidation to the corresponding indole under palladium-catalysis with air (open flask), oxygen (balloon), or copper(II) acetate as the oxidant. Indolines can be unsubstituted or substituted as C2/C3 and the reaction performs well on gram scale (250, 18 examples, 18—90% isolated yield) (140L6020).A directed C2-functionalization/C7-alkenylation was discovered by Xu,Yi, and colleagues. With a rhodium catalyst, indole derivatives were functionalized with acetates at C2 (22 examples, 62—92% yield) the newly obtained products could be alkenylated at C7 with a rhodium/copper system (251,3 examples, 68—78% yield) (14CC6483). 

The corresponding benzo-analogs (IH-indole, benzofuran, and benzo-thiophene), however, react preferentially via the C3-position. This can be rationahzed by the Wheland intermediates originating from electrophilic substitution on the C2- and C3-position. For the latter, one more resonance structure can be drawn without loss of aromaticity of the annulated benzene ring (Figure 4). C2-functionalization is less favored but can take place when the C3-position is blocked for instance (either via direct attack at C2 or via initial attack at C3 followed by 1,2-migration). 

Nucleophilic Addition to Acetals and Hemiacetals—C2 Functionalization of Lactol... 

A mixture of N (2-iodophenyl)methanesulfonamide, phenylacetylene, and catalytic amounts of PdCl2(PPh3)2 and Cut in 2 1 EtjN/DMF heated in a sealed tube at 80° for 24h l-methanesulfonyl-2-phenylindole. Y 66%. The 2-step indole synthesis via N-(o-acetylene)urethans (Chem. Pharm. Bull. 25, 1823 (1987)) was unsuiteble for preparing C2-functionalized derivs. F.e.s. T. Sakamoto et al., Chem. Pharm. Bull 26, 1305-8 (1988). 

A highly regioselective C2 functionalization strategy is also viable in arylation, olefination, and alkylation reactions when us-... 

C-H Functionalization. The last decade has seen the development of an increasing number of conditions to functionalize p5Tidine regioselectively via C-H activation. The various metal-catalyzed methodologies essentially provide access to C2 functionalized arylated, olefinated, or alkylated products, and the activation of pyridine via coordination to the nitrogen lone pair is commonly encountered. For instance, the one-pot amination/benzoylation procedure provides access to N-benzyoyliminopyridinium yUde in 96% yield (eq 29). ... 

Scheme 67 Reductive C2 functionalization mechanistic and structural implications...

Scheme 68 Common methods for the synthesis of reductive C2 functionalization precursors...

In chapter Synthesis of Saturated Tetrahydropyrans, S.D. Rychnovsky, M. A. Perry, and N. Sizemore review the common strategies to access tetrahydropyrans such as the formation of 01-C2, C2-C3, C3-C4, 01-C6, and C2-C3 bonds, as well as C2 functionalization of lactols and lactones. 

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