Regioselectivity in palladium-catalysed direct arylation of 5-membered ring heteroaromatics

Abstract

International audienceIn recent years, palladium-catalyzed arylation of heteroaroms. via C-H bond activation has become a popular method for generating carbon-carbon bonds. For this reaction, a wide variety of heteroaroms. such as (benzo)furans, (benzo)thiophenes, pyrroles, indoles, thiazoles, oxazoles, imidazoles, pyrazoles or triazoles can be employed. In most of these heterocycles, several reactive C-H bonds are present. If specific C-H bonds of such heteroarenes can be coupled with arenes, this becomes one of the most simple methods to access bi(hetero)arenes. In the past few years, several results using modified and improved catalysts and new reaction conditions have been reported permitting better control of the regioselectivity of such arylations. For example, initially only C2- or C5-arylated thiophenes were accessible via palladium-catalyzed direct arylation, whereas now regioselective C3- or C4-arylations are possible when appropriate reaction conditions are used. In this review, the influence of the reactants, catalysts and reaction conditions on the regioselectivity of palladium-catalyzed arylation of heteroaroms. is reported. The recent progress in the regioselectivity control now allows the synthesis of a wide variety of complex mols. using only a few steps, and will certainly provide simpler access to new heteroaryl derivs. in the next years

Regioselective synthesis of C3 alkylated and arylated benzothiophenes

“…Due to the ubiquity of C–H bonds, the most efficient methods of C–C bond construction are based on C–H functionalization1213. Functionalization at C2 of readily available benzothiophenes14 is generally well established due to the increased acidity of the C–H bond15. However, C3 C–H functionalization is underdeveloped.…”

Copper‐Catalyzed Oxidative Dehydrogenative C(sp3)−H Bond Amination of (Cyclo)Alkanes using NH‐Heterocycles as Amine Sources

“…As reported by Yi, [21] we have not observed the formation of the amination product 1 after heating at 135 °C over 15 h, but we did observe the formation of C-alkylated products (Table 1, entry 1). When FeCl3 (5 mol%) in the presence of phenanthroline (L1) (10 mol%) was used as the catalytic system, the amination product 1 was obtained in low yield with predominant formation of other C2, C3 and C7-alkylated products ( [11][12][13][14]. When the reaction is performed in absence of phenanthroline (L1), the yield in 1 dropped to 10% concurrent with the formation of other C2, C3 and C7-alkylated products (Table 1, entry 15).…”

“…13 C NMR (75 MHz, CDCl3) δ (ppm) 136.0, 129.0, 128.4, 127.4, 126.6, 120.3, 113.8, 109.9, 104.2, 52.4. MS(EI) m/z(%) = 182 ([M] + ,18), 91 (100), 65 (14).…”

“…[13] This lack of exploitation is probably due to the presence of competitive C(sp 2 )-H bonds on NH-heterocycles, which are generally more reactive. [14] Although synthetic tools enabling C(sp 2 )-N bond formation have been well established, [15] facile intermolecular amination of C(sp 3 )-H bonds under mild conditions still remains a challenge in synthetic chemistry. [4, 11d, 16] Recently, cross-dehydrogenative coupling reactions have attracted increasing attention owing to the use of abundant hydrocarbons (i.e., arenes, olefins, or cycloalkanes) as unreactive coupling partners for the C-C, C-O, and C-N bond formation.…”

Regiocontroled Pd-catalysed C5-arylation of 3-substituted thiophene derivatives using a bromo-substituent as blocking group

“…In 1990, Ohta and co-workers described the Pd-catalysed direct arylation of thiophene derivatives by coupling reaction with aryl halides [15–16]. This is a highly powerful method for a greener access to a very broad range of arylated thiophenes [17–25]. The method is very attractive in terms of green chemistry, because its major by-products are not metal salts but a base associated to HX, and synthesis of an organometallic derivative can be avoided.…”