Palladium-Catalyzed Direct C(sp²)–H ortho-Arylation of Anilides Using 2-Aminophenylpyrazole as the Directing Group

Abstract

Palladium-catalyzed ortho-arylation of anilides was achieved using 2-aminophenyl-1H-pyrazole (2-APP) as a new directing group. Using Pd(OAc) as the catalyst and AgO as the promoter, mono- and diarylation of anilides were realized in up to 89% isolated yield. Further manipulation of the arylation product may be accomplished by a 2-step sequence involving an acidic hydrolysis of the methylated amide. More interestingly, in the presence of KCO, tandem C-C/C-N cyclization products were obtained for a couple of substrates.

Palladium-Catalyzed Arylation of Aromatic Amides Directed by a [4-Chloro-2-(1H-pyrazol-1-yl)phenyl]amine Auxiliary

“…In general, low to no yields are usually observed for reactants with highly sterically demanding ortho-substituents, 8,12 but in this case, ortho-substituted aryl iodides reacted smoothly to afford good yields of the target products 4k-m. The directing group might circumvent the formidable steric congestion around palladacyclic intermediates in oxidative addition.…”

“…During our studies, Li's group reported a Pd-catalyzed C(sp 2 )-H ortho-arylation of anilides with APP as a directing group and mixed-valence AgO as a promoter in the preparation of 14 biaryl products [Scheme 1(A)]. 8 Here, we describe a modified pyrazolyl-based-amide bidentate directing group, [4-chloro-2-(1H-pyrazol-1-yl)phenyl]amine (ACPP), that permits a range of Pd-catalyzed ortho-C(sp 2 )-H arylations of aromatic amides [Scheme 1(B)]. In sharp contrast to the case of APP, highly sterically hindered ortho-substituted anilides and aryl iodide partners are tolerated in the reaction, giving good yields, 8 a broader substrate scope, and wider functional-group tolerance.…”

“…Our initial study focused on electronic effects on the directing ability, and we performed a brief survey of the effects of various substituents on the reaction of amides 1 (0.3 mmol) with 1-iodo-4-methoxybenzene (2a; 3.0 equiv) in the presence of Pd(OAc) 2 (10 mol%) catalyst and AgOAc (2.0 equiv) additive in toluene (2.5 mL) at 120 °C for 12 hours (Scheme 2). Pleasingly, the unmodified Li directing group 8 afforded the corresponding ortho-arylated product 3a in 40% yield. Incorporation of methyl or trifluoromethyl groups at the 3-and 4-position, respectively, of the pyrazole slightly lowered the arylation efficiency (3b and 3c).…”

Palladium-Catalyzed Late-Stage ortho-C–H Bond Aroylation of Anilines Using 4-Methoxy-2-pyridinyl as a Removable Directing Group

“…3 It is not only able to promote the reactivity but also to control the regioselectivity for the type of reaction, such as the ortho-, meta-, and para-position of a phenyl ring. 4 The pyridinyl is believed to be the most common directing group due to its good affinity with transition metals, especially for the palladium ion. Therefore, it is often used in our studies with respect to the palladium-catalyzed selective ortho-C−H bond functionalization.…”

Copper(II)-Mediated ortho-Selective C(sp2)–H Tandem Alkynylation/Annulation and ortho-Hydroxylation of Anilides with 2-Aminophenyl-1H-pyrazole as a Directing Group

“…Meanwhile, Niu and Song’s group employed Co­(II) and Ni­(II) catalysts and pyridine oxide (PyO) as an auxiliary to realize an sp 2 C–H tandem alkynylation/annulation using silver acetate as an oxidant to gain access to 3-methylene isoindolin-1-one structures [eq 2]. In 2016, we discovered that 2-aminophenyl-1 H -pyrazole (2-APP) as a new removable directing group was efficient for facilitating C–H carbon–nitrogen, carbon–chlorine, and carbon–carbon bond formations. We then proceeded to explore 2-APP’s utility as a directing group for promoting the C­(sp 2 )–H/C­(sp)–H couplings to produce 3-methyleneisoindolin-1-ones [eq 3, PP = 1-phenyl-1 H -pyrazole].…”