Synthesis of Oxindoles by Iron‐Catalyzed Oxidative 1,2‐Alkylarylation of Activated Alkenes with an Aryl C(sp²)H Bond and a C(sp³)H Bond Adjacent to a Heteroatom

Abstract

Oxindoles are important heterocycles found in a wide range of bioactive natural products and pharmaceutical molecules. [1,2] In addition, functionalized oxindoles are versatile synthetic blocks for the preparation of natural products and in asymmetric synthesis. As a result, considerable efforts were directed toward the development of efficient methods for their synthesis, [1][2][3][4][5][6][7] with metal-catalyzed cyclization/functionalization approaches becoming increasingly popular because of their particular efficiency. [2][3][4][5][6] However, these approaches suffer from use of both expensive and commercially not available ortho-functionalized anilines and noble-metal catalysts, thereby limiting their wide application in organic chemistry research and industry. [2][3][4] Recently, ortho-nonfunctionalized anilines were found to be viable substrates for metal-mediated direct aryl C(sp 2 )-H functionalization/cyclization reactions, however, these transformations are quite rare. [5, 6] In 2003, Hennessey and Buchwald first used ortho-nonfunctionalized anilines (achloroacetanilides) in the formation of oxindole by a variant of the Friedel-Crafts procedure through palladium-catalyzed CÀH functionalization in the presence of 2-(di-tert-butylphosphino)-biphenyl (ligand) and Et 3 N (base). [5a] Subsequently, Jia and Kündig developed a direct intramolecular oxidative coupling of an aryl C(sp 2 )-H bond and a C(sp 3 )-H center for the preparation of 3,3-disubstituted oxindoles, even though these reactions needed a stoichiometric amount of Cu catalyst combined with a base. [5b,c] Very recently, the groups of Neuville and Zhu [6a] and Liu and co-workers [6b-d] independently established a very useful access to oxindoles by Pdcatalyzed oxidative difunctionalization of alkenes in Narylacrylamides under acidic or neutral conditions. These Pd-catalyzed oxidative transformations are more fascinating than the methods reported earlier, [5] because additional functional groups can be introduced into the oxindole framework; however, use of highly expensive Pd/hypervalent iodine reagent systems make their application less desirable. [6] Herein, we report a new oxidative 1,2-alkylarylation of activated alkenes with an aryl C(sp 2 )ÀH bond and a C(sp 3 )À H bond adjacent to a heteroatom for selective synthesis of functionalized 3-(2-oxoethyl)indolin-2-ones. This oxidative 1,2-alkylarylation is catalyzed by economical and environmentally benign iron [8] and involves the use of tert-butyl hydrogenperoxide (TBHP) as oxidant and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, L5) as ligand (Scheme 1). To the best of our knowledge, this work represents the first example of metal-catalyzed difunctionalization of an alkene with an aryl C(sp 2 ) À H bond and a C(sp 3 ) À H bond adjacent to a heteroatom. [6b-d, 9] We initially studied the reaction of N-methyl-N-phenylmethacrylamide (1 a; 0.3 mmol) with Et 2 O (2 a; 20 equiv), FeCl 3 (5 mol %) in benzene at 120 8C under argon atmosphere (entry 1 in Table 1), and were able to isolate the d...

Progress in Synthesis of Oxindoles by Radical Addition-Cyclization

“…同年, Li 课题组 [5] 报道了在三氯化铁的催化作用下, 以 N-芳基丙烯酰胺类化合物和杂环化合物为底物, 以 DBU(L)为配体, TBHP 为氧化剂, 苯作溶剂, 在空气中 加热到 120 ℃, 经过 12 h 反应, 对含"N 或 S"的化合 物邻位碳上的 H 有活化作用, 通过自由基的生成, 进一 步加成、关环而得到含杂原子的吲哚-2-酮类衍生物 (Eq. 2).…”

Oxidative 1,2-carboamination of alkenes with alkyl nitriles and amines toward γ-amino alkyl nitriles

“…The decomposition the AgCH 2 CN intermediate B readily takes place under heating to form the alkyl radical C (supported by the results of Fig. 2b), AgHCO 3 and the Ag 0 species [Ag(s)] through single electron transfer424344454647484950515253545556575859606162636465. Subsequently, addition of the alkyl radical C across the C–C double bond in alkene 1a produces the alkyl radical intermediate D (supported by the reaction of alkene 1t ; Fig.…”

Microwave‐Assisted Copper‐Catalyzed Oxidative Cyclization of Acrylamides with Non‐Activated Ketones

“…Interestingly, the use of Et 3 N (10 mol %) as an additive increased the yield to 78 % (entry 13). Here small amount of Et 3 N might be working as a promoter to assist the copper to catalyze the reaction . Other organic and inorganic bases, such as DIPEA, DABCO, and NaHCO 3 , proved to be less efficient than Et 3 N (entries 14–16).…”

“…Further, to shed some light on the catalytic procedure, a series of deuteration reactions were carried out (Scheme , also see the Supporting Information). When [D 1 ]‐ 1 a and [D 5 ]‐ 1 a were subjected to inter‐ and intramolecular competition experiments, a kinetic isotope effect (KIE) of 1.0 was observed (Scheme 5 a and b), indicating that an electrophilic substitution or a free‐radical substitution occurs during this transformation . The intermolecular competition reaction between a 1:1 mixture of 2 a and its deuterated analogue [D 3 ]‐ 2 a and 1 a demonstrated a KIE of 4.1 (Scheme c).…”