Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated S_NAr/intramolecular cyclization cascade sequence in water or DMSO

Abstract

The synthesis of 2-substituted indoles and benzofurans was achieved by nucleophilic aromatic substitution, followed by subsequent 5-endo-dig cyclization between the nucleophile and an ortho acetylene. The acetylene serves the dual role of the electron withdrawing group to activate the substrate for SNAr, and the C1-C2 carbon scaffold for the newly formed 5-membered heteroaromatic ring. This method allows for the bond forming sequence of Ar-X-N/O-C1 to proceed in a single synthetic step, furnishing indoles and benzofurans in moderate to high yields. Since the method is not transition metal mediated, brominated and chlorinated substrates are tolerated, and benzofuran formation can be conducted using water or water-DMSO mixtures as solvent.

[(PhCH2O)2P(CH3)2CHNCH(CH3)2]2PdCl2/CuI as Cocatalyst for Coupling-Cyclization of 2-Iodophenol with Terminal Alkynes in Water

“…Compared to entries 1 and 3, the results show that both co-catalyst CuI and ligand PPh 3 play important roles in this protocol. As for the effects of base on the reaction, we discovered that the yield of product 3a was 28%, 19%, 21%, and 31% when using Cs 2 CO 3 , KOH, NaOH, and t-BuOH as a base, respectively (entries 10-12,15), and only a trace yield of product 3a in the presence of pyridine or K 2 CO 3 as bases (entries [13][14]. In comparison with entry 3, it is presumed that triethylamine functions not only as a base, but also as a co-solvent to help the organic substrates to disperse in water.…”

“…Compounds which contain 2-substituted benzo [b]furan frameworks have been found in applications in areas ranging from pharmaceuticals to natural products owing to their various biological activities, such as antibacterial [1], antifungal [2], antitumor [3], antiviral [4], anti-inflammatory [5], antioxidant [6], and antiradical activities [7]. Various methods [8][9][10][11][12][13][14] have been developed for the synthesis of 2-substituted benzo[b]furan derivatives. Pd-catalyzed one-pot synthesis of benzo[b]furans from 2-halophenols and terminal alkynes by a Sonogashira coupling-cyclization sequence is aclassical, useful, and reliable method [10,11,[15][16][17].…”

Recent Developments in the Cyclization of Alkynes and Nitrogen Compounds for the Synthesis of Indole Derivatives

“…[25] The S N Ar/intramolecular cycli- zation cascade sequence involving 2-fluoro-arylalkynes with ptoluidine or acetamide as nucleophile, in the presence of potassium t-butoxide, led to the formation of substituted 7azaindoles 8 (Table 1, entry 4). [26] Acidic conditions were also used as a convenient promoter to the cyclization of 2-amino-3alkynyl pyridines. In this case, a mixture of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) promoted the cyclization of 2-amino-3-alkynyl pyridines to 2,5-disubstituted 7azaindoles 9 (Table 1, entry 5).…”

“…Base‐induced heteroannulation was also utilized for the cyclization of 2‐amido‐3‐alkynyl pyridines in the formation of 2‐aryl‐substituted 7‐azaindoles 7 (Table 1, entry 3) [25] . The S N Ar/intramolecular cyclization cascade sequence involving 2‐fluoro‐arylalkynes with p ‐toluidine or acetamide as nucleophile, in the presence of potassium t ‐butoxide, led to the formation of substituted 7‐azaindoles 8 (Table 1, entry 4) [26] . Acidic conditions were also used as a convenient promoter to the cyclization of 2‐amino‐3‐alkynyl pyridines.…”

Gold-Catalyzed Oxidative Cascade Cyclization of 1,3-Diynamides: Polycyclic N-Heterocycle Synthesis via Construction of a Furopyridinyl Core

“…Their inherent ambivalent nature of possessing π-excessive (furan) and π-deficient (pyridine) ring systems renders them promising candidates for the discovery of novel organic fluorophores . While significant, the most explored methods to prepare these compounds rely on the annulation of functionalized pyridine or furan rings, which generally require multistep manipulations to access the parent heterocycles. − In this regard, the development of a general method to construct such a nucleus from easily accessible reactants is in high demand.…”