Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles

Abstract

Stable and easily accessible N-aroylbenzotriazoles react with indoles in the presence of a base to afford the corresponding Naroylindoles in yields averaging 70%. This method is effective even when both coupling reagents possess electron-donating substituents.N-Aroylindoles are well-known nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., indomethacin, a 5-methoxyindole derivative). 1 N-Aroyl-5-nitro-1H-indoles are utilized as intermediates for the synthesis of 2-aryl-5-nitro-1H-indoles effective as bacterial NorA efflux pump inhibitors. 2 5-Substituted N-aroylindoles also exhibit selective cyclooxygenase-2 inhibitor activity, 3 and 5-amino-1-(3,5-dimethylbenzoyl)-1H-indole possesses antiangiogenic activity. 4 Furthermore, suitably substituted Naroylindoles are used as precursors for the synthesis of benzannulated indolizidines. 5 A variety of methods have been reported for the direct Naroylation of indoles. When neither the aroylating agent nor the indole contains an electron-donating substituent, several procedures are satisfactory. 6 However, useful Naroylations of indoles to a product in which either the aryl group or indole nucleus contains a strong electron-donor substituent are rare. N-Aroylindoles have been prepared by (i) indolide anion formation with sodium hydride followed by reaction with an acid chloride (36-82%), 6a (ii) direct aroylation of indoles with carboxylic acids using boric acid (50-82%), 6c and (iii) phase-transfer-catalyzed aroylation of indoles (77-94%). 6d Most recently, Bremner et al. 6b N-aroylated 5-substituted indoles with an electronwithdrawing substituent (NO 2 , CN or F) in the 5-position with carboxylic acids via DCC/DMAP coupling to give 73-95% yields of the N-aroylindoles. However, the yields for the 5-unsubstituted indoles, were 32-46% and for 5-methoxyindole only 0-15%.N-Acylbenzotriazoles are easily prepared activated derivatives of carboxylic acids. 7 Applications of N-acylbenzotriazoles include (i) N-acylation of amines, amides, 8 and sulfonamides; 9 (ii) O-acylation of aldehydes, 10 steroids, 11 hydroxyterpenes, and alcohols; 12 (iii) many C-acylations, viz: pyrroles and indoles, 13 ketones and heteroaromatics, 14 alkyl sulfones, 15 alkyl cyanides, 16 alkyl azines, 17 a-nitroalkanes, 18 furans, and thiophenes; 19 and (iv) syntheses of peptides, 20 oxazolines, 21 esters, 22 benzodioxin-4-ones, 23 ketones, 24 benzodiazepin-2-ones, 25 thiol esters, 26 alcohols, 27 hydrazides, 28 and heteroaromatics. 29Earlier we 13a,14b and others 12 have reported regiospecific C-acylation of pyrroles and indoles using N-acylbenzotriazoles. Herein, we report the efficient synthesis of electron-rich N-aroylindoles from N-aroylbenzotriazoles in the presence of a base via N-aroylation of indoles.Commercially available indole (1a) and 5-methoxyindole (1b) were used as substrates for N-aroylation reactions. NAroylbenzotriazoles 2a-c (Figure 1) were readily prepared from 1H-benzotriazole (BtH) and the corresponding carboxylic acid in yields of 85-95% according to a literature procedure. 20 Reac...

Five‐Membered Heterocycles with Three Heteroatoms: Triazoles

“…A general synthesis of acyl azides from the corresponding N-acyl benzotriazoles have been described [160]. Stable and easily accessible N-aroylbenzotriazoles react with indoles in the presence of a base to afford the corresponding Naroylindoles [161].…”

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

“…A synthetic route seems highly relevant, since N -acylbenzotriazoles have been reported elsewhere [35–37] to be stable, easy-to-handle acylating agents and have found numerous applications for advantageous N-, O-, C- and S-acylations.…”

Conformation and Atropisomeric Properties of Indometacin Derivatives

“…First, we investigated the conformation of N ‐benzoylindoles in solution (Figure 2). Indometacin and related compounds ( 2 ,8 3 9) were characterized by using 1 H NMR spectroscopy with CDCl 3 as a solvent, which showed the characteristic resonances for H7 of indole units.…”

“…1 (2 H,s),6.65 (1 H,dd,J = 2.4,9.0 Hz),6.77 (1 H,d,J = 9.0 Hz), 6.93 (1 H,d,J = 2.4 Hz),7.39 (2 H,d,J = 8.3 Hz),7.63 ppm (2 H,d,J = 8.3 Hz); 13 C NMR (100 MHz, CDCl 3 ): d = À5.5, 18. 3,25.8,30.3,52.2,55.8,56.5,101.6,112.8,113.0,114.6,128.9,129.9,131.1,131.4,133.5,138.0,139.3,155.7,168.1,171.1 ppm;IR (neat) 4, 52.7, 56.1, 102.3, 116.3, 119.7, 125.1, 129.7, 130.0, 131.7, 133.1, 133.9, 135.0, 140.8, 157.5, 168.1, 171.0, 182.7 8,36.6,52.4,55.6,102.0,114.2,114.6,117.4,127.2,129.7,129.9,130.4,130.6,131.9,132.3,134.4,135.1,…”