Synthesis of N-Aryl and N-Alkyl Anthranilic Acids via S_NAr Reaction of Unprotected 2-Fluoro- and 2-Methoxybenzoic Acids by Lithioamides

Abstract

Substitution of the fluoro or methoxy group in unprotected 2-fluoro- and 2-methoxybenzoic acids to afford N-aryl and N-alkyl anthranilic acids occurs upon reaction with lithioamides under mild conditions in the absence of a metal catalyst.

The Construction of C–N, C–O, and C(sp2)–C(sp3) Bonds from Fluorine-Substituted 2-Aryl Benzazoles for Direct Synthesis of N-, O-, C-Functionalized 2-Aryl Benzazole Derivatives

“…However, diisopropylamine (2d) with large steric hindrance was proved not feasible to undertake the S N Ar reaction, which was inconsistent with the previous reports. 19 Furthermore, cycloalkyl amine could fuse with 1a albeit with moderate to excellent isolated yields, for example pyrrolidine (3k, 80%), piperidine (3l, 86%), morpholine (3m, 91%), azetidine (3n, 43%).…”

“…Lastly, we designed and screened two special substrates to evaluate the electronic effect on the benzoxazole fragment (1h, 1i), which demonstrated that neither electron-withdrawing nor electrondonating group on benzo[d]oxazole ring would affect the S N Ar efficiency of this reaction, both smoothly converted into substituted products (3s, 94%; 3t, 90%; 3u, 94%). Interesting, 3u was generated and fused with two imidazole molecules, one imidazole molecule was fused the standard C−F bond, while another is, determined by 19 F NMR spectra, the C−F bond ortho to oxygen atom of benzoxazole fragment (see Supporting Information). After all, we want to shed some light on the reaction mechanism.…”

“…8 Hz),159.5,159.5,148.5,148.3,141.7,132.9 (d,J = 8.6 Hz), 130.4 (d, J = 1. 3 Hz),124.5 (d,J = 3.8 Hz),123.3,117.1 (d,J = 21.5 Hz),116.9,115.7 (d,J = 10.4 Hz),109.8,35.0,31.8;19 F NMR (471 MHz, CDCl 3 ) δ −110.19 (d, J = 6.1 Hz); IR (neat/cm −1 ) 3077, 2962,2907,2869,1623,1613,1588,1546,1482,1460,1341,1274,1223,1203,1111,1024,874,829,803,777,749,704,659 2-(2-Fluorophenyl)pyrimidine (1l). A suspension of 2-bromopyrimidine (1 mmol, 157 mg, 1.0 equiv) and (2-fluorophenyl)boronic acid (1.1 mmol, 154 mg, 1.1 equiv), Pd(PPh 3 ) 4 (0.05 mmol, 57 mg, 5 mol %), Na 2 CO 3 (2 mmol, 210 mg, 2.0 equiv), EtOH (3 mL), deionic water (3 mL), N,N-dimethylacetamide (5 mL) was stirred at 120 °C under nitrogen in a sealed Shlenck tube for 18 h. After finished, the mixture was extracted with ethyl acetate (5 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified through Silica gel chromatography (PE/EA = 10/1), which afforded the desired product 1l in colorless oil (150 mg, 86%); 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 4.9 Hz, 2H), 7.99 (td, J = 7.8, 1.7 Hz, 1H), 7.44−7.31 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H); 19 1,116.8 (d,J = 22.5 Hz); IR (neat/cm −1 ) 3045,…”

Recent Progress in Amination Enabled by Transition-Metal-Free C(sp2)–O/C(sp2)–S Bond Cleavage Strategy

“…16 In 2010, Mortier and co-workers described a nucleophilic substitution of 2-methoxybenzoic acid (1) using in situ prepared lithium amides to give anthranilic acids 3 with low to excellent efficacy (14-97% yield, Scheme 2). 17 This strategy avoids the use of protection/deprotection operations for the carboxy group. Furthermore, N-aryl-and N-alkylanthranilic acids are very important synthetic blocks found in anti-inflammatory agents and candidates for therapy in neurodegenerative and amyloid diseases.…”

An Unexpected Role of Carbon Disulfide: A New and Efficient Method for the Synthesis of 2‐Substituted Benzimidazoles

“…Most of these methods have certain limitations such as tedious processes, harsh reaction conditions, application of hazardous catalysts, generation of toxic metal reagents, and low yields of products. Additionally, in view of the pharmaceutical application of arylbenzimidazoles and due to potentially toxic contamination of pharmaceutical products, effective removal of some metals such as Pd or Cu in active pharmaceutical ingredients (API) provides important health benefits [19]. So, it has been worthwhile to search for practical metal-free conditions.…”