Friedel–Crafts Acylation of Aminocarboxylic Acids in Strong Brønsted Acid Promoted by Lewis Base P₄O₁₀

Abstract

The amino group in aminocarboxylic acids is sufficiently basic to be protonated in strong acids, and consequently, ionization of the carboxylic acid to an acylium ion is blocked due to charge−charge repulsion. Thus, acylation of aromatic compounds is significantly retarded in Friedel−Craft type reactions. We found that Friedel−Crafts acylation with aminocarboxylic acids can proceed smoothly even in a strong Brønsted acid (triflic acid, TfOH) if the Lewis base P 4 O 10 is added. Here we describe the Friedel−Crafts acylation reactions of anthranilic acid and αto δ-aminocarboxylic acids with benzene derivatives in the presence of P 4 O 10 . Non-amino-containing carboxylic acids as well as N-containing heteroaromatic carboxylic acids are available, and α-amino acids can be directly utilized without any protective group. Most substrates afford acylation products in high yields, although some epimerization/racemization may occur. Density functional theory (DFT) calculations suggested that P 4 O 10 neutralizes the protonated amine, converting the N−H covalent bond to a N−hydrogen bond and allowing the carboxylic acid OH functionality to serve as a good leaving group.

[(NHC)Pd(OAc)2]: Highly Active Carboxylate Pd(II)–NHC (NHC = N-Heterocyclic Carbene) Precatalysts for Suzuki–Miyaura and Buchwald–Hartwig Cross-Coupling of Amides by N–C(O) Activation

“…C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 196.7, 143.4, 138.1, 135.1, 132.3, 130.5, 130.1, 129.1, 128.4, 21.8. NMR spectroscopic data agreed with literature values 19. …”

“…NMR spectroscopic data agreed with literature values. 19 Phenyl[4-(trifluoromethyl)phenyl]methanone (3d). According to the general procedure, the reaction of tert-butyl benzoyl-(phenyl)carbamate (0.1 mmol, 1.0 equiv), 4-trifluoromethyl phenylboronic acid (2.0 equiv), H 2 O (5.0 equiv), KF (3.0 equiv), and [(IPr)Pd(OAc) 2 ] (3.0 mol %) in THF (0.25 M) for 16 h at 23 °C afforded after filtration and chromatography the title product in 95% yield (23.7 mg): white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.83−7.78 (m, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.63 (td, J = 7.3, 1.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 195.7, 140.9, 136.9, 133.9 (q, J = 32.7 Hz), 133.2, 130.3, 130.2, 128.7, 125.5 (q, J = 3.8 Hz), 123.8 (q, J = 272.6 Hz); 19 F{ 1 H} NMR (471 MHz, CDCl 3 ) δ −63.0.…”

“…According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.1 mmol, 1.0 equiv), (4-hydroxyphenyl)boronic acid (2.0 equiv), H 2 O (5.0 equiv), KF (3.0 equiv), and [(IPr)Pd(OAc) 2 ] (3.0 mol %) in THF (0.25 M) for 16 h at 23 °C afforded after filtration and chromatography the title product in 57% yield (11. Phenyl(3,4,5-trifluorophenyl)methanone (3k). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (0.1 mmol, 1.0 equiv), (3,4,5-trifluorophenyl)boronic acid (2.0 equiv), H 2 O (5.0 equiv), KF (3.0 equiv), and [(IPr)Pd(OAc) 2 ] (3.0 mol %) in THF (0.25 M) for 16 h at 23 °C afforded after filtration and chromatography the title product in 99% yield (23.3 mg): white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 7.76 (dd, J = 8.0, 1.4 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.0 Hz, 2H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 193.1, 152.1 (dd, J = 10.3, 3.4 Hz), 150.1 (dd, J = 10.3, 3.5 Hz), 143.9 (t, J = 15.3 Hz), 141.9 (t, J = 15.4 Hz), 136.3, 133.3, 133.2 (q, J = 5.6 Hz), 129.9, 128.8, 114.7 (dd, J = 16.6, 5.4 Hz); 19 F{ 1 H} NMR (471 MHz, CDCl 3 ) δ −132.3, −153.2. NMR spectroscopic data agreed with literature values.…”

“…NMR spectroscopic data agreed with literature values. 19 (4-Methoxyphenyl)(phenyl)methanone (3c, from 1c). According to the general procedure, the reaction of 1-benzoylpyrrolidine-2,5-dione (0.1 mmol, 1.0 equiv), 4-methoxyphenyl boronic acid (2.0 equiv), H 2 O (5.0 equiv), KF (3.0 equiv), and [(IPr)Pd(OAc) 2 ] (3.0 mol %) in THF (0.25 M) for 16 h at 23 °C afforded after filtration and chromatography the title product in 57% yield ( (4-Methoxyphenyl)(phenyl)methanone (3c, from 1d).…”

Synthesis of Spirolactones and Functionalized Benzofurans via Addition of 3-Sulfonylphthalides to 2-Formylaryl Triflates and Conversion to Benzofuroisocoumarins

“…Initially, electron transfer from Zn opens the lactone ring via a ketyl radical anion or an acyloxycarbenium ion or a Zn enolate to generate the intermediate XV which then abstracts a proton from the medium and gets converted to the intermediate XVI . Later, the intermediate XVI again takes a proton from the acidic medium to form the intermediate XVIII , which then forms an acylium ion intermediate XVII by elimination of water . Now the acylium ion XVII gets neutralized by the attack from neighboring enolizable carbonyl oxygen leading to the formation of benzofuroisocoumarin 7 .…”