The Synthesis of Novel 7-(Substituted benzyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones via Tandem Ugi–Huisgen Reactions

Abstract

A convenient method for the synthesis of 2-azido-3-arylpropanoic acids via the Meerwein halogenoarylation reaction of acrylic acid esters with diazonium salts, subsequent nucleophilic substitution of the halogen by an azide, and saponification is developed. The newly formed 2-azido-3-arylpropanoic acids react under the conditions of non-catalytic four-component Ugi reactions, leading to the formation of α-azidoamides in good yields. The use of propargylamine as the amine component allows the formation of Ugi adducts with azide and acetylene motifs ready for intramolecular 1,3-dipolar Huisgen cycloaddition to give the [1,2,3]triazolo[1,5-a]pyrazine annulated system. The Ugi reaction is found to give 2-azido-3-aryl-N-(2-oxo-1,2-disubstituted ethyl)-N-(prop-2-yn-1-yl)propanamides at room temperature without azide–alkyne cycloaddition. These dipeptides are converted into 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones in near quantitative yields by heating in toluene. However, when the Ugi reaction is carried out by heating, it results in a one-pot Ugi–Huisgen tandem reaction leading to 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones in excellent yields. Moreover, the possibility of the incorporation of a bromovinyl fragment (the synthetic equivalent of an acetylene fragment) via the aldehyde component of the Ugi reaction is demonstrated in an alternative preparation of the [1,2,3]triazolo[1,5-a]pyrazine system.

Divergent cyclization of 2-(5-iodo-1,2,3-triazolyl)benzamides toward triazole-fused lactams and cyclic imidates

“…2 The discovery of catalytic approaches to 1,4-3 and 1,5-disubstituted triazoles 4 rendered them as affordable and viable starting materials for the formation of fused triazoles. 5 Thus, the common route, utilizing the thermal intramolecular Huisgen cycloaddition 6 (Scheme 1A-1), was augmented by interrupted CuAAC combined with Ullmann-type C-C coupling (Scheme 1A-2) 7 or oxidative 8 capture (Scheme 1A-3). Ag-, 9 Cu-, 10 and light/ I 2 -mediated 11 radical cyclizations (Scheme 1A-4) have demonstrated their utility for the preparation of fused triazoles, containing C-N or C-O bonds, attached to the triazole ring.…”

Cu/Ag-Mediated One-Pot Enantioselective Synthesis of Fully Decorated 1,2,3-Triazolo[1,5-a]pyrazines

“…Compound II , with potent in vitro activity against DPP-4 and good pharmacokinetic profiles, was selected as a potential new candidate for the treatment of type 2 diabetes . Clearly, the development of a modular platform to access fused 1,2,3-triazoles derivatives from readily available materials is highly appealing and has been intensively studied in recent years. − …”

“…However, previous methodologies have mainly focused on the synthesis of racemic 1,2,3-triazolo­[1,5- a ]­pyrazine derivatives . Currently, asymmetric methods to synthesize this scaffold remain scarce and are mainly relying on multiple stereospecific transformations from chiral starting materials such as α-amino acid derivatives (Figure b) .…”

Photocatalytic Radical Coupling of Organoborates with α-Halogenated Electron-Poor Olefins

“…1-(2-Bromo-2-diethoxyphosphoryl-ethyl)-4-(4-ethoxyphenyl)benzene (40). White solid (50 mg, yield 69%); HPLC (method A): Rt 3.62 min; eluent: DCM/ethyl acetate 50:50; 1 H NMR (600 MHz, DMSO-d 6 ): δ ppm 7.59 (d, J = 8.72 Hz, 2H), 7.55 (d, J = 8.36 Hz, 2H), 7.35 (d, J = 8.17 Hz, 2H), 6.99 (d, J = 8.72 Hz, 2H), 4.63 (ddd, J = 11.63, 9.45, 3.63 Hz, 1H), 4.09−4.20 (m, 4H),4.06 (q, J = 6.96 Hz, 2H), 3.41−3.52 (m, 1H), 2.93−3.02 (m, 1H), 1.34 (t, J = 6.90 Hz, 3H), 1.27 (q, J = 7.27 Hz, 6H);13 C{ 1 H} NMR (126 MHz, DMSOd 6 ): δ ppm 158.1, 138.3, 135.8−135.8 (J C,P = 14.7 Hz), 132.1, 129.6 (2C), 127.6 (2C), 125.9 (2C), 114.8 (2C), 63.0−63.1 (J C,P = 6.4 Hz), 63.0, 62.8−62.9 (J C,P = 6.4.Hz), 41.9−43.0 (J C,P = 152 Hz), 37.5, 16.3−16.3 (J C,P = 5.1 Hz), 16.2−16.2 (J C,P = 5.1 Hz); HRMS (ESI): C 20 H 26 BrO 4 P [M + H] + : calcd, 441.0825; found, 441.0818. Ethyl 2-Amino-3-(4′-ethoxy-[1,1′-biphenyl]-4-yl)propanoate (41).…”

“…Methyl 2-Chloro-5-phenyl-pentanoate (24). Colorless oil (18 mg, yield 40%); HPLC (method A): Rt 3.32; eluent: n-hexane/ethyl acetate 80:20; 1 H NMR (600 MHz, DMSO-d 6 ): δ ppm 7.25−7.32 (m, 2H), 7.15−7.21 (m, 3H), 4.66 (dd, J = 7.99, 5.81 Hz, 1H), 3.70 (s, 3H), 2.56−2.65 (m, 2H), 1.92−2.00 (m, 1H), 1.78−1.87 (m, 1H), 1.57−1.74 (m, 2H); 13 C{ 1 H} NMR (126 MHz, DMSO-d 6 ): Light yellow oil (35 mg, yield 80%); HPLC (method A): Rt 5.05 min; eluent: n-hexane; 1 H NMR (600 MHz, DMSO-d 6 ): δ ppm 7.58 (d, J = 8.90 Hz, 2H), 7.53 (d, J = 8.17 Hz, 2H), 7.24−7.36 (m, 7H), 7.01 (d, J = 8.72 Hz, 2H), 5.17 (s, 2H), 4.95 (t, J = 7.45 Hz, 1H), 4.06 (q, J = 6.90 Hz, 2H), 3.33−3.38 (m, 1H), 3.18 (dd, J = 14.08, 7.72 Hz, 1H), 1.35 (t, J = 6.90 Hz, 3H); 13 C{ 1 H} NMR (126 MHz, DMSOd 6 ): δ ppm 168.6, 158.1, 138.6, 135.2, 134.3, 131.9, 129.J = 7.08 Hz, 1H), 6.98 (d, J = 8.72 Hz, 2H), 4.77 (t, J = 7.45 Hz, 1H),4.05 (q, J = 6.90 Hz, 2H), 3.43 (dd, J = 13.81, 7.27 Hz, 1H), 3.14 (dd, J = 13.81, 7.63 Hz, 1H), 1.33 (t, J = 6.90 Hz, 3H);13 C{ 1 H} NMR (126 MHz, DMSO-d 6 ): δ ppm 166.3, 158.1, 138.4, 138.White solid (8 mg, yield 13%); HPLC (method A): Rt 3.84 min; eluent: n-hexane/ethyl acetate 95:5; 1 H NMR (600 MHz, DMSOd 6 ): δ ppm 7.58−7.64 (m, 4H), 7.45 (d, J = 8.17 Hz, 2H), 7.00 (d, J = 8.72 Hz, 2H), 5.03 (dd, J = 12.08, 1.00 Hz, 1H), 4.07 (q, J = 6.…”