Electrochemical Synthesis of Polysubstituted Sulfonated Pyrazoles via Cascade Intermolecular Condensation, Radical–Radical Cross Coupling Sulfonylation, and Pyrazole Annulation

Abstract

Electrochemical synthesis of polysubstituted sulfonated pyrazoles from enaminones and sulfonyl hydrazides was established under metal-free, exogenous-oxidant-free, and mild conditions. By judicious choice of different electrochemical reaction conditions, NH 2-functionalized enaminones or N,N-disubstituted enaminones can react with aryl/alkyl sulfonyl hydrazides to afford tetra- or trisubstituted sulfonated pyrazoles in moderate to good yields, respectively. The gram-scale electrochemical transformation demonstrated the efficiency and practicability of this synthetic strategy. In addition, the sulfonated NH-pyrazole can be obtained via the dissociation of the N-tosyl group. Mechanistic studies reveal that the electrochemical cascade reaction synthesis of polysubstituted sulfonated pyrazoles proceeded via the sequence of intermolecular condensation, radical–radical cross coupling sulfonylation, and pyrazole annulation.

Rongalite as C1 Synthon in the Synthesis of Divergent Pyridines and Quinolines

“…Eluent: V PE /V EA = 10:1; yellow liquid (51.2 mg, 73% yield); 1 H NMR (400 MHz, CDCl 3 ): δ 7.84−7.80 (m, 4 H), 7.58 (s, 1 H), 7.16 (t, J = 8.5 Hz, 4 H), 2.60 (s, 6 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ194.5, 166.2 (d, J = 256.9 Hz), 158.0, 136.0, 133.2 (d, J = 2.9 Hz), 132.6 (d, J = 9.5 Hz), 130.5, 116.1 (d, J = 22.0 Hz), 23.4; 19 195.0, 158.3, 136.3, 135.5, 132.2, 131.3, 130.2, 129.3, 23.6 ( 2,bis [(4-(trifluoromethyl)phenyl)methanone] (3g). Eluent: V PE /V EA = 10:1; yellow solid (69.5 mg, 77% yield); mp 110−112 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (d, J = 7.9 Hz, 4 H), 7.76 (d, J = 7.9 Hz, 4 H), 7.62 (s, 1 H), 2.63 (s, 6 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 194.9, 159.0, 139.5, 136.9, 135.1 (d, J = 33.0 Hz), 130.2, 129.9, 125.9 (d, J = 4.0 Hz), 123.4 (q, J = 272.9 Hz), 23.8; 19 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 195.9, 157. 7, 145.0, 136.3, 134.3, 130.8, 130.2, 129.5, 23.4, 21.8; HRMS (ESI-TOF) m/z: [M + H] + calcd for C 23 H 22 NO 2 , 344.1645;found, 344.1634.…”

“…(4-Fluorophenyl)(quinolin-3-yl)methanone (7b). 22a Eluent: V PE / V EA = 15:1; yellow solid (26.1 mg, 52% yield); mp 89−90 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 9.29 (s, 1 H), 8.53 (s,1 H),8.20 (d,J = 8.5 Hz,1 H),3 H),1 H),1 H),7.22 (t,J = 8.8 Hz, 2 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 193.3, 165.7 (d,J = 256.3 Hz),150.1,149.5,138.5,133.3,132.6 (d,J = 9.4 Hz),131.9,130.0,129.5,129.1,127.7,126.6,115.9 (d, J = 22.0 Hz); 19 F NMR (376 MHz, CDCl 3 ): δ −104.5.…”

Recent Advances in Electrochemical Cascade Cyclization Reactions

“…Heterocyclic units, such as indolizines, pyrazoles, and 1,2,4-triazoles, are often encountered in various bioactive natural products and drugs, so the construction of these units is very important and has been developed to a certain extent. 67 The electrochemical synthesis of indolizines (119 and 123), pyrazoles (126 and 128), and triazolium inner salts 130 via cascade intermolecular cyclization was reported by the groups of Sharma (2022), 68 Baell Huang (2022), 69 and Feng and Ruan (2021) 70…”

“…67 In 2021 and 2022, the electrochemical synthesis of indolizines (119 and 123), pyrazoles (126 and 128) and triazolium inner salts 130 via cascade intermolecular cyclization was reported by research groups of Sharma, Baell, Huang, Feng and Ruan (Scheme 23). [68][69][70] The electro-oxidative cascade cyclization reactions between 2-methylquinazolin-4(3H)-ones 116, pyridines 117 and chalcones 118 in the presence of NH4I and nBu4NPF6 at 90 o C for 8 h gave heterocyclic substituted indolizines 119 in 51-83% yields. 68 The experimental results showed that heterocycles 120, pyridines (or isoquinolines) 121 and 5-styrylisoxazoles 122 can also be effectively converted into 43-84% yields of indolizines 123 using the same reaction system.…”

“…68 Sulfonyl hydrazides 125 reacted with enaminones 124 or N,N-dimethyl enaminones 127 under electrochemical promotion using KI or TBAI as the redox reagent to afford sulfonated pyrazoles 126 or 128 in up to 81% or 43-72% yields, respectively. 69 Triazolium inner salts 130 were obtained in 48-90% yields from the electrochemical thiocyanation/cyclization between aldehyde hydrazones 129 and NaSCN in MeCN at 23 °C. 70 Scheme 23 Electrochemical cascade cyclization for the synthesis of indolizines, pyrazoles, and triazolium inner salts Sharma and co-workers proposed a possible reaction mechanism for the synthesis of indolizines 123 (Scheme 24).…”