Mild Synthesis of Symmetric 3,5-Disubstituted Nitrobenzenes

Abstract

A mild synthesis of 3,5-disubstituted nitrobenzenes from readily available 3-formylchromones is reported. The developed methodology follows a cascade process, promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene. The proposed mechanism involves an initial Michael addition of nitromethane at C-2 of a 3-formylchromone. The resultant intermediate undergoes another Michael reaction with a second 3-formylchromone molecule. After ring closure through intramolecular cyclization, the aromatization is completed by deformylation, affording the 3,5-disubstituted nitrobenzenes in 52–86% yield. The reported method produces three new C–C bonds in a simple and straightforward manner, and it is consistent with gram-scale synthesis.

Key words

nitrobenzenes - formylchromones - nitromethane - Michael addition - Nef reaction - cascade reaction

Publication History

Received: 28 March 2022

Accepted after revision: 13 June 2022

Accepted Manuscript online:
13 June 2022

Article published online:
20 July 2022

• References and Notes

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• 11 3,5-Disubstituted Nitrobenzenes 3a–g; General Procedure In a 25 mL round-bottom flask, MeNO₂ (2; 10.0 μL, 0.187 mmol, 0.5 equiv) and DBU (28.0 μL, 0.187 mmol, 0.5 equiv) were dissolved in CH₂Cl₂ (2 mL), and the solution was stirred for 30 min at the reflux. The appropriate 3-formylchromone 1a–g (0.374 mmol, 1 equiv) was then added and the mixture was refluxed under the normal atmosphere for 20 h (3a, 3c–e and 3g)or 40 h (3b and 3f). The reaction was quenched with H₂O and the mixture was extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by preparative TLC (10% hexane–CH₂Cl₂) and recovered by extraction with EtOAc.
• 12 Typical analytical data: (5-Nitro-1,3-phenylene)bis[(2-hydroxyphenyl)methanone] (3a) Light-yellow solid; yield: 36.0 mg (53%); mp 114–16 °C. ¹H NMR (300 MHz, CDCl₃): δ = 11.63 (s, 2 H, OH), 8.72 (d, J = 1.5 Hz, 2 H, H-2), 8.27 (t, J = 1.5 Hz, 1 H, H-4), 7.60 (ddd, J = 8.7, 7.2, 1.7 Hz, 2 H, H-9), 7.50 (dd, J = 8.2, 1.7 Hz, 2 H, H-11), 7.14 (dd, J = 8.7, 1.1 Hz, 2 H, H-8), 6.96 (ddd, J = 8.2, 7.2, 1.1 Hz, 2 H, H-10). ¹³C NMR (75 MHz, CDCl₃): δ = 197.6 (2 C, C-5), 163.6 (2 C, C-7), 148.0 (C-1), 139.7 (2 C, C-3), 137.8 (2 C, C-9), 134.5 (C-4), 132.7 (2 C, C-11), 126.4 (2 C, C-2), 119.5 (2 C, C-10), 119.1 (2 C, C-8), 118 (2 C, C-6). HRMS (ESI^–): m/z [M – H]^– calcd for C₂₀H₁₂NO₆: 362.0665; found: 362.0662. (5-Nitro-1,3-phenylene)bis[(2-hydroxy-5-nitrophenyl)methanone] (3f) Beige solid; yield: 72.9 mg (86%); mp 256–258 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.63 (d, J = 1.6 Hz, 2 H, H-2), 8.42 (t, J = 1.6 Hz, 1 H, H-4), 8.36–8.30 (m, 4 H, H-9 and H-11), 7.14 (d, J = 9.8 Hz, 2 H, H-8). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 192.1 (2 C, C-5), 162.8 (2 C, C-7), 148.5 (C-1), 139.9 (2 C, C-1), 139.0 (2 C, C-3), 134.9 (C-4), 129.4 (2 C, C-9 or C-11), 127.9 (2 C, C-9 or C-11), 127.4 (2 C, C-2), 125.2 (2 C, C-6), 118.1 (2 C, C-8). HRMS (ESI^–): m/z [M –H]^– calcd for C₂₀H₁₀N₃O₁₀: 452.0365; found: 452.0369. 8-Nitro-11H-6,10-metheno-5H-dibenzo[d,m][1,3]dioxacyclotetradecin-5,11-dione (4) Brown solid; yield: 17.8 mg (26%); mp 176–178 °C. ¹H NMR (300 MHz, CDCl₃): δ = 9.05 (d, J = 1.5 Hz, 2 H, H-2), 8.26 (t, J = 1.5 Hz, 1 H, H-3), 7.71 (dd, J = 7.6, 1.8 Hz, 2 H, H-9), 7.56 (ddd, J = 8.4, 7.4, 1.8 Hz, 2 H, H-11), 7.29–7.15 (m, 4 H, H-8 and H-10), 6.09 (s, 2 H, H-12). ¹³C NMR (75 MHz, CDCl₃): δ = 191.8 (2 C, C-5), 155.7 (2 C, C-7), 149.1 (C-1), 141.5 (C-4), 137.7 (2 C, C-3), 134.2 (2 C, C-11), 132.5 (2 C, C-9), 127.9 (2 C, C-6), 126.2 (2 C, C-2), 123.8 (2 C, C-8 or 10), 113.7 (2 C, C-8 or 10), 88.4 (C-12). HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₁H₁₄NO₆: 376.0821; found: 376.0844.
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• 18 (5-Nitro-1,3-phenylene)bis[(2-hydroxy-5-methylphenyl)methanone] (3b): Gram-Scale Synthesis In a 100 mL round-bottomed flask (100 mL), MeNO₂ (2; 142 μL, 2.65 mmol, 0.5 equiv) and DBU (397 μL, 2.65 mmol, 0.5 equiv) were dissolved in CH₂Cl₂ (28 mL), and the mixture was stirred for 30 min at the reflux. 3-Formylchromone 1b (1.0 g, 5.3 mmol) was added, and the mixture was refluxed under a normal atmosphere for 40 h. The reaction was quenched with H₂O and the mixture was extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient 20% hexane–CH₂Cl₂ to CH₂Cl₂); yield: 1.5 g (72%).