Methyl Hydrazinocarboxylate as a Practical Alternative to Hydrazine in the Wolff–Kishner Reaction

Dedicated to Professor Steven V. Ley on the occasion of his 70^th birthday.

Abstract

Herein we describe a facile protocol for the reduction of aromatic ketones and aldehydes to the corresponding methylene unit. The procedure involves isolation of a carbomethoxyhydrazone intermediate that is easily decomposed to the reduced product without the requirement for large quantities of pernicious hydrazine.

Key words

reduction - aldehydes - ketones - heterocycles - hydrazones - alkanes

• References and Notes

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• 28 General Procedure 1 To the aldehyde or ketone (1.0 g) in EtOH (5–10 mL) was added methyl hydrazinocarboxylate (1.3 equiv) followed by a few drops of AcOH. The reaction was heated at reflux overnight and then cooled to r.t. The product was either purified by recrystallization by dropwise addition of H₂O, cooling upon ice, and collection of the product by Büchner filtration, or the solvent was removed in vacuo and the crude product purified by flash column chromatography to give the carbomethoxyhydrazones. General Procedure 2 KOH (4 equiv)* was dissolved in triethylene glycol (5 mL) and the solution was heated to 100 °C, forming an orange solution. The carbomethoxyhydrazone (0.5 g) was added in one portion, and the reaction was further heated at 140 °C for 4 h after which time the reaction was cooled, diluted with H₂O, and extracted with Et₂O. The organic phase was dried (MgSO₄), filtered, and the solvent removed in vacuo. The crude product was purified by flash column chromatography to provide the desired products as pale yellow oils. *Add one more equivalent KOH per acidic group present. Representative Data for Methyl (E)-2-[1-(4-Bromophenyl)ethylidene]hydrazine-1-carboxylate (Table 1, entry 2) ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (1 H, br s, NH), 7.63 (2 H, d, J = 8.8 Hz, CH_Ar), 7.49 (2 H, d, J = 8.8 Hz, CH_Ar), 3.88 (3 H, s, OCH₃), 2.19 (3 H, s, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 147.5 (C=N), 136.8 (C_ArBr), 131.6 (C_ArH), 127.9 (C_ArH), 123.6 (C_Ar), 53.3 (OCH₃), 12.7 (CH₃). IR (neat): ν_max = 3196, 2945, 1730, 1702, 1539, 1484 cm^–1. HRMS (ESI⁺): m/z was calcd for C₁₀H₁₂O₂N₂ ⁷⁹Br: 271.0077 [M + H]⁺; found: 271.0077. Mp 152–155 °C (EtOH). Representative Data for 1-Bromo-4-ethylbenzene (Table 1, entry 2) ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (2 H, d, J = 8.4 Hz, CH_Ar), 7.06 (2 H, d, J = 8.4 Hz, CH_Ar), 2.59 (2 H, q, J = 7.6 Hz, CH₂CH₃), 1.21 (3 H, t, J = 7.6 Hz, CH₂CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 143.2 (C_Ar), 131.3 (C_ArH), 129.6 (C_ArH), 119.3 (C_ArBr), 28.3 (CH₂CH₃), 15.5 (CH₂CH₃). IR (neat): ν_max = 3022, 2963, 2928, 2871, 1485 cm^–1.