Synthesis of N,N′-Dialkylated Cyclohexane-1,2-diamines and Their Application as Asymmetric Ligands and Organocatalysts for the Synthesis of Alcohols

Abstract

A series of N,N′-dialkylated derivatives of (1R,2R)-cyclohexane-1,2-diamine were synthesized, and a new approach to the one-pot preparation of this type of amine was demonstrated. The prepared diamines were used as organocatalysts for the two-step synthesis of α-hydroxy γ-keto esters from arenes, chlorooxoacetates, and ketones; they were also used as chiral ligands for Meervein–Ponndorf–Verley reductions and Henry reactions.

Key words

aldol reaction - organocatalysis - asymmetric catalysis - hydroxy acids - diamines - Meervein–Ponndorf–Verley reaction - Henry reaction

• References and Notes

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• 12 Diamines 3a–k; General Procedure from Schiff Bases 2a–k NaBH₄ (2.1 equiv) was added portionwise over 40 min to a solution of the appropriate Schiff base 2 (1.0 equiv) in MeOH (4 mL/mmol of Schiff base) at r.t. The mixture was refluxed with stirring for 1 h then cooled to r.t. H₂O (5 mL/mmol of Schiff base) was added, the mixture was extracted with CH₂Cl₂ (3 × 4 mL/mmol of Schiff base), and the organic layer was concentrated. If any aldehyde remained in the mixture, the residue was dissolved in 35% aq HCl (1 mL/mmol of Schiff base) and the solution was washed with CH₂Cl₂ (3 × 4 mL/mmol of Schiff base). Excess K₂CO₃ (4.5 equiv) was added to the aqueous phase, which was extracted with CH₂Cl₂ (3 × 3 mL/mmol of Schiff base). The organic layers were combined, dried, and concentrated to give an oily product. If the product was not sufficiently pure, it was purified by column chromatography. (1R,2R)-N,N′-Bis(4-chlorobenzyl)cyclohexane-1,2-diamine (3e) Yellow oil; yield: 2.45 g (48%); [α]_D ²⁵ –64.7 (с 1.2, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.29 (d, J = 8.4 Hz, 4 H), 7.25 (d, J = 8.4 Hz, 4 H), 3.88 (d, J = 13.4 Hz, 2 H), 3.64 (d, J = 13.4 Hz, 2 H), 2.28–2.24 (m, 2 H), 2.17–2.12 (m, 2 H), 1.76–1.71 (m, 2 H), 1.27–1.18 (m, 2 H), 1.11–0.97 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 139.6, 132.5, 129.5, 128.6, 61.2, 50.5, 32.0, 25.5; MS (ESI): m/z = 363, 365, 367 [M + H]⁺.
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• 15 Methyl (2S)-2-Hydroxy-4-oxo-2-phenylpentanoate (5a) White crystals; yield: 31.5 mg (93%). ¹H NMR (300 MHz, CDCl₃): δ = 7.56 (dd, J = 8.1, 1.2 Hz, 2 H), 7.41–7.27 (m, 3 H), 4.50–4.40 (br s, 1 H), 3.75 (s, 3 H), 3.56 (d, J = 17.7 Hz, 1 H), 3.01 (d, J = 17.7 Hz, 1 H), 2.21 (s, 3 H).