One-Pot Carbon-Chain Extension for Nervonic/Carboxylic Acid Synthesis with the Assistance of Microwaves and Lithium Chloride

Abstract

A mild, green, and convenient synthesis of nervonic acid was developed through a one-pot carbon-chain extension with the assistance of microwaves and lithium chloride (55% total yield); this is preferable to a previous six-step method (10% total yield). Compared with the previous lengthy refluxing process (>80 hours) with corrosive reagents, which furnished a mixture of cis- and trans-isomers, this efficient microwave protocol was more than a hundred times faster and was free of configurational isomerization. Notably, LiCl played a dual role in a Krapcho decarboxylation and subsequent ester hydrolysis under neutral conditions that replace the corrosive saponification in the previously reported one-pot method. Finally, this mild and efficient protocol was successfully applied to various carboxylic acids, including natural products, verifying its wide utility, easy operations, and attractive properties in organic synthesis.

Key words

microwave heating - lithium chloride - one-pot synthesis - carbon-chain extension - nervonic acid - homologation

Publication History

Received: 20 December 2022

Accepted after revision: 21 January 2023

Accepted Manuscript online:
23 January 2023

Article published online:
13 February 2023

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• 27 Nervonic Acid (1a); ^12–15 Typical ProcedureLiAlH₄ (759 mg, 20 mmol) was added to a stirred solution of erucic acid (2-a; 3.39 g, 10 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred at rt for 1 h, then vigorously stirred with Na₂SO₄·10H₂O. The residue was extracted with EtOAc, and the extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give alcohol 4-a. This product was treated with TsCl (2.10 g, 11 mmol), Et₃N (1.53 mL, 11 mmol), and DMAP (61.1 mg, 0.5 mmol) in CH₂Cl₂ (50 mL) for 1 h at rt. The reaction was then quenched with H₂O and CH₂Cl₂, and the organic fraction was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give tosylate 8-a, which was used in the next step directly without further purification. The crude 8-a and NaI (0.15 g, 1 mmol) were simultaneously added to a microwave vessel containing a stirred solution of dimethyl malonate (1.45 g, 11 mmol) and NaOMe (594 mg, 11 mmol) in DMF (30 mL). The resulting mixture was stirred vigorously at 150 °C for 10 min under microwave irradiation (300 W), then LiCl (2.12 g, 50 mmol) and H₂O (0.2 mL) were added, followed by an additional 20 min of irradiation (300 W) under the same conditions. Finally, dil aq HCl and EtOAc were added to quench the reaction, and the organic fraction was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was crystallized from acetone to give NA (1a) as a white solid; yield: 2.02 g (55%; purity: 98.9% by HPLC); mp 40–41 ℃ (Lit.¹² 39–39.5 ℃).HPLC [Agilent 1260 LC]: ZORBAX SB-C18 (4.6 × 150 mm, 5 μm), MeOH–H₂O (98:2), 1 mL/min, 25 °C, λ = 205 nm. IR: 2915.1, 2848.8, 1692.2, 1468.6, 1202.8, 934.7, 721.0 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.39–5.30 (m, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 2.01 (q, J = 6.4 Hz, 4 H), 1.64 (q, J = 7.4 Hz, 2 H), 1.35–1.22 (m, 32 H), 0.88 (t, J = 6.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 180.2, 130.1, 34.2, 32.1, 29.93, 29.86, 29.82, 29.80, 29.75, 29.72, 29.68, 29.60, 29.5, 29.4, 29.2, 27.4, 24.8, 22.8, 14.3. HRMS (ESI^–): m/z [M – H]^– calcd for C₂₄H₄₅O₂: 365.3425; found: 365.3428.