(S)-(-)-Limonene Derivatives Containing (1H-1,2,3-Triazol-4-yl)methyl 4-Bromobenzoate

Abstract

The synthesis of (S)-(-)-limonene derivatives containing (1H-1,2,3-triazol-4-yl)methyl 4-bromobenzoate were obtained by epoxidation, azidolysis and Huisgen’s 1,3-dipolar cycloaddition. Two products were isolated and characterized by FT-IR, ¹H NMR, ¹³C NMR, ESI-MS and optical rotation.

1. Introduction

The use of natural products as starting material is a very attractive concept in order to use renewable, inexpensive and enantiomerically pure compounds. In this work, were synthesized two derivatives of (S)-(-)-limonene. These novel structures were created following the rules of click chemistry [1] and these reactions can be easily made over similar natural substrates.

2. Results and Discussions

Complete epoxidation of (S)-(-)-limonene was performed with m-chloroperbenzoic acid, followed by azidolysis of epoxides with sodium azide and ammonium chloride in refluxing methanol. In the azidolysis step, azide attacks the epoxide on the side chain of limonene at primary carbon and the epoxide of the ring by a trans-diaxial approach [2]. So this step yields a mixture of two azidoalcohols 3a and 3b. Then was performed the coupling of these azides and a terminal ethynyl block using Cu(I)-catalyzed click chemistry reaction. The Huisgen 1,3-dipolar cycloaddition using in situ reduced copper (I) as catalyst, gives only 1,4-disubstituted 1,2,3-triazoles [3]. The products 4a and 4b were obtained by flash chromatography as epimeric mixtures.

Scheme 1. Synthesis of triazol containing products from (S)-(-)-limonene.

Scheme 1. Synthesis of triazol containing products from (S)-(-)-limonene.

3. Experimental Section

(1-{2-[(1S,3R,4R)-3-(4-{[(4-bromophenyl)carbonyloxy]methyl}-1H-1,2,3-triazol-1-yl)-4-hydroxy-4-methylcyclohexyl]-2-hydroxypropyl}-1H-1,2,3-triazol-4-yl)methyl 4-bromobenzoate (4a) and {1-[(1R,2R,4S)-4-[1-(4-{[(4-bromophenyl)carbonyloxy]methyl}-1H-1,2,3-triazol-1-yl)-2-hydroxypropan-2-yl]-2-hydroxy-1-methylcyclohexyl]-1H-1,2,3-triazol-4-yl}methyl 4-bromobenzoate (4b)

A solution of m-chloroperbenzoic acid 70% w/w (930 mg, 3.76 mmol) in 8 mL of DCM was added dropwise (~ 30 min.) to solution of (S)-(-)-limonene (250 mg, 1.84 mmol) in 2 mL of DCM at 0 °C. The reaction mixture was stirred for 3 h and then washed twice with saturated NaHCO₃ solution. The aqueous layer was extracted with DCM, dried over Na₂SO₄ and the solvent was removed at low pressure to obtain colorless oil. The crude epoxide obtained, was dissolved in 5 mL of MeOH, then NH₄Cl (393 mg, 7.34 mmol) and NaN₃ (477 mg, 7.34 mmol) were added to the stirred solution. The reaction mixture was refluxed for 6 h and then it was allowed to cool to room temperature. Water was added to the mixture and was extracted with Et₂O. The organic layers were washed with brine, dried over Na₂SO₄ and the solvent was removed at low pressure to obtain dark yellow oil. The crude reaction was dispersed with compound 5 (880 mg, 3.36 mmol) into a mixture of t-BuOH/Phosphate buffer pH 7 (1:1) (9 mL). A solution (0.87 mL) of CuSO₄·5H₂O (43.5 mg, 0.17 mmol) was added. Ascorbic acid (165 mg, 0.96 mmol) was dissolved in 5 mL of water and neutralized with NaOH solution, and then this solution was added to the mixture. After TLC showed complete conversion, the mixture was diluted with water, and extracted with AcOEt. The organic layers were dried with Na₂SO₄, and the solvent was removed at low pressure. The crude reaction mixture was purified by flash silica gel column chromatography (AcOEt/i-PrOH 100:0.5) to afford 4a (552mg, 0.72 mmol, 39.5% yield) and 4b (272 mg, 0.37 mmol, 19.5% yield) as two white solids in a 59% yield for three steps.

Product 4a: Ratio of epimers (57:43). m.p.: 79–80 °C. ${\left[\alpha \right]}_D^{25}$ = + 8.4 (c 1.02, CDCl₃). ¹H NMR (CDCl₃, 400 MHz): δ = 7.90 (m, 8 H), 7.84 (s, 1 H), 7.82 (s, 1 H), 7.78 (s, 2 H), 7.58 (m, 8 H), 5.47 (m, 8 H), 4.79 (m, 2 H), 4.31 (m, 4 H), 2.38 (m, 2 H), 2.15 (m, 2 H), 1.98 (m, 2 H), 1.80 (m, 4 H), 1.52 (s, 3 H) , 1.51 (s, 3 H), 1.31 (m, 4 H), 0.95 (s, 3 H) , 0.92 (s, 3 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 165.82, 165.80, 165.78, 142.38, 142.28, 142.25, 131.79, 131.26, 128.56, 128.53, 128.49, 128.48, 126.18, 126.03, 122.16, 73.66, 73.52, 70.57, 70.53, 70.40, 64.15, 64.13, 58.29, 58.20, 58.17, 58.13, 57.63, 36.73, 36.47, 31.22, 31.06, 30.10, 28.70, 27.92, 22.56, 21.45, 21.32, 21.28, 21.11. IR (NaCl film, cm⁻¹): 2671, 1607, 1494, 1325, 1214, 1065, 988, 766, 747. HRMS (ESI): Found [M+H]⁺ 731.0822. C₃₀H₃₃Br₂N₆O₆ requires 731.0823. C₃₀H₃₃Br₂N₆O₆ requires 731.0823. Anal. calc. for C₃₀H₃₃Br₂N₆O₆. 3H₂O:C, 45.82, H, 4.87, N, 10.69. Found: C, 45.87, H, 4.72, N, 9.95.

Product 4b: Ratio of epimers (55:45). m.p.: 111–112 °C. ${\left[\alpha \right]}_D^{25}$ = + 27.2 (c 1.08, CDCl₃). ¹H NMR (CDCl₃, 400 MHz): δ = 7.89 (m, 8 H), 7.81 (s, 1 H), 7.76 (s, 1 H), 7.69 (s, 1 H), 7.68 (s, 1 H), 7.56 (m, 8 H), 5.45 (m, 8 H), 4.54 (m, 1 H), 4.50 (m, 1 H), 4.39 (m, 4 H), 2.36 (m, 2 H), 2.23 (m, 2 H), 2.03 (m, 2 H), 1.85 (m, 4 H), 1.73 (m, 4 H), 1.06 (s, 3 H), 1.04 (s, 3 H), 0.94 (s, 3 H), 0.93 (s, 3 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 165.81, 165.75, 142.42, 141.51, 131.81, 131.79, 131.76, 131.30, 128.60, 128.56, 128.49, 128.45, 128.42, 128.41, 126.03, 126.02, 125.94, 125.89, 73.88, 73.82, 70.37, 65.28, 65.23, 58.27, 58.24, 58.17, 58.13, 57.63, 39.17, 39.14, 34.31, 34.28, 28.26, 27.55, 27.25, 27.19, 22.14, 21.68, 21.35, 20.92. IR (NaCl film, cm⁻¹): 2967, 1719, 1589, 1398, 1271, 1101, 1013, 758, 737. HRMS (ESI): Found [M+H]⁺ 731.0820. Anal. calc. for C₃₀H₃₃Br₂N₆O₆. 2H₂O:C, 46.89, H, 4.72, N, 10.94. Found: C, 47.47, H, 4.84, N, 10.85.