Journal of Chemistry
Volume 2019 (2019), Article ID 9268567, 8 pages
https://doi.org/10.1155/2019/9268567

Research Article

Catalytic β-Bromohydroxylation of Natural Terpenes: Useful Intermediates for the Synthesis of Terpenic Epoxides

Saadia Oubaassine,1,2 Angela Köckritz,¹ Reinhard Eckelt,¹ Andreas Martin,¹ Mustapha Ait Ali,² and Larbi El Firdoussi²

¹Leibniz-Institut für Katalyse e. V. (LIKAT Rostock), Albert-Einstein-Str. 29 a, 18059 Rostock, Germany
²Department of Chemistry, Equipe de Chimie de Coordination et Catalyse, Faculty of Sciences Semlalia, Cadi Ayyad University, P.O. Box: 2390, 40001 Marrakech, Morocco

Correspondence should be addressed to Larbi El Firdoussi; elfirdoussi@uca.ac.ma

Received 20 September 2018; Accepted 12 December 2018; Published 23 January 2019

Academic Editor: Radhey Srivastava

Copyright © 2019 Saadia Oubaassine et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

In a one-step procedure, various β-bromoalcohols were synthesized from natural terpenes in good to excellent yields. Using different catalysts, the reaction was carried out at room temperature, with H₂O as nucleophile and N-bromosuccinimide as a bromine source under mild reaction conditions. The synthesized β-bromoalcohols were subsequently converted in situ to the corresponding epoxides in good yields.

1. Introduction

Terpenes, the major constituents of essential oils, present a class of natural products which are cheap and abundantly available. This pool of chiral substances can be transformed into valuable substances of considerable interest mostly for the industrial production of pharmaceuticals, cosmetics, fragrances, perfumes, and flavors, besides useful synthetic intermediates and chiral building blocks [1].

There is a vast literature on catalytic transformations of terpenes for a broad variety of purposes. These transformations include isomerization, oxidation, hydration, condensation, hydroformylation, hydrogenation, cyclization, rearrangement, and ring contraction or enlargement [2–4]. Among these, halogenation, co-halogenation, and epoxidation being relatively inexpensive are the preferred methods for the large-scale production of flavor chemicals [5]. On the other hand, vic-bromoalcohols are extremely versatile building blocks in synthetic organic and industrial chemistry and are widely used for the preparation of marine natural products and other biologically valuable substances [6–9]. In addition, due to their high reactivity, these compounds can be utilized for some useful synthetic transformations such as ketones [10–12], aldehydes [13], epoxides [14, 15], and other derivatives [16].

The preparation of β-bromoalcohols has been reported directly from simple olefins by reaction with N-bromosuccinimide (NBS), which is a better choice compared to hazardous molecular halogens and other brominating agents, using several catalysts such as ionic liquids [17], β-cyclodextrin as a supramolecular catalyst [18], diphenyl-diselenide (PhSeSePh) [19], NH₄OAc [20], and iodine [21]. A significant progress has been made in recent years regarding vicinal hydroxybromination of alkenes and their subsequent functionalization. However, limited examples using terpenes as a material source have been reported.

Recently, we have described an efficient process for the preparation of vic-aminoalcohols directly from simple alkenes in good yields [22]. Our approach is based initially on the preparation of bromoalcohols by treating the corresponding alkenes at room temperature in the presence of NBS as a source of bromine and a catalytic amount of SiO₂ in water, followed by in situ addition of amine to form aminoalcohols. In our efforts to develop this methodology and to continue with our interest in the valorization of natural terpenes [23–27], we report here an expanded study of this process to natural terpenes. The scope and limitations of these transformations are discussed.

2. Experimental

2.1. Characterization and Methods

NMR studies were performed on Bruker Avance 300 and Bruker Avance DRX 400 spectrometers in CDCl₃, chemicals shifts are given in ppm relative to the solvent CDCl₃ (7.27 ppm (¹H); 77.0 ppm (¹³C)), and coupling constants (J) are given in Hz. ATR-IR spectra were measured using a Bruker Alpha with diamond ATR accessory. Mass spectrograms were recorded on a Thermo Electron MAT 95-XP spectrometer. The reaction mixtures were analyzed on a Shimadzu GCMS-QP 2010 chromatograph equipped with an FID and an MS detector and Optima 5MS column (50 m × 0.32 mm × 0.5 μm).

The parameters of the GC program were injector 250°C and FID 320°C; the temperature ramp started at 60°C for 3 min, then it was raised with 10°C/min up to 160°C and with 5°C/min up to 260°C. It was left at 260°C for 7 min; column pressure 138.8 kPa, column flow 3.02 mL/min; linear velocity 39.5 cm/s; total flow 50.7 mL/min. Conversion and yield were calculated using dodecane as the internal standard. Analytical thin layer chromatography (TLC) was conducted on Merck aluminium plates 60 F-254 with 0.2 mm layer of silica gel. Most reagents and solvents used in the experiments were purchased from commercial sources. SiZr30, Ti-SBA 15, and SBA 15 were synthesized according to literature procedures [28].

2.2. General Procedure for Bromohydroxylation of Terpenes

In a typical experiment, N-bromosuccinimide (1.3 equiv.) and 0.04 g of catalyst were added to a vigorously stirred solution of terpene (0.4 g) in aqueous acetone (4 : 1, v/v). The mixture was stirred at room temperature for 15 min. The reaction was monitored by GC. At the end of the reaction, the mixture was diluted with water and extracted three times with EtOAc (10 mL). The organic layer was dried over Na₂SO₄ and then concentrated, and the residue was purified by column chromatography using silica gel with EtOAc-heptane (3 : 7, v/v) as eluent. The obtained pure bromoalcohols were characterized by mass spectrometry, ATR-IR, MS/ESI measurements, and NMR spectroscopy. Characterization data can be found in ESI.

2.3. General Procedure for In Situ Synthesis of Epoxides

First, the respective bromoalcohols were prepared by the method described above. Then, in the same reactor, two equivalents of amine were added and the resulted mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and the solvent was removed under reduced pressure. Pure epoxide was obtained by column chromatography over silica gel using a mixture of EtOAc-heptane (2 : 8, v/v) and characterized by mass spectrometry, ATR-IR, MS/ESI measurements, and NMR spectroscopy. Characterization data can be found in ESI.

The structures of 2a and 3a were confirmed by comparison with literature data [29] and an authentic sample.

6-Bromo-3,7-dimethyl-octane-1,7-diol 2b (mixture of diastereomers). ¹H NMR (400 MHz, CDCl₃, δ): 0.88, 0.90 (3H, 2d, J = 6.3 and 6.5 Hz, CH₃), 1.31 (3H, s, CH₃), 1.32 (3H, s, CH₃), 1.34–1.77 (6H, m, 3 × CH₂), 1.83–2.00 (1H, m, CH), 2.43 (2H, broad s, OH), 3.65 (2H, m, CH₂), 3.95 (1H, 2 dd, J = 11.3 and 2.0 Hz, CH); ¹³C NMR (100 MHz, CDCl₃, δ): 19.21, 19.91 (C3-CH₃), 25.99, 26.14 and 26.24, 26.39 (gem-dimethyl), 28.67, 28.90 (C3), 31.13, 31.21 (C5), 35.71, 36.03 (C4), 38.95, 39.83 (C2), 60.57 (C1), 71.09, 71.25 (C6), 72.54, 72.60 (C7); ATR-IR:  = 3348, 2952, 2927, 2872, 1459, 1378, 1131, 1052, 774, 624 cm⁻¹; MS (EI, m/z (%)): 176 (3), 121 (2), 97 (6), 70 (12), 59 (100), 41 (10); MS (ESI, 180 eV): [M + Na]⁺ 275.06135, 277.05987 calc. 275.06171, 277.05974; C₁₀H₂₁BrO₂ (253.18).

6,7-Epoxy-3,7-dimethyl-1-octanol 3b (mixture of diastereomers). ¹H NMR (400 MHz, CDCl₃, δ): 0.851, 0.853 (3H, 2 d, J = 6.5 and 6.4 Hz, CH₃), 1.20 (3H, s, CH₃), 1.24 (3H, s, CH₃), 1.27–1.38 (2H, m, CH₂), 1.38–1.61 (5H, m, 2 CH₂ and CH), 2.48, 2.55 (1H, broad, OH), 2.65 (1H, t, J = 6.0 Hz, CH), 3.58 (2H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃, δ): 18.45, 18.50 and 19.29, 19.44 (gem-dimethyl), 24.70 (C3-CH₃), 25.99, 26.21 (C5), 29.04, 29.23 (C3), 33.48, 33.50 (C4), 39.35, 39.59 (C2), 58.30, 58.41 (C7), 60.43 (C1), 64.54, 64.59 (C6); ATR-IR:  = 3396, 2958, 2925, 2871, 1459, 1378, 1057, 676 cm⁻¹; MS (EI, m/z (%)): 111 (3), 85 (22), 71 (31), 59 (100), 55 (52), 41 (42); MS (ESI, 180 eV): [M + H]⁺ 173.15374, calc. 173.15361, [M + Na]⁺ 195.13595, calc. 195.13555; C₁₀H₂₀O₂ (172.27).

6-Bromo-3,7-dimethyl-oct-2-ene-1,7-diol 2c. ¹H NMR (300 MHz, CDCl₃, δ): 1.30 (3H, s, CH₃), 1.31 (3H, s, CH₃), 1.63 (3H, s, CH₃), 1.68–1.86 (1H, m, 1H of CH₂), 1.97–2.18 (2H, m, CH₂), 2.25–2.38 (1H, m, 1H of CH₂), 2.69, 2.79 (2H, 2 broad, OH), 3.90 (1H, dd, J = 1.7 and 11.6 Hz, CH), 4.10 (2H, d, J = 6.9 Hz, CH₂), 5.42 (1H, t, J = 6.6 Hz, CH); ¹³C NMR (75 MHz, CDCl₃, δ): 16.13 (C3-CH₃), 25. 84 and 26.41 (gem-dimethyl), 31.45 (C5), 37.68 (C4), 58.80 (C1), 69.12 (C6), 72.45 (C7), 124.58 (C2), 137.34 (C3); ATR-IR:  = 3401, 2975, 2932, 2873, 1713, 1450, 1367, 1133, 1063, 818 cm⁻¹; MS (EI, m/z (%)): 153 (4), 135 (48), 119 (8), 109 (15), 93 (25), 71 (38), 68 (100), 43 (76), 41 (49); MS (ESI, 180 eV): [M + H]⁺ 251.06357, calc. 251.06393; C₁₀H₁₉BrO₂ (250.05).

6,7-Epoxy-3,7-dimethyl-oct-2-en-1-ol 3c. ¹H NMR (300 MHz, CDCl₃, δ): 1.16 (3H, s, CH₃), 1.20 (3H, s, CH₃), 1.50–1.63 (2H, m, CH₂), 1.58 (3H, s, CH₃), 1.98–2.15 (2H, m, CH₂), 2.62 (1H, t, J = 6.2 Hz, CH), 2.86 (1H, broad, OH), 4.02 (2H, d, J = 6.6, CH₂), 5.33 (1H, t of q, J = 6.8, 1.2, =CH); ¹³C NMR (75 MHz, CDCl₃, δ): 15.93 and 18.43 (gem-dimethyl), 24.54 (C3-CH₃), 26.79 (C5), 35.95 (C4), 58.31 (C7), 58.61 (C1), 63.88 (C6), 124.13 (C2), 137. 36 (C3); ATR-IR:  = 3397, 2961, 2924, 2872, 1668, 1447, 1378, 998, 676 cm⁻¹; MS (EI, m/z (%)): 152 (1), 137 (3), 119 (2), 109 (19), 85 (63), 81 (84), 59 (88), 41 (100); MS (ESI, 180 eV): [M + H]⁺ 171.13767, calc. 171.13796, [M + Na]⁺ 193.11975, calc. 193.11990; C₁₀H₁₈O₂ (170.25).

5-(1-(Bromomethyl)-1-hydroxyethyl)-2-methylcyclohex-2-en-1-one 2d (mixture of diastereomers). ¹H NMR (300 MHz, CDCl₃, δ): 1.15 (3H, s, CH₃), 1.59 (3H, s, CH₃), 2.03–2.51 (5H, m, 2 × CH₂, CH), 3.22–3.39 (3H, m, OH and CH₂Br), 6.59–6.70 (1H, m, =CH); ¹³C NMR (75 MHz, CDCl₃, δ): 15.17 (C2-CH₃), 22.12, 22.45 (C7-CH₃), 25.81, 26.72 (C4), 37.92, 38.70 (C6), 41.36, 41.50 (C5), 41.86, 42.14 (C8), 71.51, 71.60 (C7), 134.44, 134.61 (C2), 144.86, 145.48 (C3), 199.69, 199.94 (C1=O); ATR-IR:  = 3428, 2975; 1655; 1369; 1105; 960; 655 cm⁻¹; MS (EI, m/z (%)): 230 (6), 228 (6), 153 (12), 137 (29), 121 (8), 110 (100), 95 (71), 81 (30), 57 (29), 41 (21); MS (ESI, 180 eV): [M + H]⁺ 247.03314, calc. 247.03345; C₁₀H₁₅BrO₂ (246.13).

2-Methyl-5-(2-methyloxiranyl)-cyclohex-2-enone 3d (mixture of diastereomers). ¹H NMR (300 MHz, CDCl₃, δ): 1.21–1.26 (3H, m, CH₃-C-O), 1.66–1.71 (3H, m, CH₃-C=C), 1.94–2.23 (3H, m, CH₂ + CH), 2.27–2.39 (1H, m, 1H of CH₂), 2.42–2.54 (2H, m, CH₂), 2.57–2.64 (1H, m, 1H of CH₂), 6.63–6.70 (1H, m, =CH); ¹³C NMR (75 MHz, CDCl₃, δ): 15.44 (C2-CH₃), 18.20, 18.71 (C7-CH₃), 27.51, 27.70 (C4), 39.70, 40.08 (C6), 40.56, 41.08 (C5), 52.22, 52.62 (C8), 57.63, 57.73 (C7), 135.27, 135.32 (C2), 143.73, 143.96 (C3), 198.51, 198.56 (C1=O); MS (EI, m/z (%)): 151 (4), 148 (8), 133 (19), 123 (19), 109 (100), 108 (90), 91 (40), 82 (57), 67 (19), 54 (47), 39 (40); MS (ESI, 180 eV): [M + H]⁺ 167.10734, calc. 167.10725; C₁₀H₁₅BrO₂ (166.21).

6-Bromo-7-hydroxy-3,7-dimethyl-octan-1-al 2e. ¹H NMR (400 MHz, CDCl₃, δ): 0.90–0.96 (3H, m, CH₃), 1.29 (3H, s, CH₃), 1.30 (3H, s, CH₃), 1.23–1.47 (1H, m, 1H of CH₂), 1.50–1.76 (2H, m, CH + 1H of CH₂), 1.82–1.98 (1H, m, 1H of CH₂), 1.99–2.12 (1H, m, 1H of CH₂), 2.15–2.43 (2H, m, CH₂), 3.87–3.92 (2H, m, OH and Br-CH), 9.70 (1H, s, CHO); ¹³C NMR (100 MHz, CDCl₃, δ): 19.29, 19.99 (C3-CH₃), 26.06, 26.15 and 26.25, 26.36 (gem-dimethyl), 27.19, 27.60 (C3), 31.00, 31.18 (C5), 35.56, 35.84 (C4), 50.34, 51.05 (C2), 70.45, 70.54 (C6), 72.49, 72.52 (C7), 202.57, 202.64 (CHO); ATR-IR:  = 3412, 2959, 2931, 2725, 1715, 1460, 1380 cm⁻¹; MS (EI, m/z (%)): 192 (4), 153 (4), 109 (8), 95 (10), 71 (42), 59 (100), 43 (33), 41 (17); MS (ESI, 180 eV): [M + H]⁺ 251.06462, 253.06248, calc. 251.06412, 253.06215; C₁₀H₁₉BrO₂ (251.16).

6,10-Dimethyl-9,10-epoxy-undec-3-en-2-one 3e (mixture of diastereomers). ¹H NMR (300 MHz, CDCl₃, δ): 0.87, 0.92 (3H, 2d, J = 6.7 Hz, CH₃), 1.20 (3H, s, CH₃), 1.24 (3H, s, CH₃), 1.27–1.70 (5H, m, CH, 2 × CH₂), 1.96–2.27 (2H, m, CH₂), 2.18 (3H, s, CH₃), 2.62 (1H, t, J = 5.9 Hz, CH-O), 6.01 (trans), 6.26 (cis) (1H, 2 d, J = 15.8 and 15.3 Hz, =CH-C=O), 6.64–6.88 (1H, m, -CH = ); ¹³C NMR (75 MHz, CDCl₃, δ): 18.48, 18.53 and 19.36, 19.40 (gem-dimethyl), 24.70 (C6-CH₃), 26.19, 26.22 (C8), 26.27, 26.74 (C6), 32.28, 32.37 (C1), 33.17, 33.33 (C7), 39.78, 39.94 (C5), 58.00, 58.10 (C10), 64.15, 64.20 (C9), 129.87, 132.42 (C3), 146.14, 146.63 (C4), 198.26 (CHO); ATR-IR:  = 2959, 2925, 2873, 1672, 1626, 1459, 1378, 1252,980 cm⁻¹; MS (EI, m/z (%)): 152 (2), 137 (12), 124 (6), 109 (29), 95 (49), 81 (40), 67 (24), 43 (100), 41 (39); MS (ESI, 180 eV): (M + H)⁺ 211.16921, calc. 211.16926; C₁₃H₂₂O₂ (210.31).

6-Bromo-7-hydroxy-3,7-dimethyl-oct-2-en-1-al 2f (mixture of diastereomers). ¹H NMR (300 MHz, CDCl₃, δ): 1.20–1.59 (1H, m, 1H of CH₂), 1.36 (3H, s, CH₃), 1.37 (3H, s, CH₃), 1.66–1.84 (1H, m, 1H of CH₂), 1.84–2.24 (1H, m, 1H of CH₂), 1.99, 2.196 (3H, 2d, J = 1.3 and 1.2 Hz, CH₃C = ), 2.24–2.45 (1H, m, 1H of CH₂) 2.56–3.03 (1H, m, 1H of CH₂) 3.89–4.07 (2H, m, OH and Br-CH), 5.90–5.97 (1H, m, =CH), 10.00, 10.02 (1H, 2d, J = 7.8 and 7.6 Hz, CHO); ¹³C NMR (75 MHz, CDCl₃, δ): 17.70 (C3-CH₃), 24.73, 26.26 and 26.38, 26.61 (gem-dimethyl), 31.42, 32.48 (C5), 39.17 (C4), 68.76, 69.02 (C6), 72.48, 72.51 (C7), 127.71, 129.45 (C2), 162.92, 162.02 (C3), 190.76, 191.13 (CHO); MS (EI, m/z (%)): 151 (12), 133 (6), 123 (7), 109 (7), 84 (86), 59 (100), 43 (46), 41 (28); C₁₀H₁₇BrO₂ (249.15); MS (ESI, 180 eV): [M + H]⁺ 249.04866, calc. 249.04802; C₁₀H₁₅BrO₂ (248.15).

3. Results and Discussion

3.1. Synthesis of Bromoalcohol 2a

In connection with our ongoing effort to prepare aminoalcohols from terpenes, we first focused on the optimization of bromohydrin synthesis to improve published results regarding limonene substrates. In general, it is a reaction that proceeds at a yield of 70–87% [29, 30]. Hence, we studied bromohydroxylation of limonene 1a under various reaction conditions (Scheme 1).

Scheme 1: Synthesis of limonene bromoalcohol.

Limonene 1a, which contains two different double bonds, was mainly bromohydroxylated to 2a at the internal double bond, while the external double bond remained unchanged (Table 1). The reaction proceeded smoothly at room temperature under extremely mild conditions. Systematic investigation in the presence of various catalytic systems was undertaken to define the best reaction conditions.

Table 1: Influence of the catalyst on the bromohydroxylation of 1a.

Entry
Catalyst
Remarks
Conversion (%)
Yield of 2a (%)

1
SiO₂
60 Å, 70–230 mesh
79
64

2
SIRAL 1
Al₂O₃/SiO₂ 99 : 1, 280 m²/g
81
65

3
Aerosil 300
SiO₂, 300 m²/g
87
51

4
SiZr30
SiO₂/ZrO₂ = 30, 573 m²/g
85
62

5
Zeolite beta, H⁺ form
ZEO cat PBH, SiO₂/Al₂O₃ 25–60, 600 m²/g
83
57

6
Ti-SBA15
SiO₂/TiO₂ = 30, 668 m²/g
78
61

7
SBA 15
SiO₂, 850 m²/g
82
62

8
TiO₂
Hombikat UV 100 (anatase), 250 m²/g
81
50

9
Zeolite Y, H⁺ form
CBV 720 (Zeolyst), SiO₂/Al₂O₃ = 30, 780 m²/g,
86
55

10
ZrO₂
Monoclinic phase, (Alfa Aesar), 90 m²/g
81
66

11
CeO₂
Nanopowder (Aldrich), particle size ≤ 25 nm
82
70

12
Dowex Marathon A
Cl⁻ form (Aldrich), 1.3 meq/mL,
76
70

13
Montmorillonite K-10
Powder, (Aldrich), 250 m²/g
84
58

14
None

60
40

Reaction conditions: limonene 0.4 g, NBS 1.3 equiv., catalyst 0.04 g, 5 mL acetone/H₂O 4 : 1 (v/v), r.t., 15 min. Conversion and yield were calculated by GC analysis using dodecane as the internal standard.

As depicted in Table 1, among the catalysts studied, CeO₂ nanopowder and Dowex Marathon A, Cl⁻ form, appeared to be the most suitable (entries 11, 12). They produced 2a in 70% yield within 15 min. But the differences in conversion and yield were not so significant whether acidic or basic catalysts were used. Probably, the generation of electrophilic bromine species forming halonium ion intermediates with the terpene followed by the nucleophilic attack of H₂O was possible at all polar catalyst surfaces. The most efficient catalyst (Dowex Marathon A) was subsequently used for the next steps of the optimization.

The effect of NBS was also evaluated (Table 2). Hence, the increase of NBS amount had a boosting effect on the conversion of 1a. When it was treated with at least 1.7 equivalents of NBS in an aqueous solution of acetone, 1a was totally converted (entries 7, 8). However, the maximum yield of the corresponding bromoalcohol 2a (70%) was obtained with only a slight surplus of NBS (1.3 equiv.) (entry 3). Using a larger excess, various by-products coming probably from side reactions (bromohydroxylation of exo-double bond) during the formation of bromohydrin were detected by gas chromatography.

Table 2: Effect of NBS amount on bromohydroxylation of 1a.

Entry
NBS (equiv.)
Conversion (%)
Yield of 2a (%)

1
1
61
54

2
1.1
69
56

3
1.3
76
70

4
1.4
89
67

5
1.5
95
68

6
1.6
98
68

7
1.7
100
57

8
2
100
43

Reaction conditions: 1a 0.4 g, NBS, catalyst (Dowex Marathon A, Cl⁻ form) 0.04 g, 5 mL acetone/H₂O 4 : 1 (v/v), r.t., 15 min. Conversion and yield were calculated by GC using dodecane as the internal standard.

The yield of bromoalcohol 2a could be also influenced by the nature of the solvent (Table 3). As can be seen in Table 3, the highest efficient protocol was achieved in acetone, methanol DMSO and THF (entries 1–5). In nitromethane, acetonitrile, and dichloroethane less than 50% yield was obtained (entries 6–8). An improvement of conversion and yield was achieved in acetone by lowering the reaction temperature to 0°C (entry 2). The reaction of 1a with NBS in methanol led selectively to the corresponding bromomethoxylated product in good yield (entry 3).

Table 3: Solvent effect on the bromohydroxylation of 1a.

Entry
Solvent
Conversion (%)
Yield of 2a (%)

1
Acetone
76
70

2
Acetonea
89
82

3
MeOH
88
79b

4
DMSO
84
63

5
THF
80
63

6
Nitromethane
75
26

7
Acetonitrile
72
49

8
Dichloroethane
55
23

Reaction conditions: 1a 0.4 g, NBS 1.3 equiv., catalyst (Dowex Marathon A, Cl⁻ form) 0.04 g, 5 mL solvent/H₂O 4 : 1 (v/v), r.t., 15 min; aat 0°C; bformation of 2-bromo-1-methoxy-1-methyl-4-(1-methylethenyl)-cyclohexane. Conversion and yield were calculated by GC using dodecane as the internal standard.

Subsequently, the influence of the catalyst amount was also studied (Table 4). The best result was achieved with catalyst/substrate ratio of 1 : 10 (w/w; entry 2). Under high ratio the yield decreased probably due to the formation of by-products resulting from consecutive reactions (entries 3, 4).

Table 4: Influence of the catalyst amount on the bromohydroxylation of 1a.

Entry
Catalyst (g)
Conversion (%)
Yield of 2a (%)

1
0.03
89
67

2
0.04
89
82

3
0.06
81
65

4
0.08
77
61

5
None
60
40

Reaction conditions: 1a 0.4 g, NBS 1.3 equiv., catalyst (Dowex Marathon A, Cl⁻ form), 0.04 g, acetone/H₂O 4 : 1 (v/v), 15 min. Conversion and yield were generally calculated by GC analysis using dodecane as the internal standard.

3.2. In Situ Addition of Amines to β-Bromoalcohol 2a

The aim of this reaction sequence was the synthesis of vicinal limonene aminoalcohol in one-pot procedure via β-bromoalcohol under optimized conditions (e.g. 4, Scheme 2). Therefore, β-bromoalcohol 2a formed in situ was treated by different amines as nucleophiles (Table 5). However, the epoxide 3a was obtained instead of the desired aminoalcohol in spite of increasing the amount of amine. The added amine acts as a base in the HBr elimination to afford the oxirane ring [31].

Scheme 2: Synthesis of epoxide 3a via bromohydrin.

Table 5: Amine effect on the synthesis of epoxide 3a.

Entry
Amine
Conversion (%)
Yield of 3a (%)

1
Aniline
50
0

2
Diethylaminea
92
82

3
Diethylamineb
90
87

4
1-Phenylethylamine
71
38

5
1-Phenylethylaminec
69
31

6
Morpholine
94
48

7
Ammonia
90
33

Reaction conditions: 1a 0.4 g, NBS 1.3 equiv., amine 2 equiv., catalyst (Dowex Marathon A, Cl⁻form) 0.04 g, 5 mL acetone/H₂O 4 : 1 (v/v), r.t., 15 min; a2 equiv. of diethylamine; b3 equiv. of diethylamine; c reaction with THF instead of acetone. Conversion and yield were calculated by GC using dodecane as the internal standard.

As seen in Table 5, the use of aniline did not lead to any target product, neither to vic-aminoalcohol nor to the epoxide (entry 1). This study shows that diethylamine is the best base both in acetone or THF as solvent (entries 2, 3). When the less basic and more bulky phenylethylamine was used, the yield decreased, and only 38% of 3a was obtained (entry 4). It should be noted that in the case of phenylethylamine and aniline, the formation of the respective Schiff base of acetone was observed. In order to avoid this undesired competitive reaction, the conversion was carried out in THF. Then, azomethines were not found any longer. However, in the case of phenylethylamine, both conversion of 1a and yield of epoxide 3a decreased (entry 5).

3.3. Bromohydroxylation and Epoxidation of Further Terpenes

After optimization of reaction conditions using limonene, and to assess the scope and limitation of the reaction, we extended this methodology to a variety of natural terpenes such as citronellol, geraniol, carvone, citronellal, citral, and α- and β-pinene.

In a first series of experiments, the terpenes 1b–1f were converted to the corresponding β-bromoalcohols 2b–2f in very good yields (Table 6). In the case of geraniol 1c, carvone 1d, or citral 1f, the allylic hydroxy or carbonyl group prevented the bromohydroxylation at the neighbouring double bond. In contrast to limonene 1a, the double bond of the isopropenyl group reacted selectively. The products were isolated and purified by column chromatography and analytically characterized (see ESI). Afterwards, the in situ procedure optimized for limonene was applied to the other terpenes. Two equivalents of diethylamine were added to the reaction mixtures containing the intermediary bromoalcohols 2b–2f, which were converted to the corresponding epoxides after 2 h. In the case of bromoalcohol 2e, an aldol condensation between the aldehyde group and the solvent acetone beside epoxidation was observed and led to the epoxide 3e. α- and β-pinene did not react under the optimized conditions even after 24 hours. The gas chromatogram documented the formation of a variety of products with small peak areas resulting from isomerization of the pinenes.

Table 6: Bromohydroxylation and epoxidation of natural terpenes.

Entry
Terpenes 1b–1f
Bromoalcohols 2b–2f
Isolated yield 2b–2f (%)
Epoxides 3b–3d
Isolated yield 3b–3d (%)

1
1b
R₁: CH₃

93

70

R₂: CH₃

R₃: 5-hydroxy-3-methylpentyl

2
1c
R₁; CH₃

78

60

R₂: CH₃

R₃: 5-hydroxy-3-methylpent-3-enyl

3
1d
R₁: CH₃

80

60

R₂: 4-methyl-5-oxocyclohex-3-enyl

R₃: H

4
1e
R₁: CH₃

64

65

R₂: CH₃

R₃: 3-methyl-5-oxopentyl

5
1f
R₁: CH₃

50
—

R₂: CH₃

R₃: 3-methyl-5-oxopent-3-enyl

Reaction conditions: terpene 0.4 g, NBS 1.3 equiv.; diethylamine 2 equiv., catalyst (Dowex Marathon A, Cl⁻ form) 0.04 g, 5 mL acetone/H₂O 4 : 1 (v/v), r.t.

4. Conclusion

The catalytic synthesis of β-bromoalcohols of different terpenes succeeded via smooth reaction using NBS and H₂O as the nucleophile. The in situ treatment of these bromoalcohols with a variety of amines did not lead surprisingly to the expected vicinal aminoalcohols, but to the corresponding epoxides. The formed bromoalcohols underwent rapid dehydrohalogenation by the amine which played the role of base. We were subsequently able to isolate several epoxides in good yields. The synthesized β-bromoalcohols of natural terpenes can serve as an easily accessible platform for further structural elaboration.

Data Availability

NMR spectra of synthesized terpene derivatives and the device types used for recording spectra and other analytical data used to support the findings of this study are included within the supplementary materials.

Conflicts of Interest

The authors confirm that this article content have no conflicts of interest.

Acknowledgments

The authors are grateful to DAAD for financial support and fellowships. The authors thank Leibniz-Institut für Katalyse (LIKAT Rostock) for infrastructure facilities.

Supplementary Materials

Figure S1: ¹H NMR spectrum of 6-bromo-3,7-dimethyl-octane-1,7-diol (bromoalcohol from citronellol) 2b. Figure S2: ¹³C NMR spectrum of 6-bromo-3,7-dimethyl-octane-1,7-diol (bromoalcohol from citronellol) 2b. Figure S3: ¹H NMR spectrum of 6,7-epoxy-3,7-dimethyl-1-octanol (citronellol epoxide) 3b. Figure S4: ¹³C NMR spectrum of 6,7-epoxy-3,7-dimethyl-1-octanol (citronellol epoxide) 3b. Figure S5: ¹H NMR spectrum of 6-bromo-3,7-dimethyl-oct-2-ene-1,7-diol (bromoalcohol from geraniol) 2c. Figure S6: ¹³C NMR spectrum of 6-bromo-3,7-dimethyl-oct-2-ene-1,7-diol (bromoalcohol from geraniol) 2c. Figure S7: ¹H NMR spectrum of 6,7-epoxy-3,7-dimethyl-oct-2-en-1-ol (geraniol epoxide) 3c. Figure S8: ¹³C NMR spectrum of 6,7-epoxy-3,7-dimethyl-oct-2-en-1-ol (geraniol epoxide) 3c. Figure S9: ¹H NMR spectrum of 5-(1′-(bromomethyl)-1′-hydroxyethyl)-2-methylcyclohex-2-en-1-one (bromoalcohol from carvone) 2d. Figure S10: ¹³C NMR spectrum of 5-(1′-(bromomethyl)-1′-hydroxyethyl)-2-methylcyclohex-2-en-1-one (bromoalcohol from carvone) 2d. Figure S11: ¹H NMR spectrum of 2-Methyl-5-(2-methyloxiranyl)-cyclohex-2-enone one (carvone epoxide) 3d. Figure S12: ¹³C NMR spectrum of 2-Methyl-5-(2-methyloxiranyl)-cyclohex-2-enone (carvone epoxide) 3d. Figure S13: ¹H NMR spectrum of 6-bromo-7-hydroxy-3,7-dimethyl-octan-1-al (bromoalcohol from citronellal) 2e. Figure S14: ¹³C NMR spectrum of 6-bromo-7-hydroxy-3,7-dimethyl-octan-1-al (bromoalcohol from citronellal) 2e. Figure S15: ¹H NMR spectrum of 6,10-dimethyl-9,10-epoxy-undec-3-en-2-one 3e (reaction product of 2e, acetone and amine). Figure S16: ¹³C NMR spectrum of 6,10-dimethyl-9,10-epoxy-undec-3-en-2-one 3e (reaction product of 2e, acetone and amine). Figure S17: ¹H NMR spectrum of 6-bromo-7-hydroxy-3,7-dimethyl-oct-2-en-1-al (bromoalcohol from citral) 2f. Figure S18: ¹³C NMR spectrum of 6-bromo-7-hydroxy-3,7-dimethyl-oct-2-en-1-al (bromoalcohol from citral) 2f. ((Supplementary Materials))

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