Synthesis of Novel Aryl-Substituted Acetylenic Monoterpene Analogues by Sonogashira Coupling ^†

Abstract

The synthesis of new aryl-substituted acetylenic monoterpene derivatives was carried out by the Sonogashira reaction. The reactions proceed in the presence of PdCl₂(PPh₃)₂, CuI and Et₃N and provide aryl-substituted acetylenic monoterpenes with an isolated yield of 70–82%.

1. Introduction

Terpenes and terpenoids are naturally occurring secondary metabolites isolated from plants, which exhibit a broad spectrum of biological activity and provide a large library of basic structures for medicinal chemistry [1,2,3,4]. Within this class of substances, camphor and carvone have long been used as starting compounds for the synthesis of new drug candidates [5,6,7,8,9,10,11,12]. Since natural compounds typically have a complex structure, differing in the hydrocarbon framework and/or the number and position of functional groups, the search for chemo-, stereo- and regioselective methods of native molecule transformation to obtain promising pharmacologically significant analogues is of great importance. To date, numerous derivatives of camphor and carvone have been synthesized, which showed various biological effects [13,14,15]. The present work is aimed at the synthesis of new aryl-substituted propynyl analogues of camphor and carvone as promising building blocks.

2. Results and Discussion

First, the alkylation of camphor and carvone with propargyl bromide in the presence of base KN(SiMe₃)₂–Et₃B in 1,2-dimethoxyethane (DME) at room temperature provides 2-propargyl-substituted camphor and carvone derivatives with a yield of 69% and 47%, respectively [16]. Second, the synthesis of aryl-substituted acetylenic monoterpene derivatives with a yield of 70-82% was carried out by the Sonogashira reaction in the presence of PdCl₂(PPh₃)₂, CuI and Et₃N (Scheme 1).

The structure of the obtained compounds was confirmed by 1D (¹H, ¹³C) NMR experiments. Thus, in the ¹³C NMR spectrum of compound 3, a shift in the signals of the acetylene bond carbon atoms C-2′ and C-3′ to a downfield (to the region of 88.5 and 81.3 ppm, respectively) compared to the corresponding signals of carbon atoms of the terminal acetylene bond was observed. In addition to the characteristic signals of camphor, four new signals of carbon atoms appeared in the spectrum at 123.7, 127.8, 128.2 and 131.6 ppm, which were assigned to the atoms of the phenyl ring. In the ¹H NMR spectrum, the signal of the H-3′ proton at 2.00 ppm was absent and new signals of the aromatic ring were observed in the region of 7.42-7.41 and 7.30-7.29, which were assigned to H-6′-8′, H-5′ and 9′, respectively.

3. Conclusions

Thus, we have obtained new camphor and carvone analogues containing a phenyl-substituted acetylene bond via Sonogashira coupling, catalyzed with PdCl₂(PPh₃)₂ and copper (I) iodide. At present, a systematic study of this reaction is being carried out with the aim of involving a wide range of aryl iodides to obtain a set of promising structural blocks for the synthesis of new biologically active compounds.

4. Experimental Part

Camphor, carvone, BEt₃, KN(SiMe₃)₂ (1 M solution in THF), propargyl bromide, PdCl₂(PPh₃)₂, CuI, Et₃N, DMF and DME (dimethoxyethane) were purchased from Sigma-Aldrich (Acros) and used without any further purification. The alkylation reactions of the compounds were carried out under dried argon atmosphere. Compounds 2 and 5 were prepared according to the known procedure [16]. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance–500 instrument (500.13 (¹H) and 125.78 MHz (¹³C)) in CDCl₃ with Me₄Si as the internal standard. High-resolution mass spectra (HRMS) of compounds were obtained on a spectrometer MaXis impact (Bruker) using a mass analyzer (TOF) with electrospray ionization (ESI). TLC was carried out on Sorbfil plates (Sorbpolimer, Krasnodar, Russia) in hexane–EtOAc (from 50:1 to 10:1); spots were visualized with anisaldehyde. Silica gel L (KSKG grade, 50–160 μm) was employed for column chromatography.

General procedure for the synthesis of aryl-substituted acetylenic monoterpene 3 and 6 via Sonogashira coupling reaction

A mixture of corresponding terpenoid (0.6 mmol), iodobenzene (0.5 mmol) and Et₃N (0.75 mL, 5.4 mmol) was dissolved in DMF (4.5 mL). Then, CuI (11 mg, 0.06 mmol) and PdCl₂(PPh₃)₂ (21 mg, 0.03 mmol) were added to the mixture simultaneously and the resulting mixture was stirred at room temperature for 1–3 h under an argon atmosphere. The completion of the reaction was monitored by TLC analysis. The reaction was quenched by the addition of water and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried with MgSO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on SiO₂ with hexane/EtOAc (from 100:1 to 1:10) as an eluent to afford pure products 3 and 6.

1,7,7-trimethyl-3-(3-phenylprop-2-yn-1-yl)bicyclo[2.2.1]heptan-2-one (3). ¹H NMR (500 MHz, CDCl₃) δ: 0.88 (3H, s, H-8),

• 0.93 (3H, s, H-10),
• 0.97 (3H, s, H-9),
• 1.48-1.43 (1H, m, H^b-5),
• 1.57-1.51 (1H, m, H^b-6),
• 1.71-1.67 (1H, m, H^a-6),
• 2.08-2.05 (1H, m, H^a-5),
• 2.22 (1H, dd, J = 4.5 Hz, J = 11 Hz, H-4),
• 2.29 (1H, m, H-3),
• 2.39 (1H, dd, J = 12 Hz, J = 17 Hz, H^a-1′),
• 2.98 (1H, dd, J = 4 Hz, J = 17 Hz, H^b-1′),
• 7.30-7.29 (3H, m, H-6′-8’),

7.42-7.41 (2H, m, H-5′ and 9′). ¹³C NMR (125 MHz, CDCl₃) δ: 219.2 (C-2), 131.6 (C-6′, C-8′), 128.2 (C-5′, C-9′), 127.8 (C-7′), 123.7 (C-4′), 88.6 (C-2′), 81.3 (C-3′), 57.9 (C-1), 53.6 (C-3), 46.8 (C-7), 46.6 (C-4), 29.3 (C-5), 29.2 (C-6), 21.6 (C-8), 21.3 (C-1′), 20.5 (C-9), 9.5 (C-10). HRMS: m/z [M+Na]⁺, calcd for C₁₉H₂₂O: 289.1568 found 289.1583. Found (%): C 85.42; H 8.31. Calcd for C₁₉H₂₂O (%): C 85.67; H 8.32.

2-methyl-6-(3-phenylprop-2-yn-1-yl)-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (6). ¹H NMR (500 MHz, CDCl₃) δ: 1.81 (s, 3H, H-9), 1.83 (s, 3H, H-10), 2.41-2.36 (m, 1H, H^a-4), 2.5-2.47 (m, 1H, H^b-4), 2.59-2.53 (m, 2H, H-5, H-6), 3.07-3.03 (m, 2H, H^a-1′, H^b-1′), 4.95 (s, 1H, H^a-8), 4.99 (s, 1H, H^b-8), 6.75-6.74 (m, 1H, H-3), 7.27-2.76 (m, 3H, H-6′-8′), 7.37-7.36 (m, 2H, H-5′ and 9′). ¹³C NMR (125 MHz, CDCl₃) δ: 198.7 (C-1), 144.8 (C-7), 143.8 (C-3), 135.2 (C-2), 131.6 (C-6′, C-8′), 128.1 (C-5′, C-9′), 127.5 (C-7′), 124.0 (C-4′), 114.1 (C-8), 87.8 (C-2′), 81.5 (C-3′), 48.4 (C-6), 46.8 (C-5), 30.8 (C-4), 18.9 (C-9), 17.6 (C-10), 16.1 (C-1′).

HRMS: m/z [M+Na]⁺, calcd for C₁₉H₂₀O: 287.1412 found 287.1430. Found (%): C 86.35; H 7.64. Calcd for C₁₉H₂₀O (%): C 86.32; H 7.63.