Synthesis of Heterocyclic Compounds with a Cineole Fragment in Reactions of α-Pinene-Derived Diol and Monoterpenoid Aldehydes

Abstract

Monoterpenes and their derivatives are important starting compounds in the design of new biologically active substances. In particular, cineole, isolated from eucalyptus essential oil, exhibits a wide range of biological activities. Here, the synthesis of new heterocyclic compounds containing a cineole fragment by the acid-catalyzed condensation of α-pinene-derived 8-hydroxy-6-hydroxymethyllimonene with monoterpene aldehydes was carried out for the first time. The reactions of 8-hydroxy-6-hydroxymethyllimonene with cuminaldehyde, perillylaldehyde, myrtenal, citral, and geranial were studied in the presence of heterogeneous K10 clay or Lewis acid BF₃·Et₂O. The main products of these reactions were compounds with the methanopyrano[4,3-b]pyran scaffold having a 1,8-cineole fragment. As a result of this work, five new compounds with the methanopyrano[4,3-b]pyran scaffold were synthesized. The use of BF₃·Et₂O led to an increase in the yields of target products, compared with the results obtained on K10 clay.

1. Introduction

Monoterpenes and their oxygen-containing derivatives, monoterpenoids, are major components of essential oils [1] and have diverse biological activities [2,3]. Their derivatives are important starting compounds in the design of new biologically active substances [4,5,6]. Agents with antiviral [7,8,9,10,11], antimicrobial [12,13,14,15,16], antitumor [17,18], antiradical [19], anti-inflammatory and analgesic [5,20,21,22], and antidiabetic [23] activities have been developed based on monoterpenes. 1,8-Cineole, extracted from the essential oil of eucalyptus, demonstrates pronounced anti-inflammatory activity [24,25] as well as the ability to act as a bronchodilator. 1,8-Cineole is the active constituent of a medicine used for the treatment of bronchitis and other respiratory diseases [26,27,28,29,30,31]. At the same time, only a few works devoted to the functionalization of cineole have been published [32,33,34], and information on heterocyclic compounds containing a fragment of this monoterpenoid is practically absent. Thus, the synthesis of new heterocyclic compounds combining a fragment of 1,8-cineole and another monoterpenoid is an actual and promising task.

Earlier, (−)-8-acetoxy-6-hydroxymethyllimonene 1 (Scheme 1) was synthesized for the first time by the interaction of (-)-α-pinene and formaldehyde in the presence of the catalytic system H₃PO₄-AcOH [35]. The interaction of acetate (−)-1 with salicylic aldehyde resulted in complex stereoselective cascade processes, leading to the formation of heterocyclic compounds with different types of heterocyclic skeletons (Scheme 1) [36]. The formation of such diverse compounds in one reaction, on the one hand, demonstrated the enormous synthetic potential of compound (−)-1 as a starting compound in the synthesis of chiral heterocyclic substances, but, on the other hand, created problems with the selective preparation of certain target products. The problem was partly solved by hydrolyzing acetate (−)-1 to 8-hydroxy-6-hydroxymethyllymonene (−)-2 since, in this case, reactions with aldehydes lead to the formation of compounds containing fragments of 1,8-cineole and 1,4-cineole, which was demonstrated in the example of the interaction of compound (−)-2 with thiophene-2-carbaldehyde (Scheme 2) [37]. It was shown that compounds with methanopyrano[4,3-b]pyran scaffold 3 and methanofuro[3,2-c]pyran scaffold 4 containing fragments of 1,8-cineole and 1,4-cineole were formed as the main products of this reaction [37]. The first step involves the interaction of protonated aldehyde with the hydroxymethyl group of monoterpenoid (−)-2 and subsequent cyclization to form tetrahydropyran ring. Further intramolecular 1,8-cyclization involving the hydroxy group leads to the product 3 with a methanopyrano[4,3-b]pyran scaffold (Pathway A, Scheme 2). An alternative pathway (Pathway B) is the addition of H₂O and the formation of diol 6, from which, after elimination of the water molecule and 1,4-cyclization, product 4 with methanofuro[3,2-c]pyran scaffold is formed [37].

In order to find the optimal conditions for the reaction of monoterpenoid (−)-2 with thiophene-2-carbaldehyde, a series of heterogeneous catalysts (acid-modified halloysite nanotubes, montmorillonites K10 and K30, and Amberlist 15) and homogeneous catalysts (p-TSA, Sc(OTf)₃, BF₃·Et₂O, MsOH, TfOH, and H₃PO₄) were studied. It was found that the highest selectivity to product 3 with the 1,8-cineole fragment was 77% on K10, which was the same as in the presence of BF₃·Et₂O [37]. The influence of the initial aromatic aldehyde structure on the selectivity of the product with 1,8-cineol fragment formation was also studied. It was shown that the highest selectivity for the 1,8-cineole-like product was 96% in the case of 4-metoxybenzaldehyde containing an electron-donor substituent. The preparative yields [37] of these compounds were 63% for product 3 in the reaction of diol (−)-2 with thiophene-2-carbaldehyde and 82% for the reaction with 4-methoxybenzaldehyde.

The replacement of thiophene-2-carbaldehyde, used as a carbonyl component in the reaction with compound (−)-2, with monoterpenoid aldehydes could allow new heterocyclic compounds containing two monoterpenoid fragments. This is precisely the purpose of this work.

2. Materials and Methods

All reagents were purchased from commercial suppliers, including Sigma-Aldrich and Acros Organics. Montmorillonite K10 (Aldrich) was calcinated at 200 °C for 3 h. (+)-8-Hydroxy-6-hydroxymethyllimonene 2 was synthesized according to [35,37] from (+)-α-pinene (98.0%, Aldrich). Column chromatography: silica gel (SiO₂; 60–200 μ; Macherey-Nagel). Hexane with an ethyl acetate gradient (0, 10, 15, 20, 30, and 60% by volume) was used as the mobile phase.

GC/MS: Agilent 7890A (Agilent Technologies, Santa Clara, CA, USA) with a quadrupole mass spectrometer Agilent 5975C as a detector, HP-5MS quartz column, 30,000 mm × 0.25 mm, He (1 atm) as the carrier gas. HR-MS: DFS-Thermo-Scientific spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) in full-scan mode (15–500 m/z, 70 eV electron-impact ionization, direct sample introduction). ¹H- and ¹³C-NMR: Bruker Avance-III 600 (Bruker Corporation, Karlsruhe, Germany) apparatus at 600.30 MHz (¹H) and 150.95 MHz (¹³C) in CDCl₃; chemical shifts δ in ppm rel. to residual CHCl₃ (δ (H) 7.24, δ (C) 76.90 ppm), J in Hz. Structure determinations were made by analyzing the ¹H NMR spectra, including ¹H-¹H 2D homonuclear correlation (COSY), J-modulated ¹³C NMR spectra (Jmod), and ¹³C-¹H 2D heteronuclear correlation with one-bond and long-range spin–spin coupling constants (C-H COSY, ¹J(C,H) = 135 Hz; HSQC, ¹J(C,H) = 145 Hz; HMBC, ^2,3J(C,H) = 7 Hz). NMR ¹H and Jmod ¹³C spectra for products 12–16 are presented in Figures S1–S10. Optical rotation: polAAr 3005 spectrometer (Optical Activity Ltd., Huntingdon, UK).

The numbering of compound atoms in Scheme 3 is given for assigning the signals in the NMR spectra and does not coincide with that for the names according to the nomenclature of compounds.

2.1. General Procedure 1 (GP1)—Reaction (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Aldehydes 7–11 in the Presence of Montmorillonite K10

An appropriate aldehyde (1 eq.) was added to a suspension of montmorillonite K10 in CH₂Cl₂ (20 mL). A solution of (+)-8-hydroxy-6-hydroxymethyllimonene (+)-2 (1 eq.) in CH₂Cl₂ (10 mL) was added. The reaction mixture was stirred at room temperature for 24 h. Then, EtOAc (20 mL) was added, and montmorillonite K10 was separated by filtration. The solvent was distilled off, and the residue was separated by column chromatography.

2.2. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene 2 and Cuminaldehyde 7 in the Presence of Montmorillonite K10

According to GP1, the reaction of cuminaldehyde 7 (120 mg, 0.82 mmol, 1 eq.) and diol (+)-2 (150 mg, 0.82 mmol, 1 eq.) in the presence of K10 (810 mg) gave compound 12 (198 mg, 0.63 mmol) with a yield of 77% and starting diol (+)-2 (20 mg, conversion 87%).

(3R,4aR,5R,8S,8aS)-5-(4-Isopropylphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran 12. Colorless viscous compound. ${\left[\alpha \right]}_D^{23}$=+27.72 (c 0.44, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 1.17 и 1.21 (2s, Me-21, Me-22), 1.23 (s, 6H, Me-12, Me-13), 1.33 (s, 3H, Me-10), 1.38 (ddd, ²J = 13.7, J_8,1 = 4.8, J_8,7 = 2.9, 1H, H-8), 1.45 (dd, J_7,8 = 2.9, J_7,8′ = 3.4, 1H, H-7), 1.55 (ddd, ²J = 13.0, J_6,5 = 4.2, J_6,7 = 3.4, 1H, H-6), 1.59–1.67 (m, 1H, H-8′), 1.72 (dm, J = 11.0, 1H, H-5), 1.97 (dm, 1H, H-1, J = 10.9), 2.15–2.24 (м, H-6′), 2.87 (sept, 1H, H-20), 3.69 (dd, 1H, ²J = 11.4, J_4,5 = 1.9, H-4), 3.75 (dd, 1H, ²J = 11.4, J_4′,5 = 1.6, H-4′), 4.59 (br.s, 1H, H-2), 7.17 (d, J_16,15 = J_18,19 = 8.2, 2H, H-16, H-18), 7.23 (d, J_15,16 = J_19,18 = 8.2, 2H, H-15, H-19). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 22.80 (t, C-8), 23.00 (q, C-10), 23.90 (2q, C-21, C-22), 27.14 (t, C-6), 28.80 (2q, C-12, C-13), 33.35 (d, C-7), 33.59 (d, C-20), 36.63 (d, C-5), 42.13 (d, C-1), 70.24 (t, C-4), 70.98 (s, C-9), 72.07 (s, C-11), 77.28 (d, C-2), 125.34 (2d, C-15, C-19), 125.91 (2d, C-16, C-18), 138.19 (s, C-14), 147.07 (s, C-17). HR-MS: 314.2243 (M⁺, C₂₁H₃₀O₂; calc. 314.2240).

2.3. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene 2 and Perillaldehyde 8 in the Presence of Montmorillonite K10

According to GP1, the reaction of perillaldehyde 8 (120 mg, 0.82 mmol, 1 eq.) and diol (+)-2 (150 mg, 0.82 mmol, 1 eq.) in the presence of K10 (810 mg) gave compound 13 (90 mg, 0.28 mmol) with a yield of 35%, and starting diol (+)-2 (30 mg, conversion 80%).

(3R,4aR,5R,8S,8aS)-2,2,8a-Trimethyl-5-(4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)hexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran 13. Colorless viscous compound. $[\alpha {]}_{589}^{25}$ = +13.46 (c 1.5, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 1.19 (s, 3H, Me-10), 1.21 (br.s, 6H, Me-12, Me-13), 1.37–1.49 (m, 4H, H-7, H-8, H-18, H’-18), 1.61–1.68 (m, H-5), 1.67–1.74 (m, 2H, H’-8, H-17), 1.70 (s, 3H, Me-22), 1.74–1.81 (m, H-6), 1.86–1.93 (m, 2H, H-19, H’-19), 1.93–2.00 (m, H-16), 2.1–2.23 (m, 3H, H-1, H’-6, H’-16), 3.55 (dd, 1H, ²J = 11.4, J_4,5 = 1.9, H-4), 3.61 (dd, 1H, ²J = 11.4, J_4′,5 = 1.6, H-4′), 3.75 (br.s, 1H, H-2), 5.68–5.76 (m, 1H, H-15), 4.65–4.67 (m, 1H, H-21), 4.68–4.70 (m, 1H, H’-21). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 20.83 (q, C-22), 22.91 (q, C-10), 22.55 (t, C-8), 25.51 (t, C-19), 27.06 (t, C-18), 27.16 (t, C-6), 28.79 (q, C-12), 28.85 (q, C-13), 30.09 (t, C-16), 33.37 (d, C-7), 36.83 (d, C-5), 40.62 (d, C-1), 39.05 (d, C-17), 70.07 (t, C-4), 71.04 (s, C-9), 71.98 (s, C-11), 78.27 (d, C-2), 108.49 (t, C-21), 120.91 (d, C-15), 135.00 (s, C-14), 149.51 (s, C-20). HR-MS: 316.2396 (M⁺, C₂₁H₃₂O₂; calc. 316.2397).

2.4. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Myrtenal 9 in the Presence of Montmorillonite K10

According to GP1, the reaction of myrtenal 9 (120 mg, 0.82 mmol, 1 eq.) and diol (+)-2 (150 mg, 0.82 mmol, 1 eq.) in the presence of K10 (810 mg) gave compound 14 (95 mg, 0.30 mmol) with a yield of 37% and starting diol (+)-2 (30 mg, conversion 80%).

(3R,4aR,5R,8S,8aS)-5-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran 14. Colorless viscous compound. $[\alpha {]}_{589}^{25}$ = +35.07 (c 2.8, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 0.81 (s, Me-10), 1.00 (d, 1H, ²J = 8.5, H-20) 1.15 and 1.17 (2s, 6H, Me-12, Me-13), 1.16 and 1.21 (2s, 6H, Me-21, Me-22), 1.38–1.48 (m, 3H, H-6, H-7, H-8), 1.56–1.68 (m, 3H, H-1, H-5, H’-8), 1.86 (td, 1H, J = 5.6, J = 1.1, H-19), 2.00–2.06 (m, H-17), 2.06–2.14 (m, H-6), 2.19–2.25 (m, 2H, H-16), 2.30 (ddd, 1H, ²J = 8.5, J_20′,17 = J_20′,19 = 5.6, H’-20), 3.52 (dd, 1H, ²J = 11.4, J_4,5 = 1.9, H-4), 3.57 (dd, 1H, ²J = 11.4, J_4′,5 = 1.5, H-4′), 3.65 (br.s, 1H, H-2), 5.39–5.46 (m, 1H, H-15). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 20.84 (q, C-10), 22.61 (t, C-8), 22.81 and 26.13 (2q, C-21, C-22), 26.96 (t, C-6), 28.74 and 28.79 (2q, C-12, C-13), 30.95 (t, C-16), 31.30 (t, C-20), 33.39 (d, C-7), 36.68 (d, C-5), 37.81 (s, C-18), 38.03 (d, C-1), 40.95 (d, C-17), 42.65 (d, C-19), 69.88 (t, C-4), 70.84 (s, C-9), 71.87 (s, C-11), 77.77 (d, C-2), 116.48 (d, C-15), 145.40 (s, C-14). HR-MS: 316.2401 (M⁺, C₂₁H₃₂O₂; calc. 316.2397).

2.5. Reaction of 8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Citral 10 in the Presence of Montmorillonite K10

According to GP1, the reaction of citral 10 (a mixture of geranial 11 and neral in a ratio of 2:3, 280 mg, 1.84 mmol) and diol (+)-2 (150 mg, 0.82 mmol) in the presence of K10 (1290 mg) gave compound 15 (90 mg, 0.28 mmol) with a yield of 35% and starting diol (+)-2 (35 mg, conversion 77%).

2.6. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Geranial 11 in the Presence of Montmorillonite K10

Individual geranial 11 was isolated from citral 10 (a mixture of geranial 11 and neral in a ratio of 2:3) according to [38]. According to GP1, the reaction of citral 11 (315 mg, 2.07 mmol, 1 eq.) and diol (+)-2 (380 mg, 2.07 mmol) in the presence of K10 (2100 mg) gave compound 15 (210 mg, 0.66 mmol) with a yield of 32%, compound 16 (47 mg, 0.14 mmol) with a yield of 7%, and starting diol 1 (70 mg, conversion 80%).

(3R,4aR,5S,8S,8aS)-5-((E)-2,6-Dimethylhepta-1,5-dien-1-yl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran 15. Colorless viscous compound. $[\alpha {]}_{589}^{23}$ = +70.94 (c 3.2, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 1.19 and 1.20 (2s, 6H, Me-12, Me-13), 1.22 (s, 3H, Me-10), 1.45–1.53 (m, 2H, H-6, H-7), 1.55–1.67 (m, 3H, H-1, H-5, H-8), 1.56 (s, Me-20), 1.63 (s, Me-21), 1.64 (s, Me-22), 1.89–2.21 (m, 7H, H-6, 2H-8, 2H-16, 2H-17), 3.52 (dd, 1H, ²J = 11.5, J_4,5 = 1.7, H-4), 3.63 (dd, 1H, ²J = 11.5, J_4′,5 = 1.2, H-4′), 4.15 (d, 1H, J_2,14 = 7.3, H-2), 5.00–5.08 (m, H-18), 5.23 (dd, 1H, J_14,2 = 7.4, J_14,22 = 1.0, H-14). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 16.86 (q, C-22), 17.50 and 25.51 (2q, C-20, C-21), 22.72 (q, C-10), 23.25 (t, C-8), 26.25 (t, C-17), 27.21 (t, C-6), 28.74 and 28.82 (2q, C-12, C-13), 33.41 (d, C-7), 36.67 (d, C-5), 39.40 (t, C-16), 41.39 (d, C-1), 70.12 (t, C-4), 70.58 (s, C-9), 71.91 (s, C-11), 74.00 (d, C-2), 123.08 (d, C-14), 123.84 (d, C-18), 131.37 (s, C-19), 139.09 (s, C-15). HR-MS: 318.2548 (M⁺, C₂₁H₃₄O₂; calc. 318.2553).

(E)-2,6-Dimethyl-7-((3R,4aR,5S,8S,8aS)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran-5-yl)hept-6-en-2-ol 16. Colorless viscous compound. $[\alpha {]}_{589}^{23}$ = +59.74 (c 0.76, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 1.17 (s, 6H, Me-20, Me-21), 1.19 (s, 3H, Me-12), 1.20 (s, 3H, Me-13), 1.22 (s, 3H, Me-10), 1.37–1.51 (m, 6H, H-6, 2H-8, H-7, 2H-18), 1.58–1.67 (m, 3H, H-1, H-5, H-17), 1.63 (d, 3H, J_22,14 = 0.8, Me-22), 1.90–2.0 (m, 3H, 2H-16, H-17′), 2.10–2.19 (m, 1H, H-6′), 3.51 (dd, 1H, ²J = 11.3, J_4,5 = 1.5, H-4), 3.63 (dd, 1H, ²J = 11.3, J_4′,5 = 0.9, H-4′), 4.15 (d, 1H, J_2,14 = 7.3, H-2), 5.24 (dd, 1H, J_14,2 = 7.4, J_14,22 = 1.0, H-14). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 16.79 (q, C-22), 22.29 (t, C-8), 22.75 (q, C-10), 23.32 (t, C-17), 27.22 (t, C-6), 28.76 and 28.84 (2q, C-12, C-13), 29.10 and 29.13 (2q, C-20, C-21), 33.42 (d, C-7), 36.67 (d, C-5), 39.77 (t, C-16), 41.40 (d, C-1), 43.35 (t, C-18), 70.15 (t, C-4), 70.61 (s, C-9), 70.76 (s, C-19), 71.96 (s, C-11), 73.99 (d, C-2), 123.19 (d, C-14), 139.22 (s, C-15). HR-MS: 336.2656 (M⁺, C₂₁H₃₆O₃; calc. 336.2659).

2.7. General Procedure 2 (GP2)—Reaction (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Aldehydes 7–9, 11 in the Presence of BF₃·Et₂O

The solution of (+)-8-hydroxy-6-hydroxymethyllimonene 2 (1 eq.) and appropriate aldehyde 7–9, 11 (1 eq.) in 20 mL CH₂Cl₂ was cooled to 5 °C. Then, BF₃·Et₂O (1 eq.) was added and stirred at 5° C for 1 h. The reaction mixture was washed with a saturated aqueous solution of NaHCO₃ and water. The organic phase was separated and dried over Na₂SO₄. The desiccant was filtered off, the solution was evaporated, and the residue was separated by column chromatography.

2.8. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Cuminaldehyde 7 in the Presence of BF₃·Et₂O

According to GP2, the reaction of cuminaldehyde 7 (235 mg, 1.6 mmol, 1 eq.) and diol (+)-2 (300 mg, 1.6 mmol, 1 eq.) in the presence of BF₃·Et₂O (227 mg, 1.6 mmol, 1 eq.) gave compound 12 (470 mg, 1.5 mmol) with a yield of 92%.

2.9. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Perillaldehyde 8 in the Presence of BF₃·Et₂O

According to GP2, the reaction of perillaldehyde 8 (240 mg, 1.6 mmol, 1 eq.) and diol (+)-2 (300 mg, 1.6 mmol, 1 eq.) in the presence of BF₃·Et₂O (227 mg, 1.6 mmol, 1 eq.) gave compound 13 (290 mg, 0.9 mmol) with a yield of 56%.

2.10. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Myrtenal 9 in the Presence of BF₃·Et₂O

According to GP2, the reaction of myrtenal 9 (240 mg, 1.6 mmol, 1 eq.) and diol (+)-2 (300 mg, 1.6 mmol, 1 eq.) in the presence of BF₃·Et₂O (227 mg, 1.6 mmol,1 eq.) gave compound 14 (280 mg, 0.88 mmol) with a yield of 54%.

2.11. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Citral 10 in the Presence of BF₃·Et₂O

According to GP2, the reaction of citral 10 (a mixture of geranial 11 and neral in a ratio of 2:3, 310 mg, 2.03 mmol) and diol (+)-2 (150 mg, 0.82 mmol, 1 eq.) in the presence of BF₃·Et₂O (116 mg, 0.82 mmol, 1 eq.) gave compound 15 (197 mg, 0.62 mmol) with a yield of 76%.

2.12. Reaction of (+)-8-Hydroxy-6-hydroxymethyllimonene (+)-2 and Geranial 11 in the Presence of BF₃·Et₂O

According to GP2, the reaction of geranial 11 (125 mg, 0.82 mmol,1 eq.) and diol (+)-2 (150 mg, 0.82 mmol, 1 eq.) in the presence of BF₃·Et₂O (116 mg, 0.82 mmol, 1 eq.) gave compound 15 (198 mg, 0.62 mmol) with a yield of 76%.

3. Results and Discussion

In this work, we studied, for the first time, the reactions of 8-hydroxy-6-hydroxymethyllimonene 2 and commercially available monoterpene aldehydes: cuminaldehyde 7, (−)-perillaldehyde 8, (−)-myrtenal 9, and citral 10 (Scheme 3). The choice of starting aldehydes is conditioned by the presence of antioxidant, anticancer, antimicrobial, and anti-inflammatory activity of these monoterpenoids [39,40,41,42].

We began our studies with previously found optimal conditions for the interaction of diol 2 and thiophene-2-carbaldehyde [37] in methylene chloride dried at 200 °C and using K10 montmorillonite clay. However, under these conditions, the low conversion of monoterpenoid 2 was observed. We modified the previously found procedure by increasing the reaction time from 6 h to 24 h and clay K10 loading (increase by 1.5 times) to improve the conversion of starting diol (+)-2 in reactions with monoterpene aldehydes.

The reaction of aromatic cuminaldehyde 7 with diol (+)-2 in the presence of montmorillonite clay K10 proceeded with the formation of product 12 containing a 1,8-cineole fragment with a yield of 77% (Scheme 3,

Table 1. Yields of reaction products of diol (+)-2 with aldehydes 7–11.

Aldehyde	K10, CH2Cl2, 24 h		BF3·Et2O, CH2Cl2, 5 °C, 1 h
	Diol (+)-2 Conversion	Yield 1	Diol (+)-2 Conversion	Yield
7	87%	12 77%	100%	12 92%
8	80%	13 35%	100%	13 56%
9	80%	14 37%	100%	14 54%
10	77%	15 35%	100%	15 76%
11	80%	15 32%	100%	15 76%

¹ The product yields are given based on 100% conversion of (+)-8-hydroxy-6-hydroxymethyllimonene (+)-2.

). This is in good agreement with previously obtained yields [SM 37] in reactions of diol (−)-2 with aromatic aldehydes, which vary from 64% for 4-chlorobenzaldehyde to 82% for 4-methoxybenzaldehyde. Transitioning from cuminaldehyde 7 to the monocyclic unsaturated perillaldehyde 8 resulted in a notable reduction in the yield of the target product 13, which decreased to 35%. Such a decrease in yield can be explained by the lower stability of this aldehyde in acidic conditions in comparison with cuminaldehyde 7. The reaction of diol (+)-2 with unsaturated bicyclic aldehyde myrtenal 9 led to the formation of compound 14 with a low yield of 37%.

The acyclic unsaturated monoterpenoid citral 10 (Scheme 2) is a mixture of Z- and E-isomers in a ratio of approximately 1:1. It was previously shown [38] that keeping citral 10 in the presence of K10 led to the selective oligomerization of the Z-isomer (neral), which allows obtaining the individual E-isomer (geranial 11). Obviously, in the reaction of diol (+)-2 and citral 10, oligomerization of the Z-isomer occurred, and the reaction of the remaining E-isomer with compound (+)-2 led to the formation of a single stereoisomer of product 15 in 35% yield. For comparison, the interaction of individual geranial 11 obtained by the procedure [38] with diol (+)-2 in the presence of clay K10 led to a similar result, and the yield of the target product 15 was 32%. In addition, product 16 was isolated from the reaction mixture in 7% yield, which is apparently formed as a result of water addition to the double bond of compound 13 (Scheme 3).

The moderate yield of products under these conditions can be explained by the incomplete conversion of the initial monoterpenoid (+)-2 (Table 1), as well as the occurrence of competing transformations, resulting in the formation of the intramolecular cyclization product (+)-5 and products with a 1,4-cineole fragment (Scheme 2). Although these compounds, according to GC-MS data, were observed in the reaction mixtures, they were not isolated individually due to low stability under silica gel column chromatography conditions.

Since moderate yields of products and the incomplete conversion of monoterpenoid (+)-2 are observed in the reactions of (+)-8-hydroxy-6-hydroxymethyllimonene (+)-2 with monoterpene aldehydes 7–11 in the presence of K10 clay (Table 1), Lewis acid BF₃·Et₂O was also studied as a catalyst for these transformations. It was shown [37] that high selectivity toward product 3 with a 1,8-cineole fragment was observed when using BF₃·Et₂O for the condensation of diol (–)-2 and thiophene-2-carbaldehyde. We used previously found conditions but decided to lower the reaction temperature to avoid side reactions of both the diol (+)-2 and the monoterpene aldehydes. The application of BF₃·Et₂O for the reaction of diol (+)-2 with aldehydes 7–11 allowed for increasing the yield of products 12–15, and complete conversion of the starting compound (+)-2 was achieved in just 1 h. The yields of the target products with the 1,8-cineole fragment were 92% for product 12 with an aromatic fragment, about 55% for products 13 and 14 in reactions with unsaturated aldehydes 8 and 9, and 76% for product 15 in the case of acyclic unsaturated aldehydes citral 10 and geranial 11. Thus, the use of homogeneous acid BF₃·Et₂O is favored in the reactions of (+)-8-hydroxy-6-hydroxymethyllimonene (+)-2 with monoterpene aldehydes 7–11.

Thus, for both acids, the best yields were observed in the case of aromatic aldehyde 7. Apparently, this is due to the absence of intramolecular side reactions of monoterpenoid 7 under reaction conditions. When using K10 clay, the yield was less than 40% for other monoterpene aldehydes 8–11. The use of BF₃·Et₂O allowed us to increase the yields of the target products; however, in the case of cyclic monoterpene aldehydes 8 and 9, the yields were lower than in the case of acyclic aldehydes 10 and 11 (Table 1).

The reactions of (+)-8-hydroxy-6-hydroxymethyllimonene (+)-2 with monoterpene aldehydes (cuminaldehyde, perillaldehyde, myrtenal, citral, and geranial) in the presence of heterogeneous K10 clay and a homogeneous BF3·Et2O were studied for the first time in the present work. Both reaction components are monoterpenoids, and despite their lability in an acid medium, we succeeded in selecting conditions that led to the formation of the target compounds with the methanopyrano[4,3-b]pyran scaffold. It was found that target compounds containing the 1,8-cineole fragment were formed as the main products in these reactions. Despite the fact that K10 clay has obvious advantages as a heterogeneous acid, the use of BF3·Et2O is preferable due to a significantly higher yield of target products. Based on the biological activity of 1,8-cineole and monoterpene aldehydes 7–11, it can be expected that the obtained products will exhibit various types of biological activity, particularly anti-inflammatory activity.