Fluorinated Ethers of Cannabinol (CBN)

Abstract

The difluoromethoxy (OCF₂H) and trifluoromethoxy (OCF₃) fluorinated structural motifs are frequently seen as privileged functional groups in the field of medicinal chemistry and are regularly taken into account during the design and development processes of successful drugs. This paper presents the synthesis of four new fluorinated etheric derivatives of cannabinol (CBN) using fluorine chemistry. These reactions are straightforward in terms of operation and make use of easily obtainable reagents, making them suitable for the synthesis of various fluorinated CBN ethers with yields ranging from moderate to excellent. We successfully isolated all the products and characterized them in detail using spectroscopic methods. It is anticipated that they will increase the efficacy of drug candidates due to their ability to alter biological activities such as cellular membrane permeability and metabolic stability and improve their pharmacokinetic properties.

1. Introduction

Medicinal cannabinoids are gaining popularity globally, with a notable rise in the use of innovative cannabis products within communities. Cannabinoids, also known as isoprenylated resorcinyl polyketides, are produced and stored in the glandular trichomes of flower bracts [1,2]. They primarily exist in their carboxylic acid forms. The neutral form of cannabinoids is not present in significant quantities within the plant biomass but can be obtained through decarboxylation processes, such as heat, light, or chemical methods, applied to the naturally occurring acidic cannabinoids. This decarboxylation process transforms raw acidic cannabinoids into their biologically active and stable forms, provided that they are stored properly in an appropriate solvent. These neutral cannabinoids interact with the endocannabinoid system (ECS), which comprises cannabinoid receptors (CB1 and CB2) located throughout the body, including the central and peripheral nervous systems [3]. As a result, a range of effects, from euphoria to relaxation, can be observed, influenced by the presence of several major and minor cannabinoids. Following thorough investigations into prominent cannabinoids such as cannabidiol (CBD) and tetrahydrocannabinol (∆⁹-THC), the scientific community is now turning its attention to minor cannabinoids. While a number of these minor cannabinoids may exhibit significant biological effects, they have often been neglected due to their limited natural availability.

Cannabinol (CBN, 1, Figure 1) is a distinct minor phytocannabinoid that has garnered considerable attention within the scientific community globally due to its notable effects. While various plants and fungi have been identified to contain different phytocannabinoids, CBN is exclusively found in the cannabis plant. The biosynthesis of CBN and cannabinolic acid (CBNA) remains unclear [4,5]. Both CBNA and CBN are byproducts of ∆⁹-tetrahydrocannabinol (∆⁹-THC) degradation, which occurs when air oxidation induces aromatization at the menthyl moiety [4]. Nonetheless, minute quantities of CBNA have been discovered in certain hemp samples, indicating that, under certain conditions, oxidative degradation might also advance to ∆⁹-tetrahydrocannabinolic acid (THCA), the acidic precursor of ∆⁹-THC, as well as occur prior to decarboxylation.

Cannabinol (CBN) is a crucial compound due to its stability and strong chemical relationship with ∆⁹-THC, which serves as a marker for identifying narcotic cannabis in prehistoric plants [5,6,7]. CBN acts as a weak partial agonist at CB1 and CB2 and elicits varied responses from different receptor types. Compared to ∆⁹-THC, CBN has a 10-fold lower affinity for CB1 receptors and less effectively inhibits adenylyl cyclase’s CB1 receptor-mediated activity. However, CBN regulates various types of TRPs, acting as an agonist on channels such as TRPV1, TRPV2, TRPV3, and TRPV4, leading to an influx of Ca²⁺ and initiating Ca^2±dependent signaling pathways within cells. Regarding other TRP variations, CBN functions as a potent antagonist to stop icilin from activating TRPM8 (also known as CMR1, or cold and menthol receptor 1). CBN’s analgesic and anti-inflammatory properties may help treat pain and glaucoma. It also helps reduce cell damage and has antioxidant properties along with antibacterial activity against resistant strains of bacteria. Furthermore, it can serve as an appetite-stimulating medication in circumstances where boosting hunger is beneficial, as well as hold promise in the treatment of epidermolysis bullosa [8]. Recent research has indicated that its key primary metabolite, 11-OH-CBN (1a, Figure 1), attained similarly elevated concentrations in the brain, indicating that it may be involved in the sedative properties of CBN [9]. When assessed for their impact on cannabinoid CB1 receptors linked to sleep regulation, CBN and its ultimate metabolite, 11-COOH-CBN (1b), showed minimal activity. In comparison, the primary metabolite 1a functioned as a partial agonist, showcasing potency and efficacy comparable to that of Δ⁹-THC in the membrane potential assay. Overall, CBN’s unique biological activities could open up new possibilities for research and treatment.

Researchers examining the systemic absorption and bioavailability of cannabinoids are growing increasingly intrigued each day [10,11,12]. Recent clinical studies in the pharmaceutical industry have concentrated on innovations in drug delivery, while the recreational market is also progressing towards better excipients and techniques aimed at enhancing absorption throughout the body. Despite progress in scientific research, certain inherent issues, such as low bioavailability and inconsistent pharmacokinetic profiles, hinder the clinical approval of cannabinoids. These challenges impact the use of cannabinoids in both disease treatment and preventive healthcare despite their wide-ranging therapeutic potential. It is also essential to consider oxidative degradation and potential interactions with other medications when combining drugs with cannabinoids. Phytocannabinoids demonstrate complex and poorly understood pharmacological properties, making it challenging to systematically analyze them alongside unapproved synthetic cannabinoids and unknown mixtures to minimize variability. Consequently, there is a demand for strategies that enhance bioavailability and mitigate the adverse effects linked to cannabinoid use. By strategically adding one or more fluorine atoms to the molecule, such as trifluoromethoxy (-OCF₃) and difluoromethoxy (-OCF₂H) groups, the drug’s dynamic properties and pharmacokinetics can be dramatically altered [13,14]. Some of the main advantages include the strong C–F bond dissociation energy (130 kcal mol⁻¹) and the bond length, which is between the C–H and C–O bonds, albeit closer to the latter. The incorporation of fluorine substituents to block physiologically labile positions can tackle the low metabolic stability of pharmaceuticals. The electrostatic C^δ+–F^δ− component of the C–F bond makes it highly polarized and contributes to its stability. Because of their ability to mimic functional groups in biologically active compounds, medications and drugs featuring various fluorine groups are now commonly found on the market. Pharmaceuticals and agrochemicals often incorporate OCF₃ and OCF₂H groups to enhance the drug’s absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Following the recent exploration of oxidative fluorination on CBN, this report outlines the synthesis of four distinct fluorinated ether derivatives of CBN through simple aqueous base chemistry [15].

2. Results and Discussion

The -OCF₂H group has unique and different properties, such as the highly polarized C–H bond, which can act as a more competent H-bond donor (hydrogen bond acidity, i.e., A > 0.05) than its methylated analogs (A < 0.001). Therefore, it is able to interact with the heteroatom in the host protein [16,17]. It is the most suitable bioisostere/isoelectronic functional group for alcohol (-OH), amine (-NH₂), and thiol group (-SH) units in drug design, as is evident from its presence in several FDA drugs, herbicides, fungicides, and agrochemicals. Interestingly, the H bond acidity of ArOCF₂H (A = 0.10) was found to be similar to that of thiophenol (A = 0.12) and aniline (A = 0.07). The isosteric relationship between the CF₂ fragment and ethereal oxygen makes it distinguishable from other polyfluorinated motifs. Compared to ArOCF₃, ArOCF₂H compounds tend to have higher permeability and less lipophilicity (40.5% reduction in log D) in a set of lead-like drug structures studied that contain anisoles. Being the bulkier analog of OCF₃, OCF₂H is also a strong electron-withdrawing group, which could decrease the electron density of the potential drug. It is also capable of H donation, thereby improving the binding selectivity of a molecule. ArOCF₂H compounds, in contrast to ArOCF₃, have no orientational preference for either conformation (dihedral angle (θ) = 0–50°). Since they can adopt the conformation that provides the optimum binding to the target proteins, difluoromethyl ethers are more desirable in medicinal research.

The difluorination of CBN (1) started with difluoromethyltriflate (HCF₂OTf) as the fluorinating reagent, which is a non-ozone-depleting liquid [18]. The HCF₂OTf reagent can be easily made in high yield using readily available non-ozone-depleting reagents, TMSCF₃ (Ruppert–Prakash reagent) and triflic acid with catalytic TiCl₄ at room temperature. HCF₂OTf has a good leaving triflate (-OTf) group and is an air-stable, easily handled liquid. The addition of HCF₂OTf (1 equiv.) at room temperature (rt) to a CBN solution in a 1:1 combination of MeCN and aqueous KOH (6 M) did not lead to the full conversion of CBN. Increasing the concentration of HCF₂OTf (3 equiv.) with CBN in a 1:1 combination of MeCN and aqueous KOH (6 M) solution at rt resulted in complete conversion in 4–5 h. Shorter times were insufficient to complete the CBN conversion. Despite seeing a single TLC spot, the ¹⁹F NMR spectrum of the reaction mixture indicated a singlet at −73.51 ppm and a doublet at −79.68 ppm in the ratio of 53:47 (shown by arrows in Figure 2b). Similarly, characterization data, including proton and carbon NMR and mass spectra, suggest an inseparable mixture of the difluoromethyl ether of cannabinol (2) and cannabinol triflate (3), as shown in Figure 2a.

To verify the triflate formation, a separate reaction on CBN resulted in the formation of cannabinol triflate (3). The CBN reaction with triflic anhydride in the presence of 5% (w/v) aqueous LiOH and toluene, at a temperature < 10 °C, gives an 84% isolated yield of 3 [19]. The singlet peak at −73.53 ppm in the ¹⁹F NMR spectrum of 3 also confirms the formation of cannabinol triflate in the earlier HCF₂OTf reaction mixture. Afterward, the previously obtained inseparable mixture of 2 and 3 was subjected to a selective deprotection reaction. This was carried out by utilizing tetraethylammonium hydroxide (Et₄NOH) in dioxane (2 mL) solvent at rt for 4 h [20]. As a result, the triflate group hydrolyzed back into CBN, without adversely impacting the difluoromethyl ether of cannabinol (2) present within the reaction mixture (Figure 2). The isolated yield of 2 gives a doublet peak at −79.68 ppm in the ¹⁹F NMR spectrum.

Following the successful installation of OCF₂H, the OCF₃ group was selected. The O-CF₃ group in ArOCF₃ is orthogonal to the aromatic plane, which is beneficial for providing additional binding affinity in drug–target complexes [21,22,23]. This unusual configuration results from the negative hyperconjugation (n_o → σ*_C–F) and the steric interaction between the CF₃ group and the ortho-hydrogen atoms of the aromatic ring. The OCF₃ group is able to rotate freely and adopt a more stable conformation where the dihedral angle (θ) of the C=C–O–CF₃ bond is close to 90°. This is because these interactions significantly weaken the tendency of the oxygen lone pair electrons to delocalize into the aromatic ring. The trifluoromethoxy group outperforms both the methoxy (-OCH₃) and trifluoromethyl groups (-CF₃), as measured by its ability to trigger a hydrogen/metal permutation at an ortho position. Even when it is situated in a more remote meta or even para position, OCF₃ is able to have a long-range action (high electronegativity). The presence of the OCF₃ group improves metabolic stability and increases lipophilicity, resulting in improved absorption and transport in biological systems [21,22]. The addition of the OCF₃ group to organic molecules can enhance the disparity between their melting point and boiling point at normal pressure, while reducing their surface tension, dielectric constant, and pour point. This is also crucial for other fields, for example, the development of electro-optical materials, soluble organic semiconductors, and melt-processable fluoropolymers.

Moving to trifluorination on CBN, a silver triflate-mediated oxidative trifluoromethylation method by Liu et al. was applied [24]. This standard and straightforward approach uses nucleophilic CF₃SiMe₃ as the CF₃ source in the presence of oxidants for the synthesis of trifluoromethyl ethers under mild reaction conditions. The usage of both Selectfluor and NFSI as oxidants is shown to be critical for the successful trifluoromethylation reaction, resulting in a low product yield (10%) (5). It is believed that the low yield of trifluoromethylated cannabinol (5) resulted from the highly reactive properties of cannabinol when exposed to a complex reactive mixture (see Figure 3). Furthermore, even the addition of 2,4-di-tert-butylphenol as an additive to prevent competitive trifluoromethylation of the phenyl rings with electrophilic CF₃ radicals resulted in an inseparable reaction mixture.

With the intention of getting a better yield, the appealing approach of synthesis of aryltrifluoromethyl ethers (ArOCF₃) by combining O-carboxydifluoromethylation and subsequent silver-catalyzed decarboxylative fluorination was chosen [25]. This process is similar to the Hunsdiecker-type exchange of the carboxylic group in aryloxydifluoroacetic acids with fluorine. The intermediate O-carboxydifluoromethylated cannabinol (4) was prepared using sodium hydride as the base and the more reactive sodium bromodifluoroacetate (BrCF₂COONa) as a general carboxydifluoromethylation reagent (Figure 3). With a 94% yield, the novel product 4 was isolated and characterized. The “fluorodecarboxylation” process was then attempted using intermediate 4 and silver catalysis of AgNO₃ with the electrophilic fluorination reagent (Selectfluor) at 80 °C for 12 h. Unfortunately, the step 2 (Figure 3) effort to obtain trifluoromethylated cannabinol (5) from compound 4 did not yield the expected success, as hypothesized in the literature [25]. Other procedures that could effectively produce 5 in a less complex reaction mixture are currently being considered.

Cannabinoids are highly reactive and non-polar compounds, making them susceptible to degradation, even at room temperature. This degradation can reduce their potency and possibly lead to the formation of other unknown or harmful compounds. Cannabinoids possess multiple active sites that play a crucial role in their interactions within the body and their potential therapeutic effects. For example, they exert their influence by binding to specific cannabinoid receptors, primarily CB1 and CB2, located on cell surfaces, or by interacting with other receptors and ion channels, contributing to their diverse effects. The unique structure of each cannabinoid, along with its active sites, determines its binding affinity and the resulting physiological responses. Therefore, functionalizing these compounds without altering their core structure presents significant challenges, and current transformations are showing regioselectivity in the production of etheric CBN derivatives.

3. Experimental Section

3.1. General Information

Unless otherwise noted, all chemicals/reagents and solvents were purchased from commercial suppliers—Sigma Aldrich/Merck and Thermo Fischer—and used without purification. All manipulations were conducted on the benchtop without any exclusion of air or moisture, unless otherwise noted. Reactions were conducted in 5 mL vials fitted with Teflon-lined screw caps, unless otherwise noted. HCF₂OTf was prepared according to the published procedure [26]. BrCF₂COONa was prepared similarly to BrCF₂CO₂K [27]. Reactions were monitored through thin-layer chromatography (TLC silica gel F₂₅₄, glass plates) and analyzed using 254 nm UV light and iodine or ninhydrin stains; ¹H NMR, ¹⁹F NMR, and ¹³C NMR spectra were recorded with a 300 MHz Bruker Avance spectrometer (¹H = 300; ¹⁹F = 282.5 and ¹³C = 75 MHz), as presented in the Supplementary Materials. Chemical shift values of ¹H NMR spectra were recorded in parts per million (ppm, δ) relative to tetramethylsilane (TMS, 0.00 ppm). Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and coupling constants (J) were reported in Hertz (Hz) with integration value. Chemical shift values of ¹³C NMR spectra were recorded in parts per million (ppm, δ) and calibrated to the residual peak as an internal standard (CDCl₃: δ = 77.0 ppm; DMSO: δ = 39.0 ppm). Chemical shift values of the ¹⁹F NMR spectra were recorded in parts per million (ppm, δ) relative to CFCl₃, 0.00 ppm. Mass spectra were obtained using the APCI⁺ method on an Advion Expression/Plate Express TLC–mass spectrometer. IR peaks were observed on an infrared spectrometer (Thermo Scientific Nicolet iS50 FTIR).

3.2. Difluorination of CBN to a Mixture of Difluoromethyl Ether of Cannabinol and Cannabinol Triflate

1-(difluoromethoxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (2, 53% yield) and 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl trifluoromethanesulfonate (3, 47% yield). Cannabinol (1, 100 mg, 0.32 mmol, 1.0 equiv.), acetonitrile (2.0 mL), and 6 M aqueous KOH (1.0 mL) were placed into a 5 mL vial. The mixture was stirred rapidly at room temperature, and HCF₂OTf (194 µL, 0.96 mmol, 3.0 equiv.) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 4–5 h. After the TLC indicated the total consumption of the starting material, the reaction mixture was allowed to cool at ambient temperature. On a 5 cm × 10 cm TLC plate (silica gel 60 F₂₅₄) in a 5% diethyl ether: hexane solvent system, the reaction mixture showed only one spot at Rf = 0.63. The reaction was diluted with H₂O (15 mL) and extracted with ether (2 × 15 mL). The combined organic layers were dried over MgSO₄, and concentrated. The crude compound (120 mg) was then purified using silica gel chromatography (silica gel, hexane/Et₂O). Despite a single spot, all the characterization data (given below) indicated an inseparable mixture of difluoromethyl ether of cannabinol (2) and cannabinol triflate (3) in the ratio of 53:47 (as determined by the ¹⁹F NMR spectra).

¹H NMR (CDCl₃, 300 MHz) δ = 8.07 (s, 1H), 7.84 (s, 0.59H), 7.15–7.087 (m, 3H), 6.836–6.833 (m, 1H), 6.76 (s, 0.24H), 6.698–6.95 (m, 1H), 6.60 (s, 1H), 6.51 (s, 0.5H), 6.26 (s, 0.25H), 2.58–2.53 (m, 3H), 2.37 (s, 5H), 1.64–1.59 (m, 3H), 1.59 (s, 11H), 1.34–1.29 (m, 7H), 0.91–0.87 (m, 5H).

¹⁹F NMR (CDCl₃, 282.5 MHz) δ = −73.51 (s, 3F), −79.68 (d, J = 73.3 Hz, 2F).

ADVION- Unit resolution (APCI⁺) calculated for 2, C₂₂H₂₇F₂O₂ [M + H]⁺: 361.1979; observed: 361.2. Unit resolution (APCI⁺) calculated for 3, C₂₂H₂₆F₃O₄S[M + H]⁺: 443.1504; observed: 443.1.

FT-IR (neat) ν_max: 2958, 2927, 2852, 1618, 1419, 1215, 1119, 1046, 817, 600 cm⁻¹.

¹³C NMR (CDCl₃, 75 MHz) δ = 154.9, 154.7, 148.7 (t, J = 2.25 Hz, 1C), 146.0, 144.8, 144.8, 137.4, 137.3, 137.15, 137.12, 129.2, 128.4, 127.1, 126.8, 126.1, 125.1, 122.7, 122.6, 120.7, 118.0, 116.7 (t, J = 255.5 Hz, OCF₂H), 116.4, 115.5, 115.4, 115.1, 112.9, 112.8, 78.2, 77.5, 35.6, 35.5, 31.4, 31.3, 30.4, 30.3, 27.1, 26.7, 22.5, 22.4, 21.4, 21.2, 14.0, 13.9. Note: according to the literature, a standard quartet of triflate molecule (~118 ppm with J = 320 Hz) is merged with other carbon peaks.

3.3. Deprotection Reaction on the Mixture of Difluoromethyl Ether of Cannabinol and Cannabinol Triflate to Yield the Difluoromethyl Ether of CBN

1-(difluoromethoxy)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene (2, 42 mg, 92% yield). The mixture of 2 and 3 (80 mg, 0.180 mmol, 1.0 equiv.) and dioxane (2.0 mL) were placed into a 5 mL vial and stirred for 40 sec at room temperature. Et₄NOH was added dropwise (54 µL, 0.36 mmol, 2.1 equiv.), and the mixture was stirred for 4 h at the same temperature. After the indicated time, TLC indicated the formation of CBN, giving R_f = 0.40 for it; the reaction mixture was diluted with CHCl₃, washed with 1 M aq. HCl, water, and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo. The crude compound (69 mg) was then purified by silica gel chromatography (silica gel, hexane/EtOAc), resulting in 42 mg of 2 and 37 mg of CBN (1).

¹H NMR (CDCl₃, 300 MHz) δ = 8.07 (s, 1H), 7.15–7.09 (m, 2H), 6.76–6.51 (m, 3H), 2.56 (t, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.67–1.62 (m, 8H), 1.34–1.30 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H).

¹⁹F NMR (CDCl₃, 282.5 MHz) δ = −79.68 (d, J = 76.1 Hz, 2F).

ADVION- Unit resolution (APCI⁺) calculated for 2, C₂₂H₂₇F₂O₂ [M + H]⁺: 361.1979; observed: 361.3.

FT-IR (neat) ν_max: 2962, 2928, 2859, 1625, 1384, 1157, 1125, 1050, 815 cm⁻¹.

¹³C NMR (CDCl₃, 75 MHz) δ = 154.6, 148.6, 144.7, 137.12, 137.11, 128.4, 127.1, 126.1, 122.6, 116.7 (t, J = 256.05 Hz, OCF₂H), 115.4, 112.9, 112.8, 77.9, 35.6, 31.4, 30.4, 27.1, 22.5, 21.4, 14.0.

3.4. Cannabinol to Cannabinol Triflate Synthesis

6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl trifluoromethanesulfonate (3, 600 mg (84%) yield). A biphasic mixture of toluene (5 mL), 5% (w/v) aqueous LiOH (5 mL), and CBN (500 mg, 1.61 mmol, 1.0 equiv.) were placed into a cool (0 °C) vial, and Tf₂O (2.41 mmol) was added dropwise at a rate to maintain the reaction temperature < 10 °C. The reaction was allowed to warm at room temperature and stirred for 30 min. The organic toluene layer was separated and washed with water (15 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo. The crude compound (702 mg, R_f = 0.63) was then purified using silica gel chromatography (silica gel, hexane/EtOAc), resulting in 600 mg of 3.

¹H NMR (CDCl₃, 300 MHz) δ = 7.84 (s, 1H), 7.17–7.11 (m, 2H), 6.83 (s, 1H), 6.78 (s, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.37 (s, 3H), 1.66–1.59 (m, 8H), 1.37–1.32 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H).

¹⁹F NMR (CDCl₃, 282.5 MHz) δ = −73.53 (s, 3F).

ADVION- Unit resolution (APCI⁺) calculated for 3, C₂₂H₂₆F₃O₄S [M + H]⁺: 442.1426; observed: 443.2.

FT-IR (neat) ν_max: 2958, 2928, 2861, 1629, 1425, 1208, 1139, 971, 819, 604 cm⁻¹.

¹³C NMR (CDCl₃, 75 MHz) δ = 154.9, 146.0, 144.8, 137.4, 137.3, 129.2, 126.8, 125.1, 122.7, 118.6 (q, J = 318.8 Hz, SOCF₃), 118.0, 115.5, 115.2, 78.2, 35.5, 31.3, 30.3, 26.7, 22.4, 21.2, 13.9.

3.5. O-Carboxydifluoromethylated Cannabinol Ether Derivative Preparation

2,2-difluoro-2-((6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-yl)oxy)acetic acid (4, 94.2% yield). Cannabinol and 1 (200 mg, 0.644 mmol, 1.0 equiv.) were added into a 10 mL oven-dried vial equipped with a stir bar under an N₂ atmosphere; 1,4-dioxane (2.0 mL) was added to dissolve cannabinol. Then, NaH (60% purity) (21 mg, 0.708 mmol, 1.1 equiv.) and 1,4-dioxane (2 mL) were added while stirring at room temperature under N₂. The solution was stirred at room temperature for 30 min; then, BrCF₂COONa (140 mg, 0.708 mmol, 1.1 equiv.) and 1,4-dioxane (1 mL) were added. After the mixture was heated at 60 °C for 12 h (monitored by TLC), it was cooled down to room temperature and acidified with 3 M HCl (aq.) to pH = 1. The mixture was extracted with ethyl acetate 3 times. The combined organic phase was washed with saturated brine and dried over MgSO₄. After the solution was filtered and the solvent was evaporated under vacuum, the crude product (250 mg) was purified using flash column chromatography with petroleum ether and ethyl acetate as eluents to give a 94.2% yield of O-difluoromethylated cannabinol derivative, 4.

¹H NMR (CDCl₃, 300 MHz) δ = 11.62 (s, 1H), 8.08 (s, 1H), 7.13–7.05 (m, 2H), 6.82 (s, 1H), 6.77 (s, 1H), 2.56 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.67–1.588 (m, 8H), 1.33–1.28 (m, 4H), 0.88 (t, J = 6.6 Hz, 3H).

¹⁹F NMR (CDCl₃, 282.5 MHz) δ = −76.14 (s, 2F).

ADVION- Unit resolution (APCI⁺) calculated for 2, C₂₃H₂₇F₂O₄ [M + H]⁺: 404.1799; observed: 405.2.

FT-IR (neat) ν_max: 2958, 2930, 2861, 1766, 1626, 1153, 1126, 1051, 1027, 819 cm⁻¹.

¹³C NMR (CDCl₃, 75 MHz) δ = 179.2 (EtOAc), 164.0 (t, J = 42.0 Hz, 1C), 154.3, 145.9, 144.4, 137.2, 137.0, 128.6, 127.4, 126.1, 122.4, 116.5, 116.0, 115.1, 113.8 (t, J = 270.75 Hz, 1C), 78.0, 61.9 (EtOAc), 35.6, 31.4, 30.4, 26.9, 22.5, 21.2, 14.0.

3.6. O-Trifluoromethylated Cannabinol Ether Derivative Preparation

6,6,9-trimethyl-3-pentyl-1-(trifluoromethoxy)-6H-benzo[c]chromene (5, 10% yield). To a reaction tube along with a stir bar, AgOTf (2.48 g, 9.66 mmol, 5.0 equiv.), Selectfluor (1.36 g, 3.86 mmol, 2.0 equiv.), NFSI (1.21 g, 3.86 mmol, 2.0 equiv.), CsF (1.76 g, 11.5 mmol, 6.0 equiv.), and CBN (1.93 mmol, 1.0 equiv.) were all added one after the other in a nitrogen-filled glovebox. Next, under an Ar environment, the addition of toluene (5 mL), benzotrifluoride (10.0 mL), 2-fluoropyridine (938.2 mg, 9.66 mmol, 5.0 equiv.), and CF₃TMS (1.37 g, 9.66 mmol, 5.0 equiv.) was made. Stirring was carried out with the reaction mixture at room temperature. The reaction mixture was filtered through a silica plug that had been eluted with ethanol after 10 h. After the filtrate was concentrated in vacuo, column chromatography was used to purify the final product (Rf = 0.8 in a 5% diethyl ether: hexane solvent system).

¹H NMR (CDCl₃, 300 MHz) δ = 7.96 (s, 1H), 7.16–7.09 (m, 2H), 6.76 (s, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.64–1.59 (m, 8H), 1.37–1.25 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H).

¹⁹F NMR (CDCl₃, 282.5 MHz) δ = −57.11 (s, 3F).

ADVION- Unit resolution (APCI⁺) calculated for 5, C₂₂H₂₆F₃O₂ [M + H]⁺: 379.1885; observed: 379.4.

FT-IR (neat) ν_max: 2962, 2926, 2859, 1627, 1246, 1220, 1169, 1058, 815 cm⁻¹.

¹³C NMR (CDCl₃, 75 MHz) δ = 154.5, 145.9, 144.5, 137.2, 137.1, 128.6, 126.9, 126.0, 122.5, 120.6 (d, J = 255.7 Hz, 1C), 116.7, 115.1, 114.6, 77.7, 35.5, 31.3, 30.4, 26.9, 22.4, 21.4, 14.0.

4. Conclusions

In summary, we have developed the synthesis of four different and novel fluorinated ethers from cannabinol (CBN), including the -OCF₃, -OCF₂COOH, -OCF₂H, and -OSO₂CF₃ groups. These reactions are operationally simple and utilize readily accessible reagents, and thus are practical for the synthesis of different fluorinated CBN ethers in modest to excellent yields. All products were effectively isolated and fully characterized spectroscopically. Future plans are being developed for studies of the structure–activity relationships and biological properties of these compounds.