An Improved Iodine-Catalyzed Aromatization Reaction and Its Application in the Synthesis of a Key Intermediate of Cannabidiol

Abstract

In this study, the development of an improved process for the synthesis of a key cannabidiol intermediate, methyl olivetolate, is described. The process involves an improvement of the iodine-catalyzed aromatization of cyclohexanone using potassium persulfate as an oxidant. This approach enabled for the efficient synthesis of methyl olivetolate with a 90% yield and 99.84% HPLC purity on a 5 kg scale. Additionally, a total of 19 cyclohexanone substrates afforded higher yields (71–92%) of m-diphenol compounds compared to the established methods.

(–)-Cannabidiol (CBD, Figure [1]), a nonpsychotropic cannabinoid, was approved by the United States Food and Drug Administration (FDA) in June 2018 for treating seizures related to Lennox–Gastaut and Dravet syndromes in patients over the age of two.[1] [2] [3] The chemical synthesis of CBD is completed by the condensation of methyl olivatolate 1a with (+)-p-mentha-2,8-dien-1-ol (3), and following decarboxylation as illustrated in (Figure [1]).[4] [5] Methyl olivatolate 1a is the key intermediate for the preparation of cannabidiol and the useful building block for other phytocannabinoids (THC etc.)[4] [5] [6]

Several synthetic routes have been employed for the preparation of methyl olivetolate (1a), Chan et al. started the synthesis of methyl olivetolate 1a from silyl enol ether 6 and hexanoyl chloride using a combination of titanium tetrachloride and titanium tetraisopropoxide as a catalyst in chloromethane to afford 52% of the yield (Scheme [1]A).[7]

The synthesis of the cyclic diketo ester 2a was accomplished as previously outlined by Focella et al (Scheme [1]B).[8] Oxidation of the cyclic diketo ester compound 2a using bromine was reported to afford methyl olivetolate with varying degrees of success (Scheme [1]B).[4] [5] [8] However, the oxidation process by bromine required forcing conditions, which must be controlled carefully to limit the formation of overbrominated aromatic byproducts. Recently, Zhang et al. reported the synthesis of methyl olivetolate 1a from the diketo ether compound 2a using copper bromide in an ethylene glycol dimethyl ether solution (Scheme [1]C).[9] This method provided an 72% yield of the final compound.

One recent paper reported this aromatization by using catalytic iodine in DMSO as the solvent to afford methyl olivetolate 1a (Scheme [1]D).[10] DMSO played the roles of solvent and oxidant, resulting in the side product of stinky dimethyl sulfide, which brings the burden of sewage treatment during large-scale production. Meanwhile, the potential safety issue can also be caused as the decomposition of DMSO in the presence of hydrogen halides or halogens.[11] [12]

Herein, we present an improved approach for preparation of methyl olivetolate 1a from cyclic diketo ester 2a using an eco-friendly oxidant K₂S₂O₈ and an iodine catalyst (Scheme [1]E).

Our research group has recently achieved a significant development by successfully synthesizing quinolin-2(1H)-one derivatives via an oxidation aromatization approach with persulfate salts.[13] Building upon this foundation, we decided to explore the application of persulfate salts in the aromatization of cyclohexanone to produce m-diphenol compounds, a process that, to the best of our knowledge, has not been reported previously. Given the high standard redox potential of the peroxydisulfate ion, S₂O₈ ^2–, in aqueous solution,[14] it serves as a highly potent oxidant, making it an ideal candidate for our investigation.

Inspired by the successful application of persulfate salts in our previous work, we hypothesized that the oxidation aromatization of cyclic diketo ester compound 2a could also be achieved. To explore this, a range of different catalysts were screened, as summarized in Table [1]. Among them, ferrous sulfate heptahydrate (FeSO₄·7H₂O) and persulfate salts exhibited promising results, providing yields of 8%, 12%, and 15% for the desired product (Table [1], entries 1–3). In an attempt to find alternative catalysts, nickel chloride (NiCl₂) and cobalt(II) acetate (Co(OAc)₂) were tested, however, only traces of methyl olivetolate 1a were observed (Table [1], entries 4 and 5). Interestingly, in a previous report,[13] copper sulfate was identified as an effective catalyst for activating persulfate salts. Motivated by these findings, we replicated the conditions using copper sulfate and achieved a yield of 20% for methyl olivetolate 1a (Table [1], entry 6).

Table 1 Using Persulfate Salt in Metal-Catalyzed Oxidative and Aromatization Reaction of 2a ^a

Entry	Oxidant	Catalyst	Yield (%)b
1	(NH4)2S2O8	FeSO4·7H2O	8
2	K2S2O8	FeSO4·7H2O	12
3	Na2S2O8	FeSO4·7H2O	15
4	Na2S2O8	NiCl2	trace
5	Na2S2O8	Co(OAc)2	trace
6	Na2S2O8	CuSO4	20

^a The reaction was conducted using compound 2a (1 equiv), oxidant (2 equiv), and catalyst (10 mol%) in 1:1 H₂O/CH₃CN (10 mL) at reflux for 6 h.

^b Isolated yield.

Based on previously reported literature, it is a well-established fact that molecular halogens can serve as catalysts in organic compounds, promoting cyclization reactions and resulting in the formation of halogen ions. Subsequently, persulfate salts (S₂O₈ ^2–) can serve as oxidants to convert the halogen ions back into halogens, thereby ensuring the regeneration of the catalyst and enabling the system to function in a recycling mode.[15] [16]

Table 2 Effect of Catalyst to Oxidation and Aromatization Reaction of Compound 2a ^a

Entry	Catalyst	Yield (%)c
1	Br2	30
2	KBr	15
3	NaBr	10
4	NaI	20
5	KI	18
6	I 2	92
7b	I 2	45
8	CuBr	trace
9	CuI	trace

^a The reaction was conducted using compound 2a (1 equiv), K₂S₂O₈ (1.2 equiv) and catalyst (10 mol%) in CH₃CN (10 mL) at 80 ° for 16 h.

^b The reaction was conducted in 1:1 H₂O/CH₃CN (10 mL).

^c Isolated yield.

Based on the results presented in Table [2], entry 6, I₂ was selected as the preferred catalyst for further investigation. As an alternative, the reactions were carried out with Br₂ instead of I₂ in acetonitrile, resulting in a yield of 30% (Table [2], entry 1). It was evident that the oxidation and aromatization progressed at a sluggish pace when other catalyst such as potassium bromine (KBr), potassium iodine (KI), sodium bromine (NaBr), and sodium iodine (NaI) were used (Table [2], entries 2–5). Notably, the iodine catalyst exhibited excellent compatibility with the reaction in the presence of acetonitrile as the solvent, however, incorporating water into acetonitrile in this catalytic system significantly reduced the reaction yield (Table [2] entries 6 vs. 7). When copper bromide (CuBr) and copper iodide (CuI) were employed as catalysts, only trace amounts of methyl olivetolate 1a were observed (Table [2], entries 8 and 9).

Using I₂ as the catalyst, the effectiveness of various oxidants including Na₂S₂O₈, (NH₄)₂S₂O₈, and K₂S₂O₈ was evaluated, with K₂S₂O₈ showing significant improvement in the desired product yield (Table [3], entries 5 and 6). The alternative persulfate oxidants, Na₂S₂O₈ and (NH₄)₂S₂O₈, exhibited lower yields compared to K₂S₂O₈ (Table [3], entries 1–4). It is worth noting that Na₂S₂O₈ and (NH₄)₂S₂O₈ are less commonly used compared to K₂S₂O₈.[17] This preference for K₂S₂O₈ can be attributed to its higher solubility in organic solvents, enabling a more efficient transformation.[18]

Table 3 Effect of Oxidant to Oxidation and Aromatization Reaction of Compound 2a ^a

Entry	Oxidant (equiv)	Yield (%)b
1	Na2S2O8 (0.8)	70
2	Na2S2O8 (1.2)	85
3	(NH4)2S2O8 (0.8)	68
4	(NH4)2S2O8 (1.2)	80
5	K2S2O8 (0.8)	78
6	K2S2O8 (1.2)	92

^a The reaction was conducted using compound 2a (1 equiv), oxidant (1.2 equiv), and I₂ (10 mol%) in CH₃CN (10 mL) at 80 ℃ for 16 h.

^b Isolated yield.

The optimization of K₂S₂O₈ and I₂ stoichiometry for enhancing the reaction efficiency is detailed in Table [4]. Based on the results presented in Table [4], entry 1, I₂ (5 mol%) was chosen as the preferred catalyst for further investigation. The yield was further increased to 60% by increasing the amount of K₂S₂O₈ from 1 to 1.2 and 1.5 equivalents (Table [4], entries 2 and 3). Entry 4 in Table [4] illustrates the improved outcomes with increasing catalyst amount. Furthermore, the addition of TsOH did not enhance the yield (Table [4], entry 5). The reaction could be maintained for up to 16 h, as prolonging the reaction time did not promote higher yields of the desired product (Table [4], entry 6).

Table 4 Effect of Oxidant/Catalyst Stoichiometry on Oxidation and Aromatization Reaction of Compound 2a ^a

Entry	Oxidant (equiv)	Catalyst (mol%)	Yield (%)b
1	K2S2O8 (1)	I2 (5)	55
2	K2S2O8 (1.2)	I2 (5)	60
3	K2S2O8 (1.5)	I2 (5)	60
4	K2S2O8 (1.2)	I2 (10)	92
5c	K2S2O8 (1.2)	I2 (10)	90
6d	K2S2O8 (1.2)	I2 (10)	85

^a The reaction was conducted using compound 2a (1 equiv), K₂S₂O₈ (y equiv), and I₂ (x mol%) in CH₃CN (10 mL) at 80 ℃ for 16 h.

^b Isolated yield.

^c Added pTSOH·H₂O as a catalyst.

^d The reaction was conducted in CH₃CN (10 mL) at 80 °C for 24 h.

After establishing an efficient catalyst and oxidant, the focus of our study shifted towards selecting an appropriate solvent. A screening of various solvents for the oxidation and aromatization reaction identified acetonitrile (CH₃CN) as the optimal choice (Table [5], entry 2). Notably, several other solvents also demonstrated effectiveness in the reaction, such as dichloromethane (DCM), a combination of water and acetonitrile (H₂O/CH₃CN), and toluene (Table [5], entries 1, 3, and 6). Conversely, lower yields were obtained when using chlorobenzene and water as solvents (Table [5], entries 4 and 5), indicating incompatibility with the reagent system.

Table 5 Effect of Solvent to Oxidation and Aromatization Reaction of Compound 2a ^a

Entry	Solvent	Temp (°C)	Yield (%)b
1	DCM	40	25
2	CH3CN	80	92
3c	H2O/CH3CN	80	45
4	chlorobenzene	85	14
5	H2O	90	15
6	toluene	90	50

^a The reaction was conducted using compound 2a (1 equiv), K₂S₂O₈ (1.2 equiv), and I₂ (10 mol%) in solvent (10 mL) at 80 ℃ for 16 h.

^b Isolated yield.

^c 1:1 H₂O/CH₃CN.

In order to validate the optimized conditions, we proceeded with the synthesis of compound 1a from compound 2a. The reaction was carried out in 10 mL CH₃CN as the solvent (Table [5], entry 2), utilizing I₂ (10 mol%) as the catalyst (Table [2], entry 6), K₂S₂O₈ (1.2 equiv) as the oxidant (Table [3], entry 6), and conducted at 80 ℃ for 16 h. As a result, we obtained 92% yield of the desired product. This successful outcome confirmed the effectiveness of the selected catalyst, oxidant, and solvent combination.

To confirm the generality of this reaction method, we tested the optimized conditions on a 500 g batch scale resulting in 92% isolated yield of our desired product 1a.

Following the optimized oxidation and aromatization reaction involving compound 2a, the iodine catalyst was successfully recovered after filtration and subsequently reintroduced in additional oxidation and aromatization steps. The starting material 2a and product 1a were evaluated, monitored through HPLC analysis of the crude reaction mixture after each reaction cycle, with high yields of product 1a observed across three cycles, as detailed in Table [6] (cycles 1–3). This underscores the recyclability of our catalytic system for industrial-scale applications.

Table 6 Results of the Recycling Experiments^a

Cycle	Conversion (%)b	Yield (%)c
1	99	92
2	99	89
3	98	87
4	95	80

^a The reaction was conducted using compound 2a (500 g, 2 mol) in CH₃CN (10 mL/1 g), I₂ (52.9 g, 10 mol%), and K₂S₂O₈ (675 g, 2.5 mol) at 80 ℃ for 16 h.

^b Conversion was determined via HPLC analyses using an area ratio of 10/(10 + 9).

^c Isolated yield.

The optimized process for this step has been successfully applied to prepare up to a 5 kg batch size, resulting in a 90% isolated yield of 1a with a purity of 99.84% as determined by HPLC. This demonstrates the scalability and robustness of the reaction for the synthesis of methyl olivetolate 1a on a larger scale (Scheme [2]).

To thoroughly investigate the scope and limitations of our improved iodine-catalyzed aromatization method, we explored a diverse range of cyclic diketo ester compounds as substrates (Scheme [3]). Our objective was to assess the compatibility of these substrates with the optimized reaction conditions. Notably, we successfully achieved the desired outcomes using the prescribed conditions. Importantly, we observed that the electronic properties of the substituents on the phenyl group significantly influenced the reaction outcomes. In the case of substrates 2a–c, which featured a combination of methyl ether and alkyl substituents, we observed excellent yields of 90% and 92%, respectively, for the production of methyl olivetolate and its homologues 1a–c. Similarly, when substrates 2d–e, which possessed only a methyl ether substituent on the phenyl group, were employed, we obtained high reaction yields of 86% and 88%. On the other hand, substrates 2f–l, featuring electron-donating alkyl groups, as substituents, exhibited lower yields ranging from 75% to 78% when subjected to the same reaction conditions. In summary, it is evident that the electronic properties of the substituents have a pronounced impact on the efficiency of the aromatization reaction and the corresponding yields of the cyclic diketo products 1f–l.

Among the various substituents tested on the phenyl group, including hydroxymethyl, methoxy, nitrile, chloro-, bromo-, and fluoro-substituted groups, we observed excellent tolerance towards nitrile substituents. These substituents enabled the successful synthesis of the corresponding products 1m–s with satisfactory yields ranging from 71% to 83%. Intriguingly, the electron-withdrawing groups, such as nitrile and methyl ether, also displayed similarly high yields, further demonstrating the versatility and robustness of our improved iodine-catalyzed aromatization reaction.

We have successfully developed an improved iodine-catalyzed aromatization reaction for a key cannabidiol (CBD) intermediate, methyl olivetolate using an iodine catalyst, and potassium persulfate in acetonitrile.[19] [20] Our synthesis method is efficient and practical, utilizing an environmentally friendly I₂ and potassium persulfate catalytic system that demonstrates good recyclability. Gratifyingly, this process has been scaled up to 5 kg delivering related products with excellent yields of about 90% and 99.84% purity by HPLC. Further extension of this iodine-catalyzed oxidation reaction method for making methyl olivetolate and its derivatives is ongoing in our laboratory.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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  Thieme ConnectSearch in Google Scholar
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  Search in Google Scholar
• 19 General Procedure To a solution of 2 (10.4 mmol, 1 equiv) in acetonitrile (10 mL) was added potassium persulfate (12.5 mmol, 1.2 equiv) and iodine (1 mmol, 0.1 equiv). Then the reaction mixture was warmed over 16 h at 80 ℃ under nitrogen atmosphere. It was then cooled reaction mixture to 25 °C followed by the addition of ethyl acetate (30 mL) and 0.2 M sodium thiosulfate (20 mL). Afterward, the residues were washed sequentially with water (30 mL) and quenched with hydrogen chloride acid (0.5 M, 10 mL). The organic phase was dried and concentrated in a vacuum at 40–50 °C to afford the crude product. The crude product was purified by silica gel column chromatography to give compound 1.
• 20 Synthesis of Methyl 2,4-dihydroxy-6-pentylbenzoate (1a) Cyclic diketo ester compound 2a (5.7 kg, 24 mol, 1 equiv), potassium persulfate (7.5 kg, 28 mol, 1.2 equiv), and iodine (590 g, 2.3 mol, 0.1 equiv) in CH₃CN (50 L) were charged to a 100 L glass reactor that had been purged with nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The disappearance of starting material 2a was confirmed via TLC analysis and then the reaction mixture was cooled to 25 °C followed by the addition of ethyl acetate (30 L) and 0.2 M sodium thiosulfate (20 L). The water solution was collected and concentrated to 10 L under vacuum conditions, then treated with potassium persulfate (1.5 kg, 5.6 mol) at room temperature, and the catalyst was recovered after the filtration step. The reaction vessel, the filter, and the cake (I₂ catalyst) were washed with additional water (3 × 1 L), and the catalyst was reused for another batch of oxidation and aromatization reaction. The ethyl acetate phase was concentrated and dried under vacuum at 40–50 °C to afford the crude product. The crude product was crystallized with cyclohexane (7.5 L) to obtain a 4.98 kg white solid of methyl olivetolate 1a (90% of yield and 99.84% purity by HPLC); mp 105–106 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.26 (s, 1 H), 9.80 (s, 1 H), 6.26–6.04 (m, 2 H), 3.77 (s, 3 H), 2.57–2.49 (m, 5 H), 1.53–1.38 (m, 2 H), 1.27 (td, J = 8.2, 7.0, 4.8 Hz, 5 H), 0.87 (t, J = 6.9 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.9, 165.2, 160.2, 148.9, 110.7, 105, 101.3, 51.87, 36.76, 32.01, 31.42, 22.45, 14.02. HRMS (ESI): m/z [M – H]^– calcd for C₁₃H₁₇O₄: 237.1; found: 237.3.

Corresponding Authors

Publication History

Received: 12 March 2024

Accepted after revision: 06 April 2024

Accepted Manuscript online:
09 April 2024

Article published online:
22 April 2024

© 2024. Thieme. All rights reserved

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• References and Notes

• 1 Morales P, Reggio PH. ACS Med. Chem. Lett. 2019; 10: 694
  CrossrefPubMedSearch in Google Scholar
• 2 Billakota S, Devinsky O, Marsh E. Curr Opin. Neurol. 2019; 32: 220
  CrossrefPubMedSearch in Google Scholar
• 3 Gong X, Sun C, Abame MA, Shi W, Xie Y, Xu W, Zhu F, Zhang Y, Shen J, Aisa HA. J. Org. Chem. 2019; 85: 2704
  CrossrefPubMedSearch in Google Scholar
• 4 Reekie T, Scott M, Kassiou M. WO2019033168 A1, 2019
• 5 Shen J, Gong X, Zhu F, Jiang X, Zhang Y, Changliang S. US Patent EP3971158A1, 2014
• 6 Chan T, Chaly T. Tetrahedron Lett. 1982; 23: 2935
  CrossrefSearch in Google Scholar
• 7 Chan T, Stossel D. J. Org. Chem. 1986; 51: 2423
  CrossrefSearch in Google Scholar
• 8 Focella A, Teitel S, Brossi A. J. Org. Chem. 1977; 42: 3456
  CrossrefSearch in Google Scholar
• 9 Zhang T, Gong X, Mao Y, Liu X. Synthesis of methyl 2,4-dihydroxy-6-pentylbenzoate. CN 114890894A
• 10 Hurem D, Macphail BJ, Carlini R, Lewis J, McNulty J. SynOpen 2021; 5: 86
  Thieme ConnectSearch in Google Scholar
• 11 Yang Q, Sheng M, Li X, Tucker C, Vásquez Céspedes S, Webb NJ, Whiteker GT, Yu J. Org. Process Res. Dev. 2020; 24: 916
  CrossrefSearch in Google Scholar
• 12 Aida T, Akasaka T, Furukawa N, Oae S. Bull. Chem. Soc. Jpn. 1976; 49: 1117
  CrossrefSearch in Google Scholar
• 13 Chen W, Sun C, Zhang Y, Hu T, Zhu F, Jiang X, Abame MA, Yang F, Suo J, Shi J. J. Org. Chem. 2019; 84: 8702
  CrossrefPubMedSearch in Google Scholar
• 14 Minisci F, Citterio A, Giordano C. Acc. Chem. Res. 1983; 16: 27
  CrossrefSearch in Google Scholar
• 15 Hossain MD, Ikegami Y, Kitamura T. J. Org. Chem. 2006; 71: 9903
  CrossrefPubMedSearch in Google Scholar
• 16 Beukeaw D, Noikham M, Yotphan S. Tetrahedron 2019; 75: 130537
  CrossrefSearch in Google Scholar
• 17 Abdel-Kade MM, Mosaad MM, El-Kabban F. Phys. Status Solidi A 1992; 130: 351
  CrossrefSearch in Google Scholar
• 18 Jiang H, Zang N, Qian X, Fu ZJ. Chem. Ind. Eng. (China) 2006; 57: 2798
  Search in Google Scholar
• 19 General Procedure To a solution of 2 (10.4 mmol, 1 equiv) in acetonitrile (10 mL) was added potassium persulfate (12.5 mmol, 1.2 equiv) and iodine (1 mmol, 0.1 equiv). Then the reaction mixture was warmed over 16 h at 80 ℃ under nitrogen atmosphere. It was then cooled reaction mixture to 25 °C followed by the addition of ethyl acetate (30 mL) and 0.2 M sodium thiosulfate (20 mL). Afterward, the residues were washed sequentially with water (30 mL) and quenched with hydrogen chloride acid (0.5 M, 10 mL). The organic phase was dried and concentrated in a vacuum at 40–50 °C to afford the crude product. The crude product was purified by silica gel column chromatography to give compound 1.
• 20 Synthesis of Methyl 2,4-dihydroxy-6-pentylbenzoate (1a) Cyclic diketo ester compound 2a (5.7 kg, 24 mol, 1 equiv), potassium persulfate (7.5 kg, 28 mol, 1.2 equiv), and iodine (590 g, 2.3 mol, 0.1 equiv) in CH₃CN (50 L) were charged to a 100 L glass reactor that had been purged with nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The disappearance of starting material 2a was confirmed via TLC analysis and then the reaction mixture was cooled to 25 °C followed by the addition of ethyl acetate (30 L) and 0.2 M sodium thiosulfate (20 L). The water solution was collected and concentrated to 10 L under vacuum conditions, then treated with potassium persulfate (1.5 kg, 5.6 mol) at room temperature, and the catalyst was recovered after the filtration step. The reaction vessel, the filter, and the cake (I₂ catalyst) were washed with additional water (3 × 1 L), and the catalyst was reused for another batch of oxidation and aromatization reaction. The ethyl acetate phase was concentrated and dried under vacuum at 40–50 °C to afford the crude product. The crude product was crystallized with cyclohexane (7.5 L) to obtain a 4.98 kg white solid of methyl olivetolate 1a (90% of yield and 99.84% purity by HPLC); mp 105–106 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.26 (s, 1 H), 9.80 (s, 1 H), 6.26–6.04 (m, 2 H), 3.77 (s, 3 H), 2.57–2.49 (m, 5 H), 1.53–1.38 (m, 2 H), 1.27 (td, J = 8.2, 7.0, 4.8 Hz, 5 H), 0.87 (t, J = 6.9 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.9, 165.2, 160.2, 148.9, 110.7, 105, 101.3, 51.87, 36.76, 32.01, 31.42, 22.45, 14.02. HRMS (ESI): m/z [M – H]^– calcd for C₁₃H₁₇O₄: 237.1; found: 237.3.

• Supplementary Material