Oxidative Functionalization of Catechol Derivatives Substituted with Electron-Withdrawing Groups

Abstract

Catechols possessing electron-withdrawing groups at the C3 position effectively underwent oxidative functionalization at the C4 position in the presence of phenyliodine(III) diacetate (PIDA) and heteroarene nucleophiles (e.g., indole, indazole, and benzotriazole) to produce the corresponding biaryl products. The PIDA-mediated oxidation of catechol derivatives afforded the ortho-benzoquinone intermediate, which subsequently underwent regioselective nucleophilic addition to the α,β-unsaturated carbonyl moiety of ortho-benzoquinone using indole, indazole, and benzotriazole to give 4-substituted catechol derivatives in a one-pot manner. Notably, the nucleophilic substitution positions of indazole and benzotriazole were perfectly controlled. Additionally, the reaction using N-methylaniline as the nucleophile afforded a tertiary amine product.

Introduction

ortho-Benzoquinones (1,2-benzoquinones) are readily prepared by the oxidation of catechols or phenols and are utilized as reactive reaction intermediates to form complex benzene skeletons (Chart 1A). ortho-Benzoquinones, which possess two carbonyl groups and two olefin moieties, can function as enones, dienones, carbodienes, heterodienophiles, heterodienes, and dienophiles in various organic reactions.^1–3) Therefore, controlling the reaction position is challenging. Nucleophilic additions to the enone (α,β-unsaturated carbonyl) moiety of ortho-benzoquinones using alcohols,⁴⁾ phenols,^4–6) secondary-amines,²⁾ and thiols⁴⁾ have been recently accomplished. We have also recently reported the regioselective nucleophilic addition of indoles to ortho-benzoquinone intermediate (I) derived from 3-methoxycarobonylcatechol (1a) to afford arylindoles, biaryl products, in the presence of phenyliodine(III) diacetate (PIDA) with or without BF₃·Et₂O as a Lewis acid⁷⁾ (Chart 1B). While a C4-adduct (2) was selectively obtained in the absence of BF₃·Et₂O, the use of a catalytic amount of BF₃·Et₂O gave a C5-adduct (3). To expand our synthetic strategy, we performed the regioselective and oxidative functionalization of catechols substituted with an electron-withdrawing group (EWG) at the 3-position using indole, indazole, benzotriazole, and N-methylaniline (Chart 1C).

Chart 1. Oxidative Functionalizations of Catechol Derivatives

Results and Discussion

Indoles are pharmaceutically useful skeletons^8–13) and behave as electron-rich arene nucleophiles. The electron-rich arenes can be useful nucleophiles, because the preliminary functionalization, which causes the production of wastes, is not required.^14,15) In our previous work⁷⁾ (Chart 1B), BF₃·Et₂O played a key role in switching the regioselectivity of the nucleophilic position on 3-methoxycarbonyl ortho-benzoquinone (I) using an indole nucleophile. Acetic acid (AcOH) was produced during the PIDA-mediated oxidation of 1a. AcOH effectively activated the C2-carbonyl moiety on A, which facilitated the 1,4-addition of indole at the C4-position to give 2. On the other hand, catalytic BF₃·Et₂O preferentially coordinated to the C1-carbonyl group of I to produce 3 via the 1,4-addition of indole at the C5-position. When 3-nitrocatechol (1b) was used as a substrate instead of 1a to react with an indole nucleophile, a 4-adduct (4) was selectively obtained with or without BF₃·Et₂O (Chart 2). After the oxidation of 1b using PIDA in CH₂Cl₂ or tetrahydrofuran (THF), the addition of the indole afforded 4-adduct 4a as the main product in 71 and 70% yields, respectively (entry 1, left). BF₃·Et₂O (5 mol%) had no effect on the regioselectivity, affording 4a as the main product in 55% yield and 5a in 11% yield (entry 1, right). A similar behavior was observed when 5-fluoroindole and 2-methoxycarbonylindole were used as nucleophiles to produce other 4-adducts (4b and 4c; entries 2 and 3). While the reaction using 2-phenylindole gave 4-adduct 4d as the sole product in the absence of BF₃·Et₂O, the reaction using BF₃·Et₂O selectively afforded a 5-adduct (5d).¹⁶⁾ Although density functional theory (DFT) calculations have been conducted to elucidate these selectivities, the reason remains unclear.

Chart 2. Oxidative Coupling of 3-Nitrocatechol (1b) with Indole Derivatives

Next, we examined the oxidative functionalization of 1a using an indazole instead of an indole as the nucleophile (Table 1). Indazole is also a pharmaceutically useful skeleton,^17–25) and the selectivity of the nucleophilic position (N1 or N2-atom on indazole) depends on the reaction conditions.^17–25) Specifically, the reaction of 1a with indazole can possibly furnish four regioisomers [C4/N2-adduct (6a), C5/N2-adduct (7a), C4/N1-adduct (8a), and C5/N1-adduct (9a)]. After screening the reaction conditions, 6a was selectively obtained as the main product and its structure was determined by X-ray structural analysis. Compound 6a was obtained in 51% yield using BF₃·Et₂O (entry 1), while the reaction without BF₃·Et₂O gave 6a in 58% yield (entry 2). The use of other Lewis acid catalysts, such as InCl₃ and FeCl₃, was less effective in improving the yield, and the regioselectivity remained unchanged (entries 3 and 4). The use of THF instead of CH₂Cl₂ in the absence of BF₃·Et₂O improved the reaction efficiency, giving 6a in 68% yield (entry 5). Hexafluoroisopropanol (HFIP), CHCl₃, and toluene were ineffective in this reaction (entries 6–8).

Table 1. Optimization of Reaction Conditions in Oxidative Coupling of 3-Methoxycarbonyl Catechol (1a) with Indazole

Entry	Catalyst	Solvent	Yield (%)
			6a	7a, 8a, or 9a
1	BF3·Et2O	CH2Cl2	51	ND
2	—	CH2Cl2	58	ND
3	InCl3	CH2Cl2	58	ND
4	FeCl3	CH2Cl2	53	ND
5	—	THF	68	ND
6	—	HFIP	46	ND
7	—	CHCl3	38	ND
8	—	toluene	23	ND

PIDA; phenyliodine(III) diacetate, THF; tetrahydrofuran, HFIP; hexafuluoroisopropanol, ND; not detected.

The oxidative functionalization of 1a using 5-bromoindazole and 6-methoxycarbonylindazole in CH₂Cl₂ also afforded the C4/N2-adducts (6b and 6c) with or without BF₃·Et₂O (Chart 3). The use of benzotriazole also afforded a C4-adduct (6d), and CH₂Cl₂ was found to be a better solvent than THF. Although the reason for the behavior of the nucleophilic positions of indazole^17–25) and benzotriazole^26–35) is unclear, it is noteworthy that the nucleophilic positions were perfectly controlled. N-Methylaniline was also compatible in this reaction, furnishing C4-adduct 6e. The reactivity in THF was higher than that in CH₂Cl₂.

Chart 3. Oxidative Coupling of 3-Methoxycarbonyl Catechol (1a)

The scope and limitations of this study were investigated (Chart 4). The reactions of 1b, a 3-nitro compound, with indazole and N-methylaniline with or without BF₃·Et₂O resulted in a complex mixture and did not give the desired products (6f and 6g). Oxidative functionalization using benzotriazole effectively produced a C4-adduct (6h) in 68% yield. 3-Cyanocatechol 1c also underwent oxidative functionalization using benzotriazole to give C4-adduct 6l, while products (6i–6k) were not obtained from indole, indazole, and N-methylaniline, respectively, in the presence or absence of BF₃·Et₂O. In the latter reactions, the reactions resulted in complex mixture probably due to no regioselectivty of nucleophiles. Unfortunately, the structures of byproducts could not be identified.

Chart 4. Oxidative Coupling of 3-Nitrocatechol (1b) or 3-Cyanocatechol (1c)

Further functionalization of the synthesized product 6a was conducted. The catechol moiety of 6a was effectively transformed into a 1,2-methylenedioxybenzene skeleton (10) in the presence of CH₂Cl₂ and Cs₂CO₃ (Chart 5, top). Additionally, the dimethylation of the two hydroxy groups in 6a was successfully accomplished to give 11.

Chart 5. Further Functionalizations

Conclusion

We accomplished the oxidative coupling of catechol derivatives possessing an electron-donating group at the C3 position in the presence of a PIDA oxidant and nucleophiles. Our previous study showed that the regioselectivity of the nucleophilic positions changed in the absence or presence of BF₃·Et₂O when using a combination of 3-methoxycarbonylcatechol (1a) and an indole nucleophile to selectively give C4- or C5-adduct, as shown in Chart 1B.⁷⁾ In contrast, this study revealed that the use of other nucleophiles toward 1a and other substrates possessing 3-nitro- and 3-cyano groups with indole as well as indazole and benzotriazole nucleophiles afforded C4-adducts as the main products with or without BF₃·Et₂O. The biaryl skeletons obtained are pharmaceutically useful. Additionally, the use of N-methylaniline gave a tertiary amine product. The present one-pot functionalization method of catechols is valuable for the construction of various complex benzene-linked skeletons. The elucidation of the regioselectivity based on DFT calculations is currently underway.

Experimental

Typical Procedure without BF₃·Et₂O; To a suspension of catechol (1; 0.20 mmol) in CH₂Cl₂ (1.0 mL) in a dry brown test tube was added PIDA (64.4 mg, 0.2 mmol) under argon. The reaction mixture was placed on an organic reactor, Chemi Station (EYELA, Tokyo Rikakikai Co., Ltd., Tokyo, Japan), and the mixture was stirred at 25 °C for 1 h. Nucleophile (3.0 equivalents (equiv.)) and CH₂Cl₂ (1.0 mL) were added sequentially, and the mixture was stirred at 0 °C for 1 h. After quenching with H₂O, the reaction mixture was extracted with CH₂Cl₂ (10 mL×3). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Purification using flash column chromatography on silica gel (n-hexane-ethyl acetate) gave 4-adduct.

Acknowledgments

This study was partially supported by JSPS (MEXT Grant in Aid-for transformative research areas (B) Deuterium Science) KAKENHI Grant Number 20H05738 (for Y.S.), and Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number 23ama121054 (for Y.S.) and Research Foundation for the Electrotechnology of Chubu (REFEC) (for Y.S.).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

References and Note

• 1) Nair V., Menon R. S., Biju A. T., Abhilash K. G., Chem. Soc. Rev., 41, 1050–1059 (2012).
• 2) Takata T., Tajima R., Ando W., J. Org. Chem., 48, 4764–4766 (1983).
• 3) Xiao X., Wengrynluk S. E., Synlett, 32, 752–762 (2021).
• 4) Xiao X., Greenwood N. S., Wengryniuk S. E., Angew. Chem. Int. Ed., 58, 16181–16187 (2019).
• 5) Huang Z., Lumb J.-P., Angew. Chem. Int. Ed., 55, 11543–11547 (2016).
• 6) Xu W., Huang Z., Xiang J., Lumb J.-P., ACS Catal., 9, 3800–3810 (2019).
• 7) Sawama Y., Kuwata S., Mae M., Udagawa T., Akai S., Sajiki H., Chem. Commun., 58, 12935–12938 (2022).
• 8) Kochanowska-Karamyan A. J., Hamann M. T., Chem. Rev., 110, 4489–4497 (2010).
• 9) Vicente R., Org. Biomol. Chem., 9, 6469–6480 (2011).
• 10) Kaushik N. K., Kaushik N., Attri P., Kumar N., Kim C. H., Verma A. K., Choi E. H., Molecules, 18, 6620–6662 (2013).
• 11) Kale A. P., Kumar G. S., Kapur M., Org. Biomol. Chem., 13, 10995–11002 (2015).
• 12) Zhang M.-Z., Chen Q., Yang G.-F., Eur. J. Med. Chem., 89, 421–441 (2015).
• 13) Goyal D., Kaur A., Goyal B., ChemMedChem, 13, 1275–1299 (2018).
• 14) Asai S., Yabe Y., Goto R., Nagata S., Monguchi Y., Kita Y., Sajiki H., Sawama Y., Chem. Pharm. Bull., 63, 757–761 (2015).
• 15) Sawama Y., Masuda M., Honda A., Yokoyama H., Park K., Yasukawa N., Monguchi Y., Sajiki H., Chem. Pharm. Bull., 64, 778–784 (2016).
• 16) In the previous study (reference 7), the isolated one isomer (4-adduct) was never isomerized to another isomer (5-adduct) under the acidic conditions. Therefore, 4-adduct or 5-adduct was proposed to be produced by the direct nucleophilic addition of ortho-benzoquinone reaction intermediate.
• 17) Fedorov A. Y., Flnet J.-P., Tetrahedron Lett., 40, 2747–2748 (1999).
• 18) Hunt K. W., Moreno D. A., Suiter N., Clark C. T., Kim G., Org. Lett., 11, 5054–5057 (2009).
• 19) Nagaradja E., Chevallier F., Roisnel T., Dorcet V., Halauko Y. S., Ivashkevich O. A., Matulis V. E., Mongin F., Org. Biomol. Chem., 12, 1475–1487 (2014).
• 20) Riedmüllera S., Nachtsheim B. J., Synlett, 26, 651–655 (2015).
• 21) Chen Q., Mao Z., Guo F., Liu X., Tetrahedron Lett., 57, 3735–3738 (2016).
• 22) Espinosa-Bustos C., Villegas A., Salas C. O., ARKIVOC, 2017, 63–73 (2017).
• 23) Zhang R., Liu Z., Peng Q., Zhou Y., Xu L., Pan X., Org. Biomol. Chem., 16, 1816–1822 (2018).
• 24) Niu Z.-G., Han H.-B., Li M., Zhao Z., Chen G.-Y., Zheng Y.-X., Li G.-N., Zuo J.-L., Organometallics, 37, 3154–3164 (2018).
• 25) Kitamura T., Morshed M. H., Tsukada S., Miyazaki Y., Iguchi N., Inoue D., J. Org. Chem., 76, 8117–8120 (2011).
• 26) Beletskaya I. P., Davydov D. V., Moreno-Mañas M., Tetrahedron Lett., 39, 5617–5620 (1998).
• 27) Kang S.-K., Lee S.-H., Lee D., Synlett, 7, 1022–1024 (2000).
• 28) Liu Z., Larock R. C., J. Org. Chem., 71, 3198–3209 (2006).
• 29) Tang B.-X., Guo S.-M., Zhang M.-B., Li J.-H., Synthesis, 11, 1707–1716 (2008).
• 30) Ueda S., Su M., Buchwald S. L., Angew. Chem. Int. Ed., 50, 8944–8947 (2011).
• 31) Davydov D. V., Oprunenko Y. F., Beletskaya I. P., Tetrahedron Lett., 58, 4465–4467 (2017).
• 32) Garnier T., Danel M., Magné V., Pujol A., Bénéteau V., Pale P., Chassaing S., J. Org. Chem., 83, 6408–6422 (2018).
• 33) Sharghi H., Saei A. A., Aberi M., ChemistrySelect, 4, 13228–13234 (2019).
• 34) Guin A., Gaykar R. N., Bhattacharjee S., Biju A. T., J. Org. Chem., 84, 12692–12699 (2019).
• 35) Wang D., Gan X., Zhou L., Shu H., Zhou J., Tetrahedron Lett., 88, 153587 (2022).