Copper-Catalyzed Ortho-Acylation of Phenols with Aryl Aldehydes and Its Application in One-Step Preparation of Xanthones

Abstract

In the presence of triphenylphosphine, copper (II) chloride can catalyze an intermolecular ortho-acylation reaction of phenols with aryl aldehydes. The reaction proceeds smoothly with a wide range of starting materials, and furthermore, it can be used to synthesize xanthone derivatives in a single step with high-yields.

Direct acylation of the aromatic rings of phenols is an important transformation in organic synthesis since phenols are one of the most abundant aromatic compounds in nature and industry.¹ Two major synthetic pathways can be followed in this transformation, namely, the well-known Friedel-Crafts reaction,² and the transition-metal-catalyzed C-H activation pathway.³ However, classical Friedel-Crafts reactions often suffer from the harsh reaction condition and usage of air/water sensitive Lewis acid.⁴ While transition-metal-catalyzed C-H activation can convert carbon-hydrogen bond into carbon-oxygen,⁵ carbon-nitrogen,⁶ carbon-halide,⁷ carbon-sulfur⁸ or carbon-carbon bonds,⁹ till now, there is only one report about the acylation reaction of unprotected phenols.¹⁰ In that work, Miura and co-workers prepared 2-benzoyl-1-naphthol as a control experiment when they synthesized benzofuran-2(3H)-ones; however, no in-depth investigation was reported.

In the process of synthesizing a natural product, SsnB (Sparstolonin B, a xanthone derivative isolated from a Chinese herb showing effective anti-inflammatory activity),¹¹ an effective ortho-acylation of substituted phenol and a facile protocol to form the xanthone ring are needed. Herein, we established a versatile synthetic method in-depth to achieve ortho-acylation of phenols firstly, and its appliction in synthesizing different xanthone derivatives. Xanthones constitute the core of natural and biologically active family of compounds present in higher plants and microorganisms,¹² as well as the secondary metabolites found in higher plant families and lichens.¹³ They exhibit diverse physicochemical and pharmacological properties, such as antitumoral, antibacterial and antiinflammatory.¹⁴

To investigate the optimized reaction protocol, 3-methoxybenzaldehyde (1a) and 4-methoxyphenol (2a) were refluxed in toluene for 24 h in the presence of 5 mol% Pd(OAc)₂, 7.5 mol% triphenylphosphine and 2.2 equiv K₂CO₃, and the product (3aa) was obtained in 77% yield. With this promising result, a systematic screening of catalysts, ligands, and bases was carried out and the results summarized in Table S1. Based on the results of Table S1, we chose 1 mmol aldehyde, 1.3 mmol phenol in toluene at 110 °C in the presence of 5 mol% of CuCl₂, 7.5 mol% PPh₃ and K₃PO₄ (2.2 equiv.) as the standard reaction condition.

We next explored the reaction scope with various phenols and aryl aldehydes, and seventeen ortho-acylation products were synthesized (Table 1). The results showed that regardless of the substitution of aryl aldehydes, electron withdrawing or donating, all compounds furnished the desired ortho-acylation products in almost similar yields when reacted with the same phenol (70–91% entries 1–7; 63–94% entries 8–12; 42–78% entries 13–16); even 4-nitrobenzaldehyde, the corresponding product 3gb was obtained with 70% yield (entry 12). However, the substituted group of phenols played a more important role compared with that of aryl aldehyde. The stronger electron-donating group phenols possessed, the more effective the acylation reactions were. For example, the methoxy and isopropyl substituted phenols (2a and 2b) offered higher yields than unsubstituted phenol (2c); conversely with electro-deficient 4-nitrophenol (2e), no reaction was detected (entry 18). When 4-iodophenol was used, cross-coupling reaction between iodine and hydroxyl was observed besides the acylation reaction (entry 17).¹⁵ Additionally, aliphatic aldehydes were ineffective to react with phenols (data not shown).

Table 1.

Ortho-acylation of phenols with aryl aldehydes ^a

entry		R1		R2	product	Yield (%) b, c
1	1a	3-OCH3	2a	OCH3	3aa	91(79)
2	1b	4-CH3	2a	OCH3	3ba	70 (60)
3	1c	H	2a	OCH3	3ca	79 (64)
4	1d	3-Cl	2a	OCH3	3da	83 (70)
5	1e	4-F	2a	OCH3	3ea	84 (73)
7	1f	2,6-OCH3	2a	OCH3	3fa	77 (65)
8	1a	3-OCH3	2b	i-Pr	3ab	94 (82)
9	1b	4-CH3	2b	i-Pr	3bb	73 (60)
10	1c	H	2b	i-Pr	3cb	63 (48)
11	1d	3-Cl	2b	i-Pr	3db	92 (79)
12	1g	4-NO2	2b	i-Pr	3gb	70 (58)
13	1a	3-OCH3	2c	H	3ac	56 (47)
14	1b	4-CH3	2c	H	3bc	64 (50)
15	1d	3-Cl	2c	H	3dc	78 (67)
16	1g	4-NO2	2c	H	3gc	42 (31)
17d	1g	4-NO2	2d	I	3gd	62 (51)
18	1a	3-OCH3	2e	NO2	-	-

^a1 mmol aldehyde and 1.3 mmol phenol;

^b1H NMR yield;

^cIsolated yield (in parenthesis);

^dCross-coupling reaction between iodine and hydroxyl was observed besides the ortho-acylation reaction.

Interestingly, we found that when 2-substituted aryl aldehydes (1h–j) reacted with phenols, xanthones were obtained with high-yield in one step (Table 2). Albeit many methods are available for the synthesis of xanthones, most of them either require advanced starting materials, exotic reaction conditions, or involve multistep transformations.¹⁶ There are only a few one-step synthesis of xanthones existing in literature.¹⁷ Hence our method offers a concise and straightforward strategy to construct xanthones directly without the preactivation of aldehydes (Scheme 1).

Table 2.

One-step ortho-acylation of phenols with 2-substituted aldehydes to afford xanthones ^a

entry	R1		R2		product	Yield % b, c
1	1h	OCH3	2a	OCH3	4a	85(71)
2	1i	NO2	2a	OCH3	4a	87 (74)
3d	1j	Br	2a	OCH3	4a	68 (52)
4	1i	NO2	2b	i-Pr	4b	92 (81)
5 d	1j	Br	2b	i-Pr	4b	64 (56)
6	1i	NO2	2c	H	4c	81 (70)
7d	1j	Br	2c	H	4c	55 (43)
8	1i	NO2	2d	I	4d	73 (62)

^a1 mmol 2-substitued aldehydes and 1.3 mmol phenol;

^b1H NMR yield;

^cIsolated yield (in parenthesis);

^dCross-coupling reaction between bromo and hydroxyl was observed in entries 3 (17%), 5 (14%) and 7 (13%) besides the ortho-acylation reaction.

Scheme 1.

One-step synthesis of xanthones

As shown in Table 2, 2-methoxybenzaldehyde (1h) and 2-nitrobenzaldehyde (1i) produced the corresponding xanthones in good yields (62–81%) (entries 1, 2, 4, 6 and 8), while with 2-bromobenzaldehyde (1j) as the starting material, lower yields were observed, likely due to the cross-coupling reaction between bromo and hydroxyl groups (entries 3, 5 and 7, yields are listed in the footnote). It is believed that the ring-closed xanthone products are achieved via the ortho-acylation of phenols with 2-substituted aryl aldehydes first, and then under a basic condition, the ortho-substituents of aldehydes serveing as leaving groups lead to the final ring-closed xanthones.

Since nitro group gave better results than other leaving groups, the reaction substrates of 2-nitrobenzaldehydes and phenols were investigated (Table 3). It showed that alkoxy, alkyl, aryl and halide substituents were tolerated on the phenols to furnish the desired xanthones affording moderate to good yields. While an electron-donating groups on phenols can promote the reaction, a electron-withdrawing groups (NO₂ or CN) will block the reaction completely (data not shown). If the substituted group was at the para postion of the phenol, the yield was higher than it was at ortho postion, possibly due to the steric effect (4d vs 4e, 4g vs 4h). The steric effect can also explain the excellent regioselectivity of this reaction (e.g. 4i was the sole product) as was as the slugish reactivity of ortho-t-butylphenol (no product was observed). Disubstitued and trisubstitued xanthones could also be prepared via this copper-catalyzed ortho-acylation reaction affording moderate yields (4m-p and 4t).

Table 3.

Scope of reaction of 2-nitrobenzaldehydes with phenols to prepare xanthones ^a

	Product	Yield (%) b, c		Product	Yield (%) b, c
4a		87(74)	4k		69 (55)
4b		92 (81)	4l		43 (30)
4c		81 (70)	4m		75 (64)
4d		77 (62)	4n		84 (72)
4e		73 (62)	4o		90 (80)
4f		72 (59)	4p		73 (61)
4g		82 (73)	4q		83 (70)
4h		76 (60)	4r		82 (70)
4i		70 (58)	4s		80 (69)
4j		71 (55)	4t		68 (57)

^a1 mmol 2-nitrobenzaldehydes, 1.3 mmol phenols;

^b1H NMR yield;

^cIsolated yield (in parenthesis).

Although the detailed mechanism is not very definitive, it is conceivable that this reaction is a Friedel-Crafts type reaction, which involves the nucleophilic addition of phenols to aldehydes under basic condition, and then followed by a dehydrogenative oxidation in air to give ortho-acylation products.¹¹,¹⁸ If ortho-substituents of aldehydes are good leaving groups, ring-closed xanthones will form automatically. During this process, copper (serve as a Lewis acid) may interact with the phenol oxygen and stabilize the intermediates which lead to a smooth transformation.

In summary, we first demonstrated an intermolecular catalytic ortho-acylation of phenols with various aryl aldehydes in-depth using copper(II) as the catalyst in presence of triphenylphosphine. Furthermore, this method can be used to synthesize xanthones in one step with high-yield. We are currently investigating the expansion of this ortho-acylation strategy to a broader scope of substrates.