Sulfonic acid resin and copper salts: a novel heterogeneous catalytic system for direct hydroxylation of haloarenes

Abstract

A sulfonic acid resin (INDION-770) in combination with Cu salts is demonstrated to be a versatile heterogeneous catalyst for direct hydroxylation of haloarenes to give corresponding phenols in excellent yields.

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Phenols are vital intermediates in chemical, pharmaceutical and material industries.¹ The most popular industrial method for preparation of phenol is the Hock process,² which is limited merely to phenol, and suffers drawbacks such as multistep process and low overall efficiency. Functionalized phenols are prepared through nucleophilic substitution of arylsulfonic acids and activated haloarenes, copper promoted conversion of diazoarenes, and benzyne protocols.³ These methods are seldom used due to harsh reaction conditions and lack of substrate generality. An alternate method for the synthesis of phenols is by oxidative hydroxylation and copper catalyzed hydroxylation of aryl boronic acids.⁴ A milder method employing an iridium phosphine complexes based catalytic system has also been developed for the preparation of meta-substituted phenols bearing ortho- and para-directing groups, via an aromatic borylation/oxidation sequence.⁵ Recently, several homogeneous catalytic systems based on both the palladium⁶ and the copper⁷ complexes were reported for the cross-coupling of haloarenes with hydroxide salts. Among these systems, palladium based homogeneous catalysts are more reactive but suffer limitations such as high operational cost and toxicity when compared to those of copper based protocols. In both these protocols, appropriate strategies have been implemented to prevent the unwanted side reaction of phenols with unreacted haloarenes to form symmetrical diarylethers.⁸

In recent years, there has been significant progress in the design and the use of heterogeneous catalysts due to their innate advantages such as ease of product purification, catalyst recoverability and reusability for multiple reaction cycles, and also from the green chemistry point of view. In our previous study we have explored the use of a sulfonic acid resin (INDION-770) exchanged copper (I) catalyst for the direct N-arylation of haloarenes with NH-heterocycles under heterogeneous conditions.⁹ In continuation of our studies, herein, we report for the first time a copper based heterogeneous catalyst derived from a sulfonic acid resin (INDION-770) for the direct hydroxylation of haloarenes.

Initially, 4-iodooanisole was chosen as a model substrate for screening studies, and it was subjected to various reaction conditions with “INDION-770” resin and copper salts under in situ conditions in a DMSO/H₂O (2 : 1) solvent system. The results of these studies are summarized in Table 1. As depicted in Table 1, different copper precursors such as CuI, CuCl, CuBr, Cu₂O, Cu(OH)₂, Cu(OAc)₂ and copper powder promote direct hydroxylation reactions in excellent yields with CsOH as base at 125 °C (Table 1, entries 1–7). Apparently, among the various copper salts screened in the reactions, highest yield (94%) was obtained with CuI. However, when the reaction was carried out in the absence of resin additive, only moderate yield of product was obtained (Table 1, entry 8). Similarly, very poor yield of product was obtained when the reaction was carried out in the absence of both additive and Cu-catalyst (Table 1, entry 9).

Table 1 Screening of reaction parameters for copper catalyzed direct hydroxylation of haloarenes using INDION-770 resin^a

Entry^a	Catalyst	Additive	Solvent, ratio (v : v)	Base	Yield^g (%)
a Reactions (entries 1–7 and 10–21) performed on a 1.0 mmol scale with 4-iodoanisole (1.0 mmol), copper catalyst (0.1 mmol), INDION-770 resin (60 mg; ∼0.25 mmol active sulfonic acid functionality), base (3 mmol) and 0.9 mL of solvent at 125 °C for 12 h. b Reaction (entry 8) was performed without additive. c Reaction (entry 9) performed without catalyst and additive. d Reaction (entry 22) performed with Amberlyst-16 wet resin (60 mg; ∼0.30 mmol active sulfonic acid functionality). e Reaction (entry 23) performed with benzenesulfonic acid (0.30 mmol). f Reaction (entry 24) performed with preformed copper(I)-exchanged INDION-770 (65 mg, ∼0.10 mmol of copper). g Isolated yields after column chromatographic purification. h Determined by GC analysis.
1	CuI	IND-770	DMSO/H2O, 2 : 1	CsOH	94
2	CuCl	IND-770	DMSO/H2O, 2 : 1	CsOH	92
3	CuBr	IND-770	DMSO/H2O, 2 : 1	CsOH	87
4	Cu2O	IND-770	DMSO/H2O, 2 : 1	CsOH	91
5	Cu(OH)2	IND-770	DMSO/H2O, 2 : 1	CsOH	85
6	Cu(OAc)2	IND-770	DMSO/H2O, 2 : 1	CsOH	90
7	Cu	IND-770	DMSO/H2O, 2 : 1	CsOH	92
8^b	CuI	None	DMSO/H2O, 2 : 1	CsOH	62
9^c	None	None	DMSO/H2O, 2 : 1	CsOH	8
10	CuI	IND-770	DMSO/H2O, 2 : 1	LiOH	Trace^h
11	CuI	IND-770	DMSO/H2O, 2 : 1	NaOH	12
12	CuI	IND-770	DMSO/H2O, 2 : 1	KOH	25
13	CuI	IND-770	Toluene/H2O, 2 : 1	CsOH	Trace^h
14	CuI	IND-770	1,4-Dioxane/H2O, 2 : 1	CsOH	Trace^h
15	CuI	IND-770	DMF/H2O, 2 : 1	CsOH	5
16	CuI	IND-770	Glycol/H2O, 2 : 1	CsOH	35
17	CuI	IND-770	Glycol	CsOH	30
18	CuI	IND-770	PEG 300/H2O, 2 : 1	CsOH	28
19	CuI	IND-770	DMSO	CsOH	35
20	CuI	IND-770	H2O	CsOH	Trace^h
21	CuI	IND-770	DMSO/H2O, 1 : 1	CsOH	56
22^d	CuI	Amberlyst-16	DMSO/H2O, 2 : 1	CsOH	91
23^e	CuI	PhSO3H	DMSO/H2O, 2 : 1	CsOH	70
24^f	Cu–IND		DMSO/H2O, 2 : 1	CsOH	92

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Among various bases screened for the reaction, the best result was obtained with CsOH in the presence of CuI at 125 °C (Table 1, entry 1). As can be seen, the reaction showed a linear effect on the basicity of alkali metal hydroxides. For example, no product was detected when the reaction was carried out using LiOH, whereas yield of the desired product increased accordingly in the order of basicity for NaOH < KOH < CsOH (Table 1, entries 1 and 10–12). The screening studies for solvents revealed that they play a vital role in this synthesis protocol. For example, the use of nonpolar solvents like toluene in combination with water resulted in the formation of two phases, in which base is partially soluble in the organic layer, thereby retarding the reaction (Table 1, entry 13). Among polar aprotic solvents used, the reaction proceeded smoothly in DMSO in good yields, and surprisingly, the reaction failed to yield the desired product in solvents such as 1,4-dioxane and DMF (Table 1, entries 1, 14 and 15). Unlike the DMSO/H₂O (2 : 1) solvent system, significant amounts of symmetrical diarylether side product were formed when the reaction was carried out in pure DMSO in the absence of water (Table 1, entry 19). In the binary DMSO/H₂O (2 : 1) solvent system, it is likely that the phenol formed is converted into caesium phenoxide that was solvated and protected by water molecules, thereby preventing the formation of symmetrical diarylethers. Additional advantage of using water in the solvent system is that it improves the solubility of the base. Notably, the quantity of water is critical in these reactions; for example, the reaction was very slow when the ratio of DMSO/water was less than 1, the best results were obtained when the DMSO/water ratio was 2 (0.6 mL/0.3 mL) (Table 1, entries 1 and 21). These results are reasonable because basicity decreases as the concentration of water increases; indeed CsOH in DMSO is a super base. Another important observation was the use of ethylene glycol as solvent. The base was soluble in glycol and symmetrical diarylethers were not formed even in the absence of water, but an undesirable side product which had been accounted as the coupled product of phenol with glycol was formed in significant amount (55%) (Table 1, entries 16 and 17). Unfortunately, only trace amount of the product was obtained when the reaction was carried out in pure water (Table 1, entry 20). Therefore, among various optimization studies listed in Table 1 for the hydroxylation reaction of 4-iodoanisole, the most promising result was obtained with a CuI/INDION-770 resin catalytic system using 3 mmol of CsOH in 0.9 mL of a 2 : 1 DMSO/water solvent at 125 °C (Table 1, entry 1).

The above optimized reaction conditions were further extended to the hydroxylation reactions of various haloarenes, and the results are summarized in Table 2. As described in Table 2, the Cu(I)/INDION-770 resin catalytic system based protocol is rather general in nature, as it is applicable for the reactions of a variety of electron-rich and electron-deficient iodoarenes. The hydroxylation reactions of electro-deficient iodoarenes were rather fast, and furnished excellent yields of the corresponding phenols within 4–8 h at 100–110 °C. Thus 4-iodonitrobenzene, 4-trifluoromethylbenzene and 4-iodoacetophenone react smoothly with CsOH to form the respective phenols in good yields (Table 2, entries 5–7). Similarly, the reactions of electron rich iodoarenes such as 4-iodoanisole, 4-iodotoluene, 1-tert-butyl-4-iodobenzene, 3-iodotoluene, 1-chloro-4-iodobenzene and 2-iodonaphthalene also proceeded smoothly, albeit at slightly higher temperature (125 °C, Table 2, entries 1–3 and 8–10), to afford the corresponding phenols in excellent yields. Notably, this protocol is applicable to sterically hindered iodoarenes, for example, 2-iodoanisole, 2-iodophenol, 2-iodoaniline, 1-iodo-2-nitrobenzene and 1-iodonaphthalene, all undergo hydroxylation reaction smoothly under the optimized reaction conditions to afford the corresponding phenols in excellent yields (Table 2, entries 11–15). Surprisingly, the reaction of highly sterically hindered 2,6-dimethoxyiodobenzene also proceeded in 5 h to afford the product in excellent yield (Table 2, entry 16). The present protocol tolerates a wide variety of functional groups, for example as mentioned above, different groups such as OH, NO₂, OMe, CF₃, COMe and Me are unaffected in the optimized conditions. However, a complete formation of the hydrolyzed product was observed with 4-iodobenzonitrile, and hence this method is not suitable for haloarenes containing the cyano functionality in the aromatic ring.

Table 2 Copper catalyzed direct hydroxylation of haloarenes

Entry^a	ArX	X	Temp/°C	Time/h	Yield^d (%)
a Reactions (entries 1–20) performed on a 1.0 mmol scale with haloarenes (1.0 mmol), CuI (0.1 mmol), INDION-770 resin (60 mg), CsOH (3 mmol) and 2 : 1 DMSO/H2O (0.9 mL) at indicated time and temperature. b Reactions performed using 4 mmol of KOH instead of CsOH. c Reaction performed using the preformed copper(I)-exchanged INDION-770 resin (65 mg, ∼0.1 mmol of Cu) instead of in situ conditions. d Isolated yields after column chromatographic purification. e Yield after the 5th cycle.
1		I	125	8	94, 92^c, 88^c^,^e
		Br	130	48	30
2		I	125	8	92
3		I	125	8	93
4		I	125	8	94
		Br	130	48	33
		Cl	130	48	14
5		I	100	4	96
		Br	100	5	94
		Cl	100	6	92, 90^b
6		I	110	8	92
		Br	125	6	92
		Cl	125	15	88
7		I	110	6	89
		Br	125	5	85
		Cl	125	15	78
8		I	125	6	95
9		I	125	6	91
10		I	125	6	94
11		I	125	6	90
12		I	125	6	87
13		I	125	6	82
14		I	100	4	96
		Br	100	6	96
		Cl	100	8	94, 91^b
15		I	125	6	94
16		I	125	6	94
17		Br	125	8	82
18		Br	125	12	78
19		Br	125	6	81
20		Br	125	6	78

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Thereafter, the utility of a CuI/INDION-770 resin based hydroxylation protocol was explored for the reaction of bromoarenes and chloroarenes. As illustrated in Table 2, the reactions of bromoarenes and chloroarenes having electron-withdrawing groups proceeded smoothly under the standard conditions (Table 2, entries 5–7 and 14). It is noteworthy that reaction of 4-chloronitrobenzene and 2-chloronitrobenzene proceeded smoothly even in the presence of KOH as base to afford the corresponding phenols in good yields (Table 2, entries 5 and 14). However, the reactions of chlorobenzene, bromobenzene and deactivated bromoarene such as 4-bromoanisole were sluggish and furnished only low to moderate yields of respective phenols (Table 2, entries 4 and 1). These results are not surprising since most of the copper-based catalysts also show similar activity for such strongly deactivated bromoarenes and chloroarenes in coupling reactions. Finally, the scope of the present protocol was successfully extended to heterocycles such as 3-bromoquinoline, 2-bromo-4-methylpyridine, 3-bromopyridine and 2-amino-3-bromopyridine.¹⁰ These substrates also underwent hydroxylation reaction and furnished good yields for the desired coupled product (Table 2, entries 17–20).

At present there are no reports available in the literature regarding the mechanism of copper catalyzed hydroxylation of haloarenes.¹¹ Nevertheless, to better understand the function of sulfonic acid in the hydroxylation reaction, we have carried out an hydroxylation reaction using CuI in combination with benzenesulfonic acid in 2 : 1 DMSO/H₂O at 125 °C (Table 1, entry 23). This system also promoted the hydroxylation reaction of 4-iodoanisole, albeit under homogeneous conditions. This observation strongly supports the hypothesis that the active catalytic species is Cu(I)arylsulfonate. Furthermore, we have carried out a reaction between CuI (0.1 mmol), INDION-770 resin (60 mg, ∼0.25 mmol sulfonic acid groups), CsOH (3 mmol) and 2 : 1 DMSO/H₂O (0.9 mL) in a sealed tube at 125 °C under stirring for one hour. This reacted resin was filtered and then analyzed by ICP OES, which confirmed the presence of about 1.4 mmol g⁻¹ of copper in the resin. When this exchanged resin was used as catalyst instead of the in situ conditions as described in Table 1, we have obtained similar results for direct hydroxylation reaction of 4-iodoanisole (Table 1, entry 24). These studies clearly show that the complete exchange of copper from cuprous iodide to a sulfonic acid resin takes place and thus the active catalyst for the direct hydroxylation reaction is the heterogeneous copper-exchanged INDION-770 resin. An important advantage of the copper-exchanged INDION-770 resin based protocol is that the spent catalyst can be recovered from the reaction media, and can be reused for several reaction cycles. This aspect is demonstrated for the hydroxylation reaction of 4-iodoanisole. As can be seen in Table 2 (entry 1), the recovered catalyst can be reused successfully for up to five reaction cycles without significant loss in the catalytic activity.

In summary, a novel copper based heterogeneous protocol involving a cheap, commercially available and easy to use sulfonic acid resin “INDION-770” for direct hydroxylation of various haloarenes is presented. This heterogeneous protocol is shown to be very efficient for a wide variety of electron rich as well as electron deficient iodoarenes and activated bromoarenes and chloroarenes. It has also been shown that the spent catalyst can be reused for up to five reaction cycles without significant loss in the activity.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c0cy00090f

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