First direct access to 2-hydroxybenzophenones via nickel-catalyzed cross-coupling of 2-hydroxybenzaldehydes with aryl iodides

Abstract

An efficient, inexpensive and reusable NiCl₂·6H₂O/n-Bu₄NBr catalytic system is described for the direct C–H arylation of 2-hydroxybenzaldehydes with aryl iodides for the first time.

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Aryl ketones are valuable building blocks in both chemistry and biology that have been widely used in the pharmaceutical, fragrance, dye, agrochemical, and functional material industries as well as in organic synthesis.¹

Friedel–Crafts acylation in the presence of Lewis acids is one of the most useful synthetic methods for the preparation of aromatic ketones, although the reaction sometimes fails with electron-deficient arenes and generally yields the desired products as isomeric mixtures. In addition, it requires the use of a stoichiometric amount of Lewis acid.² Oxidation of secondary alcohols is another common method to access ketones. This protocol often requires the use of a stoichiometric amount of oxidant and is commonly limited by poor functional group tolerance.³ The reactions of stoichiometric organometallic compounds with carboxylic acid derivatives are also popular and well-known for the preparation of ketones.⁴ However, the poor functional group tolerance, strict handling requirement of the organometallic reagents and overaddition (resulting in the formation of tertiary alcohol products) limits their applications and thus there is a need for milder, cleaner and catalytic alternatives. During the last decade, transition-metal catalyzed cross-coupling reactions have emerged as powerful methods in synthetic chemistry. Among many methods, direct C–H bond arylation of aldehydes and their derivatives to give aryl ketones has attracted a lot of attention.⁵ However, in some of these transformations the existence of a hydroxyl group in the substrates led to main impediment. The prevalence of ortho-hydroxyl-substituted diaryl ketones in a large number of biologically active compounds,⁶ in perfumery, pharmaceutical industries and also natural products,⁷ has resulted in a continued demand for the development of general and flexible synthetic methods of this structural moiety. Generally, reports on the direct access to 2-hydroxybenzophenones from 2-hydroxyarylaldehydes via metal-catalyzed cross-coupling reactions are very rare in the literature. The first palladium-catalyzed reaction of 2-hydroxybenzaldehyde and its derivatives with aryl iodides via cleavage of the aldehyde C–H bond to obtain the corresponding ketones has been reported by Miura in 1996.⁸ This transformation gives good yields for many substrates using a catalyst system of PdCl₂/LiCl in the presence of Na₂CO₃ as base in DMF at 100 °C under nitrogen. Several years later, effort has been directed towards the preparation of 2-hydroxybenzophenones using iodonium salts as analogues of aryl iodides.⁹ These salts were used into the reaction with salicylaldehyde in the presence of PdCl₂ and LiCl as a co-catalyst in DMF to achieve corresponding ketones. In 2010, Xu reported an efficient system for the direct arylation of 2-hydroxybenzaldehydes with arylboronic acids via ligand-free palladium catalysis.¹⁰ However, the boronic acids are comparably expensive and not so widely available. Most recently, we have reported an efficient method for the palladium-catalyzed cross-coupling reaction of aryl bromides and iodides with 2-hydroxybenzaldehydes in H₂O to access 2-hydroxybenzophenones without the need for any co-catalyst and ligand.¹¹

Whiles palladium based complexes are the most common catalysts for the coupling reactions, efforts have been made to replace palladium with less expensive metals. Among the inexpensive transition metals, Ni appears the most promising for the replacement of Pd because it is active for coupling reactions and about 500 times cheaper than palladium.

Despite the fact that various nickel-catalyzed systems are available in the literature for the synthesis of aryl ketones,¹² to the best of our knowledge there is no literature precedent for the use of nickel for the preparation of 2-hydroxybenzophenones using 2-hydroxybenzaldehydes. Herein we wish to report a direct synthesis of 2-hydroxybenzophenones by the nickel-catalyzed coupling of 2-hydroxybenzaldehydes with aryl halides via an oxidative addition and reductive elimination strategy in a one-pot manner.

We began our study by examining the cross-coupling between iodobenzene (1.0 mmol) and 2-hydroxybenzaldehyde (1.0 mmol) using 50 mol% NiCl₂·6H₂O as catalyst in ethylene glycol (2 mL) at 120 °C in the presence of NaOH (2.0 mmol) as base to furnish the corresponding diaryl ketone. Table 1 provides information on the impact of various reaction parameters on the efficiency of this process. Surprisingly, we discovered that even without any reducing agent and ligand, the reaction proceeded smoothly, affording the coupling product after 24 h, albeit in low yield (Table 1, entry 1). This promising result encouraged us to do further optimization with NiCl₂·6H₂O as the catalyst precursor to improve the yield of the product. Solvent screening showed that no product could be detected when the reaction was carried out in ethanol, dioxane, and H₂O at reflux (Table 1, entries 2–4). Also, no desired product was obtained in PEG at 120 °C (Table 1, entry 5). Therefore, the subsequent reactions were performed in ethylene glycol which possesses negligible vapor pressure, is thermally stable and inexpensive. We surveyed several different organic and inorganic bases for the coupling reaction, and NaOH was found to give the best results (Table 1, entry 1). Absence of base, or changing the base to Na₂CO₃, Bu₃N and DABCO did not yield the target product at all (entries 6–9). In a further attempt to improve the yield of aryl ketone, the use of 2.0 mmol of iodobenzene was explored (Table 1, entry 10). Gratifyingly, this change afforded higher yield of the product (from 40% to 75%). No further yield improvement was achieved using greater amounts of iodobenzene (Table 1, entry 11). It was interesting to find that the significant improvement in the reaction time and the yield of 2-hydroxybenzophenone was observed following the addition of 0.5 mmol tetrabutylammonium bromide to the reaction mixture (Table 1, entry 12). The role of TBAB in this reaction is critical. It is noteworthy that the presence of TBAB as an additive not only makes the catalytic system stable by preventing undesired agglomeration and deactivation by forming a monomolecular layer around the metal core,¹³ but also acts as reducing agent for the generation of Ni(0). Next, the reaction was carried out with different amounts of NiCl₂·6H₂O (30, 40, 60 mol%). As it was shown in entries 13–15 of Table 1, at 120 °C, 40 mol% of the catalyst was sufficient to catalyze the reaction efficiently; in this case, the corresponding product was obtained in 94% yield within 2 h (Table 1, entry 14). As expected, no product could be detected in the absence of nickel catalyst (Table 1, entry 16). A temperature of 120 °C was the optimal temperature for this reaction. Decreasing the reaction temperature caused a decrease in the yield of desired product (Table 1, entry 17) and higher temperature (Table 1, entry 18) did not improve the conversion and yield. Next, the model reaction was carried out in the absence of ethylene glycol. The result indicated that the existence of ethylene glycol is necessary in this transformation (Table 1, entry 19). Finally, we decided to re-examine the coupling reaction of iodobenzene and salicylaldehyde using NiCl₂ with a purity of ≥99.99% instead of nickel salt with a purity of ≥98% under our optimized reaction conditions to confirm that the reaction was not catalyzed by a trace metal contaminant. As shown in Table 1, entry 20, the use of NiCl₂ with a purity of ≥99.99% did not led to lower yield than the same reaction with nickel salt of lower purity. This observation indicated that the presence of trace amounts of metal impurities in the commercially available nickel catalyst were not capable of catalyzing the coupling reactions.

Table 1 Effect of different reaction parameters on the coupling reaction of iodobenzene (1.0 mmol) and salicylaldehyde (1.0 mmol)

Entry	Catalyst^a (mol%)	Base	Solvent/°C	Time (h)	Yield^b (%)
a NiCl2·6H2O ≥ 98% purity was used.b Isolated yield.c 2.0 mmol iodobenzene was used.d 3.0 mmol iodobenzene was used.e NiCl2 ≥ 99.99% purity was used.
1	50	NaOH	Ethylene glycol 120	24	40
2	50	NaOH	EtOH/reflux	24	—
3	50	NaOH	Dioxane/reflux	24	—
4	50	NaOH	H2O/reflux	24	—
5	50	NaOH	PEG/120	24	—
6	50	—	Ethylene glycol 120	24	—
7	50	Na2CO3	Ethylene glycol 120	24	—
8	50	Bu3N	Ethylene glycol 120	24	—
9	50	DABCO	Ethylene glycol 120	24	—
10^c	50	NaOH	Ethylene glycol 120	24	75
11^d	50	NaOH	Ethylene glycol 120	24	75
12^c	50	NaOH	Ethylene glycol TBAB/120	2	94
13^c	60	NaOH	Ethylene glycol TBAB/120	2	93
14^c	40	NaOH	Ethylene glycol TBAB/120	2	94
15^c	30	NaOH	Ethylene glycol TBAB/120	9	75
16^c	—	NaOH	Ethylene glycol TBAB/120	24	—
17^c	40	NaOH	Ethylene glycol TBAB/100	24	70
18^c	40	NaOH	Ethylene glycol TBAB/140	2	94
19^c	40	NaOH	120/TBAB	24	Trace
20^c^,^e	40	NaOH	Ethylene glycol TBAB/120	2	93

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Under the obtained optimized conditions; NiCl₂·6H₂O (40 mol%), aryl halide (2.0 mmol), 2-hydroxybenzaldehyde (1.0 mmol), NaOH (2.0 mmol) and tetrabutylammonium bromide (0.5 mmol) in ethylene glycol (2 mL) at 120 °C, the substrate scope of the direct arylation of 2-hydroxybenzaldehydes was explored. As shown by the results in Table 2, this cross coupling is efficiently applicable to a wide range of aryl iodides. The coupling reaction with electron-neutral, electron-rich and electron-poor aryl iodides were carried out successfully at 120 °C to generate the corresponding products in good to excellent yields. The influence of steric effects was studied by introduction of an alkyl substituent into the ortho-position of the halobenzene ring. As shown by the data in entry 4 of Table 2, a substituent such as methyl at the ortho position had steric effect and in this case, no desired product was obtained even after prolonged reaction time. We then studied the applicability of this catalytic system for the reaction of aryl bromides. For this purpose, reaction of bromobenzene with salicylaldehyde under the optimal conditions was studied. The data presented in entry 12 of Table 2 show that, the reaction did not proceed at all and starting material was isolated intact after appropriate reaction time. Attempts to find reaction conditions that enabled the conversion of bromobenzene to product, such as increasing the concentration of bromobenzene or the addition of more nickel catalyst during the reaction, failed. Also, the addition of PPh₃ which is often necessary for the Pd-catalyzed coupling reactions, did not improve the conversion and yield of the coupling product.

Table 2 Nickel-catalyzed cross-coupling of 2-hydroxybenzaldehydes with aryl iodides^a

Entry	Aldehyde	ArX	Time (h)	Yield^b (%) (ref)
a Reaction conditions: iodobenzene (2.0 mmol), 2-hydroxybenzaldehyde (1.0 mmol), NiCl2·6H2O (40 mol%), n-Bu4NBr (0.5 mmol), NaOH (2.0 mmol) in 2 mL ethylene glycol at 120 °C.b Isolated yield.
1			2	94 (ref. 9)
2			8	90 (ref. 14)
3			16	83 (ref. 9)
4			48	—
5			24	60 (ref. 15)
6			18	78 (ref. 16)
7			20	80 (ref. 16)
8			8	88 (ref. 17)
9			6	89 (ref. 18)
10			24	70 (ref. 19)
11			24	75 (ref. 9)
12			24	—
13			24	—
14			24	—

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To explore the reaction mechanism, the following control experiments were performed under the standard reaction conditions. Coupling of p-hydroxybenzaldehyde with iodobenzene gave no desired 4-hydroxybenzophenone (Table 2, entry 13). Furthermore, the reaction of benzaldehyde with iodobenzene under the optimal conditions yielded no benzophenone (Table 2, entry 14). These results suggested that the phenolic function at the ortho-position of the formyl group is essential for successful performance of the reaction.

In order to gain insight about the reducing property of ethylene glycol and tetrabutylammonium bromide, we probed the ultraviolet (UV) spectrum of Ni(II) in the presence of TBAB and ethylene glycol separately. The UV spectra of these solutions are shown in Fig. 1. The peak at around 400 and 700 nm of curve A shows the presence of Ni(II) species. Curves B and C belong to the solution of NiCl₂·6H₂O in ethylene glycol and TBAB respectively. The disappearance of the peaks related to Ni(II) at 400 and 700 nm, confirms that Ni(II) has been reduced to the Ni(0) species in the presence of ethylene glycol and TBAB (Fig. 1).^20–22

Fig. 1 UV spectra of the nickel catalyst. (A) NiCl₂·6H₂O in H₂O. (B) NiCl₂·6H₂O in ethylene glycol. (C) NiCl₂·6H₂O in TBAB.

According to the above results, a proposed mechanism for the aryl ketone formation is shown in Scheme 1. Step 1 involves an oxidative addition in which Ni(0) inserts into the aryl halide bond. The formed nickel(II) species subsequently reacts with salicylaldehyde to give aryl(aryloxy)nickel intermediate I. Insertion of the aryl to the carbonyl group gives intermediate II, which then gives intermediate III via a β-hydride elimination process. Finally, the subsequent reductive elimination from III, yields 2-hydroxybenzophenone and also regenerates the nickel(0) catalyst.

Scheme 1 A possible mechanism for the cross-coupling of aryl iodides with 2-hydroxybenzaldehydes.

The reusability of catalyst is the major area of interest due to environmental and economic concerns. One of the significant advantages of the use of ammonium salts as reaction medium is possibility of catalyst recycling. Regarding this property of ammonium salts, the recyclability of the catalytic system was also examined in the reaction of iodobenzene with salicylaldehyde. After initial experimentation, the reaction mixture was extracted with diethyl ether, and the obtained Ni(0)/n-Bu₄NBr/ethylene glycol was subjected to a second run of the reaction by charging with the same substrates (iodobenzene and salicylaldehyde). As shown in Table 3, quantitative conversion to the corresponding product was observed for three runs. From the fourth run, loss of the activity of the system was observed.

Table 3 Recycling of the catalyst for the coupling reaction of iodobenzene with salicylaldehyde

Cycle	Time (h)	Yield^a, %
a Isolated yield.
1	2	94
2	3	91
3	5.5	86
4	10	71

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In summary, We have reported the first Ni(0) catalytic method for the efficient cross-coupling reaction of aryl iodides with 2-hydroxybenzaldehydes in the presence of n-Bu₄NBr in ethylene glycol to access 2-hydroxybenzophenones.²³ The absence of ligand, co-catalyst and external reducing agent in the catalytic system together with its recyclability are considered as other advantages of this system.

Acknowledgements

We thank the Persian Gulf University Research Council and Iran National Science Foundation (INSF-Grant number of 92012390) for support of this study.

Notes and references

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23. General procedure: a mixture of tetrabutylammonium bromide (0.5 mmol, 0.16 g), aryl iodide (2.0 mmol), 2-hydroxybenzaldehyde (1.0 mmol), NiCl₂·6H₂O (0.4 mmol, 0.114 g) and NaOH (2.0 mmol, 0.08 g) were added to a flask containing 2 mL of ethylene glycol. The mixture was heated in an oil bath at 120 °C with stirring and the reaction was followed by TLC analysis. When the reaction was completed, the solution was allowed to cool to room temperature and the product was extracted with diethyl ether (3 × 3 mL). The organic layer was dried over anhydrous Na₂SO₄ and purified by column chromatography over silica gel using n-hexane/ethyl acetate (5 : 1) as eluent to afford the highly pure product (Table 2). 2-Hydroxybenzophenone⁹ (Table 2, entry 1) [117–99–7]: IR (KBr): 3500, 1728 cm⁻¹. ¹H-NMR (250 MHz, CDCl₃) δ (ppm): 11.96 (s, 1H, OH), 7.62–7.40 (m, 7H, Ar), 7.02–6.98 (m, 1H, Ar), 6.83–6.77 (m, 2H, Ar). ¹³C-NMR (62.9 MHz, CDCl₃) δ (ppm): 200.01, 158.02, 140.77, 133.85, 133.76, 132.95, 132.04, 127.96, 127.46, 120.01 (overlap, two peaks). Anal. calcd for C₁₃H₁₀O₂: C, 78.77; H, 5.09. Found: C, 78.37; H, 4.96.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra18890c

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