Silver-catalyzed decarboxylative acylation of arylglyoxylic acids with arylboronic acids

Abstract

The silver-catalyzed coupling of arylboronic acids with arylglyoxylic acids was found to be an extremely efficient route for the synthesis of unsymmetrical diaryl ketones. It can be conducted on a gram scale under mild and open-flask conditions with good functional group compatibility, avoiding the addition of expensive and/or toxic metals.

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Aryl ketones are valuable building blocks of natural products endowed with a variety of biological properties in the synthesis of pharmacological compounds.¹ The classic procedures for constructing the aryl ketone framework are based on the Friedel–Crafts acylation reactions,² which involve the use of excessive Lewis acids with poor functional group compatibility and untunable regioselectivity. Furthermore, massive waste, such as hydrogen chloride, a lot of waste salt and a lack of selectivity are inevitable. The coupling reaction of acylating agents with aryl halides (or aryl metallic compounds and their equivalents) has been developed under the catalysis of palladium to overcome this drawback.³

In recent years, trans-metal-catalyzed decarboxylative coupling has emerged as a promising concept for C–C bond formation. Intensive contributions to this rapidly evolving field have been made by many groups,⁴ due to the application of air/moisture stable and easily available aromatic carboxylic acids. The application range of decarboxylative couplings has continuously been extended to arylglyoxylic acid.

Recent advances of α-oxocarboxylic acids, which were used as the source of the acyl nucleophiles, were based on cross-coupling reaction⁵ and C–H activation.⁶ The landmark contribution in this field was made by the Gooβen group, who developed Pd/Cu-catalyzed decarboxylative acylation. Decarboxylative cross-coupling of potassium arylglyoxylic acid with aryl bromides,^5a,b aryl chlorides,^5c aryl triflates^5d and diallyl carbonate^5e have been reported by Gooβen, which constitutes systematic synthetic methods of aryl ketones. Generally, the coupling of α-oxocarboxylic acids with electrophiles required various ligands and co-catalysts under harsh condition to enhance the efficiency. The Ge group^5f had concentrated on the introduction of nucleophilic organoboron compounds to couple with α-oxocarboxylic acids. They developed an efficient Pd-catalyzed decarboxylative oxidative coupling of potassium aryltrifluoroborates with α-oxocarboxylic acids at rt. However, the effort of coupling with easily available arylboronic acids was not successful, and only 21% yield of the desired product was isolated under standard Pd-catalyzed conditions. The unique work with arylboronic acids was developed by Yamamoto,^5g as a Pd-catalyzed direct conversion of phenylglyoxylic acid into ketone with p-tolylboronic acid promoted by anhydride activators in the yield of 75% (Scheme 1). However, all the efforts had been made with Pd-catalyzed or Pd/Cu co-catalyzed system, and the aryl ketone synthesis with arylglyoxylic acids by other much cheaper and easily available transition-metal catalyst is highly desirable.

Scheme 1 Aryl ketone synthesis with arylglyoxylic acid.

Traditionally, silver compounds were used as auxiliary chemicals and co-catalysts in trans-metal-catalyzed chemistry.⁷ The potential of silver-catalyzed chemistry has been unrealized until recently. Dramatic progress of research on silver-catalyzed reaction has been made,⁸ especially in decarboxylative coupling reaction⁹ and intramolecular cyclization.¹⁰ We describe here the first example of silver-catalyzed aryl ketone synthesis with arylglyoxylic acids and arylboronic acids.

We commenced our studies by examining the decarboxylative acylation between phenylboronic acid and phenylglyoxylic acid by using 10 mol% of AgOAc as a catalyst (Table 1). Gratifyingly, we obtained the benzophenone (1a) with the yield of 85% in CH₃CN at 60 °C for 1 h. Encouraged by this result, different catalysts and different solvents were used to screen for optimised conditions towards the high yield of benzophenone (Table 1). As showed in Table 1, when Pd(OAc)₂ and Cu(OAc)₂ were used as catalysts, no products were obtained (Table 1, entries 2 and 3), indicating that silver salt is important for this decarboxylative acylation reaction. When Ag₂SbF₆ was employed as a catalyst, the decarboxylative transformation proceeded more efficiently (Table 1, entry 4). Other silver catalysts were then screened, but the reactions exhibited lower efficiencies (Table 1, entries 5–10). After screening different catalysts, it was demonstrated that Ag₂CO₃ is the most positive catalyst for this coupling reaction (Table 1, entry 11). Solvent selection showed that aprotic polar solvents are necessary to achieve acceptable yields. The solvents were optional such as CH₃CN, HMPA (hexamethylphosphoramide), DMSO, DMF, NMP (1-methyl-2-pyrrolidone) and DMA (N,N-dimethylacetamide) (Table 1, entries 11–16). It is found that Ag₂CO₃ performed the best catalytic efficiency in acetonitrile. The reaction was suppressed in ethers and a complex mixture was formed in toluene (Table 1, entries 17–20). It is worth mentioning that only cross-coupled products were obtained, and homocoupling of arylboronic acids was not observed even in trace amounts under these reaction conditions, which demonstrate the superiority of this method over existing Pd-catalyzed methods.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Solvent	Yield^b (%)	Entry	Catalyst	Solvent	Yield^b (%)
a Reaction conditions: PhB(OH)2 (5.0 mmol), PhCOCO2H (5.5 mmol), catalyst (0.05 mmol), solvent (5 mL), 60 °C, 60 min.b Isolated yield.
1	AgOAc	CH3CN	85	11	Ag2CO3	CH3CN	92
2	Pd(OAc)2	CH3CN	—	12	Ag2CO3	HMPA	92
3	Cu(OAc)2	CH3CN	—	13	Ag2CO3	DMSO	90
4	AgSbF6	CH3CN	88	14	Ag2CO3	DMF	89
5	AgI	CH3CN	77	15	Ag2CO3	NMP	91
6	AgOTs	CH3CN	83	16	Ag2CO3	DMA	88
7	AgBF4	CH3CN	78	17	Ag2CO3	THF	69
8	AgNO3	CH3CN	81	18	Ag2CO3	Dioxane	74
9	Ag2O	CH3CN	80	19	Ag2CO3	DME	71
10	AgOTf	CH3CN	84	20	Ag2CO3	Toluene	Complex

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To establish a relative reactivity profile, reactions of arylboronic acids with arylglyoxylic acids, promoted by 10 mol% of Ag₂CO₃ in acetonitrile, were probed. A wide variety of electronically and structurally diverse arylboronic acids and arylglyoxylic acids can be cross-coupled efficiently under mild reaction conditions (Tables 2 and 3). Various substituted arylglyoxylic acids were subjected to coupling with phenylboronic acids, and the results are presented in Table 2. When arylglyoxylic acids with electron-donating substituents were applied to the reaction, the rate of the coupling process was increased (Table 2, 2a–2b) slightly as compared to electron-deficient arylglyoxylic acids (Table 2, entries 2c–2e). It should be noted that the coupling proceeded smoothly in the presence of di-halogenated arylglyoxylic acids (Table 2, 2f–2h). The present procedure worked very well in the case of heterocyclic glyoxylic acids, resulting in excellent yields of products (Table 2, 2i–2j). Even more exciting results were the successful introduction of the highly sterically hindered pentamethyl-phenylglyoxylic acid and perfluoro-phenylglyoxylic acid to give the corresponding coupling products in 83% and 85% yield as shown in entries 2k–2l. It is important to mention that, when attempts were made to carry out reactions of arylglyoxylic acids with free amine or free hydroxyl groups, the cross-coupling reactions proceed well with excellent functional group tolerance (Table 2, 2m–2p).

Table 2 Scope of arylglyoxylic acids^a,b

a Conditions: phenylboronic acid (5 mmol), arylglyoxylic acid (5.5 mmol), Ag₂CO₃ (0.5 mmol), CH₃CN (5 mL), 60 °C, 60 min.b Isolated yields.

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Table 3 Scope of arylboronic acids^a,b

a Conditions: arylboronic acid (5 mmol), phenylglyoxylic acid (5.5 mmol), Ag₂CO₃ (0.5 mmol), CH₃CN (5 mL), 60 °C, 60 min.b Isolated yields.

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Next, the decarboxylative acylation of phenylglyoxylic acids with various arylboronic acids was conducted under the optimized conditions. The silver-catalyzed reaction was successfully extended to various substituted arylboronic acids, and various asymmetric diaryl ketones were obtained in good to excellent yields (Table 3). A series of functional groups, including benzyloxy, methyl, fluoro, cyano, and nitro, was tolerated under the reaction conditions (Table 3, 3a–3e). High yields were obtained when di-substituted arylboronic acids were reacted with phenylglyoxylic acid (Table 3, 3f–3h). More bulky substrate, o-tolylboronic acid (3i) and o-chloro-phenylboronic acid (3j), also efficiently reacted with phenylglyoxylic acids and gave the products in 83% and 87% yield (Table 3, 3k–3l). Heterocyclic boronic acids were successfully introduced and gave the corresponding product in high yields (Table 3, 3i–3j). Free amine and free hydroxyl substituted derivatives were also worked smoothly for this reaction (Table 3, entries 3m–3p).

The above results have clearly demonstrated the generality of this decarboxylative acylation. Moreover, 4-(carboxycarbonyl)benzoic acid can be directly coupled with phenylboronic acid to obtain p-benzoylbenzoic acid in 75% isolated yield (Fig. 1). It is worth mentioning that only decarboxylative acylation products were obtained, and decarboxylative arylation products of the carboxyl group or formation of biaryl compounds were not observed even in trace amounts, which demonstrates the superiority of decarboxylative acylation over arylation under the reported reaction conditions. This synthetic method could further be extended to a one-pot decarboxylative acylation/cyclization reaction of 2-(carboxycarbonyl)benzoic acid with phenylboronic acid, as shown in Fig. 1. Acylation of 2-(carboxycarbonyl)benzoic acid followed by radical cyclization of the intermediate 2-benzoylbenzoic acid afforded fluorenone in 62% yield. The carboxyl group of the diaryl ketone can be eliminated by treatment with K₂S₂O₈ without isolation of the intermediate generated in situ.^9a The oxidative cyclization process proceeds smoothly without the need for further addition of silver catalysts. The particular suitability of this one-pot method for the synthesis of fluorenone makes it complementary to traditional synthetic methods.

Fig. 1 The selectivity of decarboxylative acylation over arylation and “one-pot” synthesis of fluorenone.

Another application of the presented decarboxylative acylation is its potential for combination with Pd-catalyzed Suzuki–Miyarau cross-coupling to synthesize (4-biphenylyl) (phenyl)methanone. The Ag₂CO₃-catalyzed decarboxylative acylation of 4-bromo-phenylglyoxylic acid in DMF, followed by consecutive Suzuki cross-coupling by the addition of catalytic Pd(OAc)₂ and K₂CO₃, provides the 4-biphenylyl-benzophenone in the yield of 87%. This approach has great potential in combination of Ag-catalyzed acylation with Pd-catalyzed arylation by the sequential addition of reagents (Fig. 2).

Fig. 2 Consecutive Ag-catalyzed acylation and Pd-catalyzed arylation.

Although the reaction mechanism is not clear at this stage, it is believed that this transformation is initiated by free radicals. To gain some understanding of the reaction, radical-trapping reagents, such as hydroquinone and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), have been added into the reaction under the standard conditions independently. No desired product is detected in each case, suggesting that a free radical course was involved in the reaction. Minisci and co-workers¹¹ showed that decarboxylation of α-oxocarboxylic acids to give the corresponding carbonyl radicals could be realized at room temperature in the presence of catalytic amounts of silver species. We hypothesized that the decarboxylative acylation might be initiated by carbonyl radicals Scheme 2.

Scheme 2 Proposed mechanism.

Conclusions

In conclusion, the decarboxylative acylation displays the utility of this reaction in the functionalization and diversification of aryl ketone synthesis. We were pleased to find that the new catalyst system is effective without modification in our recently disclosed decarboxylative synthesis of aryl ketones. In this transformation, α-oxocarboxylates were coupled directly with arylboronic acids by silver-catalyzed with good function-group compatibility in aprotic polar solvents.

Acknowledgements

Project supported by the National Natural Science Foundation of China (no. 21402123 and no. 21172149), the Zhejiang Provincial Natural Science Foundation of China (no. LQ14B020001) and the Science Technology Project of Shaoxing City (no. 2013014017).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra04361h

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