Selective palladium-catalyzed carbonylative synthesis of aurones with formic acid as the CO source

Abstract

A general and practical strategy has been developed to prepare aurone derivatives. In the presence of the palladium catalyst, 2-iodophenol and terminal alkynes were reacted by using formic acid as the CO source with acetic anhydride as the additive. A variety of aurones were obtained in moderate to good yields. Notably, this is first report on carbonylative synthesis of aurones with formic acid as the CO source.

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Flavonoids are a major class of plant natural products, exhibiting a broad variety of biological activities.¹ As a subclass of the flavonoid family, aurones² displaying a wide range of significant biological activities and have been utilized as antifungal agents,³ anticancer agents,⁴ and antioxidants.⁵ Therefore, numerous approaches for aurone synthesis have been reported. The most popular strategy is the condensation of benzofuran3(2H)-ones with benzaldehydes.⁶ This aldol-type reaction needs to prepare benzofuran3(2H)-ones from 2-phenoxyacetic acids under very harsh reaction conditions with modest yields. Other traditional synthetic methods include Wheeler aurone synthesis from chalcones dihalides,⁷ oxidative cyclization of 2′-hydroxychalcones,⁸ and ring closure of o-hydroxyaryl phenylethynyl ketones.⁹ However, these methods always result in a mixture of aurones and flavones. Thus, an selective and practical synthetic protocol for aurones synthesis is still in great demand.

Recently, palladium-catalyzed carbonylation reaction has drawn much attention for their widely application in both academy and industry.¹⁰ In these reactions, CO is used as the cheapest C1 source to prepare the carbonyl-containing compounds. Carbonylative procedures have also been applied in aurones synthesis, however problems such as the selectivity between aurones and flavones and limited substrates testing were not solved.¹¹ Additionally, gaseous CO which is toxic, odorless, flammable and difficult to handle have to be applied. Under this background, various CO surrogates were developed and applied.¹² In this regard, we wish to describe here a selective palladium-catalyzed carbonylation reaction of 2-iodophenol and terminal alkynes using formic acid as the CO precursor to provide aurone derivatives.^13,14 The reaction proceeds in a selective manner and give the desired aurones in good yields. Notably, this is first report on carbonylative synthesis of aurones with formic acid as the CO source.

Initially, 2-iodophenol and phenyl acetylene was chosen as the model substrates to screen the reaction conditions (Table 1). Fortunately, the aurone product was obtained in 27% yield using Pd(OAc)₂ as catalyst, PPh₃ as ligand, Et₃N as base in toluene at 80 °​C (entry 1). Other bases such pyridine, DBU, tBuONa, and NaHCO₃ were also studied, and Et₃N still give the best results. We then tested different solvents (entries 6–8), toluene proven to be the optimal solvent here. Furthermore, a variety of mono- and bidentate ligands were investigated (entries 9–14), DPPF, DPPPE, and Xphos resulted in similar yields compared with PPh₃, 40% and 49% yields were observed by using P(o-tolyl)₃ and BuPAd₂ (entries 13–14). The yield decreased in the absence of phosphine ligand (entry 15). To our delight, the highest yield can be obtained when the reaction was performed with preformed Pd(PPh₃)₄ as the catalyst (entry 16).

Table 1 Screening of reaction conditions^a

Entry	Catalyst	Ligand	Base	Solvent	Yield^b (%)
a Reaction conditions: 2-iodophenol (1.0 mmol), phenyl acetylene (2.0 mmol), catalyst (3 mol%), ligand (6 mol%), base (5 equiv.), HCOOH (2.0 mmol), acetic anhydride (2.0 mmol), solvent (2 mL), 14 h. b GC yield, with dodecane as the internal standard. c Ligand (4 mol%).
1	Pd(OAc)2	PPh3	Et3N	Toluene	27
2	Pd(OAc)2	PPh3	Pyridine	Toluene	25
3	Pd(OAc)2	PPh3	DBU	Toluene	6
4	Pd(OAc)2	PPh3	tBuONa	Toluene	6
5	Pd(OAc)2	PPh3	NaHCO3	Toluene	24
6	Pd(OAc)2	PPh3	Et3N	THF	9
7	Pd(OAc)2	PPh3	Et3N	DMF	20
8	Pd(OAc)2	PPh3	Et3N	CH3CN	25
9^c	Pd(OAc)2	DPPF	Et3N	Toluene	24
10^c	Pd(OAc)2	DPPPE	Et3N	Toluene	20
11^c	Pd(OAc)2	Xantphos	Et3N	Toluene	18
12	Pd(OAc)2	XPhos	Et3N	Toluene	27
13	Pd(OAc)2	P(o-tolyl)3	Et3N	Toluene	40
14	Pd(OAc)2	BuPAd2	Et3N	Toluene	49
15	Pd(OAc)2	—	Et3N	Toluene	17
16	Pd(PPh3)4	—	Et3N	Toluene	85
17	PdCl2(PPh3)2	—	Et3N	Toluene	54

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With the best reaction conditions in hand, we went on our study with a series of terminal alkynes (Table 2). First, various aromatic alkynes were examined, substrates with electron-donating groups including methoxy, tert-butyl, and methyl gave the corresponding products in very good yields (entries 2–4) those substrates with methyl group substituted at ortho-position gave higher yield than meta- and para- substitution (entry 4, 5 vs. 6). Electron-withdrawing group such as trifluoromethyl provided the desired products in 73% yields (entry 7). Subsequent examination of halide groups showed that fluoro and chloro substitutions resulted in better yields than bromo group (entry 8, 9 vs. 10). Moreover, heteroaryl groups involved thiophene, and pyridine moieties worked well to afford the desired aurone products in good yields (entries 11–12). Furthermore, alkyl alkynes were also tolerated well to provide the target products in good yields (entries 13–15).

Table 2 Carbonylative Sonogashira reaction of aryl iodides and terminal alkynes^a

Entry	Alkyne	Product	Yield^b (%)
a Reaction conditions: 2-iodophenol (1.0 mmol), terminal acetylene (2.0 mmol), Pd(PPh3)4 (3 mol%), Et3N (5 equiv.), HCOOH (2.0 mmol), acetic anhydride (2.0 mmol), toluene (2 mL), 12–18 h. b Isolated yields.
1			82
2			82
3			68
4			75
5			72
6			81
7			73
8			80
9			75
10			58
11			55
12			68
13			54
14			62
15			51

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Based on the results of aurone synthesis from 2-iodophenol and terminal alkynes, a plausible reaction mechanism was proposed in Scheme 1. Initially, Pd(0) underwent oxidative addition with 2-iodophenol to form arylpalladium species I, and aroylpalladium iodide complex II was formed by the insertion of CO, which generated from formic acid and acetate anhydride. Then alkynes attack and elimination to afford alkynyl ketone intermediate III. Then, Pd(0) inserted to the O–H bond of phenol to provide complex IV, followed by insertion and reductive elimination to give the final aurones V products. However, the insertion of the alkyne into intermediate II followed by cyclopalladation and reductive elimination cannot be excluded.

Scheme 1 A plausible reaction mechanism.

Conclusions

In conclusion, a palladium-catalyzed carbonylative reaction of 2-iodophenol and terminal alkynes has been developed. In this strategy, instead of toxic CO gas, formic acid was utilized as the CO source with acetic anhydride as the activator. Aurones were prepared in good yields with good selectivity and functional group tolerance.

Acknowledgements

The authors thank the financial supports from NSFC (21472174) and Zhejiang Natural Science Fund for Distinguished Young Scholars (LR16B020002). X.-F. Wu appreciates the general support from Professor Matthias Beller in LIKAT.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental detail. See DOI: 10.1039/c6ra13615j

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