Acid-catalyzed intramolecular oxa-Michael addition reactions under solvent-free and microwave irradiation conditions

The acid-catalyzed intramolecular oxa-Michael addition of ( E )-1-aryl-4-hydroxy-4-methyl- -pent-1-en-3-ones under solvent-free and microwave irradiation conditions has been investigated. The results showed that Bronsted acids are more efficient than Lewis acids in this reaction. Up to 90% conversion and 81% yield were obtained using trifluoromethanesulfonic acid (triflic acid) as the catalyst, with short reaction times and an environmentally benign procedure.


Results and Discussion
Effect of catalysts.In order to find the most efficient catalyst, we studied first the intramolecular oxa-Michael addition of (E)-4-hydroxy-4-methyl-1-phenylpent-1-en-3-one 1a under solvent-free and microwave irradiation conditions.The results are given in Table 1.When the Lewis acid zinc trifluoromethanesulfonate (Zn(OTf) 2 ) was used as catalyst, the conversion of 1a and the selectivity to 2,2-dimethyl-5-phenyl-dihydrofuran-3(2H)-one 2a were 32 and 83%, respectively, and the isolated yield of 2a was only 20% (entry 1).The other Lewis acid, copper trifluoromethanesulfonate (Cu(OTf) 2 ) showed higher activity, and a 59% conversion with 87% selectivity was obtained (entry 2).However, it was found that Bronsted acids are more efficient than Lewis acids in this reaction (entries 3-5).Among the tested Bronsted acids trifluoromethanesulfonic acid (triflic acid, TfOH), TsOH, and CH 3 SO 3 H, the TfOH gave the best result, with up to 88% conversion and 94% selectivity (entry 5).Organic bases, such as DBU and 1,4-diazabicyclo[2.2.2]octane (DABCO), were also examined but showed no activity in this intramolecular oxa-Michael addition (entries 6 and 7), although they have been employed as catalysts in some intermolecular oxa-Michael additions. 12,33The highest conversion (96%) of 1a was observed in the presence of (CH 3 CN) 2 PdCl 2 , but many unidentified by-products were observed and the selectivity to 2a was only 16% (entry 8).

Comparison of plausible reaction mechanism in the presence of Bronsted acids and Lewis acid
A plausible reaction mechanism for the intramolecular oxa-Michael addition of 1a, promoted with Bronsted acid, as given by Johnson's group, is outlined in Scheme 1. 31,34 The carbonyl oxygen of 1a accepts one proton from the Bronsted acid to give the protonated form I and canonical form II, and undergoes ring closure to give the enol form III of 2a.It is presumed that in the presence of Bronsted acid, there exists an equilibrium between 1a and 2a. 31 When a mixture of 2a (0.5 mmol) and TfOH (0.05 mmol) was irradiated at 650 W for 9 min, it was found that 13% of 2a did convert into 1a.
Spencer and colleagues have reported that protons generated through in situ hydrolysis of metal salts were the active catalysts in some Lewis acid mediated hetero-Michael additions. 35In order to ascertain whether protons are the actual catalysts in this intramolecular oxa-Michael addition in the presence of Lewis acids, Zn(OTf) 2 and Cu(OTf) 2 , the above experiment was repeated using Zn(OTf) 2 in place of TfOH.The experiments showed that no 2a was converted into 1a after irradiating for 9 min, while our previous experiments showed both Lewis acids and Bronsted acids could catalyze this intramolecular oxa-Michael reaction (Table 1, entries 1 and 2 versus 3-5).These results suggest that protons were not the active catalysts in this Lewis acid-catalyzed oxa-Michael addition.Based on our experimental results we propose a plausible reaction mechanism shown in Scheme 2. Zn(OTf) 2 and Cu(OTf) 2 are highly oxophilic, and could form a carbonyl-metal-ion complex IV with 1a, which would initiate the formation of a C-O bond to generate the intermediate V.This could regenerate the catalyst and give the intermediate VI.
After the intramolecular proton transfer step, 2a was obtained.
Scheme 2. Plausible reaction mechanism in the presence of M(OTf) 2 .

Intramolecular oxa-Michael addition of (E)-1-aryl-4-hydroxy-4-methylpent-1-en-3-ones
To evaluate the scope of the intramolecular oxa-Michael addition, substrates with different steric property and electron property have been investigated using TfOH as the catalyst under the microwave-assisted process.As shown in Table 2, most of the reactions proceeded efficiently, high conversions of (E)-1-aryl-4-hydroxy-4-methylpent-1-en-3-ones 1 and selectivities to the It was observed that the position of substituents on the benzene ring had little effect on the conversions and selectivities (entries 2-4, methyl as substituent; entries 5-6, chlorine as substituent).Also, the electronic properties of substituents on the benzene ring showed marginal effects on the conversions and selectivities (entry 4, p-Me; entry 7, p-Cl; entry 8, p-OCH 3 ), even with a strongly electron-withdrawing group (entry 9, p-NO 2 ).A similar result was obtained when a naphthalene ring replaced a benzene ring, the conversion of 1j and selectivity to 2j were 84 and 95%, respectively (entry 10).When (E)-1-(furan-2-yl)-4-hydroxy-4-methylpent-1-en-3-one 1k was used as the substrate, the irradiating period and reaction time must be shortened.Otherwise, the selectivity to 2k would drastically decrease, which may be due to the polymerization of 2k.Under our conditions, 17% conversion of 1k and 8% isolated yield of 2k were obtained (entry 11).The intramolecular oxa-Michael addition of (E)-4-hydroxy-4-methyl-1-(pyridin-3-yl)--pent-1-en-3-one 1l could not occur under microwave irradiation or refluxing conditions because the proton of Bronsted acid would be captured by the N-atom of the pyridinyl group.

Conclusions
The acid-catalyzed intramolecular oxa-Michael addition of (E)-1-aryl-4-hydroxy-4-methylpent--1-en-3-ones could be performed under solvent-free and microwave irradiation conditions, providing an environmentally benign method for preparing 5-aryl-2,2-dimethyl-dihydrofuran-3(2H)-ones.It was found that Bronsted acids are more efficient than Lewis acids in this reaction.Unlike traditional reactions, the solvent-free and microwave-assisted reactions could be finished within several minutes to give high conversions and selectivities.

Experimental Section
General. 1 H-and 13 C-NMR spectra were obtained on a Bruker Avance III (500 MHz) spectrometer.CDCl 3 was used as the solvent with tetramethylsilane (TMS) as the internal standard.Low and high resolution mass spectra were recorded in the EI mode on a Waters GCT Premier mass spectrometer.Melting points were measured using CRC-1 melting point instrument and are uncorrected.Microwave experiments were performed at a LWMC-201 microwave reactor.
The reaction temperature was determined by an IR thermometer (SUN-GUN SG-20).Reactions were monitored by gas chromatography (GC-6890) with an HP-5 capillary column (30m x 0.25mm).All reagents were obtained from commercial sources and used as received.

(2H)-ones (2a-k)
To an open glass tube, were added (E)-1-aryl-4-hydroxy-4-methylpent-1-en-3-one (0.5 mmol) and triflic acid (0.05 mmol).The tube was positioned in the centre of the microwave cavity, and irradiated (650 W) for 9 min (total reaction time, with alternation of 9s irradiating time and 21s of cooling time).After the last period of irradiating, the temperature (on the surface of the tube) was determined by an IR thermometer.After cooling, the reaction mixture was diluted with CH 2 Cl 2 and purified through a column of silica gel to obtain the pure products 2a-k.

HScheme 1 .
Scheme 1. Plausible reaction mechanism in the presence of Bronsted acids.

Table 1 .
Effect of catalysts in the intramolecular oxa-Michael addition of 1a a bConversion of 1a and selectivity to 2a were measured on the reaction mixture by gas chromatography.c Isolated yield.

Table 2 .
Intramolecular oxa-Michael addition of (E)-1-aryl-4-hydroxy-4-methylpent-1-en-3-ones under solvent-free and microwave conditions a a Reaction conditions: 1 (0.5 mmol), TfOH (0.05 mmol), 650 W (microwave power), 9 min (total reaction time, with an alternation between 9 s of irradiating time and 21 s of cooling time).b Isolated yield.c With an alternation between 6 s of irradiating time and 24 s of cooling time.d Total reaction time 3 min, with an alternation between 3 s of irradiating time and 27 s of cooling time.