Synthesis of 2 H -pyran-2-ones and fused pyran-2-ones as useful building blocks

A one-pot synthesis of 3-benzoylamino derivatives of 5-to 8-membered cycloalka[ b ]pyran-2-ones 5 and 2 H -pyran-2-ones 10 , starting from the appropriate alkanones 1 and 8 , respectively, N , N -dimethylformamide dimethyl acetal (DMFDMA) and hippuric acid in the presence of a large excess of acetic anhydride, is described. A comparison of conventional thermal activation with microwave activation is given in the case of synthesis of 5c . The benzoyl protective group on amino moiety of the fused pyran-2-ones 5 and derivatives 11 was successfully removed by gentle heating in sulfuric acid resulting in the formation of the corresponding 3-aminocycloalka[ b ]pyran-2-ones 7 and 3-amino-2 H -pyran-2-ones 12 in high yield.


Introduction
The importance of pyran-2-one derivatives as building blocks in the field of synthetic and medicinal chemistry has been well established and is a consequence of their interesting structural features and diverse pharmacological properties. 1 The pyran-2-one ring is highly susceptible to nucleophilic attack at the electrophilic centers C-2, C-4 and C-6, and a variety of synthetic approaches for preparation of arenes and heteroarenes starting from pyran-2-ones has been developed. 2Reactions of 2H-pyran-2-ones with different dienophiles, have been widely investigated and utilized for the preparation of a multitude of heterocyclic or carbocyclic products. 3he presence of 3-amino group on 2H-pyran-2-ones or fused pyran-2-ones opens additional possibilities for their utilization as building blocks in heterocyclic chemistry.Recently, we have described transformations of 3-benzoylamino derivatives of 2H-pyran-2-ones and fused pyran-2ones with maleic anhydride 4a,b and maleimides 4c,d under the conditions of the Diels−Alder reaction yielding different bicyclo[2.2.2]oct-7-enes and benz [e]isoindoles.We have also transformed several 3-benzoylamino-2H-pyran-2-ones into highly substituted aniline, biphenyl and terphenyl derivatives in reactions with a variety of alkynes under thermal reaction conditions, using high pressures or under the influence of microwaves.4e−g Similarly, 3-amino-2H-pyran-2-ones and 3-amino derivatives of fused pyran-2-ones have been transformed into pyridazine derivatives via a novel reaction. 5Since many of the 3-benzoylamino and 3-amino compounds we applied for some of the above-mentioned transformations have not yet been properly described, but only short notes about their syntheses were given previously, 4a,c,d,f,g,5b,c we report here high-yield synthetic procedures for the preparation of these compounds and their full characterization data.
2H-Pyran-2-ones and fused pyran-2-ones can be prepared by a variety of methods depending on the substitution pattern of the desired compounds. 1In the past we developed a onepot synthesis of 3-acylamino derivatives of a wider variety of pyran-2-one ring containing systems. 6This synthetic procedure requires compounds with highly activated methylene or methyl group (1,3-dicarbonyl compounds, methyl ketones, lactones, thiolactone or lactam) which are reacted with a one-carbon building block (DMFDMA, triethyl orthoformate, diethoxymethyl acetate, or N,N-dimethylacetamide dimethyl acetal) and an N-acylglycine in acetic anhydride.
Herein we describe a modification of this procedure which is applicable for the transformation of less activated ketones, such as cycloalkanones and arylacetones, into the corresponding 3-benzoylamino-substituted pyran-2-one derivatives in high yield.Some of these compounds, as well as some of previously described 3-benzoylamino-2H-pyran-2-ones, 6 can be effectively de-benzoylated in sulfuric acid yielding a series of the corresponding 3-amino compounds in high yield.The target products thus obtained have been used in a variety of the above-mentioned transformations.

Results and Discussion
We started our investigation with the application of a one-pot methodology toward the synthesis of a series of cycloalka[b]pyran-2-ones 5a−d and 5-aryl-6-methyl-2H-pyran-2-one derivatives 10a,b.In the first step cycloalkanones 1 were heated with two equivalents of DMFDMA for 16 h to prepare previously described α-enaminoketones 2. 7 Products 2 have not been isolated in the pure state, only the remaining DMFDMA and eliminated methanol were evaporated in vacuo.To the crude intermediate 2 hippuric acid and acetic anhydride were added and the reaction mixture was heated at 90 °C for 4 h.Upon concentration, addition of ethanol to the oily residue and cooling, the separated solid was filtered off to give a mixture of two products; namely, the expected fused pyran-2-one derivative 5 and the oxazolone derivative 6.For example, with the starting 1a the ratio of 5a to 6a was 2.8 : 1 (as determined from the 1 H NMR spectrum of the crude reaction mixture), and with 1b the ratio 5b : 6b was 1 : 1.We believe that unexpected products 6a,b appeared in a competing reaction (to the formation of 5a,b) by the acetylation of the intermediates 4 with acetic anhydride.Compounds 4 can exist in a series of tautomeric forms also possessing different configurations around exocyclic double bonds and, as a consequence, this opens up possibilities for a variety of reactions.The configuration of the exocyclic oxazolone double bond in products 6a,b was determined on the basis of the coupled 13 C NMR spectrum.Namely, the magnitude of the coupling constant between the oxazolone carbon 5-C and vicinal proton of the exocyclic CH group was determined to be 4.6 Hz at 167.9 ppm for 6a and 5.5 Hz at 168 ppm for 6b.These values are typical for the (Z)-isomers.8a−c The (Z)-structure of 6a,b is also supported by the chemical shifts of β-H atoms at the exocyclic double bond of the compounds 6a,b (7.15 and 7.17 ppm for 6a and 6b, respectively), which is the same as that of the related (4Z)-4-(3,4-dimethoxybenzylidene)-2-phenyloxazol-5(4H)-one (7.15 ppm).8d Next we investigated a possibility of transformation of oxazolone derivatives 6 into fused pyran-2-ones 5.The oxazolone derivative 6b was transformed on heating for 10 h in boiling pyridine into pyran-2-one 5b.Similarly, an equimolar mixture of compounds 5b and 6b was heated for 6 h in a mixture of pyridine and triethylamine to give fused pyran-2-one 5b almost quantitatively.We believe that during this process the acetyl moiety is removed from the cyclohexene unit to give intermediate 4, and the latter cyclizes to the pyran-2-one derivative.

Scheme 1
With the above results in hand, we have developed a new modification of the one-pot methodology for the synthesis of 5a−d, which, in the first step, requires conversion of the monoactivated cycloalkanones 1a−d into the corresponding α-enaminoketones 2a−d with a twofold excess of DMFDMA under reflux for 16 h (step 1).After evaporation of the volatile components crude 2-[(dimethylamino)methylene]cycloalkanones were reacted with hippuric acid (equimolar amount to starting alkanone) in acetic anhydride at 90 °C for 4 h (step 2).Further evaporation of volatile components afforded tarry residues which were treated with a mixture of pyridine and triethylamine under reflux for 9 h (step 3).Upon evaporation, ethanol was added to the residue and the products 5a−d were isolated in 60−73% yields in crystalline form (Scheme 2).These yields are generally significantly higher than those obtained by previously 6 published modifications.It is of interest to note that the compound 5b was already prepared in a two-step process from 4-ethoxymethylene-2-phenyloxazol-5(4H)-one and 1-piperidinocyclohexene. 9 During recent years, the application of microwaves as a green source of heating is of increasing importance in organic synthesis. 10Therefore, on the basis of our previously reported results 4b,d,g,11a,b and the results of others, 11c−f we tested the synthesis of 5c also under microwave irradiation conditions.With the use of a closed reaction vessel and higher reaction temperatures (130 °C) we have been able to significantly reduce the reaction times in all three steps.We managed to reduce the total time of heating from 29 h under conventional reaction condition to 10 h under microwave irradiation with a negligible change in the yield on 10 mmol scale (65% versus 62% yield).
In addition to monoactivated cycloalkanones we have also applied the one-pot synthetic procedure for the conversion of sterically hindered ketones, such as arylacetones 8, in order to prepare 2H-pyran-2-ones 10a,b containing a large electron-donating substituent in position 5 (Scheme 3).Here, we started from aryl-substituted acetone derivatives 8, DMFDMA and hippuric acid in acetic anhydride.For the successful preparation of the products 10a,b only modified steps 1 and 2 from the above method were required and the target compounds were isolated in high yields (78−81%).The intermediate α-enaminoketones 9 12 have not been isolated in the pure state during this process.Though the reactive site (the methylene group) of arylacetones applied in this investigation is sterically much more hindered than the methyl group of aryl methyl ketones, 6f here products 10 were isolated in higher yields than previously prepared 6-substituted 2H-pyran-2-ones.The products 10 thus obtained exhibit a novel pattern of substituents (i.e. 3-amino-5-aryl-6-methyl-) of 2H-pyran-2-one system.

Conclusions
We have developed a one-pot synthesis for the preparation of 5-to 8-membered cycloalkenefused pyran-2-one derivatives 5 starting from the appropriate cycloalkanones, DMFDMA and hippuric acid in the presence of a large excess of acetic anhydride.A modified one-pot methodology was also used for the preparation of N-(5-aryl-6-methyl-2-oxo-2H-pyran-3yl)benzamides 10.The benzoylamino moiety of the compounds 5 was successfully deprotected by gentle heating in sulfuric acid to give the corresponding 3-aminocycloalka[b]pyran-2-ones 7.
Similarly, a variety of 3-amino-6-substituted-and 3-amino-4,6-disubstituted-2H-pyran-2-ones 12 was also obtained from 11 on heating with sulfuric acid.These two high yielding synthetic procedures represent useful ways for the preparation of benzoylamino and amino derivatives of pyran-2-ones, often used building blocks in synthetic organic chemistry, as previously shown by their fruitful application in a variety of transformations.Microwave reactions were conducted in air using a focused microwave unit (Discover by CEM Corporation, Matthews, NC).The machine consists of a continuous, focused microwave power delivery system with an operator-selectable power output from 0 to 300 W. Reactions were performed in a glass vessels (capacity 10 mL) sealed with a septum.The pressure was controlled by a load cell connected to the vessel via septum.The temperature of the contents of the vessel was monitored using a calibrated infrared temperature controller mounted under the reaction vessel.The mixtures were stirred with a Teflon-coated magnetic stirring bar in the vessel.Temperature, pressure and power profiles were recorded using commercially available software provided by the manufacturer of the microwave unit.Starting 3-benzoylamino compounds 11 were prepared as described previously. 6Other reagents and solvents were used as obtained from the commercial sources.acetic anhydride (2.5 mL) were added and irradiated with microwaves for 2 h (final temperature 130 °C, power 60 W, ramp time 5 min).The volatile components were removed under reduced pressure and a mixture of pyridine and triethylamine (4 : 1, 2.5 mL) was added.The reaction mixture was irradiated for 4 h (final temperature 130 °C, power 60 W, ramp time 5 min), then it was evaporated to dryness under reduced pressure and ethanol (8 mL) was added.Upon prolonged cooling (3−5 days), the precipitate was filtered off and washed with a small amount of ethanol (1 mL) to afford the product 5c (1.585 g, 62%).

General procedure for the synthesis of 10a,b
A mixture of (4-methoxyphenyl)acetone or (3,4-dimethoxyphenyl)acetone (86 mmol) and DMFDMA (21.45 g, 180 mmol) was refluxed for 4 h.The volatile components were removed in vacuo, hippuric acid (15.41 g, 86 mmol) and acetic anhydride (110 mL) were added and the mixture was heated at 90 °C for 4 h.Thereafter, the volatile components were removed in vacuo, EtOH (55 mL) was added and cooled to −18 °C.The precipitated solid was filtered off and washed with EtOH.

General procedure for the synthesis of 7a−d and 12a−e.
A mixture of a 3-benzoylaminopyran-2-one derivative 5a−d or 11a−e (5 mmol) and 5 mL of concentrated H 2 SO 4 was heated at 60−65 °C for 2 h.Upon cooling and adding 50 g of water-ice mixture, the precipitated benzoic acid was filtered off.The filtrate was neutralized with NaHCO 3 and the precipitated product was filtered off.For the isolation of the products 12a,c extraction with CH 2 Cl 2 was used.For the isolation of the product 12b the precipitated material, formed after the addition of water-ice mixture, is filtered off, dispersed in water and neutralized with Na 2 CO 3 .Precipitated product 12b is then filtered off.
Analytical and spectroscopic data of the products.
13,c,d,f,g,5b,c Melting points were determined on a Kofler micro hot stage, and are uncorrected.1Hand13CNMR spectra were recorded at 29 ºC in DMSO-d 6 or CDCl 3 with a Bruker Avance DPX 300 spectrometer, using TMS as an internal standard.The coupling constants (J) are given in Hz. 2D NMR experiments ( 1 H-1 H and 1 H-13 C) were performed in order to fully assign the structures of the 3-benzoylamino compounds 5 and 10.IR spectra were obtained with a Bio-Rad FTS 3000 MX spectrophotometer.Mass spectra were recorded with a VG-Analytical AutoSpec Q instrument.Elemental analyses (C, H, N) were performed with a Perkin-Elmer 2400 CHNS/O analyzer.TLC was carried out on Fluka silica-gel TLC sheets.