Synthesis of Phosphonomethylated Bromoacetylfurans and Their Reactions with 1,3-Dicarbonyl Compounds

Bromination of (diethoxyphosphorylmethyl)acetylfurans with dioxane dibromide in the mixture of chloroform and acetic acid in presence of traces of hydrogen bromide at room temperature proceeds selectively at the methyl group of ketone does not involving phosphonate group. Obtained bromoacetyl derivatives were used for alkylation of acetoacetic ester and cyclohexan-1,3-dione. Reaction of 1,4-diketone prepared from acetoacetic ester with hydrazine hydrate in ethanol at room temperature leads to formation of furylpyrazines due to aromatization of intermediate azines by means of air oxygen.

DOI: 10.1134/S1070363221040101 As is known, 1,4-diketones are the starting material for the preparation of a large number of various heterocyclic systems. Continuing the study of approaches to the synthesis of furan-containing hybrid heterocyclic systems with a phosphonate group in their structure, we turned to the development of a method for obtaining functionally substituted 1,4-diketones of the furan series, based on the alkylation of 1,3-dicarbonyl compounds with phosphonomethylated bromoacetylfurans.
The currently known assortment of bromoacetylfurans is very limited. 2-Bromacetylfuran is obtained by bromination of acetylfuran with bromine in diethyl ether or in a mixture of diethyl ether and dioxane [1][2][3]. 3-Bromoacetylfuran was synthesized by bromination of 3-acetylfuran with bromine in the mixtures of acetic acid and toluene, as well as by means of bromination with copper dibromide in the boiling mixture of chloroform and ethyl acetate [4,5]. Phosphorus-containing bromoacetylfurans have not yet been obtained. At the same time, the study of bromination of esters of furylmethanephosphonic acids showed [6] that the Р-С bond is rather easily cleaved by molecular bromine, while the action of hydrogen bromide often leads to dealkylation of esters of furylmethanephosphonic acids. Therefore, it is desirable to carry out bromination of phosphonomethylated acetylfurans with complex-bound bromine at low temperatures in media with low acidity.
We have selected compounds 1-6 as starting substances (Scheme 1), the structures of which cover all six possible variants of the relative position of the acetyl and dialkylphosphonomethyl groups in the furan ring. Phosphonates 1, 3, 4, 6 were synthesized by a known method from the corresponding bromides by means of the Arbuzov reaction [7], and for compounds 2 and 5 a method was developed for their synthesis starting from the corresponding known chloromethylfurancarboxylic acids chlorides [8].
Compound 7 exists in solution as the mixture of two conformers. The signal of the proton of the methine group of acylmalonate in the 1 H NMR spectrum is observed at 4.40 ppm, the signals of the protons of the chloromethyl group appear at 5.00 and 5.03 ppm in the 1 : 0.5 ratio. The signals of the H 3 proton of the furan ring are located at 7.05 and 7.25 ppm respectively and have the same intensity ratio. The carbon nucleus of the methine group of the acylmalonate gives two signals at 61.24 (minor) and 61.26 ppm (main). The carbonyl group of the furoyl fragment is represented by two signals at 176.61 (main) and 176.67 ppm (minor). Doubling of signals is also observed for all carbon nuclei of the malonate fragment, as well as for the carbon of the methyl group and the C 2 , C 4 and C 5 nuclei of the furan ring.
Heating of compound 7 in a mixture of dilute hydrochloric and acetic acids for 3 h leads to hydrolysis and decarboxylation of both acid groups of the acylmalonic ester (Scheme 3). Acetylfuran 8 was isolated in 50% yield.
For the transfer from chloromethylfuran 8 to target phosphonate 2, two routes were used (Scheme 3). The fi rst included the Finkelstein reaction for obtaining of iodomethylfuran 9 and subsequent phosphorylation under the conditions of the Arbuzov reaction. The Finkelstein reaction was carried out in acetone at room temperature using a twofold excess of sodium iodide dihydrate.
Iodomethylfuran 9 was a colorless crystalline substance with mp 56°C. It rapidly emits iodine in the light. The formation of the iodomethyl group was confi rmed by the presence of a singlet of methylene protons at 4.20 ppm; the signal of the corresponding carbon nucleus was located at -6.49 ppm. The yield of compound 9 was 44%. When it is heated with triethyl phosphite in a molar ratio of 1 : 2.4 at 120°C, distillation of ethyl iodide begins. Phosphorylation completes within 5 minutes when the temperature of the reaction mixture reaches 160°C. By distillation of the reaction mixture, the target phosphonate 2 was isolated in 33% yield. Phosphorylation of compound 8 under the conditions of the Michaelis-Becker reaction turned out to be more successful. The reaction was carried out in benzene with a small excess of sodium diethylphosphite at 80°С for 9 h. Phosphonate 2 was isolated by distillation in vacuum in 47% yield.
A similar approach was used for the synthesis of acetylfuran 5. At the fi rst stage, treating of 4-chloromethyl-3-furoyl chloride with an ethoxymagnesium derivative of malonic ether at 10-12°С lead to formation of corresponding furoylmalonic ester 10 in 90% yield (Scheme 4). This product has no spectrally distinguishable conformers. The signal of the protons of the chloromethyl group is observed at 4.74 ppm, and the signal of the corresponding carbon nucleus is located at 36.36 ppm.
Signal of the methine proton appears at 4.90 ppm, which correlates with the signal of the carbon nucleus at 63.82 ppm. Signal of the ketone carbonyl group carbon nucleus is located at 183.23 ppm.
When boiling furoylmalonate 10 in a mixture of acetic and dilute hydrochloric acid, sequential hydrolysis and decarboxylation takes place to form 4-chloromethyl-3-acetylfuran 11, which was isolated in 57% yield (Scheme 4). The signal of the protons of the methyl group of the ketone is observed at 2.43 ppm, the signal of the corresponding carbon nucleus at 28.04 ppm, and the signal of the carbon nucleus of the carbonyl group is located at 192.87 ppm.
Chloromethyl ketone 11 was converted to iodide 12 by treating with sodium iodide in acetone at room temperature. The target compound was obtained in 93% yield (Scheme 5). In its NMR spectra, the signal of the methylene protons of the iodomethyl group is observed at 4.50 ppm, and the nucleus of the corresponding carbon atom gives a signal at -7.16 ppm.
Phosphorylation of compound 12 with triethyl phosphite at the temperature range 115-150°С for 10 min leads to the target phosphonate 5 which was obtained in 68% yield (Scheme 5).
Bromination of phosphonates 1-6 was carried out in chloroform-acetic acid mixture (Scheme 6). To create the acidity of the medium suffi cient for the enolization of the ketone at the initial moment of the reaction, several drops of 33% solution of hydrogen bromide in glacial acetic acid were added to the reaction mixture. A preliminarily prepared solution of dioxane dibromide in a mixture of chloroform and excess of dioxane was used as a brominating agent. The hydrogen bromide released during the reaction is also bound with the excess of dioxane and is deactivated to such an extent that no dealkylation of phosphonates was observed in any case. Bromination was carried out at room temperature by adding dropwise a solution of dioxane dibromide to the ketone solution. The release of heat during the reaction was almost not observed, only in the case of phosphonates 1, 3 and 4 the temperature of the reaction mixture rose on 2-3°C. The disappearance of the color of bromine occurred for phosphonates 2-6 almost at the time of addition; in the case of phosphonate 1, it took about 5 min to decolorize the reaction mixture after the addition of 2-3 drops of dioxane dibromide solution. The yields of bromoacetyl derivatives 1а-6а varied within 84-94% without a defi nite dependence on the structure of the substrate. In the case of bromination of phosphonate 4, the formation of dibromoacetyl derivative 13 was observed as a minor product. For characterization, it was specially synthesized in 69% yield by bromination of monobromide 4а under similar conditions (Scheme 7).
The synthesized bromoacetylfurans 1а-6а were used for the alkylation of such typical СН-acids as acetoacetic ester and cyclohexane-1,3-dione. The reaction was carried out in a mixture of absolute dioxane and absolute ethanol in a ratio of 10 : 1; metallization of CH acids was carried out with freshly prepared sodium ethylate. Alkylation was carried out at 90°С for 10 h. In all cases, only monoalkyl derivatives of СН-acids were obtained (Scheme 8).
In the 1 H NMR spectra of the products of the alkylation of acetoacetic ester 1b-6b, the singlet of protons of the bromoacetyl group in the range 4.2-4.5 ppm disappears, and instead of it there appeas a multiplet at 3.2-3.5 ppm. It is the AB part of ABX-system formed by the signals of the protons of the methylene and methine groups of the alkyl fragment. In all cases, the signal of the proton of the methine group is overlapped by the intense signals of the OCH 2 groups, however, two signals are clearly 3a).
Scheme 7. The coupling constant of methylene protons J AB is 18.0-18. 8 Hz. In all cases, the proton giving the upfi eld signal is denoted H A , the downfi eld signal is H B , and the proton of the methine group is H X . It turns out that the coupling constant J AX is in all cases is less than J BX . The average value of the fi rst of them is 5. 3 Hz, and of the second one 8. 3 Hz. Consequently, the dihedral angle between the H A and H X nuclei turns out to be larger than that between H B and H X . Thus, the analysis of the spectral characteristics of compounds 1b-6b proves that they all are products of monoalkylation, existing in ketone form. The yields of the alkylation products in the case of 2-bromoacetylfurans 1a and 2a with remote substituents are 61 and 54%, respectively. In the case of 2,3-disubstituted compounds 3а and 4а, the yield decreases slightly, to 50 and 49%, respectively. In the case of 3,4-disubstituted 3-bromoacetylfuran 5а, the yield is 72%, and its 2,4-disubstituted isomer 6а gives an alkylation product in 69% yield. From that it follows that 3-bromoacetylfurans, in which the bulky diethoxyphosphorylmethyl group is in the position 4 or 5 of the furan ring, react more easily with acetoacetic ether than 2-bromoacetylfurans with remote substituents, and 2,3-disubstituted compounds are the least active regardless of the location bromoacetyl group. However, these differences turn out to be very small.
An entirely different picture is observed in the NMR spectra of the alkylation products of cyclohexane-1,3dione (Scheme 9). The signals of the protons of the CH 2 CO-furan fragment represent an AB system, and the value of the J AB coupling constant in compounds 1c, 3c, 4c is 12.4, 14.2, and 14. 4 Hz, respectively, and in compound 6c, 4.0 Hz. Compound 2c exists in the form of two spectrally distinguishable conformers, the J AB constants in them are equal to 9.2 and 3.6 Hz, respectively. The signal of the carbon nucleus of the methylene group in the compounds under consideration is in the range 36.5-41.5 ppm, which corresponds to the value observed for the products of the alkylation of acetoacetic ester. On the contrary, instead of the signal at 66-67 ppm, which is characteristic of the carbon nucleus of the methine group, in the spectra of the alkylation products of acetylacetone [9], two signals are observed in the intervals 110-115 and 186-191 ppm, respectively. In the 1 H NMR spectra of compounds 2c-4c a signal is observed at 8.05-8.20 ppm. In the spectrum of compound 1c, it shifts to 7.6 ppm. The above-presented data show that the alkylation products of cyclohexane-1,3-dione exist in the monoenol form. The narrowness of the signal of the proton of the hydroxyl group and its upfi eld location non-typical for enols can be explained by the formation of a hydrogen bond between this proton and the oxygen of the carbonyl group bound to the furan ring. The yields of alkylation products in the case of 2-bromoacetylfurans 1а and 2а with substituents distant from the reaction center are in the range of 36-46%. On the contrary, in the case of 3-substituted 2-bromoacetylfuran 3a, the yield of the target product turns out to be 81%, that is, two times higher, although they differ little during the alkylation of acetoacetic ether. In the case of 3-bromoacetylfurans 4а and 6а, the opposite picture is observed. The yield of the alkylation product 4c turns out to be 29%, and of compound 6c, 63%, i.e., the tendency observed in the alkylation of acetoacetic ester remains.
The obtained esters of 2-acetyl-3-furyl-3-oxobutanoic acid 1b-6b were reacted with hydrazine hydrate in order to obtain cyclic diazines (Scheme 10). The reaction was carried out in ethanol at room temperature for 12-15 h. It turned out that under the action of atmospheric oxygen, Scheme 10. 2d). 6c). PEVZNER, PONYAEV diazine aromatization immediately occurs with the formation of esters of 3-methyl-6-furylpyridazine-4carboxylic acids 1d, 2d, and 4d-6d. In the reaction of compound 3b with hydrazine hydrate in air, a complex mixture of products is formed, which could not be separated.
In the 1 H NMR spectra of the synthesized compounds, the signals of the protons of the COCH 2 CH fragment disappear and a singlet appears at 7.6-8.1 ppm, which was assigned to the H 5 proton of the pyridazine ring. In the 13 C NMR spectra the signals located in the intervals 141-146 (C 3 ), 128.2-128.7 (C 4 ), 121-124 (C 5 ), and 137-140 ppm (C 6 ) are observed. Since all the signals of the carbon nuclei of the furan ring are split from phosphorus, the attribution of the above-presented signals to the pyridazine ring can be made unambiguously. The observed values of chemical shifts are in good agreement with the data published for esters of 3-methylpyridazine-4-carboxylic acid and their isomers [10,11]. The composition of compound 5d was confi rmed by high-resolution mass spectrometry. There is no defi nite dependence of the yield of pyridazines 1d, 2d, 4d-6d on the structure of the furan fragment. It should only be noted that compound 5d with a 3,4-disubstituted furan fragment was isolated in 74% yield, while in other cases it varied within 28-53%.
Thus, the bromination of phosphorylated acetylfurans with complex-bound bromine in weakly acidic media proceeds at the acetyl group. The dialkoxyphosphorylmethyl moiety is not touched in this case. The obtained bromoacetyl compounds smoothly alkylate such CH-acids as acetoacetic ester and cyclohexane-1,3-dione to form only the products of monoalkylation.
Derivatives of acetoacetic ether exist exclusively in ketone form, and derivatives of cyclohexane-1,3-dione in the form of monoenols. In reaction with hydrazine hydrate, esters of 2-acetyl-4-[(diethoxyphosphorylmethyl)furyl)]-4-oxobutanoic acids give cyclic diazines, which are immediately oxidized with atmospheric oxygen to 6-furylpyridazine-4-carboxylic acid esters. (4-Chloromethyl-5-methyl-2-furoyl)malonic acid diethyl ester (7). A small crystal of iodine was added to a mixture of 3.9 mL of malonic ester, 4.7 mL of absolute ethanol, and 0.78 g of magnesium turnings and the mixture was heated with stirring until a violent reaction began. The temperature of the reaction mixture was maintained within the range of 80-85°C by periodically cooling it with cold water. After the termination of heat evolution, it was heated at the same temperature for another 1 h. The resulting mixture was cooled to 40-45°С, and then absolute diethyl ether was added until the crystallized ethoxymagnesium derivative was completely dissolved. The resulting mixture was boiled with stirring until the magnesium was completely dissolved, cooled to 10°C, and a solution of 4.04 g of 4-chloromethyl-5-methyl-2furoyl chloride in 10 mL of absolute ether was added dropwise, maintaining the temperature of the reaction mixture at 10-15°C. The resulting solution was stirred for another 2 h and left overnight. On the next day, the reaction mixture was decomposed with 20% sulfuric acid until the precipitate formed overnight was completely dissolved. The organic layer was separated, washed with 20 mL of water, 20 mL of NaCl solution and dried with sodium sulfate. After removing the solvent and excess malonate in a vacuum, 6.09 g (92%) of the target product was obtained in the form of a colorless, highly viscous oil (conformer ratio 1 : 0.5). 1

4-Iodomethyl-5-methyl-2-acetylfuran (9).
To a solution of 4.00 g of sodium iodide dihydrate in 25 mL of acetone 1.92 g of chloromethylfuran 8 was added. After mixing of reagents precipitation of sodium chloride began immediately. The reaction mixture was left for 12 h at room temperature in the dark, then poured into 100 mL of 10% sodium sulfi te solution, shaken, and extracted with chloroform (3 × 20 mL). The extract was washed with 20 mL of 10% sodium sulfi te solution, 20 mL of water, 20 mL of NaCl solution, dried with sodium sulfate in the dark, and then evaporated. Yield 1.30 g (44%), mp. 56°C. b. By means of the Michaelis-Becker reaction. To a solution of sodium diethyl phosphite prepared from 0.5 g of sodium and 3.5 mL of diethyl hydrogen phosphite in 20 mL of benzene, a solution of 3.36 g of chloride 8 in 5 mL of benzene was added in one portion. The reaction mixture was boiled with stirring for 10 h, cooled to room temperature and washed with 10 mL of water. The aqueous layer was washed with 10 mL of benzene, the combined organic phases were washed with 15 mL of brine and dried over sodium sulfate. Distillation in a vacuum gave 2.52 g (47%) of phosphonate 2 with bp 165°С (1 mmHg). The NMR spectra are identical to those given above.
Diethyl (4-chloromethyl-3-furoyl)malonate (10). To a mixture of 2.6 mL of malonic ether and 3 mL of absolute ethanol 0.52 g of magnesium turnings and a small crystal of iodine was added. The resulting mixture was heated until the beginning of a vigorous reaction, and then the temperature was maintained within the range of 80-85°C by external cooling. After the completion of heat evolution, the reaction mixture was boiled for 1 h, cooled to 40-45°С, and absolute ether was added until the crystallized ethoxymagnesium derivative of malonic ether was completely dissolved. The resulting solution was boiled for 3-4 h until the complete dissolution of magnesium, cooled to 10°С, and at this temperature, a solution of 2.55 g of 4-chloromethyl-3-furoyl chloride in 5 mL of absolute ether was added dropwise with stirring. The resulting mixture was stirred at room temperature for 1 h and left overnight. On the next day, the reaction mixture was decomposed with 20% sulfuric acid until the precipitate formed overnight was completely dissolved. The organic layer was separated, washed with water, NaCl solution and dried over sodium sulfate. The solvents and excess malonate were distilled off in a vacuum, the residue obtained was the target product, yield 3.88 g (90%), a light syrup. 1

4-Chloromethyl-3-acetylfuran (11).
A mixture of 3.88 g of acylmalonate 10, 15 mL of glacial acetic acid, 2 mL of water, and 2 mL of concentrated hydrochloric acid was stirred for 4 h at 80°C. After that, the reaction mixture was diluted with 50 mL of water, the solution was saturated with sodium chloride and extracted with chloroform (3 × 15 mL). The extract was washed with 20 mL of water, 10 mL of brine and dried with sodium sulfate. Distillation in a vacuum gave 1.15 g (57%) of the target product 11, bp 95°C (1 mmHg), mp. 45°C. 1  4-Iodomethyl-3-acetylfuran (12). Chloride 11, 2.14 g, was added to a solution of 5 g of sodium iodide dihydrate in 25 mL of acetone at room temperature. The resulting mixture was kept for 24 hours at room temperature in the dark, and then poured in 100 mL of water, and 5 g of sodium sulfi te and 30 mL of chloroform were added. The resulting mixture was shaken until discoloration. The organic layer was separated, the aqueous layer was extracted with chloroform (2 × 15 mL). The combined extracts were washed with water, with brine, and dried over calcium chloride in the dark. The solution was evaporated, the residue crystallized.

4-(Diethoxyphosphorylmethyl)-3-acetylfuran (5).
A mixture of 3.13 g of iodide 12 and 5 mL of triethyl phosphite was heated with stirring. At 115°С the distillation of methyl iodide began, which was completed at 150°С. The reaction time was 10 minutes. Distillation in a vacuum gave 2.23 g (68%) of phosphonate 5, colorless oil, bp 145°C (1 mmHg). 1 Н NMR spectrum (acetone-d 6  Bromination of (diethoxyphosphorylmethyl)acetylfurans. To a solution of 10 mmol of (diethoxyphosphoryl)acetylfuran 1-6 in a mixture of 30 mL of chloroform, 4 mL of acetic acid and 3 drops of a 33% solution of hydrogen bromide in acetic acid a solution of dioxane dibromide, prepared by dissolving of 10.8 mmol of bromine in a mixture of 2 mL of dioxane and 10 mL of chloroform was added dropwise with stirring. The addition was carried out at such a rate that the color of the solution was slightly orange, and the temperature of the reaction mixture remained within the range of 20-22°C. After the end of the addition of the brominating agent, the reaction mixture was stirred at the same temperature for 2-3 h, washed with ice water (2 × 15 mL), 15 mL of saturated sodium bicarbonate solution, 15 mL of NaCl solution, and dried over sodium sulfate. After removing of the solvent, the residue was kept in a vacuum (1 mmHg) for 1 h at room temperature.   Alkylation of СН-acids with bromoacetylfurans 1а-6а. Freshly prepared sodium foil, 5.25 mg-eq, was dissolved in a mixture of 1 mL of absolute ethanol and 10 mL of anhydrous dioxane. After the formation of a homogeneous solution, 5.50 mmol of the alkylated substrate was added and stirred for 20 min, then 5.00 mmol of bromoacetylfuran was added in one portion and the resulting mixture was heated for 10 h at 90°С with vigorous stirring. After the completion of the reaction, the solvents were distilled off, the residue was dissolved in 30 mL of chloroform, washed with 10 mL of water, 10 mL of NaCl solution, and dried over sodium sulfate. After removing the solvent, the residue was kept in a vacuum (1 mmHg) for 1 h at room temperature.