6-methylthiouracil and 6-methyluracil derivatives synthesized by reaction of acetylketene with thiourea and urea compounds in presence of Yb(TFA)3

Abstract Thiouracil and uracil derivatives are among the bioactive molecules used in the treatment of many diseases, such as 6-propylthiouracil and 5-fluorouracil. A new synthesis method of 6-methylthiouracil and 6-methyluracil was developed in this study. Various 6-methylthiouracil and 6-methyluracil derivatives were obtained by reacting 2,2,6-trimethyl-4H-1,3-dioxin-4-one with thiourea and urea compounds in the presence of Yb(TFA)3 according to this new method. Optimization of this new method was performed. The structures of 6-methylthiouracil and 6-methyluracil derivatives were characterized. Graphical abstract


Introduction
Acetylketenes are reactive intermediates used to synthesize new organic compounds and to study their mechanisms. [1] Depending on the reaction conditions, acetylketenes may form new ester [2] or amide bonds [3] and may also undergo cycloaddition reactions. [4] There are several ways to obtain acetylketenes in the reaction medium. They are obtained by heating 2,2,6-trimethyl-4H-1,3-dioxin-4-one (9) above 100 C, treating 4-methylenoxetan-2-one with amine bases and reacting acetoacetyl chlorides with bases. [3][4][5] Pharmacologically important compounds are thiouracil and uracil derivatives obtained by exchanging groups at the N1, N3 and C5, C6 positions. Thiouracil and uracil derivatives such as 6-propylthiouracil (1) and 5-fluorouracil (2) are among the bioactive molecules used in the treatment of many diseases. For example, propylthiouracil (1) is a 6-substituted thiouracil derivative. It is used to treat hyperthyroidism. [6] 5-fluorouracil (2), a 5-substituted uracil derivative, is used to treat pancreatic cancer. [7] Floxuridine (3) is an analog of 5-fluorouracil and is used in the treatment of colorectal cancer. [8] Similarly, Alogliptin (4), a 6-substituted uracil derivative, is a DDP-4 inhibitor that reduces blood glucose levels. [9] Sorivudine (5) is an antiviral drug that reduces the effectiveness of the HSV-1, VZV and EBV viruses. It is a 5-substituted analog of the uracil group. [10] Zidovudine (6), on the other hand, contains the uracil ring and is one of the most effective drugs for treating AIDS. [11] Sofosbuvir (7) is a drug that is a derivative of uracil and is used in the treatment of hepatitis C. This drug works by inhibiting the NS5B protein that is found in hepatitis C. [12] Trifluridine (8) is an antiviral drug and belongs to the class of uracil derivatives. It is used to treat cold sores on the eye caused by the herpes virus. It is also part of the trifluridine/tipiracil combination used to treat stomach cancer ( Figure 1). [13] Many methods exist for synthesizing 6-methyluracil and 6-methylthiouracil. To give a few examples of these methods, 6-methyl urea and thiourea were synthesized by microwave irritation of ethyl acetoacetate with urea or thiourea. [14] Alternatively,6- methyuracil was obtained by reacting 4-methyleneoxetan-2-one with urea in the presence of pyridine. [15] 6-methythioluracil was prepared by refluxing diethylmalonate and thiourea in ethanol in the presence of potassium hydroxide. [16] Another method for the synthesis of 6-methyluracils was obtained by heating 6-methyl-2,4-pyrimidine diyl dibenzoate and diethylamine in dichloromethane. [17] The method proposed in recent years for the synthesis of 6-methyuracil was to obtain ethyl [6-methyl-2-(methylsulfonyl)pyrimidin-4-yloxy]acetate by heating with water for 1 hour. [18] In this study, 6-methyluracil and 6-methylthiouracil derivatives were synthesized in high yields using a method not found in the literature. The compound 2,2,6-trimethyl-4H-1,3-dioxin-4-one (9) is commercially available and stable at room temperature. However, when compound 9 is heated above 100 C, it converts to acetylketene intermediate. [3,4] In this new method, 9 (acetylketene adduct) was reacted with urea and thiourea derivatives in the presence of Yb(TFA) 3 catalyst, giving 6-methyluracil and 6methylthiouracil derivatives (11).
The reaction of compound 9 with urea is found in only one publication in the literature. [19] However, it can be seen that there are important shortcomings in this publication in relation to this reaction. For example, in this literature there is a lack of 1H-NMR and 13 C-NMR data, as well as the solvent in which the reaction was carried out.

Results and discussion
The study consists of two parts. In the first part, reactions of 9 with urea and thiourea derivatives (10) were studied. The second part consists of reacting the benzaldehyde semicarbazone derivatives (12) which were synthesized with 9.
In this reaction, our aim is to form acetylketene as a result of pyrolysis of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (9) compound in a suitable solvent and to ensure the addition of thiourea (10a) compound to acetylketene. For the formation of acetylketene, solvents that are 1,4-dioxane, toluene, and acetic acid with a boiling point above 100 C were tried. [4] Toluene was found to be the most suitable solvent for this reaction. Because it was seen that the yield at the end of 4 hours in 1,4-dioxane was 15%. This yield was quite low. The yield was not affected by increasing the reaction time. In the case of acetic acid, although the yield was 40% at the end of 4 hours, there were problems with the work up. The yield was 35% after 4 hours without any catalyst in toluene. No obvious increase in reaction yield was observed by extending the reaction time for toluene. It was therefore decided to use different catalysts in the reaction at this stage.
The structures of the compounds 11 have been elucidated by 1D-NMR spectroscopy. 1H-NMR of compound 11d, methyl protons resonate at 2.09 ppm, methylene protons of the benzyl group resonate at 5.01 ppm and double bond proton resonate at 5.54 ppm. On the other hand, aromatic ring protons resonate at 7.18 À 7.37 ppm and -NH proton resonate at 11.35 ppm. Compound 11d was synthesized in three steps using different methods after the structure of this compound had been characterized. [20] Compatibility of our structure with the previously synthesized compound has been checked by comparison of the NMR data. [20,21] In our opinion, the one-step synthesis of 6-methythiouracil and 6-methyluracil compounds rather than the three-step synthesis is a significant contribution to the literature in terms of synthetic chemistry. The structures of all the other compounds 11 that were synthesized are compatible with their NMR spectra.
Various thiourea and urea compounds were used to test our proposed synthesis method for the synthesis of 6-methylthiouracil and 6-methyluracil. This derivatization resulted in the synthesis of five different 6-methylthiouracil and uracil compounds ( Table 2).
Benzaldehyde semicarbazone derivatives (12) were synthesized to test the applicability of our new method with different urea-like compounds. In the synthesis of these derivatives, 1 eqv semicarbazide hydrochloride and 2 eqv sodium acetate were dissolved in 100 ml of water. On the other hand, 1 eqv aldehyde derivative was dissolved in 20 ml MeOH and added to the initially prepared mixture of semicarbazide hydrochloride and sodium acetate. The formation of benzaldehyde semicarbazone was observed simultaneously. It was taken, recrystallized and prepared for the second step reaction. [22] The compound 9 was reacted with the synthesized benzaldehyde-semicarbazone derivatives in toluene under the nitrogen in presence of Yb(TFA) 3 to give 1-benzylideneamino-6methyl-1H-pyrimidine-2,4-dione derivatives (Table 3). Using our method, which was not previously available in the literature, five different 1-benzylideneamino-6-methyl-1H-pyrimidine-2,4-dione compounds (13) were synthesized. Only one of these compounds has been reported in the literature. [23] This compound (13a) was synthesized using a different synthetic method. Comparing the 1H NMR of compound 13a prepared in this literature with the 1H NMR of compound 13a prepared by our method shows that the 1H NMRs are compatible. According to 1H-NMR of compound 13a, methyl protons resonated as singlets at 2.20 ppm, double bond proton resonated as singlets at 5.62 ppm, aromatic ring protons resonated as multiplet in the range of 7.88-7.44 ppm, olefinic proton resonated as singlet at 8.96 ppm and finally -NH proton resonated as singlet at 11.48 ppm.
The mechanism of Yb(TFA) 3 catalyzed cycloaddition of acetylketene with thiourea or urea derivatives is proposed in Scheme 1. Heating 9 converts it to acetylketene and releases acetone. The NH 2 group of low steric hindrance thiourea or urea derivatives attacks acetylketene to form an amino alcohol intermediate. The other NH 2 group of the thiourea or urea derivative attacks the acetyl carbonyl, whose reactivity is increased by Yb(TFA) 3 , and ring closure occurs, resulting in the release of 1 mol of water. 6-methylthiouracil or 6-methyluracil compounds are formed as a result of this cycloaddition. Table 2. Synthesis of 6-methylthiouracil and 6-methyluracil derivative 11. Table 3. Synthesis of 1-benzylideneamino-6-methyl-1H-pyrimidine-2,4-dione 13. Scheme 1. Proposed mechanism for the Yb(TFA) 3 catalyzed cyclization reaction of acetylketene.

Conclusion
In this study, a method not previously described in the literature was used to demonstrate ring formation between 2,2,6-trimethyl-4H-1,3-dioxin-4-one (9) and thiourea or urea derivatives. The proposed method was used to synthesize 6-methylthiouracil and 6-methyluracil derivatives, which are considered to be of pharmacological importance. This reaction was carried out both with and without a catalyst. It has been observed that the yield is low when a catalyst is not used in this type of reactions. Optimization studies of the reaction showed that the most suitable solvent was toluene and the most suitable catalyst was Yb(TFA) 3 . In our study, a new mechanism was proposed for the synthesis of 6-methylthiouracil and 6-methyluracil.

Experimental
General procedure for the synthesis of 11a-e and 13a-e Ytterbium(III) trifluoromethanesulphonate (0.093 g, 15 mol %) was added to a mixture of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.568 g, 4 mmol) and thiourea or urea derivative (4 mmol) dissolved in 15 ml of toluene and refluxed under a nitrogen atmosphere. Following TLC, the reaction was observed to have stopped after 4 hours. The reaction mixture was filtered and the solvent was removed by evaporation. The crude was recrystallized with ethyl acetate.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Supporting Information summary
Supporting Information is included in full experimental detail (1H-NMR, 13 C-NMR spectra, LC-MS, IR). This material can be found via this article's webpage's "Supplementary Content" section.