The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones

This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. In the case of o-phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33–91%).

in toluene for 4 h to produce pyridones 2a-d,f in 30-90% yields. Pivaloyl-substituted pyrone 1e did not provide the desired product, and the reaction was carried in more polar MeCN, leading to pyridone 2e in 42% yield. Compounds 2a-e underwent the deprotection of the dimethyl acetal moiety in aqueous HCl to form 3-hydroxy-3,4-dihydropyrido [2,1-c] [1,4]oxazine-1,8-diones 3a-e. For 2,5-dicarbethoxy-4-pyridone 2f, the heating in formic acid was used for the selective hydrolysis of the COOEt group at the C-2 position as a result of the promotion by the presence of the adjacent aldehyde fragment.
The 1 H NMR spectra of products 3 in DMSO-d6 demonstrates the existence of only the lactol form. The spectral feature of the tautomer is the presence of a downfield signal of the OH group at δ 8.13-8.72 ppm and an ABX system of the morpholinone moiety. For the pivaloyl-substituted compound 3e, a singlet of the methylene group and a strongly broadened singlet of the CH proton were observed probably due to the rapid interconversion between different forms.  Pyridones 3 can undergo aldehyde-lactol tautomerism [30] and exist as acyclic aldoacid or a cyclic lactol form (3-hydroxy-3,4-dihydropyrido[2,1-c] [1,4]oxazine-1,8-diones) (Scheme 2). It is interesting to note that this type of the ring-chain tautomerism for morpholinones has not been studied before.
The 1 H NMR spectra of products 3 in DMSO-d 6 demonstrates the existence of only the lactol form. The spectral feature of the tautomer is the presence of a downfield signal of the OH group at δ 8.13-8.72 ppm and an ABX system of the morpholinone moiety. For the pivaloyl-substituted compound 3e, a singlet of the methylene group and a strongly broadened singlet of the CH proton were observed probably due to the rapid interconversion between different forms.
Pyridones 3 bear the carbonyl group at the C-5 position, which can be used for further modifications of the heterocyclic fragment. Therefore, the important task included the search for selective transformations on the morpholinone fragment. We have studied the detailed influence of conditions on the ring-opening reaction of 3-hydroxy-3,4dihydropyrido[2,1-c] [1,4]oxazine-1,8-diones (3b) with 3-aminopropan-1-ol (Table 2). A Molecules 2023, 28, 1285 4 of 13 mixture of methanol-toluene was used as a solvent to increase the solubility of pyridone 3b. The reaction did not proceed without the use of catalysts even under the prolonged reflux. It was found that the transformation in the presence of acetic acid as an additive led to product 4a in 48% yield. We suggested that the formation of 3-hydroxypropylammonium acetate occurred, which acts as a nucleophile and activator of the morpholinone moiety. However, this transformation did not proceed at room temperature, as well as with the use of the 0.2 equiv. of acetic acid. Table 2. The optimization of reactions conditions for the synthesis of 4a from 3b and 3-aminopropan-1-ol a . modifications of the heterocyclic fragment. Therefore, the important task included the search for selective transformations on the morpholinone fragment. We have studied the detailed influence of conditions on the ring-opening reaction of 3-hydroxy-3,4-dihydropyrido [2,1-c] [1,4]oxazine-1,8-diones (3b) with 3-aminopropan-1-ol (Table 2). A mixture of methanol-toluene was used as a solvent to increase the solubility of pyridone 3b. The reaction did not proceed without the use of catalysts even under the prolonged reflux. It was found that the transformation in the presence of acetic acid as an additive led to product 4a in 48% yield. We suggested that the formation of 3-hydroxypropylammonium acetate occurred, which acts as a nucleophile and activator of the morpholinone moiety. However, this transformation did not proceed at room temperature, as well as with the use of the 0.2 equiv. of acetic acid.
Taking into account the effect of AcOH, we tried to use AcONH4 as a bifunctional catalyst [31,32] for this process. To our delight, the product was obtained in a good yield (69%) under reflux for 12 h (TLC monitoring) ( Table 2). The variation of the nature of the ammonium salt or temperature did not allow for the improvement of the reaction yield. We tried to extend the optimized conditions with the use of ammonium acetate (Method A) for other 5-acylpyridones 3 and binucleophiles for the synthesis of polycyclic 4-pyridones (Table 3). In most cases, the acyl fragment strongly influenced the reaction selectivity, and an alternative method included the use of acetic acid (Method B). Pyridones 3b,c bearing para-substituted benzoyl fragments underwent the transformation in the presence of ammonium acetate and led to the formation of products 4a,b in 69-75% yields. Benzoyl-and thienoyl-substituted compounds 3a,d reacted more effectively in the conditions of method B and provided products 4c,d in 31-52% yields. When propane-1,3-diamine was used as a binucleophile, we were not able to isolate the desired polycyclic products in a pure form directly. The precipitates that formed always contained the starting diamine in significant amounts. Next, binucleophiles bearing two carbon atoms in the linker was used for the heterocyclization. The reaction with ethylenediamine proceeded in good yields and led to the formation of imidazo [ Taking into account the effect of AcOH, we tried to use AcONH 4 as a bifunctional catalyst [31,32] for this process. To our delight, the product was obtained in a good yield (69%) under reflux for 12 h (TLC monitoring) ( Table 2). The variation of the nature of the ammonium salt or temperature did not allow for the improvement of the reaction yield.
We tried to extend the optimized conditions with the use of ammonium acetate (Method A) for other 5-acylpyridones 3 and binucleophiles for the synthesis of polycyclic 4-pyridones (Table 3). In most cases, the acyl fragment strongly influenced the reaction selectivity, and an alternative method included the use of acetic acid (Method B). Pyridones 3b,c bearing para-substituted benzoyl fragments underwent the transformation in the presence of ammonium acetate and led to the formation of products 4a,b in 69-75% yields. Benzoyl-and thienoyl-substituted compounds 3a,d reacted more effectively in the conditions of method B and provided products 4c,d in 31-52% yields. When propane-1,3-diamine was used as a binucleophile, we were not able to isolate the desired polycyclic products in a pure form directly. The precipitates that formed always contained the starting diamine in significant amounts. Next, binucleophiles bearing two carbon atoms in the linker was used for the heterocyclization. The reaction with ethylenediamine proceeded in good yields and led to the formation of imidazo[1,2-a]pyrido[1,2-d]pyrazine-5,7-diones 5a,b in 78-84% yields (Method A). Thienoyl-substituted pyridone 3d underwent the ring-opening process in the presence of acetic acid (Method B) to produce compound 5c in 48% yield. At the same time, we failed to isolate any products in the pure form in the reaction with ethanolamine. opening process in the presence of acetic acid (Method B) to produce compound 5c in 48% yield. At the same time, we failed to isolate any products in the pure form in the reaction with ethanolamine. The peculiarity of ammonium acetate is probably associated with its solubility in a methanol-toluene mixture and the ability to promote the ring-opening process of the morpholinone ring, which leads to the formation of the aldoacid (Scheme 3). Subsequent stages, including intermolecular attack of a binucleophile and intramolecular cyclization, can be catalyzed by both the ammonium cation and acetic acid. An experiment was carried out to study the reaction of ammonium acetate with pyridone 3b under reflux. According to the 1 H NMR spectrum of the obtained precipitate, it was found that the formation of an open-chain structure occurred (see Supplementary materials). Although we did not detect the aldehyde group, a singlet of the methylene group and absence of the 3-CH proton of the lactol form were observed in the 1 H NMR spectrum. The peculiarity of ammonium acetate is probably associated with its solubility in a methanol-toluene mixture and the ability to promote the ring-opening process of the morpholinone ring, which leads to the formation of the aldoacid (Scheme 3). Subsequent stages, including intermolecular attack of a binucleophile and intramolecular cyclization, can be catalyzed by both the ammonium cation and acetic acid. An experiment was carried out to study the reaction of ammonium acetate with pyridone 3b under reflux. According to the 1 H NMR spectrum of the obtained precipitate, it was found that the formation of an open-chain structure occurred (see Supplementary Materials). Although we did not detect the aldehyde group, a singlet of the methylene group and absence of the 3-CH proton of the lactol form were observed in the 1 H NMR spectrum.
The reaction of pyridone 3 with o-phenylenediamine proceeded in the presence of ammonium acetate at room temperature or under reflux and was accompanied by aromatization under the action of atmospheric oxygen (Scheme 4, Table 4). The intermediate C was not isolated in pure form, but was detected as by-products in all cases. Carrying out the reaction under argon did not allow the selective formation of compound C. This result can indicate that the oxidation additionally promotes the reaction leading to the most stable product 6.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 14 Scheme 3. The proposed mechanism of the ring-opening transformation.
The reaction of pyridone 3 with o-phenylenediamine proceeded in the presence of ammonium acetate at room temperature or under reflux and was accompanied by aromatization under the action of atmospheric oxygen (Scheme 4, Table 4). The intermediate C was not isolated in pure form, but was detected as by-products in all cases. Carrying out the reaction under argon did not allow the selective formation of compound C. This result can indicate that the oxidation additionally promotes the reaction leading to the most stable product 6.
To obtain compounds 6 in a pure form directly, the reaction was carried out at room temperature for 12 h and subsequent reflux for 2 h. In these conditions, the aromatization proceeded completely and pyridones 6 bearing the benzimidazole fragment were isolated in 33-91% yields. The reaction turned out to be sensitive to the nature of the acyl moiety, which probably determined the occurrence of side reactions. Pivaloyl pyridone 3e led to degradation products, which did not bear the t-Bu group. In the 1 H NMR spectra of compounds 6, the downfield singlet of methylene group was observed at δ 5.81-5.84 ppm due to the presence of two adjacent aromatic systems.   Table 4). The intermediate C was not isolated in pure form, but was detected as by-products in all cases. Carrying out the reaction under argon did not allow the selective formation of compound C. This result can indicate that the oxidation additionally promotes the reaction leading to the most stable product 6.
To obtain compounds 6 in a pure form directly, the reaction was carried out at room temperature for 12 h and subsequent reflux for 2 h. In these conditions, the aromatization proceeded completely and pyridones 6 bearing the benzimidazole fragment were isolated in 33-91% yields. The reaction turned out to be sensitive to the nature of the acyl moiety, which probably determined the occurrence of side reactions. Pivaloyl pyridone 3e led to degradation products, which did not bear the t-Bu group. In the 1 H NMR spectra of compounds 6, the downfield singlet of methylene group was observed at δ 5.81-5.84 ppm due to the presence of two adjacent aromatic systems.  To obtain compounds 6 in a pure form directly, the reaction was carried out at room temperature for 12 h and subsequent reflux for 2 h. In these conditions, the aromatization proceeded completely and pyridones 6 bearing the benzimidazole fragment were isolated in 33-91% yields. The reaction turned out to be sensitive to the nature of the acyl moiety, which probably determined the occurrence of side reactions. Pivaloyl pyridone 3e led to degradation products, which did not bear the t-Bu group. In the 1 H NMR spectra of compounds 6, the downfield singlet of methylene group was observed at δ 5.81-5.84 ppm due to the presence of two adjacent aromatic systems.
Thus, 3-hydroxy-3,4-dihydropyrido[2,1-c] [1,4]oxazine-1,8-diones have been synthesized and demonstrated to exist predominantly in the lactol tautomeric form. The new and convenient approach has been developed for the preparation of polycyclic pyridones based on the pyridomorpholinones via ring-opening reactions. The binucleophile linker and the nature of nucleophile centers strongly influence the reaction outcome. The most active binucleophiles in this heterocyclization process are ethylenediamine and 3-aminopropan-1-ol. It has been demonstrated that the reaction with o-phenylenediamine is followed by oxidation and the formation of benzimidazole-fused 4-pyridones.