Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.

In this work, we report an unprecedented dimerization reaction of 2H-azirine-2carboxylates to pyrimidine-4,6-dicarboxylates under heating in air with tertiary amine -triethylamine (Scheme 1, reaction 3). In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and the other one across the C=N bond. The detailed experimental and theoretical (DFT calculations) study of the reaction mechanism was carried out which allowed identification of the key reaction intermediates-N,Ndiethylhydroxylamine and aminooxyaziridine derivative. 2 Barroso, Kascheres 1999 Eremeev at al. 1979 Alves at al. 2003 Scheme 1. Reactions of 2H-azirines with N-nucleophiles [8,9,20].

Synthesis of Pyrimidines
In search of effective applications of 2H-azirines for the synthesis of new pyrimidine derivatives, we carried out a reaction of azirine 1a with ethyl isocyanoacetate in the presence of bases (Scheme 2). We assumed formation of pyrimidine A via a base-catalyzed (3+2)-cycloaddition of the isocyanide to the azirine followed by the ring expansion. To our surprise, after prolonged heating in the presence of triethylamine, dihydropyrimidine 2a and pyrimidine 3a were found in the reaction mixture instead of the expected pyrimidine A. Compounds 2a and 3a result from the dimerization of the starting azirine and do not comprise structural fragments of the ethyl isocyanoacetate. The same results were obtained when an analogous reaction was carried out in the absence of ethyl isocyanoacetate. Scheme 1. Reactions of 2H-azirines with N-nucleophiles [8,9,20].

Synthesis of Pyrimidines
In search of effective applications of 2H-azirines for the synthesis of new pyrimidine derivatives, we carried out a reaction of azirine 1a with ethyl isocyanoacetate in the presence of bases (Scheme 2). We assumed formation of pyrimidine A via a base-catalyzed (3+2)cycloaddition of the isocyanide to the azirine followed by the ring expansion. To our surprise, after prolonged heating in the presence of triethylamine, dihydropyrimidine 2a and pyrimidine 3a were found in the reaction mixture instead of the expected pyrimidine A. Compounds 2a and 3a result from the dimerization of the starting azirine and do not comprise structural fragments of the ethyl isocyanoacetate. The same results were obtained when an analogous reaction was carried out in the absence of ethyl isocyanoacetate. We tested various conditions to increase the yield of pyrimidine 3a and to get data for understanding the reaction mechanism (Table 1). The reactions were carried out under air in closed vials. To simplify the analysis, after complete conversion of the azirine, the reaction mixtures were treated with acetic acid (2 eqv.) and bubbled with air to oxidize dihydropyrimidine 2a into aromatic pyrimidine 3a. First, the reaction in the presence of NEt3 at 70 °С, but without the isocyanide, was carried out, and pyrimidine 3a was formed in 48% yield, along with methyl hippurate 4a (21%) (entry 1). The reaction was found to be temperature-sensitive. The reaction at 100 °С provided pyrimidine 3a in just 22% yield (entry 2), while at 40 °С it did not occur at all (entry 3). Noteworthily, the formation of pyrimidine 3a was not observed in the absence of the base, and the azirine was completely recovered (entry 4). The decrease in the NEt3 amount led to a slight decrease in yield of pyrimidine 3a (entry 5). With a stronger nitrogen base such as 1, 8diazabicyclo[5.4.0]undec-7-ene (DBU), the reaction gave lower yield (entry 6), but proceeded much more rapidly than with NEt3. When pyridine, DABCO, DIPEA, dimethylaminopyridine (DMAP), morpholine, 4-methylpiperidine, N-methylpiperidine, pyrrolidine, imidazole, piperazine, or hexamethyldisilazane (HMDS) were used as a base, the reaction did not proceed at all. Since there was no correlation between the conversion of the azirine and the base strength, the role of Et3N did not lie in a simple basic catalysis. The use of t BuOK caused rapid unselective decomposition of 1a (entry 7). The reaction with NEt3 proceeded much more slowly in low-polar or non-polar solvents such as toluene, acetone, DCE, or 1,4-dioxane (entries [8][9][10][11]. To check the formation of radical intermediates in the reaction of 1a with NEt3, experiments with such additives as (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,2′-azobis(2-methylpropionitrile) (AIBN), and 1,1′-azobis(cyclohexanecarbonitrile) (ACHN) were conducted (entries [12][13][14]. The former fully suppressed the formation of pyrimidine, while the latter accelerated the reaction and resulted in higher yield of pyrimidine 3a. It was also found that azirine 1a did not react with AIBN in the absence of NEt3 (entry 15). The use of another radical initiator, benzoyl peroxide, did not give the pyrimidine (entry 16). Finally, no reaction took place under an argon atmosphere, which definitely indicates the participation of oxygen in the reaction (entry 17). Thus, the optimal conditions for the synthesis of pyrimidine 3a were found to be heating azirine 1a with 2.6 eqv. of triethylamine at 70 °С in acetonitrile in the presence of 1 eqv. of AIBN or ACHN under air. We tested various conditions to increase the yield of pyrimidine 3a and to get data for understanding the reaction mechanism (Table 1). The reactions were carried out under air in closed vials. To simplify the analysis, after complete conversion of the azirine, the reaction mixtures were treated with acetic acid (2 eqv.) and bubbled with air to oxidize dihydropyrimidine 2a into aromatic pyrimidine 3a. First, the reaction in the presence of NEt 3 at 70 • C, but without the isocyanide, was carried out, and pyrimidine 3a was formed in 48% yield, along with methyl hippurate 4a (21%) (entry 1). The reaction was found to be temperature-sensitive. The reaction at 100 • C provided pyrimidine 3a in just 22% yield (entry 2), while at 40 • C it did not occur at all (entry 3). Noteworthily, the formation of pyrimidine 3a was not observed in the absence of the base, and the azirine was completely recovered (entry 4). The decrease in the NEt 3 amount led to a slight decrease in yield of pyrimidine 3a (entry 5). With a stronger nitrogen base such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), the reaction gave lower yield (entry 6), but proceeded much more rapidly than with NEt 3 . When pyridine, DABCO, DIPEA, dimethylaminopyridine (DMAP), morpholine, 4-methylpiperidine, N-methylpiperidine, pyrrolidine, imidazole, piperazine, or hexamethyldisilazane (HMDS) were used as a base, the reaction did not proceed at all. Since there was no correlation between the conversion of the azirine and the base strength, the role of Et 3 N did not lie in a simple basic catalysis. The use of t BuOK caused rapid unselective decomposition of 1a (entry 7). The reaction with NEt 3 proceeded much more slowly in low-polar or non-polar solvents such as toluene, acetone, DCE, or 1,4-dioxane (entries [8][9][10][11]. To check the formation of radical intermediates in the reaction of 1a with NEt 3 , experiments with such additives as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,2azobis(2-methylpropionitrile) (AIBN), and 1,1 -azobis(cyclohexanecarbonitrile) (ACHN) were conducted (entries [12][13][14]. The former fully suppressed the formation of pyrimidine, while the latter accelerated the reaction and resulted in higher yield of pyrimidine 3a. It was also found that azirine 1a did not react with AIBN in the absence of NEt 3 (entry 15). The use of another radical initiator, benzoyl peroxide, did not give the pyrimidine (entry 16). Finally, no reaction took place under an argon atmosphere, which definitely indicates the participation of oxygen in the reaction (entry 17). Thus, the optimal conditions for the synthesis of pyrimidine 3a were found to be heating azirine 1a with 2.6 eqv. of triethylamine at 70 • C in acetonitrile in the presence of 1 eqv. of AIBN or ACHN under air.  Then, under the optimized conditions, the reaction scope was evaluated (Scheme 3). Pyrimidines bearing electron-donating or weak electron-withdrawing groups in the phenyl ring were obtained, but in lower yields than the parent pyrimidine 3a. These results are likely due to a complex reaction mechanism (see below). The pyrimidines substituted by the 2-naphthyl or biphenyl group were also prepared by this method in 20% and 30% yield, respectively. The pyrimidine with tert-butyl ester groups was prepared in 34% yield. Despite the complete consumption of starting azirines 1j-1n, the pyrimidines possessing strong electron-withdrawing groups in the phenyl ring as well as pyrimidines with Ph, Me, CHO groups at the C4 and C6 of the ring could not be obtained by this method. Then, under the optimized conditions, the reaction scope was evaluated (Scheme 3). Pyrimidines bearing electron-donating or weak electron-withdrawing groups in the phenyl ring were obtained, but in lower yields than the parent pyrimidine 3a. These results are likely due to a complex reaction mechanism (see below). The pyrimidines substituted by the 2-naphthyl or biphenyl group were also prepared by this method in 20% and 30% yield, respectively. The pyrimidine with tert-butyl ester groups was prepared in 34% yield. Despite the complete consumption of starting azirines 1j-1n, the pyrimidines possessing strong electron-withdrawing groups in the phenyl ring as well as pyrimidines with Ph, Me, CHO groups at the C4 and C6 of the ring could not be obtained by this method.

Study of the Reaction Mechanism
Originally, we assumed that the reaction starts with a nucleophilic addition of triethylamine to the C=N bond of the azirine (Scheme 4, reaction 1). However, quantum chemical calculations by the DFT method (rwb97xd/6-311+g(d,p)) showed that the adduct of azirine 1a with trimethylamine (compound 5) is extremely unstable and must decompose without a barrier into the starting compounds. The formation of pyrimidine 3a was also observed in the presence of DBU (Table 1, entry 6). In contrast to bulky triethylamine, DBU can undergo nucleophilic addition to multiple bonds [28], and its reaction with azirine 1a could, in principle, start with the addition to the C=N bond. Another possible first step, the elimination of a proton from the C2 of azirine 1a, should lead to the formation of the antiaromatic azirinyl anion 6 (Scheme 4, reaction 2). Taking into account the complete inactivity of most tested nitrogen bases in the reaction, the deprotonation stage seems unlikely.

Study of the Reaction Mechanism
Originally, we assumed that the reaction starts with a nucleophilic addition triethylamine to the C=N bond of the azirine (Scheme 4, reaction 1). However, quantu chemical calculations by the DFT method (rwb97xd/6-311+g(d,p)) showed that the addu of azirine 1a with trimethylamine (compound 5) is extremely unstable and mu decompose without a barrier into the starting compounds. The formation of pyrimidin 3a was also observed in the presence of DBU (Table 1, entry 6). In contrast to bulk triethylamine, DBU can undergo nucleophilic addition to multiple bonds [28], and i reaction with azirine 1a could, in principle, start with the addition to the C=N bon Another possible first step, the elimination of a proton from the C2 of azirine 1a, shoul lead to the formation of the antiaromatic azirinyl anion 6 (Scheme 4, reaction 2). Takin into account the complete inactivity of most tested nitrogen bases in the reaction, th deprotonation stage seems unlikely. Since the addition of a radical initiator resulted in an increase in the reaction rate and product yield (see Table 1, entries 13, 14), we studied the reaction mixture containing azirine 1a, triethylamine, and acetonitrile by electron paramagnetic resonance spectroscopy (EPR). The experiment showed the presence of triplet of quintets, which corresponds to the nitroxyl radical Et2N-O· (Figure 1). This fact indicates that (a) radical Since the addition of a radical initiator resulted in an increase in the reaction rate and product yield (see Table 1, entries 13, 14), we studied the reaction mixture containing azirine 1a, triethylamine, and acetonitrile by electron paramagnetic resonance spectroscopy (EPR). The experiment showed the presence of triplet of quintets, which corresponds to the nitroxyl radical Et 2 N-O· (Figure 1). This fact indicates that (a) radical processes can take place in the formation of pyrimidines, and (b) not only triethylamine itself but also its oxidation products can be involved in the azirine dimerization process. The formation of the nitroxyl radical Et 2 N-O· from triethylamine in acetonitrile has been described in the literature [29,30].

Scheme 4. Control experiments.
Since the addition of a radical initiator resulted in an increase in the reaction rate and product yield (see Table 1, entries 13, 14), we studied the reaction mixture containing azirine 1a, triethylamine, and acetonitrile by electron paramagnetic resonance spectroscopy (EPR). The experiment showed the presence of triplet of quintets, which corresponds to the nitroxyl radical Et2N-O· (Figure 1). This fact indicates that (a) radical processes can take place in the formation of pyrimidines, and (b) not only triethylamine itself but also its oxidation products can be involved in the azirine dimerization process. The formation of the nitroxyl radical Et2N-O· from triethylamine in acetonitrile has been described in the literature [29,30]. Encouraged by this finding, we tested N,N-diethylhydroxylamine (7) as a closer potential precursor of the nitroxyl radical Et2N-O· (Scheme 4). To our surprise, the reaction of azirine 1a with 2 eqv. of hydroxylamine 7 at 70 °C was completed in 1 h. Pyrimidine 3a was not formed, but three other products were isolated: hippuric acid derivatives 4a-4c (reaction 3). The reaction proceeded similarly at room temperature in CDCl3 (reaction 4). Encouraged by this finding, we tested N,N-diethylhydroxylamine (7) as a closer potential precursor of the nitroxyl radical Et 2 N-O· (Scheme 4). To our surprise, the reaction of azirine 1a with 2 eqv. of hydroxylamine 7 at 70 • C was completed in 1 h. Pyrimidine 3a was not formed, but three other products were isolated: hippuric acid derivatives 4a-4c (reaction 3). The reaction proceeded similarly at room temperature in CDCl 3 (reaction 4). The detailed 1 H NMR monitoring of the reaction of azirine 1a with hydroxylamine 7 showed that an unstable intermediate was formed initially, within 10 min, and then transformed slowly to the final hippurates 4a-4c ( Figure 2). The NMR spectra at-40 • C of the crude reaction mixture (see Supporting information for details) was used to assign a structure of (aminooxy)aziridine 8 to the observed intermediate (a mixture of two diastereomers) (Scheme 4, reaction 4). To the best of our knowledge, aziridines with such a substituent have not been reported in the literature.
We hypothesized that unstable aziridine 8 was one of the two components that form the final pyrimidine. Another component, according to our assumption, is the starting azirine. The absence of pyrimidine derivatives 2a and 3a among the products of the reactions 3 and 4 in Scheme 4 can be explained by the rapid reaction of hydroxylamine 7 with azirine 1a, and as a result, removing the latter from the sphere of the reaction. To test this assumption, we reacted azirine 1a with 0.5 eqv. of hydroxylamine 7 (Scheme 4, reaction 5), which ensured the simultaneous presence of aziridine 8 and azirine 1a in the reaction mixture. In this case, pyrimidine 3a indeed was formed, confirming our assumption.
showed that an unstable intermediate was formed initially, within 10 min, and then transformed slowly to the final hippurates 4a-4c (Figure 2). The NMR spectra at-40 °C of the crude reaction mixture (see Supporting information for details) was used to assign a structure of (aminooxy)aziridine 8 to the observed intermediate (a mixture of two diastereomers) (Scheme 4, reaction 4). To the best of our knowledge, aziridines with such a substituent have not been reported in the literature. We hypothesized that unstable aziridine 8 was one of the two components that form the final pyrimidine. Another component, according to our assumption, is the starting azirine. The absence of pyrimidine derivatives 2a and 3a among the products of the reactions 3 and 4 in Scheme 4 can be explained by the rapid reaction of hydroxylamine 7 with azirine 1a, and as a result, removing the latter from the sphere of the reaction. To test this assumption, we reacted azirine 1a with 0.5 eqv. of hydroxylamine 7 (Scheme 4, reaction 5), which ensured the simultaneous presence of aziridine 8 and azirine 1а in the reaction mixture. In this case, pyrimidine 3a indeed was formed, confirming our assumption.
Based on the above observations, the following mechanism for the formation of dihydropyrimidine 2a was proposed (Scheme 5). The first stage is a radical oxidation of triethylamine by air oxygen facilitated by addition of a radical initiator and resulted finally in the formation of N,N-diethylhydroxylamine (7). The latter can add to azirine 1a as is or in the form of amine oxide 7′ to produce aziridine 8. Then, aziridine 8 can undergo ring opening across the C-C bond to form azomethine ylide 9. The latter can be evidenced by the presence of hippurate 4a in the reaction mixture (Table 1, entry 1), which can be interpreted as a hydrolysis product of azomethine ylide 9. The 1,3-dipolar cycloaddition Based on the above observations, the following mechanism for the formation of dihydropyrimidine 2a was proposed (Scheme 5). The first stage is a radical oxidation of triethylamine by air oxygen facilitated by addition of a radical initiator and resulted finally in the formation of N,N-diethylhydroxylamine (7). The latter can add to azirine 1a as is or in the form of amine oxide 7 to produce aziridine 8. Then, aziridine 8 can undergo ring opening across the C-C bond to form azomethine ylide 9. The latter can be evidenced by the presence of hippurate 4a in the reaction mixture (Table 1, entry 1), which can be interpreted as a hydrolysis product of azomethine ylide 9. The 1,3-dipolar cycloaddition of azomethine ylide 9 to azirine 1a affords bicyclic intermediate 10. The elimination of hydroxylamine 7 from compound 10 followed by the base-catalyzed aziridine ring expansion gives rise to dihydropyrimidine 2a. The last stages of this mechanistic scheme are partly supported by the known literature data on the synthesis of pyrimidines through the (3+2)-cycloaddition of azomethine ylide to azirine followed by aziridine ring opening [24,26]. The hippurates 4b and 4c are likely formed via the HONEt 2 -promoted elimination of NHEt 2 from aziridine 8 to form imine 12 followed by the nucleophilic addition of N,N-diethylhydroxylamine or diethylamine to the C=N bond. We assume that the success in synthesis of pyrimidines 2a/3a is based on suitable reaction conditions that provide a slow generation of N,N-diethylhydroxylamine and accordingly ensure low concentrations of aziridine 8 and azomethine ylide 9. The latter can trap the azirine 1a that is present in large excess. [24,26]. The hippurates 4b and 4c are likely formed via the HONEt2-promoted elimination of NHEt2 from aziridine 8 to form imine 12 followed by the nucleophilic addition of N,Ndiethylhydroxylamine or diethylamine to the C=N bond. We assume that the success in synthesis of pyrimidines 2a/3a is based on suitable reaction conditions that provide a slow generation of N,N-diethylhydroxylamine and accordingly ensure low concentrations of aziridine 8 and azomethine ylide 9. The la er can trap the azirine 1a that is present in large excess.

Scheme 5. Plausible reaction mechanism.
The key stages of the pyrimidine formation mechanism were calculated by the density functional theory (DFT) method (rwb97xd/6-311+g(d,p) with PCM solvent model for acetonitrile at 343 K) (Figures 3 and 4). The formation of aziridine 8 theoretically can occur in several alternative ways: the addition of N,N-diethylhydroxylamine 7, its tautomer, amine oxide 7′, or the radical species Et2N-O·, observed in the EPR spectrum. It was found that the nucleophilic addition of the hydroxylamine tautomer 7 from a less hindered side of the azirine ring is less favorable (TS1, ∆G ≠ 50.6 kcal/mol, see Supporting Information for details) than the addition of the isomeric amine oxide 7′. The a ack of the la er at a less hindered side of the azirine to form aziridine anti-8 (TS1a, 12.4 kcal/mol) has a lower barrier than the formation of aziridine syn-8 (TS1b, 16.6 kcal/mol). If calculated from hydroxylamine tautomer 7, these barriers are 20.8 and 25.0 kcal/mol, respectively. Both aziridines syn-8 and anti-8 are slightly more stable than starting azirine 1a and hydroxylamine 7 and can be formed reversibly. The a ack of the radical Et2N-O· to form N-centered aziridine radical takes place with the activation barrier of 44.7 kcal/mol (ub3lyp/6-31g(d) with PCM solvent model for acetonitrile at 343 K) and is hardly possible (see Table S2 in Supporting Information for details). Conrotatory ring opening of aziridines anti-8 (TS2a) and syn-8 (TS2b) across the C-C bond to form azomethine ylides Scheme 5. Plausible reaction mechanism.
The key stages of the pyrimidine formation mechanism were calculated by the density functional theory (DFT) method (rwb97xd/6-311+g(d,p) with PCM solvent model for acetonitrile at 343 K) (Figures 3 and 4). The formation of aziridine 8 theoretically can occur in several alternative ways: the addition of N,N-diethylhydroxylamine 7, its tautomer, amine oxide 7 , or the radical species Et 2 N-O·, observed in the EPR spectrum. It was found that the nucleophilic addition of the hydroxylamine tautomer 7 from a less hindered side of the azirine ring is less favorable (TS1, ∆G = 50.6 kcal/mol, see Supporting Information for details) than the addition of the isomeric amine oxide 7 . The attack of the latter at a less hindered side of the azirine to form aziridine anti-8 (TS1a, 12.4 kcal/mol) has a lower barrier than the formation of aziridine syn-8 (TS1b, 16.6 kcal/mol). If calculated from hydroxylamine tautomer 7, these barriers are 20.8 and 25.0 kcal/mol, respectively. Both aziridines syn-8 and anti-8 are slightly more stable than starting azirine 1a and hydroxylamine 7 and can be formed reversibly. The attack of the radical Et 2 N-O· to form N-centered aziridine radical takes place with the activation barrier of 44.7 kcal/mol (ub3lyp/6-31g(d) with PCM solvent model for acetonitrile at 343 K) and is hardly possible (see Table S2 in Supporting Information for details). Conrotatory ring opening of aziridines anti-8 (TS2a) and syn-8 (TS2b) across the C-C bond to form azomethine ylides E-9 and Z-9 has barriers of 28.6 and 30.1 kcal/mol, respectively, which can be overcome under heating. Azomethine ylides 9 turned out to be slightly less stable than aziridines 8. The 1,3-dipolar cycloaddition of azomethine ylides E-9 and Z-9 to azirine 1a to form azirinopyrrolidines anti-10 (TS3a) and syn-10 (TS3b) has rather low barriers, 19.0 and 21.0 kcal/mol, respectively, and both are thermodynamically favorable reactions. Subsequent elimination of amine oxide 7 from anti-10 (TS4a) and syn-10 (TS4b) to give azirinopyrroline 11 has barriers of 19.1 and 21.2 kcal/mol correspondingly. Azirinopyrroline 11 should be formed reversibly; further deprotonation with a base shifts the equilibrium to the right. Thus, the proposed mechanism for the formation of dihydropyrimidines is well confirmed by the DFT calculations. kcal/mol, respectively, and both are thermodynamically favorable reactions. Subsequent elimination of amine oxide 7′ from anti-10 (TS4a) and syn-10 (TS4b) to give azirinopyrroline 11 has barriers of 19.1 and 21.2 kcal/mol correspondingly. Azirinopyrroline 11 should be formed reversibly; further deprotonation with a base shifts the equilibrium to the right. Thus, the proposed mechanism for the formation of dihydropyrimidines is well confirmed by the DFT calculations.

General Instrumentation
Melting points were determined on a melting-point apparatus and were uncorrected. NMR spectra were recorded on Bruker Avance 400 and Bruker Avance 500 spectrometers in CDCl3. 1 H and 13 C{ 1 H} NMR spectra were calibrated according to the residual signal of CDCl3 (δ = 7.26 ppm) and the carbon atom signal of CDCl3 (δ = 77.0 ppm), respectively.

General Instrumentation
Melting points were determined on a melting-point apparatus and were uncorrected. NMR spectra were recorded on Bruker Avance 400 and Bruker Avance 500 spectrometers in CDCl 3 . 1 H and 13 C{ 1 H} NMR spectra were calibrated according to the residual signal of CDCl 3 (δ = 7.26 ppm) and the carbon atom signal of CDCl 3 (δ = 77.0 ppm), respectively. The following abbreviations were used: s-singlet, d-doublet, t-triplet, q-quartet, br.sbroad singlet, m-multiplet. EPR experiment was carried out on a Bruker Elexsys E580 with a modulation amplitude of 1 G and at 323 K. High-resolution mass spectra were recorded with a Bruker maXis HRMS-QTOF, electrospray ionization. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO 2 ALUGRAM SIL G/UV254. Column chromatography was performed on silica gel 60 M (0.04-0.063 mm). Acetonitrile was distilled from phosphorus pentoxide and redistilled from potassium carbonate, and 2,2 -azobis(2-methylpropionitrile) (AIBN) and 1,1 -azobis(cyclohexanecarbonitrile) (ACHN) were purchased and used as received . Azirines 1a,b,d,i,j are known compounds, which were prepared by using the reported procedure [31].

Synthesis and Characterization of 5-Methoxyisoxazoles
General procedure. To a stirred suspension of an isoxazol-5(4H)-one (4.6 mmol) in dry diethyl ether (40 mL), a solution of diazomethane in diethyl ether (50 mL), prepared from N-methyl-N-nitrosourea (9.2 mmol) and potassium hydroxide pellets (42 mmol), was added dropwise at 0 • C. The resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was subjected to column chromatography on silica gel (eluent: hexane-ethylacetate, 3:1) to give a 5-methoxyisoxazole.

EPR Detection of Nitroxyl Radical Et 2 N-O·
The reaction mixture of azirine 1a (60 mg, 0.34 mmol) and triethylamine (90 mg, 0.88 mmol) in acetonitrile (1.5 mL) was stirred at 70 • C for 12 h. After cooling, a few drops of water were added to this reaction mixture to increase the signal resolution. The mixture was transferred into an EPR vial. EPR spectrum of this reaction mixture at 50 • C showed the presence of nitroxyl radical Et 2 N-O·.

Conclusions
An unprecedented dimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air has been described. In this reaction, one azirine molecule undergoes cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key stages of the reaction mechanism includes oxidation of triethylamine by atmospheric oxygen into N,N-diethylhydroxylamine, formation of (aminooxy)aziridine, generation of azomethine ylide and its further 1,3-dipolar cycloaddition to the second azirine molecule. Success in the synthesis of pyrimidines is based on suitable reaction conditions that provide slow generation of N,N-diethylhydroxylamine. Addition of a radical initiator accelerated the reaction and resulted in higher yield of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.