Next Article in Journal
Membrane Lipid Derivatives: Roles of Arachidonic Acid and Its Metabolites in Pancreatic Physiology and Pathophysiology
Next Article in Special Issue
Formal [3 + 2] Cycloaddition of α-Imino Esters with Azo Compounds: Facile Construction of Pentasubstituted 1,2,4-Triazoline Skeletons
Previous Article in Journal
All-Solid-State Carbon Black Paste Electrodes Modified by Poly(3-octylthiophene-2,5-diyl) and Transition Metal Oxides for Determination of Nitrate Ions
Previous Article in Special Issue
Chiral Indolizinium Salts Derived from 2-Pyridinecarbaldehyde—First Diastereoselective Syntheses of (−)-1-epi-lentiginosine
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 11
10.3390/molecules28114315
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Timofei N. Zakharov
,
Pavel A. Sakharov
,
Mikhail S. Novikov
,
Alexander F. Khlebnikov
and
Nikolai V. Rostovskii
*
Institute of Chemistry, St. Petersburg State University, 7/9 Universitetskaya Nab., 199034 St. Petersburg, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(11), 4315; https://doi.org/10.3390/molecules28114315
Submission received: 4 May 2023 / Revised: 18 May 2023 / Accepted: 22 May 2023 / Published: 24 May 2023
(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

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.

1. Introduction

The 2H-azirines are the simplest unsaturated nitrogen heterocycles, possessing great potential in organic synthesis [1,2,3,4,5,6,7,8,9,10]. Mainly, this is due to the presence of an electrophilic C=N bond in a highly strained azirine ring, which can readily undergo addition of various nucleophiles. The reactions of azirines with heteroatomic nucleophiles (alcohols, thiols, phosphites, primary and secondary amines, NH-heterocycles) and C-nucleophiles (some cyclic enols, Grignard reagents) stop at the formation of three-membered heterocycles–aziridines (Scheme 1, reaction 1) [11,12,13,14,15,16,17]. The reactions of azirines with acyclic enols proceed via transient aziridines to form finally, after cyclization, pyrrole derivatives [18,19]. In some cases, addition of O- and N-nucleophiles to azirines also leads to unstable aziridines that readily undergo ring opening across the C-C bond. Such a scenario is realized for 3-(azirinyl)acrylates affording 2-azabutadienes as final products [20] (Scheme 1, reaction 2). Reactions of azirines with tertiary amines have not been reported to date.
In this work, we report an unprecedented dimerization reaction of 2H-azirine-2-carboxylates 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,N-diethylhydroxylamine and aminooxyaziridine derivative.
Interestingly, several types of azirine dimerization have been reported previously [21,22,23,24], some of which afforded pyrimidine derivatives. The palladium-catalyzed reaction of 2,3-diphenylazirine gave two types of dimerization products—dihydropyrimidine and diazabicyclohexene [23]. A one-pot procedure for the synthesis of pyrimidine derivatives from α-azidocinnamates has been developed via in situ photochemical formation of 1,3-diazabicyclo[3.1.0]hex-3-enes [24]. It should be noted that this reaction provides pyrimidine-4,5-dicarboxylates that are isomers of the pyrimidines obtained in the current work. In addition, several examples of the formation of a pyrimidine ring from azirines without dimerization are known. In particular, the reaction of methyl 3-(2-methyl-3-phenyl-2H-azirin-2-yl)acrylates with formamidine gave pyrimidines [25]. Heating ethyl 3-phenylaziridine-2-carboxylate and 2-bromo-2H-azirine in toluene afforded pyrimidine in low yield via 1,3-dipolar cycloaddition of the azomethine ylide, generated from the aziridine, and subsequent transformation of the cycloadduct [26]. The synthesis of pyrimidines by the Cu(I)-catalyzed reaction of 2-methoxy-2H-azirines with oxime acetates has recently been reported [27].

2. Results and Discussion

2.1. 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 °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 NEt3 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 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 tBuOK 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 8–11). To check the formation of radical intermediates in the reaction of 1a with NEt3, experiments with such additives as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,2′-azobis(2-methylpropionitrile) (AIBN), and 1,1′-azobis(cyclohexanecarbonitrile) (ACHN) were conducted (entries 12–14). 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 °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.

2.2. 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.
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). The detailed 1H 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.
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 HONEt2-promoted elimination of NHEt2 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.
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) (Figure 3 and Figure 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 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 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 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.

3. Materials and Methods

3.1. 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. 1H and 13C{1H} 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. The following abbreviations were used: s—singlet, d—doublet, t—triplet, q—quartet, br.s—broad 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 SiO2 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].

3.2. 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.
  • 5-Methoxy-3-(naphthalen-2-yl)isoxazole [32]. Obtained as a pink solid (320 mg, 31%) according to the general procedure. Mp: 129–130 °C (lit. 128–129 °C [32]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.21 (s, 1H), 8.00–7.84 (m, 4H), 7.63–7.50 (m, 2H), 5.69 (s, 1H), 4.09 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 174.6, 164.3, 134.1, 133.2, 128.6, 128.5, 127.8, 127.0 (2C), 126.6, 126.3, 123.5, 75.5, 58.9.
  • 3-(Biphenyl-4-yl)-5-methoxyisoxazole. Obtained as a colorless solid (740 mg, 64%) according to the general procedure. Mp: 147–148 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.88–7.83 (m, 2H), 7.73–7.68 (m, 2H), 7.67–7.63 (m, 2H), 7.52–7.46 (m, 2H), 7.43–7.38 (m, 1H), 5.59 (s, 1H), 4.09 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 174.5, 163.9, 142.9, 140.3, 128.9, 128.5, 127.8, 127.5, 127.1, 126.9, 75.4, 58.8. HRMS (ESI-TOF) calculated for C16H13NO2 [M + Na]+ 274.0838; found 274.0843.
  • 5-Methoxy-3-(quinolin-2-yl)isoxazole. Obtained as a colorless solid (730 mg, 70%) according to the general procedure. Mp: 109–110 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.25 (d, J = 8.6 Hz, 1H), 8.20–8.04 (m, 2H), 7.87 (d, J = 8.1, 1H), 7.83–7.71 (m, 1H), 7.66–7.54 (m, 1H), 6.13 (s, 1H), 4.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 174.9, 165.3, 148.9, 148.0, 136.8, 129.9, 129.7, 128.4, 127.7, 127.3, 118.5, 76.3, 59.2. HRMS (ESI-TOF) calculated for C13H10N2NaO2 [M + Na]+ 249.0634; found 249.0638.

3.3. Synthesis and Characterization of 2H-Azirines 1

General procedure. FeCl2·4H2O (10–40 mol%) was added to a solution of a 3-aryl-5-alkoxyisoxazole (1 eqv.) in acetonitrile (2.3–7.8 mL/mmol of 3-aryl-5-alkoxyisoxazole), and the resulting mixture was stirred at room temperature for 2 h (24 h for azirines 1g,h) until full consumption of the isoxazole (monitored by TLC, eluent: hexane–ethylacetate, 4:1). After completion of the reaction, the solution was filtered through a pad of Celite, concentrated in vacuo, and the product was purified by flash column chromatography on silica gel (eluent: hexane–ethylacetate, 4:1) to give azirines 1a–k.
  • Methyl 3-(3,4-dimethoxyphenyl)-2H-azirine-2-carboxylate (1c). Obtained as a colorless solid (97 mg, yield 97%) from 3-(3,4-dimethoxyphenyl)-5-methoxyisoxazole [33] according to the general procedure (40 mol% FeCl2·4H2O, 1.5 mL of acetonitrile). Mp: 96–97 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.46–7.42 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.97 (s, 3H), 3.75 (s, 3H), 2.84 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 172.3, 157.5, 153.8, 149.7, 125.4, 114.6, 111.6, 111.1, 56.18, 56.17, 52.2, 29.6. HRMS (ESI-TOF) calculated for C12H13NNaO4 [M + Na]+ 258.0737; found 258.0743.
  • Methyl 3-(4-chlorophenyl)-2H-azirine-2-carboxylate (1e) [34]. Obtained as a colorless solid (49 mg, yield 98%) from 3-(4-chlorophenyl)-5-methoxyisoxazole [35] according to the general procedure (10 mol% FeCl2·4H2O, 1.0 mL of acetonitrile). Mp: 66–67 °C (lit. 63.4–64.2 °C [34]). 1H NMR (400 MHz, CDCl3), δ, ppm: 7.88–7.82 (m, 2H), 7.61–7.56 (m, 2H), 3.77 (s, 3H), 2.89 (s, 1H).
  • Methyl 3-(4-(dimethylamino)phenyl)-2H-azirine-2-carboxylate (1f). Obtained as a yellow solid (256 mg, yield 80%) from 3-(4-(dimethylamino)phenyl)-5-methoxyisoxazole [36] according to the general procedure (10 mol% FeCl2·4H2O, 5 mL of acetonitrile). Mp: 120–121 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.76–7.71 (m, 2H), 6.81–6.76 (m, 2H), 3.74 (s, 3H), 3.11 (s, 6H), 2.76 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 173.1, 156.2, 153.8, 132.4, 111.6, 108.4, 52.1, 40.1, 28.9. HRMS (ESI-TOF) calculated for C12H14N2NaO2 [M + Na]+ 241.0947; found 241.0951.
  • Methyl 3-(naphthalen-2-yl)-2H-azirine-2-carboxylate (1g) [37]. Obtained as a colorless solid (600 mg, yield 90%) from 5-methoxy-3-(naphthalen-2-yl)isoxazole according to the general procedure (40 mol% FeCl2·4H2O, 15 mL of acetonitrile). Mp: 67–68 °C (lit. 69–70 °C [37]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.33 (s, 1H), 8.04–7.93 (m, 4H), 7.69–7.60 (m, 2H), 3.79 (s, 3H), 2.97 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 172.1, 158.5, 135.8, 132.9, 132.6, 129.4, 129.12, 129.08, 128.1, 127.3, 124.7, 119.5, 52.3, 29.7. HRMS (ESI-TOF) calculated for C14H11NNaO2 [M + Na]+ 248.0682; found 248.0685.
  • Methyl 3-(biphenyl-4-yl)-2H-azirine-2-carboxylate (1h). Obtained as a colorless solid (195 mg, yield 99%) from 3-(biphenyl-4-yl)-5-methoxyisoxazole according to the general procedure (40 mol% FeCl2·4H2O, 6 mL of acetonitrile). Mp: 104–105 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.03–7.93 (m, 2H), 7.87–7.79 (m, 2H), 7.72–7.62 (m, 2H), 7.55–7.49 (m, 2H), 7.49–7.39 (m, 1H), 3.78 (s, 3H), 2.91 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 172.1, 158.2, 146.8, 139.5, 131.0, 129.1, 128.6, 128.0, 127.3, 120.9, 52.3, 29.5. HRMS (ESI-TOF) calculated for C16H13NNaO2 [M + Na]+ 274.0838; found 274.0839.
  • Methyl 3-(quinolin-2-yl)-2H-azirine-2-carboxylate (1k). Obtained as a brown solid (50 mg, yield 40%) from 5-methoxy-3-(quinolin-2-yl)isoxazole according to the general procedure (10 mol% FeCl2·4H2O, 3 mL of acetonitrile). Mp: 110–111 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.40 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.87–7.83 (m, 1H), 7.74–7.70 (m, 1H), 3.80 (s, 3H), 3.17 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 171.6, 160.9, 148.5, 142.7, 137.5, 130.8, 130.6, 129.4, 129.3, 127.8, 121.7, 52.5, 31.5. HRMS (ESI-TOF) calculated for C13H10N2NaO2 [M + Na]+ 249.0634; found 249.0632.

3.4. Reaction of Azirine 1a with Triethylamine

To a solution of azirine 1a (60 mg, 0.34 mmol) in acetonitrile (1.5 mL), triethylamine (95 mg, 0.94 mmol, 2.6 eqv.) was added. The reaction mixture was heated at 70 °C under stirring for 5 days until full consumption of the azirine (control by TLC, eluent: benzene–ethylacetate, 5:1). The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica gel (eluent: benzene–ethylacetate, 5:1) to give compounds 2a (12 mg, yield 20%) and 3a (18 mg, yield 31%).
  • Dimethyl 2,5-diphenyl-1,6-dihydropyrimidine-4,6-dicarboxylate (2a). Colorless oil. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.90–7.86 (m, 2H), 7.76 (br.s, 1H), 7.54–7.46 (m, 3H), 7.40–7.28 (m, 5H), 5.29 (br.s, 1H), 3.71 (s, 3H), 3.63 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 171.0, 163.6, 153.9, 137.2, 133.6, 131.1, 128.8 (2C), 128.0, 127.8, 126.8, 124.3, 118.9, 65.8, 52.41, 52.36. HRMS (ESI-TOF) calculated for C20H19N2O4 [M + H]+ 351.1339; found 351.1350.
  • Dimethyl 2,5-diphenylpyrimidine-4,6-dicarboxylate (3a) [38]. Mp: 160–161 °C (lit. 161–163 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.58–8.52 (m, 2H), 7.55–7.50 (m, 3H), 7.49–7.42 (m, 3H), 7.37–7.32 (m, 2H), 3.76 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 165.4, 163.5, 158.6, 135.8, 132.8, 131.6, 128.9, 128.7, 128.61, 128.58, 128.4, 127.8, 52.8.

3.5. Synthesis and Characterization of Pyrimidines 3

General procedure. A solution of an azirine (0.34 mmol, 1 eqv.), triethylamine (95 mg, 0.94 mmol, 2.6 eqv.), and AIBN or ACHN (0.34 mmol, 1 eqv.) in acetonitrile (1.5 mL) was stirred in a screw-cap tube at 70 °C for 3–7 days (monitored by TLC, eluent: ethylacetate–benzene, 1:1). Then the reaction mixture was bubbled with air until complete conversion of dihydropyrimidine to pyrimidine (about 20 min, monitored by TLC, eluent: ethylacetate–benzene, 1:1). After that, the reaction mixture was concentrated in vacuo, and the residue was subjected to column chromatography on silica gel to give pyrimidine.
  • Dimethyl 2,5-diphenylpyrimidine-4,6-dicarboxylate (3a) [38]. Obtained as a colorless solid (42 mg, yield 70%) according to the general procedure (initiator: ACHN, 3 days, eluent: benzene–ethylacetate, 5:1).
  • Dimethyl 2,5-di(p-tolyl)pyrimidine-4,6-dicarboxylate (3b) [38]. Obtained as a colorless solid (6 mg, yield 9%) according to the general procedure (initiator: AIBN, 7 days, eluent: hexane–ethylacetate, 2:1). Mp: 145–146 °C (lit. 144–146 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.47–8.40 (m, 2H), 7.36–7.30 (m, 2H), 7.27–7.19 (m, 4H), 3.78 (s, 6H), 2.46 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 165.7, 163.4, 158.6, 142.0, 138.8, 133.2, 129.8, 129.4, 129.2, 128.7, 128.5, 127.5, 52.8, 21.6, 21.4. HRMS (ESI-TOF) calculated for C22H20N2NaO4 [M + Na]+ 399.1315; found 399.1318.
  • Dimethyl 2,5-di(3,4-dimethoxyphenyl)pyrimidine-4,6-dicarboxylate (3c) [38]. Obtained as a pale yellow solid (20 mg, yield 27%) according to the general procedure (initiator: AIBN, 7 days, eluent: hexane–ethylacetate, 3:1). Mp: 163–165 °C (lit. 164–166 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.18 (dd, J = 8.5, 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.95–6.86 (m, 3H), 4.03 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.79 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 165.8, 162.9, 158.7, 152.2, 149.5, 149.1, 148.9, 128.7, 126.3, 125.0, 122.6, 121.5, 111.8, 111.1, 111.0, 110.8, 56.1, 56.00, 55.96, 55.8, 52.9.
  • Dimethyl 2,5-di(3,4-dimethylphenyl)pyrimidine-4,6-dicarboxylate (3d). Obtained as a colorless solid (25 mg, yield 36%) according to the general procedure (initiator: AIBN, 7 days, eluent: benzene–ethylacetate, 5:1). Mp: 173–174 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.30 (s, 1H), 8.29–8.24 (m, 1H), 7.31–7.25 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H), 7.09–7.04 (m, 1H), 3.79 (s, 6H), 2.39 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3), δ, ppm: 165.8, 163.4, 158.6, 140.7, 137.4, 136.9, 136.8, 133.5, 130.2, 130.0, 129.8, 129.7, 129.6, 127.3, 126.3, 126.0, 52.8, 19.9, 19.80, 19.76, 19.7. HRMS (ESI-TOF) calculated for C24H24N2NaO4 [M + Na]+ 427.1628; found 427.1631.
  • Dimethyl 2,5-di(4-chlorophenyl)pyrimidine-4,6-dicarboxylate (3e) [38]. Obtained as a bright-yellow solid (18 mg, yield 25%) according to the general procedure (initiator: AIBN, 4 days, eluent: hexane–ethylacetate, 3:1). Mp: 137–138 °C (lit. 139–140 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.52–8.49 (m, 2H), 7.51–7.49 (m, 2H), 7.46–7.44 (m, 2H), 7.28–7.26 (m, 2H), 3.80 (s, 6H).
  • Dimethyl 2,5-di(4-dimethylaminophenyl)pyrimidine-4,6-dicarboxylate (3f). Obtained as a bright-yellow solid (22 mg, yield 30%) according to the general procedure (initiator: AIBN, 7 days, eluent: hexane–ethylacetate, 2:1). Mp: 216–217 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.41–8.38 (m, 2H), 7.19–7.17 (m, 2H), 6.77–6.73 (m, 4H), 3.79 (s, 6H), 3.08 (s, 6H), 3.02 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3), δ, ppm: 166.4, 162.9, 158.5, 152.5, 150.3, 130.1, 129.5, 125.8, 123.7, 120.2, 112.0, 111.4, 52.7, 40.24, 40.29. HRMS (ESI-TOF) calculated for C24H26N4NaO4 [M + Na]+ 457.1846; found 457.1852.
  • Dimethyl 2,5-di(naphthalen-2-yl)pyrimidine-4,6-dicarboxylate (3g) [38]. Obtained as a pale-yellow solid (15 mg, yield 20%) according to the general procedure (initiator: ACHN, 6 days, eluent: benzene–ethylacetate, 5:1). Mp: 196–197 °C (lit. 197–198 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 9.15 (s, 1H), 8.66 (dd, J = 8.6, 1.8 Hz, 1H), 8.10–8.03 (m, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.97–7.88 (m, 4H), 7.84 (s, 1H), 7.63–7.53 (m, 4H), 7.48 (dd, J = 8.6, 1.8 Hz, 1H), 3.74 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3), δ, ppm: 165.6, 163.6, 158.9, 135.2, 133.2, 133.14, 133.09, 133.0, 130.4, 129.7, 129.5, 128.5, 128.3 (2C), 128.0, 127.89, 127.87, 127.8, 127.7, 127.0, 126.8, 126.5, 126.3, 125.2, 53.0. HRMS (ESI-TOF) calculated for C28H20N2NaO4 [M + Na]+ 471.1315; found 471.1307.
  • Dimethyl 2,5-di(4-biphenyl)pyrimidine-4,6-dicarboxylate (3h). Obtained as a colorless solid (30 mg, yield 36%) according to the general procedure (initiator: ACHN, 6 days, eluent: benzene–ethylacetate, 1:1). Mp: 222–223 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 8.67–8.61 (m, 2H), 7.80–7.75 (m, 2H), 7.74–7.66 (m, 6H), 7.54–7.48 (m, 4H), 7.46–7.39 (m, 4H), 3.81 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3), δ, ppm: 165.6, 163.3, 158.7, 144.3, 141.6, 140.3, 140.0, 134.7, 131.7, 129.3, 129.1, 128.92, 128.88, 127.9, 127.8, 127.5, 127.4, 127.2, 127.13, 127.09, 53.0. HRMS (ESI-TOF) calculated for C32H24N2NaO4 [M + Na]+ 523.1628; found 523.1616.
  • Di-tert-butyl 2,5-diphenylpyrimidine-4,6-dicarboxylate (3i) [38]. Obtained as a colorless solid (25 mg, yield 34%) according to the general procedure (initiator: ACHN, 3 days, eluent: benzene–ethylacetate, 5:1). Mp: 128–129 °C (lit. 124–125 °C [38]). 1H NMR (400 MHz, CDCl3), δ, ppm: 8.61–8.57 (m, 2H), 7.56–7.49 (m, 3H), 7.49–7.43 (m, 3H), 7.41–7.34 (m, 2H), 1.28 (s, 18H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 164.3, 163.6, 159.5, 136.2, 133.7, 131.3, 129.5, 128.8, 128.53, 128.49, 128.2, 126.6, 83.8, 27.6.

3.6. Reaction of Azirine 1a with N,N-Diethylhydroxylamine

To a solution of azirine 1a (60 mg, 0.34 mmol) in acetonitrile (1.5 mL), N,N-diethylhydroxylamine (70 mg, 0.75 mmol) was added. The reaction mixture was heated at 70 °C under stirring for 1 h until full consumption of the azirine (control by TLC, eluent: benzene–ethylacetate, 5:1). The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica gel (eluent: benzene–ethylacetate, 5:1) to give compounds 4a (2 mg, yield 3%), 4b (42 mg, yield 44%) and 4c (13 mg, yield 15%).
  • Methyl 2-benzamidoacetate (4a) [39]. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.86–7.82 (m, 2H), 7.58–7.52 (m, 1H), 7.50–7.44 (m, 2H), 6.69 (br.s, 1H), 4.28 (d, J = 5.1 Hz, 2H), 3.83 (s, 3H).
  • Methyl 2-benzamido-2-((diethylamino)oxy)acetate (4b). Yellow oil. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.93–7.82 (m, 2H), 7.59–7.53 (m, 1H), 7.51–7.44 (m, 2H), 7.23 (br.d, J = 9.3 Hz, 1H), 6.07 (d, J = 9.3 Hz, 1H), 3.85 (s, 3H), 2.86 (m, 4H), 1.12 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3), δ, ppm: 168.8 (C(O)O), 166.6 (C(O)N), 133.5 (ipso-C), 132.2 (para-C), 128.7 (meta-C), 127.2 (ortho-C), 79.6 (CH), 52.6 (CH3O), 52.2 (CH2N), 11.7 (CH3). HRMS (ESI-TOF) calculated for C14H20N2NaO4 [M + Na]+ 303.1315; found 303.1311.
  • Methyl 2-benzamido-2-(diethylamino)acetate (4c). Yellow oil. 1H NMR (400 MHz, CDCl3), δ, ppm: 7.85–7.80 (m, 2H), 7.58–7.51 (m, 1H), 7.50–7.42 (m, 2H), 6.99 (br.d, J = 8.3 Hz, 1H), 5.71 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 2.76–2.60 (m, 4H), 1.18 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3), δ, ppm: 171.2 (C(O)O), 167.7 (C(O)N), 133.9 (ipso-C), 131.8 (para-C), 128.6 (meta-C), 127.1 (ortho-C), 66.5 (CH), 52.8 (CH3O), 44.1 (CH2N), 13.4 (CH3). HRMS (ESI-TOF) calculated for C14H20N2NaO3 [M + Na]+ 287.1366; found 287.1371.

3.7. NMR Detection of Aziridine 8

To a solution of azirine 1a (20 mg, 0.11 mmol) in CDCl3 (0.5 mL) in standard NMR tube, N,N-diethylhydroxylamine (11 mg, 0.11 mmol) was added. The reaction mixture was kept at room temperature for 10 min and then immediately cooled with hexane–liquid nitrogen mixture. NMR spectra of this reaction mixture at –40 °C showed the presence of two diastereomers of aziridine 8 in a 1.2:1 ratio along with unreacted starting compounds.
  • Methyl 3-(diethylaminooxy)-3-phenylaziridine-2-carboxylate (8). 1H NMR (500 MHz, CDCl3,–40 °C), δ, ppm: 7.58–7.53 (m, 2.5H, ortho-H, dia-2), 7.45–7.33 (m, 8.5H), 3.61 (s, 3H, CH3O, dia-1), 3.45 (s, 3.5H, CH3O, dia-2), 3.43 (d, J = 8.9 Hz, 1H, CH, dia-1), 3.36 (d, J = 10.2 Hz, 1.2H, CH, dia-2), 2.85–2.56 (m), 2.44 (d, J = 10.2 Hz, 1.2H, NH, dia-2), 2.19 (d, J = 8.9 Hz, 1H, NH, dia-1), 1.24–1.07 (m), 0.99 (t, J = 7.1 Hz, 3H, CH3, dia-1). 13C{1H} NMR (125 MHz, CDCl3,–40 °C), δ, ppm: aziridine carbons 78.0 (C, dia-1), 77.8 (C, dia-2), 38.7 (CH, dia-1), 37.2 (CH, dia-2).

3.8. EPR Detection of Nitroxyl Radical Et2N-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 Et2N-O·.

4. 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.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules28114315/s1. NMR spectra of compounds 1, 2a, 3, 4, 8; EPR spectroscopy details; quantum chemical calculation details. Table S1: Energies (au) and cartesian coordinates of stationary points for compounds 1a, 7, 7′, anti-8, syn-8, E-9, Z-9, anti-10, syn-10, 11 and transition states TS1, TS1a, TS1b, TS2a, TS2b, TS3a, TS3b, TS4a, TS4b (calculations in rwb97xd/6-311+g(d,p)); Table S2: Energies (au) and cartesian coordinates of stationary points for compounds 1a and Et2N-O· and transition state TS1rad (calculations in ub3lyp/6-31g(d)). Reference [40] is cited in the supplementary materials.

Author Contributions

Conceptualization, N.V.R. and T.N.Z.; methodology, N.V.R., T.N.Z., M.S.N. and A.F.K.; investigation, T.N.Z. and P.A.S.; writing—original draft preparation, N.V.R. and T.N.Z.; writing—review and editing, M.S.N. and A.F.K.; supervision, N.V.R.; project administration, N.V.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation grants 19-73-10090 (synthesis of compounds 3) and 22-73-10184 (mechanistic studies, quantum chemical calculations).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

Dedicated to the 300th anniversary of St. Petersburg State University. This research used resources of the Magnetic Resonance Research Centre, Chemical Analysis and Materials Research Centre, Cryogenic Centre, and Computing Centre of the Research Park of St. Petersburg State University. The authors would like to express their gratitude to A.O. Terent’ev (N.D. Zelinsky Institute of Organic Chemistry) for providing N,N-diethylhydroxylamine.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of compounds 1, 3, 4 are available from the authors.

References

  1. Khlebnikov, A.F.; Novikov, M.S.; Rostovskii, N.V. Advances in 2H-Azirine Chemistry: A Seven-Year Update. Tetrahedron 2019, 75, 2555–2624. [Google Scholar] [CrossRef]
  2. Darbandizadeh, S.A.; Amiri, K.; Rominger, F.; Balalaie, S. Synthesis of Naphthyridine and Azepine Backbones through Formal [4 + 3] and [4 + 2] Annulation via Cascade Ring-Opening/Cyclization Reaction of 2H-Azirines. Eur. J. Org. Chem. 2023, 26, e202201109. [Google Scholar] [CrossRef]
  3. Liu, Y.; He, Z.; Ma, W.; Bao, G.; Li, Y.; Yu, C.; Li, J.; E, R.; Xu, Z.; Wang, R.; et al. Copper(I)-Catalyzed Late-Stage Introduction of Oxime Ethers into Peptides at the Carboxylic Acid Site. Org. Lett. 2022, 24, 9248–9253. [Google Scholar] [CrossRef]
  4. Jiao, L.; Wang, Y.; Ding, L.; Zhang, C.; Wang, X.-N.; Chang, J. Synthesis of 2-Aminopyrroles Via Metal-Free Annulation of Ynamides with 2H-Azirines. J. Org. Chem. 2022, 87, 15564–15570. [Google Scholar] [CrossRef] [PubMed]
  5. Teng, Y.; Fang, T.; Lin, Z.; Qin, L.; Jiang, M.; Wu, W.; You, Y.; Weng, Z. Ring-expansion reaction for the synthesis of 2-(trifluoromethyl)oxazoles and 3-(trifluoromethyl)-1,2,4-triazines. Tetrahedron Lett. 2022, 107, 154100. [Google Scholar] [CrossRef]
  6. Sakharov, P.A.; Rostovskii, N.V.; Khlebnikov, A.F.; Novikov, M.S. Copper(II)-Catalyzed (3+2) Cycloaddition of 2H-Azirines to Six-Membered Cyclic Enols as a Route to Pyrrolo[3,2-c]quinolone, Chromeno[3,4-b]pyrrole, and Naphtho[1,8-ef]indole Scaffolds. Molecules 2022, 27, 5681. [Google Scholar] [CrossRef]
  7. Alves, M.J.; Teixeira e Costa, F. 2H-Azirines as Electrophiles in Heterocyclic Targets in Advanced Organic Synthesis; Research Signpost: Trivandrum, India, 2011; pp. 145–172. [Google Scholar]
  8. Eremeev, A.V.; Él’kinson, R.S.; Myagi, M.Y.; Liepin’sh, É.É. Reactions of 2,2-dimethyl-3-phenylazirine with amines. Chem. Heterocycl. Compd. 1979, 15, 1088–1090. [Google Scholar] [CrossRef]
  9. Alves, M.J.; Gil Fortes, A.; Gonçalves, L.F. Optically active aziridine esters by nucleophilic addition of nitrogen heterocycles to a chiral 2H-azirine-2-carboxylic ester. Tetrahedron Lett. 2003, 44, 6277–6279. [Google Scholar] [CrossRef][Green Version]
  10. Nakamura, S. Enantioselective Reaction of 2H-Azirines. Chem. Asian J. 2019, 14, 1323–1330. [Google Scholar] [CrossRef]
  11. Callebaut, G.; Meiresonne, T.; De Kimpe, N.; Mangelinckx, S. Synthesis and Reactivity of 2-(Carboxymethyl)aziridine Derivatives. Chem. Rev. 2014, 114, 7954–8015. [Google Scholar] [CrossRef]
  12. Rotstein, B.H.; Zaretsky, S.; Rai, V.; Yudin, A.K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014, 114, 8323–8359. [Google Scholar] [CrossRef]
  13. Singh, G.S.; D’hooghe, M.; De Kimpe, N. Synthesis and Reactivity of C-Heteroatom-Substituted Aziridines. Chem. Rev. 2007, 107, 2080–2135. [Google Scholar] [CrossRef] [PubMed]
  14. Sakharov, P.A.; Rostovskii, N.V.; Khlebnikov, A.F.; Khoroshilova, O.V.; Novikov, M.S. Transition Metal-Catalyzed Synthesis of 3-Coumaranone-Containing NH-Aziridines from 2H-Azirines: Nickel(II) versus Gold(I). Adv. Synth. Catal. 2019, 361, 3359–3372. [Google Scholar] [CrossRef]
  15. Hu, H.; Xu, J.; Liu, W.; Dong, S.; Lin, L.; Feng, X. Copper-Catalyzed Asymmetric Addition of Tertiary Carbon Nucleophiles to 2H-Azirines: Access to Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters. Org. Lett. 2018, 20, 5601–5605. [Google Scholar] [CrossRef] [PubMed]
  16. Vélez del Burgo, A.; Ochoa de Retana, A.M.; de los Santos, J.M.; Palacios, F. Reaction of 2H-Azirine-Phosphine Oxides and -Phosphonates with Enolates Derived from β-Keto Esters. J. Org. Chem. 2016, 81, 100–108. [Google Scholar] [CrossRef]
  17. Nakamura, S.; Hayama, D. Enantioselective Reaction of 2H-Azirines with Phosphite Using Chiral Bis(imidazoline)/Zinc(II) Catalysts. Angew. Chem. Int. Ed. 2017, 56, 8785–8789. [Google Scholar] [CrossRef]
  18. Pusch, S.; Kowalczyk, D.; Opatz, T. A Photoinduced Cobalt-Catalyzed Synthesis of Pyrroles through in Situ-Generated Acylazirines. J. Org. Chem. 2016, 81, 4170–4178. [Google Scholar] [CrossRef]
  19. Galenko, A.V.; Khlebnikov, A.F.; Novikov, M.S.; Avdontseva, M.S. Synthesis of 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-containing pyrroles. Tetrahedron 2015, 71, 1940–1951. [Google Scholar] [CrossRef]
  20. Barroso, M.T.; Kascheres, A. Electronically Mediated Selectivity in Ring Opening of 1-Azirines. The 3-Z Mode: Convenient Route to 2-Aza-1,3-dienes. J. Org. Chem. 1999, 64, 49–53. [Google Scholar] [CrossRef]
  21. Auricchio, S.; Grassi, S.; Malpezzi, L.; Sartori, A.S.; Truscello, A.M. New Cleavage of the Azirine Ring by Single Electron Transfer: The Synthesis of 2H-Imidazoles, Pyridazines and Pyrrolines. Eur. J. Org. Chem. 2001, 2001, 1183–1187. [Google Scholar] [CrossRef]
  22. Hossain, A.; Pagire, S.K.; Reiser, O. Visible-Light-Mediated Synthesis of Pyrazines from Vinyl Azides Utilizing a Photocascade Process. Synlett 2017, 28, 1707–1714. [Google Scholar] [CrossRef][Green Version]
  23. Okamoto, K.; Mashida, A.; Watanabe, M.; Ohe, K. An unexpected disproportional reaction of 2H-azirines giving (1E,3Z)-2-aza-1,3-dienes and aromatic nitriles in the presence of nickel catalysts. Chem. Commun. 2012, 48, 3554–3556. [Google Scholar] [CrossRef] [PubMed]
  24. Nguyen, T.K.; Titov, G.D.; Khoroshilova, O.V.; Kinzhalov, M.A.; Rostovskii, N.V. Light-induced one-pot synthesis of pyrimidine derivatives from vinyl azides. Org. Biomol. Chem. 2020, 18, 4971–4982. [Google Scholar] [CrossRef] [PubMed]
  25. Kascheres, A.; Oliveira, C.M.A.; De Azevedo, M.B.M.; Nobre, C.M.S. Reaction of methyl (E)-2-phenyl-1-azirine-3-acrylates with hydrazines and amidines. Synthetic and mechanistic implications. J. Org. Chem. 1991, 56, 7–9. [Google Scholar] [CrossRef]
  26. Pinho e Melo, T.M.V.D.; Cardoso, A.L.; Gomes, C.S.B.; Rocha Gonsalves, A.M. d’A. 2H-Azirines as dipolarophiles. Tetrahedron Lett. 2003, 44, 6313–6315. [Google Scholar] [CrossRef]
  27. Sun, S.; Huang, J.; Yuan, C.; Wang, G.; Guo, D.; Wang, J. Switchable assembly of substituted pyrimidines and 2H-imidazoles via Cu(i)-catalysed ring expansion of 2 methoxyl-2H-azirines. Org. Chem. Front. 2022, 9, 3006–3011. [Google Scholar] [CrossRef]
  28. Muzart, J. DBU: A Reaction Product Component. ChemistrySelect 2020, 5, 11608–11620. [Google Scholar] [CrossRef]
  29. Grossi, L. Base-catalyzed autoxidation of trialkylamines. An e.s.r study. Tetrahedron Lett. 1987, 28, 3387–3390. [Google Scholar] [CrossRef]
  30. Motyakin, M.V.; Wasserman, A.M.; Stott, P.E.; Zaikov, G.E. Possible mediators of the “living” radical polymerization. Spectrochim. Acta A 2006, 63, 802–815. [Google Scholar] [CrossRef]
  31. Funt, L.D.; Tomashenko, O.A.; Novikov, M.S.; Khlebnikov, A.F. An Azirine Strategy for the Synthesis of Alkyl 4-Amino-5-(trifluoromethyl)-1H-pyrrole-2-carboxylates. Synthesis 2018, 50, 4809–4822. [Google Scholar]
  32. Purkayastha, M.L.; Bhat, L.; Ila, H.; Junjappa, H. 4-Alkoxy-3-cyano-2(1H)-pyridones and 5-Alkoxyisoxazoles and Their Aryl Substituted and Annulated Derivatives from Acylketene O,S-Acetals. Synthesis 1995, 6, 641–643. [Google Scholar] [CrossRef]
  33. Agafonova, A.V.; Smetanin, I.A.; Rostovskii, N.V.; Khlebnikov, A.F.; Novikov, M.S. Easy Access to 2-Fluoro- and 2-Iodo-2H-azirines via the Halex Reaction. Synthesis 2019, 51, 4582–4589. [Google Scholar] [CrossRef][Green Version]
  34. An, D.; Guan, X.; Guan, R.; Jin, L.; Zhang, G.; Zhang, S. Organocatalyzed nucleophilic addition of pyrazoles to 2H-azirines: Asymmetric synthesis of 3,3-disubstituted aziridines and kinetic resolution of racemic 2H-azirines. Chem. Commun. 2016, 52, 11211–11214. [Google Scholar] [CrossRef] [PubMed]
  35. Smetanin, I.A.; Novikov, M.S.; Agafonova, A.V.; Rostovskii, N.V.; Khlebnikov, A.F.; Kudryavtsev, I.V.; Terpilowski, M.A.; Serebriakova, M.K.; Trulioff, A.S.; Goncharov, N.V. A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2,3-dihydroazetes. Org. Biomol. Chem. 2016, 14, 4479–4487. [Google Scholar] [CrossRef] [PubMed]
  36. Galenko, E.E.; Galenko, A.V.; Khlebnikov, A.F.; Novikov, M.S. Domino transformation of isoxazoles to 2,4-dicarbonylpyrroles under Fe/Ni relay catalysis. RSC Adv. 2015, 5, 18172–18176. [Google Scholar] [CrossRef]
  37. Zhang, G.; Wang, Y.; Xu, J.; Sun, J.; Sun, F.; Zhang, Y.; Zhang, C.; Du, Y. A new hypervalent iodine(iii/v) oxidant and its application to the synthesis of 2H-azirines. Chem. Sci. 2020, 11, 947–953. [Google Scholar] [CrossRef][Green Version]
  38. Zhou, N.; Xie, T.; Li, Z.; Xie, Z. CuII/TEMPO-Promoted One-Pot Synthesis of Highly Substituted Pyrimidines from Amino Acid Esters. Chem. Eur. J. 2014, 20, 17311–17314. [Google Scholar] [CrossRef]
  39. Mei, C.; Hu, Y.; Lu, W. Visible-Light-Driven Oxidation of N-Alkylamides to Imides Using Oxone/H2O and Catalytic KBr. Synthesis 2018, 50, 2999–3005. [Google Scholar]
  40. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. (Eds.) Gaussian 09, Revision C.01 & D.01; Gaussian: Wallingford, CT, USA, 2013. [Google Scholar]
Molecules 28 04315 sch001
Scheme 1. Reactions of 2H-azirines with N-nucleophiles [8,9,20].
Scheme 1. Reactions of 2H-azirines with N-nucleophiles [8,9,20].
Molecules 28 04315 sch001
Molecules 28 04315 sch002
Scheme 2. Initial discovery of azirine cyclodimerization.
Scheme 2. Initial discovery of azirine cyclodimerization.
Molecules 28 04315 sch002
Molecules 28 04315 sch003
Scheme 3. The scope of pyrimidines.
Scheme 3. The scope of pyrimidines.
Molecules 28 04315 sch003
Molecules 28 04315 sch004
Scheme 4. Control experiments.
Scheme 4. Control experiments.
Molecules 28 04315 sch004
Molecules 28 04315 g001
Figure 1. EPR spectrum of nitroxyl radical Et2N-O· found in the reaction mixture (bottom—initial spectrum, top—processed spectrum).
Figure 1. EPR spectrum of nitroxyl radical Et2N-O· found in the reaction mixture (bottom—initial spectrum, top—processed spectrum).
Molecules 28 04315 g001
Molecules 28 04315 g002
Figure 2. 1H NMR monitoring of the reaction of azirine 1a with N,N-diethylhydroxylamine (7) at rt in CDCl3 (No. 1, black—1 min; No. 2, blue—9 min; No. 3, brown—60 min).
Figure 2. 1H NMR monitoring of the reaction of azirine 1a with N,N-diethylhydroxylamine (7) at rt in CDCl3 (No. 1, black—1 min; No. 2, blue—9 min; No. 3, brown—60 min).
Molecules 28 04315 g002
Molecules 28 04315 sch005
Scheme 5. Plausible reaction mechanism.
Scheme 5. Plausible reaction mechanism.
Molecules 28 04315 sch005
Molecules 28 04315 g003
Figure 3. Calculated energy profiles for the transformation of azirine 1a and N,N-diethylhydroxylamine 7 to ylides 9.
Figure 3. Calculated energy profiles for the transformation of azirine 1a and N,N-diethylhydroxylamine 7 to ylides 9.
Molecules 28 04315 g003
Molecules 28 04315 g004
Figure 4. Calculated energy profiles for the transformation of azomethine ylides 9 and azirine 1a to azirinopyrroline 11.
Figure 4. Calculated energy profiles for the transformation of azomethine ylides 9 and azirine 1a to azirinopyrroline 11.
Molecules 28 04315 g004
Table 1. Optimization of the pyrimidine synthesis a.
Table 1. Optimization of the pyrimidine synthesis a.
Molecules 28 04315 i001
EntrySolventBaseAdditiveT, °CTime bYield of 3a, %/
Conversion of 1a, %
1MeCNNEt3 (2 eqv)-704.5 days48/100
2MeCNNEt3 (2 eqv)-10034 h22/100
3MeCNNEt3 (2 eqv)-405 days0/0
4MeCN--704.5 days0/0
5MeCNNEt3 (1 eqv)-703 weeks41/100
6MeCNDBU (1 eqv)-7018 h27/100
7MeCNtBuOK (1 eqv)-rt1 h0/100
8PhMeNEt3 (2 eqv)-706 days0/85 (1H NMR)
9AcetoneNEt3 (2 eqv)-701 week0/19 (1H NMR)
10DCENEt3 (2 eqv)-708 days0/66 (1H NMR)
111,4-DioxaneNEt3 (2 eqv)-705 days0/0
12MeCNNEt3 (2.6 eqv)TEMPO (1 eqv)705 days0/0
13MeCNNEt3 (2.6 eqv)AIBN (1 eqv)705 days70/100
14MeCNNEt3 (2.6 eqv)ACHN (1 eqv)703 days70/100
15MeCN-AIBN (1 eqv)7024 h0/0
16MeCNNEt3 (2.6 eqv)(BzO)2 (1 eqv)703 days0/100
17MeCNNEt3 (2 eqv)under Ar705 days0/0
a Isolated yields unless otherwise noted. b Time until full consumption of 1a.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zakharov, T.N.; Sakharov, P.A.; Novikov, M.S.; Khlebnikov, A.F.; Rostovskii, N.V. Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study. Molecules 2023, 28, 4315. https://doi.org/10.3390/molecules28114315

AMA Style

Zakharov TN, Sakharov PA, Novikov MS, Khlebnikov AF, Rostovskii NV. Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study. Molecules. 2023; 28(11):4315. https://doi.org/10.3390/molecules28114315

Chicago/Turabian Style

Zakharov, Timofei N., Pavel A. Sakharov, Mikhail S. Novikov, Alexander F. Khlebnikov, and Nikolai V. Rostovskii. 2023. "Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study" Molecules 28, no. 11: 4315. https://doi.org/10.3390/molecules28114315

APA Style

Zakharov, T. N., Sakharov, P. A., Novikov, M. S., Khlebnikov, A. F., & Rostovskii, N. V. (2023). Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study. Molecules, 28(11), 4315. https://doi.org/10.3390/molecules28114315

Article Metrics

Back to TopTop