Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems

Abstract

3-Aryl-2H-azirines react with acylketenes, generated by thermolysis of 5-arylfuran-2,3-diones, to give bridged 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene-2,10-diones and/or ortho-fused 6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine-4,10-diones. The latter compounds, with a new heterocyclic skeleton, are the result of the coupling of two molecules of azirine and two molecules of acylketene and can be prepared only from 3-aryl-2H-azirines having no electron-withdrawing groups in the aryl substituent. Calculations at the DFT B3LYP/6-31G(d) level for the various routes of bis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine skeleton formation revealed a new domino reaction of 3-aryl-2H-azirines occurring in the presence of furandiones: acid-catalyzed dimerization to dihydropyrazine followed by consecutive cycloaddition of the latter to two molecules of acylketenes.

Introduction

2H-Azirines, the most strained nitrogen unsaturated heterocyclic systems, are versatile building blocks for the construction of various heterocyclic nitrogen-containing compounds. Because 2H-azirines contain an activated C=N double bond and a lone pair of electrons on the nitrogen atom they are extremely reactive towards both electrophiles and nucleophiles. Though the three-membered ring can be preserved in some reactions, 2H-azirines mostly undergo ring cleavage to relieve the strain [1–21].

2H-Azirines can react with ketenes both with cleavage and preservation of the three-membered ring [22–26]. It was found that acylketenes, which are generated in situ from diazo ketones, undergo cycloaddition with 3-mono- and 2,3-disubstituted-2H-azirines to afford 2:1 or 1:1 adducts: 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene or 5-oxa-1-azabicyclo[4.1.0]hept-3-ene derivatives. From the results of DFT B3LYP/6-31G(d) computations a step-wise mechanism appears likely for the formation of [4 + 2]-monoadducts [22]. The main limitation for the synthetic application of the reaction is the nonselective mode of the Wolff rearrangement of the unsymmetrical diazo compounds. This generates a mixture of isomeric oxoketenes [27–29] and, as a result, a complex mixture of products is formed [22]. Moreover not all diazo compounds give oxoketenes easily [27–29]. In particular, unsubstituted acylketenes, the reactivity of which towards azirines is until now unknown, cannot be generated from diazo compounds. An alternative source of acylketenes can be furan-2,3-diones, which have been used in reactions with nucleophiles and various cycloadditions [30–32]. Aiming to broaden the scope of the reaction of acylketenes with 2H-azirines we tried to use furan-2,3-diones instead of diazo compounds as the source of ketenes.

Results and Discussion

Unexpectedly, with a new source of acylketenes in addition to predictable products (derivatives of 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene) derivatives of 4,11-dioxa-1,8-diazatricyclo[8.4.0.0^3,8]tetradeca-5,12-diene, a new heterocyclic system, were formed. Boiling a benzene solution of furan-2,3-dione 1a and azirine 2a (1:1) for 0.5 h gave a mixture of compounds 3a–5a, which were isolated by column chromatography (Scheme 1).

Scheme 1.

Reactions of furan-2,3-diones 1 and azirines 2.

To find the optimal reaction conditions a series of experiments was performed with furan-2,3-dione 1a and azirine 2a in different solvents (benzene, toluene, cyclohexane, THF, nitromethane) monitoring the reaction by ¹H NMR using 1-methylnaphthalene as internal standard. ¹H NMR spectra of the new compounds 4a and 5a have clearly distinguishable signals for the methylene protons. Thus, in cis-diastereomer 4а the chemical shifts of the doublet signals for the protons of the CH₂-groups differ by more than 2 ppm (3.26, 5.62 ppm), whereas in trans-diastereomer (5а) they represent an AB-system (4.56, 4.68 ppm). Attempts to initiate the reaction by UV-irradiation (at 20 or 50 °C) or catalysis by compounds of transition metals (Cu(acac)₂, Fe(acac)₃, Pd(bzac)₂, Rh₂(AcO)₄, Cu(OTf)₂, Pd/C) at 20 or 40 °C failed. Benzene was found to be a solvent of choice, and a 1:1 molar ratio of reagents results in the highest yields of the products (Table 1).

Table 1.

Yields of products of the reaction of furan-2,3-dione 1a and azirine 2a in boiling benzene solution for 0.5 h according to ¹H NMR.

Ratio 2a:1a	Conversion of 2a (%)	Yieldsa of 3a, 4a, 5a, %	Overall yieldsa of 3a–5a, %
1:2	100	2, 16, 9	27
1:1.5	89	5, 22, 17	44
1:1	42	19, 37, 15	71
1.5:1	57	2, 19, 11	32
2:1	43	4, 20, 13	37

^aYield based on consumed azirine 2a.

Reactions of azirines 2a–c and furandiones 1a–c, containing electron-donating and electron-withdrawing groups in the aryl rings, were studied to determine an influence of substituents with different electronic effects on the product distribution. The analytical and isolated yields of the reaction products are listed in Table 2. Compounds 3–5 were fully characterized using standard spectral methods. The structures of compounds 3а, 4b were confirmed by X-ray analysis (Figure 1).

Table 2.

Products of the reactions of azirines 2a–c and furandiones 1a–c.

Ar1	Ar2	Conversion of 2, %	Analytical yieldsa of 3, 4, 5, %			Yieldsa of isolated 3, 4, 5, %
Ph	Ph	2a, 71	3a, 19	4a, 37	5a, 15	3a, 15	4a, 34	5a, 13
Ph	4-MeOC6H4	2b, 74	3b, 0	4b, 45	5b, 23	–	4b, 24	5b, 20
Ph	4-NO2C6H4	2c, 50	3c, 89	4c, 0	5c, 0	3c, 79	–	–
4-MeOC6H4	Ph	2a, 70	3d, 77	4d, 14	5d, 9	3d, 42	4d + 5d, 18
4-MeOC6H4	4-MeOC6H4	2b, 72	3e, 0	4e, 41	5e, 23	–	4e + 5e, 51
4-MeOC6H4	4-NO2C6H4	2c, 50	3f, 92	4f, 0	5f, 0	3f, 85	–	–
4-NO2C6H4	Ph	2a, 87	3g, 0	4g, 58	5g, 29	–	4g + 5g, 80
4-NO2C6H4	4-MeOC6H4	2b, –	3h, 0	4h, 0	5h, 0	–	–	–
4-NO2C6H4	4-NO2C6H4	2c, 50	3i, 62	4i, 0	5i, 0	3i, 56	–	–

^aYield based on consumed azirine.

Figure 1.

Molecular structures of compounds 3а, 4b.

Furandiones 1a–c react with 3-(4-nitrophenyl)-2H-azirine (2c) to give only 1:2 adducts 3. These were easily isolated from the reaction mixtures by crystallization. In reactions of 1a with 2b, 1b with 2b, and 1c with 2a only 2:2 adducts 4 and 5 are formed and were isolated by chromatography. Thermolysis of furandione 1c in the presence of azirine 2b led to tarring. Analysis of the data obtained (Table 2) shows that the ratio of the products 3–5 is determined by the electronic effects of the substituents in the benzene rings both in arylazirine 2 and arylfurandione 1. An increase of the electron-withdrawing effect of substituents in the benzene rings of 3-aryl-2H-azirine leads to an increase of yield of 1:2 adduct 3, and in the case of 3-(4-nitrophenyl)-2H-azirine (2c) it becomes the only product, while from 3-(4-methoxyphenyl)-2H-azirine (2b) only 2:2 adducts 4 and 5 were formed. It is also worth noting that in all cases the proportion of cis-isomer 4 was larger than that of trans-isomer 5.

The formation of compounds 3 proceeds in the same way as for similar compounds obtained by reaction of azirines with acylketenes from diazo compounds (Scheme 2) [22]. According to the calculation at the DFT B3LYP/6-31G(d) level with PCM solvation model for benzene (Figure 2) the formation of the monoadducts 8a,c proceeds via the formation of zwitterionic intermediates 7a,c by nucleophilic attack of the azirine nitrogen lone pair on the C=O group of the ketene fragment of intermediate 6a. Interaction of monoadducts 8a,c with ketene 6a leads to the formation of the unstable zwitterionic intermediates 9a,c which further cyclize to bisadducts 3a,c. The barriers for addition of the azirine and aziridine nitrogen lone pair of 1a,c, and 8a,c to ketene 6a increase in passing from compounds 1a, 8a to compounds 1c, 8c, because of a decrease in the nucleophilicity of the latter due to the electron withdrawing effect of the nitro group.

Scheme 2.

The route of formation of compounds 3 and possible intermediates in route to compounds 4 and 5.

Figure 2.

Energy profiles for the reactions of azirines 2a,c and acylketene 6a, as well as acylketene 6a with monoadducts 8a,c. Relative free energies [kcal·mol⁻¹, 353 K, benzene (PCM)] computed at the DFT B3LYP/6-31G(d) level.

As for possible routes for the formation of adducts 4 and 5, the first (Scheme 2, (a)) involves cleavage of the aziridine ring of intermediate 8 to generate azomethine ylide 10, and further “dimerization” of the latter. Examples of compounds that can be considered as dimers of azomethine ylides have been published, though concerted thermal dimerization of azomethine ylides is a forbidden process [33]. According to our calculations the free energy barriers to formation of the azomethine ylides 10a–c from compounds 8a–c are 34.1, 34.7, 32.2 kcal·mol⁻¹ (353 K, benzene (PCM)), respectively, that far exceed the barriers to reactions leading to compound 3. These do not allow the possibility that azomethine ylide 10 can be a probable intermediate in the formation of adducts 4 and 5.

It has been known that imines react with acylketenes, generated from furandiones, to give derivatives of 1,3-oxazines [34–36]. Another route to compounds 4 and 5 could, therefore, involve interaction of dihydropyrazine 11 with ketene 6, leading to the monoadduct 12, which further reacts with a second molecule of 6 to give 2:2 adducts 4 and 5 (Scheme 3, (b)).

Scheme 3.

Possible intermediates in routes to compounds 4 and 5.

To evaluate the free energy barriers for the interaction of 2,5-dihydropyrazine with acylketenes the calculations of the reaction of dihydropyrazine 11a with ketene 6a, leading to adduct 12a, and the reaction of the latter with ketene 6a, leading to adducts 4a and 5a, were performed at the DFT B3LYP/6-31G(d) level (Figure 3).

Figure 3.

Energy profiles for the reactions of dihydropyrazine 11a with acylketene 6a, as well as acylketene 6a with monoadduct 12a. Relative free energies [kcal·mol⁻¹, 353 K, benzene (PCM)] computed at the DFT B3LYP/6-31G(d) level.

According to the calculation (Figure 3) the formation of monoadduct 12a proceeds via the formation of the zwitterionic intermediate 12a' by nucleophilic attack of the dihydropyrazine nitrogen lone pair on the C=O group of ketene 6a. Intermediate 12a' further easily undergoes cyclization to give monoadduct 12a. Interaction of the latter with ketene 6a leads to unsymmetrical cis-isomer 4a' with the piperazine ring in a chair conformation. The isomer 4a' transforms through a low barrier to a much more stable isomer 4a of C₂ symmetry with the piperazine ring in a boat conformation (see Supporting Information File 1). No intermediate structure was located on the way to the most stable conformation of trans-isomer 5a with the piperazine ring in a boat conformation. The free energies of the highest transition states on the pathways from 12a to cis-isomer 4a and trans-isomer 5a are practically equal, but 4a is much more stable than 5a. Therefore, one can consider the experimental 4a:5a isomer ratio of 37:15 to result from the thermodynamic control, since the barrier to the back transformation of 5a to 12a + 6a is as low as 22.7 kcal·mol⁻¹. Calculations also show (Figure 2 and Figure 3) that the reaction involving dihydropyrazines 11 on the way to 4 and 5 could be quite competitive with the reaction leading to 3, provided that a source of dihydropyrazines 11 is available. Formation of ‘dimer azirines’, dihydropyrazines [37–41], or products of their dehydrogenation, pyrazines [37–49] under different conditions is quite common. Moreover, everybody who works with 3-aryl-2H-azirines faces the problem of their storage, because these compounds, both with unsubstituted and an electron-donor substituted benzene ring, fast transform into pyrazines, even when stored in a fridge.

Different mechanisms of dimerization were assumed, such as formation and dimerization of nitrile ylides [37,40], hydrolysis to α-aminoketenes followed by condensation [37,41], intermediate formation of metal complexes in the reaction mediated by metals [41,43,46]. It was found that water [37], Brønsted [44,48] and Lewis acids [40–41,43] facilitate the formation of pyrazine derivatives. 2H-Azirines undergo ring opening on electronic excitation to give nitrile ylides [50]. Nitrile ylide formation under thermal conditions even from such strained compounds as 2H-azirines needs to overcome a quite high energy barrier. According to calculations at the DFT B3LYP/6-31G(d) level the free energy barriers to formation of nitrile ylides 13a–c from azirines 2a–c are 48.4, 47.6, 47.9 kcal·mol⁻¹ (353 K, benzene (PCM)), respectively. Therefore the process of the formation of dihydropyrazines 11 via azirine–nitrile ylide isomerization cannot compete with reaction of azirines with acylketenes (Figure 2). Dimerization of azirine 2a via nucleophilic attack of the nitrogen lone pair of one azirine molecule on the C=N bond of another is also energetically unfavourable (ΔG^# = 53.6 kcal·mol⁻¹, 353 K, benzene (PCM)). In contrast to this, the nucleophilic attack of the nitrogen lone pair of azirine 2 on the C=N bond of protonated azirine 14 and consequent cyclization to dihydropyrazine 15 proceeds via quite low barriers (Figure 4).

Figure 4.

Energy profiles for the reactions of azirines 2a,c with protonated azirines 14a,c. Relative free energies [kcal·mol⁻¹, 353 K, benzene (PCM)] computed at the DFT B3LYP/6-31G(d) level.

By comparison of the data presented on Figures 2–4 one can conclude that competitive formation of compounds 3, 4 and 5 can proceed under acidic catalysis. Probably traces of water cause hydrolysis of the furandiones 1a–c to give 4-aryl-2,4-dioxobutanoic acids, which can protonate basic azirines 2a,b. The concentration of protonated azirine 2c have to be negligible due to low basicity of this azirine, as one can see from isodesmic equation (Scheme 4).

Scheme 4.

Isodesmic equation for evaluation of relative basicity of azirines 2c,a.

Thus, the absence of 4c,f,i and 5c,f,i in the reaction of furandiones 1a–c with azirine 2c can most probably be explained by the low basicity of the latter, and this prevents the formation of 11c in any significant concentration.

We also decided to implement this theoretical conclusion into an approach to storing 3-aryl-2H-azirines. It was found that a sample of azirine 2a upon storage over anhydrous K₂CO₃ at room temperature for 2 months underwent no changes, whereas a sample stored under the same conditions but without addition of K₂CO₃ completely transformed into 2,5-diphenylpyrazine.

The reaction of 2-phenyl-substituted azirine 2d with furandione 1a leads, obviously due to steric reasons, to formation of only the exo-monoadduct 17 (Scheme 5). The structure of compound 17 was confirmed by X-ray analysis (Figure 5). In the case of the reaction of the azirine 2d “dimeric” products of type 3, 4 and 5 were not detected, most probably due to steric hindrance both for the reaction of monoadduct 17 with acylketene 3a and the “dimerization” of 2d to tetraphenyldihydropyrazole.

Scheme 5.

Reaction of furandione 1a with azirine 2d.

Figure 5.

Molecular structure of compound 17.

4,5-Diphenylfuran-2,3-dione (1d) is the source of benzoylphenylketene 6d. Reaction of ketene 6d, generated from 2-diazo-1,3-diphenylpropane-1,3-dione, with azirine 2a was studied earlier [22]. Higher temperatures are needed to generate benzoylphenylketene 6d from furanedione 1d, than from the diazo compound. Boiling an o-xylene solution of furanedione 1d and azirine 2a (1:1 ratio) gave bisadduct 18 in 34% yield (Scheme 6). This is less than when using the diazo compound as a source of acylketene, probably due to dimerization of ketene 6d under higher temperature.

Scheme 6.

Reaction of furandione 1d with azirine 2a.

Compounds 3 and 17, stable at room temperature, react with methanol under mild conditions. Thus the boiling of methanol/CH₂Cl₂ (1:2) solutions of compound 3d and 17 leads to the formation of the corresponding derivatives of 3,4-dihydro-1,4-oxazepin-5(2H)-one 19 and 20 (Scheme 7).

Scheme 7.

Reactions of compounds 3d and 18a with methanol.

Conclusion

2-Unsubstituted 3-aryl-2H-azirines 2 react with acylketenes, generated by thermolysis of 5-arylfuran-2,3-diones 1, to give 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene-2,10-diones 3 and/or cis- and trans-6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine-4,10-diones 4 and 5. The latter compounds are the products of coupling of two molecules of azirine with two molecules of acylketene. The ratio of the adducts 3–5 is determined by electronic effects of the substituents in the benzene rings both in arylazirine 2 and arylfurandione 1. The increase of the electron-withdrawing effect of the substituents in the benzene rings of the arylazirine leads to an increase in the yield of 1:2 adduct 3, and in the case of 3-(4-nitrophenyl)-2H-azirine (2c) it becomes the only product, while from 3-(4-methoxyphenyl)-2H-azirine (2b) only 2:2 adducts 4 and 5 were formed. Calculations at the DFT B3LYP/6-31G(d) level for various routes of bis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine skeleton formation revealed a new reaction of 3-aryl-2H-azirines in the presence of acylketenes from furandiones, i.e. acid-catalyzed dimerization to dihydropyrazines followed by consecutive double cycloaddition of the latter to acylketenes. According to the calculations the larger proportion of cis-isomer 4 than of trans-isomer 5 is a result of thermodynamic control. We also recommend storing liquid 3-aryl-2H-azirines, both with unsubstituted and an electron-donor substituted benzene ring, over anhydrous K₂CO₃.

Experimental

General methods

Melting points were determined on a hot stage microscope and are uncorrected. ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were determined in CDCl₃ with a Bruker DPX 300 spectrometer. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane. Electrospray ionization mass spectra were measured on MS Q-TOF and micrOTOF 10223 mass spectrometers. IR spectra were recorded on a Bruker TENSOR 27 spectrometer for tablets in KBr. Single-crystal X-ray data for 3a were collected at 100 K on a Bruker Proteum R diffractometer (FR-591 rotating anode generator, Pt-135 CCD detector) equipped with Cobra (Oxford Cryosystems) open-flow cryostat. Data for 4b and 17 were collected on an Agilent XCalibur diffractometer at the temperature 120 K maintained by Cryostream (Oxford Cryosystems) cryostat. The structures were solved by direct method and refined by full-matrix least squares on F² for all data using Olex2 [51] and SHELXTL [52] software. All non-hydrogen atoms were refined anisotropically, hydrogen atoms in the structure 3a were placed in the calculated positions and refined in riding mode. The hydrogen atoms in the structures 4b and 17 were located in the difference Fourier maps and refined isotropically. Crystallographic data for the structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC-974303-974305. Compounds 1a [53], 1b,c [32], 1d [54], and 2a,b [55], 2c [56], 2d [57] were prepared by the reported procedures.

General procedures for reactions of acylketenes from 5-arylfuran-2,3-diones 2a–c and 3-aryl-2H-azirines 1a–c. A mixture of azirine 1 (1 mmol) and furane-2,3-dione 2 (1 mmol) in anhydrous benzene (5 mL) was refluxed for 0.5–1 h. The solvent was removed in vacuum, and the residue was purified by flash chromatography on silica (eluent petroleum ether/ethyl acetate, 1:1).

4,6,8-Triphenyl-5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8-diene-2,10-dione (3a). White solid; mp 214–215 °C (benzene); yield 15% (on consumed azirine); ¹H NMR (CDCl₃) δ 4.70 (s, 2H), 6.28 (s, 2H), 7.35–7.48 (m, 9H), 7.60–7.63 (m, 6H); ¹³C NMR (CDCl₃) δ 49.1, 104.5, 113.6, 125.0, 127.0, 128.7, 129.0, 130.3, 131.1, 134.5, 137.4, 160.2, 164.9; IR (KBr, cm⁻¹) ν: 1721 (C=O); HRMS–ESI: [M + Na]⁺ calcd for C₂₆H₁₉NNaO₄⁺, 432.1206; found, 432.1192; Anal. calcd for C₂₆H₁₉NO₄: C, 76.27; H, 4.68; N, 3.42; found: C, 76.57; H, 4.47; N, 3.66; Crystal data for 3a: C₂₆H₁₉NO₄, M = 409.42, monoclinic, space group P 2₁/n, a = 14.5600(5), b = 17.9642(6), c = 17.1799(6) Å, β = 105.850(10)°, U = 4322.7(3) ų, F(000) = 1712, Z = 8, D_c = 1.258 mg m⁻³, μ = 0.692 mm⁻¹. 21195 reflections were collected yielding 5904 unique data (R_merg = 0.0506). Final wR₂(F²) = 0.1073 for all data (559 refined parameters), conventional R₁(F) = 0.0440 for 4157 reflections with I ≥ 2σ, GOF = 0.991.

(6aRS,12aRS)-2,6a,8,12a-Tetraphenyl-6,6a,1,2,12a-tetrahydrobis[1,3]oxazino[3,2-a:3’,2’-d]pyrazine-4,10-dione (4a). White solid; mp 154–156 °C (EtOAc/hexane); yield 34% (on consumed azirine); ¹H NMR (CDCl₃) δ 3.26 (d, J = 15.3 Hz, 2H), 5.62 (d, J = 15.3 Hz, 2H), 5.90 (s, 2H), 7.36–7.44 (m, 12H), 7.51–7.54 (m, 4H), 7.70–7.74 (m, 4H); ¹³C NMR (CDCl₃) δ 47.9, 91.7, 98.7, 126.0, 126.3, 128.4, 128.7, 129.6, 131.3, 131.5, 138.4, 161.5, 163.2; IR (KBr, cm⁻¹) ν 1674 (C=O); HRMS–ESI: [M + H]⁺ calcd for C₃₄H₂₇N₂O₄⁺, 527.1965; found, 527.1937.

(6aRS,12aSR)-2,6a,8,12a-Tetraphenyl-6,6a,1,2,12a-tetrahydrobis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine-4,10-dione (5a). White solid; mp 171–173 °C (EtOAc/hexane); yield 13% (on consumed azirine); ¹H NMR (CDCl₃) δ 4.56 (d, J = 14.5 Hz, 2H), 4.68 (d, J = 14.5 Hz, 2H), 5.73 (s, 2H), 7.29–7.31 (m, 2H), 7.39–7.52 (m, 9H), 7.63–7.71 (m, 9H); ¹³C NMR (CDCl₃) δ 47.5, 93.2, 97.6, 125.1, 126.3, 128.6, 129.0, 129.7, 131.3, 138.0, 162.3, 163.1; IR (KBr, cm⁻¹) ν: 2930, 1661 (C=O); HRMS–ESI: [M + K]⁺ calcd for C₃₄H₂₆N₂KO₄⁺, 565.1524; found, 565.1496.

(6aRS,12aRS)-6a,12a-Bis(4-methoxyphenyl)-2,8-diphenyl-6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine-4,10-dione (4b). White solid; mp 186–186.5 °C (EtOAc/hexane); yield 24% (on consumed azirine); ¹H NMR (CDCl₃) δ 3.22 (d, J = 14.9 Hz, 2H), 3.76 (s, 6H), 5.59 (d, J = 14.9 Hz, 2H), 5.89 (s, 2H), 6.87 (d, J = 8 Hz, 4H), 7.34–7.45 (m, 10H), 7.69 (d, J = 8 Hz, 4H); ¹³C NMR (CDCl₃) δ 47.6, 55.2, 93.1, 97.5, 114.2, 126.3, 126.5, 128.5, 129.8, 131.2, 131.4, 160.5, 162.1, 163.1; IR (KBr, cm⁻¹) ν: 1731 (C=O); HRMS–ESI: [M + H]⁺ calcd for C₃₆H₃₁N₂O₆⁺, 587.2177; found, 587.2183; Crystal data for 4b: C₃₆H₃₀N₂O₆, M = 586.62, monoclinic, space group P 2₁/c, a = 12.1236(5), b = 18.2526(7), c = 13.4793(5) Å, β = 103.738(4)°, U = 2897.46(19) ų, F(000) = 1232, Z = 4, D_c = 1.345 mg m⁻³, μ = 0.092 mm⁻¹. 16575 reflections were collected yielding 6654 unique data (R_merg = 0.0596). Final wR₂(F²) = 0.1284 for all data (517 refined parameters), conventional R₁(F) = 0.0567 for 4337 reflections with I ≥ 2σ, GOF = 1.043.

(6aRS,12aSR)-6a,12a-Bis(4-methoxyphenyl)-2,8-diphenyl-6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2-a:3′,2′-d]pyrazine-4,10-dione (5b). White solid; mp 123–124 °C (EtOAc/hexane); yield 20% (on consumed azirine); ¹H NMR (CDCl₃) δ 3.71 (s, 6H), 4.53 (d, J = 14.2 Hz, 2H), 4.62 (d, J = 14.2 Hz, 2H), 5.74 (s, 2H), 6.75–6.78 (m, 4H), 7.40–7.48 (m, 6H), 7.53–7.56 (m, 4H), 7.67–7.69 (m, 4H); ¹³C NMR (CDCl₃) δ 47.9, 55.1, 91.6, 98.6, 113.7, 126.3, 127.4, 128.7, 130.2, 131.36, 131.42, 160.3, 161.3, 163.3; IR (KBr, cm⁻¹) ν: 1733 (C=O); HRMS–ESI: [M + H]⁺ calcd for C₃₆H₃₁N₂O₆⁺, 587.2177; found, 587.2196.

Calculations. All calculations were carried out at the DFT B3LYP/6-31G(d) level [58–60] by using the Gaussian 09 suite of quantum chemical programs [61] at Resource center ‘Computer center of Saint Petersburg State University’. Geometry optimizations of intermediates, transition states, reactants, and products in benzene were performed using the PCM model. Intrinsic reaction coordinates were calculated to authenticate all transition states.

Supporting Information

Detailed experimental procedures including characterization data for all synthesized compounds, ¹H and ¹³C NMR spectra for all new compounds. Computational details: energies of molecules, transition states and their Cartesian coordinates of atoms.

File 1

Detailed experimental procedures and computational details.

File 2

Chemical information file of compound 3a.

File 3

Chemical information file of compound 4b.

File 4

Chemical information file of compound 17.

This article is dedicated to Professor Armin de Meijere on the occasion of his 75th birthday.