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Article

Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines

by
Ekaterina E. Khramtsova
*,
Aleksandr D. Krainov
,
Maksim V. Dmitriev
and
Andrey N. Maslivets
Department of Chemistry, Perm State University, ul. Bukireva, 15, 614990 Perm, Russia
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(16), 5257; https://doi.org/10.3390/molecules27165257
Submission received: 25 July 2022 / Revised: 11 August 2022 / Accepted: 16 August 2022 / Published: 17 August 2022
(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)
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Abstract

:
4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels–Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic alkaloid-like heterocycles and are also prone to decarbonylation at high temperatures resulting in generation of acyl(imidoyl)ketenes, bidentate aza- and oxa-dienes, which can react with dienophiles to form skeletally diverse products (angular tricyclic products or heterocyclic ensembles). Based on these features, we have developed an approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines and 5-heteryl-4H-1,3-oxazines) via a hetero-Diels–Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side with cyanamides. The products of these transformations are of interest for drug discovery, since compounds bearing 4H-1,3-oxazine moiety are extensively studied for inhibitory activities against anticancer targets.

1. Introduction

Diversity-oriented synthesis (DOS) is a strategy to access structurally diverse libraries of small molecules from a single set of reagents [1,2]. This approach allows efficient exploration of the chemical space for the development of new drugs [3,4].
4H-1,3-Oxazine moiety is a valuable pharmacophore. Compounds bearing this moiety were extensively studied for inhibitory activities against various targets important for the anticancer therapy (Figure 1) [5,6,7,8,9,10]. By varying the substituents around the 4H-1,3-oxazine core, it was possible to tune the selectivity of inhibition (Figure 1) [5,6,7,8]. It should be mentioned that 4H-1,3-oxazine based inhibitors (LTURM34, LTUR6) were found to be more selective than their 4H-pyran analogs (NU7441, LY294002) (Figure 1) [6,9,11,12], which is preferable for the development of new drugs and inhibitors for biological assays.
The hetero-Diels–Alder reaction (HDA) is an atom and step economic synthetic strategy for assembling six-membered heterocycles [13]. HDA of oxa-dienes and nitriles affords 4H-1,3-oxazines [14,15,16,17,18,19].
4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety (FPDs) 1 are well known to react as oxa-dienes with various electron-rich C=C dienophiles A to form angular 6/6/5/6-tetracyclic alkaloid-like pyrano[4,3-b]pyrroles B (Scheme 1, path a) [20,21,22,23]. At the same time, FPDs 1 are also known to readily undergo decarbonylation at temperatures above ~140 °C resulting in generation of highly reactive acyl(imidoyl)ketenes C (Scheme 1, path b) [24]. In turn, acyl(imidoyl)ketenes C are bidentate heterodienes prone to participate in HDA with heterodienophiles D (aldehydes, ketones, Schiff bases, carbodiimides, and etc.) both as aza- and oxa-dienes with the formation of corresponding angular heterocycles E or heterocyclic ensembles F [24,25]. Thus, FPDs 1 are suitable platforms for the development of an HDA-based DOS approaches to series of skeletally diverse heterocycles.
To the best of our knowledge, for today, there are no reported examples of a DOS, in which FPDs 1 react with a single dienophile (Scheme 1, A = D) both as oxa-dienes 1 (Scheme 1, path a) and heterodienes C (Scheme 1, path b). Herein, we present such an approach to two series of skeletally diverse 4H-1,3-oxazines via an HDA of FPDs 1 with cyanamides 2.

2. Results and Discussion

Since acyl(imidoyl)ketenes C were reported not to react with common nitriles (benzonitrile, acetonitrile) [19,24,25], we decided to develop our DOS approach to 4H-1,3-oxazines utilizing so-called push–pull nitrile system, viz. cyanamides (aminonitriles) 2, which are known to have higher reactivity in [4 + 2] cycloaddition reactions [26,27,28,29,30,31].
Initially, we tested the reaction of FPD 1a with cyanamide 2a in acetonitrile at room temperature (Table 1). According to UPLC-UV-MS data of the reaction mixture, the reaction proceeded very slowly. In a week, several unidentified side products were observed along with unreacted starting materials (conversion degree of FPD 1a of ~20%). The UPLC-UV-MS yield of the desired product 3a was ~10%. However, at elevating the reaction temperature up to 95 °C, the test reaction of FPD 1a with cyanamide 2a in acetonitrile proceeded smoothly and afforded the desired tetracyclic alkaloid-like 4H-1,3-oxazine 3a in an isolated yield of 85% (Table 1, Entry 3a). The reaction progress was monitored visually by the change of colour of the reaction mixture (FPD 1a has a deep violet colour, and product 3a is yellow). According to UPLC-UV-MS data of the reaction mixture, compound 3a was formed as a single product, and no side products were observed. Product 3a was isolated by a simple filtration directly from the reaction mixture. Since test results were satisfactory, we examined the substrate scope of this reaction by involving FPDs 1a–i, bearing various acyl substituents R1 and heteroatoms X and cyanamides 2a–f, bearing various substituents at amino nitrogen atom (Table 1).
Quinoxaline derivatives 3a–k were prepared using acetonitrile as the reaction solvent and isolated by a simple filtration directly from the reaction mixture. For the synthesis of 1,4-benzoxazine derivatives (X = O), toluene was used as a reaction solvent since compounds 3l,m were readily soluble in acetonitrile, and no precipitate was formed. In toluene compounds 3l,m formed precipitates after cooling of the reaction mixtures to room temperature, which eased their isolation.
It was found that the studied reaction proceeded well both with 5-oxa (X = O) and 5-aza (X = NH, NPh, NMe) FPDs 1. The reaction also worked well with various aryls and tert-butyl at acyl substituent R1 of FPDs 1. Expectedly, the reaction of methoxy bearing FPD 1h did not result in cycloadduct 3k, since the methoxycarbonyl group COOMe is not electrophilic enough to participate in cycloaddition as a C=O part of the heterodiene system. The examined substituents in N,N-dialkylcyanamides 2a–d did not affect the reaction noticeably. However, our attempts to involve N-arylcyanamides 2e,f in HDA with FPDs 1a,l were not successful. In this case, the reaction proceeded with formation of insoluble hard-to-purify compounds, whose structure we did not succeed to identify. We assume that in this case other reaction course could occur instead of the formation of the desired compounds 3o–q, since N-arylcyanamides 2e,f has lower nucleophilicity at C≡N nitrogen than N,N-dialkylcyanamides 2a–d.
It is worthy of note that some of products 3 had a very low solubility in organic solvents all available to us. There were problems with acquisition on NMR spectra of such products, that’s why in some cases, we had to record solid-state NMR (ssNMR) spectra.
It should be mentioned that in case of the reaction of 4-nitrophenyl substituted FPD 1d with 4-morpholinecarbonitrile 2b, the desired product 3n was observed only in trace amounts by UPLC-UV-MS of the reaction mixture. Prolongation of the reaction time (up to 14 days) and increasing the temperature (up to 120 °C) did not yield any positive results. We suppose that this phenomenon was caused by very low solubility of product 3n, which, possibly, under the examined conditions (FPDs 1 were used as suspensions in acetonitrile), formed a protective insoluble layer on the surfaces of solid particles of FPD 1d and, thus, prevented the reaction. It also should be mentioned that our attempts to perform the reaction of 4-nitrophenyl substituted FPD 1d with carbonitrile 2b in DMSO were also unsuccessful. This experiment was complicated by the fact that DMSO is a highly hygroscopic solvent and facilitated the hydrolysis reactions of the starting FPDs 1 and the products 3 (for hydrolysis studies of analogs of products 3, see [22]). In the case of compound 1d, NO2 substituent makes FPD 1d very electrophilic and very reactive towards water.
Moreover, in the case of 1,4-benzoxazine products 3l,m (X = O), there were problems with monitoring them with UPLC-UV-MS and HPLC-UV (acetonitrile–water as eluents). Chromatograms of the reaction mixtures and individual compounds 3l,m (pure according to the NMR spectra) contained a lot of overlapped broad peaks, and the mass detector data showed signals of the desired products 3l,m only in trace amounts. Furthermore, such problems were never observed with quinoxaline products 3a–j (X = NH, NMe, NPh). We think that these could be explained by the occurrence of hydrolysis of compounds 3l,m on the LC column due to the presence of an ester moiety in their structures, which is a common feature of such compounds [22].
The study of melting in a capillary of compounds 3a–i,l,m revealed that under such conditions 5-heteryl-4H-1,3-oxazines 4a–i,l,m (Table 2) were formed as sole products, and no regioisomeric pyrimidines G (Scheme 2) were observed (monitoring by UPLC-UV-MS). This transformation was then easily scaled up to 0.4 mmol (~200 mg) under solvent-free conditions. When scaling up, we found that an addition of small amounts (of about 0.1 equiv.) of the corresponding cyanamides 2a–d was required to increase the isolated yields of compounds 4a–i,l,m by reducing the side reactions leading to compounds H (monitoring by UPLC-UV-MS) (Scheme 2) characteristic of transformations involving in situ generation of acyl(imidoyl)ketenes C [24,32]. Compounds 4a–i,l,m were readily isolated by simple recrystallization of the crude reaction mixtures. No effect of the examined substituents on the formation of compounds 4a–i,l,m was observed. In the case of compound 3j (X = NH), no compound 4j was formed—instead of this compound, furoqinoxaline I was detected (monitoring by UPLC-UV-MS) (Scheme 2) [24,33].
We assume that the formation of compounds 4a–i,l,m proceeded through three stages (Scheme 2). First, compounds 3a–i,l,m underwent thermally initiated retro-HDA that afforded FPDs 1a–i and cyanamides 2a–d. Second, formed FPDs 1a–i decarbonylated (the evolution of carbon monoxide was indicated by a gas detector tube) to generate acyl(imidoyl)ketenes C. And finally, acyl(imidoyl)ketenes C reacted as oxa-dienes with cyanamides 2a–d to produce the desired 4H-1,3-oxazines 4a–i,l,m. We suppose that ketenes C reacted with cyanamides 2a–d exclusively as oxa-dienes, since this cycloaddition reaction proceeded via a charge-controlled polar transition state, as it was observed earlier in the reaction of ketenes C with carbodiimides [25].
To validate the proposed pathway of formation of compounds 4 (Scheme 2), we tested the one-pot solvent-free reaction of FPD 1a with cyanamide 2b. At heating of compound 1a with cyanamide 2b (reaction scale of 0.4 mmol, 1a:2b reagents ratio of 1:1.1) at 235–240 °C, we found that compound 4b was formed only in a yield of ~45% (monitoring by UPLC-UV-MS), which was much lower than in the case of decomposition of compound 3b. We think that it was because of violation of heat and mass transfer processes during the solvent-free reaction of compounds 1a and 2b. These violations promoted the thermolytical side reactions leading to compounds H [24,32] (monitored by UPLC-UV-MS) and decreased the yield of compound 4b. Thus, the development of a procedure to compounds 4 from the direct reaction of compounds 1 and 2 without isolation of compounds 3 is rather possible, but it requires additional optimization.
Then, to further validate the proposed pathway of formation of compounds 4 (Scheme 2), we performed the decomposition of compound 3b in the presence of FPD 1b at 240 °C and decomposition of compound 3a in the presence of cyanamide 2b at 240 °C and studied the obtained reaction mixtures by HPLC-UV. As a result, the decomposition of compound 3b (R1 = Ph, R2 = morpholino) in the presence of FPD 1b (R1 = 4-ClC6H4) at 240 °C afforded a mixture of compounds 4b (R1 = Ph, R2 = morpholino) and 4e (R1 = 4-ClC6H4, R2 = morpholino) along with a mixture of corresponding side products H. The decomposition of compound 3a (R1 = Ph, R2 = NEt2) in the presence of cyanamide 2b (R2 = morpholino) at 240 °C afforded a mixture of compounds 4a (R1 = Ph, R2 = NEt2) and 4b (R1 = Ph, R2 = morpholino) along with the corresponding side product H. These crossover experiments indirectly confirm that the proposed pathway of formation of compounds 4 (Scheme 2) includes retro-HDA stage and formation of acyl(imidoyl)ketenes C.
The structures of compounds 3a, 3i, 4b, 4f, 4g, and 4i were proved by single crystal X-ray analyses (CCDC 2192396 (3a), 2192397 (3i), 2192400 (4b), 2192399 (4f), 2192398 (4g), and 2196232 (4i)).

3. Materials and Methods

3.1. General Information

1H and 13C NMR spectra (Supplementary Materials) were acquired on a Bruker Avance III 400 HD spectrometer (Switzerland) (at 400 and 100 MHz, respectively) at 313 K in CDCl3 (stab. with Ag) or DMSO-d6 using the TMS or HMDS signal (in 1H NMR) or solvent residual signals (in 13C NMR, 77.00 for CDCl3, 39.51 for DMSO-d6; in 1H NMR, 7.26 for CDCl3, 2.50 for DMSO-d6) as internal standards. 13C ssNMR spectra were acquired on a Bruker Avance III 400 WB NMR spectrometer (Switzerland) (at 100 MHz). Melting points were measured on a Mettler Toledo MP70 apparatus (Switzerland). Elemental analyses were carried out on a Vario MICRO Cube analyzer (Germany). The reaction conditions were optimized using UPLC-UV-MS (Waters ACQUITY UPLC I-Class system (USA); Acquity UPLC BEH C18 column, grain size of 1.7 μm; acetonitrile–water (water containing 0.1% formic acid) as eluents; flow rate of 0.6 mL/min; ACQUITY UPLC PDA eλ Detector (wavelength range of 230–780 nm); Xevo TQD mass detector; electrospray ionization (ESI); positive and negative ion detection; ion source temperature of 150 °C; capillary voltage of 3500–4000 V; cone voltage of 20–70 V; vaporizer temperature of 200 °C) and HPLC-UV (Hitachi Chromaster Japan); NUCLEODUR C18 Gravity column (particle size 3 μm; eluent acetonitrile–water, flow rate 1.5 mL/min); Hitachi Chromaster 5430 diode array detector (λ 210–750 nm)). CO was indicated by gas detector tubes Gazoopredelitel GH-4 (USSR) (specifications 12.43.20-76). The single crystal X-ray analyses of compounds 3a, 3i, 4b, 4f, 4g, and 4i were performed on an Xcalibur Ruby diffractometer (Agilent Technologies, UK). The empirical absorption correction was introduced by multi-scan method using SCALE3 ABSPACK algorithm [34]. Using OLEX2 [35], the structures were solved with the SHELXS [36] program and refined by the full-matrix least-squares minimization in the anisotropic approximation for all non-hydrogen atoms with the SHELXL [37] program. Hydrogen atoms were positioned geometrically and refined using a riding model. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates using EtOAc/toluene, 1:5 v/v, toluene, EtOAc as eluents. Starting compounds 1a–j were obtained according to reported procedures [25,33,38,39]. Toluene for procedures involving compounds 1 was dried over Na before the use. Acetonitrile for procedures involving compounds 1 was dried over molecular sieves 4Å before the use. All other solvents and reagents were purchased from commercial vendors and used as received. Procedures involving compounds 1, 3 were carried out in oven-dried glassware.

3.2. Synthetic Methods and Analytic Data of Compounds

3.2.1. General Procedure to Compounds 3a–j,l,m

A suspension of the corresponding FPD 1 (0.76 mmol) [25,33,38,39] and the corresponding cyanamide 2 (0.84 mmol) in 4 mL of a solvent (anhydrous acetonitrile (for 1a–h) or anhydrous toluene (for 1i)) was stirred and heated at 95 °C for 16 h (until the disappearance of the dark violet color of the compound 1) in an oven-dried capped vial. Then the reaction mixture was cooled to room temperature, and the resulting precipitate was filtered off to afford the desired compound 3. Compound 3 was pure enough and was used further without additional purification.
5-(Diethylamino)-3,8-diphenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3a). Yield: 318 mg (85%); yellow solid; mp 200–204 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.07 (m, 2 H), 7.82 (m, 1 H), 7.74 (m, 1 H), 7.66 (m, 2 H), 7.59 (m, 2 H), 7.51 (m, 1 H), 7.27–7.18 (m, 4 H), 6.43 (m, 1 H), 3.56–3.47 (m, 2 H), 3.36–3.26 (m, 2 H), 1.15 (t, J 7.1 Hz, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 177.0, 163.2, 159.4, 159.0, 150.5, 136.9, 133.7, 132.9, 129.9 (2C), 129.8 (2C), 128.8 (2C), 128.6 (2C), 128.5 (2C), 126.5, 123.0, 122.7, 122.2, 116.0, 104.1, 71.6, 42.4 (2C), 13.3 (2C) ppm. Anal. Calcd (%) for C29H24N4O4: C 70.72; H 4.91; N 11.38. Found: C 70.59; H 5.03; N 11.28. Crystal structure of compound 3a was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2192396. Crystal Data of 3a: C29H24N4O4, M = 492.52, triclinic, a = 9.507(2) Å, b = 10.481(2) Å, c = 13.277(4) Å, α = 74.93(2)°, β = 79.69(2)°, γ = 79.352(19)°, V = 1243.4(6) Å3, T = 295(2), space group P–1, Z = 2, μ(MoKα) = 0.090 mm−1. The final refinement parameters: R1 = 0.0697 [for observed 2640 reflections with I > 2σ(I)], wR2 = 0.1951 (for all independent 5764 reflections, Rint = 0.0711), S = 1.023. Largest diff. peak and hole 0.223 and −0.217 ēÅ−3.
5-Morpholino-3,8-diphenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3b). Yield: 343 mg (89%); yellow solid; mp 223–224 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.05 (m, 2 H), 7.81 (m, 1 H), 7.74 (m, 1 H), 7.67–7.57 (m, 4 H), 7.51 (m, 1 H), 7.27 (m, 2 H), 7.21(m, 2 H), 6.41 (m, 1 H), 3.65 (m, 4 H), 3.47 (m, 4 H) ppm. 13C ssNMR (100 MHz): δ = 177.0, 163.8, 160.5, 151.3, 137.3, 134.1, 129.8, 127.7, 126.2, 122.4, 115.2, 104.4, 72.3, 66.7, 44.9 ppm. Anal. Calcd (%) for C29H22N4O5: C 68.77; H 4.38; N 11.06. Found: C 68.59; H 4.23; N 11.08.
5-(Dimethylamino)-3,8-diphenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3c). Yield: 275 mg (78%); yellow solid; mp 220–221 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.08 (m, 2 H), 7.81 (m, 1 H), 7.74 (m, 1 H), 7.65 (m, 2 H), 7.59 (m, 2 H), 7.51 (m, 1 H), 7.27 (m, 2 H), 7.20 (m, 2 H), 6.41 (m, 1 H), 3.01 (s, 6 H) ppm. 13C ssNMR (100 MHz): δ = 176.8, 162.2, 151.5, 139.4, 136.3, 131.3, 129.9, 126.9, 124.0, 116.7, 104.2, 74.0, 36.8 ppm. Anal. Calcd (%) for C27H20N4O4: C 69.82; H 4.34; N 12.06. Found: C 70.03; H 4.35; N 12.42.
3,8-Diphenyl-5-(piperidin-1-yl)-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3d). Yield: 318 mg (83%); yellow solid; mp 221–224 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.04 (m, 2 H), 7.82 (m, 1 H), 7.74 (m, 1 H), 7.65 (m, 2 H), 7.59 (m, 2 H), 7.51 (m, 1 H), 7.26–7.17 (m, 4 H), 6.41 (m, 1 H), 3.49 (m, 4 H), 1.57 (m, 6 H) ppm. 13C ssNMR (100 MHz): δ = 165.1, 160.9, 151.4, 135.8, 131.0, 128.7, 126.4, 123.1, 117.9, 104.2, 87.1, 48.2, 25.3, 21.9 ppm. Anal. Calcd (%) for C30H24N4O4: C 71.42; H 4.79; N 11.10. Found: C 71.21; H 4.82; N 11.10.
3-(4-Chlorophenyl)-5-morpholino-8-phenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3e). Yield: 362 mg (88%); yellow solid; mp 230–235 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.05 (m, 2 H), 7.81 (m, 1 H), 7.72 (m, 2 H), 7.59 (m, 2 H), 7.51 (m, 1 H), 7.27–7.16 (m, 4 H), 6.41 (m, 1 H), 3.65 (m, 4 H), 3.46 (m, 4 H) ppm. 13C ssNMR (100 MHz): δ = 178.3, 161.0, 159.1, 150.4, 141.3, 136.1, 132.7, 129.8, 127.9, 124.1, 115.0, 103.8, 66.3, 45.1 ppm. Anal. Calcd (%) for C29H21ClN4O5: C 64.39; H 3.91; N 10.36. Found: C 64.02; H 3.85; N 10.11.
3-(4-Methoxyphenyl)-5-morpholino-8-phenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3f). Yield: 371 mg (91%); yellow solid; mp 242–244 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.08 (m, 2 H), 7.81 (m, 1 H), 7.59 (m, 2 H), 7.50 (m, 1 H), 7.28–7.16 (m, 5 H), 6.40 (m, 1 H), 3.92 (s, 3 H), 3.65 (m, 4 H), 3.46 (m, 4 H) ppm. 13C ssNMR (100 MHz): δ = 178.7, 165.5, 160.2, 152.2, 134.0, 128.8, 125.9, 120.8, 114.9, 99.4, 72.7, 65.7, 56.6, 43.6 ppm. Anal. Calcd (%) for C30H24N4O6: C 67.16; H 4.51; N 10.44. Found: C 67.40; H 4.66; N 10.38.
5-(Dimethylamino)-3-(4-nitrophenyl)-8-phenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3g). Yield: 314 mg (81%); yellow solid; mp 210–211 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.46 (m, 2 H), 8.29 (m, 2 H), 7.81 (m, 1 H), 7.60 (m, 2 H), 7.51 (m, 1 H), 7.27 (m, 2 H), 7.22 (m, 2 H), 6.43 (m, 1 H), 3.02 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 177.3, 163.2, 158.6, 156.6, 151.6, 149.9, 136.8, 134.0, 132.9, 131.4 (2C), 129.9 (2C), 128.9 (2C), 128.7, 126.6, 123.4, 123.1 (2C), 122.8, 122.1, 116.0, 106.1, 71.7, 37.2 (2C) ppm. Anal. Calcd (%) for C27H19N5O6: C 63.65; H 3.76; N 13.75. Found: C 63.87; H 4.06; N 13.91.
8-Methyl-3-(4-methylphenyl)-5-morpholino-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3h). Yield: 300 mg (86%); yellow solid; mp 208–210 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 7.96 (m, 2 H), 7.74 (m, 1 H), 7.46 (m, 2 H), 7.42–7.35 (m, 2 H), 7.25 (m, 1 H), 3.60 (m, 4 H), 3.42–3.32 (m, 7 H), 2.47 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 176.5, 163.6, 159.9, 159.0, 151.2, 144.7, 132.0, 130.2 (2 C), 129.0 (2 C), 126.9, 125.7, 122.9, 122.7, 122.5, 115.5, 103.5, 71.3, 65.2 (2 C), 44.7 (2 C), 29.5, 21.3 ppm. Anal. Calcd (%) for C25H22N4O5: C 65.49; H 4.84; N 12.22. Found: C 65.57; H 4.96; N 11.99.
3-(tert-Butyl)-5-morpholino-8-phenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3i). After cooling the reaction mixture, no precipitate was formed. As such, the reaction solvent (acetonitrile) was removed on a rotary evaporator. The resulting solid was dissolved in toluene (2 mL). Then, petroleum ether (bp 70–100 °C) (6 mL) was added to the toluene solution, and the resulting precipitate was filtered off to afford compound 3i. Yield: 310 mg (79%, solvate with toluene); yellow solid; mp 176–179 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 7.75 (m, 1 H), 7.58 (m, 2 H), 7.50 (m, 1 H), 7.24–7.14 (m, 4 H), 6.38 (m, 1 H), 3.60 (m, 4 H), 3.35 (m, 4 H), 1.41 (s, 9 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 178.2, 172.9, 162.8, 158.4, 151.8, 136.9, 132.9, 129.8, 128.8 (2 C), 128.6 (2 C), 126.5, 123.1, 122.7, 122.0, 116.0, 103.1, 71.5, 65.2 (2 C), 44.8 (2 C), 37.9, 26.4 (3 C) ppm. Anal. Calcd (%) for 3C27H26N4O5 · C7H8: C 68.12; H 5.59; N 10.83. Found: C 67.81; H 5.24; N 10.50. Crystal structure of compound 3i was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2192397. Crystal Data of 3i: C27H26N4O5, M = 486.52, monoclinic, a = 18.457(11) Å, b = 9.5254(17) Å, c = 15.057(6) Å, β = 112.96(6) °, V = 2438(2) Å3, T = 295(2), space group P21/c, Z = 4, μ(Mo Kα) = 0.093 mm−1. The final refinement parameters: R1 = 0.1170 [for observed 2112 reflections with I > 2σ(I)], wR2 = 0.3010 (for all independent 6027 reflections, Rint = 0.0895), S = 1.049. Largest diff. peak and hole 0.315 and –0.257 ēÅ−3.
5-Morpholino-3-phenyl-[1,3]oxazino[4′,5′:2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-trione(3j). Yield: 301 mg (92%); yellow solid; mp 201–203 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 10.76 (s, 1 H), 8.05 (m, 2 H), 7.73 (m, 2 H), 7.65 (m, 2 H), 7.29 (m, 1 H), 7.18–7.09 (m, 2 H), 3.60 (m, 4 H), 3.40 (m, 4 H) ppm. 13C ssNMR (100 MHz): δ = 164.8, 160.9, 158.3, 149.5, 144.6, 139.4, 133.0, 128.4, 121.6, 117.9, 105.6, 89.4, 67.6, 45.6 ppm. Anal. Calcd (%) for C23H18N4O5: C 64.18; H 4.22; N 13.02. Found: C 64.01; H 4.25; N 12.99.
5-Morpholino-3-phenyl-7H-benzo[5′,6′][1,4]oxazino[4′,3′:1,2]pyrrolo[2,3-d][1,3]oxazine-1,2,7-trione(3l). Yield: 266 mg (81%); yellow solid; mp 214–219 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.06 (m, 2 H), 7.82–7.73 (m, 2 H), 7.66 (m, 2 H), 7.43–7.31 (m, 3 H), 3.62 (m, 4 H), 3.43 (m, 4 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 176.3, 161.1, 159.4, 158.7, 151.9, 143.0, 133.9, 130.2 (2 C), 128.5 (2 C), 128.1, 127.2, 124.6, 122.8, 121.3, 116.5, 103.5, 70.5, 65.2 (2 C), 44.7 (2 C) ppm. Anal. Calcd (%) for C23H17N3O6: C 64.04; H 3.97; N 9.74. Found: C 64.32; H 4.04; N 9.50.
5-(Dimethylamino)-3-phenyl-7H-benzo[5′,6′][1,4]oxazino[4′,3′:1,2]pyrrolo[2,3-d][1,3]oxazine-1,2,7-trione(3m). Yield: 219 mg (74%); yellow solid; mp 225–230 °C (decomp.). 1H NMR (400 MHz, DMSO-d6): δ = 8.08 (m, 2 H), 7.81–7.73 (m, 2 H), 7.67 (m, 2 H), 7.42–7.32 (m, 3 H), 2.97 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 176.4, 161.3, 159.5, 158.7, 152.3, 143.0, 133.9, 130.1 (2 C), 128.5 (2 C), 128.1, 127.1, 124.5, 122.8, 121.3, 116.5, 103.5, 70.5, 37.0 (2 C) ppm. Anal. Calcd (%) for C21H15N3O5: C 64.78; H 3.88; N 10.79. Found: C 64.52; H 4.01; N 10.60.

3.2.2. General Procedure to Compounds 4a–i,l,m

A mixture of the corresponding compound 3 (0.4 mmol) and the corresponding cyanamide 2 (0.04 mmol) was put into an oven-dried tube, pressed slightly, and then heated in a metal bath at 190–245 °C (the temperature for each compound is given in Table 2; caution: CO evolves during the reaction) for 3 min. The reaction mixture was cooled to room temperature and recrystallized from about 3 mL of a solvent (acetonitrile (for 3a–h) or toluene (for 3l,m)) to give the appropriate compound 4. In the case of compound 3i, the reaction mixture was cooled to room temperature, dissolved in 1 mL of ethyl acetate. Then, 5 mL of n-hexane were added to it, and the resulting precipitate was filtered off to afford compound 4i.
2-(Diethylamino)-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-6-phenyl-4H-1,3-oxazin-4-one(4a). Yield: 132 mg (71%); yellow solid; mp 271–273 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.80 (m, 1 H), 7.70–7.32 (m, 12 H), 6.65 (m, 1 H), 3.58 (m, 4 H), 1.25 (m, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.1, 158.0, 156.9, 154.1, 153.2, 135.2, 133.9, 131.9, 131.1, 130.9, 130.2, 130.1 (2 C), 129.4, 129.3, 128.9 (2 C), 128.3, 128.2, 127.5 (2 C), 123.8, 115.2, 114.0, 41.7 (2 C), 12.3 (2 C) ppm. Anal. Calcd (%) for C28H24N4O3: C 72.40; H 5.21; N 12.06. Found: C 72.20; H 5.17; N 11.93.
2-Morpholino-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-6-phenyl-4H-1,3-oxazin-4-one(4b). Yield: 163 mg (85%); yellow solid; mp 285–287 °C. 1H NMR (400 MHz, CDCl3): δ = 7.87 (m, 1 H), 7.58–7.26 (m, 11 H), 7.06 (br.s, 1 H), 6.67 (m, 1 H), 3.78 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.2, 159.6, 157.1, 153.6, 153.5, 135.6, 134.6, 132.8, 131.1, 130.9, 130.6, 130.2 (2 C), 130.0, 129.3, 128.7 (2 C), 128.6, 128.2, 128.1 (2 C), 123.7, 115.4, 114.8, 66.3 (2 C), 44.5 (2 C) ppm. Anal. Calcd (%) for C28H22N4O4: C 70.28; H 4.63; N 11.71. Found: C 70.38; H 4.41; N 11.53. Crystal structure of compound 4b was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2192400. Crystal Data of 4b: C28H22N4O4, M = 478.49, monoclinic, a = 12.995(3) Å, b = 9.3586(15) Å, c = 19.719(6) Å, β = 105.98(3) °, V = 2305.5(10) Å3, T = 295(2), space group P21/c, Z = 4, μ(Mo Kα) = 0.094 mm−1. The final refinement parameters: R1 = 0.0498 [for observed 3563 reflections with I > 2σ(I)], wR2 = 0.1360 (for all independent 5442 reflections, Rint = 0.0265), S = 1.043. Largest diff. peak and hole 0.191 and –0.230 ēÅ−3.
2-(Dimethylamino)-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-6-phenyl-4H-1,3-oxazin-4-one(4c). Yield: 143 mg (78%, solvate with acetonitrile); yellow solid; mp 279–280 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.81 (m, 1 H), 7.70–7.30 (m, 12 H), 6.63 (m, 1 H), 3.16 (m, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.1, 157.8, 157.7, 154.1, 153.1, 135.2, 133.9, 131.8, 131.1, 130.9, 130.2, 130.1 (2 C), 129.4, 129.3, 128.9 (2 C), 128.3, 128.2, 127.6 (2 C), 123.8, 115.2, 113.8, 37.0, 35.9 ppm. Anal. Calcd (%) for 2C26H20N4O3 C2H3N: C 70.96; H 4.74; N 13.79. Found: C 71.32; H 4.69; N 13.61.
5-(3-Oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-6-phenyl-2-(piperidin-1-yl)-4H-1,3-oxazin-4-one(4d). Yield: 147 mg (77%); yellow solid; mp 275–277 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.80 (m, 1 H), 7.70–7.30 (m, 12 H), 6.64 (m, 1 H), 3.69 (m, 4 H), 1.66 (m, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.2, 157.9, 156.5, 154.0, 153.1, 135.2, 133.9, 131.8, 131.1, 130.9, 130.2, 130.1 (2 C), 129.4, 129.3, 128.9 (2 C), 128.3, 128.2, 127.6 (2 C), 123.8, 115.2, 113.9, 44.7 (2 C), 24.8 (2 C), 23.4 ppm. Anal. Calcd (%) for C29H24N4O3: C 73.09; H 5.08; N 11.76. Found: C 73.41; H 5.09; N 11.92.
6-(4-Chlorophenyl)-2-morpholino-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-4H-1,3-oxazin-4-one(4e). Yield: 176 mg (86%); yellow solid; mp 311–315 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.81 (m, 1 H), 7.70–7.48 (m, 8 H), 7.38 (m, 3 H), 6.64 (m, 1 H), 3.71 (m, 8 H) ppm. 13C ssNMR (100 MHz): δ = 167.0, 157.3, 155.3, 152.6, 138.7, 134.2, 131.4, 129.5, 127.6, 124.6, 115.6, 65.6, 42.9 ppm. Anal. Calcd (%) for C28H21ClN4O4: C 65.56; H 4.13; N 10.92. Found: C 65.34; H 4.11; N 10.59.
6-(4-Methoxyphenyl)-2-morpholino-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-4H-1,3-oxazin-4-one(4f). Yield: 185 mg (91%); yellow solid; mp 293–295 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.82 (m, 1 H), 7.71–7.48 (m, 6 H), 7.42–7.35 (m, 3 H), 7.01 (m, 2 H), 6.64 (m, 1 H), 3.77 (s, 3 H), 3.72 (m, 8 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.4, 161.4, 157.8, 156.9, 154.2, 153.1, 135.3, 134.0, 131.9, 130.9, 130.1 (2 C), 129.4 (4 C), 129.3, 128.2, 123.8, 122.1, 115.2, 114.4 (2 C), 112.7, 65.3 (2 C), 55.3, 43.9 (2 C) ppm. Anal. Calcd (%) for C29H24N4O5: C 68.49; H 4.76; N 11.02. Found: C 68.78; H 4.71; N 11.08. Crystal structure of compound 4f was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2192399. Crystal Data of 4f: C29H24N4O5, M = 508.52, monoclinic, a = 13.137(2) Å, b = 10.009(3) Å, c = 19.142(4) Å, β = 101.80(2) °, V = 2463.8(10) Å3, T = 295(2), space group P21/c, Z = 4, μ(Mo Kα) = 0.096 mm−1. The final refinement parameters: R1 = 0.0651 [for observed 3086 reflections with I > 2σ(I)], wR2 = 0.2110 (for all independent 5836 reflections, Rint = 0.0479), S = 1.036. Largest diff. peak and hole 0.324 and −0.238 ēÅ−3.
2-(Dimethylamino)-6-(4-nitrophenyl)-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-4H-1,3-oxazin-4-one(4g). Yield: 152 mg (79%); pale yellow solid; mp 298–300 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.30 (m, 2 H), 7.87 (m, 2 H), 7.80 (m, 1 H), 7.70–7.34 (m, 7 H), 6.65 (m, 1 H), 3.17 (m, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 170.1, 165.6, 157.6, 155.9, 153.3, 153.1, 148.5, 136.0, 135.2, 134.1, 131.9, 131.1, 130.1 (2 C), 129.5, 129.4, 129.2 (2 C), 128.1, 124.0 (2 C), 123.8, 115.5, 115.3, 37.1, 36.0 ppm. Anal. Calcd (%) for C26H19N5O5: C 64.86; H 3.98; N 14.55. Found: C 64.89; H 4.01; N 14.19. Crystal structure of compound 4g was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2192398. Crystal Data of 4g: C26H19N5O5, M = 481.46, triclinic, a = 9.8633(13) Å, b = 10.7810(14) Å, c = 11.3896(14) Å, α = 74.960(11) °, β = 86.914(10) °, γ = 75.606(11) °, V = 1132.8(3) Å3, T = 295(2), space group P–1, Z = 2, μ(MoKα) = 0.101 mm−1. The final refinement parameters: R1 = 0.0530 [for observed 3900 reflections with I > 2σ(I)], wR2 = 0.1505 (for all independent 5227 reflections, Rint = 0.0300), S = 1.043. Largest diff. peak and hole 0.310 and −0.309 ēÅ−3.
5-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-6-(4-methylphenyl)-2-morpholino-4H-1,3-oxazin-4-one(4h). Yield: 141 mg (82%); yellow solid; mp 271–273 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.75 (m, 1 H), 7.69 (m, 1 H), 7.61 (m, 1 H), 7.43–7.36 (m, 3 H), 7.20 (m, 2 H), 3.72 (m, 8 H), 3.66 (s, 3 H), 2.26 (s, 3 H) ppm. 13C ssNMR (100 MHz): δ = 167.4, 165.9, 162.6, 161.3, 156.4, 152.6, 150.6, 143.5, 142.4, 131.6, 130.1, 127.6, 122.8, 115.0, 113.6, 110.6, 66.8, 44.5, 28.4, 22.7, 20.6 ppm. Anal. Calcd (%) for C24H22N4O4: C 66.97; H 5.15; N 13.02. Found: C 66.81; H 4.99; N 13.19.
6-(tert-Butyl)-2-morpholino-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-4H-1,3-oxazin-4-one(4i). Yield: 154 mg (84%); pale yellow solid; mp 160–162 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.88 (m, 1 H), 7.69–7.58 (m, 4 H), 7.52 (m, 1 H), 7.43–7.32 (m, 3 H), 6.65 (m, 1 H), 3.71 (m, 4 H), 3.65 (m, 4 H), 1.19 (s, 9 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 167.1 (2 C), 157.2, 155.2, 153.3, 135.3, 133.9, 131.5, 130.8, 130.2 (2 C), 129.4 (2 C), 129.3, 128.2, 123.8, 115.2, 112.9, 65.2 (2 C), 43.8 (2 C), 37.1, 28.0 (3 C) ppm. Anal. Calcd (%) for C26H26N4O4: C 68.11; H 5.72; N 12.22. Found: C 68.27; H 5.59; N 12.30. Crystal structure of compound 4i was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2196232. Crystal Data of 4i: C26H26N4O4, M = 458.51, orthorhombic, a = 17.435(7) Å, b = 15.185(4) Å, c = 17.942(4) Å, V = 4750(3) Å3, T = 295(2), space group Pbca, Z = 8, μ(MoKα) = 0.088 mm−1. The final refinement parameters: R1 = 0.0984 [for observed 1995 reflections with I > 2σ(I)], wR2 = 0.2775 (for all independent 5965 reflections, Rint = 0.1670), S = 1.025. Largest diff. peak and hole 0.255 and −0.215 ēÅ−3.
3-(2-Morpholino-4-oxo-6-phenyl-4H-1,3-oxazin-5-yl)-2H-benzo[b][1,4]oxazin-2-one(4l). Yield: 105 mg (65%); yellow solid; mp 208–211 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.73 (m, 1 H), 7.65 (m, 3 H), 7.54–7.42 (m, 5 H), 3.72 (m, 8 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.0, 159.1, 156.9, 151.4, 150.4, 146.1, 132.2, 131.5, 130.5, 129.4, 129.0, 128.9 (2 C), 128.1 (2 C), 125.8, 116.5, 112.5, 65.2 (2 C), 44.0 (2 C) ppm. Anal. Calcd (%) for C22H17N3O5: C 65.50; H 4.25; N 10.42. Found: C 65.67; H 4.12; N 10.32.
3-(2-(Dimethylamino)-4-oxo-6-phenyl-4H-1,3-oxazin-5-yl)-2H-benzo[b][1,4]oxazin-2-one(4m). Yield: 98 mg (68%); yellow solid; mp 159–163 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.73 (m, 1 H), 7.64 (m, 3 H), 7.54–7.42 (m, 5 H), 3.17 (m, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 166.0, 158.9, 157.8, 151.4, 150.6, 146.0, 132.2, 131.4, 130.5, 129.5, 129.0, 128.9 (2 C), 128.0 (2 C), 125.8, 116.5, 112.2, 37.1, 36.0 ppm. Anal. Calcd (%) for C20H15N3O4: C 66.48; H 4.18; N 11.63. Found: C 66.09; H 4.00; N 11.71.

3.2.3. Procedure to Compound I

Compound 3j (22 mg, 0.05 mmol) was put into an oven-dried tube, pressed slightly, and heated in a metal bath at 210–215 °C (caution: CO evolves during the reaction) for 3 min. The reaction mixture was cooled to room temperature and recrystallized from about 5 mL of 1,4-dioxane to give compound I.
3-Benzoylfuro[2,3-b]quinoxalin-2(4H)-one(I) [33]. Yield: 9.9 mg (68%); yellow solid; mp 273–274 °C (reported mp 274–275 °C [33]). 1H NMR (400 MHz, DMSO-d6): δ = 13.98 (br.s, 1 H), 8.20 (m, 1 H), 7.84 (m, 3 H), 7.66–7.48 (m, 5 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 188.4, 163.9, 154.6, 141.9, 137.8, 134.6, 131.8, 128.6, 128.4 (2 C), 128.3, 127.9, 127.7 (2 C), 126.4, 118.6, 91.6 ppm. Anal. Calcd (%) for C17H10N2O3: C 70.34; H 3.47; N 9.65. Found: C 70.53; H 3.37; N 9.71.

4. Conclusions

In conclusion, we have developed a novel diversity-oriented approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines 3 and 5-heteryl-4H-1,3-oxazines 4) via a hetero-Diels–Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side 1 with cyanamides 2. Tetracyclic alkaloid-like 4H-1,3-oxazines 3 were achieved through [4 + 2] cycloaddition of cyanamides 2 to oxa-diene system of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side 1. 5-Heteryl-4H-1,3-oxazines 4 were formed as the result of thermal decomposition of tetracyclic alkaloid-like 4H-1,3-oxazines 3, which proceeded via three steps (retro-Diels–Alder reaction that afforded 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side 1 and cyanamides 2; thermolytical decarbonylation of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side 1 that resulted in formation of highly reactive acyl(imidoyl)ketenes C; [4 + 2] cycloaddition of acyl(imidoyl)ketenes C as oxa-dienes with cyanamides 2 that produced 5-heteryl-4H-1,3-oxazines 4).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27165257/s1, Copies of NMR spectra for all new compounds, ORTEP images of X-ray crystal structures.

Author Contributions

Conceptualization, E.E.K. and A.N.M.; methodology, E.E.K.; validation, E.E.K., investigation, E.E.K., A.D.K. (synthetic chemistry) and M.V.D. (X-ray analysis); writing—original draft preparation, E.E.K.; writing—review and editing, E.E.K. and M.V.D.; visualization, E.E.K.; supervision, E.E.K.; project administration, E.E.K.; funding acquisition A.N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Higher Education of the Russian Federation (FSNF-2020-0008), Russian Foundation for Basic Research (project 20-43-596008) and the government of Perm Krai.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The presented data are available in this article.

Acknowledgments

The authors sincerely thank Aleksey Y. Dubovtsev (Saint Petersburg State University, Saint Petersburg, Russia) for the help with ssNMR experiments and sharing cyanamides. The authors also thank Svetlana O. Kasatkina and Ivan G. Mokrushin (Perm State University, Perm, Russia) for their help with preliminary investigations.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the all compounds are available from the authors.

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Molecules 27 05257 g001 550
Figure 1. 4H-1,3-Oxazine based inhibitors and their 4H-pyran analogs.
Figure 1. 4H-1,3-Oxazine based inhibitors and their 4H-pyran analogs.
Molecules 27 05257 g001
Molecules 27 05257 sch001 550
Scheme 1. Modes of participation of FPDs 1 as heterodienes in HDA.
Scheme 1. Modes of participation of FPDs 1 as heterodienes in HDA.
Molecules 27 05257 sch001
Molecules 27 05257 sch002 550
Scheme 2. Plausible pathway of formation of compounds 4 and G.
Scheme 2. Plausible pathway of formation of compounds 4 and G.
Molecules 27 05257 sch002
Table
Table 1. Cycloaddition reaction of FPDs 1a–i with cyanamides 2a–f.
Table 1. Cycloaddition reaction of FPDs 1a–i with cyanamides 2a–f.
Molecules 27 05257 i001
EntryFPD
1		Cyanamide
2		XR1R2Yield 1 of 3, %
3a1a2aNPhPhNEt285
3b1a2bNPhPh Molecules 27 05257 i00289
3c1a2cNPhPhNMe278
3d1a2dNPhPh Molecules 27 05257 i00383
3e1b2bNPh4-ClC6H4 Molecules 27 05257 i00288
3f1c2bNPh4-MeOC6H4 Molecules 27 05257 i00291
3g1d2cNPh4-NO2C6H4NMe281
3h1e2bNMe4-MeC6H4 Molecules 27 05257 i00286
3i1f2bNPht-Bu Molecules 27 05257 i00279
3j1g2bNHPh Molecules 27 05257 i00292
3k1h2bNPhMeO Molecules 27 05257 i00202
3l1i2bOPh Molecules 27 05257 i00281
3m1i2cOPhNMe274
3n1d2bNPh4-NO2C6H4 Molecules 27 05257 i002Traces 2
3o1a2eNPhPhNHC6H4Cl-4Traces 2
3p1a2fNPhPhNHC6H4OMe-4Traces 2
3q1l2eOPhNHC6H4Cl-4Traces 2
1 Isolated yields (reaction scale of 0.76 mmol). 2 According to UPLC-UV-MS.
Table
Table 2. Thermal decomposition of compounds 3a–j,l,m.
Table 2. Thermal decomposition of compounds 3a–j,l,m.
Molecules 27 05257 i004
EntryPrecursor 3Cyanamide
2		XR1R2Temperature 1, °CYield 2 of 4, %
4a3a2aNPhPhNEt2215–22071
4b3b2bNPhPh Molecules 27 05257 i002235–24085
4c3c2cNPhPhNMe2230–23578
4d3d2dNPhPh Molecules 27 05257 i003230–23577
4e3e2bNPhC6H4Cl-4 Molecules 27 05257 i002240–24586
4f3f2bNPhC6H4OMe-4 Molecules 27 05257 i002250–25591
4g3g2cNPhC6H4NO2-4NMe2220–22579
4h3h2bNMeC6H4Me-4 Molecules 27 05257 i002220–22582
4i3i2bNPhBu-t Molecules 27 05257 i002190–19584
4j3j2bNHPh Molecules 27 05257 i002210–2150 3
4l3l2bOPh Molecules 27 05257 i002230–23565
4m3m2cOPhNMe2240–24568
1 Bath temperature. 2 Isolated yields (reaction scale of 0.4 mmol). 3 According to UPLC-UV-MS.
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Khramtsova, E.E.; Krainov, A.D.; Dmitriev, M.V.; Maslivets, A.N. Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines. Molecules 2022, 27, 5257. https://doi.org/10.3390/molecules27165257

AMA Style

Khramtsova EE, Krainov AD, Dmitriev MV, Maslivets AN. Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines. Molecules. 2022; 27(16):5257. https://doi.org/10.3390/molecules27165257

Chicago/Turabian Style

Khramtsova, Ekaterina E., Aleksandr D. Krainov, Maksim V. Dmitriev, and Andrey N. Maslivets. 2022. "Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines" Molecules 27, no. 16: 5257. https://doi.org/10.3390/molecules27165257

APA Style

Khramtsova, E. E., Krainov, A. D., Dmitriev, M. V., & Maslivets, A. N. (2022). Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines. Molecules, 27(16), 5257. https://doi.org/10.3390/molecules27165257

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