New method for in situ generation of enolate-iminium 1,4-dipoles for [4 + 2] and [4 + 1] dipolar heterocycloaddition reactions

Abstract

Generation of hydrazoylketenes by thermal decomposition of N-(diphenylenamino)pyrrolediones is accompanied by 5-exo-trig ring closure to furnish a zwitterionic dihydropyrazolone species. In contrast to Lisowskaya's earlier report, we established that in most cycloaddition reactions such dihydropyrazolones react as 1,4-dipoles. This reactivity pattern was demonstrated in several [4 + 4]-homodimerizations and in a series of [4 + 2] and [4 + 1] cycloaddition reactions with various dipolarophiles.

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Introduction

2,3-Dihydro-2,3-pyrroldiones (B),¹ being monocyclic analogs of isatines (A),² can also be viewed as vinylogous lactams with a highly electrophilic conjugate double bond moiety. This unusual feature determines their very rich chemistry involving an array of addition and cyclo-condensation reactions allowing for expeditious assembly of various pyrrole-based scaffolds.^3,4 In addition, it is well documented that thermolysis of N-substituted pyrrolediones leads to decarbonylation to afford imidoylketenes (C) (Scheme 1).⁵ The chemical behavior of the generated ketenes generally depends on the nature of the substituent at N-1. Thus, thermolysis of non-substituted and N-alkyl-substituted pyrroldiones (A, R = H, Alk) normally does not provide any distinct isolable products due to facile decomposition and polymerization of the corresponding ketenes. However, Wentrup reported detection of azetidinones E (or their cyclic dimers) under FVP conditions.⁶ The reaction of N-aryl-substituted pyrrolediones (A, R = Ar) is typically accompanied by intramolecular C–H acylation of ketenes to provide 4-quinolones (D) (Scheme 1).⁷ In the frame of our continuous studies on the transformations of imidoylketenes,^8,9 we became interested in the possibility of generating related hydrazoylketenes F and investigating their following transformations (Scheme 1). Herein we wish to report our progress in this area.

Scheme 1

Results and discussion

In 2004 Lisowskaya reported reactions of 2-(hydrazinyl)-4-oxo-but-2-enoates 1 with oxalyl chloride.¹⁰ It was proposed that N-(diphenylenamino)pyrroledione 2 initially formed under these conditions experienced facile CO-extrusion at elevated temperatures. Then, the resulting hydrazonoketene 3 undergoes further 5-exo-trig ring closure to provide a zwitterionic dihydropyrazolone species, which can be represented by two resonance forms 4 and 5. Lisowskaya suggested that form 5 is a chief contributor, which renders it reactive as a 1,3-CNN-dipole. This proposal was supported by isolation of tert-butyl-substituted dimeric [3 + 3]-adduct 6c (Scheme 2), the structure of which was unambiguously proved by X-ray crystallography.¹⁰ By analogy, the same structure was putatively assigned to p-tolyl-substituted analog 6b (Scheme 2), for which an isolated yield of 67% was reported.¹⁰ We were very puzzled by this finding, since we felt that an alternative resonance form 4 – hosting an anionic charge on the more electronegative oxygen atom and strongly benefiting from aromatic stabilization of heterocyclic ring – should be more favored. If so, it could be able to react as a 1,4-dipole of unusual CNCO-type, which should open new avenues for expeditious assembly of heterocyclic scaffolds. Keeping this issue in mind, we decided to revisit this topic. In accordance with Lisowskaya's protocol, hydrazonoketenes were generated bearing phenyl (3a), p-tolyl (3b), and tert-butyl (3c) substituents. We confirmed that the reaction of the tert-butyl substituted starting material indeed led to the formation of [3 + 3]-cycloadduct, dipyrazolotetrazine 6c, in 89% yield (Scheme 2). However, the reactivities of aryl-substituted derivatives were drastically different. Thus, in contrast to Lisowskaya's report, no [3 + 3]-cyclodimer 6b was formed. Instead, bis-pyrazolodioxadiazocine 7b—the product of [4 + 4]-cyclodimerization—was afforded in high yield resulting from the reactivity of 1,4-dipolar resonance form 4. Similarly, in the reaction of phenyl-substituted ketene 3a, [4 + 4]-cycloadduct 7a was obtained, whose structure was proved by X-ray crystallography (CCDC #1457141, Fig. 1).

Scheme 2

Fig. 1 ORTEP drawing of 7a (CCDC #1457141) showing 50% probability amplitude displacement ellipsoids.

Inspired by these interesting initial results, we decided to elaborate on the development of various synthetic schemes utilizing the cycloaddition of this unusual 1,4-dipole. To this end, we performed the generation of ketenes 3a–c in the presence of vinyl butyl ether, targeting products of [4 + 2] dipolar cycloaddition. Gratifyingly, these reactions proceeded smoothly and corresponding pyrazolooxazines 8a–c were formed in good yields and with perfect regioselectivities (Scheme 3). Expectedly, the anionic terminus of the dipole attacks the more electropositive carbon atom of the enol ether, affording an exocyclic acetal moiety (Scheme 3). Interestingly, tert-butyl substituted ketene 3c also reacted as a 1,4-dipole in this case, and the formation of a new oxazinane ring was confirmed by X-ray crystallography (CCDC #1457144, Fig. 2). Next, we decided to investigate the reactivity of these dipoles with electron-deficient dipolarophiles, such as aldehydes and nitriles. Ketenes 3a, b, d were generated in the presence of p-bromobenzaldehyde to afford the corresponding pyrazolodioxazines 9a, b, d in good yields (Scheme 3). Again, the regiochemistry of this [4 + 2]-cycloaddition process was perfect, in which the anionic oxygen formed a bond with the carbonyl carbon bearing a partial positive charge, furnishing cyclic acetal scaffolds (Scheme 3). Reaction in the presence of benzonitriles also proceeded uneventfully, providing the corresponding pyrazolooxadiazines in good yields (Scheme 4). Formation of cyclic adducts in the described transformations with aldehydes and nitriles was proved by X-ray crystal structures of products 9a (CCDC #1457142, Fig. 3) and 10a (CCDC #1457143, Fig. 4), respectively.

Scheme 3

Fig. 2 ORTEP drawing of 8c (CCDC #1457144) showing 50% probability amplitude displacement ellipsoids.

Scheme 4

Fig. 3 ORTEP drawing of 9a (CCDC #1457142) showing 50% probability amplitude displacement ellipsoids.

Fig. 4 ORTEP drawing of 10a (CCDC #1457143) showing 50% probability amplitude displacement ellipsoids. Phenyl groups C10–C15 and C8, C16–C20 show librational and rotational disorder, respectively.

In an attempt to develop a related cascade transformation involving the [4 + 1]-cycloaddition pattern, we tested the interaction with isocyanides. As expected, this reaction was very facile and proceeded much faster than [4 + 2]-cycloadditions involving other dipolarophiles discussed above. The corresponding cycloadducts, pyrazolooxazoles 11b–d, were afforded in medium yields (Scheme 4). Formation of a five-membered ring in 11d was confirmed by single-crystal X-ray crystallography (CCDC #1457145, Fig. 5).

Fig. 5 ORTEP drawing of 11d (CCDC #1457145) showing 50% probability amplitude displacement ellipsoids.

It should be emphasized that in all the tested transformations, zwitterionic intermediates reacted as 1,4-dipoles 4. At the same time, formation of [3 + 3]-dimeric adduct 6c could be potentially explained by thermodynamic control. Indeed, this might be the case, if dimerization reactions are reversible and 6c is thermodynamically more favored than the alternative [4 + 4] adduct 7c. To check this hypothesis, we heated 4 + 4 dimers 6 in the interval of 140 to 220 °C with or without solvents. Unfortunately, at such high temperatures in the absence of dipolarophiles most of the material decomposed with the formation of polymeric resins, and we failed to detect any [3 + 3]-adducts in the reaction mixtures. However we noticed that short-term heating of the colorless solution of [4 + 4]-adducts 6 (or [3 + 3]-adducts 7 alike) in xylene at temperatures exceeding their decomposition point (110–140 °C) leads in both cases to the formation of navy-blue solution of monomeric zwitterions 4, which can be easily intercepted by appropriate dipolarophiles. Thus, addition of 1-isocyanoadamantane to a solution of [4 + 4]-dimeric compound 7b stirred in xylene at 140 °C led to the formation of [4 + 1]-cross adduct 11b, which was isolated in 32% yield. Similarly, [4 + 1]-cross adduct 11c was afforded in a yield of 67% by melting a neat mixture of [3 + 3]-dimer 6c with the same isocyanide.

Conclusions

It was confirmed, that the generation of hydrazonoketenes 3 by thermal decomposition of N-(diphenylenamino)pyrrolediones 2 is accompanied by 5-exo-trig ring closure to furnish zwitterionic dihydropyrazolone species. Lisowskaya, who previously investigated this reaction, suggested that these species have predominantly azomethine-iminium form 5 and react as 1,3-dipoles. In contrast to her report, we established that in most reactions such dihydropyrazolones have predominantly enolate-iminium form 4 and react as 1,4-dipoles. This reactivity pattern was demonstrated in several [4 + 4]-homodimerizations and in a series of [4 + 2] and [4 + 1] cycloaddition reactions with various dipolarophiles.

Experimental part

¹H and ¹³C NMR spectra were recorded on a Bruker Avance III HD spectrometer (400 or 100 MHz, respectively) in CDCl₃ using TMS (δ_H = 0.00 ppm), HMDSO (δ_H = 0.07 ppm) or the residual solvent peak (δ_H = 7.26 ppm, δ_C = 77.16 ppm) as internal standards. FT-IR spectra were recorded for mulls in mineral oil employing Perkin Elmer Spectrum Two spectrometer. The mass spectra were recorded on an Waters UPLC-MS instrument equipped with an ESI MS Xevo TQD detector. Combustion elemental analysis (CHN) was performed on a Perkin Elmer 2400 Series II Analyzer. Melting points were measured with Mettler Toledo MP70 Melting Point System. Anhydrous toluene was obtained by heating at reflux with molten sodium followed by distillation in under an atmosphere of dry nitrogen. Anhydrous chloroform was obtained by heating at reflux with phosphorus pentoxide followed by distillation in under an atmosphere of dry nitrogen. Reaction progress and purity of isolated compounds were monitored by TLC (Merck, Silica gel 60 F254), eluting with toluene/EtOAc mixtures. All reagents and solvents were purchased from commercial vendors and used as received. X-ray structural analysis of compounds 7a, 8c, 9a, 10a, and 11d were performed on an Xcalibur Ruby diffractometer using Mo X-ray source (MoKα 0.71073 Å), scanning at 295(2) K. The structures were solved by the SHELXS software and refined by full-matrix least-squares on all F² data using SHELXL-97 (ref. 11) in conjunction with the WinGX graphical user interface.¹² Full crystallographic data are deposited at the Cambridge Crystallographic Data Center (CCDC #1457141 (7a), #1457144 (8c), #1457142 (9a), #1457143 (10a), #1457145 (11d)).

Methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-phenylbut-2-enoate (1a) (typical procedure)

To a solution of methyl 2,4-dioxo-4-phenylbutanoate (4.12 g, 20 mmol, 1.0 equiv.) in toluene (20 mL) were added benzophenone hydrazone (3.93 g, 20 mmol, 1.0 equiv.) and acetic acid (114 μL, 120 mg, 2 mmol, 10 mol%). The reaction mixture was refluxed for 2 h in a flask equipped with a Dean–Stark adaptor. The solution was cooled down to RT, the formed precipitate was filtered and purified by crystallization from ethanol, affording the titled compound as yellowish crystals in 93% yield (7.14 g, 18.6 mmol); mp 158–160 °C (hexanes); ¹H NMR (400 MHz, CDCl₃) δ 12.73 (s, 1H), 7.84–7.79 (m, 2H), 7.71–7.61 (m, 3H), 7.58–7.54 (m, 2H), 7.48–7.31 (m, 8H), 6.02 (s, 1H), 4.04 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 190.5, 164.6, 153.1, 151.7, 138.8, 137.1, 132.2, 131.9, 130.2, 129.9 (2C), 129.8, 128.5 (2C), 128.4 (4C), 127.8 (2C), 127.6 (2C), 91.8, 52.9; FT IR (cm⁻¹): 3056, 1737, 1619, 1608, 1582, 1554, 1506.

Methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (1b)

This compound was prepared according to typical procedure listed for 1a employing methyl 2,4-dioxo-4-(p-tolyl)butanoate (4.40 g, 20 mmol, 1.0 equiv.) and isolated as yellowish crystals in 90% yield (7.16 g, 18.0 mmol); mp 145–147 °C (hexanes). ¹H NMR (400 MHz, CDCl₃) δ [12.71 (s) & 6.02 (s) & 4.54 (s), ∑2H], [7.86 (d, J = 8.3 Hz) & 7.72 (d, J = 8.2 Hz), ∑2H], [7.70–7.53 (m) & 7.46–7.31 (m), ∑10H], [7.22 (d, J = 8.0 Hz) & 7.18 (d, J = 8.0 Hz), ∑2H], [4.04 (s) & 3.83 (s), ∑3H], [2.39 (s) & 2.37 (s), ∑3H]. ¹³C NMR (100 MHz, CDCl₃) δ major: 190.2, 164.7, 152.7, 151.4, 142.5, 137.2, 136.2, 132.2, 130.1, 129.9 (2C), 129.7, 129.1 (2C), 128.5 (2C), 128.4 (2C), 127.8 (2C), 127.7 (2C), 91.8, 52.9, 21.6; minor: 194.5, 164.8, 162.1, 151.8, 144.3, 137.7, 134.3, 134.1, 130.7 (2C), 130.4, 129.9, 129.5 (2C), 129.4 (2C), 128.5 (2C), 128.2 (2C), 127.9 (2C), 52.9, 39.0, 21.7; FT IR (cm⁻¹): 3057, 1738, 1610, 1575, 1554, 1515.

Methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-5,5-dimethyl-4-oxohex-2-enoate (1c)

This compound was prepared according to typical procedure listed for 1a employing methyl 5,5-dimethyl-2,4-dioxohexanoate (3.72 g, 20 mmol, 1.0 equiv.) and isolated as yellowish crystals in 89% yield (6.50 g, 17.8 mmol); mp 150–152 °C (hexanes). ¹H NMR (400 MHz, CDCl₃) δ 12.17 (s, 1H), 7.65–7.55 (m, 3H), 7.52–7.47 (m, 2H), 7.37–7.28 (m, 5H), 5.48 (s, 1H), 3.98 (s, 3H), 1.08 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 206.2, 165.0, 151.7, 150.8, 137.4, 132.2, 130.1, 129.8 (2C), 129.5, 128.6 (2C), 128.3 (2C), 127.7 (2C), 91.0, 52.8, 42.7, 27.3 (3C); FT IR (cm⁻¹): 3057, 1739, 1616, 1584, 1557, 1504.

Methyl (Z)-4-(4-chlorophenyl)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxobut-2-enoate (1d)

This compound was prepared according to typical procedure listed for 1a employing methyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (4.81 g, 20 mmol, 1.0 equiv.) and isolated as yellowish crystals in 92% yield (7.70 g, 18.4 mmol); mp 165–167 °C (hexanes). ¹H NMR (400 MHz, CDCl₃) δ [12.73 (s) & 5.96 (s) & 4.51 (s), ∑2H], [7.90–7.85 (m) & 7.77–7.72 (m), ∑2H], [7.70–7.53 (m) & 7.32–7.46 (m), ∑12H], [4.04 (s) & 3.83 (s), ∑3H]. ¹³C NMR (100 MHz, CDCl₃) δ major: 188.9, 164.4, 153.5, 152.0, 138.1, 137.1, 136.9, 132.1, 130.2, 129.9 (2C), 129.9, 129.0 (2C), 128.6 (2C), 128.4 (2C), 128.4 (2C), 127.8 (2C), 91.3, 52.9; minor: 193.8, 164.7, 162.5, 151.5, 139.9, 137.5, 134.9, 134.2, 130.6 (2C), 130.0, 129.8 (2C), 129.5 (2C), 129.0 (2C), 128.2 (2C), 127.9 (2C), 53.0, 38.94; FT IR (cm⁻¹): 3056, 1737, 1609, 1594, 1576, 1550, 1505.

Dimethyl 3,9-dibenzoyl-5,5,11,11-tetraphenyl-5H,11H-dipyrazolo[5,1-b:5′,1′-f][1,5,3,7]dioxadiazocine-2,8-dicarboxylate (7a) (typical procedure A)

To a stirred solution of methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-phenylbut-2-enoate (384 mg, 1 mmol, 1.0 equiv.) in dry CHCl₃ (2 mL), oxalyl chloride (86 μL, 127 mg, 1 mmol, 1.0 equiv.) was added. The reaction mixture was refluxed for 90 min, then o-xylene (2 ml) was added. Chloroform was distilled off until the vapor temperature above the mixture reached 130 °C. After refluxing for 10 min the solution was cooled down to RT, diethyl ether (200 μL) was added, and the mixture was set aside for crystallization. Next day, the formed precipitate was filtered off and purified by re-crystallization from acetone, affording the titled compound as colorless crystals in 60% yield (246 mg, 0.3 mmol); mp 110–120 °C (acetone, with decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.37 (m, 2H), 7.37–6.95 (m, 28H), 3.52 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 185.1, 161.7, 149.1, 144.0, 136.5, 132.9, 129.9, 129.8, 128.3, 127.8, 114.8, 103.2, 52.3; FT IR (cm⁻¹): 1746, 1733, 1666, 1596, 1579, 1547; MS (ESI+): found 843.04; calcd. for C₅₀H₃₆N₄NaO₈ (M + Na)⁺ 843.24; EA (%) calcd. for C₅₀H₃₆N₄O₈: C 73.16, H 4.42, N 6.83; found: C 72.97, H 4.23, N 6.95.

Dimethyl 3,9-bis(4-methylbenzoyl)-5,5,11,11-tetraphenyl-5H,11H-dipyrazolo[5,1-b:5′,1′-f][1,5,3,7]dioxadiazocine-2,8-dicarboxylate (7b)

This compound was prepared according to the typical procedure A employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (398 mg, 1 mmol, 1.0 equiv.) and isolated as colorless crystals in 76% yield (322 mg, 0.38 mmol); mp 110–111 °C (acetone, with decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.11 (m, 24H), 7.05 (d, J = 8.0 Hz, 4H), 3.54 (s, 6H), 2.36 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 184.1, 161.1, 148.3, 143.3, 143.0, 133.6, 129.3, 129.2, 127.8, 127.6, 114.4, 102.5, 51.6, 21.1; FT IR (cm⁻¹): 1731, 1664, 1602, 1556; MS (ESI+): found 849.41; calcd. for C₅₂H₄₁N₄O₈ (M + H)⁺ 849.29; EA (%) calcd. for C₅₂H₄₀N₄O₈: C 73.57, H 4.75, N 6.60; found: C 73.46, H 4.61, N 6.64.

Methyl 3-benzoyl-5-butoxy-7,7-diphenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (8a) (typical procedure B)

To a solution of methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-phenylbut-2-enoate (384 mg, 1 mmol, 1.0 equiv.) in CHCl₃ (2 mL) was added oxalyl chloride (86 μL, 127 mg, 1 mmol, 1.0 equiv.) in one portion. The reaction mixture was refluxed for 90 min, then o-xylene (2 mL) was added, and chloroform was distilled out until the vapor temperature above the mixture reached 120 °C. After that the solution was refluxed for 15 min, butyl vinyl ether (155 μL, 120 mg, 1.2 mmol, 1.2 equiv.) was added, and the reaction mixture was refluxed for additional 20 min. The resulting solution was cooled down to RT, the solvent was evaporated under reduced pressure and the residual solid was triturated with hexanes and recrystallized from acetone to afford the titled compound as colorless crystals in 84% yield (429 mg, 0.84 mmol); mp 122–125 °C (acetone). ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.81 (m, 2H), 7.55–7.49 (m, 1H), 7.46–7.30 (m, 8H), 7.24–7.19 (m, 2H), 7.15–7.10 (m, 2H), 5.21 (dd, J = 7.5, 2.9 Hz, 1H), 3.64 (dt, J = 9.4, 6.6 Hz, 1H), 3.56 (s, 3H), 3.36 (dt, J = 9.4, 6.6 Hz, 1H), 3.10 (dd, J = 14.6, 7.5 Hz, 1H), 3.04 (dd, J = 14.5, 2.9 Hz, 1H), 1.42–1.33 (m, 2H), 1.22–1.11 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 188.4, 162.6, 151.7, 143.0, 142.0, 140.9, 139.1, 132.5, 129.2 (2C), 129.0 (2C), 128.5 (2C), 128.4, 128.4, 128.3 (2C), 128.3 (2C), 127.2 (2C), 104.0, 99.8, 69.9, 68.2, 52.1, 41.9, 31.4, 19.0, 13.8; FT IR (cm⁻¹): 1731, 1635, 1598, 1578, 1552, 1500; MS (ESI+): found 511.14; calcd. for C₃₁H₃₁N₂O₅ (M + H)⁺ 511.22; EA (%) calcd. for C₃₁H₃₀N₂O₅: C 72.92, H 5.92, N 5.49; found: C 72.80, H 5.75, N 5.38.

Methyl 5-butoxy-3-(4-methylbenzoyl)-7,7-diphenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (8b)

This compound was prepared according to typical procedure B employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (398 mg, 1.0 mmol, 1.0 equiv.) and isolated as colorless crystals in 64% yield (336 mg, 0.64 mmol); mp 133–135 °C (acetone). ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.1 Hz, 2H), 7.42–7.28 (m, 6H), 7.22 (d, J = 7.8 Hz, 4H), 7.14–7.09 (m, 2H), 5.20 (dd, J = 7.5, 2.8 Hz, 1H), 3.65 (dt, J = 9.4, 6.6 Hz, 1H), 3.58 (s, 3H), 3.36 (dt, J = 9.4, 6.6 Hz, 1H), 3.09 (dd, J = 14.5, 7.6 Hz, 1H), 3.03 (dd, J = 14.5, 2.8 Hz, 1H), 2.39 (s, 3H), 1.42–1.32 (m, 2H), 1.21–1.10 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.5, 162.0, 150.8, 142.6, 142.2, 141.4, 140.3, 135.8, 128.9 (2C), 128.3 (2C), 128.3 (2C), 127.9 (2C), 127.8, 127.7, 127.7 (2C), 126.6 (2C), 103.6, 99.1, 69.3, 67.5, 51.5, 41.3, 30.8, 21.2, 18.4, 13.1; FT IR (cm⁻¹): 1739, 1646, 1605, 1563; MS (ESI+): found 525.23; calcd. for C₃₂H₃₃N₂O₅ (M + H)⁺ 525.24; EA (%) calcd. for C₃₂H₃₂N₂O₅: C 73.26, H 6.15, N 5.34; found: C 73.42, H 6.28, N 5.35.

Methyl 5-butoxy-7,7-diphenyl-3-pivaloyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate (8c)

This compound was prepared according to typical procedure B employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-5,5-dimethyl-4-oxohex-2-enoate (364 mg, 1 mmol, 1.0 equiv.) and isolated as colorless crystals in 60% yield (294 mg, 0.60 mmol); mp 137–140 °C (acetone). ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.27 (m, 6H), 7.21–7.14 (m, 2H), 7.12–7.03 (m, 2H), 5.19 (dd, J = 7.2, 3.6 Hz, 1H), 3.85 (dt, J = 9.3, 6.6 Hz, 1H), 3.79 (s, 3H), 3.48 (dt, J = 9.3, 6.4 Hz, 1H), 3.06 (dd, J = 13.4, 6.3 Hz, 1H), 3.02 (dd, J = 13.5, 2.5 Hz, 1H), 1.56–1.46 (m, 2H), 1.34–1.22 (m, 11H), 0.87 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 204.5, 163.0, 147.9, 142.1, 142.0, 141.0, 129.0 (2C), 128.6 (2C), 128.4, 128.4, 128.3 (2C), 127.1 (2C), 104.9, 99.9, 70.1, 68.2, 52.3, 44.8, 42.2, 31.5, 26.6 (3C), 19.2, 13.8; FT IR (cm⁻¹): 1739, 1649, 1538; MS (ESI+): found 491.34; calcd. for C₂₉H₃₅N₂O₅ (M + H)⁺ 491.25; EA (%) calcd. for C₂₉H₃₄N₂O₅: C 71.00, H 6.99, N 5.71; found: C 70.89, H 6.88, N 5.64.

Methyl 8-benzoyl-2-(4-bromophenyl)-4,4-diphenyl-4H-pyrazolo[5,1-d][1,3,5]dioxazine-7-carboxylate (9a) (typical procedure C)

To a solution of methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-phenylbut-2-enoate (384 mg, 1.0 mmol, 1.0 equiv.) in CHCl₃ (2 mL) was added oxalyl chloride (86 μL, 127 mg, 1.0 mmol, 1.0 equiv.) in one portion. The reaction mixture was refluxed for 90 min, then o-xylene (2 mL) was added, and chloroform was distilled out until the vapor temperature above the mixture reached 140 °C. The solution was refluxed for 10 min, 4-bromobenzaldehyde (185 mg, 1 mmol, 1.0 equiv.) was added, and the refluxing was continued for additional 15 min. Then the mixture was cooled down to RT, the solvent was evaporated under reduced pressure, and the residual solid was recrystallized from acetone to afford the titled compound as a colorless crystalline mass in 68% yield (405 mg, 0.68 mmol); mp 167–170 °C (acetone, decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.87–7.83 (m, J = 8.5, 1.6 Hz, 2H), 7.57–7.31 (m, 17H), 6.21 (s, 1H), 3.57 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.9, 162.3, 150.6, 142.8, 139.0, 138.7, 138.6, 132.9, 132.8, 132.0 (2C), 130.2, 130.0, 129.3 (2C), 129.1 (2C), 128.6 (2C), 128.4 (2C), 128.4 (2C), 128.1 (2C), 127.3 (2C), 124.7, 104.3, 96.6, 95.6, 52.3; FT IR (cm⁻¹): 1734, 1638, 1603, 1553; MS (ESI+): Found 619.12; calcd. for C₃₂H₂₃BrN₂NaO₅ (M + Na)⁺ 619.07; EA (%) calcd. for C₃₂H₂₃BrN₂O₅: C 64.55, H 3.89, N 4.70; found: C 64.61, H 3.78, N 4.67.

Methyl 2-(4-bromophenyl)-8-(4-methylbenzoyl)-4,4-diphenyl-4H-pyrazolo[5,1-d][1,3,5]dioxazine-7-carboxylate (9b)

This compound was prepared according to typical procedure C, employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (398 mg, 1.0 mmol, 1.0 equiv.), and isolated as colorless crystals in 66% yield (402 mg, 0.66 mmol); mp 187–190 °C (acetone, decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.50–7.31 (m, 12H), 7.23 (d, J = 7.9 Hz, 2H), 6.20 (s, 1H), 3.60 (s, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 162.3, 150.3, 143.8, 142.7, 139.2, 138.8, 136.2, 133.0, 132.0 (2C), 130.2, 130.0, 129.5 (2C), 129.1 (2C), 129.1 (2C), 128.6 (2C), 128.3 (2C), 128.2 (2C), 127.4 (2C), 124.7, 104.5, 96.6, 95.6, 52.2, 21.8; FT IR (cm⁻¹): 1734, 1638, 1603, 1553; MS (ESI+): found 633.03; calcd. for C₃₃H₂₅BrN₂NaO₅ (M + Na)⁺ 633.08; EA (%) calcd. for C₃₃H₂₅BrN₂O₅: C 65.03, H 4.13, N 4.60; found: C 64.77, H 4.29, N 4.56.

Methyl 2-(4-bromophenyl)-8-(4-chlorobenzoyl)-4,4-diphenyl-4H-pyrazolo[5,1-d][1,3,5]dioxazine-7-carboxylate (9d)

This compound was prepared according to typical procedure C, employing methyl 4-(4-chlorophenyl)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxobut-2-enoate (419 mg, 1.0 mmol, 1.0 equiv.) and isolated as colorless crystals in 69% yield (435 mg, 0.69 mmol); mp 170–172 °C (acetone, decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 2H), 7.57–7.31 (m, 16H), 6.21 (s, 1H), 3.63 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.4, 162.2, 150.6, 142.7, 139.4, 139.0, 138.6, 137.1, 132.7, 132.1 (2C), 130.7 (2C), 130.2, 130.1, 129.2 (2C), 128.8 (2C), 128.6 (2C), 128.4 (2C), 128.1 (2C), 127.3 (2C), 124.9, 104.1, 96.7, 95.8, 52.3; FT IR (cm⁻¹): 1733, 1641, 1588, 1552; MS (ESI+): found 652.98; calcd. for C₃₂H₂₂BrClN₂NaO₅ (M + Na)⁺ 653.03; EA (%) calcd. for C₃₂H₂₂BrClN₂O₅: C 61.02, H 3.52, N 4.45; found: C 60.81, H 3.53, N 4.43.

Methyl 8-benzoyl-2-(4-bromophenyl)-4,4-diphenyl-4H-pyrazolo[5,1-b][1,3,5]oxadiazine-7-carboxylate (10a) (typical procedure D)

To a solution of methyl (Z)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-phenylbut-2-enoate (384 mg, 1.0 mmol, 1.0 equiv.) in CHCl₃ (2 mL) was added oxalyl chloride (86 μL, 127 mg, 1.0 mmol, 1.0 equiv.) in one portion. The reaction mixture was refluxed for 90 min, then o-xylene (2 mL) was added, and chloroform was distilled out until the temperature of vapors over the mixture reached 140 °C. The solution was refluxed for 10 min, 4-bromobenzonitrile (182 mg, 1.0 mmol, 1.0 equiv.) was added, and the reaction mixture was refluxed for additional 20 min. The resulting solution was cooled down to RT, the solvent was evaporated under reduced pressure and the residual solid was recrystallized from dichloromethane-ethanol mixture (1 : 1), to afford the titled compound as colorless crystals in 62% yield (367 mg, 0.62 mmol); mp 228–230 °C (CH₂Cl₂–EtOH, 1 : 1, decomposition). ¹H NMR (400 MHz, CDCl₃) δ 7.88–7.84 (m, 2H), 7.81–7.77 (m, 2H), 7.63–7.58 (m, 1H), 7.55–7.34 (m, 14H), 3.61 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 162.0, 145.8, 145.7, 142.4, 141.7 (2C), 138.7, 133.1, 132.1 (2C), 129.8 (2C), 129.2 (2C), 129.0 (2C), 128.7 (2C), 128.5 (4C), 127.9, 127.8, 127.7 (4C), 104.4, 80.7, 52.4; FT IR (cm⁻¹): 1736, 1651, 1596, 1564; MS (ESI+): found 594.03; calcd. for C₃₂H₂₃BrN₃O₄ (M + H)⁺ 594.09; EA (%) calcd. for C₃₂H₂₂BrN₃O₄: C 64.88, H 3.74, N 7.09; found: C 64.71, H 3.82, N 7.03.

Methyl 8-(4-methylbenzoyl)-4,4-diphenyl-2-(p-tolyl)-4H-pyrazolo[5,1-b][1,3,5]oxadiazine-7-carboxylate (10b)

This compound was prepared according to typical procedure D employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (398 mg, 1.0 mmol, 1.0 equiv.) and p-tolunitrile (117 mg, 1.0 mmol, 1.0 equiv.), and isolated as a colorless crystals in 68% yield (368 mg, 0.68 mmol); mp 165–167 °C (CH₂Cl₂–EtOH, 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.49–7.43 (m, 4H), 7.40–7.32 (m, 6H), 7.29 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 3.65 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 187.4, 162.2, 146.4, 145.9, 143.9, 143.4, 142.3, 142.1 (2C), 136.2, 129.5 (2C), 129.4 (2C), 129.3 (2C), 128.8 (2C), 128.4 (6C), 127.8 (4C), 126.3, 104.5, 80.5, 52.3, 21.8, 21.7; FT IR (cm⁻¹): 1746, 1667, 1602, 1586, 1574; MS (ESI+): found 542.26; calcd. for C₃₄H₂₈N₃O₄ (M + H)⁺ 542.21; EA (%) calcd. for C₃₄H₂₇N₃O₄: C 75.40, H 5.03, N 7.76; found: C 75.21, H 4.87, N 7.73.

Methyl 2-(4-bromophenyl)-4,4-diphenyl-8-pivaloyl-4H-pyrazolo[5,1-b][1,3,5]oxadiazine-7-carboxylate (10c)

This compound was prepared according to typical procedure D employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-5,5-dimethyl-4-oxohex-2-enoate (364 mg, 1.0 mmol, 1.0 equiv.) and 4-bromobenzonitrile (182 mg, 1 mmol, 1.0 equiv.), and isolated as colorless crystals in 57% yield (326 mg, 0.57 mmol); mp 162–164 °C (CH₂Cl₂–EtOH, 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.91 (m, 2H), 7.64–7.58 (m, 2H), 7.40–7.32 (m, 10H), 3.84 (s, 3H), 1.33 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 204.3, 162.1, 145.8, 141.9, 141.8 (2C), 140.7, 132.2 (2C), 129.6 (2C), 128.9 (2C), 128.4 (4C), 128.3, 127.7, 127.6 (4C), 105.2, 80.6, 52.5, 45.5, 26.6 (3C); FT IR (cm⁻¹): 1738, 1680, 1657, 1588, 1539; MS (ESI+): found 574.06; calcd. for C₃₀H₂₇BrN₃O₄ (M + H)⁺ 574.12; EA (%) calcd. for C₃₀H₂₆BrN₃O₄: C 62.94, H 4.58, N 7.34; found: C 62.81, H 4.40, N 7.29.

Methyl 8-(4-chlorobenzoyl)-4,4-diphenyl-2-(p-tolyl)-4H-pyrazolo[5,1-b][1,3,5]oxadiazine-7-carboxylate (10d)

This compound was prepared according to typical procedure D employing methyl 4-(4-chlorophenyl)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxobut-2-enoate (419 mg, 1.0 mmol, 1.0 equiv.) and p-tolunitrile (117 mg, 1.0 mmol, 1.0 equiv.), and isolated as colorless crystals in 76% yield (427 mg, 0.76 mmol); mp 115–117 °C (CH₂Cl₂–EtOH, 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.79 (m, 4H), 7.48–7.33 (m, 12H), 7.20 (d, J = 8.2 Hz, 2H), 3.67 (s, 3H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 186.4, 162.0, 146.3, 146.1, 143.6, 142.3, 142.0 (2C), 139.5, 137.2, 130.7 (2C), 129.5 (2C), 129.0 (2C), 128.9 (2C), 128.4 (4C), 128.3 (2C), 127.7 (4C), 126.2, 104.1, 80.6, 52.4, 21.7; FT IR (cm⁻¹): 1737, 1673, 1653, 1566; MS (ESI+): found 562.23; calcd. for C₃₃H₂₅ClN₃O₄ (M + H)⁺ 562.15; EA (%) calcd. for C₃₃H₂₄ClN₃O₄: C 70.52, H 4.30, N 7.48; found: C 70.36, H 4.27, N 7.32.

Methyl 2,4,4-triphenyl-8-pivaloyl-4H-pyrazolo[5,1-b][1,3,5]oxadiazine-7-carboxylate (10e)

This compound was prepared according to typical procedure D employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-5,5-dimethyl-4-oxohex-2-enoate (364 mg, 1.0 mmol, 1.0 equiv.) and benzonitrile (102 μL, 103 mg, 1.0 mmol, 1.0 equiv.), and isolated as colorless crystals in 75% yield (370 mg, 0.75 mmol); mp 115–117 °C (CH₂Cl₂–EtOH, 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (dt, J = 8.6, 1.8 Hz, 2H), 7.58–7.53 (m, 1H), 7.50–7.44 (m, 2H), 7.41–7.32 (m, 10H), 3.85 (s, 3H), 1.34 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 204.3, 162.2, 146.4, 142.1, 142.0 (2C), 140.8, 132.7, 129.3, 128.9 (2C), 128.8 (2C), 128.4 (4C), 128.2 (2C), 127.7 (4C), 105.2, 80.5, 52.5, 45.4, 26.6 (3C); FT IR (cm⁻¹): 1749, 1731, 1682, 1662, 1568, 1545; MS (ESI+): found 494.27; calcd. for C₃₀H₂₈N₃O₄ (M + H)⁺ 494.21; EA (%) calcd. for C₃₀H₂₇N₃O₄: C 73.01, H 5.51, N 8.51; found: C 72.89, H 5.35, N 8.43.

Methyl (Z)-2-((adamantan-1-yl)imino)-7-(4-methylbenzoyl)-3,3-diphenyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (11b) (typical procedure E)

To a solution of methyl 2-(2-(diphenylmethylene)hydrazinyl)-4-oxo-4-(p-tolyl)but-2-enoate (398 mg, 1.0 mmol, 1.0 equiv.) in CHCl₃ (2.0 mL) was added oxalyl chloride (86 μL, 127 mg, 1 mmol, 1.0 equiv.) in one portion. The reaction mixture was refluxed for 90 min, then o-xylene (2 mL) was added, and chloroform was distilled out until the temperature of vapors over the mixture reached 120 °C. The solution was refluxed 15 min, and 1-isocyanoadamantane (161 mg, 1.0 mmol, 1.0 equiv.) was added. The resulting solution was cooled down to RT, the solvent was evaporated under reduced pressure and the residual solid was recrystallized from acetone, affording the titled compound as a colorless crystalline mass in 49% yield (287 mg, 0.49 mmol); mp 205–207 °C (acetone). ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.74 (m, 2H), 7.51–7.43 (m, 4H), 7.40–7.31 (m, 6H), 7.29–7.24 (m, 2H), 3.79 (s, 3H), 2.41 (s, 3H), 2.02 (br s, 3H), 1.86–1.92 (m, 6H), 1.69–1.53 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 185.9, 162.4, 152.3, 149.8, 146.9, 143.7, 138.8 (2C), 135.8, 129.5 (2C), 129.2 (2C), 128.9 (2C), 128.7 (4C), 127.7 (4C), 100.2, 72.2, 57.8, 52.6, 42.6 (3C), 36.3 (3C), 29.7 (3C), 21.8; FT IR (cm⁻¹): 1761, 1744, 1652, 1609, 1566; MS (ESI+): found 608.16; calcd. for C₃₇H₃₅N₃NaO₄ (M + Na)⁺ 608.25; EA (%) calcd. for C₃₇H₃₅N₃O₄: C 75.88, H 6.02, N 7.17; found: C 75.82, H 5.89, N 7.15.

Methyl (Z)-2-((adamantan-1-yl)imino)-3,3-diphenyl-7-pivaloyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (11c)

This compound was prepared according to typical procedure E employing methyl 2-(2-(diphenylmethylene)hydrazinyl)-5,5-dimethyl-4-oxohex-2-enoate (3c) (364 mg, 1 mmol, 1.0 equiv.) and isolated as colorless crystals in 41% yield (227 mg, 0.41 mmol); mp 173–175 °C (acetone). ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.39 (m, 4H), 7.37–7.31 (m, 6H), 3.90 (s, 3H), 2.11 (br s, 3H), 2.02 (br d, J = 2.0 Hz, 6H), 1.75–1.64 (m, 6H), 1.32 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 200.1, 163.1, 149.6, 148.7, 147.7, 139.0 (2C), 128.9 (2C), 128.7 (4C), 127.7 (4C), 99.1, 72.1, 57.7, 52.7, 44.3, 42.8 (3C), 36.5 (3C), 29.8 (3C), 26.3 (3C); FT IR (cm⁻¹): 1741, 1677, 1580; MS (ESI+): found 552.17; calcd. for C₃₄H₃₈N₃O₄ (M + H)⁺ 552.29; EA (%) calcd. for C₃₄H₃₇N₃O₄: C 74.02, H 6.76, N 7.62; found: C 74.19, H 6.60, N 7.66.

Methyl (Z)-2-((adamantan-1-yl)imino)-7-(4-chlorobenzoyl)-3,3-diphenyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (11d)

This compound was prepared according to typical procedure E employing methyl 4-(4-chlorophenyl)-2-(2-(diphenylmethylene)hydrazinyl)-4-oxobut-2-enoate (419 mg, 1.0 mmol, 1.0 equiv.) and isolated as a colorless solid in 56% yield (339 mg, 0.56 mmol); mp 203–205 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.78 (m, 2H), 7.49–7.41 (m, 6H), 7.40–7.32 (m, 6H), 3.81 (s, 3H), 2.04 (br s, 3H), 1.93–1.86 (m, 6H), 1.72–1.54 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 184.9, 162.2, 152.6, 149.2, 146.8, 139.4, 138.7 (2C), 136.8, 130.6 (2C), 129.0 (2C), 128.8 (2C), 128.7 (4C), 127.6 (4C), 99.8, 72.3, 58.0, 52.7, 42.7 (3C), 36.3 (3C), 29.7 (3C); FT IR (cm⁻¹): 1767, 1736, 1655, 1585, 1564; MS (ESI+): found 606.24; calcd. for C₃₆H₃₃ClN₃O₄ (M + H)⁺ 606.22; EA (%) calcd. for C₃₆H₃₂ClN₃O₄: C 71.34, H 5.32, N 6.93; found C 71.16, H 5.19, N 6.87.

Procedure for interception of dipoles generated by decomposition of dimeric adducts

11b. Solution of dimethyl 3,9-bis(4-methylbenzoyl)-5,5,11,11-tetraphenyl-5H,11H-dipyrazolo[5,1-b:5′,1′-f][1,5,3,7]dioxadiazocine-2,8-dicarboxylate (7b) (424 mg, 0.5 mmol, 1.0 equiv.) in o-xylene (8 mL) was stirred at reflux for 10 min, and 1-isocyanoadamantane (161 mg, 1.0 mmol, 2.0 equiv.) was added in one portion. The resulting solution was cooled down to RT and concentrated under reduced pressure. The residual solid was recrystallized from acetone to afford compound 11b as a colorless crystalline mass in 32% yield (188 mg, 0.32 mmol).

11c. Mixture of dimethyl 1,7-dioxo-5,5,11,11-tetraphenyl-2,8-dipivaloyl-1H,5H,7H,11H-dipyrazolo[1,2-a:1′,2′-d][1,2,4,5]tetrazine-3,9-dicarboxylate (6c) (39 mg, 0.05 mmol, 1.0 equiv.) and 1-isocyanoadamantane (16 mg, 0.1 mmol, 2.0 equiv.) was heated at 220 °C in a sealed ampule for 1 min, then cooled down to RT. The crude solid was recrystallized from acetone to afford compound 11c as a colorless crystalline mass in 67% yield (37 mg, 0.067 mmol).

Acknowledgements

Financial support for this work was provided by Ministry of Education and Science of Russian Federation (grant #965).

Notes and references

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9. For contributions from other research groups, see: (a) D. Cantillo, H. Sheibani and C. O. Kappe, J. Org. Chem., 2012, 77, 2463; (b) L. George, K.-P. Netsch, G. Penn, G. Kollenz and C. Wentrup, Org. Biomol. Chem., 2006, 4, 558; (c) E. Sarıpınar and S. Karataş, J. Heterocycl. Chem., 2005, 42, 787; (d) N. A. Lisowskaya, M. Alajarin and P. Sanchez-Andrada, Eur. J. Org. Chem., 2006, 1468.
10. N. A. Lisowskaya, A. N. Maslivets and Z. A. Aliev, Tetrahedron, 2004, 60, 5319.
11. G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008, 64, 112.
12. L. J. Farrugia, J. Appl. Crystallogr., 2012, 45, 849.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. CCDC 1457141–1457145. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra21981k

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