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Introduction
Conjugated dienes constitute a seminal molecular building block due to their potential use in the construction of six-membered rings through a concerted [4+2] Diels-Alder addition [1]. Moreover, they may have an important role in the regio- and stereoselective synthesis of highly functionalized double bonds [2]. Since the Diels-Alder reaction is relevant from a theoretical [3] and synthetic viewpoint [4], a diversity of dienes has been designed and synthesized, including outer-ring o-carbodimethylenes [5]. There has been considerable interest in the preparation of exo-heterocyclic dienes for the study of their reactivity [5b,5c,6], given that their heteroatoms increase such reactivity and allow for much greater versatility in the functionalization of the cycloadducts.
Over the years, our group has described the regio- and stereoselective one-pot synthesis of novel N-substituted exo-2-oxazolidinone dienes 1-3[7] via a base-assisted condensation of α-diketones 4 and isocyanates 5 (Scheme 1). This method has been adopted for the synthesis of 1,4-disubstituted exocyclic dienes [8] and heterocycle-fused endo-cyclohexenic dienes [9], which undergo regioselective Diels-Alder cycloadditions to monosubstituted dienophiles with electron-withdrawing groups. The corresponding adducts were useful precursors for preparing 2-(3H)-benzoxazolones 6[10], which were involved in a general approach for the formation of the carbazole scaffold 7[11], being applicable in the total synthesis of natural carbazoles [12]. Furthermore, dienes 1-3 have been efficient substrates for the synthesis of Fe(CO)3 complexes and their conversion into conjugated enamido-enol Fe(CO)3 complexes [13], or new polycyclic oxazol-2-one derivatives, in the latter case by reacting them with Fischer (arylalkynyl)(alkoxy)carbenes [14].
A single-step and regioselective procedure was developed by our group to prepare 4-oxazolin-2-ones 9 and 4-methylidene-2-oxazolidinones 10 through a solvent-free condensation between isocyanates 5 and α-ketols 8, carried out under conventional heating or microwave (MW)-assisted thermal conditions (Scheme 2) [15,16]. Both heterocycles served as a building block for the divergent synthesis of propellane compounds [9], α-hydroxyamides [16], aza-polycyclic compounds [17], enantiopure heterocyclic frameworks [18], natural pyridocarbazoles [19], and functionalized indoles [20].
Due to the synthetic potential and versatility of 4-oxazolin-2-ones 9, a new approach for their formation is presently explored, starting from N-substituted exo-2-oxazolidinone dienes 1 and 2 and proceeding to a Brønsted acid-promoted addition of a variety of nucleophiles to generate a series of 4-methyl-5-substituted 4-oxazolin-2-ones.
Moreover, novel exo-imidazolidin-2-one dienes 15 and 16 were synthesized as part of our ongoing research on the elaboration of new exo-heterocyclic dienes and the examination of their reactivity in Diels-Alder reactions (Scheme 3) [21,22]. Symmetrical N,N’-substituted dienes 15 were prepared through two routes. The first one was based on the reaction of α-iminoketones 11-12 with isocyanates 5 under basic conditions [21] and the second on a bis-condensation of α-bis-imino compounds 13 with triphosgene (14) [22]. The first approach was applied in the case of unsymmetrical dienes 16, utilizing α-iminoketones 12 and isocyanates 5 substituted by different aryl rings [21]. The Diels-Alder addition of dienes 15 with symmetrical or unsymmetrical dienophiles afforded the respective adducts 17, which underwent a subsequent aromatization to give to benzimidazol-2-ones 18 (Scheme 3) [21,22]. The processes with unsymmetrical dienes and dienophiles resulted in a mixture of regioisomers, except when catalysis was performed with a Lewis acid [22].
Scheme 3 Synthesis of exo-imidazolidin-2-one dienes 15 and 16 as precursors of benzimidazol-2-ones 18.
Owing to the pharmacological value of benzimidazol-2-ones as potent antagonists of neurokinin NK1[23], calcitonin gene-related peptide (CGRP) [24], 5-HT4[25], and progesterone [26] receptors, and as anticancer agents [27], a variety of tricyclic benzo[d]imidazol-2-ones are herein synthesized through the Diels-Alder cycloadditions of dienes 15 and 16 with symmetrical dienophiles such as N-phenylmaleimide (19) and benzyne (20).
Experimental
General
Melting points were determined with a capillary Krüss KSP 1N melting point apparatus. The IR spectra were recorded on Perkin-Elmer 2000 and Smiths Detection IlluminatIR (ATR) spectrophotometers. 1H (300, 500, or 600 MHz) and 13C (75.4, 125, or 150 MHz) NMR spectra were recorded on Varian Mercury (300 MHz), Varian VNMR System (500 MHz), and Bruker 600AVANCE III (600 MHz) spectrometers, with TMS and CDCl3 as internal standards. Assignment of the NMR signals was made by HMQC, HSQC, and HMBC 2D methods. Mass spectra (MS) were obtained in the electron impact (EI) (70 eV) mode on Thermo Polaris Q-Trace GC Ultra and Hewlett-Packard 5971A spectrometers. High-resolution mass spectra (HRMS) were captured in the ionization mode on Jeol JSM-GcMateII and Bruker MicrOTOF-Q II spectrometers. MW irradiation was generated in a CEM MW reactor. Analytical thin-layer chromatography was carried out on 0.25 plates coated with silica gel 60 F254 (E. Merck), which were visualized by a long- and short-wavelength UV lamp. Flash column chromatography was performed over silica gel (230-400 mesh, Natland International Co.). All air moisture sensitive reactions were carried out under N2 atmosphere with oven-dried glassware. Triethylamine (TEA) was distilled on NaOH. Toluene and MeOH were freshly distilled over sodium, and DMF, DMSO, and CH2Cl2 over 4Å molecular sieves and then over CaH2. Li2CO3 was dried overnight at 200 °C prior to use. All other reagents were employed without further purification. Compounds 1a-c, 2a-c, 15a, 16a-b, 16d, and 32a-c were prepared as reported [7,10,15,21,22].
5-(Methoxymethyl)-4-methyl-3-phenyloxazol-2(3H)-one (22a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 1a (0.121 g, 0.65 mmol), MeOH (1.58 g, 49.4 mmol), and HCl (38 %) (0.061 g, 0.63 mmol) were mixed under N2 atmosphere at rt. The mixture was stirred for 1 h, dissolved in CH2Cl2 (10 mL), and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL) and water (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 8:2) resulting in 22a (0.131 g, 92%) as a yellow oil. Rf 0.32 (hexane/EtOAc, 7:3). IR (film): ῡ = 1759, 1598, 1505, 1380, 1191, 1096, 1045, 983, 767, 715, 695 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.95 (s, 3H, CH 3-C4), 3.42 (s, 3H, CH 3O), 4.26 (s, 2H, CH 2OMe), 7.27-7.31 (m, 2H, H-2ʼ), 7.37-7.43 (m, 1H, H-4ʼ), 7.45-7.50 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 58.1 (CH3O), 63.1 (CH2OMe), 122.9 (C-4), 126.9 (C-2ʼ), 128.5 (C-4ʼ), 129.4 (C-3ʼ), 132.5 (C-5), 133.3 (C-1ʼ), 154.2 (C-2). HRMS (EI, [M+]): m/z calcd for C12H13NO3: 219.0895; found: 219.0901.
5-(Methoxymethyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (22b). Following the method for preparing 22a, a mixture of 1b (0.050 g, 0.25 mmol), MeOH (1.58 g, 49.4 mmol), and HCl (38 %) (0.053 g, 0.55 mmol) generated 22b (0.048 g, 83%) as a yellow oil. Rf 0.21 (hexane/EtOAc, 7:3). IR (film): ῡ = 2927, 1755, 1699, 1516, 1452, 1380, 1282, 1244, 1170, 1094, 1045, 985, 820, 756, 723 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.94 (br s, 3H, CH 3-C4), 2.40 (br s, 3H, CH 3Ar), 3.42 (s, 3H, CH 3O), 4.26 (br s, 2H, CH 2OMe), 7.16-7.19 (m, 2H, H-2ʼ), 7.26-7.29 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 21.1 (CH3Ar), 58.1 (CH3O), 63.2 (CH2OMe), 123.1 (C-4), 126.9 (C-2ʼ), 130.1 (C-3ʼ), 130.7 (C-1ʼ), 132.4 (C-5), 138.7 (C-4ʼ), 154.4 (C-2). HRMS (EI, [M+]): m/z calcd for C13H15NO3: 233.1052; found: 233.1054.
5-(Methoxymethyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (22c). Following the method for preparing 22a, a mixture of 1c (0.050 g, 0.23 mmol), MeOH (1.58 g, 49.4 mmol), and HCl (38 %) (0.052 g, 0.54 mmol) gave 22c (0.048 g, 84%) as a yellow oil. Rf 0.13 (hexane/EtOAc, 7:3). IR (film): ῡ = 2933, 1756, 1516, 1444, 1383, 1299, 1250, 1168, 1094, 1044, 984, 835, 757 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.92 (br s, 3H, CH 3-C4), 3.42 (s, 3H, CH 3O), 3.83 (s, 3H, CH 3OAr), 4.25 (br s, 2H, CH 2OMe), 6.96-6.70 (m, 2H, H-3ʼ), 7.19-7.23 (m, 2H, H-2ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 55.6 (CH3O), 58.2 (CH3OAr), 63.2 (CH2OMe), 114.8 (C-3ʼ), 123.3 (C-4), 126.0 (C-1ʼ), 128.5 (C-2ʼ), 132.3 (C-5), 154.6 (C-2), 159.7 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C13H15NO4: 249.1001; found: 249.1004.
(4-Methyl-2-oxo-3-phenyl-2,3-dihydrooxazol-5-yl)methyl acetate (23a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 1a (0.029 g, 0.16 mmol) and glacial AcOH (1.05 g, 17.5 mmol) in CH2Cl2 (2 mL) were mixed under N2 atmosphere at rt and stirred for 24 h. The mixture was dissolved in CH2Cl2 (5 mL) and washed in an aqueous saturated solution of NaHCO3 (3 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 8:2) to provide 23a (0.037 g, 95%) as a yellow oil. Rf 0.25 (hexane/EtOAc, 7:3). IR (film): ῡ = 2928, 1765, 1743, 1598, 1505, 1380, 1365, 1220, 1047, 1022, 986, 768, 712, 695 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.98 (br s, 3H, CH 3-C4), 2.11 (s, 3H, CH 3CO2), 4.91 (br s, 2H, CH 2OAc), 7.28-7.31 (m, 2H, H-2”), 7.39-7.44 (m, 1H, H-4”), 7.45-7.50 (m, 2H, H-3”). 13C NMR (125 MHz, CDCl3): δ 8.9 (CH3-C4), 20.8 (CH3CO2), 55.0 (CH2OAc), 124.4 (C-4ʼ), 126.9 (C-2”), 128.7 (C-4”), 129.5 (C-3”), 130.5 (C-5ʼ), 133.1 (C-1”), 154.0 (C-2ʼ), 170.7 (CH3 CO2). HRMS (EI, [M+]): m/z calcd for C13H13NO4: 247.0845; found: 247.0845.
(4-Methyl-2-oxo-3-(p-tolyl)-2,3-dihydrooxazol-5-yl)methyl acetate (23b). Following the method for preparing 23a, a mixture of 1b (0.050 g, 0.25 mmol) and glacial AcOH (1.05 g, 17.5 mmol) in CH2Cl2 (4 mL) afforded 23b (0.053 g, 81 %) as a yellow oil. Rf 0.28 (hexane/EtOAc, 7:3). IR (film): ῡ = 1770, 1744, 1519, 1398, 1364, 1220, 1046, 1022, 988, 820, 756 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.97 (br s, 3H, CH 3-C4), 2.11 (s, 3H, CH 3CO2), 2.39 (br s, 3H, CH 3Ar), 4.91 (br s, 2H, CH 2OAc), 7.15-7.19 (m, 2H, H-2”), 7.25-7.30 (m, 2H, H-3”). 13C NMR (125 MHz, CDCl3): δ 8.9 (CH3-C4), 20.8 (CH3CO2), 21.1 (CH3Ar), 55.1 (CH2OAc), 124.6 (C-4ʼ), 126.8 (C-2”), 130.2 (C-3”), 130.4 (C-5ʼ), 130.5 (C-1”), 138.9 (C-4”), 154.2 (C-2ʼ), 170.7 (CH3 CO2). HRMS (EI, [M+]): m/z calcd for C14H15NO4: 261.1001; found: 261.1000.
(3-(4-Methoxyphenyl)-4-methyl-2-oxo-2,3-dihydrooxazol-5-yl)methyl acetate (23c). Following the method for preparing 23a, a mixture of 1c (0.050 g, 0.23 mmol) and glacial AcOH (1.05 g, 17.5 mmol) in CH2Cl2 (4 mL) furnished 23c (0.037 g, 59 %) as a yellow oil. Rf 0.13 (hexane/EtOAc, 7:3). IR (film): ῡ = 2937, 1766, 1744, 1516, 1443, 1398, 1365, 1300, 1249, 1221, 1169, 1046, 1025, 987, 837, 757 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.95 (br s, 3H, CH 3-C4), 2.11 (s, 3H, CH 3CO2), 3.84 (s, 3H, CH 3OAr), 4.91 (br s, 2H, CH 2OAc), 6.96-7.00 (m, 2H, H-3”), 7.18-7.22 (m, 2H, H-2”). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 20.8 (CH3CO2), 55.1 (CH2OAc), 55.5 (CH3OAr), 114.8 (C-3”), 124.7 (C-4ʼ), 125.8 (C-1”), 128.4 (C-2”), 130.3 (C-5ʼ), 154.4 (C-2ʼ), 159.7 (C-4”), 170.7 (CH3 CO2). HRMS (EI, [M+]): m/z calcd for C14H15NO5: 277.0950; found: 277.0949.
5-(((4-Chlorophenyl)thio)methyl)-4-methyl-3-phenyloxazol-2(3H)-one (24a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 1a (0.06 g, 0.32 mmol), 21c (0.089 g, 0.62 mmol), and H3PO4 (85 %) (0.036 g, 0.31 mmol) in CH2Cl2 (5 mL) were mixed under N2 atmosphere at rt and stirred for 24 h. The mixture was dissolved in CH2Cl2 (10 mL) and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 85:15) to obtain 24a (0.063 g, 60%) as a yellow solid. Rf 0.38 (hexane/EtOAc, 7:3); mp 106-108 °C. IR (film): ῡ = 1756, 1698, 1597, 1504, 1476, 1382, 1272, 1186, 1095, 1040, 1012, 981, 819, 766, 709, 604 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.59 (br s, 3H, CH 3-C4), 3.85 (br s, 2H, CH 2S), 7.19-7.22 (m, 2H, H-2ʼ), 7.28-7.32 (m, 2H, H-3”), 7.37-7.42 (m, 3H, H-4ʼ, H-2”), 7.44-7.49 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.6 (CH3-C4), 30.2 (CH2S), 121.3 (C-4), 126.9 (C-2ʼ), 128.6 (C-4ʼ), 129.2 (C-3”), 129.5 (C-3ʼ), 131.2 (C-5), 132.8 (C-1”), 133.3 (C-1ʼ), 134.2 (C-4”), 134.3 (C-2”), 154.0 (C-2). HRMS (ESI, [M + H]+): m/z calcd for C17H15ClNO2S: 332.0512; found: 332.0465.
5-(((4-Chlorophenyl)thio)methyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (24b). Following the method for preparing 24a, a mixture of 1b (0.040 g, 0.20 mmol), 21c (0.056 g, 0.39 mmol), and H3PO4 (85 %) (0.028 g, 0.24 mmol) in CH2Cl2 (5 mL) yielded 24b (0.052 g, 75%) as a yellow solid. Rf 0.44 (hexane/EtOAc, 7:3); mp 103-104 °C. IR (KBr): ῡ = 1751, 1694, 1516, 1478, 1387, 1270, 1191, 1092, 1039, 1011, 988, 817, 755 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.57 (br s, 3H, CH 3-C4), 2.38 (br s, 3H, CH 3Ar), 3.85 (br s, 2H, CH 2S), 7.07-7.10 (m, 2H, H-2ʼ), 7.24-7.27 (m, 2H, H-3ʼ), 7.28-7.31 (m, 2H, H-3”), 7.38-7.41 (m, 2H, H-2”). 13C NMR (150 MHz, CDCl3): δ 8.5 (CH3-C4), 21.1 (CH3Ar), 30.2 (CH2S), 121.4 (C-4), 126.7 (C-2ʼ), 129.1 (C-3”), 130.1 (C-3ʼ), 130.6 (C-1ʼ), 130.9 (C-5), 132.8 (C-1”), 134.1 (C-4”), 134.3 (C-2”), 138.7 (C-4ʼ), 154.1 (C-2). HRMS (EI, [M+]): m/z calcd for C18H16ClNO2S: 345.0590; found: 345.0589.
5-(((4-Chlorophenyl)thio)methyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (24c). Following the method for preparing 24a, a mixture of 1c (0.040 g, 0.18 mmol), 21c (0.054 g, 0.37 mmol), and H3PO4 (85 %) (0.029 g, 0.25 mmol) in CH2Cl2 (3 mL) generated 24c (0.049 g, 74%) as a yellow solid. Rf 0.38 (hexane/EtOAc, 7:3); mp 84-86 °C. IR (film): ῡ = 2930, 1759, 1698, 1515, 1476, 1387, 1300, 1251, 1169, 1095, 1036, 1012, 983, 832, 755 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.55 (br s, 3H, CH 3-C4), 3.82 (s, 3H, CH 3O), 3.84 (br s, 2H, CH 2S), 6.94-6.98 (m, 2H, H-3ʼ), 7.10-7.14 (m, 2H, H-2ʼ), 7.28-7.31 (m, 2H, H-3”), 7.37-7.41 (m, 2H, H-2”). 13C NMR (125 MHz, CDCl3): δ 8.5 (CH3-C4), 30.2 (CH2S), 55.5 (CH3O), 114.8 (C-3ʼ), 121.6 (C-4), 125.9 (C-1ʼ), 128.3 (C-2ʼ), 129.1 (C-3”), 130.8 (C-5), 132.9 (C-1”), 134.1 (C-4”), 134.3 (C-2”), 154.3 (C-2), 159.6 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C18H16ClNO3S: 361.0539; found: 361.0535.
5-(4-Hydroxybenzyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (25a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 1a (0.06 g, 0.32 mmol), 21d (0.06 g, 0.64 mmol), and H3PO4 (85 %) (0.062 g, 0.54 mmol) in CH2Cl2 (5 mL) were mixed under N2 atmosphere at rt and stirred for 24 h. The mixture was dissolved in CH2Cl2 (10 mL) and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL) and EtOAc (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 7:3), resulting in 25a (0.058 g, 64 %) as a yellow oil. Rf 0.21 (hexane/EtOAc, 7:3). IR (film): ῡ = 3328, 1737, 1699, 1614, 1597, 1515, 1504, 1388, 1265, 1227, 1171, 1044, 986, 833, 766, 695 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.86 (br s, 3H, CH 3-C4), 3.67 (br s, 2H, CH 2Ar), 6.77-6.79 (m, 2H, H-3”), 7.03-7.07 (m, 2H, H-2”), 7.26-7.28 (m, 2H, H-2ʼ), 7.35-7.38 (m, 1H, H-4ʼ), 7.42-7.46 (m, 2H, H-3ʼ). 13C NMR (150 MHz, CDCl3): δ 8.7 (CH3-C4), 30.0 (CH2Ar), 115.6 (C-3”), 118.5 (C-4), 126.9 (C-2ʼ), 127.6 (C-1”), 128.5 (C-4ʼ), 129.39 (C-2”), 129.43 (C-3ʼ), 133.3 (C-1ʼ), 135.6 (C-5), 155.0 (C-2), 155.5 (C-4”). HRMS (ESI, [M + H]+): m/z calcd for C17H15NO3: 282.1130; found: 282.1072.
5-(4-Hydroxybenzyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (25b). Following the method for preparing 25a, a mixture of 1b (0.080 g, 0.40 mmol), 21d (0.075 g, 0.80 mmol), and H3PO4 (85 %) (0.077 g, 0.67 mmol) in CH2Cl2 (5 mL) gave 25b (0.081 g, 69 %) as a yellow solid. Rf 0.21 (hexane/EtOAc, 7:3); mp 218-220 °C. IR (KBr): ῡ = 3256, 1733, 1695, 1614, 1515, 1452, 1393, 1276, 1261, 1234, 1173, 994, 825, 758 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.88 (br s, 3H, CH 3-C4), 2.38 (br s, 3H, CH 3Ar), 3.69 (s, 2H, CH 2Ar), 5.81 (br, 1H, OH), 6.80-6.83 (m, 2H, H-3”), 7.11-7.14 (m, 2H, H-2”), 7.16-7.19 (m, 2H, H-2ʼ), 7.24-7.26 (m, 2H, H-3ʼ). 13C NMR (150 MHz, CDCl3): δ 8.8 (CH3-C4), 21.1 (CH3Ar), 30.1 (CH2Ar), 115.6 (C-3”), 118.6 (C-4), 126.8 (C-2ʼ), 128.4 (C-1”), 129.6 (C-2”), 130.1 (C-3ʼ), 130.9 (C-1ʼ), 135.1 (C-5), 138.6 (C-4ʼ), 154.9 (C-2 or C-4”), 155.0 (C-4” or C-2). HRMS (EI, [M+]): m/z calcd for C18H17NO3: 295.1208; found: 295.1218.
5-(4-Hydroxybenzyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (25c). Following the method for preparing 25a, a mixture of 1c (0.065 g, 0.3 mmol), 21d (0.056 g, 0.6 mmol), and H3PO4 (85 %) (0.058 g, 0.5 mmol) in CH2Cl2 (5 mL) provided 25c (0.079 g, 85 %) as a yellow solid. Rf 0.12 (hexane/EtOAc, 7:3); mp 194-195 °C. IR (KBr): ῡ = 3359, 1751, 1702, 1611, 1596, 1515, 1444, 1401, 1300, 1247, 1227, 1168, 1028, 989, 833, 757, 683 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.84 (br s, 3H, CH 3-C4), 3.69 (br s, 2H, CH 2Ar), 3.83 (s, 3H, CH 3O), 6.81-6.84 (m, 2H, H-3”), 6.94-6.98 (m, 2H, H-3ʼ), 7.09-7.13 (m, 2H, H-2”), 7.18-7.22 (m, 2H, H-2ʼ), 7.36 (br, 1H, OH). 13C NMR (125 MHz, CDCl3): δ 8.5 (CH3-C4), 30.0 (CH2Ar), 55.4 (CH3O), 114.6 (C-3ʼ), 115.5 (C-3”), 118.5 (C-4), 126.2 (C-1ʼ), 127.8 (C-1”), 128.3 (C-2ʼ), 129.4 (C-2”), 134.8 (C-5), 154.8 (C-2), 155.5 (C-4”), 159.3 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C18H17NO4: 311.1158; found: 311.1154.
5-(1-Methoxyethyl)-4-methyl-3-phenyloxazol-2(3H)-one (26a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 2a (0.060 g, 0.30 mmol), 21a (2.37 g, 74.0 mmol), and HCl (38 %) (0.062 g, 0.65 mmol) were mixed and stirred under N2 atmosphere at -10 ºC for 24 h. The mixture was dissolved in CH2Cl2 (5 mL) and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL) and EtOAc (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 75:25), leading to 26a (0.046 g, 67%) as a yellow solid. Rf 0.31 (hexane/EtOAc, 7:3); mp 100-102 °C. IR (KBr): ῡ = 3054, 2987, 2936, 1746, 1693, 1598, 1504, 1396, 1259, 1116, 1090, 991, 767, 752, 712 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.51 (d, J = 6.5 Hz, 3H, H-2”), 1.96 (s, 3H, CH 3-C4), 3.31 (s, 3H, CH 3O), 4.25 (q, J = 6.5 Hz, 1H, H-1”), 7.30-7.33 (m, 2H, H-2ʼ), 7.39-7.43 (m, 1H, H-4ʼ), 7.46-7.51 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 18.7 (C-2”), 55.9 (CH3O), 69.4 (C-1”), 121.1 (C-4), 127.0 (C-2ʼ), 128.5 (C-4ʼ), 129.5 (C-3ʼ), 133.3 (C-1ʼ), 134.5 (C-5), 154.3 (C-2). HRMS (EI, [M+]): m/z calcd for C13H15NO3: 233.1052; found: 233.1046.
5-(1-Methoxyethyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (26b). Following the method for preparing 26a, a mixture of 2b (0.060 g, 0.28 mmol), 21a (2.38 g, 74.4 mmol), and HCl (38 %) (0.068 g, 0.71 mmol) produced 26b (0.047 g, 69 %) as a yellow solid. Rf 0.26 (hexane/EtOAc, 7:3); mp 84-86 °C. IR (film): ῡ = 2986, 2931, 1760, 1698, 1519, 1450, 1398, 1387, 1351, 1258, 1117, 1088, 994, 981, 821, 757, 723 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.50 (d, J = 6.5 Hz, 3H, H-2”), 1.94 (s, 3H, CH 3-C4), 2.39 (br s, 3H, CH 3Ar), 3.31 (s, 3H, CH 3O), 4.24 (q, J = 6.5 Hz, 1H, H-1”), 7.17-7.21 (m, 2H, H-2ʼ), 7.25-7.30 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.7 (CH3-C4), 18.7 (C-2”), 21.1 (CH3Ar), 55.9 (CH3O), 69.5 (C-1”), 121.3 (C-4), 126.9 (C-2ʼ), 130.1 (C-3ʼ), 130.7 (C-1ʼ), 134.3 (C-5) 138.6 (C-4ʼ), 154.4 (C-2). HRMS (EI, [M+]): m/z calcd for C14H17NO3: 247.1208; found: 247.1215.
5-(1-Methoxyethyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (26c). (Z)-5-Ethylidene-4-methoxy-3-(4-methoxyphenyl)-4-methyloxazolidin-2-one (26c’). Following the method for preparing 26a, a mixture of 2c (0.060 g, 0.26 mmol), 21a (2.38 g, 74.4 mmol), and HCl (38 %) (0.063 g, 0.66 mmol) afforded 26c (0.05 g, 73 %) and 26c’ (0.01 g, 15%) as yellow solids. Data for 26c: Rf 0.21 (hexane/EtOAc, 7:3); mp 88-90 °C. IR (film): ῡ = 2985, 2936, 1759, 1698, 1610, 1517, 1444, 1399, 1351, 1301, 1252, 1168, 1117, 1088, 1033, 981, 836, 758 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.50 (d, J = 6.5 Hz, 3H, H-2”), 1.93 (s, 3H, CH 3-C4), 3.31 (s, 3H, CH 3O), 3.84 (s, 3H, CH 3OAr), 4.24 (q, J = 6.5 Hz, 1H, H-1”), 6.96-7.00 (m, 2H, H-3ʼ), 7.20-7.24 (m, 2H, H-2ʼ). 13C NMR (125 MHz, CDCl3): δ 8.7 (CH3-C4), 18.8 (C-2”), 55.5 (CH3OAr), 55.9 (CH3O), 69.5 (C-1”), 114.8 (C-3ʼ), 121.4 (C-4), 125.9 (C-1ʼ), 128.5 (C-2ʼ), 134.2 (C-5), 154.6 (C-2), 159.6 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C14H17NO4: 263.1158; found 263.1158. Data for 26c’: Rf 0.57 (hexane/EtOAc, 7:3); mp 58-60 °C. IR (film): ῡ = 2938, 1785, 1713, 1515, 1376, 1298, 1250, 1169, 1120, 1065, 1035, 833 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.47 (s, 3H, CH 3-C4), 1.82 (d, J = 6.9 Hz, 3H, CH 3CH=), 3.29 (s, 3H, CH 3O), 3.82 (s, 3H, CH 3OAr), 5.03 (q, J = 6.9 Hz, 1H, CH3CH=), 6.92-6.96 (m, 2H, H-3ʼ), 7.27-7.31 (m, 2H, H-2ʼ). 13C NMR (150 MHz, CDCl3): δ 10.0 (CH3CH=), 24.8 (CH3-C4), 50.1 (CH3O), 55.5 (CH3OAr), 92.2 (C-4), 100.6 (CH3 CH=), 114.5 (C-3ʼ), 126.6 (C-1ʼ), 127.1 (C-2ʼ), 146.7 (C-5), 153.2 (C-2), 158.7 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C14H17NO4: 263.1158; found: 263.1159.
5-(1-((4-Chlorophenyl)thio)ethyl)-4-methyl-3-phenyloxazol-2(3H)-one (27a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 2a (0.050 g, 0.25 mmol), 21c (0.069 g, 0.48 mmol), and H3PO4 (85 %) (0.034 g, 0.30 mmol) in CH2Cl2 (5 mL) were mixed under N2 atmosphere at rt and stirred for 24 h. The mixture was dissolved in CH2Cl2 (10 mL) and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 9:1) to furnish 27a (0.051 g, 60%) as a yellow solid. Rf 0.50 (hexane/EtOAc, 7:3); mp 128-129 °C. IR (film): ῡ = 2979, 2930, 1760, 1694, 1598, 1504, 1475, 1395, 1384, 1261, 1167, 1094, 1013, 981, 824, 768, 709, 696 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.41 (s, 3H, CH 3-C4), 1.63 (d, J = 7.1 Hz, 3H, H-2”), 4.14 (q, J = 7.1 Hz, 1H, H-1”), 7.14-7.17 (m, 2H, H-2ʼ), 7.28-7.31 (m, 2H, H-3ʼ”), 7.37-7.41 (m, 3H, H-4ʼ, H-2ʼ”), 7.43-7.48 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.4 (CH3-C4), 18.1 (C-2”), 40.0 (C-1”), 120.2 (C-4), 126.9 (C-2ʼ), 128.6 (C-4ʼ), 129.0 (C-3ʼ”), 129.5 (C-3ʼ), 132.4 (C-1ʼ”), 133.3 (C-1ʼ), 134.3 (C-5), 135.0 (C-4ʼ”), 136.6 (C-2ʼ”), 154.0 (C-2). HRMS (EI, [M+]): m/z calcd for C18H16ClNO2S: 345.0590; found: 345.0580.
5-(1-((4-Chlorophenyl)thio)ethyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (27b). Following the method for preparing 27a, a mixture of 2b (0.050 g, 0.23 mmol), 21c (0.067 g, 0.46 mmol), and H3PO4 (85 %) (0.032 g, 0.28 mmol) in CH2Cl2 (5 mL) yielded 27b (0.053 g, 64 %) as a yellow solid. Rf 0.51 (hexane/EtOAc, 7:3); mp 109-111 °C. IR (film): ῡ = 2979, 2928, 1756, 1694, 1572, 1518, 1475, 1396, 1386, 1262, 1168, 1095, 1013, 984, 820, 754 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.38 (s, 3H, CH 3-C4), 1.62 (d, J = 7.0 Hz, 3H, H-2”), 2.37 (s, 3H, CH 3Ar), 4.13 (q, J = 7.0 Hz, 1H, H-1”), 7.00-7.05 (m, 2H, H-2ʼ), 7.23-7.27 (m, 2H, H-3ʼ), 7.28-7.31 (m, 2H, H-3ʼ”), 7.35-7.40 (m, 2H, H-2ʼ”). 13C NMR (125 MHz, CDCl3): δ 8.4 (CH3-C4), 18.1 (C-2”), 21.1 (CH3Ar), 40.0 (C-1”), 120.3 (C-4), 126.8 (C-2ʼ), 129.0 (C-3ʼ”), 130.1 (C-3ʼ), 130.6 (C-1ʼ), 132.4 (C-1ʼ”), 134.1 (C-5), 135.0 (C-4ʼ”), 136.6 (C-2ʼ”), 138.7 (C-4ʼ), 154.2 (C-2). HRMS (EI, [M+]): m/z calcd for C19H18NO2SCl: 359.0747; found: 359.0741.
5-(1-((4-Chlorophenyl)thio)ethyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (27c). Following the method for preparing 27a, a mixture 2c (0.060 g, 0.26 mmol), 21c (0.075 g, 0.52 mmol), and H3PO4 (85 %) (0.036 g, 0.31 mmol) in CH2Cl2 (5 mL) provided 27c (0.06 g, 62 %) as a yellow solid. Rf 0.37 (hexane/EtOAc, 7:3); mp 117-119 °C. IR (film): ῡ = 2931, 1754, 1694, 1516, 1475, 1397, 1388, 1301, 1251, 1165, 1095, 1032, 1013, 983, 832 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.37 (s, 3H, CH 3-C4), 1.63 (d, J = 7.0 Hz, 3H, H-2”), 3.82 (s, 3H, CH 3O), 4.13 (q, J = 7.0 Hz, 1H, H-1”), 6.93-6.98 (m, 2H, H-3ʼ), 7.04-7.08 (m, 2H, H-2ʼ), 7.27-7.32 (m, 2H, H-3ʼ”), 7.36-7.40 (m, 2H, H-2ʼ”). 13C NMR (125 MHz, CDCl3): δ 8.3 (CH3-C4), 18.1 (C-2”), 40.0 (C-1”), 55.5 (CH3O), 114.8 (C-3ʼ), 120.5 (C-4), 125.8 (C-1ʼ), 128.3 (C-2ʼ), 129.0 (C-3ʼ”), 132.5 (C-1ʼ”), 134.0 (C-5), 135.0 (C-4ʼ”), 136.6 (C-2ʼ”), 154.3 (C-2), 159.6 (C-4ʼ). HRMS (EI, [M+]): m/z calcd for C19H18NO3ClS: 375.0696; found: 375.0690.
5-(1-(4-Hydroxyphenyl)ethyl)-4-methyl-3-phenyloxazol-2(3H)-one (28a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 2a (0.06 g, 0.30 mmol), 21d (0.052 g, 0.55 mmol), and H3PO4 (85 %) (0.086 g, 0.75 mmol) in CH2Cl2 (3 mL) were mixed under N2 atmosphere at rt and stirred for 24 h. The mixture was dissolved in CH2Cl2 (5 mL) and washed in an aqueous saturated solution of NaHCO3 (2 x 5 mL) and EtOAc (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 7:3), resulting in 28a (0.053 g, 60%) as a yellow solid. Rf 0.33 (hexane/EtOAc, 7:3); mp 168-170 °C. IR (KBr): ῡ = 3398, 2979, 2930, 1732, 1689, 1610, 1594, 1515, 1504, 1389, 1263, 1224, 1174, 1057, 987, 839, 773, 761, 710, 694 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.58 (d, J = 7.5 Hz, 3H, H-2”), 1.83 (br s, 3H, CH 3-C4), 3.91 (q, J = 7.5 Hz, 1H, H-1”), 6.81-6.84 (m, 2H, H-3ʼ”), 7.17-7.22 (m, 2H, H-2ʼ”), 7.26-7.30 (m, 2H, H-2ʼ), 7.36-7.40 (m, 1H, H-4ʼ), 7.42-7.47 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 19.9 (C-2”), 35.4 (C-1”), 115.6 (C-3ʼ”), 117.1 (C-4), 127.1 (C-2ʼ), 128.3 (C-2ʼ”), 128.4 (C-4ʼ), 129.5 (C-3ʼ), 133.5 (C-1ʼ), 134.2 (C-1ʼ”), 138.9 (C-5), 154.8 (C-2), 155.0 (C-4ʼ”). HRMS (EI, [M+]): m/z calcd for C18H17NO3: 295.1208; found: 295.1199.
5-(1-(4-Hydroxyphenyl)ethyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (28b). Following the method for preparing 28a, a mixture of 2b (0.060 g, 0.28 mmol), 21d (0.047 g, 0.50 mmol), and H3PO4 (85 %) (0.081 g, 0.7 mmol) in CH2Cl2 (5 mL) gave 28b (0.058 g, 67 %) as a yellow solid. Rf 0.31 (hexane/EtOAc, 7:3); mp 197-199 °C. IR (KBr): ῡ = 3282, 2980, 1731, 1692, 1614, 1516, 1448, 1393, 1259, 1231, 1173, 835, 756 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.57 (d, J = 7.2 Hz, 3H, H-2”), 1.81 (br s, 3H, CH 3-C4), 2.37 (s, 3H, CH 3Ar), 3.90 (q, J = 7.2 Hz, 1H, H-1”), 6.55 (br, 1H, OH), 6.81-6.84 (m, 2H, H-3ʼ”), 7.13-7.16 (m, 2H, H-2ʼ), 7.17-7.20 (m, 2H, H-2ʼ”), 7.23-7.26 (m, 2H, H-3ʼ). 13C NMR (150 MHz, CDCl3): δ 8.7 (CH3-C4), 19.9 (C-2”), 21.1 (CH3Ar), 35.3 (C-1”), 115.6 (C-3ʼ”), 117.3 (C-4), 126.9 (C-2ʼ), 128.2 (C-2ʼ”), 130.1 (C-3ʼ), 130.8 (C-1ʼ), 134.0 (C-1ʼ”), 138.6 (C-4ʼ), 138.9 (C-5), 155.1 (C-2), 155.3 (C-4ʼ”). HRMS (EI, [M+]): m/z calcd for C19H19NO3: 309.1365; found: 309.1366.
5-(1-(4-Hydroxyphenyl)ethyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (28c). Following the method for preparing 28a, a mixture of 2c (0.07 g, 0.3 mmol), 21d (0.048 g, 0.51 mmol), and H3PO4 (85 %) (0.086 g, 0.75 mmol) in CH2Cl2 (3 mL) led to 28c (0.063 g, 64 %) as a yellow solid. Rf 0.15 (hexane/EtOAc, 7:3); mp 179-180 °C. IR (KBr): ῡ = 3318, 2972, 1732, 1690, 1611, 1516, 1442, 1393, 1305, 1255, 1228, 1169, 1035, 992, 834 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.58 (d, J = 7.3 Hz, 3H, H-2”), 1.79 (s, 3H, CH 3-C4), 3.82 (s, 3H, CH 3O), 3.90 (q, J = 7.3 Hz, 1H, H-1”), 6.22 (br, 1H, OH), 6.80-6.84 (m, 2H, H-3ʼ”), 6.93-6.97 (m, 2H, H-3ʼ), 7.16-7.21 (m, 4H, H-2ʼ, H-2ʼ”). 13C NMR (125 MHz, CDCl3): δ 8.7 (CH3-C4), 19.9 (C-2”), 35.4 (C-1”), 55.5 (CH 3O), 114.7 (C-3ʼ), 115.6 (C-3ʼ”), 117.4 (C-4), 126.1 (C-1ʼ), 128.2 (C-2ʼ”), 128.5 (C-2ʼ), 134.2 (C-1ʼ”), 138.7 (C-5), 155.1 (C-4ʼ”), 155.2 (C-2), 159.5 (C-4ʼ) HRMS (EI, [M+]): m/z calcd for C19H19NO4: 325.1314; found: 325.1308.
5-(Hydroxymethyl)-4-methyl-3-phenyloxazol-2(3H)-one (29a). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 23a (0.150 g, 0.60 mmol) and NaOH (0.036 g, 0.90 mmol) in MeOH/H2O (8:2) (12 mL) were mixed at rt and stirred for 30 min. The mixture was neutralized with AcOH (1.0 M) and extracted with EtOAc (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 6:4) to produce 29a (0.11 g, 90 %) as a yellow solid. Rf 0.05 (hexane/EtOAc, 7:3); mp 126-128 °C. IR (film): ῡ = 3404, 1756, 1698, 1597, 1504, 1398, 1385, 1277, 1215, 1185, 1047, 1003, 767, 712, 696 cm-1. 1H NMR (600 MHz, CDCl3): δ 1.94 (br s, 3H, CH 3-C4), 2.77 (br, 1H, OH), 4.45 (br d, J = 4.8 Hz, 2H, CH 2OH), 7.29-7.32 (m, 2H, H-2ʼ), 7.40-7.43 (m, 1H, H-4ʼ), 7.46-7.50 (m, 2H, H-3ʼ). 13C NMR (150 MHz, CDCl3): δ 8.8 (CH3-C4), 54.0 (CH2OH), 121.6 (C-4), 127.1 (C-2ʼ), 128.7 (C-4ʼ), 129.6 (C-3ʼ), 133.4 (C-1ʼ), 134.9 (C-5), 154.5 (C-2). HRMS (ESI, [M + H]+): m/z calcd for C11H12NO3: 206.0817; found: 206.0769.
5-(Hydroxymethyl)-4-methyl-3-(p-tolyl)oxazol-2(3H)-one (29b). Following the method for preparing 29a, a mixture of 23b (0.25 g, 0.96 mmol) and NaOH (0.057 g, 1.43 mmol) in MeOH/H2O (8:2) (18 mL) furnished 29b (0.19 g, 91 %) as a yellow solid. Rf 0.058 (hexane/EtOAc, 7:3); mp 128-131 °C. IR (film): ῡ = 3411, 2926, 1760, 1740, 1702, 1518, 1398, 1386, 1277, 1213, 1048, 991, 820, 757 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.92 (br s, 3H, CH 3-C4), 2.39 (br s, 3H, CH 3Ar), 2.64 (br, 1H, OH), 4.45 (br s, 2H, CH 2OH), 7.15-7.19 (m, 2H, H-2ʼ), 7.26-7.29 (m, 2H, H-3ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 21.1 (CH3Ar), 54.0 (CH2OH), 121.7 (C-4), 126.9 (C-2ʼ), 130.2 (C-3ʼ), 130.7 (C-1ʼ), 134.6 (C-5), 138.8 (C-4ʼ), 154.6 (C-2). HRMS (EI, [M+]): m/z calcd for C12H13NO3: 219.0895; found: 219.0897.
5-(Hydroxymethyl)-3-(4-methoxyphenyl)-4-methyloxazol-2(3H)-one (29c). Following the method for preparing 29a, a mixture of 23c (0.04 g, 0.14 mmol) and NaOH (0.009 g, 0.22 mmol) in MeOH/H2O (8:2) (6 mL) afforded 29c (0.03 g, 87 %) as a yellow solid. Rf 0.034 (hexane/EtOAc, 7:3); mp 162-164 °C. IR (film): ῡ = 3413, 2929, 1738, 1698, 1516, 1398, 1249, 1170, 1030, 990, 841, 757 cm-1. 1H NMR (500 MHz, CDCl3): δ 1.92 (br s, 3H, CH 3-C4), 2.00 (br, 1H, OH), 3.84 (s, 3H, CH 3O), 4.47 (br s, 2H, CH 2OH), 6.97-7.00 (m, 2H, H-3ʼ), 7.19-7.22 (m, 2H, H-2ʼ). 13C NMR (125 MHz, CDCl3): δ 8.8 (CH3-C4), 54.3 (CH2OH), 55.6 (CH3O), 114.9 (C-3ʼ), 122.0 (C-4), 126.0 (C-1ʼ), 128.5 (C-2ʼ), 134.2 (C-5), 154.6 (C-2), 159.7 (C-4ʼ). HRMS (EI, [M+]) m/z calcd for C12H13NO4: 235.0845; found: 235.0850.
4-Methyl-2-oxo-3-phenyl-2,3-dihydrooxazole-5-carbaldehyde (30a). Method A: In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, 29a (0.110 g, 0.54 mmol) and IBX (0.760 g, 2.70 mmol) in DMSO (20 mL) were mixed at rt and stirred for 24 h. The mixture was washed with water (2 x 5 mL) and extracted with EtOAc (2 x 5 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 8:2) to provide 30a (0.07 g, 64 %) as a brown solid. Method B: In a round-bottom flask (50 mL) equipped with a magnetic stirring bar, a mixture of DMF (0.042 g, 0.57 mmol) and POCl3 (0.097 g, 0.63 mmol) under N2 atmosphere at 0 ºC was stirred for 30 min. Subsequently, 32a (0.100 g, 0.46 mmol) dissolved in CH2Cl2 (3 mL) was added dropwise and the mixture was stirred at rt for 24 h. The mixture was neutralized with a 5% aqueous solution of NaOH at 0 ºC and extracted with CH2Cl2 (4 x 10 mL). The organic layer was dried with Na2SO4 and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (40 g/g crude, hexane/EtOAc, 8:2) to yield 30a (0.03 g, 51%) as a brown solid. Rf 0.18 (hexane/EtOAc, 7:3); mp 154-155 °C. IR (film): ῡ = 1776, 1723, 1667, 1499, 1401, 1332, 1270, 1056, 729 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ 2.26 (s, 3H, CH 3-C4), 7.52-7.56 (m, 3H, H-2ʼ, H-4ʼ), 7.57-7.60 (m, 2H, H-3ʼ), 9.58 (s, 1H, CHO). 13C NMR (150 MHz, DMSO-d 6): δ 8.9 (CH3-C4), 127.6 (C-2ʼ), 129.5 (C-4ʼ), 129.6 (C-3ʼ), 132.0 (C-1ʼ), 134.3 (C-5), 141.4 (C-4), 152.0 (C-2), 175.1 (CHO). HRMS (ESI, [M + H]+): m/z calcd for C11H10NO3: 204.0661; found: 204.0626.
4-Methyl-2-oxo-3-(p-tolyl)-2,3-dihydrooxazole-5-carbaldehyde (30b). Method A: Following method A for preparing 30a, a mixture of 29b (0.100 g, 0.46 mmol) and IBX (0.638 g, 2.28 mmol) in DMSO (10 mL) resulted in 30b (0.074 g, 75 %) as a brown solid. Method B: Following method B for preparing 30a, a mixture of DMF (0.039 g, 0.53 mmol), POCl3 (0.088 g, 0.57 mmol), and 32b (0.050 g, 0.26 mmol) led to 30b (0.028 g, 48 %) as a brown solid. Rf 0.21 (hexane/EtOAc, 7:3); mp 141-142 °C. IR (film): ῡ = 2925, 1773, 1668, 1516, 1408, 1337, 1271, 1062, 990, 741 cm-1. 1H NMR (500 MHz, DMSO-d 6): δ 2.24 (s, 3H, CH 3-C4), 2.38 (s, 3H, CH 3Ar), 7.35-7.38 (m, 2H, H-3ʼ), 7.39-7.42 (m, 2H, H-2ʼ), 9.57 (s, 1H, CHO). 13C NMR (125 MHz, DMSO-d 6): δ 8.9 (CH3-C4), 20.7 (CH3Ar), 127.4 (C-2ʼ), 129.4 (C-1ʼ), 130.0 (C-3ʼ), 134.2 (C-5), 139.3 (C-4ʼ), 141.6 (C-4), 152.1 (C-2), 175.0 (CHO). HRMS (EI, [M+]) m/z calcd for C12H11NO3: 217.0739; found: 217.0736.
3-(4-methoxyphenyl)-4-methyl-2-oxo-2,3-dihydrooxazole-5-carbaldehyde (30c). Method A: Following method A for preparing 30a, a mixture of 29c (0.30 g, 1.3 mmol) and IBX (1.76 g, 6.3 mmol) in DMSO (20 mL) gave 30c (0.205 g, 69 %) as a brown solid. Method B: Following method B for preparing 30a, a mixture of DMF (0.035 g, 0.48 mmol), POCl3 (0.082 g, 0.54 mmol), and 32c (0.050 g, 0.24 mmol) generated 30c (0.032 g, 56 %) as a brown solid. Rf 0.16 (hexane/EtOAc, 7:3); mp 162-163 °C. IR (film): ῡ = 2931, 1771, 1667, 1516, 1404, 1337, 1301, 1252, 1143, 1029, 837, 746 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ 2.23 (s, 3H, CH 3-C4), 3.82 (s, 3H, CH 3O), 7.08-7.12 (m, 2H, H-3ʼ), 7.43-7.47 (m, 2H, H-2ʼ), 9.56 (s, 1H, CHO). 13C NMR (150 MHz, DMSO-d 6): δ 8.9 (CH3-C4), 55.5 (CH3O), 114.8 (C-3ʼ), 124.4 (C-1ʼ), 129.0 (C-2ʼ), 134.2 (C-5), 141.9 (C-4), 152.3 (C-2), 159.8 (C-4ʼ), 175.0 (CHO). HRMS (EI, [M+]): m/z calcd for C12H11NO4: 233.0688; found: 233.0691.
6-Acetyl-3-(p-tolyl)-4,5-dihydrobenzo[d]oxazol-2(3H)-one (31b). In a round-bottom flask (50 mL) equipped with a magnetic stirring bar, KOt-Bu (0.048 g, 0.43 mmol) was added to a solution of 30b (0.050 g, 0.23 mmol) in anhydride THF (10 mL) under N2 atmosphere at -78 ºC and stirred for 40 min. Then, MVK (0.031 g, 0.44 mmol) was added dropwise and the mixture was stirred for 1 h, then at 0 ºC for 30 min before removing the solvent under vacuum. The residue was purified by column chromatography over silica gel (30 g/g crude, hexane/EtOAc, 8:2) to produce 31b (0.013 g, 21 %) as a yellow solid. Rf 0.31 (hexane/EtOAc, 7:3); mp 113-116 °C. IR (film): ῡ = 2924, 1770, 1668, 1644, 1570, 1516, 1422, 1371, 1322, 1288, 1218, 1004, 819, 748 cm-1. 1H NMR (600 MHz, CDCl3): δ 2.37 (s, 3H, CH 3CO), 2.40 (s, 3H, CH 3Ar), 2.66 (br t, J = 9.9 Hz, 2H, H-4), 2.79 (br t, J = 9.9 Hz, 2H, H-5), 7.12 (br s, 1H, H-7), 7.22-7.24 (m, 2H, H-2ʼ), 7.27-7.30 (m, 2H, H-3ʼ). 13C NMR (150 MHz, CDCl3): δ 19.9 (C-4), 20.9 (C-5), 21.1 (CH3Ar), 24.9 (CH3CO), 124.2 (C-7), 124.9 (C-2ʼ), 128.6 (C-3a), 130.2 (C-3ʼ), 130.5 (C-1ʼ), 131.4 (C-6), 134.1 (C-7a), 138.6 (C-4ʼ), 154.1 (C-2), 196.2 (CH3 CO). HRMS (ESI, [M + H]+): m/z calcd for C16H16NO3: 270.1130; found: 270.1080.
6-Acetyl-3-(4-methoxyphenyl)-4,5-dihydrobenzo[d]oxazol-2(3H)-one (31c). Following the method for preparing 31b, a mixture of 30c (0.050 g, 0.21 mmol), KOt-Bu (0.043 g, 0.38 mmol), and MVK (0.028 g, 0.40 mmol) afforded 31c (0.014 g, 22 %) as a yellow solid. Rf 0.35 (hexane/EtOAc, 7:3); mp 168-170 °C. IR (film): ῡ = 2933, 1770, 1669, 1644, 1570, 1515, 1372, 1288, 1252, 1218, 1029, 1002, 834 cm-1. 1H NMR (600 MHz, CDCl3): δ 2.37 (s, 3H, CH 3CO), 2.64 (br t, J = 9.9 Hz, 2H, H-4), 2.79 (br t, J = 9.9 Hz, 2H, H-5), 3.84 (s, 3H, CH 3O), 6.98-7.01 (m, 2H, H-3ʼ), 7.12 (br s, 1H, H-7), 7.25-7.28 (m, 2H, H-2ʼ). 13C NMR (150 MHz, CDCl3): δ 19.8 (C-4), 20.9 (C-5), 24.9 (CH3CO), 55.6 (CH3O), 114.9 (C-3ʼ), 124.3 (C-7), 125.7 (C-1ʼ), 126.6 (C-2ʼ), 128.9 (C-3a), 131.3 (C-6), 134.0 (C-7a), 154.3 (C-2), 159.5 (C-4ʼ), 196.3 (CH3 CO). HRMS (EI, [M+]): m/z calcd for C16H15NO4: 285.1001; found: 285.1011.
(E)-3-((3-Methoxyphenyl)imino)butan-2-one (11c). In a round-bottom flask (250 mL) equipped with a magnetic stirring bar, a mixture of 4a (0.98 g, 11.4 mmol) and m-anisidine (1.40 g, 11.4 mmol) in MeOH (150 mL) was stirred under N2 atmosphere at rt for 24 h. The solvent was removed under vacuum and the residue was purified by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 98:2) to furnish 11c (1.63 g, 75 %) as a yellow oil. Rf 0.75 (hexane/EtOAc, 80:20). IR (film): ῡ = 2938, 1698, 1504, 1243, 1033, 841 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.97 (s, 3H, H-4), 2.51 (s, 3H, H-1), 3.81 (s, 3H, CH 3O), 6.30-6.37 (m, 2H, H-2’, H-4’), 6.66-6.72 (m, 1H, H-6’), 7.23-7.31 (m, 1H, H-5’). 13C NMR (75.4 MHz, CDCl3): δ 14.0 (C-4), 24.5 (C-1), 55.2 (CH3O), 104.3 (C-2’), 110.0 (C-4’), 110.6 (C-6’), 129.9 (C-5’), 150.8 (C-1’), 160.2 (C-3’), 166.1 (C-3), 200.3 (C-2). MS (70 eV): m/z 191 (M+, 6), 162 (10), 148 (100), 108 (13), 92 (24), 77 (9), 63 (20). HRMS (EI, [M]+): m/z calcd for C11H13NO2: 191.0946; found: 191.0956.
1-(3-Methoxyphenyl)-4,5-dimethylene-3-(p-tolyl)imidazolidin-2-one (16c). In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, a mixture of 11c (0.499 g, 2.61 mmol), dried Li2CO3 (1.93 g, 26.1 mmol), and dried Et3N (0.659 g, 6.53 mmol) in anhydrous PhMe (30 mL) was stirred at rt under N2 atmosphere in the dark for 90 min. Subsequently, a solution of 5b (1.04 g, 7.83 mmol) in PhMe (10 mL) was added dropwise, and the mixture was stirred at rt for 24 h. The mixture was filtered over Celite and washed with CH2Cl2 (3 x 20 mL), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 95:5) to provide 16c (0.610 g, 76%) as a white solid. Rf 0.65 (hexane/EtOAc, 80:20); mp 112-113 °C. IR (film): ῡ = 1737, 1604, 1517, 1494, 1399, 1267, 1044, 818, 756 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.39 (s, 3H, CH 3Ar), 3.82 (s, 3H, CH 3O), 4.32 (d, J = 2.4 Hz, 1H, =CH), 4.39 (d, J = 2.4 Hz, 1H, =CH), 4.79 (d, J = 2.4 Hz, 1H, =CH), 4.82 (d, J = 2.4 Hz, 1H, =CH), 6.91 (dm, J = 8.1 Hz, 1H, H-4’), 6.95 (dd, J = 2.4, 2.1 Hz, 1H, H-2’), 6.99 (dm, J= 8.1 Hz, 1H, H-6’), 7.28 (s, 4H, H-2”, H-3”), 7.37 (t, J = 8.1 Hz, 1H, H-5’). 13C NMR (75.4 MHz, CDCl3): δ 21.2 (CH3Ar), 55.4 (CH3O), 82.7 (CH2=), 82.9 (CH2=), 112.9 (C-2’), 114.0 (C-4’), 119.7 (C-6’), 127.3 (C-2”), 130.0 (C-5’), 130.1 (C-3”), 131.5 (C-1”), 135.3 (C-1’), 137.9 (C-4”), 140.0 (C-4 or C-5), 140.2 (C-5 or C-4), 153.5 (C-2), 160.3 (C-3’). HRMS (EI, [M]+): m/z calcd for C19H18N2O2: 306.1368; found: 306.1376.
1,3,6-Triphenyl-4,4a,7a,8-tetrahydroimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (33a) [21]. In a round-bottom flask (100 mL) equipped with a magnetic stirring bar, a mixture of 15a (0.05 g, 0.19 mmol) and 19 (0.036 g, 0.21 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at 0 ºC under N2 atmosphere for 1 h. The solvent was removed under vacuum, and the residue was purified by column chromatography over silica gel (20 g/g crude, hexane/EtOAc, 8:2), leading to 33a (0.075 g, 90%) as a pale green solid. Rf 0.20 (hexane/EtOAc, 7:3); mp 128-129 °C [Lit. [21] 128-129 °C].
1-(4-Methoxyphenyl)-3,6-diphenyl-4,4a,7a,8-tetrahydroimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (33b). Following the procedure for 33a, a mixture of 16a (0.10 g, 0.34 mmol) and 19 (0.065 g, 0.38 mmol) yielded 33b (0.151 g, 95 %) as a pale green solid. Rf 0.40 (hexane/EtOAc, 1:1); mp 107-108 °C. IR (KBr): ῡ = 2917, 1710, 1514, 1501, 1383, 1250, 1170, 1028, 838, 735, 693 cm-1. 1H NMR (500 MHz, CDCl3): δ 2.74-2.86 (m, 2H, H-4, H-8), 3.05 (d, J = 16.0 Hz, 1H, H-4 or H-8), 3.10 (d, J = 15.0 Hz, 1H, H-8 or H-4), 3.42-3.52 (m, 2H, H-4a, H-7a), 3.82 (s, 3H, CH 3O), 6.97 (d, J = 8.5 Hz, 2H, H-3’), 7.23-7.30 (m, 4H, H-2’, 2ArH), 7.30-7.50 (m, 8H, PhH). 13C NMR (125 MHz, CDCl3): δ 19.9 (C-4 or C-8), 20.0 (C-8 or C-4), 38.7 (C-4a or C-7a), 38.8 (C-7a or C-4a), 55.5 (CH3O), 114.5 (C-3’), 114.6 (C-3a or C-8a), 115.6 (C-8a or C-3a), 126.1 (2ArH), 126.2 (2ArH), 126.9 (C-1’), 127.4 (ArH), 127.6 (2ArH), 128.7 (ArH), 129.2 (2ArH), 129.3 (2ArH), 131.7 (C-1” or C-1’”), 134.5 (C-1’” or C-1”), 152.4 (C-2), 158.9 (C-4’), 177.8 (C-5, C-7). MS (70 eV): m/z 465 (M+, 58), 444 (77), 415 (43), 339 (26), 321 (36), 291 (59), 217 (54), 122 (91), 53 (100). HRMS (EI, [M+]): m/z calcd for C28H23N3O4: 465.1689; found: 465.1692.
1-(4-Chlorophenyl)-3,6-diphenyl-4,4a,7a,8-tetrahydroimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (33c). Following the procedure for 33a, a mixture of 16b (0.100 g, 0.34 mmol) and 19 (0.059 g, 0.34 mmol) gave 33c (0.146 g, 92 %) as a pale green solid. Rf 0.40 (hexane/EtOAc, 1:1); mp 112-113 °C. IR (film): ῡ = 2970, 2932, 1735, 1708, 1596, 1505, 1388, 1279, 1059 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.74-2.90 (m, 2H, H-4, H-8), 3.06-3.18 (m, 2H, H-4, H-8), 3.43-3.58 (m, 2H, H-4a, H-7a), 7.25-7.53 (m, 14H, ArH). 13C NMR (75.4 MHz, CDCl3): δ 19.9 (C-4 or C-8), 20.0 (C-8 or C-4), 38.6 (C-4a or C-7a), 38.7 (C-7a or C-4a), 114.9 (C-3a or C-8a). 115.6 (C-8a or C-3a), 126.1 (4ArH), 127.2 (2ArH), 127.6 (ArH), 128.8 (C-4”), 129.2 (2ArH), 129.4 (2ArH), 129.5 (2ArH), 131.5 (Ar), 132.8 (Ar), 133.1 (Ar), 134.0 (Ar), 151.9 (C-2), 177.7 (C-5, C-7). HRMS (EI, [M+]): m/z calcd for C27H20N3O3Cl: 469.1193; found: 469.1184.
1-(3-Methoxyphenyl)-6-phenyl-3-(p-tolyl)-4,4a,7a,8-tetrahydroimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (33d). Following the procedure for 33a, a mixture of 16c (0.150 g, 0.49 mmol) and 19 (0.093 g, 0.54 mmol) generated 33d (0.174 g, 74 %) as a white solid. Rf 0.21 (hexane/EtOAc, 70:30); mp 175-176 °C. IR (film): ῡ = 1717, 1632, 1517, 1411, 1397, 1255, 1131, 853, 820, 785 cm-1. 1H NMR (500 MHz, CDCl3): δ 2.38 (s, 3H, CH 3), 2.75-2.88 (m, 2H, H-4, H-8), 3.06 (br d, J = 15.0 Hz, 1H, H-4 or H-8), 3.13 (br d, J =16.0 Hz, H-8 or H-4), 3.41-3.43 (m, 2H, H-4a, H-7a), 3.80 (s, 3H, CH 3O), 6.87-6.92 (m, 1H, H-4’), 6.89-6.96 (m, 2H, H-2’, H-6’), 7.20-7.52 (m, 10H, Ar-H). 13C NMR (125 MHz, CDCl3): δ 19.9 (C-4 or C-8), 20.0 (C-8 or C-4). 21.1 (CH3), 38.7 (C-4a or C-7a), 38.8 (C-7a or C-4a), 55.4 (CH3O), 111.7 (C-2’), 113.7 (C-4’), 115.0 (C-3a or C-8a), 115.4 (C-8a or C-3a), 118.3 (C-6’), 126.1 (2ArH), 126.2 (2ArH), 128.8 (C-4”), 129.2 (2ArH), 130.0 (2ArH), 130.1 (Ar-H), 131.5 (Ar), 131.6 (Ar), 135.3 (Ar), 137.6 (Ar), 152.2 (C-2), 160.3 (C-3’), 177.7 (C-5 or C-7), 177.8 (C-7 or C-5). HRMS (EI, [M+]): m/z calcd for C28H23N3O4: 465.1689; found: 465.1652.
1,3-Diphenyl-4,9-dihydro-1H-naphtho[2,3-d]imidazol-2(3H)-one (35a). In a round-bottom flask (50 mL) equipped with a magnetic stirring bar, TBAF in furane (1.0 M) (0.120 g, 0.46 mmol) was added dropwise at 0 ºC under N2 atmosphere to a mixture of 15a (0.080 g, 0.31 mmol) and 34 (0.091 g, 0.31 mmol) in anhydrous CH2Cl2 (2 mL), stirring it in the dark for 24 h while it rose from 0 ºC to rt. The solvent was removed under vacuum, and the residue was purified by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 85:15) to obtain 35a (0.058 g, 56%) as a white solid. Rf 0.61 (hexane/EtOAc, 80:20); mp 211-212 ºC. IR (film): ῡ = 1727, 1681, 1596, 1497, 1470, 1394, 1242, 1182, 1024, 857, 740, 692 cm-1. 1H NMR (300 MHz, CDCl3): δ 3.76 (s, 4H, H-4, H-9), 7.18 (br s, 6H, H-6, H-7, H-2’, H-2”), 7.34-7.40 (m, 2H, H-4’, H-4”), 7.40-7.54 (m, 8H, H-5, H-8, H-3’, H-3”, H-1’, H-1”). 13C NMR (75.4 MHz, CDCl3): δ 26.6 (C-4, C-9), 115.2 (C-3a, C-9a), 126.4 (C-2’, C-2”, C-6, C-7), 127.3 (C-4’, C-4”), 129.2 (C-3’, C-3”), 129.3 (C-5, C-8), 131.8 (C-4a, C-8a), 135.1 (C-1’, C-1”), 152.4 (C-2). HRMS (EI, [M+]): m/z calcd for C23H18N2O: 338.1419; found: 338.1422.
1-Phenyl-3-(p-tolyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-2(3H)-one (35b). Following the procedure for 35a, a mixture of 16d (0.100 g, 0.36 mmol), 34 (0.108 g, 0.36 mmol), and TBAF in furane (1.0 M) (0.141 g, 0.54 mmol) produced 35b (0.076 g, 60 %) as a white solid. Rf 0.50 (hexane/EtOAc, 1:1); 189-190 °C. IR (film): ῡ = 1726, 1680, 1603, 1518, 1501, 1473, 1398, 1246, 1175, 859, 738 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.42 (s, 3H, CH 3), 3.76 (s, 4H, H-4, H-9), 7.20 (br s, 4H, ArH), 7.26-7.44 (m, 5H, ArH), 7.46-7.54 (m, 4H, ArH). 13C NMR (75.4 MHz, CDCl3): δ 21.1 (CH3), 26.5 (C-4 or C-9), 26.6 (C-9 or C-4), 115.0 (C-9a or C-3a), 115.4 (C-3a or C-9a), 126.4 (4ArH), 126.5 (2ArH), 127.3 (ArH), 129.2 (2ArH), 129.3 (2ArH), 129.9 (2ArH), 131.8 (Ar), 131.9 (Ar), 132.3 (Ar), 135.1 (Ar), 137.3 (C-4”), 152.5 (C-2). HRMS (EI, [M+]): m/z calcd for C24H20N2O: 352.1576; found: 352.1568.
1,3,6-Triphenylimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (36a). A mixture of 33a (0.070 g, 0.16 mmoles) and DDQ (0.073 g, 0.32 mmol) in anhydrous CH2Cl2 (15 mL) was stirred at 20 ºC under N2 atmosphere for 24 h. The mixture was filtered over a mixture of Celite/silica gel (3:5 g) with CH2Cl2. The solvent was removed under vacuum, and the residue was purified by column chromatography over silica gel (20 g/g crude, hexane/EtOAc, 95:5) to provide 36a (0.058 g, 90%) as a white solid. Rf 0.52 (hexane/EtOAc, 1:1); mp 190-191 °C. IR (KBr): ῡ = 1727, 1593, 1498, 1383, 1272, 1105, 756, 692 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.37-7.41 (m, 1H, ArH), 7.42-7.45 (m, 2H, ArH), 7.47-7.54 (m, 4H, ArH), 7.58-7.64 (m, 8H, ArH), 7.62 (s, 2H, H-4, H-8). 13C NMR (125 MHz, CDCl3): δ 104.4 (C-4, C-8), 126.3 (C-2’, C-2”), 126.4 (C-4a, C-7a), 126.4 (C-2’”), 127.9 (C-4’”), 128.9 (2ArH), 129.1 (2ArH), 130.0 (C-3’, C-3”), 131.8 (C-1’”), 133.2 (C-1’, C-1”), 134.3 (C-3a, C-8a), 152.3 (C-2), 167.1 (C-5, C-7). HRMS (EI, [M+]): m/z calcd for C27H17N3O3: 431.1270; found: 431.1261.
1-(4-Methoxyphenyl)-3,6-diphenylimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (36b). Following the procedure for 36a, a mixture of 33b (0.100 g, 0.21 mmol) and DDQ (0.098 g, 0.43 mmol) yielded 36b (0.074 g, 75 %) as a yellow solid. Rf 0.53 (hexane/EtOAc, 1:1); mp 135-136 °C. IR (film): ῡ = 1738, 1592, 1483, 1395, 1264, 1236, 824, 780 cm-1. 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3H, CH 3O), 7.08-7.14 (m, 2H, H-3’), 7.35-7.54 (m, 8H, ArH), 7.56 (s, 1H, H-4 or H-8), 7.58-7.66 (m, 5H, H-4 or H-8, ArH). 13C NMR (75.4 MHz, CDCl3): δ 55.6 (CH3O), 104.2 (C-4 or C-8), 104.3 (C-8 or C-4), 115.2 (C-3’), 125.6 (Ar), 126.2 (2ArH), 126.40 (Ar), 126.42 (ArH), 127.7 (2ArH), 127.9 (2ArH), 128.9 (2ArH), 129.1 (2ArH), 130.0 (2ArH), 131.7 (Ar), 133.3 (Ar), 134.1 (Ar), 134.8 (Ar), 152.5 (C-2), 159.8 (C-4’), 167. 2 (C-5, C-7). HRMS (EI, [M+]): m/z calcd for C28H19N3O4: 461.1376; found: 461.1381.
1-(4-Chlorophenyl)-3,6-diphenylimidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (36c). Following the procedure for 36a, a mixture of 33c (0.071 g, 0.15 mmol) and DDQ (0.069 g, 0.30 mmol) gave 36c (0.071 g, 72 %) as a yellow solid. Rf 0.61 (hexane/EtOAc, 1:1); p.f. 117-118 °C. IR (film): ῡ = 1734, 1708, 1596, 1519, 1505, 1387, 1277, 1059, 874, 751 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.39-7.47 (m, 3H, Ar-H), 7.48-7.67 (m, 13H, Ar-H). 13C NMR (75.4 MHz, CDCl3): δ 104.2 (C-4 or C-8), 104.5 (C-8 or C-4), 126.2 (2Ar-H), 126.4 (2ArH), 126.5 (Ar), 126.6 (Ar), 127.5 (2ArH), 128.0 (ArH), 129.0 (ArH), 129.1 (2ArH), 130.1 (2ArH), 130.2 (2ArH), 131.6 (Ar), 131.7 (Ar), 133.0 (Ar), 133.8 (Ar), 134.3 (C-3a or C-8a), 134.7 (C-8a or C-3a), 152.1 (C-2), 167.0 (C-5, C-7). HRMS (EI, [M+]): m/z calcd for C27H16N3O3Cl: 465.0880; found: 465.0875.
1-(3-Methoxyphenyl)-6-phenyl-3-(p-tolyl)imidazo[4,5-f]isoindole-2,5,7(1H,3H,6H)-trione (36d). Following the procedure for 36a, a mixture of 33d (0.100 g, 0.21 mmol) and DDQ (0.098 g, 0.43 mmol) furnished 36d (0.074 g, 75 %) as a yellow solid. Rf 0.50 (hexane/EtOAc, 1:1); mp 113-114 °C. IR (film): ῡ = 1730, 1710, 1600, 1499, 1385, 1281, 1111, 762, 688 cm-1. 1H NMR (500 MHz, CDCl3): δ 2.47 (s, 3H, CH 3), 3.87 (s, 3H, CH 3O), 7.05 (ddd, J = 8.4, 2.7, 0.9 Hz, 1H, H-4’), 7.11-7.18 (m, 2H, H-2’, H-6’), 7.37-7.54 (m, 10H, H-5’, H-2”, H-3”, PhH), 7.57 (d, J = 0.5 Hz, 1H, H-4 or H-8), 7.64 (d, J = 0.5 Hz, 1H, H-8 or H-4). 13C NMR (125 MHz, CDCl3): δ 21.2 (CH3), 55.5 (CH3O), 104.3 (C-4 or C-8), 104.4 (C-8 or C-4), 112.1 (C-6’), 114.7 (C-4’), 118.2 (C-2’), 126.1 (2ArH), 126.2 (Ar), 126.3 (Ar), 126.4 (2ArH), 127.9 (ArH), 129.1 (2ArH), 130.4 (Ar), 130.5 (2ArH), 130.5 (ArH), 131.7 (Ar), 134.1 (Ar), 134.2 (Ar), 134.4 (Ar), 139.1 (Ar), 152.3 (C-2), 160.7 (C-3’), 167.2 (C-5, C-7). HRMS (EI, [M+]): m/z calcd for C29H21N3O4: 475.1532; found: 475.1537.
1,3-Diphenyl-1H-naphtho[2,3-d]imidazol-2(3H)-one (37a). A mixture of 35a (0.086 g, 0.25 mmol) and DDQ (0.114 g, 0.50 mmol) in anhydrous CH2Cl2 (5 mL) was stirred under N2 atmosphere at rt for 24 h. The mixture was filtered over Celite and washed with CH2Cl2 (15 mL). The filtered solution was concentrated under vacuum, and the residue purified by column chromatography over silica gel (10 g/g of crude, hexane/EtOAc, 8:2) to deliver 37a (0.084 g, 99 %) as a white solid. R f 0.52 (hexane/EtOAc, 8:2); mp 211-212 °C. IR (film): ῡ = 1728, 1497, 1471, 1394, 1245, 743, 692 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.32-7.39 (m, 2H, H-6, H-7), 7.42-7.49 (m, 4H, H-4, H-9, H-4’, H-4”), 7.55-7.63 (m, 4H, H-3’, H-3”), 7.64-7.70 (m, 4H, H-2’, H-2”), 7.70-7.78 (m, 2H, H-5, H-8). 13C NMR (75.4 MHz, CDCl3): δ 104.7 (C-4, C-9), 124.5 (C-6, C-7), 126.3 (C-2’, C-2”), 127.2 (C-5, C-8), 127.9 (C-4’, C-4”), 129.6 (C-3’, C-3”), 130.0 (C-3a, C-9a), 130.3 (C-4a, C-8a), 134.5 (C-1’), 134.7 (C-1”), 153.1 (C-2). HRMS (EI, [M+]): m/z calcd for C23H16N2O: 336.1263; found: 336.1267.
1-Phenyl-3-(p-tolyl)-1H-naphtho[2,3-d]imidazol-2(3H)-one (37b). Following the procedure for 37a, a mixture of 35b (0.080 g, 0.23 mmol) and DDQ (0.104 g, 0.46 mmol) in CH2Cl2 (15 mL) resulted in 37b (0.077 g, 97 %) as a white solid. R f 0.55 (hexane/EtOAc, 1:1); mp 178-179 °C. IR (film): ῡ = 1727, 1603, 1518, 1502, 1472, 1397, 1246, 1176, 856, 744 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H, ArCH 3), 7.33-7.38 (m, 2H, H-6, H-7), 7.38-7.42 (m, 3H, H-4 or H-9, H-3"), 7.45 (s, 1H, H-9 or H-4), 7.42-7.49 (m, 1H, H-4'), 7.51-7.56 (m, 2H, H-2"), 7.56-7.63 (m, 2H, H-3'), 7.65-7.70 (m, 2H, H-2'), 7.71-7.78 (m, 2H. H-5, H-8). 13C NMR (75.4 MHz, CDCl3): δ 21.2 (ArCH3), 104.7 (C-4, C-9), 124.4 (C-6 or C-7), 124.5 (C-7 or C-6), 126.2 (C-2"), 126.3 (C-2'), 127.1 (C-5 or C-8), 127.2 (C-8 or C-5), 127.9 (C-4'), 129.6 (C-3'), 129.9 (Ar), 130.0 (Ar), 130.26 (C-3"), 130.29 (Ar), 130.6 (Ar), 131.7 (Ar), 134.5 (Ar), 138.0 (C-4"), 153.2 (C-2). HRMS (EI, [M+]): m/z calcd for C24H18N2O: 350.1419; found: 350.1418.
Results and discussion
Regioselective functionalization of exo-oxazolidin-2-one dienes 1 and 2
The previously reported method [7,10] was applied for the preparation of dienes 1a-c, which were submitted to the Brønsted acid-catalyzed addition of a series of nucleophiles (Table 1). Thus, the addition of MeOH/HCl at room temperature (rt) for 1 h provided the series of 4-oxazolin-2-ones 22a-c in good yields (entries 1-3), while the addition of acetic acid furnished the series 23a-c in moderate to good yields (entries 4-6). Regarding the addition of 4-chlorothiophenol (21c) to afford the series of 4-oxazolin-2-ones 24a-c, the optimal catalyst (phosphoric acid) rendered satisfactory yields (entries 7-9).
Table 1 Acid-catalyzed addition of nucleophiles 21a-c to dienes 1a-c to prepare the series of 4-oxazolin-2-ones 22a-c, 23a-c, and 24a-c.a
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| Entry | 1 | 21 | H+ | Ar | 22-24 | Yield (%)b |
| 1 | 1a | 21a | HCl | Ph | 22a | 92 |
| 2 | 1b | 21a | HCl | C6H4-4-Me | 22b | 83 |
| 3 | 1c | 21a | HCl | C6H4-4-OMe | 22c | 84 |
| 4 | 1a | 21b | AcOH | Ph | 23a | 95 |
| 5 | 1b | 21b | AcOH | C6H4-4-Me | 23b | 81 |
| 6 | 1c | 21b | AcOH | C6H4-4-OMe | 23c | 59 |
| 7 | 1a | 21c | H3PO4 | Ph | 24a | 60 |
| 8 | 1b | 21c | H3PO4 | C6H4-4-Me | 24b | 75 |
| 9 | 1c | 21c | H3PO4 | C6H4-4-OMe | 24c | 74 |
a Standard conditions: 1a-c (1.0 mol equiv), 21a-c (2.0-75.0 mol equiv), and H+ (1.0-11.0 mol equiv), at rt, 1-24 h. For 21b and 21c, the reaction was performed in CH2Cl2. b Isolated yields.
Interestingly, the dienic moiety underwent a regioselective addition of the nucleophiles to the terminal C-7 carbon atom of the double bond, possibly because of the capture of the proton, liberated by the catalyst, from the terminal C-6 carbon atom of the double bond to give species I (Scheme 4). The latter C-4/C-6 vinyl bond is more likely to be activated by the heterocyclic nitrogen electron lone pair than is the C-5/C-7 double bond by the oxygen lone pair, which is more electronegative. This difference in reactivity was supported experimentally and by theoretical calculations in relation to the regioselective Diels-Alder additions of dienes 1a-c with unsymmetrical dienophiles [7a], and to the electrophilic addition to the double bond of 4-oxazolin-2-ones 9[28].
Due to the formation of the conjugated vinylogous iminium ion in I, the nucleophiles (21a-c) attack the terminal C-7 carbon atom of the C-5/C-7 vinylic moiety, which is softer [29] and less hindered than the C-4 iminium carbon atom, leading to the observed products 22-24.
Scheme 4 Mechanism of reaction of dienes 1a-c with nucleophiles 21a-d to furnish 4-oxazolin-2-ones 22-28.
Given that thiophenol 21c was an efficient nucleophile in the addition to dienes 1a-c, the reaction of phenol (21d) with the same dienic substrates was explored, using phosphoric acid as the catalyst and CH2Cl2 as the solvent (Scheme 5). In contrast to the series of 22-24, where the oxygen and sulfur atoms were the nucleophilic center, the addition of 21d took place at the para position of the aryl ring to provide the series of 4-oxazolin-2-ones 25a-c. This is probably because of the effect of the greater softness of the aryl ring than the oxygen atom of 21d when reacting with the soft conjugated iminium species I.
Dienes 2a-c were also synthesized by the reported procedure [7,10], and their reaction with nucleophiles 21a and 21c-d was catalyzed by a Brønsted acid (Table 2). With these dienes, the addition of MeOH/HCl was carried out at -10 ºC for 24 h to avoid a larger amount of polymerization, resulting in the series of 4-oxazolin-2-ones 26a-c in modest yields (entries 1-3). With diene 2c, the mixture of adducts 26c/26c’ (83:17) found by 1H NMR was separated and characterized. With dienes 2a and 2b, the 1H NMR analysis of the crude reaction mixtures detected trace signals attributed to the corresponding regioisomers 26a’ and 26b’. However, the isolation of these compounds was not viable.
Table 2 Acid-catalyzed addition of nucleophiles 21a, 21c, and 21d to dienes 2a-c for the preparation of the series 4-oxazolin-2-ones 26a-c, 27a-c, and 28a-c.a
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| Entry | 2 | 21 | H+ | Ar | 26-28 | Yield (%)b |
| 1 | 2a | 21a | HCl | Ph | 26a | 67 |
| 2 | 2b | 21a | HCl | C6H4-4-Me | 26b | 69 |
| 3 | 2c | 21a | HCl | C6H4-4-OMe | 26c/26c’ (83:17) | 73/15 |
| 4 | 2a | 21c | H3PO4 | Ph | 27a | 60 |
| 5 | 2b | 21c | H3PO4 | C6H4-4-Me | 27b | 64 |
| 6 | 2c | 21c | H3PO4 | C6H4-4-OMe | 27c | 62 |
| 7 | 2a | 21d | H3PO4 | Ph | 28a | 60 |
| 8 | 2b | 21d | H3PO4 | C6H4-4-Me | 28b | 67 |
| 9 | 2c | 21d | H3PO4 | C6H4-4-OMe | 28c | 64 |
a Standard conditions: 2a-c (1.0 mol equiv), 21a, 21c, or 21d (1.6-240.0 mol equiv), and H+ (1.2-2.5 mol equiv), at -10-25 ºC, 1-24 h. For 21c and 21d, the reactions were carried out in CH2Cl2. b Isolated yields.
The presence of 26c’ could be explained by the plausible addition of the hard nucleophile (MeOH) to the hard C-4 iminium carbon atom of species II (Scheme 4). Another factor is the greater stability of the intermediate species II in relation to species I, caused by the supplementary methyl group [30].
Of course, the addition of soft nucleophiles 21c and 21d did not result in the C-4 addition regioisomers, but rather exclusively to the expected series of 4-oxazolin-2-ones 27a-c and 28a-c, respectively, in modest yields (entries 4-9). On the other hand, the addition of acetic acid (21b) promoted the formation of complex mixtures of products.
Conversion of 4-oxazolin-2-ones 23a-c into 4,5-dihydrobenzo[d]oxazol-2(3H)-ones 31
The satisfactory preparation of 4-oxazolin-2-ones 23a-c allowed for an exploration of a further transformation in route to the construction of a fused six-membered ring, as with 4,5-dihydrobenzo[d]oxazol-2(3H)-ones 31a-c (Scheme 6). The synthetic route comprised the consecutive saponification and oxidation of 4-oxazolin-2-ones 23a-c to provide alcohols 29a-c and aldehydes 30a-c, respectively. The first step consisted of the common and efficient hydrolysis with NaOH in a mixture of MeOH/H2O (8:2) to give the desired alcohols 29a-c in high yields. Analogous alcohols prepared with reported procedures have shown great value as synthons in the construction of molecules with potential synthetic and pharmacological activity [31].
Although diverse reagents were employed, including PCC, PDC, MnO2, and IBX [32], it was very difficult to establish the optimal oxidation conditions for the conversion of alcohols 29a-c into aldehydes 30a-c. The reaction of IBX in DMSO at rt for 24 h turned out to be the best procedure, furnishing the desired products in good yields (Scheme 6). On the other hand, the starting material was recovered with the use of PCC, and the decomposition of the substrate was observed with PDC or MnO2.
The Staunton-Weinreb annulation is a valuable strategy for the synthesis of a six-membered ring based on the condensation of an ortho-toluate (as the nucleophile) with a conjugated carbonyl compound (as the electrophile), involving a Michael addition followed by a Dieckmann condensation and, if possible, a subsequent aromatization [33]. Hence, the exocyclic crotonaldehyde-like moiety of the 4-oxazolin-2-one scaffold (30a-c) was examined as a potential synthon in the construction of 4,5-dihydrobenzo[d]oxazol-2(3H)-ones 31a-c through a Staunton-Weinreb-like reaction (Scheme 6).
The classical procedure of the Staunton-Weinreb cascade annulation involves a strong base, such as LDA or LiHMDS. With either of these two bases, the reaction of 30b-c with MVK as the electrophile led a complex mixture of products. With the base KOt-Bu, the reaction provided the desired products 31b-c, but in low yields. It is likely that the presence of the heteroatoms in the 4-oxazolin-2-one ring decreased the acidity of the C-4 methyl protons and consequently diminished the stability of the conjugated anion species III. The conjugated addition of the latter species to MVK afforded species IV, which underwent the Dieckmann condensation to generate the isolated adducts 31b-c. When the process was carried out with 30a, the starting material was recovered and only a trace amount of the expected adduct 31a was obtained.
Owing to the interest in insuring a readily supply of aldehydes 30a-c, a shorter synthetic route was designed. Thus, the straightforward construction of the 4-oxazolin-2-ones 32a-c was achieved in accordance with the previously reported methodology [15], involving a solvent-free addition/cyclization/dehydration cascade reaction between ketol 8a and isocyanates 5a-c under MW irradiation (Scheme 7). With slight modifications in the reaction conditions, such as a reduction in the MW potency (from 200 to 150 W) and an increase in the temperature (from 120 to 150 ºC) and reaction time (from 1.5 to 5.0 h), the yields of 5-formyl-4-oxazolin-2-ones 32a-c were improved. The application of the usual Vilsmeier-Haack reaction conditions to 32a-c gave the desired products 30a-c in modest yields.
Synthesis of tricyclic benzimidazol-2-ones via Diels-Alder cycloadditions of exo-imidazolidin-2-one dienes 15a and 16a-f
The symmetrical diene 15a and unsymmetrical dienes 16a-d (R = H) were elaborated based on previously described methods [21,22]. The reaction of α-iminoketones 11a-c with the corresponding isocyanates 5a-d furnished the desired dienes 15a and 16a-d in good yields. The new diene 16c was obtained starting from α-iminoketone 11c with isocyanate 5b (Scheme 8).
Preliminary results shown that diene 15a undergoes Diels-Alder cycloaddition with N-phenylmaleimide (19) under mild conditions (CH2Cl2, 0 ºC, 1 h) to furnish adduct 33a in high yield [21]. In order to gain more insight into the reactivity of unsymmetrical dienes, analogues 16a-c were submitted to cycloaddition with 19 under the same reaction conditions, leading to adducts 33b-d in high yields (Table 3, entries 2-4). As can be appreciated, the cycloaddition takes place regardless of the substituents located at the aryl ring of the dienes. Hence, reactivity is not dependent on the perturbation of the electron density of N,N’-aryl rings on the conjugated dienic moiety, a phenomenon that can be attributed to the almost orthogonal orientation of the aryl ring with respect to the heterocycle. This conformational preference of the substituted aryl rings, shown by quantic calculations and X-ray crystallography [22], impedes their conjugation with the nitrogen lone pairs of the imidazolidin-2-one ring. Thus, the aryl rings do not have any significant electronic effect, which agrees with previous results [21,22].
Table 3 Diels-Alder cycloaddition of dienes 15a and 16a-d to dienophiles 19 and 20 to afford adducts 33a-d and 35a-b.a
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| Entry | Diene | Dienophile | Ar | Ar’ | 33 or 35 | Yield (%)b |
| 1 | 15a | 19 | Ph | Ph | 33a | 90 |
| 2 | 16a | 19 | Ph | C6H4-4-OMe | 33b | 95 |
| 3 | 16b | 19 | Ph | C6H4-4-Cl | 33c | 92 |
| 4 | 16c | 19 | C6H4-3-OMe | C6H4-4-Me | 33d | 74 |
| 5 | 15a | 20 | Ph | Ph | 35a | 56 |
| 6 | 16d | 20 | C6H4-4-Me | Ph | 35b | 60 |
a Standard conditions: Method A: 15a and 16a-c (1.0 mol equiv) with 19 (1.1 mol equiv), in CH2Cl2, 0 ºC, 1 h. Method B: 15a and 16d (1.0 mol equiv) with 34 (1.0 mol equiv) and TBAF (1.5 mol equiv) in CH2Cl2 0 ºC-rt, 24 h. b Isolated yields.
Benzyne (20), an in situ-formed highly reactive molecule [34], is one of the most important dienophiles in Diels-Alder cycloadditions, generating linear and non-linear homologation of aromatic multicyclic six-membered rings [4,35], and be involved in natural product synthesis [36]. 2-(Trimethylsilyl)phenyl triflate (34) reacts under mild conditions with TBAF to generate 20 (Table 3) [35,36].
Dienes 15a and 16d were evaluated in Diels-Alder cycloadditions with benzyne (20) (Table 3, entries 5-6). The latter was generated in situ by reacting 34 with TBAF in the presence of the corresponding diene at 0 ºC. The mixture was stirred until reaching rt (for about 24 h), to obtain adducts 35a-b in moderate yields. Despite the high reactivity of 20, the conversion rate is not always complete, due to the well-known behavior of 20. Once formed, this molecule undergoes dimerization, thus decreasing its concentration in the reaction medium [34].
In the Diels-Alder additions with dienophiles 19 and 20, derivatives 15a and 16a-d proved to be potent dienes capable of providing a series of tricyclic tetrahydrobenzo[d]imidazol-2-ones 33a-d and 35a-b, which in turn can serve as precursors of aromatic analogues with potential synthetic and pharmacological value [23-27].
With the aim of exploring a preliminary synthetic application of adducts 33a-d and 35a-b, they were aromatized with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) under mild conditions, converting them into aromatic tricyclic benzo[d]imidazol-2-ones 36a-d (Scheme 9, Eq. 1) and naphtho[2,3-d]imidazol-2-ones 37a-b (Eq. 2), respectively, in high to excellent yields. The yields for the second series of aromatic products were higher, because of the greater stability gained by the formation of a naphthalene ring.
Scheme 9 Synthesis of tricyclic benzo[d]imidazol-2-ones 36a-d (Eq. 1) and naphtho[2,3-d]imidazol-2-ones 37a-b (Eq. 2).
All the structures of the intermediates and products of these synthetic pathways were characterized by IR, 1H and 13C NMR spectroscopy, assisted by 2D (HMQC, HSQC, and HMBC) experiments and high-resolution mass spectrometry (HRMS).
Conclusions
Dienes 1-2 proved to be versatile compounds not only as reactive and regioselective dienes in Diels-Alder additions, as previously demonstrated, but also as substrates for the regioselective synthesis of functionalized 4-oxazolin-2-ones 22-28. The latter compounds were uncommon substrates in a Staunton-Weinreb-like annulation, converting aldehydes 30b-c into 4,5-dihydrobenzo[d]oxazol-2(3H)-ones 31b-c, although in low yields. A shorter synthetic approach for an alternative preparation of aldehydes 30a-c was carried out through a two-step route starting from ketol 8a.
Symmetrical exo-2-imidazolidinone diene 15a and unsymmetrical dienes 16a-d were reactive substrates in the Diels-Alder cycloadditions with dienophiles N-phenylmaleimide (19) and benzyne (20). The corresponding adducts were efficiently aromatized to furnish a series of benzo- and naphtho[d]imidazol-2-ones, which potentially have pharmacological activity.
