HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 6, 2016, pp. 1054-1062
Received, 24th February, 2016, Accepted, 29th March, 2016, Published online, 14th April, 2016.

■ An Efficient Route for Synthesis and Reactions of Seleno-[2, 3-c]coumarin

Shams H. Abdel-Hafez,* Ahmed Elkhateeb, Adel A. Gobouri, Islam H. El Azab, and Gilbert Kirsch

Department of Chemistry, Faculty of Science, Taif University, Taif-Al-Haweiah 888/21974, Saudi Arabia

Abstract

Synthesis of new selenium-containing coumarin moiety via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbonitrile with selenium and sodium borohydride gave 3-Cyano-4-coumarinselenol which reacted with different halo-acids, such as chloroacetonitrile, ethyl chloroacetate and chloroacetamide to give the corresponding 3-amino-4-oxo-4H-seleno[3,2-c]chromene-2- derivatives. Hydrazonolysis of the obtained new ethyl 3-amino-4-oxo-4H-seleno[3,2-c] chromene-2-carboxylate afforded the corresponding hydrazino compound. The hydrazino compound was used as a versatile precursor for synthesis of new other heterocyclic compounds containing selenocoumarin moiety. The newly synthesized compounds were characterized using the spectroscopic tools (IR, 1H NMR, 13C NMR and mass spectroscopy) as well as microanalysis.

INTRODUCTION
Coumarins natural and synthetic have been found to exhibit a variety of pharmacological activities like anti-HIV,1 anticoagulant,2 antibacterial,3 antioxidant,4 and anti-inflammatory.5 Among the diverse biological activities of coumarin the most intriguing bioactivity is the effect against breast cancer. 6-9 On the other hand, in last years, many kinds of selenophene derivatives have been increased remarkably in organic synthesis due to their chemical properties and biological activities.10-18 For example a series of selenophene derivativies are reported as potent inhibitors CHK1 kinase.19 Therefore, many medicinal preparations have been produced on the basis of organic derivatives of selenophene. In continuation of our program on selenium containing heterocyclic systems,14-18 here in this paper we discuss the synthesis of selenophene based on coumarin moiety to discover new useful compounds for the treatment of many diseases and act as antioxidant and anti-inflammatory agents with significant analgesic effect.

RESULTS AND DISCUSSION
To achieve our target compounds, we started from compound, 4-hydroxycoumarin (1), which undergoes Vilsmeier formylation onto 4-chloro-3-formylcoumarin (2). Compound 2 showed different reactivity depending on the reaction conditions. Its reaction with hydroxylamine gives a variety of products which described before in the last our paper.20 The obtained products were 4-chloro-3-cyanocoumarin (4); 4H-coumarino[3,4-d]isoxazol-4-one (5); ethyl 5-(2-hydroxyphenyl)isoxazole-4-formate (6) via the intermediate compound (3) (Scheme 1).

Those compounds were separated in good yields by preparative TLC. Chlorocyanocoumarin 4 was used as a versatile precursor for synthesis of new 3-cyano-4-coumarinselenol (7) by refluxing with selenium metal and sodium borohydride in ethanol. Compound 7 was characterized by 1H NMR spectrum which showed singlet peak at (δ, ppm): 14.02 due to (-SeH). Compound 7 reacted with different halo-acids such as chloroacetonitrile or ethyl chloroacetate or chloroacetamide in DMF and excess of NaOH underwent Thorpe-Ziegler cyclization to afford the corresponding compounds selenochromene carbonitrile (8), selenochromenecarboxylate (9) and selenochromenecarboximide (10) derivatives (Scheme 2). All the newly synthesized compounds 2-10 were confirmed by IR, 1H NMR, 13C NMR and mass spectroscopy as well as microanalysis.

Selenochromenecarboxylate 9 was used as a key in the synthesis of different new heterocyclic system based on coumarin. The reactivity of the ester group in 9 was tested via its hydrazonolysis with hydrazine hydrate which, afforded the corresponding selenochromenecarbohydrazide (11). Compound 11 would be served as precursor of other heterocyclic compounds as follows: compound 11 was reacted with triethyl orthoformate in ethanol in the presence of catalytic drops of acetic acid to give chromenoselenopyrimidine (12). Also, compound 11 reacted with sodium nitrite solution in acetic acid to give the corresponding carbonylazide derivative (13) which underwent Curtius rearrangement upon boiling in dry xylene giving chromenoselenoimidazole derivative (14). On the other hand condensation of carbohydrazide 11 with acetylacetone in ethanol afforded pyrazolylselenochromen derivative (15) (Scheme 3).

Finally, the reaction of selenochromenecarboxylate 9 with alcoholic sodium hydroxide under reflux afforded 3-amino-4-oxo-4H-seleno[3,2-c]chromene-2-carboxylic acid (16) which reacted with acetic anhydride under reflux to give 8-methyl-6,10-dihydro-chromeno[3',4':4,5]seleno[3,2-d][1,3]- oxazine-6,10-dione (17). Refluxing of compound 17 with aniline gave 8-methyl-6,10-dihydro-7(6H)- chromeno[3',4':4,5]seleno[3,2-d]pyrimidine-6,10-dione (18) (Scheme 4).

Chemical structures of all products obtained 11-18 were confirmed by IR and NMR spectroscopy, mass spectrometry and elemental microanalysis.

EXPERIMENTAL
General Methods. The melting points were determined by using the Kofler melting point apparatus, and were uncorrected. IR (KBr, cm-1) spectra were recorded on a Pye-Unicam SP3–100 instrument at Taif University. 1H NMR spectra were obtained on a Varian (400 MHz) EM 390 USA instrument at King Abdel-Aziz University. 13C NMR spectra were recorded on a JNM-LA spectrometer (100 MHz) at King Abdel-Aziz University, Saudi Arabia. For both 1H and 13C NMR, DMSO-d6 or (CDCL3) was used. Spectra were internally referenced to TMS. Peaks are reported in ppm downfield of TMS. Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q). Mass spectra were recorded on ISQ Thermo Scientific GC-MS. GC column TG-SQC, Trace GC ultra at Taif University KSA for compounds 2-6. Purity of the compounds was checked by thin layer chromatography (TLC) using silica gel plates.
Note: Compounds 7-18 were determined by using EI-MS on JEOL-JMS-AX 500 at Cairo National Research Center Cairo, Egypt.
4-Chloro-3-coumarincarbaldehyde (2). Compound 2 was prepared as previously describe by Sabitae et al. with a little modification.20-21 The pale yellow solid was collected by filtration and recrystallized from acetone to give 10.5 g (84%) of 2; mp 133-135 °C (lit. 130 °C).20 1H NMR (DMSO-d6) δ, ppm: 10.39 (1H, s, CH=O), 8.16–7.28 (4H, m, Ar-H); IR ν 1720 (C=O-pyrone), 1663 (CHO) cm–1. EI-MS m/z: 208 (M+, 11), 182 (31), 180 (100), 154 (31), 152 (91), 124 (20), 101 (11), 89 (80), 63 (37), 62 (31), 61 (14); EI-HRMS: m/z 207.9909 (calculated for C10H5ClO3 207.9927)
3-Cyano-4-chlorocoumarin (4), 4H-chromeno[3,4-d]isoxazol-4-one (5), ethyl 5-(2-hydroxyphenyl)- isoxazole-4-carboxylate (6): were prepared as previously described.20
Compound 4 as yellow crystal mp 198-200 °C (Lit, 199-200 °C).22
4H-Chromeno[3,4-d]isoxazol-4-one (5), mp 222-224 °C; 1H NMR (DMSO-d6) δ, ppm: 10.21 (1H, s, CH-isoxazole), 8.03–7.41 (4H, m, Ar-H); 13C NMR δ, ppm: 165.50, 155.04, 154.90, 152.80, 133.36, 125.29, 124.07, 117.67, 110.24, 107.83. IR ν 1761 (C=O-pyrone), 1608 (C=N) cm–1. EI-MS m/z: 187 (M+, 100), 159 (33), 131 (11), 119(4), 103 (54), 76 (26). EI-HRMS: m/z 187.0268 (calculated for C10H5NO3: 187.0269)
Ethyl 5-(2-hydroxyphenyl)isoxazole-4-formate (6), mp 218-220 °C; 1H NMR (CDCl3) δ, ppm: 9.02 (1H, s, CH-isoxazole), 8.12–7.01 (4H, m, Ar-H), 4.37 (2H, q, J= 6.80 Hz, CH2); 1.36 (3H, t, J= 6.80 Hz, CH3).13C NMR δ, ppm: 175.80, 163.49, 160.60, 155.68, 134.01, 125.66, 122.80, 118.68, 116.20.93.54, 60.29, 13.72.IR ν 1669 (C=O…H-bond), 1601 (C=N) cm–1. EI-MS m/z 233 (M+, 33), 187 (100), 159 (41), 131 (12), 119 (4), 103 (35), 76 (8); EI-HRMS: m/z 233.0684 (calculated for C12H11NO4: 233.0688).
3-Cyano-4-coumarinselenol (7).
A mixture of compound 4 (2.05 g, 0.01 mol), selenium powder (1g, 0.12 mol) and NaBH4 (1.2 g, 0.031 mol) were refluxed in 50 mL of EtOH for 3 h, and then the reaction mixture cooled and poured onto 50 mL crushed ice/HCl. The precipitated compound was collected, dried and recrystallized from EtOH as orange precipitate in 85% yield, mp 218-220 °C. IR: 2223 (CN), 1719 (C=O chromene) cm–1. 1H NMR (DMSO-d6) δ, ppm: 14.02 (s, 1H, SeH), 7.20–7.80 (4H, m, Ar-H). 13C NMR δ, ppm: 160.1, 155.4, 128.3, 127.8, 126.8, 125.4, 119.9, 104.8, 100.4, 115.3. Mass: m/z: 251 [M+ + 1, 27%]. Anal. Calcd for C10H5NO2Se (250.11): C, 48.02; H, 2.01; N, 5.60%. Found: C, 47.99; H, 2.00; N, 5.55%.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carbonitrile (8), Ethyl 3-amino-4-oxo-4H-seleno[3,2-c]- chromene-2-carboxylate (9), 3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carboximide (10)
General procedure:
A mixture of seleno compound (7) (2.51 g, 0.01 mol) and halo compounds (chloroacetonitrile or ethyl chloroacetate or chloroacetamide) (0.012 mol) was dissolved in DMF (30 mL) containing aq. KOH (10%, 5 mL). The reaction mixture was stirred for 1 h, after that another KOH solution (5 mL) was added and stirred for another 1 h. The precipitate product that formed was collected, dried and recrystallized from EtOH affording compounds 8-10 respectively.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carbonitrile (8), as a yellow crystal in 85% yield, mp 275–277 °C; IR: 3460, 3350 (NH2), 1725 (C=O chromene), 2217 (CN) cm–1. 1H NMR (DMSO-d6): δ, ppm: 6.90 (2H, s, NH2), 7.20–7.80 (4H, m, Ar-H). ). 13C NMR δ, ppm: 175.1, 160.1, 155.4, 128.3, 127.8, 126.8, 125.4, 119.9, 139.1, 131.5, 113.9, 75.3. Mass: m/z: 289 [M+, 20%]. Anal. Calcd for C12H6N2O2Se (289.15): C, 49.85; H, 2.09; N, 9.69%. Found: C, 49.68; H, 2.00; N, 9.54%.
Ethyl 3-amino-4-oxo-4H-seleno[3,2-c]chromene-2-carboxylate (9), as a yellow crystal in 88% yield, mp 200–202 °C; IR: 3470, 3367 (NH2), 1725 (C=O chromene), 1695 (C=O ester) cm-1. 1H NMR (CDCl3): δ, ppm: 1.35–1.40 (3H, J = 7.0 Hz, t, CH3), 4.30–4.50 (2H, J = 6.0 Hz, q, CH2), 7.19 (2H, s, NH2), 7.20–7.80 (4H, m, Ar-H). 13C NMR δ, ppm: 166.9, 165.4, 160.1, 155.4, 139.7, 131.5, 128.3, 127.8, 126.8, 125.4, 119.9, 95.6, 63.1, 14.8. Mass: m/z: 337 [M+ + 1, 100%]. Anal. Calcd for C14H11NO4Se (336.20): C, 50.01; H, 3.30; N, 4.17%. Found: C, 49.88; H, 3.25; N, 4.01%.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carboximide (10), as an orange crystal in 80% yield, mp 280–282 °C; IR: 3500, 3460, 3350, 3250 (2NH2), 1725 (C=O chromene), 1660 (C=O) cm–1. 1H NMR (DMSO-d6): δ, ppm: 7.19 (2H, s, NH2), 5.90 (2H, s, NH2); 7.20–7.80 (4H, m, Ar-H). 13C NMR δ, ppm: 168.3, 164.3, 160.1, 155.4, 139.0, 131.0, 128.3, 127.8, 126.8, 125.4, 119.9, 97.5. Mass: m/z: 307 [M+, 20%]. Anal. Calcd for C12H8N2O3Se (307.16): C, 46.92; H, 2.63; N, 9.12%. Found: C, 46.76; H, 2.55; N, 9.00%.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carbohydrazide (11).
A mixture of compound (9) (3.36 g, 0.01 mol) and hydrazine hydrate (3 mL, 0.06 mol) was refluxed for 1 h then absolute EtOH (20 mL) was added. The reaction mixture was refluxed for additional 2 h. The precipitated product which formed was dried and recrystallized from EtOH to give pale yellow crystals in 66% yield, mp 270–272 °C. IR: 3450, 3350, 3180 (NH, NH2), 1725 (C=O chromene), 1650 (CONH) cm-1. 1H NMR (DMSO-d6): δ, ppm: 4.45 (2H, s, NH2), 6.90 (2H, s, NH2), 7.20–7.50 (4H, m, Ar-H), 8.85 (1H, s, NH). 13C NMR δ, ppm: 166.5, 164.3, 160.1, 155.4, 139.0, 131.0, 128.3, 127.8, 126.8, 125.4, 119.9, 97.5. Mass: m/z 322 [M+, 30%]. Anal. Calcd for C12H9N3O3Se (322.18): C, 44.74; H, 2.82; N, 13.04%. Found: C, 44.58; H, 2.77; N, 13.00%.
(E)-Ethyl N-(6,10-dioxo-6H-chromeno[3',4':4,5]seleno[3,2-d]pyrimidin-9(10H)-yl)formimidate (12).
A mixture of compound (11) (3.22 g, 0.01 mol) and triethyl orthoformate (8 mL, 0.027 mol) was refluxed in presence of glacial acetic acid (3 mL) for 3 h. The precipitate product which formed on hot was filtered off, dried and recrystallized from DMF/EtOH mixture giving pale yellow crystals in 55% yield, mp > 300 °C. IR: 1720 (C=O chromene), 1660 (C=O pyrimidine) cm-1. 1H NMR (DMSO-d6): δ, ppm: 1.25–1.40 (3H, t, CH3, J=7 Hz), 4.30–4.40 (2H, q, CH2, J=7.1 Hz); 7.60–8.50 (6H, m, Ar-H + CH-pyrimidine+ CH=N). 13 C NMR δ, ppm: 168.0, 163.5, 160.1, 157.4, 150.8, 149.5, 139.6, 131.01, 128.3, 127.8, 126.8, 125.4, 119.9, 115.05, 63.4, 15.3. Mass: m/z 388 [M+, 25%]. Anal. Calcd for C16H11N3O4Se (388.24): C, 49.50; H, 2.86; N, 10.82%. Found: C, 49.45; H, 2.77; N, 10.59%.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carbonylazide (13).
To a stirred solution of compound (11) (3.22 g, 0.01 mol) in glacial acetic acid (15 mL) sodium nitrite solution (4.5 g, 0.07 mol) was added dropwise at 0-5 °C for 15 min, a brown precipitate was formed and then filtered off, washed with water, dried and used without recrystallization for the following step, in 47% yield, mp 145–147 °C. IR: 3450, 3350 (NH2), 2100 (N3), 1725 (C=O chromene), 1660 (C=O azide) cm-1. 1H NMR (CDCl3): δ, ppm: 7.19 (2H, s, NH2), 7.25–7.60 (4H, m, Ar-H). 13C NMR δ, ppm: 189.5, 172.0, 160.1, 155.4, 139.3, 131.6, 128.3, 127.8, 126.8, 125.4, 119.9, 107.01. Mass: m/z 333[M+, 30%]. Anal. Calcd for C12H6N4O3Se (333.16): C, 43.26; H, 1.82; N, 16.82%. Found: C, 43.10; H, 1.76; N, 16.78%.
7,9-Dihydro-6H,8H-chromeno[3',4':4,5]seleno[2,3-d]imidazole-6,8-dione (14).
A mixture of 13 (1 g, 0.003 mol) in dry xylene (10 mL) was refluxed for 2 h. The solid product which formed on hot was filtered off, washed three times by xylene, dried and recrystallized from xylene as dark green crystals in 50% yield, mp > 300 °C. IR: 3450, 3350 (2NH), 1725 (C=O chromene), 1645 (C=O imidazole) cm-1. 1H NMR (DMSO-d6): δ, ppm: 5.90 (2H, s, 2NH); 7.20–7.75 (4H, m, Ar-H). 13C NMR δ, ppm: 160.1, 155.4, 151.01, 139.5, 131.08, 128.3, 127.8, 126.8, 125.4, 119.9, 118.68, 99.5. Mass: m/z 305 [M+, 50%]. Anal. Calcd for C12H6O3N2Se (305.15): C, 47.23; H, 1.98; N, 9.18%. Found: C, 47.11; H, 1.80; N, 9.11%.
3-Amino-2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-4H-seleno[3,2-c]chromen-4-one (15).
A mixture of carbohydrazide (11) (3.22 g, 0.01 mol) and acetylacetone (1.2 mL, 0.013 mol) was refluxed in EtOH (10 mL) for 3 h. The precipitate product was filtered off and recrystallized from EtOH as yellow crystals in 60% yield, mp 250–252 °C. IR: 3350, 3250 (NH2), 1720 (C=O chromene), 1690 (C=O) cm-1. 1H NMR (DMSO-d6): δ, ppm: 2.30–2.45 (6H, 2s, 2CH3), 6.90 (2H, s, 2NH2), 5.50 (1H, s, CH-pyrazole), 7.20–7.50 (4H, m, Ar-H). 13C NMR δ, ppm: 188.8, 170.2, 164.0, 161.9, 160.1, 152.3, 155.4, 143.2, 131.7, 128.3, 127.8, 126.8, 125.4, 119.9, 105.5, 13.7, 13.2. Mass: m/z 386 [M+, 45%]. Anal. Calcd for C17H13N3O3Se (386.26): C, 52.86; H, 3.39; N, 10.88%. Found: C, 52.66; H, 3.29; N, 10.78%.
3-Amino-4-oxo-4H-seleno[3,2-c]chromene-2-carboxylic acid (16).
A suspension of ester compound (9) (3.36 g, 0.01 mol) in 10% ethanolic sodium hydroxide (40 mL) was heated under reflux for 3 h, and then allowed to cool. The reaction mixture was diluted with 50 mL of water, filtered, and then acidified with dilute acetic acid. The precipitate was filtered off and recrystallized from dioxane to give orange crystals, yield 68%; mp 245–247 ºC. IR: 3420, 3300 (NH2), 1720 (C=O chromene), 1640 (C=O) cm-1. 1H NMR (DMSO-d6): δ, ppm: 10.55 (1H, s, COOH); 7.20-7.75 (6H, m, H-Ar + NH2). 13C NMR δ, ppm: 168.0, 164.4, 160.1, 155.4, 139.1, 131.8, 128.3, 127.8, 126.8, 125.4, 119.9, 93.5. Mass: m/z 309 [M+ +1, 35%]. Anal. Calcd for C12H7NO4Se (308.15): C, 46.77; H, 2.29; N, 4.55%. Found: C, 46.55; H, 2.15; N, 4.44%.
8-Methyl-6,10-dihydrochromeno[3',4':4,5]seleno[3,2-d][1,3]oxazine-6,10-dione (17).
Compound 16 (3.08 g, 0.01 mol) in acetic anhydride (25 mL) was heated under reflux for 3 h, and allowed to cool at room temperature. The crystalline product was collected, dried in air, and applied in the next reaction without recrystallization, yield 35%; mp 265–267 ºC. IR: 1720 (C=O chromene), 1640 (C=O) cm-1. 1H NMR (DMSO-d6): δ, ppm: 7.20–7.55 (4H, m, H-Ar); 1.95 (3H, s, CH3). 13C NMR δ, ppm: 175.1, 164.0, 161.8, 160.1, 140.0, 134.2, 155.4, 128.3, 127.8, 126.8, 125.4, 119.9, 112.6, 16.3. Mass: m/z 333 [M+ +1, 15%]. Anal. Calcd for C14H7NO4Se (332.17): C, 50.62; H, 2.12; N, 4.22%. Found: C, 50.33; H, 2.11; N, 4.10%.
8-Methyl-6,10 dihydro-7(6H)-chromeno[3',4':4,5]seleno[3,2-d]primidine-6,10-dione (18)
A mixture of compound 17 (3.32 g, 0.01 mol) and aniline (1 mL) in glacial acetic acid (10 mL) was heated under reflux for 3 h. The reaction mixture was cooled and diluted with water. The solid precipitate was collected and recrystallized from an EtOH/DMF mixture to give pale yellow crystals, yield 35%; mp 235–237 ºC. IR: 1720 (C=O chromene), 1660 (C=O) cm-1. 1H NMR (DMSO-d6): δ, ppm: 7.20-7.95 (9H, m, H Ar); 2.10 (3H, s, CH3). 13C NMR δ, ppm: 168.1, 164.5, 160.1, 157.9, 140.1, 133.4, 155.4, 128.3, 127.8, 126.8, 125.4 (2-Ar), 119.9, 115.4, 25.8. Mass: m/z 408 [M+ +1, 65%]. Anal. Calcd for C20H12N2O3Se (407.28): C 58.98; H 2.97; N 6.88% . Found: C 58.88; H 2.78; N 6.77%.

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