HETEROCYCLES

Short Paper | Special issue | Vol. 90, No. 1, 2015, pp. 645-658
Received, 3rd April, 2014, Accepted, 9th May, 2014, Published online, 21st May, 2014.
DOI: 10.3987/COM-14-S(K)21

■ Diversity Oriented Approach to Oxepine Derivatives: Further Expansion via Diels‒Alder Reaction

Sambasivarao Kotha* and Rashid Ali

Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India

Abstract

Oxepine derivatives have been assembled via Diels‒Alder (DA) reaction as a key step and the latent dienes suitable for the DA reaction have been generated in situ from the sultine derivatives, which in turn were achieved by using commercially available rongalite. The “drug like” molecules assembled here may find useful applications in medicinal as well as bioorganic chemistry.

Heterocycles containing oxygen are prevalent1 in a number of biologically active substances. They have attracted a great deal of attention of synthetic as well as medicinal chemists. More specifically, unsaturated 7-membered oxacycle (oxepine) frameworks shows a wide range of biological properties such as ion channel blocking, antiplasmodial activity, antiviral, antipsychotic, and antifungal activities.2 Various natural and marine natural products3 containing oxepine motif play a vital role in biological processes. Some important natural products containing oxepine structural motif are shown in Figure 1.4 Since, oxepine containing compounds shows a wide range of applications, several efforts have been directed towards the synthesis of these useful building blocks by different groups using diverse synthetic methods, these include: (a) Lewis-acid and base catalyzed intramolecular cyclization; (b) carbocyclization by rhodium-catalysis; (c) intramolecular acyl radical cyclization and; (d) metathesis sequences etc.5 Although, the above methods are useful to generate oxepine derivatives, some of these methods have several drawbacks such as use of expensive catalysts, require high temperature, longer reaction time and low yields of the products. To address these problems, complimentary methods involving waste free and environmentally benign strategies are desirable. To this end, we have conceived a very simple methodology to synthesize oxepine derivatives in diversity oriented manner6 by using DA sequence.

Our strategy towards the synthesis of oxepine derivatives began with the preparation of known 1,2,4,5-tetrakis(bromomethyl)benzene 8.7 Later, the tetrabromide 8 was treated with indane-1,3-dione 8a using K2CO3 in MeCN to deliver the compounds 9 (8%), and 10 (30%) along with the dimer 11 (18%) (Scheme 1). On the other hand, under Cs2CO3 condition, we isolated the compounds 10 (39%) and 11 (14%). Having the compound 10 in hand, it was treated with rongalite in DMF to deliver the inseparable mixture of sultine derivatives 12a and 12b in 61% yield. Later, these derivatives 12a and 12b were rearranged to sulfone 13 (75%) under toluene reflux conditions. In addition, they were also treated with different dienophiles in a DA fashion to deliver the corresponding DA adducts in 14 (84%), 17 (68%) and 18 (89%) (Scheme 1). When the DA adducts 14 and 18 were treated with MnO2/DDQ (2,3-dichloro5,6-dicyano-1,4-benzoquinone) in refluxing toluene, we did not observe the corresponding dehydrogenated products 16 and 21. Surprisingly, the DA adduct 14 on treatment with MnO2 in toluene under microwave conditions gave [1,3]-sigmatropic rearranged product 15 (51%) instead of expected product 16. On the other hand, the compound 18 on treatment with MnO2 in toluene under similar reaction conditions gave unexpected compound 19 (48%) along with the rearranged product 20 (25%) instead of product 21. The compounds 15, 19 and 20 were confirmed by 1H and 13C NMR spectral data and further supported by HRMS. To our surprise, the compounds 10 and 11 under microwave condition did not afford the corresponding [1,3]-sigmatropic rearranged products 9 and 11a (Scheme 2).

To generalize our strategy, we have also selected commercially available cyclohexane-1,3-dione 22 and 5,5-dimethylcyclohexane-1,3-dione 27 as a coupling partners with the tetrabromo compound 8 to generate oxepine derivatives. Coupling of the dione 22 with the tetrabromide 8 using Cs2CO3 as a base in MeCN delivered the oxepine derivative 23 in 47% yield along with a minor amount of unidentified product. Later, the oxepine derivative 23 was transformed into the inseparable mixture of sultine derivatives 24a and 24b by treating with rongalite in DMF, which were further rearranged to sulfone derivative 25 (90%) under toluene reflux conditions (Scheme 3). Later, these sultine derivatives 24a and 24b were treated with tetracyanoethylene to deliver the cycloadduct 26 in 89% (Scheme 3). Along similar lines, treatment of 5,5-dimethylcyclohexane-1,3-dione 27 with the tetrabromide 8 using Cs2CO3 as a base in MeCN gave the compound 28 in 58% yield (Scheme 4). Later, the compound 28 was treated with rongalite in DMF to deliver the inseparable mixture of sultine derivatives 29a and 29b in 75% yield. Having the sultine derivatives 29a and 29b in hand, they were treated with tetracyanoethylene and dimethyl acetylenedicarboxylate (DMAD) to deliver the corresponding DA adducts 30 (95%) and 31 (72%) respectively (Scheme 4).

In summary, we have developed a very simple and useful method for the synthesis of oxepine derivatives via DA reaction as a key step. Our strategy involves the use of rongalite for the sultine formation and the sultine derivatives act as latent diene equivalents in the DA sequence. These sultine derivatives can be trapped with various dienophile to generate a range of complex oxepine derivatives and also these can be rearranged to sulfone derivatives.8 Since oxepine derivatives are valuable in medicinal chemistry, our approach is useful to generate a library of “drug like” molecules by varying the diene and dienophile components in DA reaction. Moreover, these sulfones can be used to expand the library by the alkylation of the active methylene of sulfones and also by desulfonation sequence.

EXPERIMENTAL
Commercially available reagents were used without purification and reactions involving air sensitive reagents or catalysts were performed in degassed solvents. Moisture sensitive materials were transferred by using standard syringe-septum techniques and the reactions were maintained under nitrogen atmosphere. Analytical thin layer chromatography (TLC) was performed on (7.5×2.5 cm) glass plates coated with Acme’s silica gel GF 254 (containing 13% calcium sulfate as a binder) by using appropriate mixture of ethyl acetate and petroleum ether for development. Column chromatography was performed by using Acme’s silica gel (100-200 mesh) with an appropriate mixture of ethyl acetate and petroleum ether. The coupling constants (J) are given in hertz (Hz) and chemical shifts are expressed in parts per million (ppm). The abbreviations, s, d, t, q, m, dd and td, refer to singlet, doublet, triplet, quartet, multiplet, doublet of doublet, and triplet of doublet respectively. Reported yields refer to the isolated yields after column chromatography technique. Infrared (IR) spectra were recorded on Nicolet Impact-400 FT IR spectrometer in CHCl3. Proton nuclear magnetic resonance (1H NMR, 400 MHz and 500 MHz) spectra and carbon nuclear magnetic resonance (13C NMR, 100 MHz and 125 MHz) spectra were recorded on a Bruker spectrometer. The high-resolution mass measurements were carried out by using electrospray ionization (ESI, Q-ToF) spectrometer. Melting points were recorded on a Veggo melting point apparatus.
Preparation of compound 8: The 1H and 13C spectra matched with the literature reported spectral data.9
Synthesis of compound 10: The solution of the dione 8a (1.5 g, 10.27 mmol), K2CO3 (7.08 g, 51.35 mmol) and TBAHS (870 mg, 2.57 mmol) in dry MeCN (40 mL) was stirred at rt for 15 min. Later, the tetrabromide 8 (4.62 g, 10.27 mmol) was added and the stirring was continue for 8 h at same temperature. At the conclusion of the reaction (TLC monitoring), excess amount of K2CO3 was filtered through sintered funnel and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (10% EtOAc-petroleum ether) to afford the spirodibromide 9 (355 mg, 8%) as a yellow solid and continue elution with 20% EtOAc-petroleum ether gave the oxepine derivatives 10 (1.33 g, 30%) and 11 (770 mg, 18%) as yellow solids.
Compound 9: The 1H and 13C spectra matched with the literature reported spectral data.10
Compound 10: Mp 187-188 °C; Rf = 0.54 (silica gel, 25% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 2H), 4.60 (s, 2H), 4.64 (s, 2H), 5.39 (s, 2H), 7.09 (d, J = 7.04 Hz, 1H), 7.21-7.31 (m, 3H), 7.37-7.39 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 26.04, 29.18, 29.35, 71.97, 107.12, 118.18, 121.17, 129.81, 131.30, 131.80, 132.42, 133.08, 134.91, 135.47, 138.20, 139.56, 143.09, 173.21, 194.04; IR (CHCl3): υmax. 1621, 1696, 2925, 3021 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C19H14Br2NaO2 [M+Na]+ 454.9253, found: 454.9254. and other fragments are 437.1941, 443.1934, 456.9236, 457.9268, 458.9216, 459.9249.
Compound 11: Mp 174-175 °C; Rf = 0.50 (silica gel, 25% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.34 (s, 4H), 3.76 (s, 2H), 5.42 (s, 2H), 7.08-7.13 (m, 2H), 7.22-7.29 (m, 3H), 7.37-7.39 (m, 1H), 7.86-7.89 (m, 2H), 8.00-8.03 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 26.39, 40.38, 40.77, 58.99, 72.94, 107.96, 118.08, 118.20, 121.02, 123.92, 124.60, 126.37, 129.65, 129.75, 130.62, 132.06, 132.29, 132.40, 132.92, 136.17, 139.31, 139.83, 140.95, 141.59, 142.34, 173.45, 194.32, 202.83; IR (CHCl3): υmax. 1625, 1704, 1736, 2923, 3016 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C28H18NaO4 [M+Na]+ 441.1097, found: 441.1097 and other fragments are 413.2663, 442.1130, 443.1159.
Synthesis of compound 12a and 12b: To a solution of the oxepine dibromide 10 (600 mg, 1.38 mmol) in DMF (10 mL), was added TBAB (445 mg, 1.38 mmol) and rongalite (2.13 g, 13.8 mmol) at 0 ᴏC and stirred the reaction mixture for 3 h at 0 ᴏC and at rt for another 3 h. At the conclusion of the reaction (TLC monitoring), the compound was extracted with EtOAc and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (40% EtOAc-petroleum ether) to afford the sultine derivatives 12a and 12b (284 mg, 61%) as a yellow solid.
Mp 140-142 °C; Rf = 0.58 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.57 (dd, J1 = 6.12 Hz, J2 = 15.21 Hz, 1H), 3.75 (s, 2H), 4.32 (d, J = 15.41 Hz, 1H), 4.92-4.97 (m, 1H), 5.24-5.30 (m, 1H), 5.36-5.45 (m, 2H), 7.00-7.13 (m, 2H), 7.21-7.31 (m, 3H), 7.37 (d, J = 6.84 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 25.93, 55.75, 56.12, 62.45, 72.09, 107.18, 118.07 120.98, 124.47, 125.71, 127.53, 127.59, 129.69, 129.94, 131.66, 131.84, 132.12, 132.31, 133.39, 134.07, 134.69, 139.40, 141.45, 142.08, 173.09, 193.87; IR (CHCl3): υmax. 1625, 1696, 2923, 3016 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C19H14NaO4S [M+Na]+ 361.0505, found: 361.0505 and other fragments are 242.2845, 274.2744, 296.2562, 318.3005, 340.2825.
Synthesis of sulfone 13: The solution of sultine derivatives 12a and 12b (100 mg, 0.29 mmol) in toluene (20 mL) was refluxed for 15 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford the sulfone derivative 13 (75 mg, 75%) as a yellow solid.
Mp 157-158 °C; Rf = 0.56 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.78 (s, 2H), 4.36 (d, J = 3.80 Hz, 4H), 5.43 (s, 2H), 7.10 (d, J = 7.00 Hz, 1H), 7.23-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 26.27, 56.75, 56.91, 72.16, 107.08, 118.22, 121.23, 126.19, 128.00, 129.89, 130.15, 131.77, 132.46, 133.01, 134.67, 139.42, 142.76, 173.18, 193.90; IR (CHCl3): υmax. 1625, 1700, 2929, 3020 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C19H14NaO4S [M+Na]+ 361.0505, found: 361.0508 and other fragments are 353.2670, 362.0541, 363.0505.
General procedure for DA reaction: The solution of sultine derivatives and dienophiles (1.5 equiv) in toluene (20 mL) was refluxed for 10-24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude products were purified by silica gel column chromatography (appropriate mixture of EtOAc-petroleum ether) to afford the DA adducts.
Compound 14: The solution of sultine derivatives 12a and 12b (50 mg, 0.15 mmol) and naphthoquinone (36 mg, 0.23 mmol) in toluene (20 mL) was refluxed for 24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (40% EtOAc-petroleum ether) to furnish the DA adduct 14 (54 mg, 84%) as a yellow solid.
Mp 170-171 °C; Rf = 0.75 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 2.95 (d, J = 16.29 Hz, 2H), 3.25 (d, J = 15.12 Hz, 2H), 3.56 (s, 2H), 3.63-3.73 (m, 2H), 5.28-5.40 (m, 2H), 7.00 (s, 1H), 7.06 (d, J = 7.00 Hz, 1H), 7.12 (s, 1H), 7.18-7.25 (m, 2H), 7.35 (d, J = 6.76 Hz, 1H), 7.74-7.79 (m, 2H), 8.03-8.12 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 25.94, 28.17, 28.35, 47.10, 47.13, 72.57, 107.87, 118.04, 120.97, 127.10, 127.14, 129.15, 129.61, 131.06, 131.75, 131.94, 132.08, 132.26, 133.96, 134.04, 134.64, 134.68, 134.76, 139.61, 139.77, 173.32, 194.31, 197.72; IR (CHCl3): υmax. 1626, 1696, 2928, 3020 cm-1; HRMS (Q-Tof) m/z: calculated for C29H20NaO4 [M+Na]+ 455.1254, found: 455.1254 and other fragments are 318.3008, 330.3372, 346.3320, 362.3269, 437.1937, 456.1289.
Compound 15: The solution of the DA adduct 14 (30 mg, 0.07 mmol) and MnO2 (61 mg, 0.70 mmol) in toluene (20 mL) was heated at 120 °C for 30 min under microwave condition. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to deliver the rearranged product 15 (15 mg, 51%) as a yellow solid. The 1H and 13C spectra matched with the literature reported spectral data.8
Compound 17: The solution of sultine derivatives 12a and 12b (50 mg, 0.15 mmol) and tetracyanoethylene (29 mg, 0.23 mmol) in toluene (20 mL) was refluxed for 24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to deliver the DA adduct 17 (40 mg, 68%) as a yellow solid.
Mp 150-151 °C; Rf = 0.77 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.78 (s, 2H), 3.80 (s, 2H), 3.81 (s, 2H), 5.42 (s, 2H), 7.10-7.14 (m, 2H), 7.23-7.30 (m, 3H), 7.39 (d, J = 6.88, 1H); 13C NMR (100 MHz, CDCl3): δ 26.06, 35.36, 35.47, 38.42, 38.45, 71.75, 106.79, 110.46, 110.48, 118.33, 121.31, 124.03, 126.82, 129.10, 129.98, 131.00, 131.70, 132.55, 135.29, 139.35, 143.21, 173.15, 193.90; IR (CHCl3): υmax. 1628, 1701, 2306, 2986, 3054 cm-1; HRMS (Q-Tof) m/z: calculated for C25H15N4O2 [M+H]+ 403.1195, found: 403.1196 and other fragments are 179.0975, 214.0958, 301.1468, 401.1181, 404.1292.
Compound 18: The solution of sultine derivatives 12a and 12b (30 mg, 0.09 mmol) and dimethyl acetylenedicarboxylate (0.02 mL, 0.14 mmol) in toluene (20 mL) was refluxed for 24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (60% EtOAc-petroleum ether) to deliver the DA adduct 18 (33 mg, 89%) as a yellow solid.
Mp 163-165 °C; Rf = 0.68 (silica gel, 40% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 4H), 3.72 (s, 2H), 3.83 (s, 6H), 5.38 (s, 2H), 7.04-7.23 (m, 3H), 7.217-7.29 (m, 2H), 7.36 (d, J = 6.92 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 25.96, 31.05, 31.27, 52.61, 72.49, 107.75, 118.07, 121.00, 128.08, 129.65, 130.00, 130.29, 131.90, 132.29, 132.50, 133.16, 133.24, 139.69, 140.11, 168.07, 168.15, 173.30, 194.26; IR (CHCl3): υmax. 1627, 1710, 1723, 3020 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C25H20NaO6 [M+Na]+ 439.1152, found: 439.1154 and other fragments are 412.3400, 422.3608, 428.3347.
Compound 19: The solution of DA adduct 18 (20 mg, 0.05 mmol) and MnO2 (44 mg, 0.50 mmol) in toluene (20 mL) was heated at 120 °C for 30 min under microwave condition. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (30% EtOAc-petroleum ether) to deliver the compounds 20 (5 mg, 25%) and further elution gave 19 (7 mg, 48%) as a yellow solid.
Mp 145-146 °C; Rf = 0.59 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 3.99 (s, 6H), 5.54 (s, 2H), 8.02 (s, 1H), 8.32 (s, 1H), 8.48 (s, 1H), 8.59 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 53.15, 53.19, 69.79, 122.14, 125.70, 126.26, 127.98, 129.55, 130.13, 131.82, 131.95, 132.23, 133.23, 136.34, 142.91, 167.35, 167.83, 170.09; IR (CHCl3): υmax. 1724, 1761, 2924, 3020 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C16H12NaO6 [M+Na]+ 323.0526, found: 323.0527 and other fragments are 320.2037, 324.0561, 325.0595.
Compound 20: The 1H and 13C spectra matched with the literature reported spectral data.8
Synthesis of compound 23: The solution of dione 22 (498 mg, 4.44 mmol), Cs2CO3 (3.6 g, 11.11 mmol) in dry MeCN (20 mL) was stirred at rt for 15 min. Later, tetrabromo compound 8 (2 g, 4.44 mmol) was added and the stirring was continue for 30 min at same temperature. At the conclusion of the reaction (TLC monitoring), excess amount of Cs2CO3 was filtered through sintered funnel and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (25% EtOAc-petroleum ether) to afford the dibromo derivative 23 (836 mg, 47%) as a white solid.
Mp 180-181 °C; Rf = 0.50 (silica gel, 25% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 1.82-1.89 (m, 2H), 2.05-2.39 (m, 4H), 3.90 (s, 2H), 4.61 (s, 2H), 4.64 (s, 2H), 5.21 (s, 2H), 7.24 (s, 1H), 7.27 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 20.45, 27.26, 29.49, 29.58, 31.09, 36.99, 70.44, 112.26, 131.16, 131.48, 135.26, 136.17, 137.69, 143.22, 173.12, 198.29; IR (CHCl3): υmax. 1603, 1736, 2942, 3023 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C16H16Br2NaO2 [M+Na]+ 420.9409, found: 420.9410 and other fragments are 418.0558, 422.9388, 425.3239.
Synthesis of compounds 24a and 24b: To a solution of dibromo derivative 23 (200 mg, 0.50 mmol) in DMF (10 mL), was added TBAB (161 mg, 0.50 mmol) and rongalite (770 mg, 5.00 mmol) at 0 ᴏC and stirred the reaction mixture for 3 h at 0 ᴏC and at rt for another 3 h. At the conclusion of the reaction (TLC monitoring), the compound was extracted with EtOAc. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford sultine derivatives 24a and 24b (120 mg, 79%) as a yellow sticky liquid.
Rf = 0.55 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 1.81-1.87 (m, 2H), 2.31-2.38 (m, 4H), 3.57 (dd, J1 = 6.05 Hz, J2 = 15.35 Hz, 1H), 3.91 (s, 2H), 4.33 (dd, J1 = 6.20 Hz, J2 = 15.50 Hz, 1H), 4.94 (dd, J1 = 4.65 Hz, J2 = 13.80 Hz, 1H), 5.21-5.28 (m, 3H), 7.10-7.16 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 20.33, 27.10, 30.94, 36.84, 55.94, 56.28, 62.59, 62.70, 70.50, 112.27, 112.28, 124.29, 125.69, 125.86, 127.01, 129.87, 130.02, 132.01, 134.32, 134.61, 135.30, 141.60, 142.24, 173.06, 198.21; IR (CHCl3): υmax. 1602, 1711, 2956, 3021 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C16H16NaO4S [M+Na]+ 327.0662, found: 327.0662 and other fragments are 328.0692, 329.0649.
Synthesis of sulfone 25: The solution of sultine derivatives 24a and 24b (30 mg, 0.09 mmol) in toluene (20 mL) was refluxed for 10 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford the sulfone derivative 25 (27 mg, 90%) as a yellow sticky liquid.
Rf = 0.53 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 1.83-1.86 (m, 2H), 2.32-2.38 (m, 4H), 3.92 (s, 2H), 4.33 (s, 2H), 4.34 (s, 2H), 5.25 (s, 2H), 7.20 (s, 1H), 7.22 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 20.41, 27.32, 30.98, 36.90, 56.72, 56.88, 70.54, 112.22, 126.07, 126.23, 129.86, 132.46, 135.75, 142.78, 173.09, 198.21; IR (CHCl3): υmax. 1604, 1727, 2943, 3002 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C16H16NaO4S [M+Na]+ 327.0662, found: 327.0662 and other fragments are 242.2861, 305.0854.
Synthesis of compound 26: The solution of sultine derivatives 24a and 24b (40 mg, 0.13 mmol) and tetracyanoethylene (25 mg, 0.19 mmol) in toluene (20 mL) was refluxed for 12 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford the DA adduct 26 (43 mg, 89%) as a yellow solid.
Mp 203-204 °C; Rf = 0.75 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3): δ 1.86-1.89 (m, 2H), 2.36-2.40 (m, 4H), 3.80 (s, 4H), 3.93 (s, 2H), 5.24 (s, 2H), 7.12 (s, 1H), 7.13 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 20.42, 27.17, 31.03, 35.49, 35.58, 36.94, 38.48, 38.51, 70.22, 110.55, 112.04, 123.77, 126.31, 129.00, 129.17, 136.43, 143.36, 173.10, 198.21; IR (CHCl3): υmax. 1642, 1725, 2953, 3019 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C22H16N4NaO2 [M+Na]+ 391.1165, found: 391.1166 and other fragments are 301.1419, 317.1125, 369.1353.
Synthesis of compound 28: The solution of dione 27 (622 mg, 4.44 mmol), Cs2CO3 (3.61 g, 11.11 mmol) in dry MeCN (20 mL) was stirred at rt for 15 min. Later, the tetrabromide 8 (2 g, 4.44 mmol) was added and the stirring was continue for 45 min at the same temperature. At the conclusion of the reaction (TLC monitoring), excess amount of Cs2CO3 was filtered through sintered funnel and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (20% EtOAc-petroleum ether) to afford the dibromo derivative 28 (1.10 g, 58%) as a white solid.
Mp 224-225 °C; Rf = 0.57 (silica gel, 25% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 0.99 (s, 6H), 2.19 (s, 2H), 2.23 (s, 2H), 3.89 (s, 2H), 4.59 (s, 2H), 4.60 (s, 2H), 5.20 (s, 2H), 7.24 (s, 1H), 7.26 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 26.97, 28.32, 29.49, 29.61, 31.37, 44.62, 50.70, 70.44, 111.03, 131.20, 131.41, 135.19, 136.17, 137.66, 143.27, 171.24, 198.09; IR (CHCl3): υmax. 1670, 1728, 2963, 3018 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C18H21Br2O2 [M+H]+ 426.9903, found: 426.9904 and other fragments are 353.2665, 379.0850, 428.9883, 430.9799.
Synthesis of compound 29a and 29b: To a solution of the dibromide 28 (300 mg, 0.70 mmol) in DMF (10 mL), was added TBAB (237 mg, 0.70 mmol) and rongalite (1.08 g, 70.00 mmol) at 0 ᴏC and stirred the reaction mixture for 3 h at 0 ᴏC and at rt for another 1 h. At the conclusion of the reaction (TLC monitoring), the compound was extracted with EtOAc and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford the sultine derivatives 29a and 29b (174 mg, 75%) as a yellow sticky liquid.
Rf = 0.57 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 0.94 (s, 6H), 2.16 (s, 2H), 2.19 (s, 2H), 3.52 (dd, J1 = 5.85 Hz, J2 = 15.50 Hz, 1H), 3.88 (s, 2H), 4.30 (dd, J1 = 7.40 Hz, J2 = 15.50 Hz, 1H), 4.90 (dd, J1 = 7.40 Hz, J2 = 15.50 Hz, 1H), 5.12-5.24 (m, 3H), 7.07-7.12 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 26.91, 28.19, 28.26, 31.33, 44.57, 50.62, 56.01, 56.35, 62.58, 62.71, 70.59, 111.16, 121.95, 124.30, 125.54, 125.78, 125.89, 127.05, 128.45, 129.95, 130.03, 132.02, 134.37, 134.70, 135.41, 141.73, 142.37, 171.29, 198.11; IR (CHCl3): υmax. 1601, 1725, 2987, 3059 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C18H21O4S [M+H]+ 333.1155, found: 333.1155 and other fragments are 251.1430, 269.1538, 291.1357, 309.1456.
Synthesis of compound 30: The solution of sultine derivatives 29a and 29b (50 mg, 0.15 mmol) and tetracyanoethylene (29 mg, 0.23 mmol) in toluene (20 mL) was refluxed for 12 h. At the conclusion of the reaction (TLC monitoring), solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (40% EtOAc-petroleum ether) to afford the DA adduct 30 (56 mg, 95%) as a white solid.
Mp 240-242 °C; Rf = 0.75 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 1.01 (s, 6H), 2.23 (s, 2H), 2.26 (s, 2H), 3.80 (s, 4H), 3.92 (s, 2H), 5.24 (s, 2H), 7.11 (s, 1H), 7.13 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 26.86, 28.26, 31.36, 35.34, 35.42, 38.47, 38.50, 44.50, 50.60, 70.18, 110.56, 110.58, 110.79, 123.71, 126.25, 129.01, 129.06, 136.40, 143.30, 171.26, 198.04; IR (CHCl3): υmax. 1603, 1716, 2256, 2962, 3021 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C24H21N4O2 [M+H]+ 397.1659, found: 397.1662 and other fragments are 398.1691, 399.1724.
Synthesis of compound 31: The solution of sultine derivatives 29a and 29b (55 mg, 0.16 mmol) and dimethyl acetylenedicarboxylate (30 mg, 0.24 mmol) in toluene (20 mL) was refluxed for 20 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (50% EtOAc-petroleum ether) to afford the DA adduct 31 (49 mg, 72%) as a white semi solid.
Rf = 0.78 (silica gel, 50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3): δ 0.99 (s, 6H), 2.19 (s, 2H), 2.24 (s, 2H), 3.69 (s, 4H), 3.84 (s, 6H), 3.88 (s, 2H), 5.22 (s, 2H), 7.04 (s, 1H), 7.06 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 26.96, 28.31, 31.18, 31.38, 31.41, 44.69, 50.76, 52.57, 70.96, 111.63, 123.70, 128.06, 128.17, 130.14, 132.78, 133.21, 133.47, 133.76, 140.37, 168.18, 171.25, 198.27; IR (CHCl3): υmax. 1602, 1725, 2975, 3019 cm-1; HRMS (ESI, Q-ToF) m/z: calculated for C24H26NaO6 [M+Na]+ 433.1622, found: 433.1626 and other fragments are 397.0539, 411.1808.

ACKNOWLEDGEMENTS
R. A. thanks University Grants Commission (UGC), New Delhi for the award of a research fellowship. S. K. thanks the Department of Science and Technology for the award of a J. C. Bose fellowship. We also grateful to DST-New Delhi for the financial support.

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