https://sciforce.org/index.php/IJOC/issue/feed International Journal of Organic Chemistry: Synthesis 2021-07-05T18:53:43+00:00 Dr. Suryakiran Navath, Ph. D., editor@sciforce.org Open Journal Systems <p>International Journal of Organic Chemistry: Synthesis (IJOC) of Sciforce Publications is a broad field of Chemistry and chemical Sciences which includes Organic Chemistry and Organic Synthesis. IJOC The journal publishes original research articles, book chapters, reviews, letters and short communications, rapid communications, and abstracts. Organic Chemistry is the branch of chemistry that deals with carbon compounds (other than simple salts such as carbonates, oxides, and carbides). Study of structure includes many physical and chemical methods to determine the chemical composition and the chemical constitution of organic compounds and materials. Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one of the most important branches of organic chemistry. There are several main areas of research within the general area of organic synthesis: total synthesis, semi synthesis, and methodology</p> https://sciforce.org/index.php/IJOC/article/view/7 β-Cyclodextrin mediated sterioselective total synthesis of (+)-cytoxazone and (-)-5-epi-cytoxazone 2021-04-04T18:36:58+00:00 Suryakiran Navath sURYAKIRAN.NAVATH@gmail.com <p>&nbsp;</p> <p>β-Cyclodextrin mediated stereoselective synthesis of a potent cytokine modulator cytoxazone has been achieved from 2,3-isopropylidene D-glyceraldehyde involving the Grignard reaction, reduction of azide to aminodiol and finally cyclization of N-<em>Boc</em> diol, synthesis of (+)-cytoxazone and (-)-5-<em>epi</em>-cytoxazone is described.&nbsp;</p> <p><strong>&nbsp;</strong></p> <p><strong>Introduction</strong></p> <p>The synthesis of biologically active natural products from carbohydrate substrates is an important tool for rapid accesses to the desired constitution and stereochemistry. This certainly correlated with the discovery of highly chemo and stereoselective methods of modern organic synthesis. The subject of total synthesis of biologically active natural products has been covered in several surveys.<sup>1</sup> Cytoxazone (1) containing a 4,5-disubstituted 2-oxazolidinone ring was isolated from the fermentation broth of Streptomyces sp. in low yield<sup>2</sup> and its absolute configuration has been determined by X-ray crystallographic analysis and CD-spectroscopy. As the importance of cytoxazone, synthesis of recemic mixture of this natural product has been reported in the literature,<sup>3-5</sup> however the sterio-selective synthesis is significant in natural product synthesis.<sup>6-9</sup> Our approach for the sterio-selective synthesis of (-)-cytoxazone and 5-<em>epi</em>-cytoxazone in the presence of β-cyclodextrin<sup>10</sup> employs inexpensive and readily available starting material, mannitol diacetonide (3) which on chopping with NaIO<sub>4</sub> in dichloromethane at room temperature afforded (R)-2,3-O-isoproplidene glyceradehyde (4). This on reaction with p-methoxyphenyl magnesium bromide in dry THF gave a diastereomeric mixture of alcohols 5 (85%), and 5a (15%) based on HPLC analysis. The diastereomeric mixture treated with PDC, DCM, Ac<sub>2</sub>O converted to corresponding ketone (6). And reaction of 6 with sodium borohydride in presence of β-cyclodextrin gave exclusively (5a) 99% yield. The diastereomers 5 and 5a were also</p> <p>separated by silica gel column chromatography. Compound 5 was converted to corresponding mesylate (7), which on further treatment with sodium azide in acetone gave azide (8) in excellent yield 98%. Reduction of azide 8 with lithium aluminum hydride gave the amine (9) which was protected with di-<em>tert</em>-butyldicarbonate gave 1,2,5,6-Di-O-isopropylidene-α-D-mannitol (13), it was further treatment with sodium azide in presence of DMF in nitrogen atmosphere underwent cyclization and gave the title compound 1.</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/25"></p> <p><strong>Figure 1</strong>.</p> <p>To a solution of anhydrous ZnCl<sub>2</sub> (60 g) in dry acetone (300 mL) was added in one portion finely powdered D-mannitol (10 g). The mixture was stirred for 3 h at 20 <sup>o</sup>C. The stirring was continued further for 12 h at room temperature. The reaction mixture is then poured into a&nbsp;&nbsp; solution of potassium carbonate (70 g) in water (70 mL) which is extracted with diethyl ether (300 mL). The mixture is stirred for 0.5 h when the organic layer is filtered and washed under vacuum to remove zinc carbonate, and the combined filtrates evaporated</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/26"></p> <p><strong>Scheme 1</strong>.</p> <ol start="3"> <li>a) (i) Dri acetone, ZnCl<sub>2</sub>, K<sub>2</sub>CO<sub>3</sub>. (ii) NaIO<sub>4</sub>, NaHCO<sub>3</sub>, DCM. (b) <em>p</em>-MeOPhMgBr, dri THF, rt. c) (i) PDC, DCM, Ac<sub>2</sub> (d) NaBH<sub>4</sub>, β-CD. 0.1 mol% e) (i) Mesylchloride, Et<sub>3</sub>N, DCM, rt. (ii) NaN<sub>3</sub>, dry acetone, reflux. (iii) LAH, DCM, rt. f) (i) Boc<sub>2</sub>O, DCM, DMAP, rt (g) NaH, DMF h) Mesylchloride, Et<sub>3</sub>N, DCM, rt (ii) NaN<sub>3</sub>, dry acetone, reflux. (iii) Triphenyl phosphine (iv) Boc<sub>2</sub>O, DCM, DMAP, rt (i) NaH, DMF</li> </ol> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/27"></p> <p><strong>β-CD =</strong></p> <p><strong>&nbsp;</strong></p> <p><strong>Scheme 2.</strong></p> <p><strong><br> </strong></p> <p>to dryness on a rotary evaporator. The dry residue is successively extracted with hexane (5 x 50 mL) and combined extracts slowly cooled and filter to give the product in 55% yield (7.9 g). m.p 119 <sup>o</sup>C. <sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz): δ, 1.37 (s, 6H), 1.40 (s, 6H), 2.49 (br d, 2H), 3.68-3.72 (m, 2H), 3.96-3.99 (m, 2H), 4.05-4.10 (m, 2H), 4.12-4.19 (m, 2H).</p> <p>FABMS (M+ 1):263</p> <p>&nbsp;(2<em>R</em>, 3<em>S</em>)-3-Hydroxy-1,2-<em>O</em>-isopropylidene-3-<em>p</em>-methoxyphenyl-1,2-propanediol (5): To a solution of compound 3 (5 g, 21 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (15 mL) was added NaIO<sub>4</sub> (8.94 g, 42.01 mmol), saturated aqueous NaHCO<sub>3</sub> (0.5 mL) and stirred for 3 h. After completion of the reaction, the reaction mixture was extracted into dichloromethane (3 x 15 mL), dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give (R)-2,3-<em>O</em>-isopropylidene glyceradehyde (4) in 81% yield (1.59 g, 19.91 mmol). This was immediately reacted with <em>p</em>-methoxyphenyl magnesiumbromide (3.90 g, 18.57 mmol) in dry THF (20 mL) under nitrogen atmosphere for 3 h at room temperature. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (15 mL) and extracted into ethyl acetate (3 x 15 mL). The organic layer was dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, concentrated under reduced pressure to give a crude diastereomeric mixture of 5 (85%) and 5a (15%). This diastereomeric mixture was separated by silica gel chromatography eluting with ethyl acetate:hexane (1:9) to give 5 (3.09&nbsp; g, 14.43 mmol) in 85 % yield.</p> <p>[α]D25 9.27 ( c 1, CHCl<sub>3</sub>),</p> <p>&nbsp;<sup>1</sup>H NMR(CDCl<sub>3</sub>, 200 MHz): δ 1.37 (s, 3H), 1.48 (s, 3H), 3.64 (dd, <em>J</em> = 5.5, 8.5 Hz, 1H, Ha-31), 3.74 (dd, <em>J</em> = 5.5, 8.5 Hz, 1H, Hb-31), 3.80 (s, 3H, OMe), 4.18 (dd,&nbsp; <em>J</em> = 5.5, 8.0 Hz, 1H, H-21), 4.48 (d, <em>J</em> = 6 Hz, 1H, H-11), 6.84 (d, <em>J</em> = 7Hz, 2H, Ar), 7.3 (d, <em>J</em> = 7 Hz, 2H, Ar).</p> <p>(2<em>R</em>, 3<em>S</em>)-1,2-<em>O</em>-Isopropylidene-3-<em>O</em>-mesyl-3-<em>p</em>-methoxyphenyl-1,2-propanediol (7): To an ice cooled solution of compound 4 (2.80 g, 13.08 mmol) in dry dichloromethane (15 mL) and PDC (3.76 g, 10 mmol), Ac<sub>2</sub>O (10 mmol) and&nbsp; stirred at room temperature for 0.5 h. After completion of the reaction water was added to the reaction mixture and extraction done with dichloromethane (3 x 20 mL). The crude reaction mixture was further reduced with NaBH<sub>4</sub>, β-CD. 0.1 mol% in THF After completion of the reaction water was added to the reaction mixture and extraction done with dichloromethane (3 x 20 mL). The combined organic layer was dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, concentrated under reduced pressure. It was further reacted with triethyl amine (5.46 mL, 39.25 mmol), and methanesulphonyl chloride (0.9 mL, 14.39 mmol) and stirred at room temperature for 3 h. After completion of the reaction water was added to the reaction mixture and extraction done with dichloromethane (3 x 20 mL). The combined organic layer was dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, concentrated under reduced pressure to give mesylate 6 (3.50 g) in 85%, which was used for the next reaction without further purification.</p> <p>(2<em>S</em>, 3<em>R</em>)-3-Azido-1,2-<em>O</em>-isopropylidene-3-<em>p</em>-methoxyphenyl-1,2-propanediol (8): To a solution of compound 7 (2.7 g, 9.24 mmol) in dry acetone (15 mL) was added sodium azide (0.66 g, 10.17 mmol) and refluxed for 3 h. After completion of the reaction, acetone was removed under reduced pressure, water was added and the contents extracted into EtOAc, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated to give a crude product which was purified by silica gel column chromatography to afford the pure compound 7 (1.85 g, 7.03 mmol) in 84% yield.</p> <p>&nbsp;<sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz): δ, 1.39 (s, 3H), 1.5 (s, 3H), 3.58 (dd, <em>J</em> = 5.6, 10.0 Hz, 1H, Ha-31), 3.68 (dd, <em>J</em> = 5.6, 10.0 Hz, 1H, Hb-31), 3.8 (s, 3H, OMe), 3.92 (dd, <em>J</em> = 5.6, 8.5 Hz, 1H, H-21), 4.3 (d, <em>J</em> = 6 Hz, 1H, H-11), 6.88 (d, <em>J</em> = 8 Hz, 2H, Ar), 7.22 (d, <em>J</em> = 8 Hz, 2H, Ar).</p> <p>(2<em>S</em>, 3<em>R</em>)-3-Amino-1,2-<em>O</em>-isopropylidene-3-<em>p</em>- methoxyphenyl-1,2-propanediol (9): To an ice cooled solution of compound 8 (1.50 g, 5.70 mmol) in dry THF (15 mL) was added LAH (0.211 g, 5.7 mmol) and stirred at room temperature. After 3 h, the reaction was quenched with ethyl acetate, water was added, extraction done with ethyl acetate, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give the crude amino compound, which was purified by silica gel column chromatography eluting with ethyl acetate hexane (6:4) to give title compound 9 (0.94 g 3.96 mmol) in 70% yield.</p> <p>&nbsp;<sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz): δ, 1.38 (s, 3H), 1.43 (s, 3H), 3.59 (dd, <em>J</em> = 6, 8 Hz, 1H, Ha-31), 3.68 (dd, <em>J</em> = 6, 8 Hz, 1H, Hb-31), 3.8 (s, 3H, OMe), 3.84 (d, <em>J</em> = 6 Hz, 1H, H-21), 4.1 (dd, <em>J</em> = 6, 8 Hz, IH, H-11), 6.81 (d, <em>J</em> = 7 Hz, 2H, Ar), 7.24 (d,&nbsp; <em>J</em> = 7 Hz, 2H, Ar).</p> <p>(2<em>S</em>, 3<em>R</em>)–3–<em>tert</em>–Butoxycarbonylamino-1,2–<em>O</em>-sopropylidene-3-<em>p</em>-methoxyphenyl-1,2-propanediol (10): To an ice cooled solution of compound 9 (0.8 g, 3.37 mmol) in dry dichloromethane (15 mL) was added triethylamine (1.4 mL, 10.12 mmol) and di-<em>tert</em>-butyl dicarbonate (0.8 g, 3.71 mmol) under nitrogen atmosphere and&nbsp; stirred at room temperature. After 3 h, water was added, extracted into dichloromethane (3 x 15 mL), dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give the crude product which was purified by silica gel column eluting with ethyl acetate hexane (2:8) to give the title compound 10 (0.93 g) in 82% yield. [α]D25 –7.76 ( c&nbsp; 1, CHCl<sub>3</sub>), <sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz), δ 1.31 (s, 3H), 1.39 (s, 9H),1.48 (s, 3H), 3.7 (dd, <em>J</em> = 5, 8 Hz, 1H, Ha-31),3.78 (s, 3H, OMe) 3.91 (dd, <em>J</em> = 5, 8 Hz, 1H, Hb-31), 4.28 (m, 1H, H-21), 5.17 (d, <em>J</em> = 8 Hz, 1H, H-11 ), 6.81 (d, <em>J</em> = 8 Hz, 2H, Ar), 7.21 (d, <em>J</em> = 8 Hz, 2H, Ar).</p> <p>&nbsp;(2<em>S</em>, 3<em>R</em>)-3-<em>tert</em>–Butoxycarbonylamino-3-<em>p</em>-methoxyphenyl-1,2-propanediol (11): To a solution of compound 10 (0.7 g, 2.07 mmol) in methanol (10 mL) was added <em>p</em>-TSA (0.39 g, 2.07 mmol) and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was neutralized with saturated NaHCO<sub>3</sub>, extracted with ethyl acetate, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give the crude product 11 which was purified by silica gel column to give pure diol 11 (0.46 g) 76% yield. M.p.125-128 <sup>o</sup>C, [α]D25 1.09 ( c&nbsp; 1, CHCl<sub>3</sub> ), 1H NMR (CDCl<sub>3</sub>, 200 MHz ), δ 1.41( s , 9H), 3.48 (d, <em>J</em> = 7Hz, 2H, Ha-31, Hb-31), 3.61 ( m, 1H, H-21), 3.77 ( s, 3H, OMe ), 3. 8.2-3.89 (m, 1H, H-11), 6.8 (d, <em>J</em> = 8Hz, 2H, Ar), 7.24 (d, <em>J</em> = 8 Hz, 2H, Ar). FABMS (m/z): 320 (M + Na)<sup>+</sup>.</p> <p>(2<em>R</em>,3<em>R</em>)-3-<em>tert</em>–Butoxycarbonylamino-3-<em>p</em>-methoxyphenyl-1,2-di-4-nitrobenzoate (12): To a stirred solution of compound 11 (0.220 g 0.74 mmol) in dry THF (15 mL) were added triphenyl phosphine (0.98 g 0.37 mmol), <em>p</em>-nitrobenzoic acid (0.61 g, 3.68 mmol) and diethylazadicarboxylate in 5 mL THF (0.20 mL, 1.12 mmol). Reaction mixture was allowed to stir at room temperature for 24 h, under nitrogen atmosphere. THF was removed under vacuo and to crude compound water was added extracted in ethylacetate (3 x 20 mL) dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give the crude product 12 which was purified by silica gel column to give pure protected compound 12.</p> <p>[α]D25 -3.99 ( c&nbsp; 0.5 , MeOH),</p> <p>&nbsp;<sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz )): δ, 1.45 (s, 9H), 3.80 (s, 3H), 4.48-4.58 (m, 1H,), 4.69-4.78 ( m, 1H,), 4.97-5.05 (m, 1H,), 5.10-5.20 (m, 1H), 5.80 (br d, 1H )&nbsp; 6.83-6.90 (d, <em>J</em> = 8Hz, 2H, Ar), 7.24-7.30 (d, <em>J</em> = 8 Hz, 2H, Ar) 8.02-8.19 (m, 4H, Ar), 8.11-8.36 (m, 4H, Ar),&nbsp;&nbsp; FABMS (m/z): 582 (M + 1) <sup>+</sup>.</p> <p>(2<em>R</em>, 3<em>R</em>)-3-<em>tert</em>–Butoxycarbonylamino-3-<em>p</em>-methoxyphenyl-1,2-propanediol (13): To compound 12 (0.015 g, 0.257 mmol) in THF (2.5 mL) and water (7.5 mL) was added LiOH (0.037 g, 0.154 mmol) at 0 <sup>o</sup>C. Reaction mixture was allowed to stir at room temperature for 2 h after that THF was removed under vacuo and to crude compound water was&nbsp; added extracted into ethylacetate (3 x 15 mL) dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give the crude product&nbsp; 12 which was purified by silica gel column to give pure protected compound 13 in 81% yield&nbsp; m.p.115-116<sup>o</sup>C, [α]D25 -51.2&nbsp; ( c&nbsp; 1, CHCl<sub>3</sub> ), <sup>1</sup>H NMR (CDCl<sub>3</sub>, 200 MHz ), δ 1.44 (s, 9H), 2.31 (br s,1H), 2.96 (br s,1H), 3.62-3.72 (m, 2H), 3.73-3.81 (m, 1H ), 3.82 (s, 3H), 4.59 (ddd,1H), 5.02 (br s, 1H), 6.89 (d, 2H, <em>J</em> = 8.5Hz), 7.25 (d, 2H <em>J</em> = 8.5Hz).&nbsp;</p> <p>(4<em>R</em>,5<em>R</em>)–5-Hydroxymethyl–4-(4-methoxyphenyl)-2-oxazolidinone (1): To a solution of compound 13 (0.1 g, 0.336 mmol) in dry THF (10 mL) was added sodium hydride (0.016 g, 0.67 mmol) at room temperature and the mixture was stirred under nitrogen atmosphere for 2 h. After completion of the reaction, the solvent was removed, water was added extracted with ethyl acetate, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give 5-<em>epi</em>-cytoxazone (2), which was purified by silica gel column chromatography using ethyl acetate hexane (4:6) to give pure 5-<em>epi</em>-cytoxazone (2) (0.067 g) in 90% as a white solid (-)- cytoxazone.</p> <p>&nbsp;m.p.118-120 <sup>o</sup>C,</p> <p>[α]D25 -71.0 (c, 1.32, MeOH)</p> <p><sup>1</sup>H NMR (DMSO-d6, 200MHz): δ, 2.96 (m, 2H), 3.76 (s, 3H), 4.62-4.79 (m, 1H), 4.84 (t,&nbsp; 1H, <em>J</em> = 5Hz), 4.90 (D, 1H, <em>J</em> = 8 Hz), 6.94 (d, 2H, <em>J</em> = 8.5Hz), 7.15 (d, 2H, <em>J</em> = 8.5Hz), 13C NMR (acetone-d6, 50 MHz), δ160.27, 159.22, 129.86, 128.62, 114.23 ,81.11, 62.17, 57.48, 55.19. EIMS (m/z): 223 (M <sup>+</sup>).&nbsp;&nbsp;&nbsp;</p> <p>(4<em>R</em>,5<em>S</em>)–5-Hydroxymethyl–4-(4-methoxyphenyl)-2-oxazolidinone (2): To a solution of compound 11 (0.1 g, 0.336 mmol) in dry THF (10 mL) was added sodium hydride (0.016 g, 0.67 mmol) at room temperature and the mixture was stirred under nitrogen atmosphere for 2 h. After completion of the reaction, the solvent was removed, water was added extracted with ethyl acetate, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and concentrated under reduced pressure to give 5-<em>epi</em>-cytoxazone (2), which was purified by silica gel column chromatography using ethyl acetate hexane (4:6) to give pure 5-<em>epi</em>-cytoxazone (2) (0.067 g) in 90% as a white solid. (+)-5-<em>epi</em>- cytoxazone, m.p.155-158<sup>o</sup>C [α]D25 70.10 (c, 1.32, MeOH), <sup>1</sup>H NMR (DMSO, 200MHz), δ 3.61 (dd, <em>J </em>= 5, 8Hz, 1H,Ha-6), 3.75 (dd, <em>J</em> = 5, 8Hz, 1H, Hb-6), 3.81 (s, 3H, OMe), 4.21 (m, 1H, H-5), 4.73 (d, <em>J</em> = 7 Hz, 1H, H-4), 6.89 (d, <em>J</em> = 8Hz, 2H, Ar ), 7.28 (d, <em>J</em> = 8Hz, 2H,Ar), 7.65 (br d, <em>J</em> = 8 Hz, 1H, H-3). <sup>13</sup>C NMR (DMSO, 50 MHz), δ 55.0, 57.0, 83.75, 114.0, 128.0, 133.0, 158.0, 159.0; EIMS (m/z): 223 (M <sup>+</sup>).</p> <p><strong>Acknowledgements</strong>: The authors are thankful to Director IICT for his constant encouragement and CSIR New Delhi for providing the fellowship</p> <p>&nbsp;</p> <p><strong>References</strong>:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p> <ol> <li>a) Izabel, L. M.; Ítala, K. B. L.; Marisa, A. N. Diaz.; Gaspar, D. <em>Molecules</em> <strong>2016</strong>, <em>21</em>,1176. b) In, S. K.; Ji, D. K.; Chae, B. R.; Ok, P. Z.; Young, H. 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Wiley, New York <strong>1984</strong>, Vol.<em>6</em>, p.141.</li> <li>Izabel, L. M.; Suélen, K. S.; Marisa, A. N. D.; Gaspar, D. M. <em>J</em>. <em>Braz</em>. <em>Chem</em>. <em>Soc</em>. <strong>2019</strong>, <em>30</em>, 585-591.</li> <li>a) Chang, C. B.; Bing, R. T.; Tian, Z.; Qing, H.; Zhi Z. W. <em>Molecules</em> <strong>2017</strong>, <em>22</em>, 1475. b) Ali, T. M.; Julien, B.; Juan, X.; François, B.; Sylvie, R.; Daoud, N.; Ogaritte, Y.; David, J. A. <em>J</em>. <em>Org</em>. <em>Chem</em>. <strong>2017</strong>, <em>82</em>, 9832–9836.</li> </ol> <p>&nbsp;</p> 2021-01-28T00:00:00+00:00 ##submission.copyrightStatement## https://sciforce.org/index.php/IJOC/article/view/12 β-Cyclodextrin promoted stereoselective synthesis of β-hydroxysufones from β-keto-sulfones using NaBH4-CaCl2 as an efficient reagent in water 2021-07-05T18:53:43+00:00 Krishna Reddy Jakkidi krishnareddyiict@gmail.com <p>β-Cyclodextrin promoted stereoselective synthesis of β-hydroxysufones from β-keto-sulfones using NaBH<sub>4</sub>-CaCl<sub>2</sub> as an efficient reagent in water is described. Obtained products were purified with column chromatography and crystallization and all products were characterized by <sup>1</sup>H NMR and mass spectral data</p> <p>&nbsp;</p> <p><strong>Introduction</strong></p> <p>Sulfones are very important and fascinating branch of organic chemistry.<sup>1</sup> The presence of the sulfone group, in an organic compound adds variety to its chemical architecture and also enhances the biological activity of the compound. Among sulfones, β-keto-sulfones are very important group of intermediates, as they are precursors in Michael, Knoevenagel reactions,<sup>2-3 </sup>in the preparation of acetylenes, allenes, chalcones,<sup>4-9</sup> vinylsulfones,<sup>10</sup> and polyfunctionalized 4H-pyrans.<sup>11</sup> β-Keto-sulfones are useful for the synthesis of ketones by facile reductive elimination of the sulfone group.<sup>12</sup> In addition to this β-keto-sulfones are useful for the synthesis of optically active β-hydroxysulfones,<sup>13</sup> they are also obtained both by chemical methods, for example, via oxidation of chiral β-hydroxysulfoxides, and by the biocatalytic approaches. The latter comprise of baker’s yeast-mediated reduction of β-ketosulphones leading to the (S)-enantiomers of the corresponding β-hydroxysulfones and a lipase catalyzed acylation of recemic β-hydroxysulfones, performed under kinetic resolution conditions.<sup>14-20</sup></p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/29"></p> <p><strong>Scheme 1</strong>.</p> <p>&nbsp;</p> <p>The optically active β-hydroxysulfones<sup>21</sup> are of great utility in organic synthesis, they have been used as building blocks in the synthesis of a variety of enantio-pure cyclic compound classes such as recemic and non-recemic lactones, tetra hydrofurans and furanones, and in the preparation of other β-hydroxysulfones. Recently, compounds of this class have proved its efficiency as a chiral controller in asymmetric Diels-Alder and alkylation reactions. Although several methods synthesis of β-hydroxysulfones has been reported in literature, but not explored much.<sup>22</sup> We report here our extensive studied developments of new synthetic methodologies on β-keto-sulfones,<sup>23</sup> β-cyclodextrin promoted synthesis of β-hydroxysulfones from β-keto-sulfones, using NaBH<sub>4</sub>-CaCl<sub>2</sub> as an efficient reagent in water.</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/28"></p> <p>β-CD</p> <p><strong>Figure 1</strong>.</p> <p>In recent years β-Cyclodextrins<sup>24</sup> have gained very much attention in organic trance formations, they are cyclic oligosaccaharides possessing hydrophobic cavities, which binds substrates selectively and which catalyze chemical reactions by supramolecular catalysis involving eversible formation of host-guest complexes by non-covalent binding as seen in enzymes. Complexation depends on the size, shape and hydrophobicity of the guest molecules, thus mimicking biochemical selectivity, which is due to the orientation of the substrate by complex formation. This positions only certain regions for attack and can be superior to chemical selectivity, which involves random attack dependent on the intrinsic reactivity of the substrate at different positions.</p> <p>We first examined the reaction of p-toluene sulfonyl acetophenone with NaBH<sub>4</sub>-CaCl<sub>2</sub> in the presence of catalytic amount of β-cyclodextrin in aqueous medium to yield corresponding β-hydroxysulfones, in excellent yield (&gt;95%) with high enantioselectivity (99%).</p> <p>&nbsp;<strong>Table 1</strong>. β-Cyclodextrin promoted synthesis of β-hydroxysulfones from β-keto-sulfones, using NaBH<sub>4</sub>-CaCl<sub>2</sub>.</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/30"> <br> <img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/31"></p> <p><sup>a</sup>Isolated yields after column chromatography/crystallization and all products gave satisfactory spectral data</p> <p>&nbsp;This result were encouraged us to carry out the reaction in the presence of NaBH<sub>4</sub>-CaCl<sub>2</sub> and β-cyclodextrin, several β-keto-sulfones was reacted to afford corresponding products in excellent yields (Table 1).</p> <p>The NaBH<sub>4</sub> acts as efficient reducing reagent in the presence of catalytic amount of CaCl<sub>2</sub>. The sodium borohydride first reacts with CaCl<sub>2</sub> to give calcium borohydride, which acts as efficient reducing reagent, due to presence of its vacant d-orbitals, more surface area and variable valancy of calcium ion, it stabilizes the hydride ion and act as efficient reducing reagent.</p> <p>In conclusion we have described β-cyclodextrin promoted synthesis of various β hydroxysulfones from β keto-sulfones using NaBH<sub>4</sub>-CaCl<sub>2</sub> as an efficient reagent.</p> <p><strong>Typical experimental procedure</strong></p> <p>To a solution of β-ketosulfone (10 mmol) water (10 mL) was added β-cyclodextrin (5 mol%), NaBH<sub>4</sub> (10 mmol) and CaCl<sub>2</sub> (5 mol%). The mixture stirred at room temperature for the appropriate time (Table 1). After completion of the reaction, as monitored by TLC, the reaction mass was quenched with aqueous ammoniumchloride and the product was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulphate, evaporated under reduced pressure to give crude product, which was purified by silica column chromatography and all products gave satisfactory spectral data.</p> <p>&nbsp;<strong>Acknowledgements </strong></p> <p>The authors are thankful to CSIR and DOD, New Delhi for financial assistance and, Director IICT for his constant encouragement.</p> <p><strong>References</strong>:</p> <ol> <li>Simpkins, N. S.; Sulfones in organic synthesis; Ed. Baldwin, J. E. <em>Pergamon</em> <em>Press</em>: <em>Oxford</em>, <strong>1993</strong>.</li> <li>Macro, J. L.; Fernandez, I.; Khira, N.; Fernandez, P.; Romero, A. <em>J</em>. <em>Org</em>. <em>Chem</em>. <strong>1995</strong>, <em>60</em>, 6678.</li> <li>Reddy, M. V. 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K.; Ramanandham, J. <em>Indian</em> <em>J</em>. <em>Chem</em>. <strong>1999</strong>, <em>38</em>, 297.</li> <li>Xiaobing, W.; Qinghua, M.; Hongwei, Z.; Yanhui, S.; Weizheng, Fan.; Zhaoguo, Zhang. <em>Org</em>. <em>Lett</em>. <strong>2007</strong>, <em>9</em>, 26, 5613–5616</li> <li>Lin, Tao.; Congcong, Yin.; Xiu, Dong. -Q.; Xumu, Zhang. <em>Org</em>. <em>Biomol</em>. <em>Chem</em>. <strong>2019</strong>, <em>17</em>, 785-788</li> <li>Suryakiran, N.; Srikanth Reddy, T.; Asha Latha, K.; Lakshman, M.; Venkateswarlu, Y. <em>Tetrahedron</em> <em>Lett</em>. <strong>2006</strong>, <em>47</em>, 3853–3856.</li> <li>a) Chang, C. B.; Bing, R. T.; Tian, Z.; Qing, H.; Zhi Z. W. <em>Molecules</em> <strong>2017</strong>, <em>22</em>, 1475. b) Ali, T. M.; Julien, B.; Juan, X.; François, B.; Sylvie, R.; Daoud, N.; Ogaritte, Y.; David, J. A. <em>J</em>. <em>Org</em>. <em>Chem</em>. <strong>2017</strong>, <em>82</em>, 9832–9836</li> </ol> 2021-01-29T06:42:11+00:00 ##submission.copyrightStatement## https://sciforce.org/index.php/IJOC/article/view/15 Tetrabutylammonium bromide (TBAB) a facile phase transfer catalyzed direct synthesis of α, α-dihalo methyl sulfones 2021-04-04T18:58:53+00:00 Suryakiran Navath suryakiran.navath@gmail.com <p>Tetrabutylammonium bromide (TBAB) a facile phase transfer catalyzed direct synthesis of α, α-dihalo methyl sulfones by the reaction of sodium alky/ aryl sulphinate with halofom is described. Obtained products were purified with column chromatography and crystallization and all products were characterized by <sup>1</sup>H NMR and mass spectral data</p> <p>&nbsp;<strong>Introduction</strong></p> <p>Sulfones are of great importance in organic synthesis, among them a-halo methyl aryl/ alkyl sulfones, a, a-dihalo methyl alkyl/ aryl sulfones are excellent a-carbanion-stabilizing substituents,<sup>1</sup> they are precursors for the preparation of alkenes,<sup>2</sup> aziridines,<sup>3</sup> and epoxides,<sup>4</sup> Makosza<sup>5</sup> have been utilized chloromethyl phenyl sulfones and chloromethyl <em>p</em>-tolyl sulfones in vicarious nuclephilic substitution (VNS) reactions with nitro arenes to afford VNS adducts. These adducts have been elaborated into both 3-sulfonyl substituted indole derivatives and the analogues indazoles.<sup>6</sup> Halo alkyl sulfones are useful preventing aquatic organisms from attaching to fishing nets and shiphulls,<sup>7</sup> in herbicides compositions,<sup>8</sup> bactericidal,<sup>9</sup> anti fungal,<sup>[10] </sup>algaecides,<sup>[11]</sup> and insecticides.<sup>12</sup> All though the methods of synthesis of a-halo methyl sulfones and a, a-dihalo methyl sulfones have been reported in literature,<sup>13-17</sup> but not explored much. Now we wish to report a facile phase transfer catalysed direct synthesis of a-halo methyl sulfones and a, a-dihalo methyl sulfones.</p> <p>Typically, one or more of the reactants are organic liquids or solids dissolved in a nonpolar organic solvent and the coreactants are salts or alkali metal hydroxides in aqueous solution. Reactions between these substances which are located partly in an organic phase and partly in an aqueous phase are usually very slow. Employing nonpolar organic solvents alone frequently leads to heterogeneous reaction mixtures and the use of polar, aprotic solvents like DMSO, DMF, etc. under elevated reaction temperature conditions to achieve homogeneous solutions increases both the cost and the difficulties encountered in the work-up procedures. The use of alcoholic solvents to maximize the solubility of both reactants usually leads to slow reaction rates owing to extensive solvation of the anions, and reactions of the nucleophilic solvent complicate the product mixtures. A Phase-transfer catalysis (PTC) is a technique by which reactions between substances located in different phases are brought about or accelerated.</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/32"></p> <p><strong>Scheme</strong> 1.</p> <p>A phase-transfer catalyst is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but insoluble in an organic phase in the absence of the phase-transfer catalyst. The catalyst functions like a detergent for solubilizing the salts into the organic phase. Phase-transfer catalysis refers to the acceleration of the reaction upon the addition of the phase-transfer catalyst. By using a PTC process, one can achieve faster reactions, obtain higher conversions or yields, make fewer byproducts, eliminate the need for expensive or dangerous solvents that will dissolve all the reactants in one phase, eliminate the need for expensive raw materials and/or minimize waste problems<sup>18</sup>. Phase-transfer catalysts are especially useful in green chemistry by allowing the use of water, the need for organic solvents is reduced.<sup>19-20</sup></p> <p><strong>Results and Discussions</strong></p> <p>Reaction of halo form <strong>2 </strong>with sodium aryl / alkyl sulphinate salt<sup>18 </sup><strong>1</strong> refluxing with aqueous alkali for 12 hrs results in the formation of a, a- dihalo methyl sulfones <strong>3</strong> in about 7-60% yield. However by using of TBAB as PTC in acetonitrile as reaction medium, the product in over 90% yield in one hour. In order to optimize the reaction conditions changing the solvents Table 1, temperature and type of phase transfer catalysts (TBAB, TEBAC, TBAI). It has been observed best results are obtained by refluxing the reaction mixture in acetonitrlle by using of TBAB as phase transfer catalyst a,a-dihalo methyl <em>p</em>-toluene sulfone in 90% yield. The poor yield in case of hydroxylic solvents and less polar solvents are probably due to the lower solubility of the sulphinate salt in the solvents. The phase transfer catalyst, apart from increasing the solubility of <strong>1</strong> in the solvents, increases the effectiveness of the nucleophile.</p> <p><strong>Table 1</strong>: Solvent effect on the reaction of sodium <em>p</em>-toluenesulphinate with Chloroform and TBAB as phase transfer catalyst under reflux conditions</p> <p>Using optimum conditions, different types of a-halo methyl sulphones, a, a-dihalo methyl sulphones, have been synthesized in facile manner (Table 2). In the course of our study, the sodium alkyl/ aryl sulphinate salt having reductive dehalogenating nature. So, making it likely that product formation takes place by reductive dehalogenation of halo form, di halo methane followed by nucleophilic attack of sulphinate sulphur. In the case of sodium <em>t</em>-butyle sulphinate on prolonged heating with halo form, mixer of mono halo, dihalo methyle sulfone was observed. It may be due to reductive de halogenation of dihalomethylesulfone by sodium <em>t</em>-butyl sulphinate. The product formation was not achieved with sodium methyl sulphinate and sodium benzyl sulphinate because it known to form Ramberg backlind rearrangement<sup>19 </sup>after formation of α, α-dihalo methylsulfonesulfone. The products has been characterized by its spectral data and by its alternative chemical method, the latter was achieved by reaction of sodium sulfinate salt with a-halo ketone yilds, b-keto sulfone, it is on halogenation, follwed by base induced cleavage of α, α-dihalo alkyl/ aryl sulfonyl acetophenone<sup>17</sup> with aqueous alkali gave the corresponding product.</p> <p>TBAB + NaOH TBAOH + NaBr</p> <p>TBAOH + CHCl<sub>3</sub> :CCl<sub>2</sub> + H<sub>2</sub>O</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/33"></p> <p><strong>Scheme 2. Plausible Mechanism</strong></p> <p>In conclusion we described a facile direct synthesis of different types of a, a-dihalo methyl sulphones, on the reaction of sodium alkyl aryl sulphinate with chloroform and bromoform in the presence of catalytic amount of phase transfer catalyst.</p> <p><strong>Acknowledgements</strong></p> <p>The authors are thankful to CSIR and DOD, New Delhi for financial assistance and Director IICT for his constant encouragement.</p> <p><strong>Typical Experimental procedure</strong></p> <p>A mixture of sodium alkyl/ aryl sulphinate (10 mmol) haloform (15 mmol) and NaOH (10 mmol) was taken in 20 ml of acetonitrile refluxed in the presence of TBAB for appropriate time (Table 2) then extracted into ethyl acetate solvent was evaporated under reduced pressure crude product was purified by silica column chromatography. Dichloromethyl <em>p</em>-tolyl sulfone (1). M.p. 89-90.5<sup>0</sup>C. <sup>1</sup>HNMR (CDCl<sub>3­</sub>): d 2.5 (3H, s), 6.25 (1H, s), 7.4 (2H, d), 7.81 (2H, d), MS (EI) <em>m/z</em>: 139 (M<sup>+.</sup>). Dichloromethyl phenyl sulfone (2). M.p. 79-80<sup>0</sup>C. <sup>1</sup>HNMR (CDCl<sub>3­</sub>): d 6.20 (1H, s), 7.45 (2H, d), 7.65 (1H, m) 7.99 (2H, d), MS (EI) <em>m/z</em>: 225 (M<sup>+.</sup>). Dibromomethyl <em>p</em>-tolyl sulfone (3). M.p. 115<sup>0</sup>C. <sup>1</sup>HNMR (CDCl<sub>3­</sub>): d 2.5 (3H, s), 6.19 (1H, s), 7.4 (2H, d), 7.8 (2H, d), MS (EI) <em>m/z</em>: 328 (M<sup>+.</sup>). Dibromomethyl phenyl sulfone (4). M.p. 112<sup>0</sup>C. <sup>1</sup>HNMR (CDCl<sub>3­</sub>): d 6.18 (1H, s), 7.4 (2H, d), 7.7 (1H, m) 7.9 (2H, d), MS (EI) <em>m/z</em>: 312 (M<sup>+.</sup>).</p> <p><img src="https://www.sciforce.org/index.php/IJOC/libraryFiles/downloadPublic/34"></p> <p><strong>Table 2</strong><strong>. </strong>Synthesis of a, a-dihalo methyl sulfones using phase transfer catalyst<strong>.</strong> Isolated yields after column chromatography / crystallization and all products gave satisfactory spectral and analytical data</p> <p>&nbsp;</p> <p><strong>References</strong></p> <ol> <li>Simpkins, N. S. Sulfones in organic synthesis; Ed. Baldwin, J. E. <em>Pergamon press: oxford</em>,<strong> 1993</strong>.b) Jonczyk, A.; Banko, K.; Makoza, M. <em>J</em>. <em>Org</em>. <em>Chem</em>. <strong>1975</strong>, <em>40</em>, 266.</li> <li>Lee, J. W.; Oh, D. Y. S. <em>Synth</em>. <em>Commun</em>. <strong>1990</strong>, <em>20</em>, 273. b) Bardwell, F. G.; Coopert, G. 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K.; Gill, G. H.; Cameron, T. S.; Gardner, P. A. <em>Can</em>. <em>J</em>. <em>Chem</em>. <em>1984</em>, 62, 174.</li> <li>Vogel’s Textbook of practical organic chemistry, 5 th edition p 888.</li> <li>Rigby, J. H.; Warshakoon, N. C. <em>J</em>. <em>Org</em>. <em>Chem</em>. 1996, 61, 7644.</li> <li>Katole, D. O.; Yadav, G. D. <em>Mol</em>. <em>Cat</em>. 2019, <em>466</em>, 112.</li> <li>Metzger, J. O. <em>Ang</em>. <em>Int</em>. <em>Ed</em>. 1998, <em>37</em>, 2975–2978.</li> <li>Makosza, M. <em>Pure</em> <em>Appl</em>. <em>Chem</em>. <em>72</em>, 1399–1403.</li> </ol> 2021-01-29T00:00:00+00:00 ##submission.copyrightStatement## https://sciforce.org/index.php/IJOC/article/view/86 Can Organic Compounds Help Build Better Capacitors? 2021-07-05T18:51:30+00:00 Suryakiran Navath suryakiran.navath@gmail.com <p>Want to know about the latest innovation in capacitor technology? Here's how researchers are building better capacitors with organic compounds.</p> <p><strong>Introduction</strong></p> <p>Capacitors are one of the most fundamental passive components in electrical circuits.<sup>1</sup> Like batteries, they store a charge, but unlike batteries, they do not discharge at a fairly constant rate. Instead, it depends on the change in voltage between their terminals and the inherent capacitive properties they possess.<sup>2-3</sup> Since the voltage between the terminals of a capacitor cannot change instantaneously, they can be used in applications where it needs to be stabilized, governed, and tuned.</p> <p>Capacitors haven't seen much innovation over the years; however, newer high-voltage electrical applications in smart grids, electric vehicles, and signal processing have called for scientists and researchers to design better capacitors that can prevent bottlenecks in future technologies.<sup>4-5</sup> Organic compounds may soon change that. But how?</p> <p><strong>Why Problems Plague Capacitors?</strong></p> <p>Before we elaborate on how organic compounds can help us, we need to discuss the problems facing capacitors. Capacitors have two plates of conducting materials separated by an insulating layer. Charged gets stored on the plates by virtue of an electric field when a difference in voltage is applied between the two plates.</p> <p>The insulating layer (dielectric) in the middle facilitates the electric field by preventing an electrical connection between the two plates, determining the capacitance of the component and the energy it stores. Common dielectric materials used in capacitors include paper, metal oxides, and plastics.</p> <p>The problem lies in material selection for the dielectric. These materials tend to break down, degrade, and leak out depending on the voltage, frequency, temperature, and environment of the capacitor. This impacts their longevity and makes them a common point of failure in many electrical and electronic applications. In some cases, their failure may lead to short circuits that impact other components of the electrical circuit.</p> <p><strong>Figure 1</strong>.</p> <p>An image of a printed circuit board with different electronic components</p> <p><strong>How Can Organic Compounds Address These Problems?</strong></p> <p>Organic compounds are a class of materials that deal with carbon and its bond with other atoms. Carbon forms strong covalent bonds with other atoms to form compounds that require a strong electric field to strip away electrons; however, at the molecular level, weaker interactive bonds allow the electric current to pass, making organic compounds, as a whole, a weak dielectric material for capacitors.</p> <p>The answer lies in hydrogels and their interaction via supramolecular assembly chemistry. In a paper published in the American Chemical Society in 2018, researchers claimed to have fabricated a solid-state capacitor with plates and dielectric made out of organic compounds PEDOT (poly(3,4-ethylenedioxythiophene)) and PVA poly-vinyl alcohol.</p> <p>The resultant hydrogel electrode and electrolyte enables the flexible capacitor to withstand higher voltages, store more energy, and make it more durable. Although, in its infancy, more researchers are now following the same principle and trying different organic compound configurations that result in better hydrogel combinations.</p> <p><strong>References</strong></p> <ol> <li>Hua-Zhong, Yu.; Sylvie, Morin.; Danial, D. M. W.; Philippe, A.; Catherine, H. de V. <em>J</em>. <em>Phys</em>. <em>Chem</em>. <em>B</em> <strong>2000</strong>, <em>104</em>(47), 11157–11161.</li> <li>Knotts, G.; Bhaumik, A.; Ghosh, K.; Guha1, S. <em>Appl</em>. <em>Phys</em>. <em>Lett</em>. <strong>2014</strong>, <em>104</em>, 233301.</li> <li>Marco, S.; Alessandra, V.; Nicolò, R.; Alain, F.; Marco, P.; Paolo, Ariano. <em>Polymer</em> <strong>2015</strong>, <em>56</em>, 131-134.</li> <li>Marco, S.; Mariangela, L.; Andrea, G.; Galder, K.; Inaki, M.; Fabrizio, Pirri, L.; Montanaro, M. <em>Mater</em>. <u>Eng</u>. <strong>2013</strong>, <em>298</em>, 634-643.</li> <li>Pengxian, H.; Gaojie, X.; Xiaoqi, H.; Jingwen, Z.; Xinhong, Z.; Guanglei, Cui. <em>Adv</em>. <em>Ener</em>. <em>Mater</em>. <strong>2018</strong>, <em>8</em>, 1801243.</li> </ol> 2021-07-05T18:50:34+00:00 ##submission.copyrightStatement##