A broadly applicable synthesis of unsymmetrical 1,2,4,5- tetraoxanes (ol-2008-023874) Prasanta Ghorai and Patrick H. Dussault Department of Chemistry, University of Nebraska–Lincoln Lincoln, NE 68588-0304
[email protected] Supporting Information A: Experimental Procedures Subject
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Caution General experimental procedures Standard procedure for stepwise synthesis Standard procedure for one-pot synthesis One-pot synthesis, gram-scale Dihydroperoxide 10b Tetraoxane 11 Tetraoxane 12 Tetraoxane 13 Tetraoxane 14 Tetraoxane 15 Tetraoxane 16 Tetraoxane 17 Tetraoxane 18 Tetraoxane 19 Tetraoxane 20 Tetraoxane 21 Tetraoxane 22 Tetraoxane 23 Tetraoxane 24
2 2 2 2 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5
Literature Cited:
6
SI-part A, p 1
Caution: While we experienced no hazards in the course of this work, any preparative work with peroxides, particularly those with a high active oxygen content, should be conducted with an awareness of the potential for spontaneous and exothermic decomposition reactions. Readers are directed to some leading references to the properties and handling of organic peroxides.1,2,3,4,5,6 General Experimental Procedures: All reagents and solvents were used as supplied commercially, except CH2Cl2, which was distilled from CaH2. Commercial Re2O7, ranging in color from yellow to brown-black, were stored in a dessicator over CaSO4; samples heated to flame temperatures under an atmosphere of O2 invariably assumed a yellowish color.7 All samples of Re2O7, whether commercial or dried, exhibited similar reactivity for tetraoxane formation. Ketones 1a, 2a, and 4a were used as received. Ketone 10a was prepared by a modification of a reported procedure using CH3CN in place of toluene; the product displayed spectra matching literature reports.8 Known dihydroperoxides 1b,9 2b,9a,10 3b,11 4b,9ab 5b,9ab,10 6b,9b 7b,9b,10 8b,12 9b,12 and 10b8 were prepared using a recently reported procedure for peroxyacetalization of ketones.12 Melting points are uncorrected. Unless noted, NMR spectra were acquired at 400 MHz 1 ( H) or 100 MHz (13C) in CDCl3; individual peaks are reported as: multiplicity, integration, coupling constant in Hz. IR spectra were recorded as neat films on a ZrSe crystal with selected absorbances reported in cm-1. Reactions involving peroxides were monitored by TLC, using one of two immersion dips for development: 1) N,N’-dimethyl-p-phenylenediamine and acetic acid in water/methanol (hydroperoxides yield an immediate reddish-pink spot while dialkyl or silyl/alkyl peroxides exhibit a pink or green-red color after standing or mild charring);13 2) 1% ceric sulfate/2.5% ammonium molybdate in 10% aq. H2SO4 (charring). Mass spectroscopy was conducted at the Nebraska Center for Mass Spectrometry, using electrospray (NaOAc in CH3OH/H2O). Standard procedure for stepwise synthesis of tetraoxanes from 1,1-bishydroperoxide and carbonyl compounds: To a stirred solution of ketone (0.75 mmol) and Re2O7 (0.01 mmol, 2 mol %) in CH2Cl2 (1.5 mL) at rt was added 1,1-bishydroperoxide (0.50 mmol) in 1.5 mL of CH2Cl2. After stirring for 0.5-1h at same temperature, the reaction mixture was passed through a plug of silica gel, the solvent was removed, and the crude was purified by flash column chromatography (EtOH/Hexane) on silica gel. One-pot procedure for the synthesis of 1,2,4,5-tetraoxanes from ketones and H2O2: To a stirred solution of ketone (0.50 mmol) and catalyst (0.015 mmol, 3 mol%) in CH3CN (3 mL), was added 50% aqueous H2O2 (112 μL). The reaction was stirred until the bishydroperoxide could no longer be detected (TLC), whereupon the majority of solvent was removed under reduced pressure and a solution containing the second carbonyl (2 mmol) and additional catalyst (0.01 mmol, 2 mol%) in CH2Cl2 or CF3CH2OH (3 ml) was added. The reaction was stirred for 0.5-2 h and then concentrated, with the crude product purified by flash column chromatography (EtOH/Hexane) on silica gel.
SI-part A, p 2
One-pot procedure (large scale): To a stirred solution of ketone (1 equiv.) and catalyst (3 mol%) in CH3CN (0.2 M), was added 50% aqueous H2O2 (4 equiv.). After the ketone could no longer be detected (TLC), the majority of solvent was removed under reduced pressure and a stirred solution of the second carbonyl (2 mmol) and additional catalyst (2 mol%) in CF3CH2OH (3 ml) was added. After the dihydroperoxide had been consumed (0.5-2 h), the reaction was partially concentrated and then diluted with water. The combined ether extracts (2 x 25 mL) were dried over anhydrous Na2SO4, and the residue obtained upon concentration was purified by flash column chromatography (EtOH/hexane) on silica gel.
O 1-(4-Morpholinylcarbonyl)-4,4-piperidinonyl dihydroperoxide (10b) HO O N has been reported as the intermediate in a two-step one-pot synthesis of HO O N tetraoxanes:8 79% yield; white solid, mp 155-157°C, Rf = 0.20 (100% O EA); IR: 3258, 2899, 1585, 1495, 1436, 1358, 1268, 1240, 1112, 1068, 992, 936, 861 cm-1; 1H (300 MHz, MeOD) δ 4.86 (s, 2H), 3.67 (t, J = 5.0 Hz, 4H), 3.33 (4H), 3.27 (t, J = 5.0 Hz, 4H), 1.90 (t, J = 5.8 Hz, 4H); 13C δ 163.5, 107.2, 66.2, 46.7, 43.3, 29.3.
6,14-Di-tert-butyl-1,2,9,10-tetraoxadispiro[5.2.5.2]hexadecane O O (11):14 83% yield; white solid, mp 190-192°C, Rf = 0.30 (2% t-Bu t-Bu O O EA/hex); IR: 2967 (br), 2860, 1437, 1366, 1264, 1195, 1067, 936, 908, 736, 704 cm-1; 1H δ 3.20 (bs, 2H), 1.75 (bs, 6H), 1.55-1.40 (4H), 1.39-1.20 (4H), 1.16-1.02 (2H), 0.88 (s, 18H); 13C δ; HR-FAB calc. for C20H36NaO4: (M-H)+: 363.2511; found: 363.2513, 0.5 ppm.
O O 6-tert-Butyl-1,2,9,10-tetraoxadispiro[5.2.5.2]hexadecane (12): white t-Bu solid, 81% yield; mp 100-102°C, Rf = 0.29 (2% EA/hex); IR: 2946, 1554, O O 1366, 1264, 1067, 942, 849 cm-1; 1H δ 3,12 (bs, 1H), 2.29 (bs, 3H), 1.941.17 (16H), 1.16-0.97 (1H), 0.87 (s, 9H); 13C δ 108.16, 108.10, 47.5, 32.3, 31.9 (br), 30.7 (br), 29.6 (br), 27.6, 25.4, 23.7 (br), 22.7; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C16H28NaO4 (M+Na)+: 307.1885; found: 307.1888, 0.9 ppm.
O O
14-tert-Butyl-1,2,6,9,10-pentaoxadispiro[5.2.5.2]hexadecane (13): tBu O O O white solid, 86% yield; mp 85-87°C, Rf = (10% EA/hex); IR: 2958, 2866, 1469, 1442, 1366, 1347, 1267, 1229, 1147, 1104, 1062, 914, 839 cm-1; 1H δ 3.90-3.62 (4H), 3.17 (s, 1H), 2.46 (s, 2H), 2.10-1.58 (6H), 1.49 (2H), 1.27 (2H), 1.17-0.98 (1H), 0.91 (s, 9H); 13C δ 108.6, 105.6, 64.7, 63.3, 47.4, 32.3, 31.9 (br), 30.9 (br), 29.6 (br), 27.6, 23.1(br); HRMS (ESI, MeOH/H2O, NaOAc), calc. for C15H26NaO5 (M+Na)+: 309.1678; found:, ppm.
SI-part A, p 3
Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-spiro-4"-tert-butylO O tBu 1"-cyclohexane (14): white solid, 71% yield; mp 134-136°C, Rf = 0.29 O O (2% EA/hex); IR: 2941, 1450, 1264, 1061, 997, 732, 703 cm-1; 1H δ 3.20 (bs, 1H), 2.49-0.95 (16H), 0.88 (s, 9H); 13C δ 110.3, 108.0, 47.5, 36.9, 33.2, 32.35, 32.33, 27.6, 27.5, 27.1; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C20H32NaO4 (M+Na)+: 359.2198; found: 359.2197, 0.4 ppm.
O O Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-spiro-1"-cyclohexane 15 (15): white solid, 69% yield; mp 55-58°C; Rf = 0.30 (2% EA/hex); IR: O O 2936, 2859, 1450, 1361, 1265, 1105, 1061, 996, 924, 785 cm-1; 1H δ 3.15 (bs, 1H), 2.28 (bs, 2H), 2.10-1.26 (22H); 13C δ 109.7, 107.5, 36.6, 32.7, 27.2, 25.1; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C16H24NaO4 (M+Na)+: 303.1572; found: 303.1567, 1.7 ppm.
O O Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-spiro-4"-oxo-1"O cyclohexane (16): Used CH2Cl2/CH3CN assolvent: white solid, 91% O O yield; mp 66-69°C, Rf = 0.27 (10% EA/hex); IR: 2937, 2911, 2860, 1470, 1451, 1348, 1300, 1266, 1230, 1147, 1104, 1061, 996, 923, 844 cm-1; 1H δ 3.89-3.64 (4H), 3.18 (bs, 1H), 2.47 (1.7H), 2.16-1.83 (7H), 1.82-1.53 (8H); 13C δ 110.8, 105.5, 64.6, 36.9, 33.1, 31.6, 27.0, 22.7, 14.2; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C15H22NaO5: (M+Na)+: 305.1365; found: 305.1367, 0.7 ppm.
O O Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-spiro-1"-cyclopentane (17): Sticky liquid, 61% yield; Rf = 0.29 (2% EA/hex); IR: 2935, 2908, 2858, O O 1451, 1180, 1104, 1061, 996, 922 cm-1; 1H δ 3.20 (bs, 1H), 2.61-2.24 (2H), 2.20-1.41 (22H); 13C δ 119.5, 110.2, 46.9, 39.3, 37.3 36.0 (br); HRMS (ESI, MeOH/H2O, NaOAc), calc. for C15H22NaO4 (M+Na)+: 289.1416; found: 289.1412, 1.2 ppm.
4-tert-butyl-1-spiro-3’-1’,2’,4’,5’-tetraoxane-6’-spiro-5”-nonane O O C4 H9 t-Bu (18): low melting solid, Rf = 0.27 (2% EA/hex); IR: 2958 (br), 2870, O O C4 H 9 1367, 1264, 1193, 1065, 906, 785, 704 cm-1; 1H δ 3.19 (s, 1H), 2.24 (2H), 1.95-1.00 (18H), 0.99-0.80 (15H); 13C δ 111.0, 108.14, 107.8, 47.4, 32.3, 29.7 (br), 27.6, 22.9, 13.9; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C19H36NaO4: (M-H)+: 351.2511; found: 351.2504, 2.1 ppm.
3-phenyl-9-tert-butyl-1,2,4,5-tetraoxaspiro[5.5]undecane (19):16 O O Bu white solid, 66% yield; mp 123-125°C, Rf = 0.25 (2% EA/hex); IR: O O 2954, 1455, 1360, 1257, 1192, 1122, 1065, 1008, 996, 923 cm-1; 1H δ 7.52-7.36 (5H), 6.69 (s, 1H), 3.32 (dt, J = 3.5, 14.0 Hz, 0.8H), 2.41 (0.27H), 1.93-1.51 (5H), SI-part A, p 4
1.50-1.22 (2H), 1.22-1.09 (1H), 0.91 (s, 9H); 13C δ 132.6, 131.6, 128.7, 127.6, 108.7, 107.9, 47.5, 32.4, 32.1, 30.3, 27.7, 27.6, 23.2, 22.8; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C17H24NaO4 (M+Na)+: 315.1572; found: 315.1579, 2.1 ppm.
3-(4-chloro-phenyl)-9-tert-butyl-1,2,4,5O O Cl tetraoxaspiro[5.5]undecane (20): white solid, 91% yield; mp 114- Bu O O 116°C, Rf = 0.23 (2% EA/hex); IR: 2956, 2868, 1599, 1468, 1366, 1264, 1091, 1065, 1011, 997, 836, 810, 737, 704 cm-1; 1H δ 7.41 (s, 4H), 6.66 (s, 1H), 3.27 (dt, J = 3.5, 14.0 Hz, 0.77H), 2.41 (0.33H), 1.92-1.50 (5H), 1.50-1.22 (2.7H), 1.20-1.08 (1H), 0.91 (s, 9H); 13C δ 137.2, 130.0, 129.0, 128.9, 108.9, 107.1, 47.4, 32.4, 32.0, 30.3, 27.6, 23.2, 22.8; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C17H23ClNaO4 (M+Na)+: 349.1183; found: 349.1187, 1.3 ppm. O O
Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-benzene (21): white O O solid, 83% yield; mp 60-64°C, Rf = 0.28 (2% EA/hex); IR: 2913, 2858, -1 1 1452, 1268, 1105, 1015, 993, 921 cm ; H δ 7.52-7.33 (5H), 6.70 (s, 1H), 3.33 (s, 1H), 2.22-1.56 (13H); 13C δ 131.7, 131.0, 128.7, 127.6, 110.8, 107.7, 77.4, 77.1, 47.0, 39.3, 36.9, 34.5, 33.3, 33.1, 30.9, 27.0; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C17H20NaO4: (M+Na)+: 311.1259; found: 311.1264, 1.5 ppm. O O Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-(4"Cl chlorobenzene) (22): white solid, 86% yield; mp 70-72°C, Rf = O O 0.29 (2% EA/hex); IR: 2910, 2859, 1600, 1493, 1451, 1409, 1340, 1300, 1090, 1061, 1014, 992, 911, 810 cm-1; 1H δ 7.40 (4H), 6.67 (s, 1H), 3.28 (s, 1H), 2.18-1.62 (13H); 13C δ 137.1, 130.0, 129.0, 128.9, 111.0, 106.9, 77.4, 77.0, 76.7, 36.9, 34.5, 33.2, 33.1, 30.9, 27.0; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C17H19ClNaO4 (M+Na)+: 345.0870; found: 345.0870, 0.1 ppm.
O O Me
Adamantane-2-spiro-3'-1',2',4',5'-tetraoxane-6'-spiro-2’’-(4”-phenyl)Ph O O butane (23): Sticky liquid, % yield; Rf = 0.25 (2% EA/hex); IR 2935, 2910, 2859, 1496, 1453, 1374, 1207, 1128, 1104, 1062, 996, 922 cm-1; 1H δ 7.40-7.113 (5H), 3.20 (s, 1H), 2.76 (2H), 2.60 (1H), 2.15-1.55 (16H), 1.34 (1H); 13C δ 141.1, 128.5, 128.4, 128.3, 126.1, 112.5, 110.1, 37.0, 34.2, 33.2, 30.3, 27.1, 18.9 (br); HRMS (ESI, MeOH/H2O, NaOAc), calc. for C20H26NaO4: (M+Na)+: 353.1729; found: 353.1743, 4.0 ppm.
O O
Methanone, Dispiro[piperidine-4,3'-[1,2,4,5]tetroxane-6',2''tricyclo[3.3.1.13,7]decan]-4-yl-4-morpholinyl methanone (24):8 white
SI-part A, p 5
O O
O N N O
solid, 82% yield; mp 161-164°C, Rf = 0.33 (10% EA/hex); IR: 2917, 2859, 1716, 1643, 1418, 1264, 1116, 1060, 996, 781 cm-1; 1H δ 3.70 (4H, t, J 4.3, 4H), 3.30 (4H, m, 4H), 3.20 (4H, t, J 4.5, 4H), 2.50 (2H, bs, 2H), 1.50-2.05 (16H, m, 2H); 13C δ 163.7, 110.9, 106.5, 66.6, 47.4, 42.5, 37.1, 33.5, 31.8, 30.6, 27.4; HRMS (ESI, MeOH/H2O, NaOAc), calc. for C20H30N2NaO6 (M+Na)+: 417.2002; found: 417.1992, 2.3 ppm.
Literature Cited 1
Medard, L. A. Accidental Explosions: Types of Explosive Substances; Ellis Horwood Limited: Chichester, 1989; Vol. 2. 2 Patnaik, P. A. Comprehensive Guide to the Hazardous Properties of Chemical Substances, 2nd ed. John Wiley & Sons: New York, 1999. 3 Shanley, E. S. In Organic Peroxides; Swern, D., Ed.; Wiley-Interscience: New York, 1970; Vol. 3, p 341. 4 “Safety And Handling Of Organic Peroxides” (AS-109) The Society Of The Plastics Industry, Inc., August, 1999. www.socplas.org/about/Safety_Guide.pdf 5 Zabicky, J. In The Chemistry of the Peroxide Group, v. 2, Rappoport, Z., ed.; John Wiley & Sons; Chichester, 2006; pt 2, p. 597. 6 Sanchez, J.; Myers, T. N. “Organic Peroxides”, in Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed., John Wiley & Sons, Hoboken, NJ; 2006, v. 18, 489. 7 Ogawa, E. Bull. Chem. Soc. Japan 1932, 7, 265-273 8 Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesús, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. J. Med. Chem. 2008, 51, 2170-77 9 a. Terent'ev, A. O.; Platonov, M. M.; Ogibin, Y. N.; Nikishin, G. I. Synth. Commun. 2007, 37, 1281; b. Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J., Org. Lett. 2006, 8, 2491. 10 Das, B.; Krishnaiah, M.; Veeranjaneyulu, B.; Ravikanth, B., Tetrahedron Lett. 2007, 48, 6286. 11 Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J., J. Org. Chem. 2007, 72, 6534-6540. 12 Ghorai, P.; Dussault, P. H. Org. Lett. 2008, 10, 4577–4579. 13 Smith, L. L.; Hill, F. L. J. Chromatogr. 1972, 66, 101. 14 Dong, Y.; Vennerstrom, J. L., J. Org. Chem., 1998, 63, 8582-8585; Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra, J., Tetrahedron 2006, 62, 1479-1484. 15 Terent'ev, A. O.; Kutkin, A. V.; Starikova, Z. A.; Antipin, M. Yu.; Ogibin, Yu. N.; Nikishin, G. I., Synthesis 2004, 14, 2356-2366. 16 H.-S. Kim, K. Tsuchiya, Y. Shibata, Y. Wataya, Y. Ushigoe, A. Masuyama, M. Nojima, K. J. McCullough, J. Chem. Soc., Perkin Trans. 1, 1999, 1867 - 1870
SI-part A, p 6
