CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 493-498
DOI: 10.1055/s-0037-1610403
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Selective Phthalimido-N-oxyl (PINO)-Catalyzed C–H Cyanation of Adamantane Derivatives

Jan-Philipp Berndt
,
Frederik R. Erb
,
Lukas Ochmann
,
Jaqueline Beppler
,
Peter R. Schreiner  *
Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany   eMail: prs@uni-giessen.de
› InstitutsangabenThis work was supported by the Justus Liebig University.
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Publikationsverlauf

Received: 05. Oktober 2018

Accepted after revision: 09. November 2018

Publikationsdatum:
14. Dezember 2018 (online)

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Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

We present a new method for the selective C(sp3)–H cyanation of adamantane derivatives with PINO as the hydrogen abstracting reagent. A cyano radical is thereby transferred from p -toluenesulfonyl cyanide, allowing the cyanation of adamantane derivatives in up to 71% yield. The protocol presents a novel way to orthogonally functionalized adamantanes that are otherwise difficult to prepare. Mechanistic studies support the hypothesis of a radical pathway.

Key words

adamantane - C–H activation - cyanation - N-hydroxyphthalimide - NHPI - PINO

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610403.
  • Supporting Information
 

  • References and Notes

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  • 30 1-Cyano-3-methyladamantane (5) Yield 0.062 g (0.359 mmol, 71%). Rf = 0.40 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C12H17NNa+: 198.1253; found: 198.1254 [M + Na+]+. IR (ATR): 2906, 2850, 2232, 1532, 1456, 1360, 1343, 1162, 1112, 974, 923, 756, 692 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.09–2.02 (m, 2 H), 2.00–1.87 (m, 4 H), 1.73 (s, 2 H), 1.64–1.57 (m, 2 H), 1.49–1.41 (m, 4 H), 0.84 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 125.2 (C), 46.4 (C), 42.9 (CH2), 39.4 (2 CH2), 35.1 (2 CH2), 31.0 (CH2), 30.5 (C), 29.8 (CH3), 27.9 (2 CH) ppm.
  • 31 1-Cyano-3,5-dimethylcyanoadamantane (6) Yield 0.031 g (0.164 mmol, 33%). Rf = 0.43 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C13H19NNa+: 212.1410; found: 212.1412 [M + Na+]+. IR (ATR): 2902, 2848, 2235, 1455, 1378, 1359, 1342, 1232, 1144, 965, 934, 912, 772, 733 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.11 (hept, J = 3.1 Hz, 1 H), 1.86–1.83 (m, 2 H), 1.70–1.59 (m, 4 H), 1.41–1.31 (m, 4 H), 1.17 (s, 2 H), 0.85 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 125.1 (C), 50.1 (CH2), 45.9 (2 CH2), 42.2 (2 CH2), 38.7 (CH2), 31.8 (C), 30.6 (C), 30.1 (2 CH3), 28.5 (2 CH) ppm.
  • 32 1-Cyano-3,5,7-trimethyladamantane (7) Yield 0.028 g (0.138 mmol, 28%). Rf = 0.71 (n-hexane/EtOAc, 5:1). HRMS (ESI): m/z calcd for C14H21NNa+ m/z = 226.1566; found: 226.1563 [M + Na+]+. IR (ATR): 2948, 2918, 2865, 2843, 2230, 1455, 1377, 1358, 1257, 1233, 912, 788 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 6 H), 1.16–1.02 (m, 6 H), 0.86 (s, 9 H) ppm.13C NMR (101 MHz, CDCl3): δ = 125.0 (C), 49.5 (3 CH2), 45.3 (3 CH2), 32.5 (C), 31.5 (3 C), 29.7 (3 CH3) ppm.
  • 33 Olah GA, Farooq O, Surya Prakash GK. Synthesis 1985; 1140
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  • 34 1-Cyanoadamantane-3,5-acetic Acid Methyl Ester (8) Yield 0.054 g (0.177 mmol, 35%). Rf = 0.23 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C17H23NNaO4 +: 328.1519; found: 328.1516 [M + Na+]+. IR (ATR): = 2910, 2857, 2235, 1731, 1438, 1330, 1242, 1162, 1128, 1057, 1022, 851 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.65 (s, 6 H), 2.21–2.17 (m, 1 H), 2.16 (s, 4 H), 1.93–1.87 (m, 4 H), 1.87–1.80 (m, 2 H), 1.62–1.55 (m, 2 H), 1.55–1.46 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.2 (2 C), 124.2 (C), 51.5 (2 CH3), 47.1 (2 CH2), 45.6 (CH2), 43.4 (2 CH2), 39.8 (2 CH2), 38.5 (CH2), 33.1 (2 C), 31.6 (C), 28.0 (CH) ppm.
  • 35 1-Cyanoadamantane-3-acetic Acid Methyl Ester (9) Yield 0.039 g (0.149 mmol, 30%). Rf = 0.08 (n-pentane/Et2O, 10:1). HRMS (ESI): m/z calcd for C16H23NNaO2 +: 284.1621; found: 284.1623 [M + Na+]+. IR (ATR): 2950, 2924, 2900, 2866, 2849, 2232, 1735, 1456, 1356, 1312, 1231, 1192, 1147, 1087, 1012 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 3 H), 2.16 (s, 2 H), 1.76 (s, 2 H), 1.62 (s, 4 H), 1.33–1.20 (m, 4 H), 1.20–1.10 (m, 2 H), 0.88 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.5 (C), 124.5 (C), 51.5 (CH3), 49.4 (CH2), 47.2 (2 CH2), 47.0 (CH2), 45.2 (2 CH2), 43.0 (CH2), 34.06 (C), 32.37 (C), 31.4 (2 C), 29.7 (2 CH3) ppm.
  • 36 1-Cyano-3-bromoadamantane (10) Yield 0.040 g (0.167 mmol, 34%). Rf = 0.16 (n-pentane/Et2O, 20:1). HRMS (ESI): m/z calcd for C11H14BrNNa+: 262.0202; 262.0204 [M + Na+]+. IR (ATR): 2948, 2925, 2862, 2228, 1455, 1344, 1330, 1311, 1245, 1121, 1097, 966, 990, 822, 726, 677, 457 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.58 (s, 2 H), 2.35–2.26 (m, 4 H), 2.25–2.17 (m, 2 H), 2.04 (d, J = 2.9 Hz, 4 H), 1.75–1.69 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 123.2 (C), 59.6 (C), 50.1 (CH2), 47.4 (2 CH2), 38.4 (2 CH2), 33.9 (CH2), 33.5 (C), 31.0 (2 CH) ppm.
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  • 38 1-Cyano-3-phenyladamantane (11) Yield 0.056 g (0.236 mmol, 47%). Rf = 0.23 (n-pentane/Et2O, 20:1). HRMS (ESI): m/z calcd for C17H19NNa+: 260.1410; 260.1411 [M + Na+]+. IR (ATR): = 2926, 2853, 2234, 1599, 1498, 1447, 1343, 1261, 1106, 1080, 1031, 978, 758, 700, 532 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.39–7.31 (m, 4 H), 7.25–7.20 (m, 1 H), 2.27–2.23 (m, 2 H), 2.20 (s, 2 H), 2.12–2.04 (m, 4 H), 1.95–1.89 (m, 4 H), 1.80–1.73 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 148.6 (C), 128.6 (2 CH), 126.5 (CH), 125.0 (CN), 124.7 (2 CH), 45.1 (CH2), 41.6 (2 CH2), 39.3 (2 CH2), 36.0 (C), 35.1 (CH2), 31.5 (C), 28.1 (2 CH) ppm.
  • 39 1-Cyano-3-ethynyladamantane (12) Yield 0.038 g (0.204 mmol, 41%). Rf = 0.56 (n-hexane/EtOAc, 1:1). HRMS (ESI): m/z calcd for C13H15NNa+: 208.1097; 208.1095 [M + Na+]+. IR (ATR): 3261, 2917, 2857, 2236, 2110, 1726, 1579, 1451, 1345, 1260, 1088, 1014, 869, 795, 688, 50 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.15 (s, 1 H), 2.14 (s, 2 H), 2.13–2.09 (m, 2 H), 1.99 (d, J = 3.0 Hz, 4 H), 1.89–1.84 (m, 4 H), 1.70–1.66 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 124.3 (C), 90.2 (C), 68.5 (CH), 44.4 (CH2), 41.3 (2 CH2), 39.0 (2 CH2), 34.6 (CH2), 30.5 (C), 29.2(C), 27.2 (2 CH).
  • 40 ​3-Cyanoadamantane-1-​carboxylic Acid Methyl Ester (13) Yield 0.055 g (0.250 mmol, 50%). Rf = 0.47 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C13H17NNaO2 +: 242.1152; 242.1149 [M + Na+]+. IR (ATR): 2952, 2915, 2859, 2229, 1720, 1480, 1446, 1346, 1323, 1265, 1240, 1192, 1151, 1125, 1106, 1029, 952, 866, 777, 747, 728, 570, 481, 445 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 2.19–2.13 (m, 4 H), 2.04–1.96 (m, 4 H), 1.93–1.80 (m, 4 H), 1.70 (s, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.2 (C), 124.4 (C), 52.1 (CH3), 40.7 (CH2), 40.3 (C), 39.1 (2 CH2), 37.5 (2 CH2), 34.8 (CH2), 30.6 (C), 27.2 (2 CH).
  • 41 1-O-(tert-Butyldiphenylsilyl)-3-cyanoadamantanol (14a) Yield 0.080 g (0.193 mmol, 39%). Rf = 0.39 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C27H33NNaOSi+: 438.2224; found: 438.2226 [M + Na+]+. IR (ATR): 3071, 2931, 2858, 2235, 1590, 1472, 1455, 1428 1357, 1337, 1316, 1155, 1143, 1110, 1068, 975, 903, 821, 740, 702, 610, 503 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.74–7.70 (m, 4 H), 7.45–7.36 (m, 6 H), 2.09 (s, 2 H), 1.99 (s, 2 H), 1.84–1.73 (m, 4 H), 1.70–1.64 (m, 4 H), 1.50–1.37 (m, 2 H), 1.02 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 136.1 (4 CH), 135.7 (2 C), 129.7 (2 CH), 127.6 (4 CH), 124.2 (C), 71.0 (C), 47.5 (CH2), 44.3 (2 CH2), 38.8 (2 CH2), 34.4 (CH2), 33.0 (C), 29.9 (3 CH3), 27.1 (2 CH), 19.3 (C) ppm.
  • 42 1-Cyano-3-acetamidoadamantane (15) Yield 0.024 g (0.110 mmol, 22%). Rf = 0.46 (CH2Cl2/MeOH, 20:1). HRMS (ESI): m/z calcd for C13H18N2NaO+: 241.1311; found: 241.1317 [M + Na+]+. IR (ATR): 3295, 3078, 2918, 2856, 2232, 1731, 1651, 1548, 1456, 1366, 1307, 1144, 1061, 1007, 702, 602, 541, 452 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.32 (s, 1 H), 2.35 (s, 2 H), 2.21 (s, 2 H), 2.11–2.06 (m, 2 H), 2.03–1.93 (m, 4 H), 1.92 (s, 3 H), 1.88–1.80 (m, 2 H), 1.67 (s, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.8 (C), 124.1 (C), 51.0 (C), 42.9(CH2), 40.3 (2 CH2), 39.0 (2 CH2), 34.8 (CH2), 31.8 (C), 28.5 (2 CH), 24.6 (CH3) ppm. 1-N-Adamantylphthalimide-3-cyano (16) Yield 0.033 g (0.108 mmol, 22%). Rf = 0.28 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C19H18N2NaO2 +: 329.1261; found: 329.1262 [M + Na+]+. IR (ATR): 2926, 2863, 2226, 1768, 1703, 1611, 1468, 1361, 1341, 1313, 1155, 1111, 1070, 999, 980, 969, 870, 790, 715, 643, 532, 407 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.79–7.74 (m, 2 H), 7.72–7.66 (m, 2 H), 2.80 (s, 2 H), 2.58–2.46 (m, 4 H), 2.30 (s, 2 H), 2.14–1.98 (m, 4 H), 1.82–1.66 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.5 (2 C), 134.1 (2 CH), 131.8 (2 C), 124.01 (C), 123.0 (2 CH), 58.6 (C), 41.8 (CH2), 38.9 (2 CH2), 38.9 (2 CH2), 34.6 (CH2), 32.3 (C), 28.8 (2 CH) ppm. 1-Azido-3-cyano-adamantane (17) Yield 0.027 g (0.133 mmol, 27%). Rf = 0.13 (n-pentane/Et2O, 20:1). HRMS (ESI): m/z calcd for C11H14N4Na+: 225.1114; found: 225.1111 [M + Na+]+. IR (ATR): 2919, 2861, 2230, 2087, 1456, 1360, 1339, 1318, 1244, 1130, 1108, 997, 925, 872, 836, 714, 678, 561, 489 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.33–2.27 (m, 2 H), 2.04 (s, 2 H), 2.02–1.93 (m, 4 H), 1.84–1.76 (m, 4 H), 1.69–1.63 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 123.6 (C), 57.3 (C), 43.7 (CH2), 40.1 (2 CH2), 38.8 (2 CH2), 34.3 (CH2), 32.2 (C), 28.9 (2 CH) ppm.
  • 43 4-Cyanodiamantane (18a) Rf = 0.23 (n-pentane/Et2O, 10:1). HRMS (ESI): m/z calcd for C15H19NNa+: 236.1410; found: 236.1411 [M + Na+]+. IR (ATR): 2908, 2884, 2847, 2228, 1440, 1377, 1358, 1314, 1258, 1126, 1090, 1047, 984, 902, 799, 572, 545, 462 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.03–1.97 (m, 6 H), 1.85 (s, 3 H), 1.83–1.79 (m, 1 H), 1.77–1.74 (m, 3 H), 1.73–1.69 (m, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 125.5 (C), 40.9 (3 CH2), 37.6 (3 CH2), 36.4 (3 CH), 36.1 (3 CH), 28.8 (C), 25.4 (CH) ppm. 1-Cyanodiamantane (18m) Rf = 0.27 (n-pentane/Et2O, 10:1). HRMS (ESI): m/z calcd for C15H19NNa+: 236.1410; found: 236.1408 [M + Na+]+. IR (KBR): 2918, 2889, 2850, 2227, 1636, 1460, 1443, 1340, 1314, 1260, 1057, 1048, 984, 800, 615 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.23–2.15 (m, 2 H), 2.05–2.00 (m, 2 H), 2.00–1.92 (m, 3 H), 1.87 (s, 3 H), 1.71 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 124.6 (C), 41.4 (CH2), 39.0 (2 CH), 38.1 (C), 37.7 (CH2), 37.1 (2 CH2), 36.6 (2 CH), 36.3 (CH), 35.1 (2 CH2), 25.6 (CH), 25.0 (CH) ppm.
  • 44 1-Cyano-3-diamantane Carboxylic Acid Methyl Ester (19m1) Rf = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for C17H21NnaO2 +: 294.1465; found: 294.1467 [M + Na+]+. IR (ATR): 2909, 2890, 2858, 2227, 1726, 1463, 1433, 1280, 1254, 1228, 1215, 1133, 1115, 1068, 1033, 985, 889, 846, 790, 767, 739, 709, 632, 507 433, 422 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 2.22 (s, 1 H), 2.20–2.16 (m, 3 H), 2.01–1.98 (m, 2 H), 1.97–1.94 (m, 2 H), 1.92–1.83 (m, 6 H), 1.77–1.73 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.5 (C), 123.6 (C), 52.1 (CH3), 42.1 (CH2), 39.1 (C), 38.8 (2 CH2), 38.5 (C), 38.2 (2 CH), 37.1 (CH2), 36.5 (2 CH), 35.3 (CH), 34.3 (2 CH2), 24.7 (CH) ppm. 1-Cyano-4-diamantane Carboxylic Acid Methyl Ester (19m2) Rf = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for C17H21NnaO2 +: 294.1465; found: 294.1462 [M + Na+]+. IR (ATR): 2906, 2881, 2853, 2224, 1714, 1466, 1444, 1427, 1341, 1321, 1283, 1247, 1221, 1142, 1123, 1091, 1072, 1060, 1045, 1012, 980, 949, 883, 860, 814, 787, 758, 744, 698, 628, 566, 543, 519, 490, 427 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 2.34 (s, 1 H), 2.31 (s, 1 H), 2.10–2.03 (m, 4 H), 1.96 (q, J = 3.1 Hz, 1 H), 1.92–1.90 (m, 1 H), 1.89–1.82 (m, 6 H), 1.77–1.72 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 177.1 (C), 123.9 (C), 52.0 (CH3), 40.8 (CH2), 39.4 (CH2), 38.9 (2 CH), 38.4 (C), 37.3 (C), 36.5 (2 CH2), 36.5 (2 CH2), 36.1 (CH), 35.6 (2 CH), 25.3 (CH) ppm.
    • 45a Glass RW, Martin TW. J. Am. Chem. Soc. 1970; 92: 5084
      Crossref
    • 45b Fokin AA, Peleshanko SA, Gunchenko PA, Gusev DV, Schreiner PR. Eur. J. Org. Chem. 2000; 3357
  • 46 Mella M, Freccero M, Soldi T, Fasani E, Albini A. J. Org. Chem. 1996; 61: 1413
    Crossref
  • 47 PINO-Catalyzed Cyanations of Adamantane Derivatives – General Procedure 1 equiv substrate, 2 equiv TsCN, 1 equiv CAN, 1 equiv Li2CO3, 0.2 equiv NHPI and 5 mL DCE were stirred for 16 h at 75 °C. The reactions mixture was allowed to cool down to room temperature and filtered over silica gel (50 mL EtOAc, 50 mL MeCN, 50 mL EtOAc).