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

doi:10.1055/s-0037-1610403

Synlett, Table of Contents

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

› Author Affiliations

Abstract

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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

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References

References and Notes

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30 1-Cyano-3-methyladamantane (5) Yield 0.062 g (0.359 mmol, 71%). R_f = 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%). R_f = 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%). R_f = 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
34 1-Cyanoadamantane-3,5-acetic Acid Methyl Ester (8) Yield 0.054 g (0.177 mmol, 35%). R_f = 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%). R_f = 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%). R_f = 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.
37 Chanmiya Sheikh M, Takagi S, Ogasawara A, Ohira M, Miyatake R, Abe H, Yoshimura T, Morita H. Tetrahedron 2010; 66: 2132
38 1-Cyano-3-phenyladamantane (11) Yield 0.056 g (0.236 mmol, 47%). R_f = 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%). R_f = 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%). R_f = 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%). R_f = 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%). R_f = 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%). R_f = 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%). R_f = 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) R_f = 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) R_f = 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 (19_m1) R_f = 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 (19_m2) R_f = 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
45b Fokin AA, Peleshanko SA, Gunchenko PA, Gusev DV, Schreiner PR. Eur. J. Org. Chem. 2000; 3357

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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).

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