Synlett 2010(3): 423-426  
DOI: 10.1055/s-0029-1218579
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of N-Boc-Protected Bis(2-benzimidazolylmethyl)amines

Paulina R. Martínez-Alanisa, Manuel López Ortizb, Ignacio Regla*b, Ivan Castillo*a
a Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México, D. F., 04510, México
Fax: +52(55)56162217; e-Mail: joseivan@unam.mx;
b Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de mayo esq. Fuerte de Loreto, Ejército de Oriente, México, D. F., 09230, México
Fax: +52(55)56230795; e-Mail: regla@unam.mx;
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Publikationsverlauf

Received 8 September 2009
Publikationsdatum:
17. Dezember 2009 (online)

Abstract

Preparation of bis(1-tert-butoxycarbonyl-2-benzimidazolylmethyl)amines from N-tert-butoxycarbonyl-protected 2-chloromethylbenzimidazole is described. The reaction with primary amines containing several functional groups afforded bis(1-tert-­butoxycarbonyl-2-benzimidazolylmethyl)amines in good yields. Hydrogenolysis of bis(2-benzimidazolylmethyl)benzylamine, catalyzed by Pd(OH)2/C, cleaved the benzyl group, leaving the tert-­butoxycarbonyl and 2-benzimidazolylmethyl groups intact. The product of the latter reaction, bis(1-tert-butoxycarbonyl-2-benzimidazolylmethyl)amine, was thus obtained in 56% yield; the presence of the tert-butoxycarbonyl groups at the N-benzimidazole positions makes it amenable to further functionalization at the central nitrogen atom.

    References and Notes

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    Diispropylethylamine was replaced by Et3N, without a significant drop in the yield.

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8

3˙2HCl (220 mg, 1.00 mmol), Et3N (111 mg, 1.10 mmol), and (Boc)2O (240 mg, 1.10 mmol) in DMF (10 mL) were stirred at 40 ˚C for 4 h to give crystals upon cooling to 4 ˚C (212 mg, 55%). tert-Butyl 2-[(tert-butoxycarbonylamino)-methyl]-1H-benzo[d]imidazole-1-carboxylate: ¹H NMR: δ = 1.48 (s, 9 H), 1.72 (s, 9 H), 4.79 (s, 2 H), 5.85 (br s, 1 H), 7.31 (m, 2 H), 7.68 (m, 1 H), 7.93 (m, 1 H). MS (EI): m/z (%) = 347 (3) [M]+.

12

Synthesis of bis(1-tert-butoxycarbonyl-2-benzimidazolyl-methyl)amines 5-10; General procedure: To K2CO3 (7.74 g, 40 mmol), 4 (5.00 g, 18.7 mmol) and NaI (280 mg, 1.87 mmol) in MeCN (75 mL), were added the amines (9.35 mmol), and the mixture was heated to reflux for 10 h. After filtering and washing the solid with CH2Cl2, the combined organic layers were concentrated. Cooling to -25 ˚C resulted in the formation of colorless crystals; alternatively, purification could be achieved by column chromatography on silica gel.
Compound 5: 68% yield; mp 145-146 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.61 (s, 18 H), 4.25 (s, 2 H), 4.63 (s, 4 H), 7.16 (m, 3 H), 7.28 (m, 6 H), 7.71 (m, 2 H), 7.84 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 27.81, 52.23, 56.80, 84.86, 114.42, 119.67, 123.60, 124.05, 126.46, 127.71, 128.64, 132.87, 139.10, 142.04, 148.51, 153.61. IR (KBr): 3025, 2975, 2923, 2859, 1743, 1542, 1453, 1365, 1344, 1258, 1209, 1155, 1118, 1090, 976, 939, 887, 840, 767, 741, 699, 571, 478 cm. Anal. Calcd for C33H40N5O5.5 (5˙1.5H2O): C, 66.65; H, 6.78; N, 11.78. Found: C, 66.27; H, 6.31; N, 11.53.
Compound 7: 87% yield; mp 150-151 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.64 (s, 18 H), 4.45 (s, 2 H), 4.63 (s, 4 H), 6.84 (m, 2 H), 7.14 (dd, J = 1.8, 4.6 Hz, 1 H), 7.30 (m, 4 H), 7.70 (m, 2 H), 7.87 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 28.02, 51.36, 51.90, 85.12, 114.66, 119.90, 123.81, 124.25, 124.69, 125.99, 126.22, 133.05, 142.17, 142.84, 148.68, 153.63. IR (KBr): 3060, 2977, 2925, 2855, 1745, 1608, 1542, 1479, 1452, 1364, 1343, 1258, 1209, 1157, 1118, 1090, 971, 939, 887, 842, 767, 741, 692 cm. Anal. Calcd for C31H35N5O4S (7˙1.5H2O): C, 61.98; H, 6.38; N, 11.66. Found: C, 61.79; H, 5.89; N, 11.41.
Compound 8 was generated from (N-benzyloxycarbonyl)-2-aminoethyl (2,4-dimethyl)benzenethioether hydrobromide (6˙HBr), which was prepared from 2,4-dimethylbenzene-thiol and 2-tosyl-benzylformylaminoethane, and treatment with HBr/AcOH. 6˙HBr: mp 105-108 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 2.24 (s, 3 H), 2.36 (s, 3 H), 3.22 (m, 4 H), 6.9 (d, J = 1.8 Hz, 1 H), 6.98 (s, 1 H), 7.30 (d, J = 1.8 Hz, 1 H), 8.04 (br s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 20.74, 21.07, 30.47, 39.09, 127.64, 128.34, 131.60, 137.65, 139.75. IR (KBr): 3015, 2918, 2817, 2624, 2430, 1866, 1580, 1500, 1478, 1435, 1375, 1260, 1130, 1054, 1006, 930, 878, 812, 781, 745, 617 cm.
Compound 8: 57% yield; ¹H NMR (300 MHz, CDCl3): δ = 1.65 (s, 18 H), 2.18 (s, 3 H), 2.21 (s, 3 H), 3.09 (br t, 2 H), 3.30 (br t, 2 H), 4.65 (s, 4 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.82 (s, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 7.30 (m, 4 H), 7.68 (m, 2 H), 7.87 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 20.34, 20.92, 28.20, 31.34, 53.08, 53.31, 85.40, 114.87, 120.05, 124.00, 124.51, 127.09, 128.08, 130.93, 132.00, 133.19, 135.08, 137.24, 142.24, 148.83, 153.62. IR (KBr): 3058, 2978, 2930, 2868, 1746, 1607, 1541, 1478, 1452, 1348, 1296, 1259, 1209, 1154, 1118, 1088, 1059, 973, 939, 881, 842, 766, 744 cm. HRMS-FAB+: m/z calcd for C36H44N5O4S [M + H]+: 642.3114; found: 642.3121.
Compound 9: 68% yield; mp 130-133 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 1.8, 7.3 Hz, 3 H), 1.02 (m, 2 H), 1.68 (s, 18 H), 3.18 (m, 1 H), 3.41 (t, J = 9.8 Hz, 1 H), 3.62 (m, 1 H), 4.61 (s, 4 H), 7.18 (m, 4 H), 7.53 (m, 2 H), 7.71 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 11.77, 21.50, 28.19, 50.57, 63.40, 67.23, 85.49, 114.74, 119.60, 123.86, 124.35, 133.12, 141.63, 148.86, 155.86. IR (KBr): 3357, 2971, 2934, 2872, 1741, 1607, 1534, 1345, 1294, 1260, 1155, 1119, 1090, 845, 769, 746, 561 cm. Anal. Calcd for C30H39N5O5: C, 65.55; H, 7.15; N, 12.74. Found: C, 65.56; H, 7.12; N, 12.40. [α]D ²0 -33.6 (c 10 mg/mL, CH2Cl2).
Compound 10: Compound 5 (2.60 g, 4.60 mmol), 20% Pd(OH)2/C (400 mg, 9.35 mmol), and tartaric acid (361 mg, 2.40 mmol) in EtOH (120 mL), were stirred under 60 lb/in² H2 at 45 ˚C for 18 h. After neutralization with K2CO3 (330 mg, 2.40 mmol), the product was dissolved in CH2Cl2, filtered through Celite, dried with Na2SO4, and concentrated. Purification by column chromatography afforded 10: 56% yield (1.22 g); mp 161-162 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.20 (s, 9 H), 1.73 (s, 9 H), 4.82 (s, 2 H), 5.13 (s, 2 H), 7.23 (m, 2 H), 7.40 (m, 2 H), 7.57 (br m, 1 H), 7.72 (br m, 1 H), 7.82 (m, 1 H), 7.95 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 27.94, 28.05, 49.92, 50.89, 81.32, 110.69, 114.96, 115.16, 118.93, 119.23, 121.40, 122.01, 124.62, 124.89, 125.07, 133.09, 133.87, 140.88, 143.73, 153.97, 154.33. IR (KBr): 3051, 2979, 2868, 2792, 2696, 1748, 1697, 1621, 1547, 1454, 1418, 1393, 1363, 1323, 1259, 1209, 1153, 1118, 1092, 1014, 947, 890, 835, 751, 642 cm. Anal. Calcd for C33H40N5O5.5: C, 65.39; H, 6.54; N, 14.66. Found: C, 65.53; H, 6.69; N, 14.73.