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

Paulina R. Martínez-Alanis; Manuel López Ortiz; Ignacio Regla; Ivan Castillo

doi:10.1055/s-0029-1218579

LETTER

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

Paulina R. Martínez-Alanis^a, Manuel López Ortiz^b, 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;

Abstract

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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.

Key words

chemoselectivity - benzimidazoles - protecting groups - ligands

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References and Notes

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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]⁺.

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

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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^-¹. Anal. Calcd for C₃₃H₄₀N₅O_5.5 (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^-¹. 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^-¹.
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^-¹. 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^-¹. 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/in^² 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^-¹. Anal. Calcd for C₃₃H₄₀N₅O_5.5: C, 65.39; H, 6.54; N, 14.66. Found: C, 65.53; H, 6.69; N, 14.73.

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