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DOI: 10.1055/s-0029-1218579
Synthesis of N-Boc-Protected Bis(2-benzimidazolylmethyl)amines
Publikationsverlauf
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.
Key words
chemoselectivity - benzimidazoles - protecting groups - ligands
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
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]+.
12Synthesis 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 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-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/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-¹. Anal.
Calcd for C33H40N5O5.5:
C, 65.39; H, 6.54; N, 14.66. Found: C, 65.53; H, 6.69; N, 14.73.