N- versus O-Group Protection in Hydroxypropylbenzimidazoles
825
Separation of small amounts of the regioisomers was achieved by
further chromatography to give firstly the less-polar compound, an oil
(25): δH (400 MHz, CDCl3) 2.07 (2 H, tt, J 6.9 and 5.8, CH2CH2CH2),
2.96 (2 H, t, J 6.9, CCH2), 3.73 (2 H, t, J 5.8, CH2OH), 5.29 (2 H, s,
CH2Ph), 6.95–7.30 (5 H, m, ArH), 7.05 (1 H, d, J 8.6, ArH), 7.29 (1 H,
dd, J 8.6 and 1.8, ArH), 7.84 (1 H, d, J 1.8, ArH). δC (100 MHz) 24.7,
29.6, 47.0, 61.6, 110.8, 115.1, 121.9, 125.5, 126.0, 128.1, 129.1, 134.2,
135.3, 143.3, 156.3.
Next was obtained the more-polar compound, an oil (24): δH
(400 MHz, CDCl3) 2.06 (2 H, tt, J 7.0 and 5.9, CH2CH2CH2), 2.94
(2 H, t, J 7.0, CCH2), 3.73 (2 H, t, J 5.9, CH2OH), 5.26 (2 H, s, CH2Ph),
6.95–7.01 (2 H, m, ArH), 7.25–7.30 (3 H, m, ArH), 7.32 (1 H, dd, J 8.6
and 1.8, ArH), 7.35 (1 H, d, J 1.6, ArH), 7.57 (1 H, d, J 8.6, ArH). δC
(100 MHz) 24.7, 29.5, 46.9, 61.6, 112.6, 115.7, 120.3, 125.4, 125.9,
128.0, 129.0, 135.2, 136.4, 140.9, 156.0.
sodium hydrogen carbonate solution. The basic solution was extracted
with dichloromethane (3 × 20 mL), and the combined organic layers
were dried (Na2SO4) and filtered. The solvent was removed under
reduced pressure to give the crude product, which was purified by
flash chromatography (silica; 9 : 1 ethyl acetate/hexanes) to give (21)
(4.7 mg, 57%). This compound was identical (1H NMR spectrum) to
that obtained previously.
Acetylation of 3-(6ꢀ-Bromo-1ꢀH-benzimidazol-2ꢀ-yl)propan-1-ol (23)
To a stirred solution of the bromobenzimidazole (23) (0.5 g, 1.9 mmol)
in dichloromethane (5 mL) and triethylamine (5 mL) at 0◦C was added
a catalytic amount of DMAP, and then acetic anhydride (0.2 mL,
2.1 mmol). The reaction was monitored by TLC. When the reaction
was complete (2 h), water (30 mL) was added, and the product was
extracted into dichloromethane (3 × 30 mL).The combined organic lay-
ers were dried (Na2SO4) and filtered. The solvent was removed under
reduced pressure to give the crude product which was purified by flash
chromatography (90% ethyl acetate/hexanes) to give 3-(6ꢀ-bromo-1ꢀH-
benzimidazol-2ꢀ-yl)propyl acetate (28) as a dark brown solid (0.51 g,
88%). Mp 93–96◦C. (Found: M+• 296.0160. C12H1379BrN2O2 requires
Mitsunobu Coupling of the N-Benzylbromobenzimidazoles
(24) and (25)
Methyl 4-hydroxybenzoate (0.06 g, 0.38 mmol) and triphenylphosphine
(0.20 g, 0.77 mmol) were dissolved in anhydrous THF (3 mL). To this
stirred solution, a solution of (24), (25) (0.2 g, 0.6 mmol), and diethyl
azodicarboxylate (0.12 mL, 0.77 mmol) inTHF (1 mL) was added drop-
wise. The reaction was monitored using TLC. After 1 h, further DEAD
(0.1 mL) was added and the reaction was stirred for an additional
1 h. Water (25 mL) was added and the product was extracted into
dichloromethane (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and filtered.The solvent was removed under reduced pressure
to give the crude product which was purified by flash chromatography
(silica; 17 : 3 ether/hexanes) to give methyl 4-[3ꢀ-(1ꢀ-benzyl-6ꢀ-bromo-
1ꢀH-benzimidazol-2ꢀ-yl)propyloxy]benzoate (26) and methyl 4-[3ꢀ-(1ꢀ-
benzyl-5ꢀ-bromo-1ꢀH-benzimidazol-2ꢀ-yl)propyloxy]benzoate (27).
The less-polar compound (27) (0.05 g, 27%) had mp 149–150◦C.
•
M+ 296.0160. Found: [M + 2]+• 298.0144. C12H1381BrN2O2 requires
[M + 2]+• 298.0140). νmax (neat)/cm−1 2959, 1739, 1622, 1538, 1444,
1233, 1044, 911. δH (200 MHz, CDCl3) 2.07 (3 H, s, COCH3), 2.20
(2 H, tt, J 7.1 and 6.5, CH2CH2CH2), 3.02 (2 H, t, J 7.1, CCH2), 4.16
(2 H, t, J 6.5, OCH2), 7.31 (1 H, dd, J 8.4, 1.6Hz, ArH), 7.40 (1 H, d,
J 8.4, ArH), 7.68 (1 H, d, J 1.6, ArH). δC NMR (50 MHz) 20.7, 25.6,
27.1, 63.2, 115.2, 115.9, 117.6, 125.4, 136.9, 139.7, 155.2, 177.3. Mass
•
spectrum m/z 298 (30% [M + 2]+ ), 296 (31%, M+•), 255 (13), 253
(14), 225 (96), 223 (100), 212 (78). 210 (75), 144 (29).
Reaction of the Bromoacetate (28) with Dihydropyran
To a stirred solution of the bromoacetate (28) (1.2 g, 4.0 mmol) in
chloroform (25 mL) was added 3,4-dihydropyran (0.7 mL, 8.0 mmol)
and a catalytic amount of PPTS. The reaction mixture was heated
under reflux, and was monitored by TLC. After 2 days more 3,4-
dihydropyran (0.7 mL, 8.0 mmol) and a catalytic amount of PPTS were
added. The reaction was stopped after 5 days by the addition of water
(50 mL). The product was extracted into dichloromethane (3 × 40 mL),
and the combined organic layers were dried (Na2SO4) and filtered. The
solvent was removed under reduced pressure to give the crude prod-
uct which was purified by flash chromatography (silica; 17 : 3 ethyl
acetate/hexanes) to give a mixture of 3-[6ꢀ-bromo-1ꢀ-(tetrahydropyran-
2ꢀ-yl)-1ꢀH-benzimidazol-2ꢀ-yl]propyl acetate (29) and 3-[5ꢀ-bromo-1ꢀ-
(tetrahydropyran-2ꢀ-yl)-1ꢀH-benzimidazol-2ꢀ-yl]propyl acetate (30) as
a colourless viscous oil (1.28 g, 84%).
•
•
(Found: M+ 478.0889. C25H2379BrN2O3 requires M+ 478.0869.
•
•
Found: [M + 2]+ 480.0875. C25H2381BrN2O3 requires [M + 2]+
480.0872). νmax (neat)/cm−1 2933, 1715, 1605, 1505, 1455, 1277, 1256,
1166, 1105, 772. δH (300 MHz, CDCl3) 2.38 (2 H, tt, J 7.1 and 6.0,
CH2CH2CH2), 3.03 (2 H, t, J 7.1, CCH2), 3.87 (3 H, s, OCH3), 4.10
(2 H, t, J 6.0, CH2O), 5.30 (2 H, s, CH2Ph), 6.83 (2 H, d (broad), J
8.9, ArH), 6.95–7.02 (2 H, m, ArH), 7.07 (1 H, d, J 8.5, ArH), 7.21–
7.28 (3 H, m, ArH), 7.29 (1 H, dd, J 8.5 and 1.8, ArH), 7.89 (1 H, d, J
1.8, ArH), 7.95 (2 H, d (broad), J 8.9, ArH). δC (75 MHz) 23.7, 26.6,
46.9, 51.8, 66.6, 110.7, 114.0, 115.0, 122.2, 122.6, 125.4, 126.0, 128.1,
129.1, 131.5, 134.4, 13•5.4, 143.9, 155.4, 162.4, 166.8. Mass spectrum
m/z 480 (4% [M + 2]+ ), 478 (4%, M+•), 329 (11), 327 (11), 302 (70),
300 (70), 210 (10), 208 (10), 91 (100).
The mixture was separated by further chromatography. The less-
polar compound (30) was obtained as an oil. (Found: C, 53.4; H, 5.7;
N, 7.4%. C17H21BrN2O3 requires C, 53.5; H, 5.5; N, 7.3%). νmax
(NaCl)/cm−1 2946, 2863, 1733, 1507, 1453, 1242, 1040, 1001, 907, 800.
δH (200 MHz, CDCl3) 1.60–1.90 (4 H, m, 3 × tetrahydropyranyl CH2),
2.01–2.40 (2 H, m, 3 × tetrahydropyranyl CH2), 2.05 (3 H, s, COCH3),
2.24 (2 H, tt, J 7.2, 6.2, CH2CH2CH2), 2.99 (3 H, t, J 7.2, CCH2),
3.70 (1 H, m, tetrahydropyranyl OCH2), 4.21–4.29 (1 H, m, tetrahydro-
pyranyl OCH2), 4.22 (2 H, t, J 6.2, OCH2), 5.43 (1 H, dd, J 11.1 and
2.3, NCHO), 7.30 (1 H, dd, J 8.7 and 1.7, ArH), 7.49 (1 H, d, J 8.6,
ArH), 7.81 (1 H, d, J 1.6,ArH). δC (50 MHz) 20.9, 23.1, 24.8, 24.9, 26.6,
30.7, 63.5, 69.2, 84.2, 113.3, 114.9, 122.0, 125.1, 132.4, 144.2, 153.8,
The more-polar compound (26) (0.05 g, 26%) had mp •116–117◦C.
•
(Found: M+ 478.0908. C25H2379BrN2O3 requires M+ 478.0905.
•
•
Found: (M + 2)+ 480.0890. C25H2381BrN2O3 requires (M + 2)+
480.0872). νmax (neat)/cm−1 2953, 1712, 1600, 1509, 1280, 1252,
1169, 1105, 770. δH (300 MHz, CDCl3) 2.39 (2 H, tt, J 7.0 and 6.1,
CH2CH2CH2), 3.02 (2 H, t, J 7.2, CCH2), 3.87 (3 H, s, OCH3), 4.11
(2 H, t, J 6.0, OCH2), 5.28 (2 H, s, CH2Ph), 6.83 (2 H, d (broad), J 8.9,
ArH), 6.97–7.05 (2 H, m, ArH), 7.23–7.28 (3 H, m, ArH), 7.34 (1 H,
dd, J 8.4 and 1.5, ArH), 7.36 (1 H, d, J 1.5, ArH), 7.61 (1 H, d, J 8.4,
ArH), 7.95 (2 H, d (broad), J 8.9, ArH). δC (75 MHz) 23.7, 26.5, 46.9,
51.8, 66.7, 112.5, 113.9, 115.6, 120.5, 122.6, 125.4, 126.0, 128.1, 129.1,
131.5, 135.3, 136.5, 141.6, 155.1, 162.4, 166.7. Mass spectrum m/z 480
•
170.9. Mass spectrum m/z 382 (16% [M + 2]+ ), 380 (16%, M+•), 298
(4% [M + 2]+ ), 478 (4%, M+•), 329 (11), 327 (11), 302 (78), 300 (79),
•
(29), 296 (33), 225 (50), 223(51), 212 (36), 210 (37), 144 (10), 85 (100).
The more-polar compound (29) was obtained as an oil. (Found:
287 (4), 285 (4), 210 (11), 208 (10), 91 (100).
•
•
M+ 380.0738. C17H2179BrN2O3 requires M+ 380.0715. Found:
Hydrogenolysis of N-Benzyl Bromoethers (26) and (27)
•
•
[M + 2]+ 382.0713. C17H2181BrN2O3 requires [M + 2]+ 380.0715).
νmax (NaCl)/cm−1 2944, 2857, 1737, 1512, 1455, 1431, 1241,
1084, 1042, 908. δH (200 MHz, CDCl3) 1.60–1.90 (4 H, m,
2 × tetrahydropyranyl CH2), 2.04 (3 H, s, CH3CO2), 2.00–2.40 (2 H,
m, tetrahydropyranyl CH2), 2.24 (2 H, tt, J 7.3 and 6.3, CH2CH2CH2),
2.98 (2 H, t, J 7.3, CCH2), 3.70 (1 H, m, tetrahydropyranyl OCH2),
4.15–4.30(1 H, m, tetrahydropyranylOCH2), 4.22(2 H, t, J 6.1, CH2O),
5.41 (1 H, dd, J 11.0, 2.2, NCHO), 7.31 (1 H, dd, J 8.7 and 1.3, ArH),
To a solution of the mixture of N-benzyl bromoethers (26) and (27)
(0.01 g, 0.02 mmol) in 95% ethanol/ethyl acetate (2 mL) was added 10%
Pd/charcoal (0.003 g), and 2–3 drops of concentrated sulfuric acid. The
reaction mixture was placed under a hydrogen atmosphere at 1 atm. The
reaction was monitored by TLC. After 22 h, the catalyst was filtered
off and the solvent was removed under reduced pressure. The result-
ing oil was dissolved in water (5 mL) and made basic with saturated