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NJC
and heated to reflux 16 h. After filtration, the crude mixture was Ethanol was evaporated and the aqueous phase brought to pH 7
concentrated under reduced pressure and purified by column with 1 N HCl was extracted with dichloromethane (3 ꢁ 30 mL).
chromatography (Al2O3, CH2Cl2/petroleum ether, 10/90) to The organic layer was dried over anhydrous MgSO4 and the filtrate
afford 3 as a pale yellow solid (1.40 g, 90%). 1H NMR (300 MHz, was concentrated under reduced pressure and purified by column
CDCl3): d = 7.78 (s, 2H), 4.68 (s, 2H), 3.99 (s, 6H), 1.47(s, 9H). chromatography (Al2O3, CH2Cl2/MeOH, 97/3) to afford 7 as a
13C NMR (75 MHz, CDCl3): d = 166.1 (Cq), 166.0 (Cq), 164.9 (Cq), white solid (525 mg, 81%). 1H NMR (300 MHz, CDCl3):
149.8 (Cq), 114.5 (CH), 83.5 (Cq), 65.2 (CH2), 53.2 (CH3), 27.9 (CH3). d = 7.69–7.65 (m, 4H), 7.45–7.40–7.37 (m, 6H), 6.69 (s, 2H), 4.67
tert-Butyl 2-((2,6-bis(hydroxymethyl)pyridine-4-yl)oxy) acetate (s, 4H), 3.99 (t, J = 6.5 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 1.82–1.73
(4). To a solution of 3 (100 mg, 0.31 mmol) in ethanol (7 mL) at (m, 2H), 1.63–1.55 (m, 2H), 1.45–1.41 (m, 4H), 1.05 (s, 9H). 13C
0 1C, CaCl2 (103 mg, 0.92 mmol) and sodium borohydride (35 mg, NMR (75 MHz, CDCl3): d = 166.6 (Cq), 160.3 (Cq), 135.5 (CH), 134.0
0.92 mmol) were added gradually. The mixture was stirred 4 h and (Cq), 129.5 (CH), 127.6 (CH), 105.6 (CH), 68.1 (CH2), 64.4 (CH2),
then water (5 mL) was added. Ethanol was evaporated and the 63.7 (CH2), 32.3 (CH2), 28.8 (Cq), 26.8 (CH3), 25.6 (CH2), 25.5
aqueous phase brought to pH 7 with 1 N HCl, and was then (CH2), 19.2 (CH2). MS (ESI+): m/z, 494.3 [M + H]+ (100%).
extracted with dichloromethane (3 ꢁ 10 mL). The organic layer was
(4-((6-((tert-Butyldiphenylsilyl)oxy)hexyl)oxy)pyridine-2,6-diyl)-
dried over anhydrous MgSO4 and the filtrate was concentrated bis(methylene)bis(4-methylbenzenesulfonate) (8). A mixture of 7
under reduced pressure to afford 4 as a white solid (67 mg, 80%). (80 mg, 0.16 mmol), potassium iodide (11 mg, 66 mmol) and
1H NMR (300 MHz, CDCl3): d = 6.70 (s, 2H), 4.69 (s, 4H), 4.57 silver oxide (113 mg, 0.49 mmol) in anhydrous dichloromethane
(s, 2H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 166.8 (Cq), (3.5 mL) was stirred at ꢀ20 1C under argon atmosphere.
165.5 (Cq), 160.5 (Cq), 105.4 (CH), 83.1 (Cq), 65.1 (CH2), 64.4 (CH2), p-Toluenesulfonyl chloride (62 mg, 0.32 mmol) was then added
28.0 (CH3).
and the mixture was stirred overnight at room temperature
tert-Butyl 2-((2,6-bis(bromomethyl)pyridine-4-yl)oxy)acetate under argon atmosphere. After Celite filtration and washing with
(5). To a solution of 4 (723 mg, 2.69 mmol) and PPh3 (1.833 g, dichloromethane, the filtrate was concentrated under reduced
6.99 mmol) in dry CH2Cl2 (30 mL) at 0 1C under argon atmo- pressure and purified by column chromatography (Al2O3, AcOEt/
sphere, NBS (1.244 g, 6.991 mmol) was added gradually (in petroleum ether, 10/90) to afford 8 as a colorless oil (110 mg,
1
4 times) and the mixture was stirred for 90 minutes at room 87%). H NMR (300 MHz, CDCl3): d = 7.85–7.82 (m, 4H), 7.70–
temperature. The mixture was concentrated to dryness. The pale 7.66 (m, 4H), 7.46–7.26 (m, 10H), 6.79 (s, 2H), 4.97 (s, 4H), 3.93
yellow solid obtained (4.17 g) was purified by column chromato- (t, J = 6.4 Hz, 2H), 3.69 (t, J = 6.3 Hz, 2H), 2.43 (s, 6H), 1.79–1.71
graphy (SiO2, CH2Cl2) to afford 5 as a white solid (775 mg, 73%). (m, 2H), 1.63–1.56 (m, 2H), 1.45–1.40 (m, 4H), 1.05 (s, 9H).
1H NMR (300 MHz, CDCl3): d = 6.87 (s, 2H), 4.58 (s, 2H), 4.46 13C NMR (75 MHz, CDCl3): d = 166.8 (Cq), 155.0 (Cq), 145.1
(s, 4H), 1.49 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 166.6 (Cq), (Cq), 135.5 (CH), 134.0 (Cq), 132.7 (Cq), 129.9 (CH), 129.5 (CH),
165.7 (Cq), 158.3 (Cq), 109.3 (CH), 83.3 (Cq), 65.3 (CH2), 33.4 (CH2), 128.0 (CH), 127.6 (CH), 107.6 (CH), 71.2 (CH2), 68.4 (CH2), 63.7
28.1 (CH3).
(CH2), 32.4 (CH2), 28.8 (Cq), 26.9 (CH3), 25.6 (CH2), 25.5 (CH2),
Diethyl 4-((6-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)pyridine- 21.6 (CH3), 19.2 (CH2).
2,6-dicarboxylate (6). A solution of 2b (500 mg, 2.09 mmol) in
Compound 9. The mixture of 1 (289 mg, 0.646 mmol) and
anhydrous THF (48 mL) was placed under argon atmosphere. sodium carbonate (690 mg, 6.46 mmol) in anhydrous aceto-
HO(CH2)6OSiPh2tBu (1.53g, 4.31 mmol) dissolved in THF nitrile (300 mL) was refluxed for 90 minutes under argon
(12 mL) and triphenylphosphine (1.13 g, 4.31 mmol) were atmosphere. A solution of 5 (256 mg, 0.646 mmol) in anhydrous
added and the mixture was stirred until a homogeneous acetonitrile (30 mL) was added and the mixture was stirred and
solution was obtained. DIAD (0.82 mL, 4.18 mmol) was added heated to reflux 16 h under argon atmosphere. After filtration,
drop by drop and the mixture was heated to reflux and stirred the filtrate was concentrated under reduced pressure and
overnight under argon atmosphere. After concentration under purified by column chromatography (Al2O2, CH2Cl2/MeOH,
reduced pressure, the residue was purified by column chroma- 100/0 then 98/2). The first recovered fraction was a mixture of
tography (SiO2, petroleum ether/AcOEt, 80/20) to afford 6 as a the macrocycle in its free form and its sodium salt form
colorless oil (1.12 g, 93%). 1H NMR (300 MHz, CDCl3): d = 7.76 (sodium adduct) while in the second recovered fraction, only
(s, 2H), 7.69–7.65 (m, 4H), 7.44–7.34 (m, 6H), 4.47 (q, J = 7.2 Hz, the sodium adduct was obtained. However, subsequent treat-
4H), 4.10 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 1.86–1.77 (m, ment of both fractions by a saturated aqueous solution of EDTA
J = 6.5 Hz, 2H), 1.62–1.55 (m, 2H), 1.45 (m, 10H), 1.04 (s, 9H). to remove sodium species afforded 9 as a yellow oil (285 mg,
13C NMR (75 MHz, CDCl3): d = 167.0 (Cq), 164.7 (Cq), 150.1 (Cq), 65%). Sodium adduct: 1H NMR (300 MHz, CDCl3): d = 6.61
135.5 (CH), 134.0 (Cq), 129.5 (CH), 127.5 (CH), 114.3 (CH), 68.9 (s, 2H), 4.57 (s, 2H), 4.02 (d, JAB = 15 Hz, 2H), 3.61 (d, JAB
(CH2), 63.7 (CH2), 62.3 (CH2), 32.3 (CH2), 28.7 (Cq), 26.8 (CH3), 15 Hz, 2H), 3.48 (d, JAB = 17.5 Hz, 2H), 3.38 (d, JAB = 17.5 Hz,
25.5 (CH2), 25.4 (CH2), 19.2 (CH2), 14.2 (CH3). 2H), 3.05 (s, 2H), 2.60–2.40 (m, 4H), 2.20–1.80 (m, 2H), 1.84–2.04
=
(4-((6-((tert-Butyldiphenylsilyl)oxy)hexyl)oxy)pyridine-2,6- (m, 2H), 1.46 (s, 9H), 1.44 (s, 18 H), 1.42 (s, 9H).13C NMR
diyl)dimethanol (7). To a solution of 6 (760 mg, 1.31 mmol) (75 MHz, CDCl3): d = 172.8 (Cq), 172.4 (Cq), 166.8 (Cq), 165.6
in ethanol (95 mL) at 0 1C, CaCl2 (440 mg, 3.95 mmol) and (Cq), 160.0 (Cq), 107.7 (CH), 82.9 (Cq), 82.1 (Cq), 82.1 (Cq), 65.2
sodium borohydride (150 mg, 3.95 mmol) were added gradually. (CH2), 62.1 (CH2), 59.2 (CH2), 55.7 (CH2), 53.8 (CH2), 52.9
The mixture was stirred 4 h and then water (30 mL) was added. (CH2), 28.1 (CH3), 27.9 (CH3), 27.8 (CH3). Free form: 1H NMR
New J. Chem.
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