References and Notes
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10 A multikilogram process has been successfully
carried out by us based on this protocol.
11 In our original process for the particular
drug candidate, the very expensive 3,4,7,8-tetramethyl-1,10-phenanathroline (20
mol%, MW = 236.3. $63.9/g,
from Aldrich) was used as ligand.
12 For the consideration of less stable
substrate, intead of 110 ˚C as the original literature
reported (ref. 6k), 100 ˚C was chosen for screening
purpose.
13 In the case of NaOt-Bu,
toluene is detected as the major product from reduction of 4-bromotoluene. Bacon RG.
Ressison SC.
J. Chem. Soc. C
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14 Cu(II) salts were found slightly less
effective.
15 The presence of other functional groups
such as ester, carboxylic acid, nitro, and cyano were not successful
under this protocol.
16
General Procedure
for the Etherification of Arylbromides
To a 10 mL
seal tube were charged alcohol (2.0 mL) and LiOt-Bu
(480 mg, 6.0 mmol). The resulting suspension was stirred at r.t.
for 5 min to form a clear solution. Arylbromide (2.0 mmol) and CuI
(38 mg, 0.2 mmol) were added to the above solution. The mixture
was stirred at r.t. for 5 min to form a nearly clear solution which
was sealed and stirred at 80-110 ˚C for
18-28 h. The reaction was cooled to r.t. and quenched with
AcOH (pH = 7-8) and diluted
with CH2Cl2. The mixture was washed with H2O
(2 × 5 mL) and solvent removed. The crude residue was purified
by silica gel column chromatography to give the desired product.
The identity and purity of the products are confirmed by ¹H NMR, ¹³C
NMR, and HRMS spectroscopic analysis.
5-(Pentyloxy)pyrimidin-2-ol
(Table 2, Entry 8)
Off-white solid. ¹H
NMR (400 MHz, CDCl3): δ = 8.04 (s,
2 H), 3.86 (t, J = 8
Hz, 2 H), 1.77 (m, 2 H), 1.40-1.45 (m, 4 H), 0.94 (t, J = 8 Hz,
3 H) ppm. ¹³C NMR (100 MHz, CDCl3):
δ = 157.9,
144.8, 142.2, 70.5, 28.7, 28.0, 22.4, 14.0 ppm. HRMS: m/z
calcd for C9H14N2O2:
182.1055; found: 182.1053.
3-(2-Methoxyethoxy)pyridine
(Table 2, Entry 9)
Colorless oil. ¹H
NMR (400 MHz, CDCl3): δ = 8.35 (s,
1 H), 8.23 (m, 1 H), 7.23 (m, 2 H), 4.17 (t, J = 4
Hz, 2 H), 3.77
(t, J = 4
Hz, 2 H), 3.46 (s, 3 H) ppm. ¹³C NMR
(100 MHz, CDCl3): δ = 155.0, 142.4,
138.0,. 123.8, 121.4, 70.9, 67.7, 59.3 ppm. HRMS: m/z calcd
for C8H11NO2: 153.0790; found:
153.0785.