References and Notes
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<A NAME="RS10110ST-2">2</A> Among the 22 small molecules marketed
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<A NAME="RS10110ST-10">10</A>
A multikilogram process has been successfully
carried out by us based on this protocol.
<A NAME="RS10110ST-11">11</A>
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.
<A NAME="RS10110ST-12">12</A>
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.
<A NAME="RS10110ST-13">13</A> In the case of NaOt-Bu,
toluene is detected as the major product from reduction of 4-bromotoluene.
Bacon RG.
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<A NAME="RS10110ST-14">14</A>
Cu(II) salts were found slightly less
effective.
<A NAME="RS10110ST-15">15</A>
The presence of other functional groups
such as ester, carboxylic acid, nitro, and cyano were not successful
under this protocol.
<A NAME="RS10110ST-16">16</A>
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.