O.M. Demchuk et al. / Tetrahedron 72 (2016) 6668e6677
6675
in short column and crude 3 was eluted with about 500 mL of
chloroform. After evaporation of the solvent, the product was
refluxed in 70 mL of methyl tert-butyl ether for 60 min, cooling
down to rt, filtered, and dried under reduced pressure (1 mmHg) at
90 ꢀC for 1 h. The product contains traces of naphthoquinone,
whose complete removal is possible by prolonged gently heating
under reduced pressure. Yield: 2.88 g (88%). Mp¼182e183 ꢀC. 1H
product and formed crystalline 4 was filtered and dried under
the reduced pressure. Yield: 21.4 g (82%).
Mp¼109e110 ꢀC. 1H NMR (500.13 MHz, CDCl3):
¼1.17e2.18 (m,
d
22 H, Cy), 3.59 (s, 3H, OCH3), 3.66 (s, 6H, OCH3), 3.86 (s, 3H, OCH3),
4.07 (s, 3H, OCH3), 6.17 (s, 2H, CH), 7.52e7.58 (m, 2H, CH), 8.08 (d,
J¼8.20, 1H, CH), 8.16 (d, J¼8.20, 1H, CH). 31P NMR (202.45 MHz,
CDCl3):
d
¼49.60. 13C NMR (75.52 MHz, CDCl3):
¼26.4e27.3 (CH2-
d
NMR (500.13 MHz, CDCl3):
6.21 (s, 2H, CH), 6.96 (s, 1H, CH), 7.73e7.75 (m, 2H, CH), 8.11e8.14
(m, 2H, CH). 13C NMR (DEPT 135, 125.75 MHz, CDCl3):
¼55.4
d
¼3.74 (s, 6H, OCH3), 3.87 (s, 3H, OCH3),
Cy), 39.5 (CH-Cy), 40.4 (CH-Cy), 55.3 (OCH3), 55.5 (OCH3), 61.5
(OCH3), 62.7 (OCH3), 62.7 (OCH3), 90.3 (CH), 123.9 (CH), 123.9 (CH),
124.0 (CH), 126.0 (CH), 127.4 (CH). IR (neat): vmax/cmꢁ1 3467, 3406,
2924, 2850, 2168, 1611, 1591, 1505, 1467, 1449, 1412, 1341, 1271,
1223,1204,1182,1155,1126,1072,1041, 995, 963, 948, 887, 815, 780,
738, 699, 584, 529. HRMS (ESI): m/z¼567.2881 [C33H43O6PþH]þ, m/
z (theor.)¼567.2870, diff.¼1.94 ppm.
d
(COCH), 55.8 (OCH3)3, 90.8 (CH), 125.9 (CH), 126.8 (CH), 133.2 (CH),
133.4 (CH), 138.7 (CH). IR (neat): vmax/cmꢁ1 3302, 3062, 3002, 2946,
2841, 1655, 1624, 1609, 1590, 1511, 1469, 1437, 1385, 1328, 1296,
1249, 1187, 1152, 1100, 1023, 1000, 925, 903, 869, 796, 772, 745, 716,
671, 565, 522. HRMS (ESI): m/z¼325.1056 [C19H16O5þH]þ, m/z
(theor.)¼325.1071, diff.¼4.61 ppm.
4.4. 2-(Dicyclohexylphosphoryl)-3-(2,4,6-trimethoxyphenyl)-
naphthalene-1,4-diol (I2b)
4.3. MeOSym-PhosO (4)
100 mL round-bottom flask containing magnetic stir bar was
charged with 3 (10 mmol, 3.3 g), dicyclophenylphosphine oxide
(20 mmol, 4.3 g), 80 mL of DMF, and Bi(OTf)3 (0.30 mmol, 200 mg,
3 mol %). The reaction was stirred at 110 ꢀC for 48 h. After that time
the reaction was cooled down to ambient temperature and con-
centrated under the reduced pressure, than an equal volume of
toluene was added. I2b was isolated by filtration as a white solid.
Yield: 4.9 g (91%). Mp¼dec 262e268 ꢀC. 1H NMR (500.13 MHz,
100 mL round-bottom flask containing magnetic stir bar was
charged with 3 (3 mmol, 972 mg), dicyclophenylphosphine oxide
(4.7 mmol, 1 g), 15 mL of THF, and Bi(OTf)3 (0.12 mmol, 80 mg,
4 mol %). The reaction was stirred at 75 ꢀC for 24 h. Next, the
mixture was cooled down to room temperature, and equipped
with U-shape bubbler filled with silicone oil. The reactor was
evacuated and backfilled with argon, then Cs2CO3 (0.9 mmol;
0.3 g), tetrabutylammonium hydrogen sulfate (0.3 mmol, 0.1 g),
and DMF (10 mL) were added. Under the vigorous stirring solid
NaH (60% in Nujol, 17 mmol, 0.7 g) was added to a reactor in
small portion to maintain slow liberation of hydrogen. Excessive
foaming of the reaction mixture may be prevented by gentle
vacuumating and backfilling with argon (via the bubbler). After
the deprotonation is completed (approx. 2 h), the reaction mix-
ture was cooled down to approx. 10 ꢀC and CH3I (16 mmol;
2.28 g; 1 mL) was slowly added. The reaction mixture was stirred
next at room temperature for 24 h. After that, solvents were
evaporated off under the reduced pressure, 50 mL of water was
added and product 4 was extracted with methylene chloride
(3ꢂ15 mL). A combined organic layer was dried over MgSO4,
filtered, and after the evaporation of solvent 4 was purified by
column chromatography in hexane/ethyl acetate/methanol¼5/3/
0.2. Yield: 1.6 g (95%).
The synthesis was scaled up to 46 mmol scale. 500 mL round-
bottom flask containing magnetic stir bar was charged with 3
(46 mmol, 15 g), dicyclophenylphosphine oxide (70 mmol, 15 g),
150 mL of DMF, and Bi(OTf)3 (0.46 mmol, 300 mg, 1 mol %). The
reaction was stirred at 95 ꢀC for 48 h. Next, the mixture was
cooled down to room temperature, and equipped with U-shape
bubbler filled with silicone oil. The reactor was evacuated and
backfilled with argon, then Cs2CO3 (15.4 mmol; 5 g), tetrabuty-
lammonium hydrogen sulfate (3 mmol, 1 g). Under the vigorous
stirring solid NaH (60% in Nujol, 150 mmol, 6 g) was added to
a reactor in small portion to maintain slow liberation of hydro-
gen. Excessive foaming of the reaction mixture may be prevented
by gentle vacuumating and backfilling with argon (via the bub-
bler). After the deprotonation is completed (approx. 3 h), the
reaction mixture was cooled down to approx. 10 ꢀC and CH3I
(370 mmol, 52.4 g, 23 mL) was slowly added. The reaction mix-
ture was stirred next at room temperature for 24 h. After that,
solvents were evaporated off under the reduced pressure, 150 mL
of water was added and product 4 was extracted with methylene
chloride (3ꢂ100 mL). A combined organic layer was dried over
MgSO4, filtered, and after the evaporation of solvent 4 was pu-
rified by column chromatography in hexane/ethyl acetate/
methanol¼5/3/0.2. After the evaporation of solvents from the
collected eluant, diethyl ether (10 mL) was added to a crude
CDCl3):
d¼13.52, (br s,1H, OH), 8.40 (d, J¼8.2,1H, CH), 8.13 (d, J¼9.0,
1H, CH), 7.54 (p, J¼8.4, 2H, CH), 6.30 (s, 2H, CH), 4.58 (s, 1H, OH),
3.93 (s, 3H, CH3), 3.71 (s, 6H, CH3), 1.87e1.47 (m, 18H, Cy), 1.28e0.98
(m, 4H, Cy). 13C NMR (75.53 MHz, CDCl3):
d
¼25.8, 25.8, 26.2, 26.2,
26.5, 26.7, 26.9, 38.0, 38.8, 55.6, 56.0, 76.6, 77.0, 77.4, 91.4, 102.1,
103.3,103.9,110.8,111.0,122.0,123.5,125.7, 126.4,126.6,127.7,141.2,
141.3, 158.6, 160.2, 163.0. 31P NMR (202.45 MHz, CDCl3):
d
¼66.98. IR
(neat): vmax/cmꢁ1 3492, 2986, 2931, 2900, 2858, 2839, 1601, 1575,
1495, 1464, 1401, 1384, 1365, 1335, 1275, 1203, 1179, 1145, 1156,
1122, 1097, 1083, 1063, 1032, 1019, 949, 887, 876, 848, 811, 789, 775,
747, 645, 538. HRMS (ESI): m/z¼539.2579 [C31H39O6PþH]þ, m/z
(theor.)¼539.2557, diff.¼4.08 ppm.
4.5. Sym-Phos (6)
An argonated 10 mL microwave reactor containing magnetic stir
bar was charged with MeO-Sym-PhosO (1 mmol, 567 mg), 4 mL of
CPME, and TMDS (6 mmol, 1 mL) and Ti(OBu)4 (1 mmol, 0.34 mL).
The reactor was closed by snap cap and stirred under microwave
heating at 130 ꢀC for 30 min (note: reaction generate a significant
pressure inside the reactor!). Next, the reaction was cooled down to
ambient temperature, and formed gases were liberated. After that,
the reaction mixture was subjected to microwave heating to
maintain 160 ꢀC for 5 h of stirring. Reaction mixture was then
chilled down to ꢁ10 ꢀC, formed crystalline precipitate was filtered,
and washed with methanol to yield 376 mg (72%) of pure 6. The
filtrate was concentrated under the reduced pressure, mixed with
15 mL of pentane, formed participate was filtered and subjected to
a column chromatography in hexane/acetone¼6/1, this brought an
additional 80 mg (15%) of 6. Mp¼186e188 ꢀC. Solubility in
CH3CNd4 mg/mL, in MeOHdless than
(300.33 MHz, benzene-d6):
1
mg/mL. 1H NMR
¼1.09e1.87 (m, 22H, Cy), 3.66 (s, 6H,
d
OCH3), 3.60 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.22 (s, 2H, CH),
7.48e7.51 (m, 2H, CH), 7.81e7.82 (m, 1 H, CH), 7.89e7.91 (m, 1H,
CH), 8.14e8.16 (m, 1H, CH). 31P NMR (121.57 MHz, benzene-d6):
d
¼ꢁ8.87. 13C NMR (DEPT 135, 125.75 MHz, benzene-d6):
¼27.1e30.5 (CH2-Cy), 34.8 (CH-Cy), 35.1 (CH-Cy), 54.6 (OCH3-Ph),
d
55.0 (OCH3-Ph), 55.2 (OCH3-Ph), 60.9 (OCH3), 90.7 (CH), 123.1 (CH),
126.1 (CH), 128.2 (CH), 128.3 (CH), 128.6 (CH), 128.8 (CH). IR (neat):
vmax/cmꢁ1 3004, 2921, 2845, 1604, 1586, 1502, 1485, 1447, 1408,