Synthesis of the Vaulted Biaryl Ligand Vanol
75 MHz): d=108.41, 118.73, 121.39, 123.47, 125.34, 126.86, 127.20, 127.37,
127.99, 128.75, 134.85, 138.73, 140.67, 151.47 ppm; m/z (% rel intensity),
220 [m]+ (100), 191.0 (45), 189.0 (30), 165.0 (23), 95 (23), 55 (21), 43 (25).
hexane/ethyl acetate (6:1) to give 0.5288 g (2.40 mmol, 51%) of 11 as
white flakes. The spectral data matched those presented above for 11.
Preparation of 4-Chloro-1-Naphthol 17 via Chlorination of
1-Naphthol 16
Synthesis of Ethyl-3-Hydroxy-3,4-Diphenylbutanoate 34 by the
Reformatsky Reaction
A solution of freshly sublimed 1-naphthol 16 (120 g, 832.3 mmol) in
900 mL 1,2-dichloroethane (DCE) was added to a 2 L 3-necked round-
bottomed flask that was warmed gently with a heat gun to dissolve the
solid. The flask was equipped with a 48ꢂ18 mm oval magnetic stirrer
bar, a pressure compensating addition funnel and the other two necks
were sealed with glass stoppers. The top of the addition funnel was
vented to a bubbler and then into a beaker filled with aqueous NaOH to
trap acidic gases (HCl and SO2). The flask and its contents were cooled
to 08C and SO2Cl2 (90.0 mL, 149.9 g, 97%, 1076.9 mmol) was added over
3.5 h from the addition funnel as the reaction mixture was stirred. After
addition, the mixture was stirred for an additional 0.5 h at 08C, and then
the ice-water bath was removed and the mixture was warmed to room
temperature over 2.5 h. Upon completion of the reaction, the contents of
the flask were purged for 30 min with N2 introduced through a glass tube
below the surface of the solution to remove excess gasses prior to
workup. The solvent was removed on a rotary evaporator and the crude
product was crystallized from a minimum amount of boiling DCE (about
200 mL). After allowing the hot solution to slowly cool to room tempera-
ture, filtration gave 83.62 g (468.1 mmol, 56.2%) of 4-chloro-1-naphthol
17 as light silver–green needle-like crystals (m.p. 118–119.58C, lit[20a] 120–
1218C). The filtrate was poured into 500 mL of hexanes and additional
product (20.00 g, m.p. 113.0–114.08C) could be isolated after cooling to
À208C and filtration. This material was recrystallized from a minimum
amount of boiling DCE (about 30 mL) to give 13.75 g (76.98 mmol,
9.2%, m.p. 117.1–118.18C) of 17 as needle-like crystals that had essential-
ly the same coloration as the first crop. The combined yield of 17 for the
first two crops is 65.4%.
Activation of Zinc: Zinc dust (10 g, 40 mesh) was stirred with 2% aq.
HCl (100 mL) at 258C for 15 min. After filtration, the Zn was washed
with 100 mL of 2% aq. HCl, followed by 100 mL water, 100 mL ethanol
and then three times with 100 mL of diethyl ether. The Zn dust was
dried under high vacuum (1 mmHg) overnight.
A flame-dried 50 mL 3-necked flask was charged with a stirrer bar and
fitted with a condenser. To the flask was then added 2.50 g activated Zn
(38.5 mmol), deoxybenzoin 36 (0.9873 g, 5.037 mmol), and 3 small I2 crys-
tals. Then the system was flushed with N2 gas, followed by the addition of
10 mL of a mixture of benzene and diethyl ether (1:1) as solvent. A solu-
tion of ethyl-a-bromoacetate 35 (2.50 mL, 22.5 mmol) in 2.5 mL benzene
was slowly added to the flask by syringe pump over 75 min under mild
reflux. The reaction mixture was then refluxed for 4.5 h. The Zn was re-
moved by filtration and washed with diethyl ether (3ꢂ50 mL). The or-
ganic layer was combined with 50 mL 2m HCl and after separation, the
aqueous layer was extracted with diethyl ether (3ꢂ25 mL), dried with
MgSO4 and filtered. The workup and purification procedure were the
same as the original procedures. The diethyl ether was removed by
rotary evaporation and the residue was dissolved in minimum of CH2Cl2
and loaded onto a silica gel column, which was eluted with a mixture of
ethyl acetate and hexane (1: 10) to give 1.3810 g (4.86 mmol, 97%) of the
b-hydroxy ester 34 as a white solid.
Spectral data for 34: wax-like white solid; m.p. 58.5–60.08C (lit[37] 57–
88C); Rf =0.36 (1:5 EtOAc/hexane); 1H NMR (CDCl3, 300 MHz): d=
1.05 (t, 3H, J=6.9 Hz), 2.82 (d, 1H, J=15.9), 2.95–3.09 (m, 3H), 3.95 (q,
2H, J=7.2 Hz), 4.20 (s, br, 1H); 6.97–7.34 ppm (m, 10H); 13C NMR
(CDCl3, 75 MHz): d=13.57, 43.32, 49.60, 60.37, 74.94, 124.91, 126.20,
126.62, 127.44, 127.68, 130.48, 136.01, 145.09, 172.50 ppm. Anal calcd for
C18H20O3: C 76.03, H 7.09. Found: C 75.91, H 6.99.
Additional product can be obtained by column chromatography on silica
gel. The combined filtrates from the first two crops were dried of solvent
and the residue (about 50 g) was dissolved in 200 mL CH2Cl2 and then
combined with 80 g (about 200 mL) of dry silica gel in a single-necked
flask. The solvent was removed from the silica gel by purging with a ni-
trogen stream that was vented to a bubbler. A chromatography column
(6 cm diameter) was prepared by filling the column with a 1:50 mixture
of ethyl acetate and hexanes and then the addition of silica gel, such that,
after settling, a depth of ca. 35 cm had been reached. The dried silica gel
with the pre-adsorbed product was added to the solvent above the pre-
pared bed and allowed to settle. The solvent level was lowered to the top
of the gel and then a layer of sand was applied. The silica gel column was
first eluted with a 50:1 mixture of hexanes/ethyl acetate under gravity for
at least 1 h, then switched to 10:1 mixture of hexanes/ethyl acetate under
nitrogen pressure. The byproducts (56 and 57) were first eluted, followed
by 17 (11.37 g, 63.65 mmol, 7.6%, m.p. 116.8–117.88C). The combined
yield of 4-chloro-1-naphthol 17 is 108.7 g (608.7 mmol, 73.0%).
Synthesis of b-Hydroxy acid 33 by the Hydrolysis of 34
The b-hydroxy ester 34 (2.52 g, 8.80 mmol) was refluxed with aqueous
KOH (5.6 g, 100 mmol in 75 mL water) and MeOH (20 mL) in a 250 mL
flask for 2 h. After cooling to room temperature, the reaction mixture
was washed with 50 mL hexane and then acidified with 6 m HCl until the
pH was ca. 0. The resulting mixture was extracted with diethyl ether (3ꢂ
50 mL). The diethyl ether layer was dried over MgSO4 and the solvent
was subsequently removed to give 2.06 g (8.0 mmol, 92% yield) of the b-
hydroxy acid 33 as a white solid. Spectral data for 33: wax-like white
solid; m.p. 118–119.58C (lit[37] 1208C); Rf =0.11 (1:5 EtOAc/hexane);
1H NMR (CDCl3, 300 MHz): d=2.90 (dd, 2H, J=16.5, 75 Hz), 2.93–3.09
(m, 3H), 6.95 (s, 1H), 7.06–7.50 ppm (m, 9H); 13C NMR (CDCl3,
75 MHz): d=43.04, 49.54, 74.88, 124.78, 126.39, 126.88, 127.56, 127.87,
130.41, 135.53, 144.53, 177.42 ppm.
Spectral data for 17: needle-like gray solid; m.p. 119–120.58C (lit[21a] 120–
18C); Rf =0.41 (1:3 EtOAc/hexane); 1H NMR (CDCl3, 300 MHz): d=
5.10 (br s, 1H), 6.71 (d, 1H, J=9.0 Hz), 7.36 (d, 1H, J=9 Hz), 7.51–7.63
(m, 2H), 8.20 ppm (d, 2H, J=9 Hz); 13C NMR (CDCl3, 75 MHz): d=
108.04, 121.95, 123.25, 124.16, 125.30, 125.54, 125.76, 127.44, 131.28,
150.45 ppm.
Synthesis of 3-Phenyl-1-Naphthol 11 via Cyclization of Acid Chloride 37
with SnCl4
Preparation of the acid chloride of 37. The acid 33 1.20 g (4.70 mmol)
was refluxed for 3 h with 5 mL (58.2 mmol) oxalyl chloride in 40 mL dry
benzene. Excess oxalyl chloride and benzene were removed under re-
duced pressure and the residue flushed three times with dry benzene,
then exposed to high vacuum for 1 h. The residue was used directly with-
out further purification. The crude acid chloride 37 was dissolved in
40 mL benzene under argon and cooled to 08C. Anhydrous SnCl4
(2.5 mL, 21.8 mmol) was injected into the stirred solution, which turned
red immediately. The reaction mixture was stirred at 08C for 3 h before
quenching with an ice-cold solution of 5 mL of concentrated HCl in
50 mL water and the resulting solution refluxed for 30 min. After extrac-
tion of the aqueous layer with diethyl ether (3ꢂ30 mL), the combined or-
ganic layer was dried over MgSO4, filtered and the solvent removed
under vacuum. The residue was dissolved in a minimum amount of
CH2Cl2 and loaded onto a silica gel column, which was eluted with
Chlorination of 1-Naphthol 16 and the Determination of the Side-
Products
A mixture of freshly sublimed 1-naphthol 16 (3.60 g, 25.0 mmol) and
20 mL 1,2-dichloroethane was gently heated in a 100 mL flask equipped
with a stirrer bar under a nitrogen atmosphere until 16 was dissolved.
The resulting solution was then cooled to 08C for 30 min. Crystals
formed at this temperature. A solution of SO2Cl2 (2.5 mL, 29.9 mmol) in
5 mL DCE was slowly added to the solution by a syringe pump over a
period of 3 h. The ice-water bath was then removed and the reaction mix-
ture was stirred for 30 min. To the reaction mixture was added 100 mL
hexanes and the solvents were removed under vacuum. The 1H NMR
spectrum of the residue revealed the presence of 4-chloro-1-naphthol 17,
Chem. Asian J. 2011, 6, 2130 – 2146
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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