The Journal of Organic Chemistry
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at 70 °C for 1 h. To this solution was added the appropriate
hydrogen/hydride source at the temperature specified. At regular
intervals, aliquots (∼100 μL) were removed. To this aliquot were
added 1 M HCl and EtOAc. The solution was then shaken and the
organic phase was filtered through SiO2 (10% MeOH/CH2Cl2). The
sample was then analyzed by gas chromatography (GC) using the
conditions outlined in the Supporting Information.
this solution was added CF3CO2H (820 μL, 11 mmol). The reaction
mixture was heated at 70 °C for 24 h. After cooling, the mixture was
diluted with Et2O and washed sequentially with 1 M HCl, saturated
NH4Cl three times, H2O three times, and brine. The organic extracts
were dried over Na2SO4 and concentrated at ambient temperature and
pressure by slow evaporation on the benchtop. The resulting residue
was chromatographed in 20% Et2O/Pentanes to afford 8a (R = H)
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General Procedure for H NMR Reaction Monitoring. To a
(152 mg) in quantitative yield as a pale yellow oil: H NMR (500
solution of 6a (12 mg, 0.066 mmol) in DMSO-d6 (0.75 mL) was
added palladium(II) trifluoroacetate (26 mg, 0.079 mmol). A 1H NMR
spectrum was then taken. The mixture was then warmed to the
indicated temperature and spectra were taken periodically throughout
the course of the reaction. If a hydrogen/hydride source was being
studied the reaction was then cooled to room temperature, a 1H NMR
spectrum was taken, the hydrogen/hydride source was added and the
mixture was heated to the indicated temperature.
MHz, CDCl3) δ 7.19 (t, J = 8.2 Hz, 1H), 6.52 (dd, J = 2.4, 8.2 Hz,
2H), 6.48 (t, J = 2.4 Hz, 1H), 3.80 (s, 6H).
3,5-Dimethoxytoluene (8b).119 General procedure B was
employed with the following alterations: compound 6b (R = Me)
was employed. Compound 8b (R = Me) (134 mg) was isolated in 80%
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yield as a pale yellow oil: H NMR (300 MHz, CDCl3) δ 6.35−6.34
(m, 2H), 6.30−6.29 (m, 1H), 3.78 (s, 6H), 2.31 (s, 3H).
1-Chloro-3,5-dimethoxybenzene (8c).120 General procedure B
was employed with the following alterations: compound 6c (R = Cl)
was employed. Compound 8c (R = Cl) (169 mg) was isolated in 89%
Computational Methods. All calculations were carried out using
B3LYP113−115 functionals using 6-31G(d) basis for main group
elements and SDD for Pd in solvent (dichloromethane) using
CPCM116 solvation model. All stationary points were characterized as
minima or transition state structures using frequency analysis.
1,3,7-Trimethoxynaphthalene (3). General Procedure A. To a
solution of 1 (10 mg, 0.038 mmol) in 5% DMSO−DMF (0.5 mL)
were added palladium(II) trifluoroacetate (14.3 mg, 0.043 mmol) and
Ag2CO3 (10.5 mg, 0.038 mmol). The mixture was then heated to 90
°C for 1 h. After cooling, 1 N HCl was added, and the mixture was
extracted with EtOAc. The organic phase was washed with H2O and
brine, dried over Na2SO4, and concentrated. This material was then
dissolved in THF (1.0 mL) and stirred under a H2 atmosphere for 5
min. After filtration through Celite, the material was chromatographed
in 20% EtOAc/hexanes to afford 3 (8.2 mg) in 99% yield as a brown
amorphous solid: mp 69−71 °C; 1H NMR (500 MHz, CDCl3) δ 7.59
(d, J = 8.9 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.9, 2.6 Hz,
1H), 6.70 (d, J = 2.1 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 3.98 (s, 3H),
3.91 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.6,
156.0, 155.7, 130.2, 128.1, 122.3, 119.5, 100.9, 98.2, 98.1, 55.7, 55.5,
55.4; IR (film) 2988, 2945, 2907, 1737, 1606 cm−1; HRMS (CI) m/z
[M]+ calcd for C13H14O3 218.0943, found 218.0939.
5,5′-Bis(benzyloxy)-2,2′,4,4′,6,6′-hexamethoxy-7,7′-
dipropyl[1,1′]binaphthalene (5). General procedure A was used
with the following alterations: compound 4 was employed and
Ag2CO3 was excluded in the first step. Compound 5 (27 mg) was
obtained in 99% yield as a resin: 1H NMR (500 MHz, CDCl3) δ 7.62
(d, J = 7.0 Hz, 4H), 7.43 (t, J = 7.3 Hz, 4H), 7.37 (t, J = 7.3 Hz, 2H),
6.76 (s, 2H), 6.64 (s, 2H), 5.10 (m, 4H), 3.99 (s, 6H), 3.92 (s, 6H),
3.74 (s, 6H), 2.46−2.53 (m, 4H), 1.35−1.42 (m, 4H), 0.75 (t, J = 7.2
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 157.1, 154.9, 148.8, 147.2,
138.9, 137.0, 133.7, 129.0, 128.5, 127.8, 122.1, 116.5, 112.5, 95.9, 76.2,
61.4, 57.5, 56.1, 32.8, 23.6, 14.0; IR (film) 2933, 1338 cm−1; HRMS
(ESI) m/z [M + Na]+ calcd for C46H50O8Na 753.3403, found
753.3427.
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yield as a pale yellow oil: H NMR (300 MHz, CDCl3) δ 6.53 (m,
2H), 6.36 (m, 1H), 3.78 (s, 6H).
1,3,5-Trimethoxybenzene (8d).121 General procedure B was
employed with the following alterations: compound 6d (R = OMe)
was employed. Compound 8d (R = OMe) (183 mg) was isolated in
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99% yield as a white solid; H NMR (300 MHz, CDCl3) δ 6.10 (s,
3H), 3.77 (s, 9H).
1,3,5-Trimethylbenzene (17).122 General Procedure C. To a
solution of 2,4,6-trimethylbenzoic acid (16) (300 mg, 1.8 mmol) in
MeOH (15 mL) was added potassium tert-butoxide (210 mg, 1.8
mmol). The suspension was stirred at room temperature for 4 h and
then concentrated by rotary evaporation to afford 16a (370 mg) in
quantitative yield and was used without further purification.
To a solution of 16a (100 mg, 0.49 mmol) in DMSO (3.0 mL) was
added palladium(II) trifluoroacetate (200 mg, 0.59 mmol). This
solution was heated to 80 °C for 24 h. Trifluoroacetic acid (370 μL,
4.9 mmol) was added, and the solution was heated at 70 °C overnight.
After cooling, the mixture was diluted with Et2O and washed three
times with saturated NH4Cl, three times with H2O, and once with
brine. The organic extracts were dried over Na2SO4 and concentrated
at ambient temperature and pressure by slow evaporation on the
benchtop. The resultant residue was chromatographed in 50% Et2O/
Pentane to afford 17 (25 mg) in 42% yield as a brown amorphous
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solid: H NMR (500 MHz, CDCl3) δ 6.90 (s, 3H), 2.43 (s, 9H).
1,2,4-Trimethoxybenzene (19).123 General procedure B was
employed with the following alterations: Compound 18 was
employed. Compound 19 (46 mg) was isolated in 25% yield as a
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yellow oil: H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 8.7 Hz, 1H),
6.51 (d, J = 2.8 Hz, 1H), 6.39 (dd, J = 8.7, 2.8 Hz, 1H), 3.85 (s, 3H),
3.83 (s, 3H), 3.76 (s, 3H).
General procedure C was used to form 19 from 18a with the
following alterations: the initial heating time before addition of
trifluoroacetic acid was 30 min. Compound 19 (102 mg) was isolated
in 55% yield as a yellow oil.
4-Chloro-2,6-dimethoxybenzoic Acid (6c). Procedure adapted
from previously reported method to synthesize the ester variant.117
A
1,3,7-Trimethoxy-4-methyl-2-naphthoic Acid (26). To a
solution of methyl 1,3-dihydroxy-7-methoxynaphthalene-2-carboxylate
(200 mg, 0.85 mmol) in 3.9 mL of THF/H2O (1.0:0.3) were added n-
Bu4NBr (28 mg, 0.085 mmol) and KOH (478 mg, 8.4 mmol). To this
solution was added dimethyl sulfate (810 μL, 8.4 mmol), and the
mixture was stirred at room temperature for 4 h. The reagents were
quenched with 30% NH4OH for 30 min. The resultant mixture was
extracted with Et2O and washed three times with 30% NH4OH and
one time with H2O and brine. The organic phase was dried over
Na2SO4 and concentrated. The resulting residue was chromatographed
in 5% EtOAc/hexanes to afford methyl 1,3,7-trimethoxy-4-methyl-2-
naphthoate (31) (48 mg) in 19% yield: mp 38−40 °C; 1H NMR (500
MHz, CDCl3) δ 7.87 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H),
7.22 (dd, J = 9.2, 2.7 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.93 (s, 3H),
3.82 (s, 3H), 2.53 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.5,
157.4, 151.3, 150.1, 130.1, 126.2, 126.1, 121.6, 120.0, 101.3, 62.9, 62.6,
55.5, 52.6, 11.3; IR (film) 2999, 2949, 2872, 2845, 1733, 1602 cm−1;
HRMS (CI) m/z [M]+ calcd for C16H18O5 290.1154, found 290.1156.
solution of 1-chloro-3,5-dimethoxybenzene (8c) (840 μL, 5.8 mmol)
in THF (40 mL) was cooled to −20 °C. To this solution was added n-
butyllithium (2.6 mL, 6.4 mmol). The solution was stirred for 1 h at
−20 °C and quenched with powdered CO2 (29 g, 670 mmol). The
mixture was allowed to warm to room temperature and concentrated
under reduced pressure. The mixture was then diluted with saturated
Na2CO3 and extracted twice with Et2O. The aqueous layer was
acidified with 6 M HCl and extracted twice with CHCl3. The CHCl3
organic extracts were dried with Na2SO4 and concentrated to yield 6c
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in 5% yield (60 mg) as a white powder: mp 179−181 °C; H NMR
(500 MHz, CDCl3) δ 6.60 (s, 2H), 3.86 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 170.1, 158.3, 137.8, 110.4, 105.2, 56.5; IR (film) 3398, 2950,
2873, 2657, 2587, 2541, 1699, 1591, 1460, 1406 cm−1; HRMS (FT-
MS) m/z [M − OH]− calcd for C9H8ClO3 199.0162, found 199.0157.
1,3-Dimethoxybenzene (8a).118 General Procedure B. To a
solution of 6a (R = H) (200 mg, 1.1 mmol) in 5% DMSO−DMF (10
mL) was added palladium(II) trifluoroacetate (73 mg, 0.22 mmol). To
O
dx.doi.org/10.1021/jo400222c | J. Org. Chem. XXXX, XXX, XXX−XXX