The Journal of Organic Chemistry
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78.0, 96.8, 110.2, 126.8, 130.2, 130.9, 133.0, 159.9, 194.3. Anal. Calcd for
C27H34O7: C, 68.92; H, 7.28. Found: C, 68.81; H, 7.32.
light brown solid, mp 174−175 °C. 1H NMR (500 MHz, CDCl3): δ 4.03
(6H, s, 2 × OCH3), 7.12 (2H, d, J = 8.7 Hz, 5,5′-H), 8.06 (2H, dd, J =
8.7, 2.3 Hz, 6,6′-H), 8.18 (2H, d, J = 2.3 Hz, 2,2′-H), 10.46 (2H, s, 2 ×
CHO). 13C NMR (125 MHz, CDCl3): δ 56.4, 112.2, 124.4, 130.3, 131.1,
137.5, 164.8, 189.0, 193.1. Anal. Calcd for C17H14O5: C, 68.45; H, 4.73.
Found: C, 68.52; H, 4.67.
3,3′-Bis(5,5-dimethyl-1,3-dioxan-2-yl)-2,2′-dimethoxyben-
zophenone (14c). Acetal 13c (9.50 g, 31.5 mmol), 2.5 M n-
butyllithium (12.6 mL, 31.7 mmol), and ethyl N,N-dimethylcarbamate
(2.00 g, 17.0 mmol) were reacted under the previous conditions.
Recrystallization from ethanol gave the ketone (4.43 g, 9.41 mmol, 60%)
as a white powder, mp 135−136 °C. 1H NMR (500 MHz, CDCl3): δ
0.79 (6H, s), 1.38 (6H, s), 3.62 (4H, d, 11.2 Hz), 3.63 (6H, s), 3.74 (4H,
d, J = 11.2 Hz), 5.35 (2H, s), 6.90 (2H, d, J = 8.2 Hz), 7.61−7.64 (4H,
m). 13C NMR (125 MHz, CDCl3): δ 22.1, 23.3, 30.4, 56.0, 77.9, 101.5,
111.6, 129.0, 129.9, 130.5, 131.0, 159.0, 194.5. Anal. Calcd for
C27H34O7: C, 68.92; H, 7.28. Found: C, 68.87; H, 7.40.
6,6′-Dimethoxybenzophenone-3,3′-dicarbaldehyde (9c).
Using the foregoing procedure, 14c (1.00 g, 2.1 mmol) was deprotected
in formic acid (15 mL). Recrystallization from ethanol−water gave the
dialdehyde (0.58 g, 1.9 mmol, 92%) as a light brown solid, mp 150−152
°C. 1H NMR (500 MHz, CDCl3): δ 3.74 (6H, s, 2 × OCH3), 7.05 (2H,
d, J = 8.6 Hz, 5,5′-H), 8.04 (2H, dd, J = 8.6, 2.2 Hz, 4,4′-H), 8.08 (2H, d, J
= 2.2 Hz, 2,2′-H), 9.94 (2H, s, 2 × CHO). 13C NMR (125 MHz,
CDCl3): δ 56.3, 111.8, 129.9, 130.3, 133.1, 134.4, 163.0, 190.4, 192.7.
Anal. Calcd for C17H14O3: C, 68.45; H, 4.73. Found: C, 68.30; H, 4.78.
2,2′,4,4′-Tetramethoxybenzophenone (16). In a 250 mL three-
neck round-bottom flask fitted with a thermometer, a pressure-equalized
addition funnel, and a septum, 2.5 M n-butyllithium (18.2 mL, 45.8
mmol) was added to diethyl ether (70 mL) at −78 °C and the mixture
stirred for 15 min. A solution of 1-bromo-2,4-dimethoxybenzene (9.95
g, 45.8 mmol) in diethyl ether (80 mL) was then added dropwise while
maintaining the reaction temperature below −70 °C. Ethyl N,N-
dimethylcarbamate (2.80 g, 23.9 mmol) in diethyl ether (40 mL) was
added to the solution, maintaining the temperature below −65 °C, and
the resulting mixture was stirred at −78 °C for 15 min and then
subsequently stirred at −20 °C for 1 h. Saturated ammonium chloride
solution (35 mL) was added to quench the reaction, and the resulting
inorganic precipitate was removed by suction filtration. The organic
phase was separated and the aqueous solution extracted with ether. The
combined organic solutions were washed with water and dried over
sodium sulfate. The solvent was evaporated under reduced pressure, and
the residue was recrystallized from ethanol to give the tetramethox-
ybenzophenone (4.33 g, 14.3 mmol, 63%) as a white solid, mp 138−140
°C (lit.21 mp 138−142 °C). 1H NMR (500 MHz, CDCl3): δ 3.66 (6H,
s), 3.85 (6H, s), 6.42 (2H, d, J = 2.3 Hz) 6.50 (2H, dd, J = 8.5, 2.3 Hz),
7.50 (2H, d, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3): δ 55.6, 55.9,
98.7, 104.6, 124.1, 132.7, 160.3, 163.6, 193.1.
3,3′-Bis(1,3-dioxolan-2-yl)-2,2′,4,4′-tetramethoxybenzophe-
none (12). p-Toluenesulfonic acid (25 mg) was added to a solution of
ethylene glycol (4 mL, 4.44 g, 71.5 mmol) and 5-bromo-2,4-
dimethoxybenzaldehyde (6.10 g, 24.9 mmol) in benzene (50 mL),
and the resulting mixture was heated under reflux overnight using a
Dean−Stark apparatus to azeotropically remove water. The solution was
cooled to room temperature and then washed consecutively with water,
saturated aqueous sodium bicarbonate solution, and water. The aqueous
layers were back-extracted with ether, and the combined organic layers
were dried over sodium sulfate. The solvent was evaporated under
reduced pressure to yield acetal 11 (6.84 g, 23.6 mmol, 95%) as a pale
yellow oil. 1H NMR (500 MHz, CDCl3): δ 3.75 (3H, s), 3.78 (3H, s),
3.85−3.93 (2H, m), 3.96−4.05 (2H, m), 5.96 (1H, s), 6.35 (1H, s), 7.58
(1H, s). 13C NMR (125 MHz, CDCl3): δ 56.0, 56.3, 65.2, 96.4, 98.6,
101.9, 119.7, 128.4, 157.3, 158.3. HRMS (EI): calcd for C11H12BrO4
286.9919, found 286.9927. The acetal is very unstable and was used
immediately in the next step. A solution of the acetal (6.94 g, 24.0 mmol)
in diethyl ether (50 mL) was added dropwise over a 15 min period to a
stirred solution of 2.5 M n-butyllithium (11.5 mL, 28.9 mmol) in diethyl
ether (30 mL), maintaining the temperature below −50 °C. The
solution was stirred for 15 min before a solution of ethyl N,N-
dimethylcarbamate (1.22 g, 10.4 mmol) in diethyl ether (10 mL) was
added dropwise over a period of 10 min. The resulting mixture was
stirred at −50 °C for 15 min and then at −20 °C for 1 h. The reaction
was quenched by the addition of saturated aqueous ammonium chloride
solution (30 mL), the layers were separated, and the aqueous phase was
extracted with ether. The combined organic layers were washed with
water and dried over sodium sulfate and the solvent evaporated under
reduced pressure. The residue was recrystallized from ethanol to yield
the protected dialdehyde (1.52 g, 3.4 mmol, 28%) as a white solid, mp
224−225 °C. 1H NMR (500 MHz, CDCl3): δ 3.69 (6H, s), 3.92 (6H, s),
3.97−4.02 (4H, m), 4.05−4.10 (4H, m), 6.10 (2H, s), 6.41 (2H, s), 7.70
(2H, s). 13C NMR (125 MHz, CDCl3): δ 56.0, 56.2, 65.4, 95.2, 99.5,
118.3, 123.0, 130.6, 161.1, 161.5, 192.5. HRMS (EI): calcd for C23H26O9
446.1577, found 446.1577.
Benzophenone-3,3′-dicarbaldehyde (9d). Diacetal 14d (14.00
g, 34.1 mmol) was dissolved in formic acid (150 mL) and stirred under
reflux overnight. The resulting solution was taken up in 600 mL of ether
and washed with water (200 mL × 3), followed by saturated sodium
bicarbonate solution (200 mL). The organic layer was dried over sodium
sulfate and filtered and the solvent evaporated under reduced pressure.
The residue was recrystallized from 3:1 ethanol−water to give the
dialdehyde (6.73 g, 28.2 mmol, 83%) as a light brown solid, mp 116−
117 °C. 1H NMR (500 MHz, CDCl3): δ 7.72 (2H, t, J = 7.7 Hz, 5,5′-H),
8.09 (2H, dt, J = 7.7, 1.5 Hz, 6,6′-H), 8.16 (2H, dt, J = 7.6, 1.4 Hz, 4,4′-
H), 8.28 (2H, t, J = 1.6 Hz, 2,2′-H), 10.11 (2H, s, 2 × CHO). 13C NMR
(125 MHz, CDCl3): δ 129.8, 131.2, 133.6, 135.5, 136.8, 138.0, 191.4,
194.5. Anal. Calcd for C15H10O3: C, 75.62; H, 4.23. Found: C, 75.51; H,
4.08.
4,4′,6,6′-Tetramethoxybenzophenone-3,3′-dicarbaldehyde
(9a). Phosphorus oxychloride (5 mL, 8.2 g, 53.5 mmol) was added
dropwise to DMF (4 mL, 3.80 g, 51.9 mmol) in a 25 mL round-bottom
flask, while maintaining the temperature of the mixture below 10 °C. A
solution of 2,2′,4,4′-tetramethoxybenzophenone (1.00 g, 3.3 mmol) in
DMF (14 mL) was added dropwise to the stirred mixture over a period
of 10 min. The resulting mixture was heated at 95 °C for 3 h and then
poured into 100 mL of ice−water and neutralized with triethylamine.
The resulting precipitate was filtered and washed well with hot ethanol
to yield the dialdehyde (0.99 g, 2.8 mmol, 84%) as a brown solid, mp
1
264−265 °C. H NMR (500 MHz, DMSO-d6): δ 3.77 (6H, s, 6,6′-
OCH3), 4.03 (6H, s, 4,4′-OCH3), 6.78 (2H, s, 5,5′-H), 7.79 (1H, s, 2,2′-
H), 10.19 (1H, s, 2 × CHO). 13C NMR (125 MHz, DMSO-d6): δ 57.0,
57.1, 96.5, 117.8, 123.1, 131.2, 165.2, 166.1, 187.6, 190.5. Anal. Calcd for
C19H18O7: C, 63.68; H, 5.06. Found: C, 63.31; H, 5.02.
15,19-Diethyl-2,10-dimethoxy-14,20-dimethyl-6-oxo-adj-di-
benziphlorin (7b). In a 250 mL pear-shaped flask, dipyrrylmethane-
dicarboxylic acid 18 (123 mg, 0.39 mmol) was dissolved in TFA (5 mL)
under nitrogen. The resulting solution was diluted with dichloro-
methane (185 mL), and dialdehyde 9b (100 mg, 0.33 mmol) was added
immediately. The resulting mixture was stirred under nitrogen at room
temperature overnight. The solvent was then evaporated under reduced
pressure and the residue dissolved in chloroform (15 mL). The solution
was diluted with hexanes (200 mL) and placed in the refrigerator
overnight. The resulting precipitate was suction-filtered and vacuum-
dried to give the oxophlorin analogue TFA salt (165 mg, 0.27 mmol,
82%) as a red-purple powder, mp >300 °C. UV−vis (1% Et3N−CHCl3):
λmax (log ε) 492 (4.03), 567 nm (3.86). UV−vis (1% TFA−CHCl3):
4,4′-Dimethoxybenzophenone-3,3′-dicarbaldehyde (9b).
14b (5.05 g, 10.7 mmol) was dissolved in formic acid (55 mL) and
stirred under reflux overnight. The resulting solution was taken up in
300 mL of chloroform and washed with water (150 mL × 3), followed by
saturated sodium bicarbonate solution (150 mL). The organic layer was
dried over sodium sulfate and filtered and the solvent evaporated under
reduced pressure. The residue was recrystallized from 3:1 ethanol−
water to give the benzophenone dialdehyde (2.67 g, 9.0 mmol, 84%) as a
1
λmax (log ε) 550 (4.11), 631 nm (4.08). H NMR (500 MHz, Et3N−
CDCl3): δ 1.13 (6H, t), 2.12 (6H, s), 2.44 (4H, q, J = 7.6 Hz), 3.92 (6H,
s), 5.29 (1H, s), 6.50 (2H, s), 7.03 (2H, d, J = 8.7 Hz), 7.97 (2H, dd, J =
8.7, 2.2 Hz), 8.55 (2H, d, J = 2.2 Hz), 10.90 (1H, br s). 1H NMR (500
MHz, CDCl3): δ 1.14 (6H, t, J = 7.6 Hz, 2 × CH2CH3), 2.22 (6H, s,
G
dx.doi.org/10.1021/jo401756q | J. Org. Chem. XXXX, XXX, XXX−XXX