The Journal of Organic Chemistry
Article
Upon concentration of chamber 2 in vacuo the crude product was
purified by column chromatography.
2-(2-(2-(p-Tolyloxy)ethoxy)ethoxy)ethanol. To p-cresol (2.2 g,
20 mmol) in DMF (8 mL) was added K2CO3 (5.2 g, 30 mmol), NaI
(0.3 g, 2 mmol), and triethylene glycol monohydrinhydrin (4.1 g, 24
mmol), and the reaction mixture was heated to 95 °C for 18 h. The
reaction mixture was cooled to rt and diluted with EtOAc. The organic
phase was washed twice with water and once with brine, dried over
Na2SO4, and concentrated under vacuum. Flash chromatography using
pentane/EtOAc 1:1 → EtOAc as eluent resulted in 4.1 g (86% yield)
of the title product obtained as a colorless liquid. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.06 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz),
4.11−4.09 (m, 2H), 3.85−3.83 (m, 2H), 3.74−3.60 (m, 8H), 2.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 156.6, 130.1, 129.8 (2C),
114.5 (2C), 72.5, 70.8, 70.4, 69.8, 67.4, 61.7, 20.4; HRMS C13H20O4
[M + Na+]; calculated 263.1259, found 263.1265.
2-(n-Hexyloxy)benzaldehyde (25).34 Flash chromatography
using pentane/EtOAc 30:1 as eluent resulted in 75 mg (72% yield)
of the title product obtained as a colorless liquid. 1H NMR (400 MHz,
CDCl3) δ (ppm) 10.52 (s, 1H), 7.82 (dd, 1H, J = 7.9, 1.9 Hz), 7.52
(dt, 1H, 1.9 Hz, 8.6 Hz), 7.1−6.96 (m, 2H), 4.07 (t, 2H, J = 6.8 Hz),
1.82−1.80 (m, 2H), 1.52−1.45 (m, 2H), 1.39−1.25 (m, 4H), 0.93−
0.88 (m, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 189.9, 161.6,
135.9, 128.2, 124.9, 120.4, 112.5, 68.5, 31.5, 29.0, 25.7, 22.6, 14.0.
HRMS C13H18O2 [M + H+]; calculated 207.1385, found 207.1381.
N-Allyl-4-formylbenzamide (26). Flash chromatography using
pentane/EtOAc 2:1 as eluent resulted in 68 mg (72% yield) of the title
1
product obtained as a colorless solid. H NMR (400 MHz, CDCl3) δ
2-(2-(2-(p-Tolyloxy)ethoxy)ethoxy)ethyl 4-methylbenzene-
sulfonate. To 2-(2-(2-(p-tolyloxy)ethoxy)ethoxy)ethanol (2.4 g, 10
mmol) in CH2Cl2 (8 mL) under cooling were added TsCl (2.3 g, 12
mmol), Et3N (7 mL, 50 mmol) and a catalytic amount of DMAP. The
reaction mixture was maintained at 0 °C for 0.5 h and left at rt for 1 h.
The mixture was then washed twice with water and once with brine,
dried over Na2SO4, and concentrated in vacuum. Flash chromatog-
raphy using pentane/EtOAc 1:1 → EtOAc as eluent resulted in 3.8 g
(ppm) 9.82 (s, 1H), 7.40−7.37 (m, 2H), 6.97 (d, 2H, J = 8.94), 4.34−
4.27 (m, 4H). 13C NMR (100 MHz, CDCl3) δ (ppm) 190.7, 149.2,
143.9, 130.6, 124.2, 118.4, 117.8, 64.7, 64.0. HRMS C11H11NO2 [M +
H+]; calculated 190.0868, found 190.0863.
Isoquinoline-4-carbaldehyde (27).35 Flash chromatography
using pentane/EtOAc 1:1 as eluent resulted in 35 mg (45% yield)
of the title product obtained as a colorless solid. 1H NMR (400 MHz,
CDCl3) δ (ppm) 10.52 (s, 1H), 9.21 (d, 1H, J = 4.3 Hz), 9.02 (dd, 1H,
J = 8.5; 1.5 Hz), 8.22 (d, 1H, J = 8.5 Hz), 7.83 (dt, 1H, J = 7.0; 1.5
Hz), 7.80 (d, 1H, J = 4.3 Hz), 7.74 (dt, 1H, J = 7.0; 1.5 Hz). 13C NMR
(100 MHz, CDCl3) δ (ppm) 192.8, 150.4, 149.2, 136.8, 130.2, 130.0,
129.4, 125.8, 124.4, 123.9. HRMS C10H8NO [M + H+]; calculated
158.0606, found 158.0602.
1
(97% yield) of the title product obtained as a colorless liquid. H
NMR (400 MHz, CDCl3) δ (ppm) 7.79 (d, 2H, J = 8.30 Hz), 7.32 (d,
2H, J = Hz), 7.06 (d, 2H, J = 8.7 Hz), 6.8 (d, 2H, J = 8.7 Hz), 4.17−
4.14 (m, 2H), 4.08−4.06 (m, 2H), 3.81−3.78 (m, 2H), 3.70−3.67 (m,
2H), 3.66−3.64 (m, 2H), 3.61−3.59 (m, 2H), 2.42 (s, 3H), 2.28 (2,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 156.6, 144.8, 133.0,
130.0, 129.84 (2C), 129.79 (2C), 128.0 (2C), 114.5 (2C), 70.77,
70.73, 69.9, 69.4, 68.7, 67.5, 21.6, 20.4.
1-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-4-methylben-
zene.40 To a solution of 2-(2-(2-(p-tolyloxy)ethoxy)ethoxy)ethyl 4-
methylbenzenesulfonate (1.3 g, 3.3 mmol) in THF was added TBAF
(1.0 M in THF, 9 mL). The reaction was heated in a microwave
reactor at 110 °C for 0.5 h. After cooling and concentration in vacuum,
the residue was purified by flash chromatography using pentane/
EtOAc 5:1 as eluent to afford the title compound as a colorless liquid.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.07 (d, 2H, J = 8.6 Hz), 6.81
(d, 2H, J = 8.6 Hz), 4.63−4.61 (m, 1H), 4.51−4.49 (m, 1H), 4.12−
4.10 (m, 2H), 3.86−3.84 (m, 2H), 3.80−3.78 (m, 1H), 3.76−3.70 (m,
5H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 156.6,
130.0, 129.8, 114.5, 83.2 (d, J = 169 Hz), 70.8, 70.5, 70.3, 69.9, 67.5,
20.4. 19F NMR (376 MHz, CDCl3) δ (ppm) 7.79 (tt, J = 29.5, 47.7
Hz); HRMS C13H19FO3 [M + Na+]; calculated 265.1216, found
265.1210.
1-(Bromomethyl)-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-
benzene.40 A mixture of 1-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-4-
methylbenzene (0.72 g, 3.0 mmol), NBS (0.56 g, 3.3 mmol), and
benzoyl peroxide (50 mg) in dry CCl4 was heated to reflux for 4 h and
cooled to rt, and the white precipitate was removed by filtration. The
filtrate was concentrated under vacuum and subjected to flash
chromatography to afford the product (0.72 g, 75%) as a colorless
liquid. Some impurities were still evident and the compound was used
without further purification.
2,3-Dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (28).36
Flash chromatography using pentane/EtOAc 10:1 as eluent resulted
in 65 mg (81% yield) of the title product obtained as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.82 (s, 1H), 7.40−7.37 (m,
2H), 6.97 (d, 2H, J = 8.94), 4.34−4.27 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 190.7, 149.2, 143.9, 130.6, 124.2, 118.4, 117.8, 64.7,
64.0. HRMS C9H8O3 [M + H+]; calculated 165.0552, found 165.0548.
3-Chloro-4-methoxybenzaldehyde (29).37 Flash chromatogra-
phy using pentane/EtOAc 10:1 as eluent resulted in 75 mg (88%
yield) of the title product obtained as a colorless solid. 1H NMR (400
MHz, CDCl3) δ (ppm) 9.83 (s, 1H), 7.88 (d, 1H, J = 1.9 Hz), 7.75
(dd, 1H, J = 8.4, 1.9 Hz), 7.02 (d, 1H, J = 8.4 Hz), 3.97 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 189.7, 159.8, 131.1, 130.6, 130.2,
123.6, 111.7, 56.5. HRMS C8H8ClO2 [M + H+]; calculated 171.0213,
found 171.0208.
4-(n-Decyloxy)-3,5-dimethoxybenzaldehyde (30). Flash chro-
matography using pentane/EtOAc 30:1 as eluent resulted in 110 mg
1
(68% yield) of the title product obtained as a colorless liquid. H
NMR (400 MHz, CDCl3) δ (ppm) 9.84 (s, 1H), 7.10 (s, 2H), 4.05 (t,
2H, J = 6.7 Hz), 3.89 (s, 6H), 1.74 (quin., 2H, J = 7.2 Hz), 1.46−1.39
(m, 2H), 1.34−1.23 (m, 12 H), 0.86 (t, 3 H, J = 7.6 Hz). 13C NMR
(100 MHz, CDCl3) δ (ppm) 191.1, 153.9 (2C), 142.0, 131.5, 106.7
(2C), 73.7, 56.2 (2C), 31.9, 30.1, 29.6, 29.5, 29.4, 29.3, 25.7, 22.7,
14.1. HRMS C19H30O4 [M + H+]; calculated 323.2222, found
323.2218.
4-(Morpholine-4-carbonyl)benzaldehyde (31).38 Flash chro-
matography using EtOAc/pentane 2:1 as eluent resulted in 80 mg
(73% yield) of the title product obtained as a colorless solid. 1H NMR
(400 MHz, CDCl3) δ (ppm) 10.02 (s, 1H), 7.92 (d, 2H, J = 8.3 Hz),
7.54 (d, 2H, J = 8.3 Hz), 3.77−3.37 (m, 8H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 191.4, 168.9, 140.9, 137.0, 129.9 (2C), 127.7 (2C),
66.7 (4C). HRMS C12H14NO3 [M + H+]; calculated 220.0974, found
220.0968.
Diethyl 4-(2-(2-(2-Fluoroethoxy)ethoxy)ethoxy)-
benzylphosphonate (33).40 To a solution of 1-(bromomethyl)-4-
(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzene (0.51 g, 1.6 mmol) in
dry CH2Cl2 were added triethyl phosphite (0.33 g, 2 mmol) and ZnBr2
(0.33 mmol, 74 mg). The reaction mixture was stirred at rt for 18 h,
concentrated in vacuum, and subjected to flash chromatography to
1
afford the product (0.37 g, 61%) as a colorless liquid. H NMR (400
4-n-Butylbenzaldehyde (32).39 Flash chromatography using
pentane/EtOAc 50:1 as eluent resulted in 79 mg (98% yield) of the
title product obtained as a colorless solid. 1H NMR (400 MHz,
CDCl3) δ (ppm) 9.96 (s, 1H), 7.79 (d, 2H, J = 8.3 Hz), 7.33 (d, 2H, J
= 8.3 Hz), 2.68 (t, 2H, J = 7.8 Hz), 1.62 (quin., 2H, J = 7.8 Hz), 1.36
(hex., 2H, J = 7.8 Hz), 0.93 (t, 3H, J = 7.8 Hz). 13C NMR (100 MHz,
CDCl3) δ (ppm) 191.9, 150.4, 134.4, 129.9 (2C), 129.0 (2C), 35.9,
33.2, 22.3, 13.9. HRMS C11H14O [M + H+]; calculated 163.1123,
found 163.1123.
MHz, CDCl3) δ (ppm) 7.19 (d, 2H, J = 9.0 Hz), 6.84 (d, 2H, J = 9.0
Hz), 4.55 (dt, 2H, J = 47.5, 4.6 Hz), 4.10 (t, 2H, J = 4.7 Hz), 4.03−
3.93 (m, 4H), 3.84 (t, 2H, 4.7 Hz), 3.80−3.77 (m, 1H), 3.75−3.68 (m,
5H), 3.06 (d, 2H, J = 21.6 Hz), 1.22 (t, 6H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3) δ (ppm) 157.7 (d, J = 3.5 Hz), 130.7 (d, 2C, J =
6.7 Hz), 123.7 (d, J = 9.3 Hz), 114.7 (d, 2C, J = 3.0 Hz), 83.2 (d, J =
169.4 Hz), 70.8 (d, J = 1.2 Hz), 70.5, 70.3, 69.8, 67.4, 62.0 (d, J = 6.8
Hz), 32.8 (d, 2C, J = 138.8 Hz), 16.4 (d, 2C, J = 6.1 Hz). 19F NMR
(376 MHz, CDCl3) δ (ppm) 7.79 (tt, J = 28.9, 48.0 Hz). 31P NMR
G
dx.doi.org/10.1021/jo400741t | J. Org. Chem. XXXX, XXX, XXX−XXX