9-Demethyl-9-halo-retinals by WadsworthϪEmmons Coupling
FULL PAPER
using 6 (436 mg, 1.98 mmol), lithium bromide (343 mg, 3.96 mmol)
and acetic acid (15 mL). The desired product was obtained
(519 mg, 93%) as a 1:3 mixture of E/Z isomers.
133.4 (C-10), 137.9 (C-12), 138.1 (C-5), 138.2 (C-6), 138.6 (C-7),
156.7 (C-13), 193.4 (C-15) ppm.
(9Z,11Z)-9-Bromo-9-demethylretinal [(9Z,11Z)-3]: The general pro-
cedure was repeated as described for the preparation of (9Z,11Z)-
1 using 4-(diphenoxyphosphoryl)-3-methyl-2-butenenitrile (122 mg,
0.39 mmol), sodium hydride (15 mg, 0.37 mmol) in THF (10 mL)
and (all-E)-9 (111 mg, 0.39 mmol). This procedure gave a 9:1 mix-
ture of (9Z,11Z)- and (9Z)-retinonitrile isomers, giving, after DI-
BAL-H reduction (0.93 mL, 1.0 in hexane) of the pure (9Z,11Z)
nitrile, pure (9Z,11Z)-retinal (122 mg, 97%).
1
(2Z)-9: H NMR (300.1 MHz, CDCl3): δ ϭ 1.08 (s, 6 H, 2 ϫ 6Ј-
CH3), 1.50 (m, 2 H, 5Ј-H), 1.63 (m, 2 H, 4Ј-H), 1.77 (s, 3 H, 2Ј-
CH3), 2.09 (m, 2 H, 3Ј-H), 6.28 (d, 3J4-H,5-H ϭ 15.1 Hz, 1 H, 4-H),
3
6.34 (d, J2-H,1-H ϭ 6.9 Hz, 1 H, 2-H), 7.22 (d, 3J5-H,4-H ϭ 15.1 Hz,
3
1 H, 5-H), 10.08 (d, J1-H,2-H ϭ 6.9 Hz, 1 H, 1-H) ppm. 13C NMR
(75.5 MHz, 1H-noise-decoupled, CDCl3): δ ϭ 18.9 (C-4Ј), 21.7 (2Ј-
CH3), 28.8 (C-2 and 6Ј-CH3), 33.5 (C-3Ј), 34.2 (C-6Ј), 39.6 (C-5Ј),
127.4 (C-2), 129.8 (C-4), 135.6 (C-2Ј), 136.4 (C-1Ј), 141.4 (C-5),
143.1(C-3), 193.6 (C-1) ppm.
1
(9Z,11Z)-3: H NMR (300.1 MHz, CD3OD): δ ϭ 1.04 (s, 6 H, 16-
H and 17-H), 1.50 (m, 2 H, 2-H), 1.62 (m, 2 H, 3-H), 1.73 (s, 3 H,
18-H), 2.06 (m, 2 H, 4-H), 2.36 (s, 3 H, 20-H), 5.98 (d,
(all-E)-9: 1H NMR (300.1 MHz, CDCl3): δ ϭ 1.09 (s, 6 H, 2 ϫ 6Ј-
CH3), 1.49 (m, 2 H, 5Ј-H), 1.64 (m, 2 H, 4Ј-H), 1.80 (s, 3 H, 2Ј-
3
3J14-H,15-H ϭ 8.0 Hz, 1 H, 14-H), 6.20 (d, J12-H,11-H ϭ 11.4 Hz, 1
3
3
CH3), 2.01 (m, 2 H, 3Ј-H), 6.51 (d, J2-H,1-H ϭ 6.7 Hz, 1 H, 2-H),
H, 12-H), 6.25 (d, J8-H,7-H ϭ 15.2 Hz, 1 H, 8-H), 6.72 (d,
3
3
3J7-H,8-H ϭ 15.2 Hz, 1 H, 7-H), 6.76 (dd, J11-H,10-H ϭ 11.4,
7.05 (s, 1 H, 4-H), 7.05 (s, 1 H, 5-H), 9.93 (d, J1-H,2-H ϭ 6.7 Hz, 1
1
H, 1-H) ppm. 13C NMR (75.5 MHz, H-noise-decoupled, CDCl3):
3
3J11-H,12-H ϭ 11.4 Hz, 1 H, 11-H), 7.01 (d, J10-H,11-H ϭ 11.4 Hz, 1
3
H, 10-H), 10.03 (d, J15-H,14-H ϭ 8.0 Hz, 1 H, 15-H) ppm. 13C
δ ϭ 18.9 (C-4Ј), 21.8 (2Ј-CH3), 28.9 (C-2 and 6Ј-CH3), 33.6 (C-3Ј),
34.2 (C-6Ј), 39.6 (C-5Ј), 124.8 (C-2), 130.3 (C-4), 136.0 (C-2Ј), 136.6
(C-1Ј), 144.2 (C-5), 146.9 (C-3), 186.9 (C-1) ppm.
NMR (5.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ 17.8 (C-20),
20.2 (C-3), 22.0 (C-18), 29.4 (C-16 and C-17), 34.2 (C-4), 35.3 (C-
1), 40.7 (C-2), 40.7 (C-2), 132.3 (C-14), 132.6 (C-9), 133.0 (C-11),
133.1 (C-8), 135.1 (C-12), 137.0 (C-7), 138.0 (C-5), 138.1 (C-6),
157.8 (C-13), 193.4 (C-15) ppm.
(9Z)-9-Bromo-9-demethylretinal [(9Z)-3]: The general procedure
was repeated as described for the preparation of (9Z)-1 now
using 4-(diethoxyphosphoryl)-3-methyl-2-butenenitrile (109.7 mg,
0.503 mmol), LDA prepared from diisopropylamine (49.9 mg,
0.493 mmol) and n-butyllithium (302 µL, 1.6 in hexane), (all-E)-
9 (145 mg, 0.513 mmol) and DIBAL-H (1.2 mL, 1.0 in hexane).
This procedure gave a total yield of 160 mg (95%) of the desired
product of (9Z)-3 isomer.
3-Iodo-5-(2Ј,6Ј,6Ј-trimethyl-1Ј-cyclohexen-1Ј-yl)penta-2,4-dien-1-al
[(all-E)-10 and (2Z)-10]: The general procedure was repeated as de-
scribed for the preparation of (all-E)-8 and (2Z)-8. 6 (262 mg,
1.19 mmol) was added to a solution of lithium iodide (319 mg,
2.38 mmol) in acetic acid (10 mL) to yield 369 mg (94%) of the
desired product as a 1:3 mixture of E/Z isomers.
(9Z)-3: 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.05 (s, 6 H, 16-H
1
and 17-H), 1.51 (m, 2 H, 2-H), 1.64 (m, 2 H, 3-H), 1.73 (s, 3 H,
(2Z)-10: H NMR (300.1 MHz, CDCl3): δ ϭ 1.08 (s, 6 H, 2 ϫ 6Ј-
3
18-H), 2.07 (m, 2 H, 4-H), 2.36 (s, 3 H, 20-H), 6.00 (d, J14-H,15-
CH3), 1.50 (m, 2 H, 5Ј-H), 1.63 (m, 2 H, 4Ј-H), 1.77 (s, 3 H, 2Ј-
3
CH3), 2.08 (m, 2 H, 3Ј-H), 5.96 (d, 3J4-H,5-H ϭ 14.9 Hz, 1 H, 4-H),
ϭ 8.1 Hz, 1 H, 14-H), 6.26 (d, J8-H,7-H ϭ 15.1 Hz, 1 H, 8-H),
H
3
3
3
6.31 (d, J2-H,1-H ϭ 6.6 Hz, 1 H, 2-H), 7.11 (d, 3J5-H,4-H ϭ 14.9 Hz,
6.66 (d, J12-H,11-H ϭ 15.3 Hz, 1 H, 12-H), 6.74 (d, J10-H,11-H
ϭ
3
3
1 H, 5-H), 9.86 (d, J1-H,2-H ϭ 6.6 Hz, 1 H, 1-H) ppm. 13C NMR
10.4 Hz, 1 H, 10-H), 6.77 (d, J7-H,8-H ϭ 15.1 Hz, 1 H, 7-H), 7.28
(dd, 3J11-H,10-H ϭ 10.4, 3J11-H,12-H ϭ 15.3 Hz, 1 H, 11-H), 10.09 (d,
(75.5 MHz, 1H-noise-decoupled, CDCl3): δ ϭ 18.9 (C-4Ј), 21.8 (C-
CH3Ϫ2Ј), 28.9 (C-2 and 6Ј-CH3), 33.5 (C-3Ј), 34.3 (C-6Ј), 39.7 (C-
5Ј), 131.6 (C-2), 132.7 (C-4), 135.6 (C-2Ј), 136.4 (C-1Ј), 145.4 (C-
5), 147.9 (C-2), 197.6 (C-1) ppm.
3J15-H,14-H ϭ 8.1 Hz, 1 H, 15-H) ppm. 13C NMR (75.5 MHz, H-
1
noise-decoupled, CD3OD): δ ϭ 13.0 (C-20), 20.2 (C-3), 22.0 (C-
18), 29.4 (C16 and C17), 34.2 (C-4), 35.3 (C-1), 40.8 (C-2), 131.3
(C-10), 131.7 (C-14), 133.3 (C-9), 135.1 (C-11), 136.7 (C-7), 137.1
(C-8), 138.0 (C-5), 138.1 (C-6), 139.0 (C-12), 156.6 (C-13), 193.5
(C-15) ppm.
1
(all-E)-10: H NMR (300.1 MHz, CDCl3): δ ϭ 1.08 (s, 6 H, 2 ϫ
6Ј-CH3), 1.48 (m, 2 H, 5Ј-H), 1.61 (m, 2 H, 4Ј-H), 1.79 (s, 3 H, 2Ј-
CH3), 2.09 (m, 2 H, 3Ј-H), 6.59 (d, 3J4-H,5-H ϭ 15.0 Hz, 1 H, 4-H),
3
6.83 (d, J5-H,4-H ϭ 15.0 Hz, 1 H, 5-H), 6.87 (d, 3J2-H,1-H ϭ 6.6 Hz,
(all-E)-9-Bromo-9-demethylretinal [(all-E)-3]: The general pro-
cedure was repeated as described for the preparation of (9Z)-1
using 4-(diethoxyphosphoryl)-3-methyl-2-butenenitrile (67 mg,
0.31 mmol), LDA prepared from diisopropylamine (30.3 mg,
0.30 mmol) and n-butyllithium (181 µL, 1.6 in hexane), (all-E)-9
(93.3 mg, 0.33 mmol) and DIBAL-H (0.73 mL, 1.0 in hexane).
This procedure gave a total yield of 93 mg (92%) of the desired
product of (all-E)-3 isomer.
3
1 H, 2-H), 9.88 (d, J1-H,2-H ϭ 6.6 Hz, 1 H, 1-H) ppm. 13C NMR
(75.5 MHz, 1H-noise-decoupled, CDCl3): δ ϭ 18.9 (C-4Ј), 21.9 (C-
CH3Ϫ2Ј), 28.9 (C-2 and 6Ј-CH3), 33.6 (C-3Ј), 34.3 (C-6Ј), 39.7 (C-
5Ј), 127.7 (C-2), 128.3 (C-3), 136.1 (C-2Ј), 136.6 (C-1Ј), 138.7 (C-
4), 148.0 (C-5), 186.2 (C-1) ppm.
(9Z)-9-Demethyl-9-iodoretinal [(9Z)-4]: The general procedure was
repeated as described for the preparation of (9Z)-1 using 4-(di-
ethoxyphosphoryl)-3-methyl-2-butenenitrile (166 mg, 0.503 mmol),
LDA prepared from diisopropylamine (50 mg, 0.493 mmol) and n-
1
(all-E)-3: H NMR (300.1 MHz, CD3OD): δ ϭ 1.06 (s, 6 H, 16-H
and 17-H), 1.50 (m, 2 H, 2-H), 1.65 (m, 2 H, 3-H), 1.77 (s, 3 H,
18-H), 2.07 (m, 2 H, 4-H), 2.33 (s, 3 H, 20-H), 6.00 (d,
butyllithium (302 µL, 1.6
in hexane), (2Z)-10 (169 mg,
3
3J14-H,15-H ϭ 8.1 Hz, 1 H, 14-H), 6.50 (d, J12-H,11-H ϭ 15.0 Hz, 1
0.513 mmol) and DIBAL-H (1.2 mL, 1.0 in hexane). This pro-
cedure gave a total yield of 182 mg (96%) of the desired product of
(9Z)-4 isomer.
3
H, 12-H), 6.65 (d, J8-H,7-H ϭ 15.1 Hz, 1 H, 8-H), 6.72 (d,
3
3J7-H,8-H ϭ 15.1 Hz, 1 H, 7-H), 6.76 (d, J10-H,11-H ϭ 11.5 Hz, 1 H,
3
3
10-H), 7.19 (dd, J11-H,10-H ϭ 11.7, J11-H,12-H ϭ 15.0 Hz, 1 H, 11-
H), 10.06 (d, J15-H,14-H ϭ 8.1 Hz, 1 H, 15-H) ppm. 13C NMR (9Z)-4: 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.04 (s, 6 H, 16-H
(75.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ 13.1 (C-20), 20.2
and 17-H), 1.50 (m, 2 H, 2-H), 1.66 (m, 2 H, 3-H), 1.76 (s, 3 H,
(C-3), 22.1 (C-18), 29.4 (C-16 and C-17), 34.2 (C-4), 34.1 (C-1), 18-H), 2.06 (m, 2 H, 4-H), 2.36 (s, 3 H, 20-H), 5.92 (d, J8-H,7-H
3
3
ϭ
3
40.6 (C-2), 127.3 (C-8), 129.7 (C-9), 131.1 (C-11), 131.2 (C-14),
15.0 Hz, 1 H, 8-H), 5.99 (d, J14-H,15-H ϭ 8.0 Hz, 1 H, 14-H), 6.65
Eur. J. Org. Chem. 2004, 2166Ϫ2175
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2173