3640 J . Org. Chem., Vol. 62, No. 11, 1997
Groesbeek and Smith
6H). 13C NMR: δ 191.3; 144.8; 138.4; 136.2; 125.8; 46.9; 40.0;
34.1; 33.9; 28.8; 21.7; 18.8. Anal. Calcd for C13H19OCl: C,
68.86; H, 8.45. Found: C, 68.70; H, 8.39.
Vinylic fluorides in retinal at positions C8, C10, C12,
and C14 have previously been prepared through the use
of fluorophosphonate.14,15 A few methods have been
reported for the synthesis of (trifluoromethyl)retinals. We
have described here a novel route to the monofluoro-
methyl methyl group that is compatible with our carbon-
13 labeling schemes.16,17 These procedures are easily
expanded to various other carotenoids and polyenes and
complement recently published elegant work on fluori-
nated methyl groups.18 The number of fluorine-contain-
ing starting materials commercially available is still
extremely limited, and although the synthesis of com-
pounds containing both carbon-13 and fluorine-19 labels
in the same molecule is primarily of interest for NMR
studies, the methods developed may lead to new orga-
nofluorides with application in biochemical and medicinal
chemistry, where the demand for fluorinated analogs is
high.
3-(Ch lor om eth yl)-5-(2,6,6-tr im eth ylcycloh exen yl)-2,4-
p en ta d ien en itr ile (3). (Diethylphosphono)acetonitrile (0.55
g, 3.1 mmol) was dissolved in THF (40 mL), and BuLi (3.0
mmol) was added at -60 °C. The mixture was stirred for 10
min; then 2 (0.6 g, 2.6 mmol) was added at -60 °C and the
mixture was stirred for 15 min. Water was added, and the
product was isolated and purified, yielding 0.41 g (63%) of the
corresponding chloro nitrile as a mixture of isomers. 1H
NMR: trans, δ 6.76 (d, J ) 16.3 Hz, 1H), 6.62 (d, J ) 16.4 Hz,
1H), 5.49 (s, 1H), 4.34 (d, J ) 0.7 Hz, 2H), 2.08 (m, 2H), 1.79
(s, 3H), 1.64 (m, 2H), 1.49 (m, 2H), 1.08 (s, 6H); 9-cis, 6.89 (d,
J ) 16.4 Hz, 1H), 6.08 (d, J ) 16.3 Hz, 1H), 5.33 (s, 1H), 4.48
(s, 2H), 2.07 (m, 2H), 1.75 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H),
1.07 (s, 6H). Anal. Calcd for C15H20ClN: C, 72.13; H, 8.07;
N, 5.61. Found: C, 72.31; H, 8.19; N, 5.45.
3-(H yd r oxym et h yl)-5-(2,6,6-t r im et h ylcycloh exen yl)-
2,4-p en ta d ien en itr ile (4). To a solution of chloro nitrile (0.41
g, 1.6 mmol) in 50 mL of acetone were added a solution of
sodium acetate (1.0 g, 12 mmol) and NaI (0.5 g, 3.4 mmol) in
10 mL of water. After 12 h of reflux, the mixture was
concentrated and the product was isolated and purified,
yielding 0.38 g (85%) as a mixture of isomers. 1H NMR: δ
6.62 (s, 1H); 5.39 (br s, 1H), 4.93 (d, J ) 1.4 Hz, 2H), 2.16 (s,
3H), 2.06 (m, 2H), 1.77 (s, 3H), 1.62 (m, 2H), 1.48 (m, 2H),
Exp er im en ta l Section
THF was distilled prior to use from LiAlH4, and diethyl
ether, petroleum ether (bp 35-60 °C), and n-hexane from P2O5.
Other chemicals (reagent grade) were used without purifica-
tion. N-Methoxy-N-methyl-3-(2,6,6-trimethylcyclohexenyl)pro-
penoic acid amide (1), N,5-dimethyl-N-methoxy-7-(2,6,6-
trimethylcyclohexenyl)heptenoic acid amide (7), and (2-chloro-
2,1,1-trifluoroetyl)diethylamine19 were prepared according to
published methods. DIBALH was used as a 1.0 M solution in
hexanes, n-butyllithium (BuLi) as a 1.6 M solution in hexanes,
and methyllithium (MeLi) as a 1.4 M solution in diethyl ether.
These solutions were introduced into the reaction mixture
dropwise via a syringe. Reactions were carried out under a
nitrogen atmosphere.
After completion of the reaction (according to TLC), the
products were isolated as follows. First, unless stated other-
wise, water was added to the reaction mixture. The layers
were separated, and the aqueous phase was extracted three
times with diethyl ether. The combined organic layers were
washed with brine and dried with MgSO4. The solids were
filtered off over a glass-fritted funnel. The residue was rinsed
with diethyl ether. The solvents in the filtrate were evapo-
rated in vacuo (20 mmHg). Unless stated otherwise, purifica-
tion was performed by column SiO2 chromatography (60-200
mesh), using petroleum ether/diethyl ether mixtures as eluent.
Proton and proton-decoupled carbon NMR spectra were run
in CDCl3 with tetramethylsilane (δ ) 0 ppm) as an internal
standard at 500 and 125 MHz, respectively. Fluorine NMR
spectra were recorded at 461 MHz, with CCl3F (δ ) 0 ppm) as
an internal standard. UV/vis spectra were run in methanol.
FT-IR absorbance spectra were run on pure material dried
down on a germanium crystal. The HRMS were recorded
using EI at 70 eV. HPLC was performed using straight phase
isocratic elution with diethyl ether/petroleum ether mixtures
and detection of the absorbance at 360 nm.
1.05 (s, 6H). IR: 2214, 1749, 1607, 1456 cm-1
.
The acetate (0.38 g, 1.4 mmol) was dissolved in methanol
(30 mL). At 0 °C 200 mg of KOH in water (1 mL) was added
and the mixture was stirred at 0 °C for 10 min. Then acetic
acid (2 mL) was added, and the mixture was concentrated in
vacuo. Water was added, and the product was extracted with
CH2Cl2. The organic layer was washed (brine) and dried
(MgSO4), and the solvents were evaporated, yielding 0.28 g
(87%) of 4. 1H NMR: δ 6.59 (d, J ) 16.6 Hz, 1H), 6.54 (d, J )
16.7 Hz, 1H), 5.56 (s, 1H), 4.52 (d, J ) 3.3 Hz, 2H), 2.77 (s,
1H), 2.05 (t, J ) 6.2 Hz, 2H), 1.76 (s, 3H), 1.62 (m, 2H), 1.49
(m, 2H), 1.04 (s, 6H). 13C NMR: δ 159.1; 136.6; 134.7; 133.3;
127.1; 117.4; 92.5; 61.0; 39.3; 34.0; 33.1; 28.8; 21.6; 18.9. IR:
2212 cm-1. Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N,
6.05. Found: C, 78.03; H, 9.34; N, 5.98.
3-(F lu or om eth yl)-5-(2,6,6-tr im eth ylcycloh exen yl)-2,4-
p en ta d ien en itr ile (5). Alcohol 4 (0.28 g, 1.2 mmol) was
dissolved in methylene chloride, and DAST (2.5 mmol) was
added dropwise at -60 °C. The mixture was allowed to warm
to room temperature and stirred for 30 min at -20 °C. After
workup, a 78% yield (0.22 g) was obtained. 1H NMR: δ 6.58
(dd, J ) 16.3 Hz, 2.4 Hz, 1H), 6.48 (d, J ) 16.5 Hz, 1H), 5.42
(s, 1H), 5.24 (d, J ) 46.0 Hz, 2H), 2.05 (m, 2H), 1.75 (s, 3H),
1.63 (m, 2H), 1.46 (m, 2H), 1.03 (s, 6H). 13C NMR: δ 153.8 (d,
J ) 14.0 Hz); 136.5; 135.7; 134.0; 116.4; 126.1; 93.7 (d, J )
16.6 Hz); 80.8 (d, J ) 176.0 Hz); 39.4; 34.0; 33.2; 28.8; 21.7;
18.9. 19F NMR: δ -224.1 (t, J ) 48.8 Hz). IR: 2210 cm-1
.
Anal. Calcd for C15H20FN: C, 77.22; H, 8.64; N, 6.00. Found:
C, 77.18; H, 8.79; N, 5.76.
7-(F lu or om eth yl)-3-m eth yl-9-(2,6,6-tr im eth ylcycloh ex-
en yl)-2,4,6,8-n on a tetr a en a l (6). Nitrile 5 (0.22 g, 0.94 mmol)
was dissolved in hexanes, and DIBALH (2 mmol) was added
at -60 °C. The mixture was stirred for 10 min; then a slurry
of 2 g of SiO2 and 0.5 g of water was added. The mixture was
allowed to warm to room temperature, MgSO4 was added, and
the solids were filtered off over Celite. After evaporation of
the solvents, a 0.2 g (90%) yield was obtained. 1H NMR: δ
10.18 (dd, J ) 1.3 Hz, 7.6 Hz, 1H), 6.88 (d, J ) 16.5 Hz, 1H),
6.52 (d, J ) 16.5 Hz, 1H), 6.09 (d, J ) 7.6 Hz, 1H), 5.23 (d, J
) 46.7 Hz, 2H), 2.06 (t, J ) 6.1 Hz, 2H), 1.76 (s, 3H), 1.63 (m,
2H), 1.49 (m, 2H), 1.05 (s, 6H). 13C NMR: δ 190.2; 151.6;
137.1; 136.9; 133.4; 124.3 (d, J ) 10.8 Hz); 123.9; 81.8 (d, J )
175.9 Hz); 39.4; 34.1; 33.2; 28.9; 21.8; 18.9. 19F NMR: δ -220.8
1-Ch lor o-4-(2,6,6-tr im eth ylcycloh exen yl)-3-bu ten on e (2).
To a stirred solution of chloroiodomethane (1.1 g, 6.5 mmol)
and 1 (1.0 g, 4.2 mmol) in 30 mL of THF was added MeLi (4.2
mmol) at -78 °C. The solution was stirred for 15 min at -78
°C. Then water was added, and the product was isolated and
purified, yielding 0.60 g (91%). 1H NMR: δ 7.51 (d, J ) 16.5
Hz, 1H), 6.38 (d, J ) 16.3 Hz, 1H), 4.22 (s, 2H), 2.10 (t, J )
6.2 Hz, 2H), 1.81 (s, 3H), 1.63 (m, 2H), 1.51 (m, 2H), 1.09 (s,
(14) Machleidt, H.; Hartmann, V.; Bunger, H. Liebigs Ann. Chem.
1963, 667, 35.
(15) Liu, R. S. H.; Matsumoto, H. Methods Enzymol. 1982, 81, 694.
(16) Groesbeek, M.; Rood, G. A.; Lugtenburg, J . Rec. Trav. Chim.
Pays-Bas 1992, 111, 149.
(17) Groesbeek, M.; Lugtenburg, J . Photochem. Photobiol. 1992, 56,
903.
(18) Dolence, J . M.; Poulter, C. D. Tetrahedron 1996, 52, 119.
(19) van der Steen, R.; Groesbeek, M.; van Amsterdam, L. J .P.;
Lugtenburg, J .; van Oostrum, J .; de Grip, W. J . Rec. Trav. Chim. Pays-
Bas 1989, 108, 20.
(t, J ) 46.4 Hz). IR: 1671 cm-1
.
Triethyl 3-methyl-4-phosphonocrotonate (0.26 g, 1 mmol)
was dissolved in THF, and LDA (0.95 mmol) was added. The
fluoro aldehyde (0.2 g, 0.85 mmol) was added at -40 °C, and
the mixture was stirred at 0 °C for 20 min. After workup and