Synthesis of Monoterpene gem-Difluoro Analogues
,3-Diflu or o-4,4-d im et h ylh ex-5-en -2-on e 2,4-Din it r o-
J . Org. Chem., Vol. 66, No. 12, 2001 4351
3
mL) at 0 °C under argon was added BuLi (25 mL, 2.5 M in
hexane, 62.6 mmol) dropwise. After 45 min, a 9:1 mixture of
ketones 1, 6 (5 g, 30.9 mmol) was added dropwise and the
mixture was stirred for 1 h at 0 °C and 18 h at room
temperature. The reaction was quenched with water and
extracted with diethyl ether (3 × 60 mL). The organic layer
1
4
p h en ylh yd r a zon e (6 DNP H). H NMR δ 1.25 (t, J HF ) 2.2
3
Hz, 6H), 2.11 (s, 3H), 5.14 (d, J HH ) 11.1 Hz, 1H), 5.20 (d,
3
3
3
J
HH ) 17.5 Hz, 1H), 6.05 (dd, J HH ) 17.5 Hz, J HH ) 11.1
3 3
Hz, 1H), 7.93 (d, J HH ) 9.5 Hz, 1H), 8.38 (dd, J HH ) 9.5 Hz,
4
1
4
J HH ) 2.5 Hz 1H), 9.13 (d, J HH ) 2.5 Hz, 1H), 11.09 (s, 1H);
9
F NMR δ -108.0 (s).
4
was washed with brine and dried over MgSO , and the solvent
Syn th esis of Diflu or olin a lool 7. To a solution of a 9:1
was evaporated under reduced pressure. The crude mixture
was purified by silica gel column chromatography (9:1 petro-
leum ether/CH Cl ) to give an inseparable 9:1 mixture of esters
mixture of ketones 1 and 6 (1.35 g, 8.3 mmol) in dry diethyl
ether (15 mL) under argon was added, dropwise, at 0 °C, a
solution of vinylmagnesium bromide (16.7 mL, 1 M in diethyl
ether, 16.7 mmol). After stirring for 6 h at room temperature,
the reaction was quenched with 1 M aqueous HCl and
extracted with diethyl ether (3 × 50 mL). The organic layer
2
2
9 and 10 (4.3 g, 60%) as a colorless liquid.
(
2E)-Eth yl 4,4-Diflu or o-3,7-d im eth ylocta -2,6-d ien oa te
1
3
(
9). H NMR δ 1.30 (t, J HH ) 7.2 Hz, 3H), 1.63 (s, 3H), 1.73
4 3
(
s, 3H), 2.18 (d, J HH ) 1.5 Hz, 3H), 2.67 (td, J HF ) 16.4 Hz,
was washed with brine and dried over MgSO
4
and the solvent
3
3
J
J
HH ) 7.2 Hz, 2H), 4.20 (q, J HH ) 7.2 Hz, 2H) 5.07 (tq,
4
was evaporated under reduced pressure. The crude mixture
was purified by silica gel column chromatography (7:3 petro-
3
HH ) 7.2 Hz, 4
J
HH ) 1.5 Hz, 1H), 6.07 (q, J HH ) 1.5 Hz,
3 13
H); 19F NMR δ -101.7 (t, J HF ) 16.4 Hz); C NMR δ 14.1,
1
leum ether/CH
mg, 6%) and 7 (900 mg, 57%).
()-4,4-Diflu or o-3,7-d im eth ylocta -1,6-d ien -3-ol (7). Col-
2
Cl
2
) to give pure fractions of alcohols 8 (100
2
1
7.9, 21.2, 25.7, 34.9 (t, J CF ) 27.6 Hz), 60.3, 113.9, 118.7 (t,
CF ) 8.8 Hz), 118.9, 121.9 (t, J CF ) 244.1 Hz), 137.3, 165.9;
IR (neat) 2984, 2934, 1726, 1666, 1238 cm ; MS m/z 232 (M ,
), 212 (25), 187 (20), 164 (24), 139 (100). Anal. Calcd for
: C, 62.05, H, 7.81. Found: C, 62.33, H, 7.70.
(2E)-E t h yl 4,4-Diflu or o-3,5,5-t r im et h ylh ep t a -2,6-d i-
3
J
(
-1
+
1
orless liquid. H NMR δ 1.39 (s, 3H) 1.62 (s, 3H), 1.76 (s, 3H),
5
3
2
1
.41 (s, 1H), 2.63 (m, 2H), 5.24-5.27 (m, 2H), 5.47 (d, J HH )
12 18 2 2
C H O F
3
3
7.2 Hz, 1H), 6.02 (dd, J HH ) 17.2 Hz, J HH ) 10.7 Hz, 1H);
1
9
F NMR δ -111.4 (ddd, 2J FF ) 247.0 Hz,
3
J
HF ) 25.8 Hz,
1
3
3J HF ) 10.7 Hz, 1F), -114.7 (ddd, J FF ) 247.0 Hz, J HF ) 27.2
2
3
en oa te (10). H NMR δ 1.16 (s, 6H), 1.30 (t, J HH ) 7.2 Hz,
4 3
3
13
3H), 2.15 (d, J HH ) 1.5 Hz, 3H), 4.20 (q, J HH ) 7.2 Hz, 2H),
3
Hz, J HF ) 11.6 Hz, 1F); C NMR δ 17.8, 21.8, 25.7, 30.5 (t,
5.07 (d, 3
J HH ) 17.5 Hz, 1H), 5.14 (d, J HH ) 11.0 Hz, 1H),
3 3 4
2
2
3
J
CF ) 24.6 Hz), 75.7 (t, J CF ) 27.6 Hz), 114.4 (d, J CF ) 3.9
3
5.94 (dd, J HH ) 17.5 Hz, J HH ) 11.0 Hz, 1H), 5.98 (q, J HH )
Hz), 114.5, 123.8 (t, J CF ) 250 Hz), 136.0, 138.4 (d, J CF ) 3.0
1.5 Hz, 1H); 19F NMR δ -108.4 (s); MS (CI with NH
(M + 18, 6), 213 (12), 195 (100), 167 (26), 151 (32).
-
1
3
) m/z 250
Hz); IR (neat) 3462, 2997, 2936, 1454, 1373, 1064 cm ; MS
+
m/z 190 (M , 2), 172 (12), 152 (36), 150 (42), 137 (48), 135 (56),
Red u ction of 9 a n d 10. To a solution of LAH (196 mg, 5.2
mmol) in dry diethyl ether (2 mL) under argon was added,
dropwise, at room temperature, a solution of a 9:1 mixture of
esters 9 and 10 (1.0 g, 4.3 mmol) in dry diethyl ether (5 mL).
After stirring for 18 h at room temperature, the reaction was
7
1 (100).
()-4,4-Diflu or o-3,5,5-tr im eth ylh ep ta -1,6-d ien -3-ol (8).
(
1
Colorless liquid. H NMR δ 1.21 (s, 3H) 1.23 (s, 3H), 1.35 (s,
3
3
1
H), 2.14 (s, 1H), 5.02-5.18 (m, 3H), 5.38 (d, J HH ) 17.1 Hz,
3
3
H), 6.07 (dd, J HH ) 17.1 Hz, J HH ) 10.6 Hz, 1H), 6.13 (dd,
3
2
3
19
quenched with saturated aqueous NH Cl and extracted with
J
J
HH ) 17.9 Hz, J HH ) 10.5 Hz, 1H); F NMR δ -113.4 (d,
4
2
13
diethyl ether (3 × 50 mL). The organic layer was washed with
FF ) 255.6 Hz, 1F), -115.9 (d, J FF ) 255.6 Hz, 1F); C NMR
3
3
3
δ 22.4 (t, J CF ) 3.9 Hz), 23.4 (t, J CF ) 4.9 Hz), 24.5 (t, J CF
)
4
brine and dried over MgSO , and the solvent was evaporated
2
2
4
.9 Hz), 29.6 (t,
J
CF ) 23.6 Hz), 77.9 (dd,
J
CF ) 29.5 Hz,
under reduced pressure. The crude mixture was purified by
silica gel column chromatography (4:1 petroleum ether/ethyl
acetate) to give an inseparable 9:1 mixture of alcools 11 and
12 (614 mg, 75%) as a colorless liquid. A pure sample of
difluorogeraniol 11 (57 mg) was be obtained after separation
of the mixture (110 mg) by HPLC with a Lichrosorb Si 60 (7
µm) column (99:1 hexanes/2-propanol elution).
2
J
CF ) 27.6 Hz), 112.9, 113.2, 123.4 (t, J CF ) 258 Hz), 140.4
d, 3J CF ) 4.9 Hz), 142.8 (t,
922, 2847, 1454, 1379, 1240 cm ; MS (CI with NH
M + 18, 1), 162 (15), 144 (46), 127 (100).
()-2,2-Diflu or o-1,5-d im et h yl-1-vin ylh ex-4-en yl 3,5-
3
J CF ) 3.9 Hz); IR (neat) 3474,
1
(
2
(
-
3
) m/z 208
(
Din itr oben zoa te (7 DNBz). To a solution of 7 (275 mg, 1.4
mmol) in pyridine (8 mL) was added 3,5-dinitrobenzoyl
chloride (991 mg, 4.3 mmol), and the mixture was refluxed
for 5 h. The reaction mixture was then poured in water (30
mL) and extracted with diethyl ether (4 × 30 mL). The organic
layer was, successively, washed with 1 M aqueous HCl (20
(2E)-4,4-Diflu or o-3,7-dim eth ylocta-2,6-dien -1-ol (11). Col-
1
orless liquid.
H NMR δ 1.63 (s, 3H), 1.73 (s, 6H), 2.47 (s, 1H),
3
3
2.66 (td,
5.10 (tm,
J HF ) 15.7 Hz, J HH ) 7.2 Hz, 2H), 4.36 (m, 2H),
J HH ) 7.2 Hz 1H), 5.93 (tm,
3
3
) 6.1 Hz 1H); 19
F
J
HH
3
) 15.7 Hz); 13C NMR δ 11.7, 17.9, 25.7,
NMR δ -99.6 (t,
J
HF
mL), brine (15 mL), and a saturated NaHCO
20 mL) and dried over MgSO , and the solvent was evaporated
3
aqueous solution
2
3
3
4.8 (t, J CF ) 27.6 Hz), 58.8, 114.7 (t, J CF ) 5.0 Hz), 122.4 (t,
(
4
3
2
J
CF ) 241.1 Hz), 128.2 (t, J CF ) 8.8 Hz), 132.7 (t, J CF ) 25.6
under reduced pressure. The crude mixture was purified by
silica gel column chromatography (9:1 petroleum ether/ethyl
acetate) and recrystallized from petroleum ether to give pure
-1
Hz), 136.4; IR (neat) 3325, 2972, 2920, 2883, 1678, 1450 cm
;
MS m/z 191 (M + 1, 5), 173 (22), 170 (50), 140 (95), 139 (100).
Anal. Calcd for C10
H, 8.64.
2
H16OF : C, 63.14, H, 8.48. Found: C, 63.30,
3
,5-dinitrobenzoate derivative 7 DNBz (108 mg, 20%) as white
1
4
needles: mp 73 °C. H NMR δ 1.57 (s, 3H), 1.78 (d, J HH ) 1.2
(
2E)-4,4-Diflu or o-3,5,5-tr im eth ylh epta-2,6-dien -1-ol (12).
3
Hz, 3H), 1.92 (s, 3H), 2.76 (tm, J HF ) 18.2 Hz, 2H), 5.31 (tm,
1
H NMR δ 1.13 (s, 6H), 1.63 (s, 3H), 1.79 (s, 1H), 4.25 (m, 2H),
3
3
3
J
J
HH ) 7.2 Hz, 1H), 5.46 (d,
J
HH ) 17.5 Hz, 1H), 5.53 (d,
3
5
.02-5.15 (m, 2H), 5.83 (tm, J HH ) 6.1 Hz, 1H), 5.96 (dd,
3 19
3
3
HH ) 11.1 Hz, 1H), 6.04 (dd, J HH ) 17.5 Hz, J HH ) 11.1
3
J
HH ) 17.5 Hz, J HH ) 11.1 Hz, 1H); F NMR δ -107.0 (s);
MS (CI with NH ) m/z 208 (M + 18, 1), 171 (4), 155 (100), 151
64).
4
4
Hz, 1H), 9.12 (d, J HH ) 2.3 Hz, 2H), 9.24 (t, J HH ) 2.3 Hz,
3
1
9
3
13
1
H); F NMR δ -112.3 (t, J HF ) 18.2 Hz); C NMR δ 16.8 (t,
2
(
3
J
J
CF ) 3.9 Hz), 17.9, 25.9, 31.1 (t,
J
CF ) 24.6 Hz), 86.2 (t,
2
3
CF ) 27.5 Hz), 113.3 (t, J CF ) 3.9 Hz), 119.5, 121.8 (t, J CF
)
3
2
1
3
1
51 Hz), 122.5, 129.4, 134.0 (t, J CF ) 2 Hz), 134.3, 137.6, 148.7,
Ack n ow led gm en t. We are grateful to the Ministere
-
1
60.2; IR (neat) 3104, 2932, 1743, 1552, 1344 cm ; MS m/z
de la Recherche for a doctoral fellowship (O. L.), to
BAYER A. G. (Dr A. Marhold) for a generous gift of
TFMTMS, and to D. Saleur, H. Baillia, and S. Lanthony
for their technical assistance.
+
84 (M , 19), 364 (18), 332 (27), 245 (15), 195 (85), 149 (48),
11 (100). Anal. Calcd for C17
18 2 2 6
H F N O : C, 53.13, H, 4.72,
N, 7.29. Found: C, 53.38, H, 4.37, N, 7.16.
Wa d sw or th -Em m on s Olefin a tion . To a solution of tri-
ethyl phosphonoacetate (12.3 mL 60 mmol) in dry THF (70
J O010245+