8
250 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
resulting alcohol was quite volatile and resisted isolation
in good yields; nonetheless, the crude alcohol could be
directly treated with butyryl chloride to provide ester 5
in 51% overall yield from alcohol 2. This route to 5 is
much better than the only other published route, which
uses an ene reaction to produce 13 as a mixture of
isomers.15 Similarly, use of a MOM-protected ω-bromo
alcohol gave compound 14, which was readily (TBSCl,
imidazole, DMF, 94%) converted to compound 6, a
compound previously prepared by a much more lengthy
route (six steps, 39% overall yield compared to three
steps, 68% overall yield using the present procedure).16
Gen er a l P r oced u r e for Meta la tion a n d Alk yla tion of 2.
Meth od A. A three-necked flask equipped with a mechanical
stirrer was charged with TMEDA (4 mL, 26 mmol) and Et
15 mL). The solution was cooled to 0 °C, n-BuLi (1.56 M in
2
O
(
hexanes, 13 mL, 20 mmol) was added, and the resulting solution
was stirred at room temperature for 1 h. The solution was then
cooled (0 °C), and alcohol 2 (1.0 mL, 10 mmol) was added slowly.
The resulting solution was stirred at room temperature for 6 h
to generate the desired dianion as a heterogeneous brown
suspension. This slurry was cooled to -78 °C and the appropriate
electrophile (5 mmol) in ether (3 mL) was added slowly. The
reaction was then allowed to warm to room temperature slowly
overnight and stirred at room temperature for 3 h (halides) or
6 h (sulfonates). The reaction was quenched with 20 mL of sat.
We also observe a much higher yield of 3 compared to
NH
extracted with ether (3 × 30 mL), and the organic layers were
combined, dried (MgSO ), and concentrated in vacuo to give the
crude product. The product was purified by column chromatog-
raphy (10-20% ethyl acetate/hexanes)
Meth od B. This method was used with volatile halides and
is the same as method A except that a slight excess of n-BuLi
(14 mL of 1.56 M solution in hexanes, 22 mmol) was used and
12 mmol of electrophile was added.
7-Meth yl-3-m eth ylen e-7-octen -1-yl P r op a n oa te (1). Al-
cohol 9 (3.08 g, 20 mmol) was treated with propionic anhydride
4
Cl and the layers were separated. The aqueous layer was
reactions carried out in hexanes (28-33%).13
4
To prepare alcohol 9, the alcohol required for prepara-
tion of pheromone 1, a homoallylic halide was required
as the coupling partner (as we had already shown that
sulfonates 8 and 11 give side reactions). Iodide 15 was
chosen as the corresponding bromide is too volatile to
4
b
isolate easily in high yield. Treatment of 2 with Ph
3
P‚
provided iodide 15 in 84% yield; alternatively, tosy-
late 8 could be treated with NaI in acetone to prepare
5 more conveniently and economically on larger scales.4b
1
9
I
2
(5.2 g, 40 mmol) in pyridine (10 mL) at room temperature. The
1
mixture was stirred at ambient temperature for 2 h and then
poured into ice cold 1 M HCl. Standard extractive workup with
Treatment of the dianion of 2 with 15 proceeded smoothly
to give 9 in reasonable yield. It is likely that competing
1
ether provided pheromone 1 (4.13 g, 98%) as a colorless oil. H
E
2
elimination (to form isoprene) is responsible for the
NMR (CDCl
3
, 300 MHz) δ 4.82 (br s, 1H), 4.78 (br s, 1H), 4.71
(
br s, 1H), 4.68 (br s, 1H), 4.18 (t, J ) 7.0 Hz, 2H), 2.34 (m, 4H),
modest yield as all of iodide 15 is consumed in the
reaction and an isomeric alcohol 7, prepared using an
allylic halide, can be isolated in much higher yield
2
.03 (m, 4H), 1.72 (s, 3H), 1.56 (m, 2H), 1.13 (t, J ) 7.5 Hz, 3H);
1
3
C NMR (75 MHz, CDCl
3
) δ 173.8, 145.1, 145.0, 110.9, 109.8,
+
6
2.4, 37.1, 35.4, 34.8, 27.2, 25.3, 22.0, 8.8; MS(EI) m/z 181 (M
(suggesting that volatility is not an issue here; compare
-
29, 0.1), 136 (12), 121 (28), 93 (43), 57 (100).
Table 2, entries 3 and 4). Attempts to suppress elimina-
tion by formation of organocopper reagents20 met with
limited success: treatment of the dianion with 1 equiv
of CuCN or CuI gave reagents that were essentially
unreactive toward iodide 15 while use of 0.5 equiv of CuI
3-Met h ylen e-6-h ep t en -1-ol (3). Method B was used with
allyl bromide (1.2 mL, 13.8 mmol). Care was taken to keep the
rotovap bath below 25 °C to minimize loss of the volatile product.
Purification by flash chromatography (10-20% ethyl acetate/
1
hexanes) afforded 0.62 g (49%) of 3 as a colorless oil whose H
NMR spectrum matched literature13 data: 1H NMR (CDCl
, 300
3
(presumably to form a Gilman reagent) gave a reasonable
MHz) δ 5.78 (ddt, J ) 17.1, 10.3, 6.1 Hz, 1H), 5.01 (ddt, J )
17.1, 1.6, 1.6 Hz, 1H), 4.95 (br d, J ) 10.3 Hz, 1H), 4.86 (br s,
1H), 4.83 (br s, 1H), 3.69 (t, J ) 6.3 Hz, 2H), 2.28 (br t, J ) 6.3
(58%) yield of 9 but with other side products that made
purification difficult. Thus direct alkylation of the di-
lithium salt seems to be the method of choice. Alcohol 9
was readily acylated (propionic anhydride, pyridine, 98%)
to complete a short, simple synthesis of pheromone 1
Hz, 2H), 2.15 (m, 4H); 13C NMR (75 MHz, CDCl
) δ 145.3, 138.1,
3
+
1
1
14.8, 111.9, 60.3, 39.2, 35.0, 31.9; MS(EI) m/z 126 (M , 0.1),
08 (6), 93 (81), 79 (100).
-Meth ylen e-1-d od eca n ol (4).14 This compound was pre-
3
(three steps, 43% overall yield from 2).
pared under a number of different reaction conditions in the
yields shown in Table 1. Method A was followed except that
hexanes (15 mL) was sometimes used as the metalation solvent
and 1-bromooctane was added as a solution in hexanes (3 mL,
entry 1), ether (10 mL, entry 2) or THF (10 mL, entry 3). Where
In summary, metalation of alcohol 2 (n-BuLi, TMEDA,
ether) followed by treatment of the resulting dianion with
alkyl halides is a general route to 3-methylene-1-al-
kanols. Sulfonates may be used but give competing side-
reactions. This chemistry could be used advantageously
for the preparation of compounds such as the San J ose
scale sex pheromone 1.
ether was used as the metalation solvent, 0.97 g (94%) of 4 was
1
isolated as a colorless oil: H NMR (CDCl
3
, 300 MHz) δ 4.84
(
br s, 1H), 4.78 (br s, 1H), 3.68 (t, J ) 6.3 Hz, 2H), 2.27 (br t, J
) 6.3 Hz, 2H), 2.00 (br t, J ) 7.5 Hz, 2H), 1.49 (s, 1H), 1.40 (m,
3
2
H), 1.24 (m, 12H), 0.86 (br t, J ) 7.2 Hz, 3H); 1 C NMR (75
MHz, CDCl ) δ 146.3, 111.2, 60.3, 39.0, 35.8, 31.8, 29.52, 29.47,
3
Exp er im en ta l Section
+
2
8
9.30, 20.27, 27.7, 22.6, 14.0; MS(EI) m/z 198 (M , 0.6), 180 (4),
1 (97), 68 (100).
-Meth ylen eh ex-1-yl Bu ta n oa te (5).15 Method B was fol-
All reactions were carried out under argon using flame-dried
glassware. NMR data were recorded on 200 or 300 MHz
instruments. Ether was distilled from Na/benzophenone while
3
lowed using 1.75 g (16 mmol) of ethyl bromide to give alcohol
1
1
3: H NMR (CDCl
1H), 3.65 (t, J ) 6.5 Hz, 2H), 2.23 (br t, J ) 6.5 Hz, 2H), 2.05
br s, 1H), 1.41 (m, 2H), 0.86 (t, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl ) δ 146.0, 111.3, 60.3, 39.0, 37.9, 20.7, 13.7; MS(EI)
14 (M , 0.5), 96 (14), 81 (100). The crude alcohol was treated
with butyryl chloride (1.33 g, 12.5 mmol) and Et N (2 mL) in
CH Cl to give 0.94 g (51% from 2) of ester 5 as an oil after flash
chromatography (30% CH Cl , 300
in hexanes): 1H NMR (CDCl
3
, 300 MHz) δ 4.79 (br s, 1H), 4.75 (br s,
2
hexanes and TMEDA were distilled from CaH . n-BuLi was
2
1
titrated using N-benzylbenzamide. Tosylate 8 and benzene-
sulfonate 11 (both quantitative) were prepared as described by
(
4
b
3
Weiler; iodide 15 was also prepared by Weiler’s method (60%
+
1
yield in two steps from 2) or by the method noted below. MOM
ether 16 was prepared by standard methods16 from 11-bromo-
3
-undecanol (Aldrich or from 1,11-undecanediol22).
2
2
1
2
2
3
MHz) δ 4.78 (br s, 1H), 4.74 (br s, 1H), 4.15 (t, J ) 7.0 Hz, 2H),
2.30 (t, J ) 7.0 Hz, 2H), 2.25 (t, J ) 7.5 Hz, 2H), 1.99 (br t, J )
(
19) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473-
1
479.
(
(
20) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
21) Burchat, A. F.; Chong, J . M.; Nielsen, N. J . Organomet. Chem.
(22) Chong, J . M.; Heuft, M. A.; Rabbat, P. J . Org. Chem. 2000, 65,
5837-5838.
1
997, 542, 281-283.