New syntheses of 1,7-dimethylnonyl propanoate, the western corn rootworm pheromone, in four different ways via cross metathesis, alkylation and coupling reactionsss

Article abstract of DOI:10.1271/bbb.90805

A mixture of the four stereoisomers of 1,7-dimethylnonyl propanoate, the female sex pheromone of the western corn rootworm (Diabrotica virgifera virgifera LeConte), was synthesized in four different ways by employing one of the following four reactions as the key step: (i) cross metathesis using the Grubbs I catalyst, (ii) cross metathesis using the Grubbs II catalyst, (iii) alkylation of an alkynide anion, and (iv) Grignard coupling in the presence of dilithium tetrachlorocuprate. Although the cross metathesis approaches enabled two short syntheses (4 or 6 steps) of the pheromone to be achieved, the cheapest and most efficient synthesis was possible via Grignard coupling to give the desired pheromone in a 40% overall yield based on 2-methyl-1-butanol (8 steps).

Full text of DOI:10.1271/bbb.90805

Biosci. Biotechnol. Biochem., 74 (3), 595–600, 2010
New Syntheses of 1,7-Dimethylnonyl Propanoate, the Western Corn
Rootworm Pheromone, in Four Different Ways via Cross Metathesis,
*
Alkylation and Coupling Reactions
Kenji MORI
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd.,
4-2-1 Wakahagi, Inba-mura, Inba-gun, Chiba 270-1609, Japan
Received November 2, 2009; Accepted November 20, 2009; Online Publication, March 7, 2010
[doi:10.1271/bbb.90805]
A mixture of the four stereoisomers of 1,7-dimethyl-
nonyl propanoate, the female sex pheromone of the
western corn rootworm (Diabrotica virgifera virgifera
LeConte), was synthesized in four different ways by
employing one of the following four reactions as the key
step: (i) cross metathesis using the Grubbs I catalyst, (ii)
cross metathesis using the Grubbs II catalyst, (iii)
alkylation of an alkynide anion, and (iv) Grignard
coupling in the presence of dilithium tetrachlorocup-
rate. Although the cross metathesis approaches enabled
two short syntheses (4 or 6 steps) of the pheromone to be
achieved, the cheapest and most efficient synthesis was
possible via Grignard coupling to give the desired
pheromone in a 40% overall yield based on 2-methyl-1-
butanol (8 steps).
to find the most economical way to prepare a substantial
amount of 1 for monitoring the population of D. v.
virgifera in Europe.
This paper reports my results to choose a relatively
classical route employing Schlosser modification of
Grignard coupling and acetoacetic ester synthesis for
constructing the carbon skeleton of 1, although the cross
metathesis strategy was also carefully examined.
Results and Discussion
At the initial stage of this work, there was a need to
supply at least 2 g of 1 within two months to carry out
trapping tests against D. v. virgifera in Europe and the
USA. Both the modern cross metathesis and classical
reactions were to be examined to find out the most
appropriate one for the synthesis of 1. Target molecule 1
could be dissected into two building blocks by bond
dissection at A, B or C (Fig. 1). Since the metathesis
strategy seemed to provide 1 in short steps, two routes
based on cross metathesis were first explored (dissection at
A or C), and then two additional routes based on classical
reactions were examined afterwards (dissection at B or C).
Key words: cross metathesis; Diabrotica virgifera virgi-
fera LeConte; 1,7-dimethylnonyl propa-
noate; Grignard coupling; pheromone
The western corn rootworm (Diabrotica virgifera
virgifera LeConte) is one of the most invasive insect
species against maize monoculture, and owes its
notoriety to worldwide trade and commercial connec-
tions. This American beetle became endemic after about
1990 in Europe where it arrived as a hitchhiker aboard
freight airplanes.2) In order to monitor the population of
D. v. virgifera, traps baited with the species-specific sex
pheromone are employed.2)
First route based on cross metathesis
Grubbs’s works on the olefin cross metathesis
reaction revolutionized organic synthesis.11,12) Several
syntheses of aliphatic pheromones have been achieved
via cross metathesis.13–16)
The female-produced sex pheromone of D. v.
virgifera was isolated and identified in 1982 by Guss
et al. as 1,7-dimethylnonyl propanoate (1, Fig. 1).3)
Sonnet et al. then synthesized the four stereoisomers of
1, and tested their bioactivity against D. v. virgifera.4,5)
Males of the beetle responded strongly to (1R,7R)-1 and
secondarily to (1S,7R)-1. No synergism or inhibition
was detected when various mixtures of the stereoisomers
of 1 were tested. These results justify the use of a
stereoisomeric mixture of 1 as the attractant.
We recorded our synthesis of (1R,7R)-1 in 1984,6) and
there have been reported a number of different syntheses
of 1 in the past.7–10) On the present occasion, however, at
the request of Professor H.E. Hummel of Giessen
University (Germany), I decided to evaluate various
synthetic routes leading to a stereoisomeric mixture of 1
Scheme 1 summarizes a simple and rapid synthesis of
1 via olefin cross metathesis to connect the A bond of 1
(Fig. 1). A solution of 4-methyl-1-hexene (2) and 5-
hexen-2-one (3, 3 equivalents to 2) in dichloromethane
was heated under reflux in the presence of the Grubbs I
catalyst (1 mol % to 2) under argon to give a mixture of
hydrocarbon 4, desired ketone 5, and diketone 6, which
were separated by chromatography to give pure 5 in a
24% yield (based on 2) after distillation. Hydrogenation
of 5 over palladium-charcoal in ethyl acetate gave 7,
which was reduced to alcohol 8 by a treatment with
lithium aluminum hydride. Finally, acylation of 8 with
propanoyl chloride and pyridine afforded 1, whose mass
spectrum was identical to the published one.4) Its IR and
NMR spectra were also in good accord with our data
published in 1984.6)
*
Pheromone Synthesis, Part 242. See ref. 1 for Part 241.
Correspondence: Fax: +81-3-3813-1516; E-mail: kjk-mori@arion.ocn.ne.jp

596
K. MORI
The overall yield of 1 was 18% based on 2 (4 steps).
Second route based on cross metathesis
About 2.2 g of 1 could be prepared very quickly, and its
field test by Prof. Hummel fully proved its high
attractancy against male D. v. virgifera. The drawback
of this route is the high cost of the chemicals employed,
such as 2, 3, and the Grubbs I catalyst.
The second synthesis of 1 via cross metathesis to
connect bond C of 1 (Fig. 1) is illustrated in Scheme 2.
2-Methyl-1-butanol (9) was tosylated to give 10 which
was treated with a Grignard reagent prepared from
3-butenyl bromide (11) in the presence of dilithium
tetrachlorocuprate under Schlosser conditions17) to give
12 in a 61% yield. Cross metathesis of 6-methyl-1-
octene (12) with 3-buten-2-ol (13, 3.2 equivalents to 12)
was successful with the Grubbs II catalyst (0.6 mol % to
12) in dichloromethane under argon to give a separable
mixture of 14 and desired alcohol 15. After chromato-
graphic purification, 8-methyl-3-decen-2-ol (15, E=Z ¼
96.6:3.4 as estimated by GC-MS) was obtained in a 67%
yield. The next hydrogenation step over palladium-
charcoal in ethyl acetate was problematic due to the side
OCOC2H5
OCOC2H5
A
B C
(1R,7R)-1
1
Fig. 1. Structure of the Pheromone of the Western Corn Rootworm (1).
O
a
+
2
3
O
O
b
+
c
+
O
4
5
6
O
OH
d
7
1
8
PCy3
Ru
OCOC2H5
Cl
Cl
Ph
PCy3
Grubbs I catalyst
Scheme 1. Synthesis of 1 via Cross Metathesis (1).
Reagents and conditions: (a) Grubbs I catalyst, CH2Cl2, reflux, 5 h (24% based on 2); (b) H2, 10% Pd–C, EtOAc, room temp., 2 h (93%); (c)
LiAlH4, Et2O, 0–5 ꢀC, 1 h (88%); (d) EtCOCl, C5H5N, C6H6, 0–5 ꢀC, 1.5 h (93%).
b
c
OR
OH
Br
9
R = H
12
a
11
10 R = Ts
13
OH
d
+
15
14
O
OH
e
+
+
16
7
8
N
N
OCOC2H5
Cl
f
Ru
8
Cl
Ph
PCy3
Grubbs II catalyst
1
Scheme 2. Synthesis of 1 via Cross Metathesis (2).
Reagents and conditions: (a) TsCl, C5H5N, 0–5 ꢀC, 3 h (quant.); (b) Mg, 11, THF; add the Grignard reagent to 10 in THF, ꢁ78 ꢀC to ꢁ60 ꢀC;
Li2CuCl4, ꢁ60 ꢀC to room temp. (61%); (c) 13, Grubbs II catalyst, CH2Cl2, reflux, 30 min (67% based on 12); (d) H2, 10% Pd–C, EtOAc (10%
of 16, 10% of 7, and 80% of 8); (e) LiAlH4, Et2O, 0–5 ꢀC, 30 min (quant.); (f) EtCOCl, C5H5N, C6H6, 1.0 h (93%).

New Syntheses of the Western Corn Rootworm Pheromone
597
Ref. 18
(85%)
O
c
a
X
Br
OH
19 X = Br
b
17
18
20 X = I
21
OH
O
d
e
+
+
8
16
7
22
OH
OCOC2H5
f
8
1
Scheme 3. Synthesis of 1 Starting from 17.
Reagents and conditions: (a) H2, PtO2, AcOH, room temp., 5 h (58%); (b) NaI, acetone, reflux, 3 h (84%); (c) 21, n-BuLi, THF, HMPA,
ꢁ50 ꢀC to room temp., overnight (71%); (d) H2, 10% Pd–C, EtOAc, room temp., 3 h; (e) LiAlH4, Et2O (68%, 2 steps); (f) EtCOCl, C5H5N,
C6H6 (93%).
reactions giving 16 and 7 in addition to desired product
8. Hydrocarbon 16 was generated by hydrogenolysis,
and 7 might have been generated by double bond
migration of 15. After removing hydrocarbon 16 by
chromatography, the later-eluting mixture of 7 and 8
was reduced with lithium aluminum hydride to give pure
8. Acylation of 8 yielded 1.
The overall yield of 1 by this route was 30% based
on 9 (6 steps). However, the high cost of 11 and 13,
together with the extremely high cost of the Grubbs II
catalyst, make this route impractical.
however, was not satisfactory (33%, 3 steps). I therefore
changed to a new route leading to chloride 28 and
iodide 29.
3-Chloro-1-propanol (26) was converted to corre-
sponding tosylate 27 which was treated with a Grignard
reagent prepared from 23 in the presence of dilithium
tetrachlorocuprate under the Schlosser conditions.17)
Resulting chloride 28,21) however, lacked sufficient
reactivity, and was therefore converted to more reactive
iodide 29 by a Finkelstein exchange reaction. Alkylation
of ethyl acetoacetate with 29 was achieved in the
presence of potassium carbonate in acetone and N,N-
dimethylformamide to give 30. Treatment of ꢀ-keto
ester 30 with potassium hydroxide in aqueous methanol
effected hydrolysis and decarboxylation to give ketone 7
which was converted to 1 via 8.
Third route based on dianion alkylation
Scheme 3 summarizes the third synthesis of 1 which
was achieved by a slight modification of the route
reported by Sonnet et al.4) Cyclopropyl methyl ketone
(17) was converted to 4-methyl-3-hexenyl bromide (18)
according to the method of Julia et al.18) Hydrogenation
of 18 over Adams’ platinum oxide in acetic acid
afforded 4-methylhexyl bromide (19),4) which was
treated with sodium iodide in refluxing acetone to give
iodide 20.19) Alkylation of the dianion derived from
3-butyn-2-ol (21) with 20 furnished 8-methyl-3-decyn-
2-ol (22) in a 71% yield. Hydrogenation of 22 over
palladium-charcoal in ethyl acetate yielded a mixture of
16, 7, and 8, as in the case of hydrogenation of 15 (see
Scheme 2). Hydrocarbon 16 was removed from the rest
by chromatography, and the mixture of 7 and 8 was
treated with lithium aluminum hydride to give pure
alcohol 8 in a 68% yield after distillation. Finally,
acylation of 8 with propanoyl chloride afforded desired
pheromone 1.
The overall yield of 1 by this route was 40% based on
9 (8 steps). There was no very expensive starting
material in this case. Although rather lengthy, this route
was chosen as one suitable for the practical manufacture
of pheromone 1.
Conclusion
After examining four different syntheses of 1, the
route shown in Scheme 4 was chosen as the most
practical method for manufacturing western corn root-
worm pheromone 1. Although cross metathesis is an
effective method to quickly prepare 1, it is not practical
at present due to the high cost of the catalysts and the
rather expensive nature of the starting materials.
The overall yield of 1 by following this route was
19% based on 17 (9 steps). This synthesis was lengthy
and suffered from the high cost of 17 and 21.
Experimental
General. Refractive indices (nD) were measured with an Atago
DMT-1 refractometer. IR spectra were measured with a Jasco FT/IR-
410 spectrometer. 1H-NMR spectra (400 MHz, TMS at ꢁ ¼ 0:00 as an
internal standard) and 13C-NMR spectra (100 MHz, CDCl3 at ꢁ ¼ 77:0
as an internal standard) were recorded by a Jeol JNM-AL 400
spectrometer. GC-MS data were measured with an Agilent Technol-
ogies 5975 inert XL instrument, and HRMS data were recorded by a
Jeol JMS-SX 102A spectrometer. Column chromatography was carried
out on Merck Kieselgel 60 Art 1.07734.
Fourth route based on Schlosser modification of
Grignard coupling and acetoacetic ester synthesis
The final attempt to prepare 1 cheaply was to employ
such 5-methylheptyl halides as 25, 28, and 29 in
classical acetoacetic ester synthesis to give ketone 7
via 30 (Scheme 4). Bromide 25 was prepared for that
purpose from 2-methyl-1-butanol (9) via 23 and 24
according to the known method.20) The yield of 25,
8-Methyl-5-decen-2-one (5). Grubbs I catalyst (Aldrich, 152 mg,
0.18 mmol) was added to a solution of 2 (Tokyo Kasei, 3.5 g,

598
K. MORI
Mg, ether
Br
1) B2H6
2) Br2, NaOCH3
X
Br
(46%)
Ref. 20
(71%)
Ref. 20
9
X = OH
24
25
a
b
10 X = OTs
23 X = Br
O
c
e
f
RO
Cl
X
CO2C2H5
26 R = H
27 R = Ts
28 X = Cl
29 X = I
30
a
d
O
OH
OCOC2H5
g
h
7
8
1
Scheme 4. Synthesis of 1 Starting from 9.
Reagents and conditions: (a) TsCl, C5H5N, 0–5 ꢀC, 1.5 h (94% to quant.); (b) LiBr, DMF, 60 ꢀC, 1 h (87%); (c) 23, Mg, Et2O; add the
Grignard reagent to 27 in THF, ꢁ70 ꢀC to ꢁ60 ꢀC; Li2CuCl4, ꢁ60 ꢀC to room temp. (82%); (d) NaI, acetone, DMF, reflux, 6 h (80%);
(e) MeCOCH2CO2Et, K2CO3, acetone, DMF, reflux, 7 h (quant.); (f) KOH, MeOH, H2O, reflux, 1.5 h (91%, 2 steps); (g) LiAlH4, Et2O (83%);
(h) EtCOCl, C5H5N, C6H6 (92%).
25
35.7 mmol) and 3 (Tokyo Kasei, 10.6 g, 108 mmol) in dry CH2Cl2
(15 ml). The dark red solution was stirred and heated under reflux for
1.5 h under argon, an additional amount of Grubbs I catalyst (100 mg,
0.12 mmol) was added, and heating and stirring was continued under
argon for 3.5 h. Ethylene evolution could be observed during this
period. After having been left to stand for 3 d at room temperature, the
solution was concentrated in vacuo, and the dark residue was
chromatographed over SiO2 (100 g). Elution with hexane gave 4
(0.17 g), and further elution with hexane/EtOAc (15:1) gave crude 5
(2.50 g). Final elution with hexane/EtOAc (5:1) gave crude 6 (1.02 g).
Crude 5 (4.89 g) obtained from two batches by the foregoing reaction
was distilled to give 2.40 g (24%) of pure 5 as a colorless oil, bp 76–
of 7 as a colorless oil, bp 80–81 ꢀC at 5 Torr, nD ¼ 1:4291. IR ꢂmax
(film) cmꢁ1: 2960 (s), 2929 (s), 2856 (s), 1720 (s, C=O), 1464 (m),
1360 (m), 1165 (m). 1H-NMR ꢁH (CDCl3): 0.84 (3H, d, J ¼ 6:4 Hz),
0.85 (3H, t, J ¼ 6:8 Hz), 1.05–1.20 (2H, m), 1.20–1.40 (7H, m), 1.50–
1.60 (2H, m), 2.13 (3H, s, COCH3), 2.42 (2H, t, J ¼ 7:2 Hz, COCH2).
GC-MS (same conditions as those for 5) tR: 9.23 min (99.9%). MS
(70 eV, EI) m=z: 170 (2) (Mþ), 152 (1), 141 (5), 123 (10), 112 (9), 110
(10), 96 (10), 95 (11), 82 (17), 71 (48), 58 (100), 43 (78). HRMS:
calcd. for C11H20O (Mþ), 170.1671; found, 170.1676.
8-Methyl-2-decanol (8). A solution of 7 (2.10 g, 12 mmol) in dry
Et2O (10 ml) was added dropwise to a stirred and ice-cooled
25
77 ꢀC at 4 Torr, nD ¼ 1:4421. IR ꢂmax (film) cmꢁ1: 3005 (m), 2960
suspension of LiAlH4 (0.3 g, 8 mmol) in dry Et2O (25 ml). The stirring
was continued for 1 h at 0–5 ꢀC. Excess LiAlH4 was then destroyed by
adding H2O dropwise. The mixture was acidified with dil. HCl and ice,
and extracted with Et2O. The extract was successively washed with
water, an NaHCO3 solution and brine, dried (MgSO4), and concen-
trated in vacuo. The residue was distilled to give 1.86 g (88%) of 8 as a
(s), 2920 (s), 2875 (s), 1720 (s, C=O), 1362 (m), 1161 (m), 970 (m).
1H-NMR ꢁH (CDCl3): 0.80–0.92 (6H, m), 1.06–1.20 (1H, m), 1.26–
1.42 (2H, m), 1.75–1.92 (1H, m), 1.94–2.06 (1H, m), 2.136 (1.6H, s),
2.142 (1.4H, s), 2.24–2.34 (2H, m), 2.48 (2H, q, J ¼ 7:2 Hz), 5.30–
5.50 (2H, m). GC-MS [HP-5MS column, 5% phenylmethylsiloxane,
30 m ꢂ 0:25 mm i.d.; 60.7 kPa pressure; 70–230 ꢀC (+10 ꢀC/min)
temperature] tR: 9.02 min [58.6%, (Z)-5], 9.06 min [41.4%, (E)-5]. MS
of 5 (70 eV, EI) m=z: 168 (3) (Mþ), 150 (14), 110 (26), 95 (21), 81
(25), 69 (12), 58 (39), 43 (100). HRMS: calcd. for C11H20O (Mþ),
168.1514; found, 168.1519.
colorless oil, bp 88–89 ꢀC at 4 Torr, nD ¼ 1:4370. IR ꢂmax (film)
25
cmꢁ1: 3352 (m, O–H), 2962 (s), 2927 (s), 2856 (s), 1462 (m), 1377
(m), 1119 (m, C–O). 1H-NMR ꢁH (CDCl3): 0.84 (3H, d, J ¼ 6:4 Hz),
0.85 (3H, t, J ¼ 7:6 Hz), 1.05–1.15 (2H, m), 1.19 (3H, d, J ¼ 6:4 Hz),
1.20–1.50 (12H, m), 3.79 (1H, m, CHOH). GC-MS (same conditions
as those for 5) tR: 9.32 min (99.7%). MS (70 eV, EI) m=z: 171 (0.1)
(Mþ–H), 157 (4) (Mþ–CH3), 125 (20), 97 (13), 83 (37), 70 (49), 69
3,8-Dimethyl-5-decene (4). IR ꢂmax (film) cmꢁ1: 3006 (w), 2960 (s),
2925 (s), 2875 (s), 968 (m). 1H-NMR ꢁH (CDCl3): 0.80–0.92 (12H, m),
1.08–1.20 (2H, m), 1.22–1.42 (4H, m), 1.78–1.90 (2H, m), 1.96–2.08
(2H, m), 5.35–5.42 (2H, m). GC-MS (same conditions as those for 5)
tR: 7.22 min [57.4%, (Z)-4], 7.31 min [42.6%, (E)-4]. MS of 4 (70 eV,
EI) m=z: 168 (29) (Mþ), 139 (4), 111 (3), 97 (13), 83 (44), 70 (100), 69
(76), 57 (82), 41 (49).
(37), 57 (45), 55 (41), 45 (100), 41 (28). HRMS: calcd. for C10H21
(Mþ–CH3), 157.1592; found, 157.1599.
O
1,7-Dimethylnonyl propanoate (1). A solution of EtCOCl (1.5 ml,
1.6 g, 17 mmol) in dry benzene (5 ml) was added dropwise to a stirred
and ice-cooled solution of 8 (1.80 g, 10.5 mmol) in benzene (5 ml) and
dry pyridine (5 ml). The mixture was stirred for 1.5 h at 0–5 ꢀC,
quenched with ice-cooled water, and extracted with Et2O. The extract
was successively washed with dil. HCl, water, an NaHCO3 solution
and brine, dried (MgSO4), and concentrated in vacuo. The residue was
distilled to give 2.20 g (93%) of 1 as a colorless oil, bp 107–108 ꢀC at
5-Decene-2,9-dione (6). IR ꢂmax (film) cmꢁ1: 3000 (m), 2920 (m),
2854 (m), 1712 (s, C=O), 1363 (s), 1163 (s), 972 (m). 1H-NMR ꢁH
(CDCl3): 2.13, 2.14 (total 6H, both s), 2.20–2.35 (4H, m), 2.45–2.52
(4H, m), 5.34 (0.4H, m), 5.43 (1.6H, m). GC-MS (same conditions as
those for 5) tR: 10.63 min [17%, (Z)-6], 10.66 min (83%, (E)-6). MS of
6 (70 eV, EI) m=z: 168 (0.5) (Mþ), 110 (33), 67 (13), 43 (100).
5 Torr, nD ¼ 1:4286. IR ꢂmax (film) cmꢁ1: 2960 (s), 2931 (s), 2858
25
(m), 1738 (s, C=O), 1468 (m), 1377 (m), 1194 (s), 1126 (m), 1082 (m).
1H-NMR ꢁH (CDCl3): 0.84 (3H, d, J ¼ 6:4 Hz), 0.85 (3H, t,
J ¼ 7:6 Hz), 1.13 (3H, t, J ¼ 7:6 Hz), 1.05–1.20 (2H, m), 1.20 (3H,
d, J ¼ 6:4 Hz), 1.20–1.40 (9H, m), 1.40–1.52 (1H, m), 1.52–1.65 (1H,
m), 2.29 (2H, q, J ¼ 7:6 Hz), 4.85–4.96 (1H, m). 13C-NMR ꢁC
(CDCl3): 9.2, 11.4, 19.2, 20.0, 25.4, 27.0, 27.9, 29.5, 29.8, 34.4, 36.0,
36.5, 70.7, 174.0. GC-MS (same conditions as those for 5) tR:
8-Methyl-2-decanone (7). 10% Pd–C (0.2 g) was added to a solution
of 5 (2.35 g, 14 mmol) in EtOAc (20 ml), and the mixture was stirred
under H2 for 2 h at room temperature. The mixture was then filtered
through a pad of Celite to remove the catalyst, and the filtrate was
concentrated in vacuo. The residue was distilled to give 2.20 g (93%)

New Syntheses of the Western Corn Rootworm Pheromone
599
12.18 min (99.9%). MS (70 eV, EI) m=z: 213 (0.1) (Mþ–CH3), 154 (5),
125 (31), 101 (28), 83 (24), 70 (43), 57 (100), 55 (25), 41 (17). HRMS:
calcd. for C13H25O2 (Mþ–CH3), 213.1855; found, 213.1859.
1.30–1.50 (3H, m), 1.75–1.90 (2H, m), 3.39 (2H, t, J ¼ 7:2 Hz).
GC-MS (same conditions as those for 5) tR: 5.40 min (91%). MS (70 eV,
EI). m=z: 178 (0.5) (Mþ–1), 151 (96), 149 (100), 69 (90), 57 (70),
41 (57).
6-Methyl-1-octene (12). A Grignard reagent was prepared from 11
(33.7 g, 250 mmol) and Mg (7.2 g, 300 mmol) in dry THF (130 ml).
This was added dropwise to a cooled and stirred solution of 10 [58.5 g,
prepared from 20.8 g (236 mmol) of 9] in dry THF (100 ml) at ꢁ78 ꢀC
to ꢁ60 ꢀC under argon. A solution of Li2CuCl4 in dry THF (0.1 M,
5 ml, 0.5 mmol) was added dropwise to the cooled and stirred mixture,
and its temperature was allowed to rise to ꢁ10 ꢀC over 1 h. After 2 d at
room temperature, the mixture was poured into an ice-cooled NH4Cl
solution and then extracted with a small amount of pentane. The
extract was successively washed with water and brine, dried (MgSO4),
and concentrated under atmospheric pressure in a Vigreux column. The
residue was distilled to give 18.1 g (61%) of 12 as a colorless oil, bp
74–75 ꢀC at 106 Torr. IR ꢂmax (film) cmꢁ1: 3078 (w), 2962 (s), 2929
(s), 2875 (m), 2860 (m), 1641 (m, C=C), 1462 (m), 1378 (m), 993 (m),
910 (s). 1H-NMR ꢁH (CDCl3): 0.85 (3H, d, J ¼ 6:8 Hz), 3.85 (3H, t,
J ¼ 6:8 Hz), 1.05–1.20 (2H, m), 1.20–1.45 (5H, m), 2.02 (2H, q-like,
J ¼ 6:8 Hz), 4.90–5.04 (2H, m), 5.75–5.88 (1H, m). GC-MS (same
conditions as those for 5) tR: 3.82 min (11.4%, 23), 4.78 min (81%, 12),
6.07 min (5.4%, 3,6-dimethyloctane). MS (70 eV, EI) m=z: 126 (0.5)
(Mþ), 97 (72), 83 (32), 70 (70), 69 (50), 55 (100), 41 (50). This crude
12 was employed in the next step without further purification.
4-Methylhexyl iodide (20). NaI (30.0 g, 200 mmol) was added to a
solution of 19 (11.4 g, 64 mmol) in acetone (150 ml). The solution was
stirred and heated under reflux for 3 h to precipitate generated NaBr.
After concentrating in vacuo, the residue was diluted with water and
extracted with hexane. The extract was successively washed with a dil.
Na2S2O3 solution and brine, dried (MgSO4), and concentrated
in vacuo. The residue was distilled to give 12.0 g (84%) of 20 as an
oil, bp 105–108 ꢀC at 52 Torr. IR ꢂmax (film) cmꢁ1: 2960 (s), 2927 (s),
2873 (m), 1462 (m), 1378 (m), 1223 (m), 1174 (m). 1H-NMR ꢁH
(CDCl3): 0.868 (3H, d, J ¼ 6:4 Hz), 0.869 (3H, t, J ¼ 7:6 Hz), 1.10–
1.25 (2H, m), 1.29–1.43 (3H, m), 1.75–1.91 (2H, m), 3.17 (2H, m).
GC-MS (same conditions as those for 5) tR: 8.81 min (88%). MS
(70 eV, EI) m=z: 226 (9) (Mþ), 155 (12), 99 (19), 57 (100), 41 (32).
8-Methyl-3-decyn-2-ol (22). A solution of n-BuLi in hexane (1.6 M,
100 ml, 160 mmol) was added over 15 min to a stirred and cooled
solution of 21 (5.5 g, 80 mmol) in dry THF (100 ml) and dry HMPA
(15 ml) at ꢁ50 ꢀC to ꢁ40 ꢀC under argon. To the resulting paste-like
suspension of the dianion of 21 was added dropwise over 10 min while
vigorously stirring a solution of 20 (12.0 g, 53 mmol) in dry THF
(10 ml) at ꢁ40 to ꢁ20 ꢀC. Most of the white solid of the dilithium salt
gradually disappeared, and the mixture was stirred overnight with a
gradual rise of temperature to room temperature. The mixture was
diluted with water and extracted with hexane. The extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was distilled to give 6.3 g (71%) of
(E)-8-Methyl-3-decen-2-ol (15). Grubbs II catalyst (Aldrich,
100 mg, 0.12 mmol) was added to a solution of 12 (2.4 g, 19 mmol)
and 13 (4.4 g, 61 mmol) in dry CH2Cl2 (15 ml). The dark red solution
was stirred and heated under reflux and an argon atmosphere. Ethylene
evolution ceased after 30 min, and the dark red color of the solution
faded. The mixture was concentrated in vacuo, and the residue was
chromatographed over SiO2 (50 g). Elution with hexane gave 14
(0.52 g) and further elution with hexane/EtOAc (5:1) gave 2.18 g (67%
based on 12) of 15 as a colorless oil, bp 87–89 ꢀC at 4 Torr,
26
22 as a colorless oil, bp 87–90 ꢀC at 2 Torr, nD ¼ 1:4536. IR ꢂmax
(film) cmꢁ1: 3348 (m), 2960 (s), 2933 (s), 2873 (s), 1462 (m), 1377
(m), 1329 (m), 1155 (m), 1078 (s), 1003 (m), 881 (w). 1H-NMR ꢁH
(CDCl3): 0.85 (3H, d, J ¼ 7:2 Hz), 0.86 (3H, t, J ¼ 7:2 Hz), 1.10–1.21
(2H, m), 1.26–1.40 (3H, m), 1.43 (3H, d, J ¼ 6:8 Hz), 1.43–1.60 (2H,
m), 1.85–1.95 (1H, br), 2.14–2.22 (2H, m), 4.51 (1H, m). GC-MS
(same conditions as those for 5) tR: 9.51 min (89%). MS (70 eV, EI)
m=z: 153 (1) (Mþ–CH3), 135 (7), 121 (53), 109 (12), 97 (33), 95 (32),
26
nD ¼ 1:4461. IR ꢂmax (film) cmꢁ1: 3344 (m, O–H), 2962 (s), 2927
(s), 2873 (m), 2858 (m), 1670 (w, C=C), 1462 (m), 1377 (m), 1063
(m), 968 (m). 1H-NMR ꢁH (CDCl3): 0.84 (3H, d, J ¼ 6:4 Hz), 0.85
(3H, t, J ¼ 7:6 Hz), 1.05–1.20 (2H, m), 1.22 (3H, d, J ¼ 7:6 Hz), 1.25–
1.42 (6H, m), 1.55–1.65 (1H, br), 2.00 (2H, q-like, J ¼ 6:8 Hz), 5.48–
5.56 (1H, m), 5.60–5.68 (1H, m). 13C-NMR ꢁC (CDCl3): 11.4, 19.1,
23.4, 26.7, 29.4, 32.4, 34.3, 36.1, 68.9, 131.1, 133.9. GC-MS (same
conditions as those for 5) tR: 9.13 min (96.6%). MS (79 eV, EI) m=z:
170 (0.5) (Mþ), 152 (7) (Mþ–H2O), 123 (19), 110 (11), 96 (22), 95
(27), 82 (27), 81 (44), 71 (100), 67 (31), 55 (31), 43 (45). HRMS:
calcd. for C11H22O (Mþ), 170.1671; found, 170.1684.
93 (30), 83 (88), 69 (58), 55 (100), 43 (36). HRMS: calcd. for C10H17
(Mþ–CH3), 153.1279; found, 153.1274.
O
8-Methyl-2-decanol (8). 10% Pd–C (0.8 g) was added to a solution
of 22 (6.2 g, 37 mmol) in EtOAc (40 ml), and the mixture was stirred
under H2 for 3 h at room temperature. The catalyst was filtered off
through a pad of Celite, and the filtrate was concentrated in vacuo. The
residue was chromatographed over SiO2 (70 g). The column was first
washed with hexane, and elution with hexane/EtOAc (30:1) yielded
4.0 g of a mixture of 7 and 8 (4:1). Further elution with hexane/EtOAc
(5:1) gave 2.1 g of a mixture of 7 and 8 (1:4). These were combined
and reduced with LiAlH4 in Et2O to give 4.3 g (68%) of 8, bp 90–92 ꢀC
at 3 Torr. This was converted to 1 in a 93% yield.
3,12-Dimethyl-7-tetradecene (14). IR ꢂmax (film) cmꢁ1: 2960 (s),
2927 (s), 2873 (m), 2858 (m), 1462 (m), 1377 (m), 966 (m). GC-MS
(same conditions as those for 5) tR: 12.61 min [23%, (Z)-14], 12.68 min
[77%, (E)-14]. MS (70 eV, EI) m=z: 224 (7) (Mþ), 125 (13), 111 (17),
97 (31), 83 (48), 70 (100), 55 (43), 41 (27).
2-Methylbutyl bromide (23). Powdered LiBr (33.0 g, 379 mmol) was
added to a solution of 10 (57.1 g, 235 mmol) in DMF (160 ml) while
shaking. LiBr dissolved completely with an exothermic reaction. The
mixture was stirred at 60 ꢀC for 1 h, poured into ice-cooled water, and
the lower layer of 23 was separated. The aqueous layer was extracted
with a small amount of pentane. The pentane solution was added to 23,
and the resulting solution was successively washed with water and
brine, dried (MgSO4), and concentrated under atmospheric pressure in
a Vigreux column. The residue was distilled to give 30.9 g (87%) of 23
as a colorless oil, bp 117–119 ꢀC at atmospheric pressure. IR ꢂmax
(film) cmꢁ1: 2964 (s), 2931 (m), 2875 (m), 1459 (m), 1379 (w), 1230
(m), 650 (m), 617 (w).
8-Methyl-2-decanol (8). 10% Pd–C (0.7 g) was added to a solution
of 15 (4.95 g, 29.1 mmol) in EtOAc (40 ml), and the mixture was
stirred under H2 for 1 h at room temperature. The mixture was filtered
through a pad of Celite, and the filtrate was concentrated to give 5.0 g
(quant.) of crude 8 which contained about 10% of 16 and 10% of 7.
Chromatographic purification of this mixture gave a mixture of 7 and 8
which was reduced with LiAlH4 in Et2O to give pure 8 (80% based on
15). This was converted to 1 in a 93% yield.
4-Methylhexyl bromide (19). Adams PtO2 (0.3 g) was added to a
solution of 18 (19.8 g, 112 mmol) in AcOH (80 ml), and the mixture was
stirred vigorously for 5 h under H2. The mixture was filtered through a
pad of Celite to remove the catalyst. The filtrate was diluted with water,
and extracted with hexane. The extract was successively washed with
water, an NaHCO3 solution and brine, dried (MgSO4), and concentrated
in vacuo. The residue was distilled to give 11.5 g (58%) of known 19,4)
bp 95–103 ꢀC at 58 Torr. IR ꢂmax (film) cmꢁ1: 2960 (s), 2929 (s), 2873
(m), 1462 (m), 1379 (m), 1259 (m), 1246 (m). 1H-NMR ꢁH (CDCl3):
0.87 (3H, t, J ¼ 7:6 Hz), 0.87 (3H, d, J ¼ 6:0 Hz), 1.10–1.30 (2H, m),
3-Chloropropyl tosylate (27). TsCl (57.0 g, 300 mmol) was added
portionwise to a stirred and ice-cooled solution of 26 (Tokyo Kasei,
25.6 g, 271 mmol) in dry C5H5N (90 ml). A small amount (0.2 g) of 4-
(dimethylamino)pyridine was added to the mixture, and stirring was
continued for 1.5 h at 0–5 ꢀC. The mixture was then diluted with ice-
cooled water and extracted with Et2O. The extract was successively
washed with water, dil. HCl, an NaHCO3 solution and brine, dried

600
K. MORI
(MgSO4), and concentrated in vacuo to give 63.0 g (94%) of 27 as a
colorless oil. IR ꢂmax (film) cmꢁ1: 3066 (w), 2970 (w), 2925 (w), 1599
(m), 1363 (s), 1190 (s), 1176 (s), 1097 (m), 1001 (m), 984 (m), 935 (s),
833 (s), 816 (m), 665 (s), 555 (s). 1H-NMR ꢁH (CDCl3): 2.10 (2H,
quint-like, J ¼ 6 Hz), 2.46 (3H, s), 3.57 (2H, t, J ¼ 6:0 Hz), 4.19 (2H,
t, J ¼ 6:0 Hz), 7.36 (2H, d, J ¼ 8:4 Hz), 7.80 (2H, d, J ¼ 8:4 Hz). This
was employed in the next step without further purification.
conditions as those for 5) tR: 8.86 min (4.7%), 9.25 min (87.6%, 7),
13.77 min (1.9%), 14.56 min (3.2%). This was employed in the next
step without further purification.
8-Methyl-2-decanol (8). Redution of 7 (15.0 g, 88 mmol) with
LiAlH4 (2.0 g, 53 mmol) in dry Et2O (150 ml) gave 14.5 g of crude 8
which was chromatographed over SiO2 (100 g) in hexane. Elution with
hexane gave 0.7 g of hydrocarbons. Subsequent elution with hexane/
EtOAc (5:1) gave 12.6 g (83%) of 8. Its IR and 1H-NMR spectra were
identical with the authentic spectra. GC-MS (same conditions as those
for 5) tR: 5.86 min (1.7%, 5-methyl-1-heptanol), 9.33 min (98.3%, 8).
5-Methylheptyl chloride (28). A Grignard reagent was prepared in
the conventional manner from 23 (29.4 g, 194 mmol) and Mg (5.4 g,
225 mmol) in dry THF (100 ml). The resulting reagent was added
slowly to a stirred and cooled solution of 27 (34.9 g, 140 mmol) in dry
THF (70 ml) at ꢁ70 ꢀC to ꢁ60 ꢀC under argon. Immediately after the
addition, a solution of Li2CuCl4 in THF (0.1 M, 5 ml, 0.5 mmol) was
added dropwise to the mixture. Stirring was continued overnight,
allowing the reaction temperature to rise gradually to room temper-
ature. The mixture was poured into an ice-cooled NH4Cl solution and
extracted with pentane. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was distilled to give 18.7 g (82%) of 28 as a colorless oil, bp
1,7-Dimethylnonyl propanoate (1). Treating 8 (12.5 g, 73 mmol) in
pyridine (40 ml) with EtCOCl (10.0 g, 108 mmol) in benzene (20 ml)
for 1.5 h at 0–5 ꢀC yielded 15.2 g (92%) of 1, bp 100–101 ꢀC at 4 Torr.
Its IR and 1H-NMR spectra were identical with the authentic spectra of
1. GC-MS (same conditions as those for 5) tR: 9.33 min (3.4%),
12.19 min (96.4%, 1).
Acknowledgments
23
90–95 ꢀC at 51 Torr, nD 1.4292. IR ꢂmax (film) cmꢁ1: 2960 (s), 2933
(s), 2873 (s), 1462 (m), 1379 (m), 735 (m), 656 (m). 1H-NMR ꢁH
(CDCl3): 0.85 (3H, d, J ¼ 7:2 Hz), 0.86 (3H, t, J ¼ 7:6 Hz), 1.05–1.20
(2H, m), 1.25–1.50 (5H, m), 1.70–1.80 (2H, m), 3.54 (2H, t,
J ¼ 6:8 Hz). 13C-NMR ꢁC (CDCl3): 11.4, 19.1, 24.4, 29.4, 32.9,
34.3, 35.8, 45.1. GC-MS [same column as that used for 5; 48.7 kPa
pressure, 40–230 ꢀC (+5 ꢀC/min) temperature] tR: 8.87 min (8.2%,
3,6-dimethyloctane generated by self-coupling of 23), 11.72 min
(87.5%, 28), 17.88 min (2.5%, 3,9-dimethylundecane generated by
coupling 28 with 23). The two by-products could be identified by MS.
MS of 28 (70 eV, EI) m=z: 147 (<1) (Mþ–1), 119 (38), 91 (67), 83
(89), 57 (100), 56 (61), 55 (84), 41 (60). HRMS: calcd. for C7H14Cl
(Mþ–CH3), 133.0784; found, 133.0761.
My thanks are due to Mr. M. Kimura (President, Toyo
Gosei Co., Ltd.) for his support. I thank Professor H. E.
Hummel (Justus-Liebig-Universitat Giessen) for his
¨
initiative to undertake this work. I also thank Mr. Y.
Shikichi (Toyo Gosei Co., Ltd.) for NMR and GC-MS
measurements. HRMS analyses were carried out by Dr.
T. Nakamura (RIKEN), and the Figure and Schemes
were prepared by Dr. T. Tashiro (RIKEN). I thank both
of them.
References
5-Methylheptyl iodide (29). A solution of 28 (18.4 g, 124 mmol),
NaI (50 g, 333 mmol) and DMF (10 ml) in acetone (200 ml) was stirred
and heated under reflux for 6 h. Sodium chloride was gradually
precipitated out. The mixture was then concentrated in vacuo, diluted
with water, and extracted with Et2O. The extract was successively
washed with water and brine, dried (MgSO4) and concentrated in
1) Mori K, Biosci. Biotechnol. Biochem., 73, 2727–2730 (2009).
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vacuo. The residue was distilled to give 23.3 g (80%) of 29 as a
colorless oil, bp 67–68 ꢀC at 5 Torr, nD 1.4826. IR ꢂmax (film) cmꢁ1
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23
:
2958 (s), 2929 (s), 2871 (s), 2856 (s), 1462 (m), 1377 (m), 1215 (m),
1174 (m). 1H-NMR ꢁH (CDCl3): 0.85 (3H, d, J ¼ 7:6 Hz), 0.86 (3H, t,
J ¼ 6:8 Hz), 1.05–1.20 (2H, m), 1.25–1.50 (5H, m), 1.75–1.85 (2H,
m), 3.20 (2H, t, J ¼ 6:8 Hz). 13C-NMR ꢁC (CDCl3): 7.3, 11.4, 19.2,
28.0, 29.4, 33.8, 34.2, 35.7. GC-MS (same conditions as those for 5) tR:
5.71 min (5.4%, unreacted 28), 8.40 min (87.3%, 29), 8.86 min (5.2%,
3,9-dimethylundecane). MS of 29 (70 eV, EI) m=z: 240 (10) (Mþ), 183
(7), 169 (s), 155 (16), 113 (15), 71 (91), 57 (100), 55 (32), 43 (42), 41
(38). HRMS: calcd. for C8H17I (Mþ), 240.0375; found, 240.0361.
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Ethyl 2-acetyl-7-methylnonanoate (30). Powdered K2CO3 (41.4 g,
600 mmol) was added to a solution of 29 (23.2 g, 97 mmol), ethyl
acetoacetate (26.0 g, 200 mmol) and DMF (25 ml) in acetone (100 ml).
The mixture was stirred and heated under reflux for 7 h. It was then
concentrated in vacuo. The residue was diluted with water and
extracted with Et2O. The Et2O solution was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo to give
31.1 g of crude 30 containing unreacted ethyl acetoacetate. IR ꢂmax
(film) cmꢁ1: 2960 (s), 2931 (m), 2873 (m), 2860 (m), 1743 (vs), 1718
(vs), 1633 (w), 1242 (s), 1151 (s), 1041 (m). This was employed in the
next step without further purification.
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´
18) Julia M, Julia S, and Guegan R, Bull. Soc. Chim. France, 1072–
8-Methyl-2-decanone (7). An aqueous solution of KOH [24.0 g
(428 mmol) in 200 ml] was added to a solution of foregoing crude 30
(31.1 g) in MeOH (200 ml). The solution was stirred and heated under
reflux for 1.5 h, and then concentrated in vacuo. The residue was
diluted with water and extracted with Et2O. The extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo to give 15.0 g (91%) of crude 7. IR ꢂmax (film)
cmꢁ1: 2958 (s), 2929 (s), 2873 (m), 2856 (m), 1718 (s), 1624 (w,
impurity), 1462 (m), 1375 (m), 1360 (m), 1163 (m). GC-MS (same
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