Concise syntheses of (7Z,11Z,13E)-hexadecatrienal and (8E,18Z)- tetradecadienal

Article abstract of DOI:10.1055/s-0031-1290338

Concise and efficient syntheses of (7Z,11Z,13E)-hexadecatrienal, a sex-pheromone component of the citrus leaf miner, and (8E,10Z)-tetradecadienal, the sex pheromone of the horse-chestnut leaf miner were described, starting from the commercially available acetylene and acrolein. The stereoselective formation of E,Z-conjugated double bond relied on cross-coupling between Grignard reagent and (E,Z)-bromodiene. The present syntheses achieved high overall yield (26% of the former and 23% for the latter) and high isomeric purity (97% for the former and 99% for the latter). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290338

LETTER
581
Concise Syntheses of (7Z,11Z,13E)-Hexadecatrienal and
(8E,18Z)-Tetradecadienal
(
7
Z
,11
Z
,13
E
)-H
e
exadecatrie
n
na
l
and
(
8
E
,
g
18
Z
)-Tetrade
x
cadienal iao Ma,a Xiaomei Yang,b Yushun Zhang,a Xiangzhong Huang,c Yunhai Tao*a,d
a
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. of China
Fax +86(871)5035538; E-mail: cloudsea2000@sina.com
b
c
d
Yunnan University of Traditional Chinese Medicine, Kunming 650200, P. R. of China
Yunnan University of Nationalities, Kunming 650031, P. R. of China
State Key Laboratory of Elementoorganic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Received 19 October 2011
A few of the syntheses of (7Z,11Z,13E)-hexadecatrienal
(1) were developed, and the reported synthetic routes to
the pheromone are complicated.4,5a,6 Leal et al. achieved
the synthesis of the pheromone by employing the
Abstract: Concise and efficient syntheses of (7Z,11Z,13E)-hexade-
catrienal, a sex-pheromone component of the citrus leaf miner, and
(8E,10Z)-tetradecadienal, the sex pheromone of the horse-chestnut
leaf miner were described, starting from the commercially available
acetylene and acrolein. The stereoselective formation of E,Z-conju- C6+C5+C5 strategy.4 The introduction of the 7Z double
gated double bond relied on cross-coupling between Grignard re-
bond in this synthesis was achieved by cross-coupling be-
agent and (E,Z)-bromodiene. The present syntheses achieved high
tween suitable haloalkane and lithioalkyne and subse-
overall yield (26% of the former and 23% for the latter) and high
quent stereoselective reduction; The introduction of
isomeric purity (97% for the former and 99% for the latter).
11Z,13E-conjugated double bonds was achieved by the
Key words: (7Z,11Z,13E)-hexadecatrienal,
(8E,10Z)-tetradeca-
Wittig reaction as the key step. Another synthesis of the
pheromone reported by Ando et al. (C7+C4+C5 strategy),
employing the Wittig reaction as the key step.6 However,
these methods do not afford a product with high enough
chemical or isomeric purity.
dienal, 7-bromo-(4Z,6E)-heptadienal, Kumada cross-coupling, hy-
droboration–oxidation
The citrus leaf miner, Phyllocnistis citrella Stainton, is an
important pest of citrus and related Rutaceae almost
worldwide.1 Damages caused by the citrus leaf miner in-
clude loss of photosynthetic capacity from mining, stunt-
ing, and malformation of leaves.2a Besides those damages,
the larval mining increases the susceptibility of trees to
the citrus canker disease, caused by Xanthomonuas axo-
nopodis pv citri.2
The horse chestnut leaf miner, Cameraria Ohridella, is a
new pest that is causing more and more damage in horse
chestnut trees7 and it is found throughout Europe.8 The
most obvious damage consists of course of the mines
caused by larvae. This can evolve to such an extent that
leaves turn brown and fall off prematurely.7
The control of the horse chestnut leaf miner with chemical
products is very difficult since it lives inside the leaf
mines during most of its life cycle. Furthermore, in some
countries, strict regulations about pesticide use limit the
number of chemical products that can be used against this
pest. Thus biological alternatives will become more and
more important in the future.7 (8E,10Z)-Tetradecadienal
(2) was identified by Svatos et al. as the female sex pher-
omone of the horse chestnut leaf miner.9a Recently, the
synthetic sex pheromone has been used in integrated man-
agement of the pest.7
Effective chemical control of the citrus leaf miner is diffi-
cult to achieve since the feeding larvae and pupae are pro-
tected by the leaf cuticle and the rolled leaf margins.3
Moreover, the general utility of insecticides is limited by
high cost, persistence of residue in tubers, and the envi-
ronment and development of this insecticide-resistant
pest. Considerable efforts have been made for the devel-
opment and evaluation of new integrated pest-manage-
ment techniques. So the development of new integrated
pest-management techniques with pheromone com-
pounds is a very desired goal.3 The semiochemicals of the
pest have been identified as (7Z,11Z,13E)-hexadecatrie-
nal (1, Figure 1), (7Z,11Z)-hexadecadienal, and (7Z)-
hexadecenal in a ratio of 30:10:1, respectively.4 Recently,
the synthetic sex pheromone has been used in control of
the pest via mass trapping and mating disruption tech-
niques.2a,4,5
The reported synthetic routes to (8E,10Z)-tetradecadienal
(2) were based on both strategies including reduction of
enyne precursor8,9 and Wittig-type olefination.10,11 The
first synthesis of 2 was achieved via reduction of (6E)-14-
(tert-butoxy)tetradecen-4-yne, which was prepared by
Sonogashira cross-coupling of 1-iodo-9-(tert-butoxy)-
(1E)-nonene with 1-pentyne.9 Although the strategy can
afford a product with high enough chemical or isomeric
purity, preparation of 1-iodo-9-(tert-butoxy)-(1E)-non-
ene, the key intermediate of the Sonogashira protocol, is
complicated and expensive (via five steps from 1,7-hep-
tanediol). Recently, Grodner developed a new synthesis
SYNLETT 2012, 23, 581–584
x
x
.
x
x
.
2
0
1
1
Advanced online publication: 08.02.2012
DOI: 10.1055/s-0031-1290338; Art ID: W57511ST
© Georg Thieme Verlag Stuttgart · New York

582
Z. Ma et al.
LETTER
of aldehyde 2 based on reduction of enyne precursor, rolein with acetylene in the presence of Pd(OAc)2.14
which was prepared using Pd(0)-catalyzed cross-coupling Aldehyde 3 is so pure as to be used in the next step without
of Grignard reagent with the corresponding vinyl iodides.8 purification by column chromatography. The construction
Another synthetic strategy of aldehyde 2 was reported by of the 7Z double bond relied on the Wittig reaction. To en-
Francke et al., employing the Wittig reaction as the key sure cis selectivity of this Wittig olefination, potassium
step.10 Christmann et al. reported a synthesis of aldehyde bis(trimethylsilyl)amide was chosen as the base. The
2 using a combination of two Wittig reactions.11 However, ylide, prepared from phosphonium salt 7 by treatment
a relatively low isomeric purity of the product and a high with potassium bis(trimethylsilyl) amide as base in dry
cost of removal of triphenylphosphine oxide make both THF at –78 °C, reacted with aldehyde 3 to afford tetraene
strategies less desirable alternatives, considering the po- 8 in 85% yield and 98% isomeric purity.15,16 Kumada
tential commercial application.
cross-coupling of tetraene 8 with ethylmagnesium bro-
mide via catalysis of NiCl2(dppp) in dry THF at room
temperature gave tetraene 9 in 93% yield and 97% iso-
meric purity.17,18 Kumada cross-coupling maintain the ex-
cellent isomeric purity owing to the moderate conditions.
Tetraene 9 was transformed into alcohol 10 via the 9-
BBN–H2O2 system in 80% yield.19 Due to the high regio-
selectivity of the 9-BBN–H2O2 system, this reaction gave
less than 1% of the secondary alcohol byproduct as mea-
sured by GC. In the final step, (7Z,11Z,13E)-hexadecatri-
enal (1) was prepared by oxidation of alcohol 10 using
pyridinium chlorochromate/Celite in dichloromethane in
83% yield.15 The overall yield of the target product 1 from
aldehyde 3 was 52%; the overall yield of the product 1
from acrolein was 26%. Since aldehyde 3 is a highly ste-
reodefined compound (the isomeric purity >99%) and the
Wittig reaction achieves 98% isomeric purity, the present
synthesis achieved high stereoselectivity (97% isomeric
purity).
Considering that both pheromones are increasingly used
in large-scale field tests, the development of the concise,
cost-effective, and operationally simple synthetic ap-
proaches is necessary. Previously, we reported an effi-
cient synthesis of (5Z,7E)-dodecadien-1-ol, the sex
pheromone of Dendrolimus Spp., from aldehyde 3.12 As a
part of an ongoing program, we report herein concise and
stereoselective syntheses for (7Z,11Z,11E)-hexadecatrie-
nal (1) and (8E,10Z)-tetradecadienal (2) from aldehyde 3,
which successfully overcome the major limitations of the
strategies published previously. In both syntheses, E,Z-
conjugated double bonds of 1 and 2 were achieved by
cross-coupling between Grignard reagents and (E,Z)-bro-
modienes.
CHO
1
OHC
2
a
Br
Br
CHO
3
8
Figure 1
b
c
Bromide 6, an important intermediate for both syntheses,
was firstly prepared from 4-bromobutan-1-ol (4,
Scheme 1). Alcohol 4 in THF was treated with 2.1 equiv-
alents of allylmagnesium chloride in the presence of dil-
ithium tetrachlorocuprate to give 6-hepten-1-ol (5), which
was treated with triphenylphosphine–bromine complex in
acetonitrile to afford 7-bromohept-1-ene (6). The bromide
was heated with triphenylphosphane in acetonitrile to fur-
nish phosphonium salt 7 in 71% overall yield based on 4
(3 steps).13
9
d
OH
10
1
CHO
Scheme 2 Reagents and conditions: (a) phosphonium salt 7,
KN[Si(Me)3]2, THF, –78 °C, 12 (85%); (b) EtMgBr, cat.
h
NiCl2(dppp), THF, r.t., 12 h (93%); (c) (i) 9-BBN, r.t., 60 min; (ii)
H2O2–NaOH, 1.5 h (80%); (d) PCC/Celite, CH2Cl2, r.t., 5 h (83%).
a
b
Br
OH
OH
4
5
7
c
+
In the synthesis of (8E,10Z)-tetradecadienal, aldehyde 3
was treated with zinc-modified cyanoborohydride and (p-
tolylsulfonyl)hydrazine in methanol to afford diene 11 in
72% yield (Scheme 3).20,21 Kumada cross-coupling of di-
ene 11 with (6-hepten-1-yl)magnesium bromide prepared
from bromide 6 in dry THF at room temperature gave
triene 12 in 91% yield and 99% isomeric purity.17,22
Triene 12 was transformed into alcohol 13 via hydrobora-
tion–oxidation in 85% yield as described before.19 In the
final step, (8E,10Z)-tetradecadienal (2) was also prepared
by oxidation of alcohol 13 in 84% yield as described be-
PPh3Br –
Br
6
Scheme 1 Reagents and conditions: (a) CH2=CHCH2MgCl (2.1
equiv), Li2CuC14 (20 mol%), THF, r.t., 15 h (90%); (b) Ph3P, Br2,
MeCN, –10 °C, 1 h (85%); (c) Ph3P, MeCN, 80 °C, 48 h (93%).
(7Z,11Z,13E)-Hexadecatrienal (1) was synthesized by an
unambiguous stereoselective route, as outlined in
Scheme 2. 7-Bromo-(4Z,6E)-heptadienal (3) was pre-
pared in 50% yield by the tandem addition reaction of ac-
Synlett 2012, 23, 581–584
© Thieme Stuttgart · New York

LETTER
(7Z,11Z,13E)-Hexadecatrienal and (8E,18Z)-Tetradecadiena
Bento, J. M. S.; Vilela, E. F.; Leal, W. S. Florida
583
fore.15 The overall yield of the target product 2 from alde-
hyde 3 was 47%; the overall yield of the product 2 from
acrolein was 23%. Because of the high isomeric purity of
aldehyde 3, the present synthesis achieved a high stereo-
selectivity (99% isomeric purity).
Entomologist 2006, 89, 274.
(6) Vang, L. V.; Islam, M. A.; Do, N. D.; Hai, T. V.; Koyano, S.;
Okahana, Y.; Ohbayashi, N.; Yamamoto, M.; Ando, T.
J. Pestic. Sci. 2008, 33, 152.
(7) Biobest Technical sheet. Pheromone of horse-chestnut leaf
miner (www.biobest.be).
(8) Grodner, J. Tetrahedron 2009, 65, 1648.
a
(9) (a) Svatos, A.; Kalinova, B.; Hoskovec, M.; Kindl, J.;
Hovorka, O.; Hrdy, I. Tetrahedron Lett. 1999, 40, 7011.
(b) Hoskovec, M.; Saman, D.; Svatos, A. Collect. Czech.
Chem. Commun. 2000, 65, 511.
(10) Francke, W.; Franke, S.; Bergman, J.; Tolasch, T.; Subchev,
M.; Mircheva, A.; Toshova, T.; Svatos, A.; Kalinova, B.;
Karpati, Z.; Szocs, G.; Toth, M. Z. Naturforsch., C: J. Biosci.
2002, 57, 739.
Br
CHO
Br
3
11
b
c
12
13
2
HO
d
OHC
(11) Figueiredo, R. M.; Berner, R.; Julis, J.; Liu, T.; Turp, D.;
Christmann, M. J. Org. Chem. 2007, 72, 640.
(12) Tao, Y. H.; Cheng, W. X.; Zhang, Y. S.; Gu, K. Chem. J.
Chin. Univ. 2005, 26, 1072.
(13) Toru Nakayama, T.; Mori, K. Liebigs Ann./Rec1. 1997, 839.
(14) Wang, Z.; Lu, X.; Lei, A.; Zhang, Z. J. Org. Chem. 1998, 63,
3806.
Scheme
3
Reagents and conditions: (a) TsNHNH2/ZnCl2–
NaBH3CN, MeOH, 65 °C, 2 h (72%); (b) hept-6-enyl -magnesium
bromide, cat. NiCl2(dppp), THF, r.t., 12 h (91%); (c) (i) 9-BBN, r.t.,
60 min; (ii) H2O2–NaOH, 1.5 h (85%); (d) PCC/Celite, CH2Cl2, r.t., 5
h (84%).
(15) Ragoussis, V.; Perdikaris, S.; Karamolegkos, A.; Magkiosi,
K. J. Agric. Food Chem. 2008, 56, 11929.
(16) Preparation for Tetraene 8
Both synthetic approaches employed low-cost reagents,
familiar operation, and mild conditions, thus the present
strategies may become a more desirable alternative for
both target products in high stereoselectivity and high
yield. The simplicity and the low cost of the present syn-
theses suggest the potentially practical use of the above
pheromones in integrated management programs for both
serious insect pests.
Potassium bis(trimethylsilyl) amide (75 mL, 75 mmol, 1 M
solution in THF) was added dropwise over 30 min to a
suspension of freshly prepared phosphonium salt 7 (33 g, 75
mmol) in dry THF (75 mL) at 0 °C, under nitrogen. The
resulting orange solution was stirred for 1 h at 0 °C and then
cooled to –78 °C. A solution of aldehyde 3 (9.5 g, 50 mmol)
in dry THF (100 mL) was added dropwise over 1 h,
maintaining the temperature below –70 °C. The resulting
yellow solution was allowed to warm slowly to r.t. over a
period of 3 h and left overnight. Then the reaction mixture
was quenched with a sat. solution of NH4Cl (150 mL). After
THF was removed by evaporation, the reaction mixture was
extracted with PE (3 × 40 mL). The extract was washed with
H2O and brine, dried over Na2SO4, and concentrated. The
residue was purified through a silica gel column (eluent: PE)
to afford tetraene 8 as a colorless oil (11.48 g, 85%, isomeric
purity >98%, chemical purity 96%). 1H NMR (500 MHz,
CDCl3): d = 6.97 (ddd, J = 13.3, 11.6, 1.2 Hz, 1 H, CH=CH),
6.32 (dd, J = 13.3, 1.3 Hz, 1 H, CH=CH), 5.93 (ddd,
J = 11.6, 11.1, 1.3 Hz, 1 H, CH=CH), 5.80 (ddt, J = 17.1,
10.1 Hz, 1 H, CH=CH2), 5.43–5.23 (m, 3 H, CH=CH,), 4.98
(d, J = 17.1 Hz, 1 H, Z-CH=CH2), 4.92 (d, J = 10.1 Hz, 1 H,
E-CH=CH2), 2.15–1.95 (m, 8 H, CH2), 1.42–1.32 (m, 4 H,
CH2CH2). 13C NMR (125 MHz, CDCl3): d = 139.3, 133.2,
131.4, 128.9, 128.3, 126.5, 114.6, 109.3, 33.4, 29.5, 28.9,
28.4, 27.5, 26.8. ESI-HRMS: m/z calcd for C14H21Br [M]+:
268.0827; found: 268.0812.
In summary, we have developed highly efficient and ste-
reoselective syntheses of (7Z,11Z,13E)-hexadecatrienal
(1) and (8E,10Z)-tetradecadienal (2) with very good over-
all yield. The stereoselective formation of E,Z-conjugated
double bond relied on cross-coupling between Grignard
reagent and (E,Z)-bromodiene.
Acknowledgment
We gratefully acknowledge State Key Laboratory of Elementoorga-
nic Chemistry, Nankai University (Grant No. 0703) for financial
support.
References and Notes
(1) (a) Heppner, J. B. Trop. Lepid. 1993, 4, 49. (b) Argov, Y.;
Rossler, Y. Phytoparasitica 1996, 24, 33.
(2) (a) Parra-Pedrazzoli, A. L.; Leal, W. S.; Vilela, E. F.;
Mendonca, M. C.; Bento, J. M. S. Pesq. Agropec. Bras.,
Brasília 2009, 44, 676. (b) Leite, R. P. J.; Mohan, S. K.
Brazil Crop Protection 1990, 9, 3.
(3) Mafi, S. A.; Vang, L. V.; Nakata, Y.; Ohbayashi, N.;
Yamamoto, M.; Ando, T. J. Pestic. Sci. 2005, 30, 361.
(4) Leal, W. S.; Parra-Pedrazzoli, A. L.; Cosse, A. A.; Murata,
Y.; Bento, J. M. S.; Vilela, E. F. J. Chem. Ecol. 2006, 32,
155.
(5) (a) Moreira, J. A.; McElfresh, J. S.; Millar, J. G. J. Chem.
Ecol. 2006, 32, 169. (b) Stelinski, L. L.; Miller, J. R.;
Rogers, M. E. J. Chem. Ecol. 2008, 34, 1107. (c) Lapointe,
S. L.; Hall, D. G.; Murata, Y.; Parra-Pedrazzoli, A. L.;
(17) Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth., Coll.
Vol. VI 1988, 407.
(18) Preparation for Tetraene 9
A solution of tetraene 8 (10.72 g, 40 mmol) and NiCl2(dppp)
(54.2 mg, 0.1 mmol) in dry THF (40 mL) was stirred at r.t.
for 30 min under an argon atmosphere. EtMgBr (60 mmol)
in dry THF (60 mL) was added to the mixture cooled in an
ice bath over 30 min. The nickel complex reacts immediately
with the Grignard reagent, and the resulting clear-tan
reaction mixture is allowed to warm up to r.t. with stirring
for 12 h. After the reaction was completed, the mixture was
poured into H2O. After THF was removed by evaporation,
the reaction mixture was extracted with PE (3 × 30 mL). The
extract was washed with H2O and brine, dried over Na2SO4,
© Thieme Stuttgart · New York
Synlett 2012, No. 4, 581–584

584
Z. Ma et al.
LETTER
1.2 Hz, 1 H, CH=CH), 6.26 (dd, J = 13.3, 1.3 Hz, 1 H,
and concentrated. The residue was purified through a silica
gel column (eluent: PE) to afford tetraene 9 as a colorless oil
(8.11 g, 93%, isomeric purity >97%, chemical purity 96%).
1H NMR (500 MHz, CDCl3): d = 6.30 (ddd, J = 15.0, 11.0,
1.0 Hz, 1 H, CH=CH), 5.99 (ddd, J = 11.0, 10.7, 1.1 Hz, 1 H,
CH=CH), 5.80 (ddt, J = 17.1, 10.1 Hz, 1 H, CH=CH2), 5.71
(dtd, J = 15.0, 7.5, 1.1 Hz, 1 H, CH=CH), 5.46–5.26 (m, 3
H, CH=CH), 4.99 (d, J = 17.1 Hz, 1 H, Z-CH=CH2), 4.93 (d,
J = 10.1 Hz, 1 H, E-CH=CH2), 2.15–1.95 (m, 10 H, CH2),
1.42–1.32 (m, 4 H, CH2CH2), 1.02 (t, 3 H, J = 7.5 Hz, CH3).
13C NMR (125 MHz, CDCl3): d = 139.4, 136.8, 130.3, 129.7,
129.5, 129.4, 125.1, 114.6, 33.1, 29.6, 29.0, 28.3, 27.8, 27.5,
26.3, 14.0. ESI-HRMS: m/z calcd for C16H26 [M]+:
CH=CH), 5.89 (ddd, J = 11.6, 11.1, 1.3 Hz, 1 H, CH=CH),
5.47 (dtd, J = 11.1, 7.5, 1.2 Hz, 1 H, CH=CH), 2.10 (m, 2 H,
CH2), 1.42 (m, 2 H, CH2), 0.90 (t, J = 7.5 Hz, 3 H, CH3). 13
NMR (125 MHz, CDCl3): d = 133.5, 133.3, 125.9, 108.6,
C
29.9, 22.6, 13.7. ESI-HRMS: m/z calcd for C7H11Br [M]+:
174.0044; found: 174.0062.
(22) Spectral Data for Triene 12
1H NMR (500 MHz, CDCl3): d = 6.30 (ddd, J = 15.0, 11.0,
1.0 Hz, 1 H, CH=CH), 5.99 (ddd, J = 11.0, 10.7, 1.1 Hz, 1 H,
CH=CH), 5.80 (ddt, J = 17.1, 10.1 Hz, 1 H, CH=CH2), 5.65
(dtd, J = 15.0, 7.5, 1.1 Hz, 1 H, CH=CH), 5.30 (dtd, J = 10.7,
7.5, 1.0 Hz, 1 H, CH=CH), 4.99 (d, J = 17.1 Hz, 1 H, Z-
CH=CH2), 4.93 (d, J = 10.1 Hz, 1 H, E-CH=CH2), 2.15–2.00
(m, 6 H, CH2), 1.42–1.32 (m, 8 H, CH2CH2), 0.9 (t, 3 H,
J = 7.5 Hz, CH3). 13C NMR (125 MHz, CDCl3): d = 139.5,
134.9, 130.8, 130.3, 126.1, 114.6, 34.1, 32.9, 32.3, 30.1,
29.7, 29.1, 23.1, 14.1. ESI-HRMS: m/z calcd for C14H24
[M]+: 192.1878; found: 192.1861.
218.2035; found: 218.2023.
(19) Brown, C. A.; Coleman, R. A. J. Org. Chem. 1979, 44, 2328.
(20) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org.
Chem. 1985, 50, 1927.
(21) Spectral Data for Diene 11
1H NMR (500 MHz, CDCl3): d = 6.97 (ddd, J = 13.3, 11.6,
Synlett 2012, 23, 581–584
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.