GENERAL METHODOLOGY FOR THE SYNTHESIS OF CONJUGATED DIENIC INSECT SEX PHEROMONES

Article abstract of DOI:10.1016/S0040-4020(01)96893-0

A general methodology for the synthesis of various type of dienic insect sex pheromones (Z-E, E-Z, Z-Z) is based on the carbocupration of acetylene by functionalised or non-functionalised lithium dialkyl cuprates, followed by the coupling of the resulting Z dialkenyl cuprates with functionalised or non-functionalised E or Z alkenyl iodides under Pd⁰ catalysis.The following compounds were efficiently synthesized with a high degree of stereoisomeric purity: (E-Z)7,9-dodecadien,-1-yl acetate 1 (Lobesia botrana), (E-Z)10,12-hexadecadien,-1-ol 2 (Bombyx mori), (Z-E)9,11-tetradecadien,-1-yl acetate 3 (Spodoptera littoralis), (Z-E)5,7 dodecadien-1-ol 4 (Malascoma disstria), (Z-Z)11, 13-Hexadecadien-1-al 5 (Amyelois transitella), (Z)9,11-dodecadien-1-yl acetate 6 (Diparopsis castanea) and (Z-Z)9,11-tridecadien-1-yl acetate 22 (a known "pseudo-pheromone").

Full text of DOI:10.1016/S0040-4020(01)96893-0

Vol.
No. 14, pp. 2741 to
1984
$3.00
in the U.S.A.
Ltd
GENERAL METHODOLOGY FOR THE SYNTHESIS OF
CONJUGATED DIENIC INSECT SEX PHEROMONES
M.
N. JABRI
,
A.
and J. F.
4 Place Jussieu, 75230,
Laboratoire de
des Organo-Elements, Tour
05, France
(Received in France 18 July 1983)
general methodology for the synthesis of various types of
E-Z, Z-Z) is based on the carbocupration of acetylene by
dialkyl cuprates, followed by the coupling of the resulting Z
insect sex pheromones (Z-E,
or non-functionalised lithium
with fimctionalised or
non-functionalised E or Z alkenyl iodides under Pd” catalysis. The following compounds were efficiently
synthesized with a high degree of stereoisomeric purity:
acetate 1
acetate 3
2
1
Spoabptera littoralis),
4
disstria),
1,
5
acetate 6
and
acetate 22 (a known “pseudo-pheromone”).
present a general methodology for the synthesis of
pheromones of Z-Z, E-Z, and Z-E
which, we believe, meets the above
requirements. This methodology is illustrated by the
synthesis of the following typical pheromones (or by
the synthesis of their known direct precursor):
Insect sex pheromones are a class of biologically
active compounds of growing interest and many new
methodologies have been developed for their syn-
thesis.’ The chemical structure of many of these
pheromones contains a long carbon chain with a
terminal functionality Y
and which often incorporates a conjugated
system:
diene
This diene system may be of E-E type, of
Z-Z type or, more frequently, of E-Z and Z-E type.
In these two last cases the terminal functionality
could be on the “Z part” of the molecule or on the
“E part”:
E
pa r t
part
Many syntheses of these pheromones have been
developed’ and may be roughly divided into four
classes: (a) the Wittig type
in which the Z
double bond is created by reaction of an E alkenal
with an alkyl triphenylphosphonium ylide; (b) the
carbon chain
of an already prepared diene
system bearing an allylic functionality; (c) the syn
reduction of the triple bond of an E which can
be prepared by various ways; (d) the direct coupling
3
of two alkenyl
one of Z configuration and
one of E configuration (this highly convergent ap-
proach is the most recently developed).
Among these various approaches, few
a
product of high stereoisomeric purity and even fewer
may be considered to be of preparative value. The
need for preparative syntheses stems from the fact
that these pheromones are more and more used for
large scale field tests. In this respect, a synthesis of
preparative value should satisfy two major require-
ments. First, it should use low cost reagents and
starting materials and second it should avoid the
expensive chromatographic purification or low tem-
perature ( 35”) recrystallization which are needed
when the synthesis does not afford a product of high
12
D i p a r o p s i s
6
enough chemical or
purity. In this article we
2741

M.
2742
GENERAL METHODOLOGY
In the second preliminary study we optimized the
carbocupration of acetylene with
in order to be able to introduce the func-
tionality on the “Z part” of a dienic pheromone:
The syntheses shown below are of the convergent
type, linking together in a “one-pot” operation two
alkenyl moieties of which the Z alkenyl moiety is
brought about by an organometallic species. This
organometallic reagent is a Z dialkenyl
obtained by the known carbocupration of
easily
2
e q.
4
e q.
1
Among the various functionalities Y, we found that
the most convenient and efficient one was the alcohol
group, protected as an ethoxyethyl ether.” With this
functionality, the experimental conditions of the
bocupration reaction are only slightly different from
the standard ones.
2
+
l
Having secured the two key reactions (eqns 2-4) on
which we based our synthetic strategy, we turned our
attention to the preparation of the E alkenyl iodides
which are the other partners of the coupling reaction
(eqn 1). Among the various methods for the synthesis
of these alkenyl iodides, the most efficient and straight-
forward are based on the hydrometallation of a
terminal
or non-conjugated
pheromones have already been
by the reaction of these Z dialkenyl
Many
with an
appropriate electrophile. These pheromones have been
shown to be of greater than 99.9% Z purity and they
are obtained in high yield by simple distillation of the
crude product.
H- M
I 2
,
R- CE CH
H'
'
I
In our syntheses of the
needed to couple the Z dialkenyl
pheromones we
with an
The products obtained by this way are usually pure
enough ( 99%) to avoid any further purification
alkenyl moiety of E configuration (eqn 1). Toward
this end, two preliminary studies have been under-
taken on model systems. In the first one we optimized
the conditions of the coupling of the Z dialkenyl
and separation of isomers.
hydro-
hydro-
and
are the most often used reactions, but
as far as cost is concerned, the hydroalumination
with E iodo-alkenes. These
usually inert towards iodo-alkenes. However, we
found that upon transmetallation into the zinc
reagent, they are able to couple with and
iodides in the presence of catalytic amounts of
Pd” complex.
are
reagent
(diisobutyl aluminum hydride) is
by far the less expensive. The non-functionalised E
alkenyl iodides prepared by this way are of high
purity
and they are also ob-
The main drawback
tained in good yield
lies in the fact that functionalised alkynes (bearing an
oxygenated functionality) do not react as
but
this difficulty was easily circumvented as shown be-
low.
Synthesis of E-Z pheromones
Among the pheromones which possess a conju-
gated diene system of E-Z type the most representa-
tive are the pheromone of
3% Pd"
and
the European grape vine moth 1 and the
pheromone of Bombyx mori, the silkworm moth 2.
Due to the importance of the damage caused by the
grape vine moth, compound 1 has been synthesized
In this reaction, only one alkenyl group of the
is used. This loss is not a serious drawback when the
alkenyl iodide is the valuable partner of the coupling
many
using
all the known meth-
reaction. On the contrary, when the
is the
odologies. The diene system of this pheromone is of
E-Z type with the functionality lying on the “E part”
of the molecule. This means, that, for a convergent
approach, the alcohol or acetate functionality will be
carried by the E alkenyl iodide moiety (see eqn 1).
valuable partner, this loss becomes an evident disad-
vantage. Thus, we were led to seek conditions where
both alkenyl groups are transfered, and we found that
this is possible, if the lithium
formed-into a magnesium
is first trans-
+
e q.
3
2
+
3% Pd"

General methodology for the synthesis of conjugated dienic insect sex pheromones
2743
This reaction
in a one-pot procedure the
Thus, for the synthesis of the pheromone of Lobesia
botrana 1 we needed to prepare I-iodo, (E)
or its acetate. The standard
pheromone in a 78% distilled yield and with a 97.3%
1
E-Z purity. The increase in stereoisomeric purity of
the diene 1 as compared to the starting iodide 8 was
not unexpected since we observed in the preliminary
study that E iodo-alkenes were much more reactive
alumination of
l-o protected as THP ether,
afforded, as expected, less than
iodide
of the desired
than their Z
Noteworthy is also
the fact that the acetate functionality was com-
pletely unaffected by the organometallic reagent used.
Thus, we demonstrated that our key coupling reac-
tion was highly efficient for pheromone synthesis. It
is clear that if the iodo-alkene was of higher
1) DI BAH
isomeric purity, the pheromone would have been
obtained in an even higher steroisomeric purity. The
main drawback of our synthesis of the pheromone of
Lobesia
1 does not lie in the key coupling
reaction, but in the preparation of the functionalised
E iodo-alkene. This drawback was circumvented for
the synthesis of the other typical E-Z dienic pher-
omone bomyko12.
However, Zweifel et al. reported recently that
terminal alkynes protected by a trimethylsilyl group
may be hydroaluminated even in the presence of an
After reduction and
dination, the trimethylsilyl group may removed
oxygenated functionality.
Bombykol 2 is the pheromone of Bombyx mori,
the silkworm moth. This compound owes its notoriety
to the fact that it was the
Since then, bombykol 2 has been synthesized by all
known methods as representative of E-Z dienic
Here again the functionality lies in the “E
part” of the molecule, and therefore it will be carried
by the E iodo-alkene moiety, which in the case of
bombyko12 would be the 1-iodo-l(E)-undecen-1
9.
without isomerisation of the stereochemistry of the
newly created double bond. Unfortunately, in our
hands, this procedure afforded only a 18% yield of
iodo-alkene 7 with only 94.5% isomeric purity:
isolated pheromone.*
I
1) DI BAH,
_
Since the hydroalumination of alkynes bearing an
oxygenated functionality was not
we chose
another functionality which tolerates a strong Lewis
acid, such as DIBAH. A halogen functionality, for
example, is unaffected during hydroahunination and
is easily transformed into an alcoholic one with the
same or a higher number of carbon atoms. Thus,
alkenyl iodide 9 could be prepared according to the
following scheme:
l
7
1) DI BAH
18%
5. 5)
2
Nevertheless, we carried out the synthesis of the
pheromone 1 with this material in order to explore
the feasability of our key coupling reaction. Thus, the
iodo-alkene 7 was directly transformed into the cor-
responding acetate 8 by treatment with
a c e t one
11
(10:
This direct acetylation procedure preserves
the geometrical integrity of the double bond. The
acetate 8 was then added admixed with 3%
5% c ux
11
to a THF solution of Z dibutenyl
which had
previously been transmetallated into the zinc species
by addition of one equivalent of zinc bromide:
Et
2
2
79%
9 7 . 3 %)
3%

M.
et al.
2744
following scheme:
Hydroalumination of
followed
by iodination, proceeded without any trouble,
affording in
(E purity
isolated yield the alkenyl iodide
An attempted carbon chain
1 0
a c e t one
extention on compound 10 to obtain directly 9 was
since functionalised Grignard reagent
in the presence of catalytic amounts of
reacted mainly at the
carbon-iodine bond instead
of the carbon-chlorine bond. The chloro-iodide 10
could be easily transformed into the di-iodide 11 by
halogen exchange with sodium iodide in acetone” (or
methanol) with complete retention of the stereo-
chemistry of the double bond. Compound 1 1 , in turn,
14
reacted with the Grignard reagent
under cop-
per(1) catalysis, to give mainly, but not exclusively
(70% selectivity) the expected iodo-alcohol 9. Thus,
5% c ux
this
which
chromatographic
route,
needed
The key coupling reaction between the diiodide 11
and the dialkenyl previously transmetallated
into the zinc species, proceeded quantitatively with
purification, was abandonned since it was not in
agreement with one of the above requirements.
Another approach, also based on the use of alkenyl
iodide 10, is depicted below:
exclusive attack at the alkenyl iodide
This
remarkable selectivity of the palladium catalysed
contrasts with the above-mentioned cop-
per catalysed coupling at the alkyl iodide group with
the Grignard reagent 12. The crude iodide 14 was not
further purified and was used directly in the next
carbon chain extention step. Thus, the
3% Pd"
Grignard 12 reacted easily, under copper(I) catalysis,
with iodide 14 to
the expected pheromone 2.
Crude bombykol 2 was distilled through a
,
Pr
Vigreux column to afford a
yield (based on the
a c e t one
alkenyl iodide 10) of purified material. This
ykol 2 showed a 99.8% stereoisomeric purity upon
examination by capillary glass chromatography.
This preparative synthesis of bombyko12 is repre-
sentative of our general methodology for the syn-
thesis of E-Z dienic pheromones. Although we have
not synthesized other pheromones of this type, we
may consider that the same route can be applied for
the synthesis of many other pheromones using a Z
14
5% c ux
2
The iodide 10 reacts easily with Z dipentenyl
in the presence of zinc bromide and 3%
to
dialkenyl
and a functionalised Grignard with
give chloro-diene 13 in 89% yield. As expected in this
case, the organemetallic reagent completely discrimi-
nates between the alkenyl iodide and alkyl chloride
the appropriate carbon chain length. In this context,
the common intermediate
easily prepared in bulk and conveniently stored in the
refrigerator without noticeable decomposition, is the
keystone for various E-Z pheromone syntheses.
functionalities in favor of the
At this stage,
chloro-diene 13 showed a high stereoisomeric
purity
99.5%) as checked by
lary glass chromatography
NMR and capil-
20m). According to
Synthesis of Z-E pheromones
our synthetic scheme, this compound has to be
elongated by six carbon atoms for the obtention of
the pheromone 2. The attempted reaction of the
Pheromones with a conjugated dienic system of
Z-E type, have the functionality lying on the “Z
part” of the molecule. Using our general meth-
odology, this means that the functionality has to be
chloride 13 with the
Grignard reagent
12 under copper(I) catalysis failed completely. The
recovered chloro-diene 13 was, then, transformed
into the more reactive iodide 14 by the usual
acetone (or methanol) method. Unfortunately this
reaction was very slow at room temperature and even
at reflux temperature it needs two days for completion.
However, under these stringent conditions, the ob-
tained iodide 14 was partially
introduced by the Z dialkenyl
moiety:
probably due to the presence of traces of free iodine
which is known to isomerise the conjugated dienic
systems.
Another similar synthetic route was also in-
vestigated, in which the transhalogenation step pre-
ceded the key coupling reaction, according to the
The pheromone of Spodopteru
3, the Egyp-
tian cotton leafworm, is the most trivial example of
this class of pheromone, and a very large number of
syntheses have been
Our approach is
for the
based on the use of
preparation of the Z dialkenyl
and is

2745
methodology for the synthesis of conjugated dienic insect sex pheromones
picted below:
Li
0. 5
l
Et 20
2
3%
15
CH
I 3
EEO-
seems that the acidic deprotection step is responsible
for that fact. Nevertheless, this purity is high enough
for field tests in the case of this pheromone.
Another example of Z-E type pheromone is
compound 4, the pheromone of
the forest tent caterpillar.” The same methodology as
above is used for this synthesis as depicted below:
The easily available
protected
Na content)
as an ethoxyethyl ether, is transformed into the
lithium reagent with lithium metal
in ether under the usual reaction conditions
with an average yield of 65%. This
organolithium reagent”’ affords a stable
when the complex
is used, and its
0. 5
Li
,
+
3%
16
In this case, the functional&d
coupled with
16 is used and
addition to acetylene occurs under the standard
reaction The Z dialkenyl
15 has, now, to be coupled with
to the required pheromone
3. In contrast to the previous examples of this key
coupling reaction, the most valuable of the two
partners is, here, the functionalised Z dialkenyl
and not the non-functional&d alkenyl iodide. There-
fore, it is imperative to use efficiently both alkenyl
After deprotection
of the alcohol, the pheromone is purified by dis-
tillation and obtained in 37% yield. The stereo-
isomeric purity was here, also, lower than we wished:
98.1%. If, however, the crude pheromone was
purified by short flash chromatography, the yield is
increased to 53%. This different behaviour points to
the sensitivity of these compounds to prolonged
heating. It is also interesting to note that dienic
pheromones bearing an acetate functionality seem to
be less sensitive than the ones bearing a free alcohol.
groups of the
and we found in our pre-
liminary study,” that this is indeed possible when the
lithium
nesium
is first transformed into the mag-
and then transmetallated into the zinc
Synthesis of Z-Z and
Z
pheromones
reagent. Under these experimental conditions, the
pheromone was obtained in high overall yield (based
on the lithium reagent), after removal of the protec-
ting group and acetylation. Distillation of the crude
pheromone 3 afforded a product of 97.2% stereo-
Pheromones with a conjugated dienic system of
Z-Z type are less frequently encountered. The main
example is the pheromone of Amyelois transitella
5, the navel orange
odology, this kind of pheromone may be synthesised
by either of these two ways:
Using our meth-
isomeric purity in
overall yield. The stereo-
isomeric purity is not as high as we wished and it
or
:
9
or 10 a c c or di ng t o
:
0

M.
et
dienic system seems to be too sensitive towards
prolonged heating. On the other hand, the simple
through silica gel (10 1 ratio of silica gel to
In both of these two ways the Z alkenyl iodide is
prepared by iodination of a Z dialkenyl
In the first approach we synthesized the func-
tional&d Z alkenyl iodide 18 in the following way:
product) with elution with pentane, then ether,
afforded pure dienic alcohol 21 in 72% yield. This
material was homogeneous by TLC and GLPC and
showed an isomeric purity
99% as judged by
2
C0'
and NMR. The obtention of 21 constitutes a
formal synthesis of the pheromone 5 since its
vertion to the aldehyde by pyridinium
C0
chromate oxidation is already
Thus, we
can consider that our general methodology may be
easily extended to the synthesis of Z-Z dienic pher-
omones.
71%
18
17
Another example of synthesis of Z-Z dienic sys-
tems is the preparation of (Z, Z), 1
acetate 22. This compound has been shown to give a
higher response on the antennae of males of some
processionary moths than their corresponding pher-
omones, and more material was needed for further
tests?
This iodide 18, obtained in 71% yield and with a high
isomeric purity ( 99.9%) was coupled with Z
butenyl
under the usual conditions:
22
19
The key coupling reaction afforded a 74% crude yield
of the diene 19 which was homogeneous by TLC and
This compound was synthesized, also, by coupling
of two alkenyl moieties one of which is a Z propenyl
GLPC. The Z-Z stereoisomeric purity of this diene group and the other one a functionalised Z alkenyl
was estimated to be.
according to
and iodide. The previously used functionalised Z
alkenyl
15 was iodinated and the crude
spectra. Capillary glass chromatographic
analysis showed a single peak, but since the other
stereoisomers were not available, it is hard to appre-
ciate more accurately this purity. The aldehyde func-
tionality of diene 19 had to be deprotected for the
obtention of the pheromone 5. Treatment of diene 19
with oxalic acid in methanol at room temperature
overnight resulted in an only 10% conversion to the
aldehyde 5. On the other hand, treatment with pure
anhydrous formic acid afforded, indeed, the expected
aldehyde 5 but the pheromone was partially
product was deprotected and acetylated with
23
(
under these vigorous conditions.
These difficulties were circumvented using the sec-
ond possible approach. According to this scheme we
The iodide 23 was obtained in 70% isolated yield
and its
purity was 99.9% as usually found
reacted the functionalised
with
for all Z alkenyl iodides obtained by carbocupration
of acetylene. The needed organometallic partner of
the key coupling reaction is, in the present case, the
Z propenyl moiety, which, unfortunately cannot be
prepared by carbocupration of acetylene, since lith-
I-iodo-i(Z)-butene under the coupling conditions
where
alkenyl groups of the
are
2
10
ium
this
does not add satisfactorily to
Therefore we prepared the required
20
with 96.4% Z
purity
from trans. crotonic
verted into the lithium
This bromide was con-
(Li metal,
85% yield) which was transmetallated into the
zinc reagent for the coupling reaction with 22 in the
presence of a catalytic amount of
21
H+
3
3
THF
After deprotection of the alcohol, the crude dienic
alcohol 21 could be either distilled or purified by
short filtration through silica gel. Attempted dis-
23
tillation through a
Vigreux column
3% Pd"
only a
yield of alcohol 21 which, however, was
The Z-Z conjugated
partially

General methodology for the synthesis of conjugated dienic insect sex pheromones
2747
model 457 spectrometer. GLPC analyses were
After distillation through a 10 cm Vigreux column the
required diene 22 was isolated in 92% yield and its
performed on a Carlo Erba gas
1 and 2150) using a 3 m glass
10% LAC 860 on chromosorb
capillary glass
matograph was coupled to an integrator LTT 9400. All
reactions are performed under nitrogen in a flask
equipped with a low temperature thermometer, a mechani-
cal stirrer and a pressure addition funnel.
l(Z)-butene was prepared according to Ref.
(models G
(10% SE 30 or
mesh) and
purity was found to be
almost as high as that
of the starting Z bromopropene. This loss in
purity is due to the slight isomerisation
a
(OV 101). The gas
which
during the preparation of the Z
lithium.%. In the synthesis of the
pheromone” 22 the carbocupration reaction has been
used only for the preparation of the required func-
tional&d Z alkenyl iodide. This class of compounds
is very useful1 for the synthesis of a large variety of
natural products, including of course pheromones.
A last example of the use of such functionalised Z
alkenyl iodides is given by the synthesis of the
1-Iodo-l(E)-butene and
according to Ref. 28.
are prepared
Preparation of
The organolithium reagent (50mmol) prepared in ether
(from the corresponding bromide and lithium metal) was
added to a suspension of copper(I) iodide (5.35 g, 28 mmol)
pheromone of
(Hamps) 6 the red
This pheromone is the typical
or (in the case of
organolithium reagent)
(1 1 com-
example of a terminal conjugated dienic system of Z
configuration. Our synthesis requires the same
kenyl iodide 23 which was needed for the above
“pseudo-pheromone” 22. In the present case the
coupling reaction was performed with the vinyl zinc
reagent obtained by transmetallation of the vinyl
Grignard reagent, according to:
copper(I) bromide-dimethyl sulphide
plex; 5.75 g, 28 mmol) in ether (100 ml) at 35”. The
mixture was stirred for 20 min at 35” until a clear solution
is obtained. Acetylene, from which acetone was removed by
passage through a dry ice cooled trap was measured in a
water gasometer (50
1.2 L) and bubbled into the
reaction mixture after being dried over a column packed
with calcium chloride. The temperature was allowed to rise
from -50” (at the start) to -25”. Stirring of the greenish
solution was maintained for 30 min at
whereupon the
solution of
further use.
(25mmol) was ready for
THF
23
acetate
3% Pd"
To a
of
protected as THP ether
(50mmol) in 50 ml THF, was added, at
50mmol
in 50 ml
of
(ethereal solution).
A f t e r
methylchlorosilane (100 mmol) was added in
The pheromone 6 is obtained in 67% distilled yield
and also with a high stereo-isomeric purity 99%. Due
to difficulties in the separation of the two
isomers on capillary glass gas chromatography this
purity was determined by
trometry.
THF. The mixture was stirred for 2 h at room temp, then
hydrolysed with aq ammonium chloride. After usual work-
up and evaporation of the solvent, the crude alkynylsilane
was added, in another flask, to a soln of diisobutyl alumi-
num hydride (55 mmol) in 55 ml hexane containing 55
and
THF. The mixture was heated 4 h at
then cooled to
CONCLUSION
and a soln of iodine (50 mmol) in 40ml THF was
slowly added. After this addition, the mixture. is brought to
From the syntheses shown above, it is clear that
our general methodology is applicable to the syn-
thesis of a large array of pheromones bearing a
conjugated dienic system of Z-E, E-Z, or Z-Z
configuration. This general methodology is based on
a pool of three useful reactions: (1) the
0” for 30 min, then hydrolysed with 250 ml
aqs sodium
hydroxide. The organic layer is washed twice with water,
once with aqs sodium thiosulphate and then with sat aq
sodium chloride. After evaporation of the solvents, the
crude product is dissolved in 45 ml methanol and added to
a solution of 13
hydroxide in 45 ml methanol. The
cupration of acetylene; (2) the coupling of the ob-
mixture is heated at 40” for 4 h, whereupon 300 ml of
water are added. The product is extracted 4-5 times with
ether, then washed once with sat aqs sodium chloride, and
dried over magnesium sulphate. After evaporation of the
solvents, the crude product is added to a 10 1 mixture of
(50ml) and left at room temperature over-
tained Z alkenyl
with alkenyl iodides, and
(3) the iodination of the functionalised Z dialkenyl
which the often required
tionalised Z alkenyl iodides. Each of these reactions
is completely stereoselective and the whole meth-
night. This mixture is then added to 200ml
water
odology
products of very high
and 200ml hexane and partitioned. The organic phase is
purity. In all the cases where the final pheromone was
sufficiently stable, the purification method was a
simple distillation, which is necessary when a large
amount of material is needed. The preparative poten-
tial of this methodology is also emphasized since all
the above syntheses were performed on multigram
scale. We believe finally, that many other pher-
omones and, of course, many other natural products
may be efficiently synthesized following the same
general methodology.
washed with
aq sodium bicarbonate, then with water,
dried over magnesium sulphate and concentrated in
The residue is distilled through a 10 cm Vigreux column to
afford 2.67 of pure acetate 8. Yield 18%.
mm
Hg;
950;
1.4965; IR (neat)
NMR 6.86
4.21
3H): NMR
64.3
3050, 1740, 1655, 1240,
dt,
t,
6.33 (CH=,
t, 2.09
170.9 (COO), 146.3
(CH=), 74.5
acetate
(100 ml) of Z dibutenyl
mmol) is prepared as described above. 40 ml of THFare
1
An ethereal
added at
EXPER IMENTAL
NMR spectra were recorded on
MH 100
followed by 2.7 (12 mmol) of
dissolved in 25ml THF. A mixture of
acetate 8 and 0.31 (0.27 mmol) of
bromide
(9mmol) of
in 30 ml THF
ppm from TMS), C NMR on Jeol FX 90 Q
ppm) spectrometers. IR spectra were obtained on a

M.
et al.
2748
is then added at -20” and the whole mixture is stirred at column to afford 3.65 g of pure “bombykol” 2. Yield 76%.
Hg;
and the aq layer extracted 3320, 3020, 1650, 980, 945, 720;
twice with ether. The combined organic phases are concen- (CH=, dd, 6.10 dd,
trated and
residue. The salts am
1.4722; IR (neat)
+ 10” for 1 h, then hydrolysed with 60 ml aq ammonium
chloride. The salts am
NMR
5.78
6.46
dt,
of pentane is added to the 5.44 (CH=, dt,
11 Hz, 3.68
NMR (CDCI,, 6): 134.5, 129.7, 128.9,
2H);
again, the organic phase
washed with aq ammonia, then with aq ammonium chloride
and finally dried over magnesium sulphate. After evapo-
ration of the solvents, the residue is distilled through a 10 cm
Vigreux column to afford 1.58 g of the title pheromone 1 .
125.7 (CH=), 67.2
acetate
An ethereal
1 5 is
(150 ml) of functionalised Z
Yield 78%.
mm Hg;
1.4739;
NMR
5.76 (CH=, dt,
4.18
NMR (CDCI,,
6): 170.9 (COO), 134.2 131.6, 128.1, 125.8 (CH=), 64.5
as described above (15
40
of THF are added at
followed by a THF
of
3020, 1745, 1650,980, 725;
6): 6.48
magnesium chloride (15 mmol) (freshly prepared by
(CH=, dd,
5.42 (CH=, dt,
t, 2.06
6.04
dd,
tion of
on magnesium turnings). To the
obtained magnesium
is added a THF of
3H);
bromide
15 mmol) at -30”. A mixture of 6.0 g
and 1.05 g of
in 50ml THF is then added and the whole
mixture is stirred at + for one hour, then hydrolysed and
hydride worked-up as described above for 1 . Th e obtained crude
of
100 ml of a
(DIBAH) in hexane
12.25 g (100 mmol) of
M
of diisobutyl
product is dissolved in 30
methanol and added to 1.2 ml
mmol) are added to a solution of
acetic acid in 40 ml methanol and 30 ml water. The mixture
is stirred at room temperature overnight. Most of the
solvents are then removed at reduced pressure and
in 50 ml of
ane at room temperature. After heating at 50” for 2 h, the
mixture is cooled to
followed by a
1OOmmol)in
and hydrolysed with dilute
is washed with aq sodium
and 50 ml of THF are added,
addition of iodine
-10”
of pentane am added along with
layer is washed twice with 50
water. The aqueous
pentane and the combined
acid. The organic layer organic phases are washed with aq sodium bicarbonate,
then with sat aq sodium chloride and then dried over
magnesium sulphate. After evaporation of the solvents the
crude residue is dissolved in 50 ml dry pyridine, cooled to
then with sat aq
sodium chloride and dried over magnesium sulphate. The
solvents are removed
1 0 is obtained in an average of
Hg; IR (neat) cm-‘: 3050, 1610, 950;
6.69 dt, 6.25 (ICI-I=, d,
3.64 NMR (CDCI,, 6): 144.2
and the residue d istille d . Pure
and 5.4 ml (75 mmol) of
The mixture is stirred 2 h at room temperature whereupon
200 ml pentane and water are added. The
chloride are added dropwise.
yield.
NMR
organic layer is washed once with dilute hydrochloric acid,
then with aq sodium bicarbonate, then with aq sodium
bicarbonate, then with sat aq sodium chloride and finally
dried over sodium sulphate. After evaporation of the sol-
: 16
(CH=), 71.1 (ICH=), 43.7
1 1
vents the residue is distilled through a
Vigreux
of pure pheromone 3. Yield
Hg; 1.4581; IR (eat)
11.5 (50
of alkenyl iodide1 0 are added, at room
of (250 mmol) of sodium iodide
acetone. The mixture is stirred at reflux for two
to
to a
in
days (at room temperature during the night) whereupon the
conversion was essentially complete. To the cooled mixture
3020, 1745, 1650,
HNMR
6):
6.42
dd,
6.08
dd,
16 Hz,
s, 3H):
5.80 (CH=, dt,
5.48 (CH=,
11
NMR
4.16
( +
are added 100
of pentane in order to precipitate
most of the inorganic salts which are filtered on a sintered
t,
2.07
S). 1 7 1 .0 (COO), 1 3 6 .0 , 1 2 9 .9 , 1 2 8 .7 , 1 2 4 .8 (CH=), 6 4 .6
glass funnel. The filtrate is concentrated
and 100 ml
of pentane am again added in order to precipitate all the
residual inorganic salts. This filtrate is concentrated in
to
quantitatively, the diiodide 1 1 which is used as
such. NMR
6): 6.62 (CH=, dt,
6.23 (ICH=,
Same procedure as for 3 using fimctionahsed
and I-iodo,(E)l-hexene. The acetylation step is omitted,
1.4891: IR (neat) cm-‘: 3350, 3020,
16
3.23
t, 2H); NMR
137.1
69.9 CH=), -0.7
1650, 1620, 980,945, 730;
dd, 6.05 (CH=, dd,
(CH=, dt,
NMR
5.72 (CH=, dt,
16 Hz, 11 3.64
6.48 (CH=,
“bom bykol”
ethereal soln (150 ml) of Z
as described above. 40 ml of THF are
by 5.7 g (25 mmol) of zinc bromide
dissolved in 40 ml THF. A mixture of 6.45 g (20 mmol) of
5.38
NMR (CDCI,, 6): 134.8, 129.4, 129.1, 125.6 (CH=), 62.4
(25 mmol) is
added at
1
diiodide1 1 and 0.7 g (0.6 mmol) of
in 50 ml THF
is then added at -20” and the whole mixture is stirred at
Same procedure as for 3 using fimctionahsed
and
The acetylation step is omitted.
1.4757; IR (neat) cm-‘:
+ 10” for
then hydrolysed and worked-up as
described above for 1. The obtained crude
14 is dissolved under nitrogen in
3810, 1640,
d,
NMR
3.64
S):
a separate flask in 100
THF and 0.15 g (0.1 mmol) of 6.28
5.50
m,
NMR
bromide is added. This mixture is cooled to 15”
6): 133.3, 131.8, 123.6, 123.1 (CH=), 62.4
a
prepared
(40
of functionalised
from
reagent
hexanol)
is added dropwise. After-the-end of the addition, the mixture
23
is stirred 30 min at +
then hydrolysed, at
with aq
An ethereal
of functionalised
is prepared
(
of finely
as described above (50 mmol). To this cooled
are added, in ten portions,
ammonium chloride. The organic phase is concentrated in
and 200ml of pentane are added to the residue in
crushed iodine. The mixture is warmed, carefully, to
stirred for 30 min and then hydrolysed with
order to precipitate the
of the
(formed during the preparation
reagent 12). The organic phase is washed
aq
ammonia, then with aq ammonium chloride and ammonium chloride. After filtration of the salts, the organic
layer, to which 150 ml of pentane have been added, is
washed successively with aq sodium thiosulphate, then with
dried over magnesium sulphate. After evaporation of the
solvents the residue is distilled through a
Vigreux

General methodology for the synthesis of conjugated dienic insect sex pheromones
2749
aq ammonia and with aq ammonium chloride, then dried
over magnesium sulphate. After removal of the solvents the
residue is added to of a mixture of
(10 1) and at room temperature overnight. The mixture
is then added to 400 ml water and 400 ml hexane and
partitioned. The organic phase is washed with aq
sodium bicarbonate, then with water, dried over magnesium
sulphate and concentrated in The residue is distilled
through a 10 cm Vigreux column to afford 22.7 g of the title
M. G. Quirici, Tetrahedron
therein.
(1981) and Refs. cited
a representative example see G. Cassani, P. Massardo
Tetrahedron Letters 24, 2513 (1983) and
Refs. cited therein.
and P.
W. L. Roelofs, J. Kochensky, R. Carde, H. Am and S.
Ruscher:
Schweiz. Entomol. Ges. 46, 71 (1973).
and D. Stamm,
Butenandt, R. Beckman, E.
Physiol. Chem. 324, 71, 81 (1961).
F. Nesbitt, P. S. Beevor, R. A. Cole, R. Lester and R.
product 23. Yield
1.4942; IR (neat)
Hg;
G.
Nature New Biol. 244, 208 (1973).
NMR
2.03
6.16 (CH=, m,
s, 3H); NMR
4.07
t,
D. Chisholm, E. W. Underhill, W.
K. N. Slessor
6): 170.6
and G. G. Grant, Environ. Entomol. 9, 278 (1980).
A. Coffelt. K. W. P. E. Sonnet and R. E. Doolittle.
5, 955
(COO), 141.1 (CH=), 82.4 (ICH=), 64.3
F. Nesbitt, P. S. Beevor, R. A. Cole, R. Lester and R.
1
acetate 22
G.
Insect
21, 1091 (1975).
To an ethereal solution of Z propenyl lithium (30 mmol)
Alexakis, J. F.
Letters 3461 (1976);
and J. Villieras, Tetrahedron
Alexakis, G. Cahiez and J. F.
1 7 7 . 2 9 3 (1979).
(prepared from
are added 50 ml THF and then a
and lithium metal)
of 30 of
bromide in 30 ml THF, at -20”. After stirring for 10 min,
the iodide 23 ((8.1 g, 25 mmol) admixed with 0.9 g
in 30ml THF is added and the
a review
F.
and A.
Synthesis
841 (1981).
Cahiez, A. Alexakis and J. F.
Letters 21, 1433 (1980).
Tetrahedron
mixture is warmed to room temperature for
then
hydrolysed with aq ammonium chloride. The organic phase
is dried over magnesium sulphate and after removal of the
solvents under vacuum, the residue is distilled to afford 5.5 g
Gardette, A. Alexakis and J. F.
9
219 (1983).
Alexakis, G. Cahiez and F.
Letters 2027 (1978).
Tetrahedron
of the title compound 22. Yield
1.4924; (neat)
NMR 6): 6.20 (CH=, d,
1.98
NMR
Hg;
1740, 1650, 1600,
Gardette, A. Alexakis and J. F.
Ecol 9, 225 (1983).
700;
5.41 (CH=, m,
1.76
6): 171.0 (COO),
4.01 (CH,O-, t,
d, 3H);
a review on pheromone synthesis based on the
cupration reaction see: A. Alexakis,
de
(1982).
Tetrahedron
131.7, 125.7, 124.7, 123.4 (CH=), 64.6
No. 7, Ed. I.N.R.A.
Jabri, A. Alexakis and J. F.
Letters 22, 959 (1981).
Jabri, A. Alexakis and J. F.
(1981).
pp.
acetate 6
To a THF solution of vinyl magnesium chloride
(40mmol) are added at a solution of zinc bromide
(40mmol) in 50ml THF. After stirring for the
with 0.9 g (0.75 mmol)
Ibid. 22, 3851
Jabri, A. Alexakis and J. F.
Ibid. 23, 1589
iodide (8.1 g, 25 mmol),
(1982);
Jabri, A. Alexakis and J. F.
Bull.
in 30ml THF, is added and the mixture is
Chim.
P II, 321, 332 (1983).
warmed to room temperature and stirred for 2 h. The
Gardette, A. Alexakis and J. F.
Letters 23, 5155 (1982).
Tetrahedron
mixture is hydrolysed with
aq ammonium chloride,
the aqueous phase extracted once with 100 ml ether and the
combined organic phases washed with aq ammonium chlo-
ride, dried over magnesium sulphate and concentrated in
The residue is distilled to afford 3.8 of
pheromone 6. Yield: 67%.
a general discussion on hydrometallation of alkynes
see: P. F. Hudrlik and A. M. Hudrlik, Applications of
Acetylenes in organic synthesis. The Chemistry of the
Carbon-Carbon Triple Bond (Edited by S. Patai). Wiley,
New York (1978).
1.4705: Ir (neat) cm-‘: 3080.
3010. 1745. 1645. 1595. 1240.
995, 965;
(CH=, dd,
d,
NMR
5.42
6.68
6.02
5.07
2.03
C. Brown and J. B. Campbell Jr.
14,
in Organic
3
(1981).
M. L. Cragg.
d,
t,
Synthesis. Marcel Dekker, New York (1973).
11 HZ, 4.08
NMR
P. Coutrot and J. F.
3H);
170.8 (COO),
64.5
226,
W. Hart, T. F.
97, 679 (1975).
Zweifel and C. C. Whitney, Ibid. 89, 2753 (1967).
Ann. 618, 267 (1958).
(1982).
132.6, 132.3, 129.4 (CH=), 116.6
and J. Schwartz,
Am.
Acknowledgements-The authors gratefully acknowledge
support from the
National de la
Scientifique (A.T.P. “Mediateurs chimiques” and E.R.A.
Wilke, H. Miiller:
F.
M. B. Floyd, J. F. Poletto
825).
Weiss. J.
44. 438 (1979):
I. Neaishi.
REFERENCES
in Organic’ Synthesis, Vol. 1. Wiley-New
‘For recent reviews see C. A.
1845 (1977);
Tetrahedron 33,
York (1980).
Synthesis 817 (1977);
J.
“See Refs. 1 and 2 for syntheses performed before 1979. For
stmann and 0. Vostrowski Chem. Phys. Lipids 24, 335
(1979).
more recent syntheses see.:
J. Bestmann, J.
and 0.
Ref. 4;
Vostrowski, Tetrahedron Letters 2467 (1979);
Mori, The synthesis of insect pheromones. The Total
Cassani, P. Massardo and P. Piccardi Tetrahedron
Synthesis of Natural Products (Edited J.
Wiley,
Letters 21, 3497 (1980);
strumelle: Ibid. 22. 315
P. On, W. Lewis
Ratovelomanana, G.
New York (1981).
Ref. 5:
Ref. 6.
Zweifel. Synthesis 999 (1981).
‘For a representative example see H. J. Bestmann, K. H.
and R. M. Waters, Synthesis 567 (1972).
Koschatzky, H.
J.
0. Vostrowsky, W.
G. Burghardt and I. Schneider, Liebigs Ann.
1359
“Syntheses described prior to 1979 are reviewed in Refs.and
(1982) and Refs. cited therein.
more recent syntheses see:
Samain and C.
‘For a representative example
Langlois,
G. Dressaire and Y.
(1980) and Refs. cited
Descoins, Bull.
Yokoi and Y. Matsubara,
Kenkyu Hokoku 59 (1979) (14); Chem. Abstr. 93, 25825f
(1980); ‘A. Commercon, J. F. and J. Villieras:
France P II, 71 (1979).
Daigaku Rikogakubu
therein.
a representative example see R.
A.
and

2 7 5 0
M.
et
36, 1215 (1980);
J. Bestmann, J.
and
previous syntheses of this pheromone see:
D.
0. Vostrowsky, Liebigs Ann.
2117 (1981);
Chisholm, W. F.
B. K. Bailey and E. W. Underhill,
boi, T. Masuda and A. Takeda, J.
Chem. 47 4478
J. Chem.
159 (1981);
Ref. 3;
and A.
E.
(1982);
Miyaura, H. Suginome and A. Suzuki, Tet-
Camita.Tetrahedron 39.287 (1983).
rahedron Letters 24, 1527 (1983).
previous syntheses. of this
see:
Harre, P. Raddatz, R. Walenta and E.
Sonnet and R.
Heath,
6,221 (1980);
E. Bishop and G. W.
Chem.
Ed. 21,480 (1982);
Raddatz:
Michelot, Synthesis 130 (1983);
(1979).
Morrow, J. Org. Chem. 48, 657 (1983).
A. Alexakis and J. F.
(1978).
Tetrahedron
Alexakis. G. Cahiez and J. F.
Organic
Letters
Syntheses
in press.
a selectivity has also been observed by E. I. Negishi
(private communication).
Gorgues, Bull.
Chim. France 529 (1974).
C. Descoins
private communication.
thank Dr. Descoins, Mrs.
and Mrs.
P. Norris: J. Org.
24,
(Institut National de la Recherche Agronomique) for the
gas chromatographic analyses.
“A. S. Dreiding and R. J. Pratt, J. Am.
76, 1902
(1954).
syntheses performed before 1979 see Refs. 1 and 2.
I. Negishi, N. Okukado, A. 0. King, D. E. Van Horn
and B. I.-Spiegel, Ibid.
I. Negishi, L.
I.
For more
syntheses see:
S. Neumark, M.
Jacobson, J. Klug, A. Shani and R. M. Waters,
Ado. Res. Inst. 1978
F. Valente and M. Kobvashi. Ibid. 102 3298
Negishi,
Chem.
340 (1982).
(Edited by F. J. Ritter). Elsevier, Amsterdam (1979).
Seyferth and L. G. Vaughan, J. Am. Chem.
86,883
Abstr. 9 1 .
(1979):
G. Dressaire
Ref. 31a;
Ratovelomanana
1 1 , 9 1 7 (1981).
(1964).
and Y. Langlois,
“Previous syntheses of
F. Nesbitt, P. S. Beevor, R. A.
Letters 4669
Ref.
Ref. 34d;
and G. Linstrumelle, Synth.
Ref. 5;
Cole, R. Lester and R. G.
(1973);
A.
and M. L. Gaudenzi, Syn-
thesis 359 (198 1);
A.
M. G.
M.
lithium reagent may be stored for 1-2
L. Gaudenzi, Tetrahedron 38, 631 (1981);
Ref. 43b.
months under argon atmosphere at
without no-
loss in one month).
ticeable change in normality
Brandsma, Preparative Acetylenic Chemistry. Elsevier,
Amsterdam (1971).
0. House, C. Y. Chu, M. Wilkins and M. J.
J.
Org. Chem. 40, 1460 (1975).