Pd-catalyzed cross-coupling of allylsilane-vinylcopper species with aryl and vinyl halides: the first total synthesis of (-)-nomadone

Article abstract of DOI:10.1016/j.tet.2009.01.118

The reaction of allene with a lower order silylcuprate 3 leads to an allylsilane-vinylcopper intermediate 4, which undergoes palladium-catalyzed cross-coupling reaction with both vinyl and aryl halides. The influence of several factors such as the nature

Full text of DOI:10.1016/j.tet.2009.01.118

Tetrahedron 65 (2009) 5535–5540
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Pd-catalyzed cross-coupling of allylsilane-vinylcopper species with aryl
and vinyl halides: the first total synthesis of (ꢀ)-nomadone
*
*
´
´
Francisco J. Pulido , Asuncion Barbero , Carlos Garcıa
´
Departamento de Qu´ımica Organica, Universidad de Valladolid, C/Dr. Mergelina s/n, 47011 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of allene with a lower order silylcuprate 3 leads to an allylsilane-vinylcopper intermediate 4,
which undergoes palladium-catalyzed cross-coupling reaction with both vinyl and aryl halides. The
influence of several factors such as the nature of the transition metal used as catalyst, the temperature of
the reaction, and the order of addition are studied. This simple methodology allows the synthesis in one
step of isoprenylsilanes, which can be conveniently coupled with different isoprenic aldehydes to give
several acyclic natural terpenes. Thus, we were able to synthesize, in two steps from allene, the natural
monoterpenes (G)-ipsdienol and (G)-ipsenol, which are the principal components of the aggregation
pheromone of the bark beetle Ips paraconfusus. On the other hand, the allyl-terminated reaction of
isoprenylsilane 7 with the natural monoterpene (S)-citronellal leads to an intermediate, which is readily
converted into the natural sesquiterpene (ꢀ)-Nomadone in two almost quantitative steps. The nomadone
sesquiterpene is a component of the cephalic gland’s secretion of Nomada bees. As far as we know this is
the first reported total synthesis of (ꢀ)-nomadone.
Received 9 December 2008
Received in revised form 30 January 2009
Accepted 31 January 2009
Available online 14 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
coupling reactions can be a variety of main group metals (Fig. 1),
including both the so-called ‘first-generation’ Pd-catalyzed cross-
The search and development of efficient and highly selective
methods for the synthesis of complex molecules of both natural
and unnatural origin continue to be a challenge in organic synthesis
and much effort has been directed toward this goal. Thus, the ste-
reospecific synthesis of conjugated dienes is of considerable im-
portance since a great variety of aliphatic natural products contain
the 1,3-diene unit or even higher degrees of conjugation.1–3 In this
sense, metal-catalyzed cross-coupling reactions have shown to be
the most reliable strategy for the synthesis of such conjugated al-
kenes since the method allows the reaction to proceed under very
mild conditions and with very high stereoselectivities.4–6 In par-
ticular, palladium-catalyzed cross-coupling reactions of vinyl ha-
lides with vinylic metals are now powerful tools for the
stereospecific synthesis of polyunsaturated molecules.7,8 The rate,
yield, and scope of the palladium-catalyzed cross-coupling re-
actions are influenced by both the reaction partners and the choice
of ligands of the metal.9 Historically, palladium-catalyzed cross-
coupling reactions used iodides and bromides as the organic ac-
ceptors, though the reaction has now being extended to aryl
chlorides. The organometallic donors in palladium-catalyzed cross-
couplings [Zn (Negishi reaction),10 Al,11 Zr or Mg (Kumada–Tamao–
Corriu reaction)12] and the ‘second-generation’ cross-couplings
with more electronegative metals such as B (Suzuki–Miyaura re-
action),13 Sn (Stille reaction),14 and Si (Hiyama reaction).15
However, less well developed is the Pd-catalyzed cross-coupling
of organocuprates. In fact, whereas alkyl copper or cuprate reagents
couple easily with alkyl, alkenyl, aryl or alkynyl halides, the cor-
responding alkenylcopper or cuprate reagents only react with alkyl
and alkynyl halides. Normant et al. reported that lithium alkenyl-
cuprates as well as alkenylcopper reagents showed very little re-
activity toward vinyl halides, under Pd catalysis, unless they are
transmetallated with zinc halides or activated with magnesium
salts, respectively (Scheme 1).16–18
On the other hand, allylsilanes display a multitude of functions
in organic synthesis as valuable intermediates for the construction
of natural occurring products.19 The usefulness of these versatile
building blocks in stereoselective reactions can be attributed both
to their ability to react with electrophiles via selective formation of
a carbocation b to the silyl group (the so-called b-effect) and to their
stability toward a large number of functional groups and reaction
conditions. For many years, our research group has been involved in
the study of the metallocupration of allenes as a simple and useful
methodology for the synthesis of vinyl- and allylsilanes or stan-
nanes.20 Silylcupration of allene occurs syn-stereospecifically
* Corresponding authors. Fax: þ34 83 423013.
E-mail addresses: pulido@qo.uva.es (F.J. Pulido), barbero@qo.uva.es (A. Barbero).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.118

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F.J. Pulido et al. / Tetrahedron 65 (2009) 5535–5540
Negishi Reaction
now an allylsilane-vinylcopper intermediate 4, which offers the
possibility of obtaining functionalized allylsilanes (Scheme 2).22,23
In a preliminary communication we reported the palladium
mediated coupling reaction of the allylsilane-vinylcopper reagent 3
with alkenyl halides as an alternative isoprenylation method,
which can be applied to the construction of terpenoid structures.24
Here we report in full the scope of this methodology depending on
the nature of the catalyst and the vinyl halide used and their ap-
plication in the synthesis of natural mono- and sesquiterpenes.
Pd catalyst
R1 R2
R2
X
R1 ZnR
+
R1 = vinyl, aryl, alkynyl, alkyl, benzyl, allyl
R
2 = vinyl, aryl, allyl, benzyl, acyl
X = Br, I, Cl, OTf, OTs
Kumada-Tamao-Corriu Reaction
Pd/Ni catalyst
R1 R2
R2
X
R1 MgX
+
R1 = aryl, vinyl, alkyl
R
2 = vinyl, aryl, alkyl
2. Results and discussion
X = Br, Cl, I
Suzuki-Miyaura Reaction
Silylcupration of allene, at ꢀ40 ꢁC, using the lower order cuprate
3 gives an allylsilane-vinylcuprate intermediate 4, which upon
treatment with a wide variety of electrophiles affords functional-
ized allylsilanes in high yields. The only limitation to this otherwise
general method is the lack of reactivity of the intermediate 4 with
vinyl halides. Encouraged by previous results16–18 we decided to
explore the palladium-catalyzed reaction of our vinylcuprate 4 with
vinyl bromide. The results are shown in Table 1.
As it is shown in Table 1 the Pd(II) catalyst, used in entries 1 and
2, is ineffective toward the cross-coupling reaction, giving rise to
a rather complex mixture of byproducts (the hydrolysis products 5
and 6,25 together with the dimer 8 obtained by homocoupling of
the copper reagent). Better results are achieved in the nickel-cat-
alyzed coupling, though the reaction is not clean and moderated
yields are obtained. In contrast, the best results are achieved using
palladium(0) Pd(PPh3)4 as the catalyst (Table 1, entries 5 and 6).
Moreover an increase of the reaction temperature (from ꢀ40 to
0 ꢁC) produces more side products (Table 1, entry 7). The fact that
the homo-coupled dimer 8 was obtained as a minor side product in
every reaction was not an inconvenient since it could be easily
separated on chromatography. We then examined the reaction with
other substrates to evaluate the generality of the reaction and the
influence of the nature of the halide (Table 2).
Pd catalyst
R1 R2
R2
X
R1 BR2
+
R1 = vinyl, aryl, alkynyl, alkyl
R2 = vinyl, aryl, benzyl, alkynyl, alkyl
X = Br, I, Cl, OTf, OTs
Stille Reaction
Pd catalyst
R1 R2
R1 = vinyl, aryl, alkynyl, alkyl
R2
X
R1 SnR3
+
R
2 = vinyl, aryl, benzyl, allyl, alkynyl, acyl
X = Br, I, Cl, OTf, OAc
Hiyama Reaction
Pd catalyst
R1 R2
R2
X
R1 SiR3
+
F-
R1 = vinyl, aryl, alkynyl, allyl
R
2 = vinyl, aryl, alkyl, allyl
X = Br, I, OTf
Figure 1. The most commonly used palladium-catalyzed cross-coupling reactions.
R3
R1
R1
1. ZnBr2 (1 eq)
2.
R3
Pd(PPh3)4 (5%)
)2CuLi
The results shown in Table 2 indicate that Pd(PPh3)4 is always
more effective for this coupling than Ni(acac)2. Moreover vinyl io-
dides give better yields of the Pd-catalyzed cross-coupling product
than the bromide derivatives (Table 2, entries 8 and 10) though
both are reasonable. On the contrary, the Ni-catalyzed reaction is
only acceptable when vinyl bromides are used (Table 2, entries 2
R2
R2
I
80-96%
Scheme 1. Palladium-catalyzed cross-coupling of alkenyl halides and alkenylcuprates
in the presence of ZnBr2.
giving rise to the formation of intermediate cuprates, which react
with electrophiles to afford either vinyl or allylsilanes.21 The
regiochemistry of the addition depends on various factors such as
the nature of the cuprate, the substitution of the allene, the tem-
perature of the reaction, the nature of the silyl group, and the na-
ture of the electrophile. Thus, the reaction of 1,2-propadiene with
Table 1
Cross-coupling reaction of vinylcuprate
catalysts
4
with vinyl bromide under different
PhMe2SiCu(CN)Li
3
+
-40ºC
SiMe2Ph
SiMe2Ph
higher order silylcyanocuprates
1
containing the phenyl-
dimethylsilyl group gives, at any temperature between ꢀ78 ꢁC and
0 ꢁC, a vinylsilane-allylcuprate intermediate 2, which readily reacts
with a wide variety of electrophiles leading to the corresponding
vinylsilanes.21 However, the use of a lower order cuprate PhMe2-
SiCu(CN)Li 3 shows the opposite regioselectivity pattern, giving
5
6
(Cu)
Br
and/or
SiMe2Ph
cat.
4
SiMe2Ph
SiMe2Ph
SiMe2Ph
7
8
(PhMe2Si)2Cu(CN)Li2
1
SiMe2Ph
(Cu)
2
SiMe2Ph
E
Entry
Catalysta
Conditionsb
5
6
7
8
EX
1
2
3
4
5
6
7
PdCl2 (MeCN)2
PdCl2 (MeCN)2
Ni(acac)2
Ni(acac)2
Pd(PPh3)4
A
B
A
B
A
B
C
35%
30%
10%
5%
40%
35%
20%
15%
10%
15%
60%
65%
85%
86%
50%
10%
10%
5%
10%
8%
-78 ºC or 0 ºC
(Cu)
E
PhMe2SiCu(CN)Li
3
EX
SiMe2Ph
SiMe2Ph
Pd(PPh3)4
Pd(PPh3)4
10%
30%
10%
4
-40 ºC
a
10 mol % of catalyst is used.
b
Scheme 2. Silylcupration of 1,2-propadiene using higher order or lower order
cuprates.
Conditions A: ꢀ40 ꢁC, 2 h; then ꢀ40 to 0 ꢁC, 1 h; conditions B: ꢀ40 ꢁC, 4 h; then
ꢀ40 to 0 ꢁC, 1 h; conditions C: 0 ꢁC, 4 h.

F.J. Pulido et al. / Tetrahedron 65 (2009) 5535–5540
5537
Table 2
OH
CHO
Cross-coupling reaction of vinylcuprate 4 with vinyl halides
EtAlCl2, Tol, 0ºC
87%
(+)- Ipsenol
Entry
1
Vinyl halide
Catalysta
Productb
Yield (%)
90
SiMe2Ph
SiMe2Ph
I
Pd(PPh3)4
SiMe2Ph
SiMe2Ph
8
7
I
OH
2
3
Ni(acac)2
Pd(PPh3)4
N.R.
Bu
COCl
SiMe2Ph
I
1.
AlCl3, DCM, -60ºC
2. DIBAH
85%
(+)- Ipsdienol
Bu
89
SiMe2Ph
Scheme 3. Synthesis of (G)-ipsenol and (G)-ipsdienol.
9
Bu
in the catalytic cycle. Remarkably, an array of functionality is tol-
erated including esters and ketones (Table 3, entries 4 and 5).
The most attractive aspect of this strategy is the possibility of
introducing an isoprenyl moiety in a single and high yielding step.
In effect, diene 7 can be formally considered as a synthetic equiv-
alent of an isoprenyl anion since allylsilanes are known to be ex-
cellent nucleophiles. This methodology has been successfully
applied to the synthesis of three isoprenylated naturally occurring
products, which are (G)-ipsenol, (G)-ipsdienol and (ꢀ)-noma-
done. Natural monoterpenes ipsenol and ipsdienol are the principal
components of the aggregation pheromones of the bark beetle of
California Ponderosa Pine Ips Paraconfusus Lanier and have been
synthesized several times using different approaches.26,27
Thus reaction of isoprenylsilane 7 with isovaleraldehyde in the
presence of ethyldichloroaluminum in toluene at 0 ꢁC afforded in
87% yield natural (G)-ipsenol. The use of other catalysts such as
BF3, TiCl4 or TBAF lowers significantly the yield. The corresponding
synthesis of (G)-ipsdienol was done by reaction of 7 with 3,3-
dimethylacryloyl chloride and subsequent reduction of the enone
derivative (Scheme 3).
The interesting acyclic sesquiterpene nomadone 17, which is
a constituent of the mandibular gland secretion of Nomada bees
that plays an important role in intra- and interspecific territorial
behavior, has received much less attention.28,29 This compound was
first described by Francke et al. in 1989,28 which suggested the
name ‘nomadone’ for the most common sesquiterpene of the genus
Nomada. It was synthesized29 in 1991 by the former group as
a mixture of Z/E stereoisomers in racemic form and used for
identification purposes. However, investigation of the absolute
configuration of the natural nomadone was never attempted and
remains unknown.30 In any case, whatever is the chiral configura-
tion of natural nomadone, it can be easily achieved following the
methodology depicted in Scheme 4 and choosing simply (R) or (S)-
citronellal as starting material.
4
5
Ni(acac)2
Pd(PPh3)4
N.R.
I
I
Oct
Oct
81
75
SiMe2Ph
10
Ph
Ph
6
7
Pd(PPh3)4
Br
SiMe2Ph
11
Ph
Ph
Ni(acac)2
Pd(PPh3)4
11
30
87
Br
I
8
11
a
Compound 4 is added to a cooled solution of the catalyst (10 mol %) and the vinyl
halide in THF at ꢀ40 ꢁC.
b
Reaction conditions A shown in Table 1.
and 9 vs 4 and 6). In general, all the reactions proceeded in high
yields when 10 mol % of the palladium catalyst is used. Moreover,
inverse addition was proved to be advantageous for both higher
yield and purity.
As expected, aryl halides also undergo cross-coupling with our
allylsilane-vinylcuprate 4 providing excellent coupling partners
(Table 3). However, whereas aryl iodides are coupled in high yield
(Table 3, entries 1, 4, and 5) the reaction is ineffective with the
bromide derivatives (Table 3, entries 2 and 3), which may be as-
cribed to their lower ability to undergo oxidative addition to Pd(0)
Table 3
Cross-coupling reaction of vinylcuprate 4 with aryl halides
Entry
1
Aryl halide
Catalysta
Product
Ph
Yield (%)
88
The synthesis of natural (ꢀ)-nomadone was accomplished in
three high yielding steps. Thus reaction of (S)-citronellal with iso-
prenylsilane 7 under fluoride catalysis (TBAF) gave the Sakurai
Phl
Pd(PPh3)4
SiMe2Ph
12
2
3
PhBr
PhBr
Pd(PPh3)4
Ni(acac)2
N.R.
N.R.
OH
CHO
SiMe2Ph
TBAF/DMF/HMPA
7
15 70%
CO2Et
CO2Et
4
Pd(PPh3)4
70
73
SiMe2Ph
I
PCC, rt, 4 h
O
13
O
NaOH
rt,1 h
COMe
I
COMe
SiMe2Ph
5
Pd(PPh3)4
97%
17 (-)-Nomadone
16
99%
14
a
Catalytical amount (10 mol %) of catalyst is used.
Scheme 4. Synthesis of (ꢀ)-nomadone.

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F.J. Pulido et al. / Tetrahedron 65 (2009) 5535–5540
alcohol in 70% yield. Two standard transformation such as the PCC
oxidation of the alcohol to the ketone and a basic catalyzed isom-
erization of the double bond to the conjugate position afforded
natural (ꢀ)-nomadone in 67% overall yield (Scheme 4). To our
knowledge, the reported synthesis of (ꢀ)-nomadone constitutes
the first total synthesis described for this compound.
(6 mmol) in THF at 0 ꢁC. After 30 min at this temperature the so-
lution of dimethylphenylsilylcopper 3 (6 mmol) was cooled at
ꢀ40 ꢁC and a slight excess of allene was added from a balloon. The
mixture was stirred for 1 h and then used immediately.
4.3. General conditions for the cross-coupling reaction
between vinyl halides and the allylsilane-vinylcopper 4
3. Conclusion
The solution previously prepared was added, over a period of
30 min, to a flask containing a solution of the vinyl halide (6 mmol)
and the catalyst (0.6 mmol) in 10 ml of dry THF at ꢀ40 ꢁC. The
mixture was stirred for an additional period of 2 h at ꢀ40 ꢁC and
then allowed to warm to 0 ꢁC. The reaction mixture was then
quenched with basic saturated ammonium chloride solution and
extracted with ether. The organic layer was dried (MgSO4), evap-
orated, and chromatographed to give the corresponding products:
5,25 6,25 7,31 and 8–11 in good yields (see Tables 1 and 2).
The silylcupration of allene, at ꢀ40 ꢁC, using a lower order
cuprate affords an allylsilane-vinylcuprate intermediate 4, which
effectively participates in metal-catalyzed cross-coupling reactions
with vinyl halides. The scope and yield of the reaction are influ-
enced by the choice of the transition metal, the ligands, the tem-
perature of the reaction, and the nature of the reaction partners.
The best results are obtained when a 10 mol % of the palladium(0)
catalyst is used and the reaction is carried out at ꢀ40 ꢁC. Both vinyl
and aryl halides are effective as the coupling partner. However,
whereas coupling with both vinyl iodides and bromides is allowed,
for the aryl derivatives only the iodides are coupled in high yield
(possibly due to the lower ability of aryl bromides to undergo
oxidative addition to Pd(0) in the catalytic cycle).
The most interesting aspect of this reaction is the possibility of
obtaining the isoprenyl intermediate 7 in a single a high yielding
step. Moreover diene 7 contains a nucleophilic allylsilane unit,
which can participate in Sakurai type’s reactions. We have suc-
cessfully applied this methodology to the synthesis of three natural
occurring terpenes, which are (ꢀ)-nomadone, (G)-ipsenol, and
(G)-ipsdienol.
Thus, starting from allene and in two simple and high yielding
steps we are able to obtain natural ipsenol and ipsdienol, which are
the principal components of the aggregation pheromones of the
bark beetle of California Ponderosa Pine I. Paraconfusus Lanier. On
the other hand, the Nomada-sesquiterpene 3,7,11-trimethyl-1,3,10-
dodecatrien-4-one (commonly known as nomadone) is a constitu-
ent of the mandibular gland secretion of Nomada bees that plays an
important role in intra- and interspecific territorial behavior. We
here present the total synthesis of the acyclic (S)-(ꢀ)-sesquiterpene
starting from natural monoterpene (S)-(ꢀ)-citronellal, which un-
dergoes addition of the isoprenylsilane 7, in the presence of TBAF, to
give an intermediate, which is converted into the desired natural
product by means of standard transformations. As far as we know
this is the first reported total synthesis of (ꢀ)-nomadone.
4.3.1. 2,3-Bis(dimethylphenylsilylmethyl)butadiene 8
Colorless oil; IR: nmax 1600, 1240, 1110, 875 cmꢀ1 1H NMR
;
(CDCl3)
d 7.59–7.39 (m, 10H), 4.98 (s, 2H), 4.76 (s, 2H), 2.03 (s, 4H),
0.33 (s, 12H); 13C NMR (CDCl3)
d 145.2, 139.4, 133.6, 128.9, 127.7,
111.9, 23.2, ꢀ2.6; MS (CI) m/z 350 [M]þ, 335, 270,135. Anal. Calcd for
C22H30Si2: C, 75.36; H, 8.6. Found: C, 75.02; H, 8.30.
4.3.2. (E)-2-(Dimethylphenylsilylmethyl)octa-1,3-diene 9
Colorless oil; IR: nmax 1600, 1250, 1110, 965 cmꢀ1 1H NMR
;
(CDCl3)
d
7.58–7.38 (m, 5H), 6.08 (d, J¼15.6 Hz, 1H), 5.57 (dt, J¼15.6
and 7.0 Hz, 1H), 4.83 (s, 1H), 4.67 (s, 1H), 2.08 (q, J¼7.0 Hz, 2H), 1.97
(s, 2H), 1.35 (m, 4H), 0.93 (t, J¼7.0 Hz, 3H), 0.32 (s, 6H); 13C NMR
(CDCl3)
d 143.3, 139.3, 133.6, 132.7, 131.2, 128.8, 127.6, 112.2, 32.4,
31.5, 22.3, 21.3, 13.9, ꢀ2.8; MS (CI) m/z 258 [M]þ, 201, 183, 167, 135.
Anal. Calcd for C17H26Si: C, 79.00; H, 10.14. Found: C, 79.41; H, 10.40.
4.3.3. (E)-2-(Dimethylphenylsilylmethyl)dodeca-1,3-diene 10
Colorless oil; IR: nmax 1600, 1250, 970 cmꢀ1 1H NMR (CDCl3)
;
d
7.56–7.35 (m, 5H), 6.06 (d, J¼15.6 Hz, 1H), 5.54 (dt, J¼15.6 and
7.0 Hz, 1H), 4.81 (s, 1H), 4.65 (s, 1H), 2.04 (q, J¼7.0 Hz, 2H), 1.95 (s,
2H), 1.41–1.20 (m, 12H), 0.91 (t, J¼7.0 Hz, 3H), 0.30 (s, 6H); 13C NMR
(CDCl3)
d 143.3, 139.3, 133.6, 132.7, 131.2, 128.9, 127.6, 112.2, 32.8,
31.9, 29.5, 29.4, 22.7, 21.4, 14.1, ꢀ2.8; MS (CI) m/z 314 [M]þ, 223, 201,
169,135. Anal. Calcd for C21H34Si: C, 80.18; H,10.89. Found: C, 79.85;
H, 10.55.
4. Experimental section
4.1. General
4.3.4. (E)-3-(Dimethylphenylsilylmethyl)-1-phenylbuta-1,3-
diene 11
Colorless oil; IR: nmax 1600, 1580, 1250, 1110, 950 cmꢀ1; 1H NMR
(CDCl3)
d
7.61–7.27 (m, 10H), 6.81 (d, J¼16.2 Hz, 1H), 6.40 (d,
All experiments were carried out under a nitrogen atmosphere.
Unless otherwise stated, commercial reagents were used as received
without further purification. The reactions were carried out in sol-
vents distilled from standard drying agents. THF were freshly dis-
tilled from sodium benzophenone ketyl under nitrogen. Aldehydes
were freshly distilled under reduced pressure before use. Reactions
were monitored by analytical thin-layer chromatography on com-
mercial aluminum sheets pre-coated (0.2 mm layer thickness) with
silica gel 60. Product purification by flash chromatography was
performed on silica gel (E. Merck 230–400 mesh). 1H and 13C NMR
spectra were recorded on a Bruker AC 300 spectrometer. Optical
rotations were determined on a Perkin–Elmer polarimeter at rt.
J¼16.2 Hz, 1H), 5.08 (s, 1H), 4.88 (s, 1H), 2.10 (s, 2H), 0.35 (s, 6H); 13C
NMR (CDCl3)
d 145.7, 143.4, 139.1, 132.9, 132.7, 131.8, 129.1, 127.9,
127.8,127.4,127.7,115.6, 21.6, ꢀ2.7; MS (CI): m/z: 278 [M]þ, 200,187,
183, 136, 135. Anal. Calcd for C19H22Si: C, 81.95; H, 7.96. Found: C,
82.32; H, 8.28.
4.4. General conditions for the cross-coupling reactions
between aryl halides and the allylsilane-vinylcopper 4
A solution of 7 (6 mmol) was added, over a period of 30 min, to
a flask containing a solution of the aryl halide (6 mmol) and the
catalyst (0.6 mmol) in 10 ml of dry THF at ꢀ40 ꢁC. The mixture was
stirred for an additional period of 2 h at ꢀ40 ꢁC and then allowed to
warm to 0 ꢁC. The reaction mixture was then quenched with basic
saturated ammonium chloride solution and extracted with ether.
The organic layer was dried (MgSO4), evaporated, and chromato-
graphed to give products 12–14 in good yields (see Table 3).
4.2. General conditions for the obtention of the allylsilane-
vinylcopper reagent 4
A solution of dimethylphenylsilyl-lithium (6 mmol) in THF was
added by syringe to a stirred suspension of copper(I) cyanide

F.J. Pulido et al. / Tetrahedron 65 (2009) 5535–5540
5539
4.4.1. 2-Phenyl-3-dimethylphenylsilylprop-1-ene 12
Colorless oil; IR: nmax 1610, 1250, 1110, 880 cmꢀ1
chromatographed to give a mixture of diastereomeric alcohols 15 in
69% yield as a colorless oil; IR: nmax 3600, 3500, 1600, 1000,
;
1H NMR
(CDCl3)
d
7.53–7.26 (m,10H), 5.19 (d, J¼1.2 Hz,1H), 4.89 (d, J¼1.2 Hz,
900 cmꢀ1; 1H NMR (CDCl3)
d
6.40 (dd, J¼17.6 and 10.7 Hz, 1H), 5.25
1H), 2.30 (s, 2H), 0.20 (s, 6H); 13C NMR (CDCl3)
d
146.0, 142.7, 138.9,
(d, J¼17.6 Hz, 1H), 5.18–5.17 (m, 4H), 3.84 (m, 1H), 2.51 (td, J¼13.8
and 3.5 Hz, 1H), 2.17 (dd, J¼13.8 and 8.8 Hz, 1H), 1.98 (m, 2H), 1.68
(s, 3H), 1.60 (s, 3H), 1.64–1.20 (m, 5H) 0.94 (d, J¼6.7 Hz, 3H); 13C
133.6, 129.0, 128.2, 127.8, 127.3, 126.5, 111.1, 25.3, ꢀ2.9; MS (CI): m/z:
252 [M]þ, 197, 174, 159, 135. Anal. Calcd for C17H20Si: C, 80.89; H,
7.99. Found: C, 81.11; H, 8.22.
NMR (CDCl3) d 143.1, 138.4, 131.2, 124.7, 118.5, 114.2, 67.5, 44.7, 40.7,
36.6, 29.3, 25.7, 25.4, 20.2, 19.1; MS (CI) m/z 222 [M]þ, 207, 205, 195,
193, 189, 136, 135, 121, 109. Anal. Calcd for C15H26O: C, 81.02; H,
11.79. Found: C, 81.36; H, 12.09.
4.4.2. Ethyl 2-(3-(dimethylphenylsilyl)prop-1-en-2-yl)benzoate 13
Colorless oil; IR: nmax 1720, 1600, 1280, 1110, 880 cmꢀ1; 1H NMR
(CDCl3)
d
7.78 (dd, J¼7.6 and 1.6 Hz, 1H), 7.49–7.26 (m, 7H), 7.13 (dd,
J¼7.6 and 1.6 Hz,1H), 4. 79 (s,1H), 4.91 (s,1H), 4.36 (q, J¼7.1 Hz, 2H),
4.7.2. (S)-7,11-Dimethyl-3-methylenedodeca-1,10-dien-5-one 16
A suspension of the alcohols 15 and PCC/aluminium oxide in
hexane was stirred for 4 h at rt. The solution is filtered and the
oxidation reagent washed three times with ether. The combined
2.91 (s, 2H), 1.39 (t, J¼7.1 Hz, 3H), 0.18 (s, 6H); 13C NMR (CDCl3)
d
168.1, 147.5, 145.2, 138.6, 133.5, 131.2, 129.9, 129.5, 128.8, 127.6,
126.9, 112.3, 61.0, 27.8, 14.1, ꢀ3.0. Anal. Calcd for C20H24SiO2: C,
74.03; H, 7.45. Found: C, 74.37; H, 7.79.
filtrates are evaporated to give compound 16 in 99% yield as a color-
20
less oil, which doesn’t need further purification; [
a
]
ꢀ14 (c 0.5,
D
4.4.3. 2-(3-(Dimethylphenylsilyl)prop-1-en-2-yl)phenyl methyl
ketone 14
CHCl3); IR: nmax 1710, 1600, 930, 850 cmꢀ1; 1H NMR (CDCl3)
d 6.42
(dd, J¼17.5 and 10.8 Hz, 1H), 5.26 (s, 1H), 5.13 (d, J¼17.5 Hz, 1H), 5.12
(s, 1H), 5.11 (d, J¼10.8 Hz, 1H), 5.08 (t, J¼6.5 Hz, 1H), 3.27 (s, 2H),
2.44 (dd, J¼16.5 and 5.5 Hz, 1H), 2.27 (dd, J¼16.5 and 8.0 Hz, 1H),
2.04–1.89 (m, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.35–1.23 (m, 2H), 0.88
Colorless oil; IR: nmax 1680, 1620, 1250, 1110, 880 cmꢀ1; 1H NMR
(CDCl3)
d
7.40–7.30 (m, 9H), 5.00 (s, 1H), 4.96 (s, 1H), 2.54 (s, 3H),
203.6, 147.3, 143.2, 138.9,
2.11 (s, 2H), 0.17 (s, 6H); 13C NMR (CDCl3)
d
138.3, 133.5, 130.8, 129.7, 128.9, 128.0, 127.6, 127.2, 126.5, 113.6, 29.9,
28.2, ꢀ3.1. Anal. Calcd for C19H22SiO: C, 77.50; H, 7.53. Found: C,
77.81; H, 7.82.
(d, J¼6.5 Hz, 3H); 13C NMR (CDCl3)
d 208.4, 140.0, 138.0, 131.4, 124.3,
120.2, 115.0, 48.5, 47.4, 36.8, 28.5, 25.7, 25.4, 19.6, 17.6; MS (CI) m/z
220 [M]þ, 207, 202,187,177,159,109, 69, 41. Anal. Calcd for C15H24O:
C, 81.76; H, 10.98. Found: C, 82.06; H, 11.26.
4.5. Synthesis of (G)-ipsenol
4.7.3. (S)-3,7,11-Trimethyldodeca-1,3,10-trien-5-one 17
To a solution of EtAlCl2 (1 mmol, 1.8 M in toluene) in 5 ml of dry
toluene, at 0 ꢁC and under nitrogen, was added dropwise a mixture
of isovaleraldehyde (1 mmol) and the diene 7 (1.2 mmol) in 2 ml of
dry toluene. The mixture is stirred for 30 min at 0 ꢁC and then
quenched with NaHCO3 satd solution, and extracted with ether. The
organic layer was dried (MgSO4), evaporated, and chromato-
graphed to give the corresponding natural product in 87% yield. All
the analytical data were in agreement with those reported in the
literature.26e
To a solution of the enone 16 in 2 ml of H2O, 2 ml of EtOH, and
2 ml of THF was added 5 ml of a solution of 0.5 M NaOH. The
mixture was stirred at rt for 1 h and then extracted with ether,
washed with brine, dried, evaporated, and chromatographed to
20
give (ꢀ)-nomadone 17 in 90% yield as a colorless oil; [
a
]
ꢀ21.3 (c
D
1.0, CHCl3); IR: nmax 1680, 1620, 1590, 1050, 980 cmꢀ1
(CDCl3)
J¼17.4 Hz, 1H), 5.43 (d, J¼10.6 Hz, 1H), 5.08 (br t, J¼7.1 Hz, 1H),
2.46 (dd, J¼15.1 and 5.7 Hz, 1H), 2.25 (dd, J¼15.1 and 8.1 Hz, 1H),
2.22 (s, 3H), 2.04–1.92 (m, 3H), 1.66 (s, 3H), 1.58 (s. 3H), 1.38–1.20
;
1H NMR
d
6.35 (dd, J¼17.4 and 10.6 Hz, 1H), 6.12 (s, 1H), 5.64 (d,
4.6. Synthesis of (G)-ipsdienol
(m, 2H), 0.90 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3)
d 201.9, 149.6,
140.5, 131.3, 127.3, 124.3, 120.3, 52.1, 37.0, 29.4, 25.7, 25.4, 19.7, 17.6,
13.3; MS (CI) m/z 220 [M]þ, 203, 193, 187, 177, 163, 135, 109, 69, 43,
41. Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 82.12; H,
11.31.
To a solution of AlCl3 (1 mmol, 134 mg) in 3 ml of dry DCM, at
ꢀ60 ꢁC and under nitrogen, was added dropwise a solution of 3,3-
dimethylacryloyl chloride (1 mmol) in 1 ml of dry DCM. This solu-
tion was transferred to another flask containing a solution of
1 mmol of diene 7 in 3 ml of dry DCM at ꢀ60 ꢁC. The mixture is
stirred for 15 min, then quenched with saturated ammonium
chloride and extracted with ether. The organic layer was dried
(MgSO4), evaporated, and used immediately.
Acknowledgements
We thank the Ministry of Science and Technology of Spain
´
(BQU2003-03035) and the ‘Junta de Castilla y Leon’ (VA050/2004)
To a solution of the previously prepared enone in 5 ml of dry
toluene, at ꢀ40 ꢁC and under nitrogen, was added 2 mmol of DIBAL
(1.33 ml, 1.5 M in toluene). The mixture is stirred for 4 h at ꢀ40 ꢁC
and then allowed to warm to 0 ꢁC. The reaction mixture is
quenched with saturated ammonium chloride and extracted with
ether. The organic layer was dried (MgSO4), evaporated, and
chromatographed to give the natural product in 85% overall yield.
All the analytical data were in agreement with those reported in the
literature.26d
for financial support. We appreciate Prof. Francke correspondence
and commentaries regarding his nomadone studies.
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