Homologation of monoterpenoids into new sesquiterpenoids via tandem isomerisation/claisen rearrangement reactions with three-component ruthenium catalysts, and Ru(methallyl)2 (COD) revealed by high throughput screening techniques

Article abstract of DOI:10.1002/adsc.200404391

A catalytic system B based on a ruthenium source Ru₃(CO) ₁₂, a bulky imidazolinium salt and Cs₂CO₃ appears very efficient for the transformation of a 1,7-diene into a γ,δ-unsaturated aldehyde via tandem isomeris

Full text of DOI:10.1002/adsc.200404391

FULL PAPERS
Homologation of Monoterpenoids into New Sesquiterpenoids via
Tandem Isomerisation/Claisen Rearrangement Reactions with
Three-Component Ruthenium Catalysts, and Ru(methallyl)2
(COD) Revealed by High Throughput Screening Techniques
a
a, b
Jerome Le Notre, Rachid Touzani, Olivier Lavastre,a, b Christian Bruneau,a,*
´ ˆ
ˆ
Pierre H. Dixneufa,*
Institut de Chimie de Rennes, UMR 6509 CNRS-Universite de Rennes 1, ꢀOrganometalliques et Catalyseꢁ, Campus de
Beaulieu, 35042 Rennes Cedex, France
a
´
´
Fax: (þ33)-2-23-23-69-39, e-mail: pierre.dixneuf@univ-rennes1.fr
Institut de Chimie de Rennes, Centre dꢁInnovations Technologiques de Rennes, Campus de Beaulieu, 35042 Rennes
Cedex, France
b
Received: December 23, 2004; Accepted: March 8, 2005
Abstract: A catalytic system B based on a ruthenium multicomponent catalysts: metal source/ligand/base
source Ru3(CO)12, a bulky imidazolinium salt and for these tandem reactions. An unexpected catalyst
Cs2CO3 appears very efficient for the transformation was found to be Ru(methallyl)2(COD) which can op-
of a 1,7-diene into a g,d-unsaturated aldehyde via tan- erate without additional ligand or reagent.
dem isomerisation/Claisen reactions. 1,6-Dienes aris-
ing from the terpenoids menthone and myrtenal
were selectively transformed into the corresponding Keywords: alkene isomerisation; Claisen reaction;
unsaturated aldehydes with catalyst B. High through- high throughput screening; ruthenium catalysts; ter-
put experiments were undertaken to evaluate other penoids; unsaturated aldehydes
Introduction
um catalysts for RCM of 1,6-dienes and 1,6-enynes[12–14]
we found initial results[15] showing that these catalysts
Since its discovery in 1912,[1] the Claisen reaction and re- did not perform RCM or cycloisomerisation of 1,7-dien-
lated [3,3]-sigmatropic rearrangements represent pow- yl ethers but selectively led to tandem isomerisation/
erful methods for the formation of carbon-carbon Claisen rearrangement affording g,d-unsaturated alde-
bonds.[2] However, the required initial synthesis of vinyl hydes (Scheme 1).
ethers constitutes, most of the time, a difficulty in the ac-
We now report on (i) the use of in situ prepared cata-
cess to the starting materials.[3] A potential alternative lysts, using imidazolinium salts and a ruthenium source,
method consists in the combination of the isomerisation especially Ru3(CO)12, for the isomerisation/Claisen rear-
of allyl ethers into vinyl ethers followed by thermal rangement of 1,7- and 1,6-dienyl ethers into g,d-unsatu-
Claisen rearrangement in the same reaction process.
rated aldehydes, allowing the transformation of natural
Ruthenium species such as ruthenium hydride[4] or monoterpenoids into new sesquiterpenoids, and (ii) the
ruthenium carbonyl[5] derivatives are well-known cata- use of high throughput experiments for the discovery of
lyst precursors to perform alkene isomerisation, even a simple and highly active new catalyst, Ru(methallyl)2-
in an enantioselective way.[6] Ruthenium alkene meta- (COD), for alkene isomerisation and to perform this tan-
thesis catalysts have also shown propensity to isomerise dem reaction, without any additional ligand or reagent.
alkenes, in competition with the metathesis reaction.[7,8]
The Claisen rearrangement of diallyl ethers is catalysed
by RuCl2(PPh3)3 at high temperature (1508C),[9] where- Results and Discussion
as milder conditions are possible with iridium[10] and
rhodium[11] complexes. Recently, it has been shown
The Catalytic System A: Discovery and Tuning
that an indenylidene-ruthenium catalyst was able to per-
form ring closing metathesis (RCM), isomerisation and
Claisen rearrangement, successively.[8] By contrast, in In our preliminary study,[15] the first evidence of the use
the study of in situ prepared imidazolinylidene-rutheni- of an in situ generated catalytic system based on a ruthe-
Adv. Synth. Catal. 2005, 347, 783–791
DOI: 10.1002/adsc.200404391
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Scheme 1.
Table 1. Catalytic transformation of the dienyl ether 1.[a]
Entry
Ru source
Imidazolinium
Time [h]
Conversion [%]
Compounds
1
2
3
4
5
6
RuCl2(p-cymene)(PCy3)
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
RuCl3 ·x H2O
Ru3(CO)12
Ru3(CO)12
None
16
12
12
6
1
1
100
50
50
100
100
100
4
3
3
3
4
3
Im(Mes)2þClꢀ
Im[(i-Pr)2Ph]2þClꢀ
Im[(i-Pr)2Ph]2þClꢀ
Im(Mes)2þClꢀ
Im[(i-Pr)2Ph]2þClꢀ
[a]
All reactions are performed at 1208C in toluene.
nium source and an imidazolinylidene precursor, for
Starting from these observations, variations on the
the tandem isomerisation/Claisen rearrangement was catalytic system and especially the use of bidentate li-
established (Scheme 1).
gands such as bisbenzoxazole,[16] chiral bisoxazoline
In the presence of the 1,7-diene 1, the catalytic system and diimine,[17] associated with a ruthenium source,
A, based on [RuCl2(p-cymene)]2, 1,3-bis(mesityl)imida- have shown isomerisation capability. The most efficient
zolinium chloride and cesium carbonate, did not give the catalytic system B was then evaluated for terpenoids.
expected cycloisomerisation product 2,[14] but rather the
g,d-unsaturated aldehyde 3 with 50% conversion.
A study on this three-component catalytic system, by Terpenoid Transformations
combination oftwo types of imidazolinium salt with four
ruthenium sources, led us to the most effective catalyst Previous work on the modification of natural terpe-
B, based on Ru3(CO)12, 1,3-bis(2,6-diisopropylphenyl)- noids, with a silylated enyne structure, via ruthenium-
imidazolinium chloride and cesium carbonate, which catalysed ring closing metathesis reactions has shown
gave complete conversion of 1 into compound 3 (Ta- potential for the synthesis of new polycyclic mole-
ble 1). Ru3(CO)12 especially reveals the strong differen- cules.[18] 1,6-Diene derivatives of terpenoids have been
ces in behaviour of the two imidazolinium salts: both al- evaluated towards the three-component catalytic sys-
low isomerisation but only one, with isopropyl groups, tem B, based on Ru3(CO)12, 1,3-bis(2,6-diisopropylphe-
favours the subsequent Claisen reaction (entries 5 and nyl)imidazolinium chloride and cesium carbonate.
6) This observation supports that the catalyst not only Starting from natural (ꢀ)-menthone (5) and (ꢀ)-myrte-
favours the isomerisation but also the Claisen rear- nal (6), the 1,6-dienes 7 and 8 have been first prepared in
rangement.
good yields by reaction with vinylmagnesium bromide in
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Scheme 2.
Screening of the Catalytic System using High
Throughput Experiments
To investigate the activity of new multicomponent cata-
lytic systems toward this isomerisation/Claisen reaction,
the use of high throughput screening techniques ap-
peared to be the best way to explore new combinations.
Starting from the catalytic system B, based on a rutheni-
um source, an N-heterocyclic carbene precursor and a
base, we have adopted a screening strategy to test new
sources for each of these three components with the
aim of discovering better or new catalysts for the trans-
formation of dienes into g,d-unsaturated aldehydes.
The 1,6-diene 11 has been selected as test substrate for
these experiments because it was easily obtained in two
steps from benzophenone, and the isomerisation/Clais-
en rearrangement transformation led to the g,d-unsatu-
rated aldehyde 12 as the sole possible isomer. Reaction
of diene 11 with 5 mol % of catalyst B at 1208C for 2
hours leads to the aldehyde 12 isolated in 90% yield.
(Scheme 4).
Scheme 3.
the presence of cerium trichloride followed by an allyla-
tion reaction of the resulting allyl alcohols (Scheme 2).
These dienes 7 and 8 have been reacted with the three- Choice of the Catalytic Components
component catalytic system B (Scheme 3). The dienes 7
and 8 with 5/3 mol % of Ru3(CO)12, 5 mol % of imidazo- The high throughput screening has been performed us-
linium salt and 10 mol % of Cs2CO3 were heated in tol- ing a 96-hole plate composed of 8 rows and 12 columns.
uene at 1208C. After 1 hour at 1208C, the dienes 7 and 8 On the columns 1–12 (Table 2) were introduced differ-
were completely converted and the g,d-unsaturated al- ent combinations of ligand L and bases B, except in the
dehydes 9 and 10 were isolated in 56% and 65% yield, column 12 which was free from any L and B sources for
ꢀ
respectively.
reference. On the rows (A H) were placed the selected
Starting from the natural carbonyl compounds 5 and 6 metallic source M except for the H row in which no met-
these simple three successive modifications actually in- al complex was introduced for reference (Figure 1, Ta-
¼
corporate, into the C O bond of 5 and 6, a five-carbon ble 2).
fragment and represent a formal homologation of mon-
oterpenoids into original non-natural sesquiterpenoids
9 and 10 by insertion of an isoprene skeleton into the car-
bonyl function.
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Scheme 4.
Table 2. Arrangement of the catalytic systems on the 96-tube plate and conversion (%) of diene 11 into aldehyde 12.
1
2
3
L3
B1
4
L4
B1
5
L2
B2
6
L3
B2
7
L4
B2
8
9
10
L3
–
11
L4
–
12
–
–
L1 L2
B1 B1
L1 L2
–
–
A M1¼[RuCl2(p-cymene)]2
B
C
M2¼(p-cymene)RuCl2(PCy3)
M3¼Ru3(CO)12
9%
D M4¼[Ru2(CO)4(HCO2)2]n
E
F
M5¼Ru2(CO)4(HCO2)2(PCy3)2
M6¼Ru(methallyl)2(COD)
0% 100% 100% 100% 100% 100% 100% 1% 100% 100% 100% 100%
13% 20%
G M7¼[Ir(COD)Cl]2
H
–
1
Conversions are determined by H NMR when aldehyde 12 was detected by TLC.
Figure 1.
HTS Reaction Preparation and Results
Each of the 96 tubes on the plate contained 350 mL of
solution for the reaction. Thus, titrated solutions of the
HTS reactions have been performed in a glove-box un- 1,6-diene 11 (0.1 mol/L), metal complex M1–M7
der an argon atmosphere and for practical reasons, in (0.005 mol/L of metal atom) and ligands L1–L4
toluene at 808C over a sand bath without stirring. (0.005 mol/L) have been prepared. Due to the poor sol-
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ubility of the bases, Cs2CO3 B1 and K2CO3 B2, in tol- (CO)12 (M3), 1,3-bis(2,6-diisopropylphenyl)imidazoli-
uene, saturated solutions were prepared by 4 h stirring nium chloride (L3) and cesium carbonate (B1), operat-
in toluene at room temperature and then used as such ed in tube C3. Under the experimental conditions (808C
for the reaction. The tubes werefirst filled with the metal without stirring), the conversion into aldehyde 12 by 1H
complex and ligand, followed by the heterogeneous NMR was only 9% (instead of 90% after 2 h at 1208C).
base/toluene mixture containing the substrate. The 96- Starting from this result as reference, all the tubes pre-
tube plate was then placed onto the sand bath at 808C senting higher conversions were expected to contain a
during 16 hours.
better catalytic system. Thus, the tubes G4 and G7, pre-
The 96-tube plate was removed from the glove box senting the dimer [Ir(COD)Cl]2 M7 as the metallic
(Figure 2) and thin layer chromatographic analyses of source, showed better conversions than the catalytic sys-
each tube were performed. By using an adequate elution tem B. But the most impressive result came from the
system (diethyl ether/heptane, 1/20), the formation of tubes of the line F for which the conversions were com-
the aldehyde 12 (Rf ¼0.3) can be easily observed as com- plete, except for F1 and F8. These tubes contained the
pared to the starting diene 11 (Rf ¼0.9). Only the tubes complex Ru(methallyl)2(COD) M6 as the metal source.
presenting the formation of the aldehyde 12 were evapo- Thus, this complex is a better precursor than Ru3(CO)12
rated to dryness and analysed by proton NMR. The re- for the catalytic isomerisation/Claisen rearrangement
action conversion was determined by measuring the ra- reaction, F1 and F8 correspond to the addition of one
tio between the aldehyde proton of 12 and the protons of equiv. of PCy3 per metal atom, showing that this ligand
the terminal double bond of the starting compound 11. inhibits the catalytic transformation. The most surpris-
The measured conversions (%) are indicated in Table 2 ing result was observed in tube F12 containing the com-
and Table 3.
plex Ru(methallyl)2(COD) M6 alone without any addi-
According to the preparation of the HTS reaction tional ligand.
plate, our previous catalytic system B, based on Ru3
Ru(methallyl)2(COD): New Efficient Catalyst for the
Tandem Isomerisation/Claisen Rearrangement
Reactions
From these primary results, the tandem reaction cata-
lysed by 5 mol % of the complex Ru(methallyl)2-
(COD) has been reproduced on a larger scale (see
Scheme 5).
In toluene, at 808C, 0.95 mmol of the 1,6-diene 11 was
completely converted, in 16 hours, into the aldehyde 12,
which was isolated in 93% yield after distillation. Differ-
ent reaction temperatures and catalyst amounts have
been tested and the conversions of the reaction have
been followed by GC-MS (see Table 4).
At 808C, the diene 11 was converted in 85% into the
aldehyde 12 after 4 hours of reaction. Only 15 minutes
were necessary to totally convert the starting diene at
1208C, which confirmed the impressive activity of the
complex Ru(methallyl)2(COD) revealed by HTS. How-
ever, no activity has been observed at 608C or at lower
temperature. By using 1 mol % of the complex Ru(me-
thallyl)2(COD), 84% of the diene 11 was converted, af-
ter 3 hours of reaction at 1208C. At lower temperature,
the same amount of catalyst gave only 5% conversion af-
Figure 2. View of the 96-hole plate after reaction according
to Table 2.
Table 3. Conversion of diene 11 into aldehyde 12 observed
by proton NMR:
Tubes
Catalytic System
Conversion[a]
C3
D10
F3
M3þL3þB1
M4þL3
9%
4%
M6þL3þB1
M6þL1
100%
1%
100%
13%
20%
F8
F12
G4
G7
M6
M7þL4þB1
M7þL4þB2
[a]
¼
% based on 12 aldehyde proton versus 11 ( CH2) protons.
Scheme 5.
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Table 4. Variations of the catalytic reaction conditions for the transformation of 11 into 12.
Catalytic System
Temperature
Reaction Time
Conversion in 12
5% Ru(methallyl)2(COD)
5% Ru(methallyl)2(COD)
5% Ru(methallyl)2(COD)
5% Ru(methallyl)2(COD)
1% Ru(methallyl)2(COD)
1% Ru(methallyl)2(COD)
1% Ru(methallyl)2(COD)þ1% L3þ2% B1
408C
608C
808C
1208C
1208C
808C
808C
4 h
4 h
4 h
15 min
3 h
18 h
4 h
0%
3%
85%
100%
84%
5%
27%
OV1, 25 mꢁ0.35 mm, 0.1–0.15 mm) chromatograph linked to
ter 18 hours but, at 808C, if a ligand source such as an
imidazolinium salt L3 and cesium carbonate B1 were
used, the conversion reached 27% after only 4 hours.
an Automass II Finnigan MAT (70 eV) apparatus.
Procedure A: Synthesis of the Allylic Alcohols
A Schlenk tube under a nitrogen atmosphere containing anhy-
drous CeCl3 (0.1 equiv.) was first heated at 1508C for 5 min and
then cooled down to room temperature. Tetrahydrofuran
(2 mL per mmol of ketone or aldehyde) was introduced fol-
lowed by the ketone or the aldehyde (1 equiv.) and the reaction
mixture was stirred for 30 min at room temperature. After a
cooling down to 08C, vinylmagnesium bromide (1.0 M solution
in tetrahydrofuran, 1.2 equivs.) was added dropwise. The reac-
tion mixture was stirred for 1 h at 08C and then for 16 h at room
temperature. After quenching by slow addition of a 1 N HCl
solution and extraction with diethyl ether, the corresponding
allylic alcohol was obtainedand used in the following step with-
out purification.
Conclusion
The above results show that tandem isomerisation/
Claisen rearrangement of 1,7- and 1,6-dienyl ethers is
catalysed by in situ prepared ruthenium catalysts to se-
lectively produce g,d-unsaturated aldehydes. An excel-
lent catalyst appears to consist in the combination of
Ru3(CO)12 and a bulky heterocyclic carbene precursor,
an imidazolinium salt, and cesium carbonate. Applica-
tion of this reaction has allowed the transformation of
natural terpenoids such as (ꢀ)-menthone and (ꢀ)-myr-
tenal into new sesquiterpenoids.
After a high throughput screening of several catalytic
precursors, more efficient and unpredictable catalytic
systems have been discovered. Especially the complex
Ru(methallyl)2(COD), without any ligand or reagent
addition, has presented an impressive activity for the
tandem isomerisation/Claisen rearrangement. Its activ-
ity is by contrast totally inhibited by the simple addition
of one equivalent of the bulky, electron-releasing PCy3
ligand, expected to displace the COD group. Ru(me-
thallyl)2(COD) has shown a high efficiency to perform
this tandem reaction with small amount of catalyst.
This study shows another example of the use of HTS
to reveal a novel catalytic system that knowledge and
reasoning cannot predict. The capacity of Ru(methall-
yl)2(COD) to interact with double bonds suggests that
it has also potential for other catalytic alkene transfor-
mations.
Procedure B: Allylation Reaction
In a Schlenk tube under a nitrogen atmosphere was introduced
sodium hydride (1.2 equivs.) and dry dimethylformamide
(1.5 mL per mmol of alcohol). The reaction mixture was then
cooled down to 08C and the alcohol (1 equiv.) in dimethylform-
amide (1 mL per mmol of alcohol) was slowly added. After
30 min stirring at 08C, allyl bromide (1.3 equivs.) was added
dropwise and the stirring was continued for 30 min at 08C
and 4 h at room temperature. The reaction mixture was then
slowly hydrolysed by water and extracted twice with diethyl
ether. The collected organic layers were then washed three
times with water, dried over MgSO4, filtered and evaporated
to dryness. The crude product was then purified by flash chro-
matography over silica gel using a diethyl ether/heptane mix-
ture.
Procedure C: General Procedure for Tandem
Isomerisation/Claisen Rearrangement Reaction using
Ru3(CO)12
Experimental Section
In a Schlenk tube under a nitrogen atmosphere was introduced
Ru3(CO)12 (5 mol %), the 1,3-bis(2,6-diisopropylphenyl)imi-
dazolinium chloride (5 mol %), cesium carbonate (10 mol %)
and toluene (7.5 mL per mmol of diene). The reaction mixture
was stirred for 5 min at room temperature and the diene was
then added. After 1 hour heating at 1208C, the solvent was re-
moved under reduced pressure and the crude residue was ex-
General Experimental Procedures
All experiments were carried out in Schlenk tubes under an in-
ert atmosphere of nitrogen. The solvents were dried and distil-
led prior to use. 1H and 13C NMR analyses were recorded with a
Bruker AC 200 MHz spectrometer and GC-MS were per-
formed with a CE Instrument GC 8000 Top (capillary column
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tracted with heptane, filtered and evaporated to dryness. This
material was then purified by chromatography over silica gel
using the appropriate elution system (diethyl ether/heptane)
or by a bulb-to-bulb distillation to afford the corresponding al-
dehyde as a colourless oil as a mixture of diastereoisomers.
ent to afford the corresponding 1,6-diene 8 as a colourless oil;
1
yield: 1.98 g (72%); H NMR (200 MHz, CDCl3): d¼0.75 (s,
3H, CH3), 1.02–1.10 [m, 1H, C(CH3)2CH(CH2)CH2], 1.23 (s,
¼
3H, CH3), 1.96–2.52 [m, 5H, C(CH3)2CH(CH2)C CH, CH2,
¼
CH2], 3.80–4.08 (m, 2H, OCH2CH CH2), 4.94–5.27 [m, 4H,
¼
2ꢁ(CH CH2)], 5.44–5.61 [m, 1H, CH(O-allyl)(vinyl)],
5.71–5.99 [m, 3H, 2ꢁ(CH CH2), C CHCH2]; 13C NMR
(50 MHz, CDCl3): d¼20.6/20.7 (CH3), 26.3 (CH3), 31.0/31.1
¼
¼
1-Allyloxy-2-(S)-isopropyl-5-(R)-methyl-1-
vinylcyclohexane (7)
(CH2),
37.3/37.5
(C(CH3)2),
40.4/40.9
41.7/41.9
¼
[HC CCH(C(CH3)2)(CH2)],
[CH2CH(C(CH3)2)(CH2)], 42.6/42.9 (CH2), 68.5/68.7 (OCH2
Following Procedure A: To CeCl3 (0.14 g, 0.58 mmol,
0.1 equiv.) in 15 mL of tetrahydrofuran was added (ꢀ)-men-
thone (5; 1.0 mL, 5.8 mmol, 1 equiv.) at room temperature. Vi-
nylmagnesium bromide (7.0 mL, 7.0 mmol, 1.2 equivs.) was
then added at 08C. Subsequent treatment afforded the corre-
sponding allylic alcohol as a pale yellow oil which was used
without purification for the next step.
¼
CH CH2), 75.6/75.9 [CH(OR)(vinyl)], 115.5/115.7 [CH(O-al-
¼
¼
lyl)CH CH2], 116.9/117.1 (OCH2CH CH2), 121.6/121.7
¼
¼
(C CHCH2), 134.5 (OCH2CH CH2), 143.3 [CH(O-al-
¼
¼
lyl)CH CH2], 145.8 (C CHCH2); MS (EI): m/z (%)¼218
([M]þ, <1), 160 (15), 149 (29), 145 (15), 117 (67), 115 (12),
107 (21), 105 (19), 93 (29), 91 (56), 79 (66), 77 (36), 69 (18),
67 (37), 55 (25), 53 (13), 41 (100), 39 (28).
Following Procedure B: The allylic alcohol (5.8 mmol, 1
equiv) in 6 mL of dimethylformamide was added to a solution
of sodium hydride (60% in mineral oil, 0.28 g, 7.0 mmol,
1.2 equivs.) in 12 mL of dimethylformamide. After addition
of allyl bromide (0.69 mL, 7.5 mmol, 1.3 equivs.) and subse-
quent treatment, the crude material was purified by flash chro-
matography over silica gel using diethyl ether/heptane (1:40)
as eluent to afford the corresponding 1,6-diene 7 as a colourless
[1-Phenyl-1-(isoprop-2-enyloxy)prop-2-en-1-
yl]benzene (11):
Following Procedure A: To CeCl3 (0.41 g, 1.65 mmol,
0.1 equiv.) in 30 mL of tetrahydrofuran was added benzophe-
none (3.0 g, 16.5 mmol, 1 equiv.) at room temperature. Vinyl-
magnesium bromide (20.0 mL, 20.0 mmol, 1.2 equiv.) was
then added at 08C. Subsequent treatment afforded the corre-
sponding allylic alcohol as a pale yellow oil that was used with-
out purification for the next step.
1
oil; yield: 1.02 g (79%); H NMR (200 MHz, CDCl3): d¼0.80
(d, 3H, 3J¼6.8 Hz, CH3), 0.95 [d, 3H, 3J¼7.1 Hz, CH(CH3)2],
3
0.97 [d, 3H, J¼7.1 Hz, CH(CH3)2], 1.00–1.11 [m, 1 H, CH2-
3
CH(CH3)], 1.40–1.81 (m, 6H, 3ꢁCH2), 1.91 [dm, 1H, J¼
3
3
14.1 Hz, CHCH(CH3)2], 2.15 [heptꢁd, 1H, J¼7.0 Hz, J’¼
¼
Following Procedure B: The allylic alcohol (16.5 mmol,
1 equiv.) in 15 mL of dimethylformamide was added to a solu-
tion of sodium hydride (60% in mineral oil, 0.86 g, 19.8 mmol,
1.2 equivs.) in 25 mL of dimethylformamide. After addition of
2-methylpropene chloride (2.2 mL, 19.8 mmol, 1.3 equivs.)
and subsequent treatment, the crude residue was purified by
flash chromatography over silica gel using diethyl ether/hep-
tane (1:20) as eluent to afford an orange oil which was then
bulb-to-bulb distilled to give the corresponding 1,6-diene 11
1.8 Hz, CHCH(CH3)2], 3.72–3.90 (m, 2H, OCH2CH CH2),
¼
5.04–5.39 [m, 4H, 2ꢁ(CH CH2)], 5.79–6.00 [m, 2H, 2ꢁ
(CH CH2)]; 13C NMR (50 MHz, CDCl3): d¼18.5 (2ꢁCH3),
¼
20.7 [(CH3)2CHCHCH2CH2], 22.4 [CH2CH2CH(CH3)], 23.8
[CH2CH2CH(CH3)], 27.5 [(CH3)2CHCHCH2CH2], 35.4
[CH2CH2CH(CH3)], 41.2 [CH2C(OR)], 51.8 [(CH3)2-
¼
CHCHCH2CH2], 62.4 (OCH2CH CH2), 80.4 [C(OR)(vinyl)],
¼
¼
114.0 [C(R)2CH CH2], 114.2 (OCH2CH CH2), 136.2
¼
¼
(OCH2CH CH2), 143.2 [C(R)2CH CH2]; MS (EI): m/z
(%)¼222 ([M]þ, 1.3), 207 (19), 179 (30), 165 (26), 151 (17),
137 (100), 125 (26), 123 (27), 111 (39), 109 (59), 97 (34), 95
(84), 93 (34), 83 (45), 81 (75), 79 (43), 69 (60), 67 (66), 57
(39), 39 (34).
1
as a colourless oil; yield: 3.74 g (86%); H NMR (200 MHz,
CDCl3): d¼2.00 (s, 3H, CH3), 3.94–4.00 [m, 2H, OCH2-
¼
¼
C(CH3) CH2], 5.15–5.63 [m, 4H, C(CH3) CH2, C(Ph)2-
¼
¼
CH CH2], 6.69–6.84 [m, 1H, C(Ph)2CH CH2], 7.42–7.55
(m, 6H, H arom.), 7.62–7.72 (m, 4H, H arom.); 13C NMR
¼
(50 MHz, CDCl3): d¼20.6 (CH3), 68.0 [OCH2C(CH3) CH2],
¼
84.8 [C(Ph)2(R)2], 111.1 [C(Ph)2CH CH2], 117.0 [OCH2-
2-(1-Allyloxyprop-2-enyl)-6,6-
dimethylbicyclo[3.1.1]hept-2-ene (8)
¼
C(CH3) CH2], 127.8, 128.5, 128.7 (CH arom.), 141.0
¼
[C(Ph)2CH CH2],
143.4
(C
quat.
arom.)þ, 144.9
¼
[OCH2C(CH3) CH2]; MS (EI): m/z (%)¼264 ([M] , 1), 193
(32), 191 (15), 178 (18), 165 (14), 144 (12), 116 (19), 115
(100), 106 (43), 103 (19), 91 (40), 77 (45), 55 (69), 41 (13), 39
(25).
Following Procedure A: To CeCl3 (0.32 g, 1.28 mmol,
0.1 equiv.) in 25 mL of tetrahydrofuran was added (ꢀ)-myrte-
nal (6; 2.0 mL, 12.6 mmol, 1 equiv.) at room temperature. Vi-
nylmagnesium bromide (15.2 mL, 15.2 mmol, 1.2 equivs.) was
then added at 08C. Subsequent treatment afforded the corre-
sponding allylic alcohol as a pale yellow oil that was used with-
out purification for the next step.
Following Procedure B: The allylic alcohol (12.6 mmol,
1 equiv.) in 13 mL of dimethylformamide was added to a solu-
tion of sodium hydride (60% in mineral oil, 0.60 g, 15.2 mmol,
1.2 equivs.) in 20 mL of dimethylformamide. After addition of
allyl bromide (1.5 mL, 16.4 mmol, 1.3 equivs.) and subsequent
treatment, the crude residue was purified by flash chromatog-
raphy over silica gel using diethyl ether/heptane (1:40) as elu-
Tandem Isomerisation/Claisen Rearrangement
Reaction to 4-(2-(S)-Isopropyl-5-(R)-
methylcyclohexylidene)-2-methylbutyraldehyde (9)
Following Procedure C: Ru3(CO)12 (9.6 mg, 0.045 mmol,
5 mol % of ruthenium), 1,3-bis(2,6-diisopropylphenyl)imida-
zolinium chloride (15.4 mg, 0.045 mmol, 5 mol %), Cs2CO3
(29.3 mg, 0.09 mmol, 10 mol %), 7.5 mL of toluene and diene
Adv. Synth. Catal. 2005, 347, 783–791
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
789

´ ˆ
ˆ
Jerome Le Notre et al.
FULL PAPERS
7 (200 mg, 0.9 mmol) were placed in a Schlenk tube under ni-
trogen. After 1 h at 1208C, treatment and distillation, the alde-
hyde 9 was obtained as a colourless oil as a mixture of diaster-
eoisomers; yield: 112 mg (56%); 1H NMR (200 MHz, CDCl3):
d¼0.79–0.90 [m, 9H, CH(CH3)2, CH2CH2CH(CH3)], 1.04 [d,
3H, 3J¼7.1 Hz, CH(CH3)CHO], 1.16–1.25 [m, 1 H, CH2-
CH(CH3)], 1.59–1.99 [m, 7H, 3ꢁCH2, CHCH(CH3)2], 2.10–
Cs2CO3 B1 and K2CO3 B2 in toluene were obtained after 4
hours stirring at room temperature.
The 96 tubes, each one containing 350 mL of reaction mix-
ture, were prepared following the combinations described in
Table 2. The metallic sources (100 mL per tube) were first intro-
ꢀ
duced over the lines (A G) followed by the ligands (100 mL per
tube) and the bases (50 mL per tube) over the columns (1–11).
Line H was filled without metallic source and column 12 with-
out ligand and base to use them as reference experiments. The
tubes were shaken by hand over two minutes before the addi-
tion of the diene 11 (100 mL per tube). The tubes were then
heated at 808C over a sand bath. After 16 hours, the 96-tube
plate was taken out of the glove-box and thin layer chromatog-
raphy on each sample on silica was performed using a mixture
of diethyl ether/heptane (1/20) as eluent [Rf (11)¼0.9; Rf
(12)¼0.3]. The conversion into the aldehyde 12 in the selected
tubes was determined by 1H NMR analysis after evaporation of
these samples to dryness.
¼
2.46 [m, 4H, CH(CH3)CHO, CHCH(CH3)2, (R)2C CHCH2],
3
¼
5.08 [t, 1H, J¼7.2 Hz, (R)2C CHCH2], 9.61–9.65 (m, 1H,
CHO);
[CH(CH3)CHO],
13C NMR
(50 MHz,
CDCl3):
d¼13.0/13.1
19.7
[CH2CH2CH(CH3)],
20.4/20.5
¼
[CH(CH3)2], 26.4/26.6 [(R)2C CHCH2], 28.2/28.4 [CH2CH2-
CH(CH3)], 29.6/29.8 [CH(CH3)2], 31.6/31.7 [CH2CH2-
CH(CH3)], 32.2 [CH2CH2CH(CH3)], 35.0/35.1 [CH2-
¼
C(R) CHCH2],
[CH(CH3)CHO],
47.0/47.2
117.5/117.6
[CHCH(CH3)2],
51.2/51.3
¼
[(R)2C CHCH2], 142.5
¼
[(R)2C CHCH2], 205.2/205.3 (CHO); MS (EI): m/z (%)¼
222 ([M]þ, 18), 204 (39), 179 (61), 164 (49), 162 (35), 151
(12), 149 (29), 137 (36), 135 (27), 123 (23), 119 (63), 111 (41),
109 (39), 107 (62), 97 (28), 95 (34), 93 (21), 91 (100), 83 (52),
81 (35), 79 (21), 77 (69), 69 (53), 67 (29), 57 (30), 53 (33), 43
(77), 39 (33).
Tandem Isomerisation/Claisen Rearrangement
Reaction Catalysed by the Complex Ru(methylallyl)2
(COD) to give 2,2-Dimethyl-5,5-diphenylpent-4-
enal[19] (12)
Into a Schlenk tube under a nitrogen atmosphere were intro-
duced Ru(methylallyl)2(COD) (15.0 mg, 0.047 mmol,
5 mol %) and 7 mL of toluene. The reaction mixture was stirred
during 5 min at room temperature and the diene 11 (250 mg,
0.95 mmol) was then added. After 16 h heating at 808C, the sol-
vent was removed under reduced pressure and the crude resi-
due was extracted with heptane, filtered and evaporated to dry-
ness. This material was then purified by a bulb-to-bulb distilla-
tion to afford the aldehyde 12 as a colourless oil; yield: 232 mg
(93%); 1H NMR (200 MHz, CDCl3): d¼1,12 (s, 6H, 2ꢁCH3),
Tandem Isomerisation/Claisen Rearrangement
Reaction to 5-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-
yl)-2-methylpent-4-enal (10)
Following Procedure C: Ru3(CO)12 (48.9 mg, 0.23 mmol,
5 mol % of ruthenium), 1,3-bis(2,6-diisopropylphenyl)imida-
zolinium chloride (97.7 mg, 0.23 mmol, 5 mol %), Cs2CO3
(149.2 mg, 0.46 mmol, 10 mol %), 30 mL of toluene and diene
8 (1.0 g, 4.6 mmol) were placed in a Schlenk tube under nitro-
gen. After 1 h at 1208C, treatment and distillation, the alde-
hyde 10 was obtained as a colourless oil as a mixture of diaster-
3
3
2,39 (d, 2H, JHH ¼7.6 Hz, CH2), 6,09 [t, 1H, JHH ¼7.6 Hz,
1
eoisomers; yield: 0.65 g (65%); H NMR (200 MHz, CDCl3):
¼
(Ph)2C CHCH2], 7.18–7.30 (m, 6H, CH arom.), 7.38–7.49
d¼0.74 (s, 3H, CH3), 0.98 [d, 3H, 3J¼6.9 Hz, CH(CH3)CHO],
(m, 4H, CH arom.), 9.48 (s, 1H, CHO); 13C NMR (50 MHz,
CDCl3): d¼21.2 (2ꢁCH3), 36.6 (CH2), 46.5 [C(CH3)2], 123.6
1.03–1.12 [m, 1H, C(CH3)2CH(CH2)CH2], 1.23 (s, 3H, CH3),
2.07–2.52
[m,
8H,
CH2CH(CH3)CHO,
C(CH3)2
¼
[(Ph)2C CHCH2], 127.0, 127.1, 128.0, 128.2, 129.7 (C arom.),
¼
¼
CH(CH2)C CH, CH2, CH2], 5.26–5.35 [m, 1H, C CHCH2],
¼
139.5, 142.2 (C arom.), 144.3 [(Ph)2C CH], 205.5 (CHO); MS
(EI): m/z (%)¼264 ([M]þ, 2), 193 (43), 180 (100), 178 (36),
¼
5.43–5.73 [m, 2H, CH CHCH2CH(CH3)CHO], 9.51–9.61
(m, 1H, CHO); 13C NMR (50 MHz, CDCl3): d¼11.7/12.0
[CH(CH3)CHO], 21.2/21.3 (CH3), 26.2/26.3 (CH3), 31.2/31.3/
31.4/31.5 [CH2CH(CH3)CHO, CH2], 37.7/37.8 [C(CH3)2],
¼
165 (37), 115 (87), 91 (38), 51 (10), 43 (14), 41 (16), 39 (14).
40.5/40.7
[HC CCH(C(CH3)2)(CH2)],
42.8/42.9
52.7/52.8
[CH2CH(C(CH3)2)(CH2)],
44.0/44.1
(CH2),
References
¼
[CH(CH3)CHO], 118.8/118.9 (C CHCH2), 122.0/122.2
¼
¼
[CH CHCH2CH(Me)CHO], 133.8/134.0 [CH CHCH2-
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Adv. Synth. Catal. 2005, 347, 783–791
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
791