Synthesis of cis,cis,cis-1-alkylidene-2,3,4,5-tetrakis(diphenylphosphinomethyl)cyclopentanes

Article abstract of DOI:10.1016/j.tet.2009.07.016

A new strategy to prepare tetradentate or pentadentate diphenylphosphine ligands has been explored from Diels-Alder adducts of fulvenes and maleic anhydride. A tetradentate phosphine ligand, bearing a side chain allowing the formation of a bond with polys

Full text of DOI:10.1016/j.tet.2009.07.016

Tetrahedron 65 (2009) 7440–7448
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Synthesis of cis,cis,cis-1-alkylidene-2,3,4,5-tetrakis(diphenyl-
phosphinomethyl)cyclopentanes
a
a
a
,
,
a,
*
Celine Reynaud , Yacoub Fall , Marie Feuerstein y, Henri Doucet b , Maurice Santelli
*
´
a Laboratoire de Synthe`se Organique, UMR CNRS 6263, Universite´ d’Aix-Marseille, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
b Institut Sciences Chimiques de Rennes, ‘Catalyse et Organometalliques’, Universite´ de Rennes1, Campus de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2009
Received in revised form 1 July 2009
Accepted 4 July 2009
Available online 9 July 2009
A new strategy to prepare tetradentate or pentadentate diphenylphosphine ligands has been explored
from Diels–Alder adducts of fulvenes and maleic anhydride. A tetradentate phosphine ligand, bearing
a side chain allowing the formation of a bond with polystyrene resin, has been prepared in seven steps
from cyclopentadiene. The cis,cis,cis-1-cyclohexylidene-2,3,4,5-tetrakis(diphenylphosphinomethyl)-
cyclopentane (Cyclo-Tedicyp) in combination with [PdCl(C3H5)]2 led to an efficient catalyst for the Heck,
Suzuki and Sonogashira coupling reactions.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Palladium catalysis
Tetratertiary phosphines
Pentatertiary phosphine
Ozonolysis
Fulvenes
PPh2
Ph
P
1. Introduction
Ph2P
P
PPh2
Ph2P
P
Chelating polyphosphine ligands are useful tools for stabilising
unusual geometries in transition metal complexes. Since the last
decade, our group has been investigating the synthesis and also the
use in palladium-catalysed Tsuji-Trost, Heck, Suzuki, Sonogashira
or Negishi coupling reactions and also the direct arylation via C–H
bond activation of new tetradentate phosphine ligands, such as the
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane
(Tedicyp),1,2 and the cis,cis,cis-3-(2-diphenylphosphinoethyl)-
1,2,4-tris(diphenylphosphinomethyl)-cyclopentane (Ditricyp),3
(Scheme 1). Tedicyp, and in selected cases Ditricyp, in combi-
PPh2
Ph
a
b
Ph2P
Ph2P
PPh2
Ph2P
Ph2P
PPh2
Ph2P
Ph2P
PPh2
PPh2
PPh2
PPh2
c
e
d
Ph2P
Ph2P
PPh2
PPh2
Ph2P
Ph2P
PPh2
PPh2
g
f
nation with [(h
3-C3H5)PdCl]2 affords catalyst precursors, which
PPh2
PPh2
are amongst the most active for the aforementioned coupling
reactions.4
t-Bu
t-Bu
Ph Ph
Fe
P
P
Ph2P
PPh2
PPh2
PPh2
Ph2P
Ph2P
Ph2P
Ph2P
PPh2
PPh2
PPh2
h
i
PPh2
t-Bu
Me
P t-Bu
Tedicyp
Scheme 1.
Ditricyp
PPh2
P
PPh2
PPh2
t-Bu
Me
P
P
t-Bu
j
* Corresponding authors. Tel.: þ33 4 91288825; fax: þ33 4 91289112.
E-mail addresses: henri.doucet@univ-rennes1.fr (H. Doucet), m.santelli@univ-
cezanne.fr (M. Santelli).
PPH2
k
Scheme 2.
y
Present address: Johnson Matthey Catalysts, Orchard Road, Royston, Hertford-
shire, SG8 5HE, England.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.016

C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
7441
So far, only a few polypodal diphenylphosphine ligands have
been synthesised5 and generally they were only employed for hy-
drogenation or hydroformylation reactions.6 It should be noted that
among the tetradentate diphenylphosphino derivatives ligands,
which have been prepared,7,8 only a few of them present the spe-
cific geometry, which allows the formation of tetracoordinated
complexes using only one transition metal atom (Tedicyp, a[7a,b],
b[7a,b], d[7d], h[7h,i,l], j[7k]) (Scheme 2). In recent years, there has
been an increasing interest of such polydentate ligands for the
preparation of dinuclear organometallic complexes, due to their
large potential in optical and/or electronic materials chemistry. On
the other hand, these tetradentate ligands have been generally
poorly exploited in palladium catalysis.
We believe that the efficiency of the ligand Tedicyp in palladium
catalysis is due to its specific geometry, where the four diphenyl-
phosphinomethyl groups are stereospecifically bound to the same
face of the cyclopentane ring. The structure of [(
Tedicyp complex has been investigated by 1H, 13C and 31P NMR
spectra.4 All attempts to obtain crystals from [( 3-C3H5)PdCl]2 and
h
3-C3H5)PdCl]2/
h
Tedicyp failed. However, it would be interesting to determine the
geometry of the Pd/Tedicyp species. Fortunately, Tedicyp reacted
with palladium(II) bromide gave a crystallised binuclear complex,
suitable for X-ray analysis, which reveals that the ligand is co-
ordinated to two palladium atoms in a symmetrical bidentate
fashion (Scheme 3 and Fig. 1). The cis-PdBr2P2 unit is almost per-
fectly planar (the sums of the angles about Pd(1) and Pd(2) being
360.98 and 360.24ꢀ). As expected, the largest angle in each unit is
between the two phosphorus atoms, whereas the smallest angle is
between the two bromines of the seven-membered chelate ring
(Fig. 2). The structure of ligands 9b and 24 (vide infra) is very
similar to the structure of Tedicyp ligand.
Ph
P
Ph
P
Ph2P
Ph2P
Ph
Ph
PPh2
PPh2
Br
Br
+
PdBr2
Pd
Pd
Br
P
P
Br
Ph Ph
Ph Ph
Actually, one of the major drawbacks of the organometallic
homogeneous catalysis is the need for separation of the relative
expensive, and in some cases toxic, catalysts from the reaction
mixture at the end of the processes. In recent years, there has been
an increasing interest in developing greener catalysed processes. In
this context, supported homogeneous complexes so that catalysts
can be recovered from the reaction mixture by simple filtration and
reused should be convenient.9,10 The catalyst recovery allows to
decreases the contamination of the desired products with hazard-
ous or unhealthy compounds, and also environmental pollution
caused by residual toxic metals can be reduced. Consequently, the
development of new polymer supported catalysts is desired.
Here, we report a new strategy, which allows the preparation of
new polydentate phosphine ligands, bearing resemblance with
Tedicyp, which could either be easily supported with polymers, or
directly employed in palladium-catalysed reaction. In order to ob-
tain such Tedicyp derivatives substituted on the free site of the
cyclopentane ring, we have investigated a synthetic strategy in-
volving fulvene intermediates.
Scheme 3.
Bond length (Å)
Bond angle (°)
7 1 2: 100.27
7 1 8: 85.58
8 1 9: 87.67
2 1 9: 87.46
1 2 3: 119.37
2 3 4: 112.40
3 4 5: 112.04
4 5 6: 116.32
5 6 7: 115.98
6 7 1: 121.60
Ph 7 Ph: 108.60
Ph 2 Ph: 108.20
1 2: 2.283
1 7: 2.276
1 8: 2.473
1 9: 2.465
2 3: 1.838
3 4: 1.531
4 5: 1.538
5 6: 1.523
6 7: 1.826
Ph
Ph
6
7P
1Pd
5
8Br
4
2
3
9
Br
P
Ph
Ph
Torsional angle (°)
1 2 3 4: 42.64; 2 3 4 5: 107.92
3 4 5 6: 44.11; 4 5 6 7: 59.16
5 6 7 1: 70.61; 6 7 1 2: 3.78
Figure 1.
Figure 2. ORTEP diagram of Tedicyp–palladium(II) bromide complex.

7442
C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
2. Results
reacts with ozone to give, after treatment with an ethanolic solu-
tion of NaBH4, 5a or 5b in 60% yield.3 The next steps have been
conducted as usual,1 but only with the cyclohexylidene derivatives
5b, to give the tetraphosphine ligand Cyclo-Tedicyp 9b in 13.4%
overall yield (Scheme 5).
First, the condensation of acetone or cyclohexanone with
cyclopentadiene affords fulvenes 1a or 1b in quantitative yields.11
Then, the Diels–Alder reaction with maleic anhydride quantita-
tively gave rise to a mixture of endo and exo-isomers 2a or 2b,
which were easily separated by crystallisation (Scheme 4).12,13
It should be noted that, when the ozonolysis of 4b was carried out
at ꢁ60 ꢀC in absence of pyridine, the tetrasubstituted cyclopen-
tanone 10 has been obtained in 20% yield, after the addition of NaBH4
(Scheme 6).
R
R
R
R
pyrrolidine
MeOH
O
+
O3
CH2Cl2,
HO
HO
1a or 1b, 100%
a, R = CH ; b, R-R = -(CH ) -
O
O
3
2 4
4b
NaBH4
O
R
R
10, 20%
R
O
R
O
O
Scheme 6.
+
O
O
O
This new strategy should allow the synthesis Tedicyp de-
rivatives bearing a tether, able to be bound to a polystyrene resin.
By employing ethyl levulinate as precursor of fulvene, we have
prepared the fulvene derivative 11 in quantitative yield and then,
the corresponding Diels–Alder adduct 12 (Scheme 7).
CH Cl
2
2
O
O
O
2a or 2b endo
2a or 2b exo
100%, Ratio endo:exo = 40 : 60
Scheme 4.
EtO2C
EtO2C
pyrrolidine
MeOH
+
After reduction of the anhydride moiety of 2a or 2b, and pro-
O
tection of the diols 3a,b, the resulting acetonides 4a,b have been
14
ozonolyzed at ꢁ60 ꢀC in the presence of pyridine
and an ozo-
nizable red dye (sudan III, Eastman Kodak) as internal standard.15 In
these conditions, only the double bond of the norbornene moiety
O
11
, 100%
EtO2C
O
EtO2C
O
O
O
R
R
R
R
+
O
CH2Cl2
LiAlH4
THF
OMe
/ H(+)
O
O
2endo
O
12
, 100%, 40 : 60
O
OH
OH
O
Scheme 7.
3a 3b
, 100%
4a
,
, 73%
After reduction of the endo isomer 12 into the triol 13 and partial
hydroxyl protection using an excess of 2-methoxypropene, the
acetonide 15 was obtained in 41% yield. The formation of 14 in 15%
yield was also observed (with an excess of 2-methoxypropene, 14
was prepared in 85% yield) (Scheme 8).
4b, 96%
O3
H2O
/ H(+)
pyridine
CH2Cl2
HO
HO
O
O
NaBH4
R
R
EtO2C
5a 5b
,
, 60%
HO
HO
HO
TsO
TsO
OH
OH
OTs
OTs
LiAlH4
THF
OMe
/ H(+)
TsCl
O
pyridine
CH2Cl2
OH
OH
O
O
endo-12
13, 100%
6b, 100%
H3B
7b, 60%
HO
BH3
PPh2
PPh2
MeO
O
Ph2PLi
/ THF
PPh2
PPh2
H3B
Et2NH
+
BH3
BH3
O
O
O
O
8b
, 31%
14, 15%
Scheme 8.
15, 41%
PPh2
PPh2
PPh2
PPh2
From acetonides 14 and 15, two strategies for the access either
to the desired supported ligands or to a pentadentate ligand have
been investigated. From 15, we can prepare the pentaphosphine
ligand 19 (Scheme 9), while 14 gave rise to a tetraphosphine with
Cyclo Tedicyp
9b, 72%
Scheme 5.

C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
7443
O3
pyridine
CH2Cl2,
an auxiliary chain available to establish a bond with polystyrene
resin (Scheme 10). The new pentatertiary phosphine ligand 19 is
a chiral molecule (geometrical enantiomorphisme),16 which should
allow the formation of several cyclic chelates with transition
metals.
HO
HO
H2O
O
O
/ H(+)
14
NaBH4
O
OMe
16, 45%
After protection of the hydroxyl group of the side chain of 15
using benzyl bromide to form 20, the norbornene double bond has
been ozonolyzed in the presence of pyridine (Scheme 10). Again,
only the double bond of the norbornene moiety reacts with ozone
to give 21. After deprotection of 21, the tetrahydroxyl moiety was
transformed into diphenylphosphino groups using an excess of
Ph2PK. Previous reports should allow the access to the supported
ligand by reaction with the side chain. In the literature, several li-
gands, such as Binap, have been bound on commercially available
polymers.17 Our proposal was to incorporate the Tedicyp frame-
work onto an insoluble polymer and thus provide a heterogeneous
catalyst that could be isolated from the reaction medium and
reused if necessary. The deprotection of benzyl group in ligand 24
can be done by reductive cleavage with calcium in liquid ammo-
nia,18 or with 6 N hydrochloric acid.19 A very similar reaction has
been reported by Kagan and co-workers.20
Here, we wish also to report the first results obtained for the
catalysed Suzuki cross-coupling, Heck vinylation or Sonogashira
alkynylation using Cyclo-Tedicyp 9b as the ligand. First, we studied
the Heck type coupling of an activated aryl bromide, 4-bromo-
benzaldehyde, with an acrylate (Scheme 1, Table 1). When
0.001 mol % of [PdCl(C3H5)]2/Cyclo-Tedicyp was used, 100% conver-
sion of the aryl bromide was observed (Table 1, entry 1). In the
presence of 0.0001 mol % catalyst a TON (turnover number) of
460,000 was obtained (Table 1, entry 2). Next we studied the re-
activity of a deactivated aryl bromide, 4-bromoanisole. As expected,
a lower TON of 500 was observed, due to a slower oxidative addition
of this reactant to palladium (Table 1, entry 4). Then, we examined
the efficiency of ligand 9b for the copper-free ‘Sonogashira reaction’
of aryl bromides with phenylacetylene. With 4-bromobenzaldehyde
a TON of 1000 was obtained (Table 1, entry 6), whereas, 4-bromo-
anisole gave the coupling product 28 in 300 TON (Table 1, entry 8).
HO
TsO
TsO
OH
OH
OTs
OTs
HO
TsCl
pyridine
CH2Cl2
OH
OTs
17, 93%
18, 43%
PPh2
PPh2
PPh2
PPh2
Ph2PK
/ THF
PPh2
19, 25%
Scheme 9.
BnO
O3
pyridine
CH2Cl2,
NaH
15
BnBr
THF
NaBH4
O
O
20, 72%
HO
HO
OH
OH
HO
HO
H2O
O
O
/ H(+)
TsCl
pyridine
CH2Cl2
OBn
OBn
OBn
21, 55%
22, 100%
TsO
TsO
PPh2
PPh2
OTs
OTs
PPh2
PPh2
Ph2PK
/ THF
OBn
23, 45%
24, 30%
Scheme 10.
Table 1
Palladium/Cyclo-Tedicyp 9b catalysed reactions
Entry
1
Aryl bromide
Alkene, alkyne
or arylboronic acid
Ligand
Ratio substrate/catalyst
100,000
Product
Yielda(%)
100 (92)
100
9b
O
H
O
O
nBu
O
Br
O
H
nBu
2
3
9b
Tedicyp
1,000,000
1,000,000
O
,4a
46b
25
O
O
nBu
4
5
9b
1000
50 (45)
974a
O
nBu
MeO
Br
MeO
O
Tedicyp
10,000
26
O
O
H
6
7
9b
9b
1000
250
100 (90)
100 (88)
Br
H
27
O
MeO
Br
H
28
8
1000
30
O
H
O
H
9
10
11
1000
10,000
100,000
100 (92)c
61c
9b
9b
(HO)2B
(HO)2B
Br
100 (87)c
29
MeO
MeO
Br
30
,4b
(93)c,d
12
Tedicyp
100,000
Conditions: Pd–Cyclo-Tedicyp catalyst, ArBr (1 equiv), alkene, alkyne or arylboronic acid (2 equiv), K2CO3 (2 equiv), DMF, 130 ꢀC, 20 h.
a
GC and NMR conversion; yields in parenthesis are isolated.
Reaction time 40 h.
Reaction performed in xylene.
Reaction time 24 h.
b
c
d

7444
C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
Quite surprising results were obtained for Suzuki cross-coupling. The
reaction of phenylboronic acid with 4-bromobenzaldehyde gave 29
in only 6100 TON (Table 1, entry 10), whereas, in the presence of
4-bromoanisole, 30 was obtained in 100,000 TON. In summary, the
reaction rates obtained with electron-deficient aryl bromides are not
extremely high with this catalytic system. On the other hand, good
results were obtained in the presence of the more challenging aryl
bromide, 4-bromoanisole.
solution was filtered and concentrated in vacuo to give a mixture of
exo and endo isomers, which was recrystallised in petroleum ether–
diethyl ether to give endo-2b (first crystallised) as white crystals
(9.8 g, 40 mmol, 40%). Compound endo-2b, mp 132 ꢀC; 1H NMR
(CDCl3, 300 MHz)
d
6.44 (m, 2H), 3.96 (m, 2H), 3.52 (m, 2H), 2.03
170.7 (s) (2C),
(m, 4H), 1.46 (m, 6H); 13C NMR (CDCl3, 75 MHz)
d
143.1 (s), 135.8 (d) (2C), 120.8 (s), 46.7 (d) (2C), 44.7 (d) (2C), 30.4 (t)
(2C), 27.7 (t) (2C), 26.3 (t).
3. Conclusion
4.4. (1S ,2R
* *
,3S
*
,4R )-7-Cyclohexylidene-2,3-
*
di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene (3b)
A straightforward and versatile synthetic route leading to vari-
ous tetra- or pentaphosphine ligands has been developed from
cheap reagents. The purification steps are simpler than for the
previously reported synthesis of Tedicyp.1 One of the new ligands
prepared using this new strategy should allow the easy access to
supported catalysts useful in organometallic chemistry. An other
new tetraphosphine ligand prepared by this strategy, in combina-
tion with [PdCl(C3H5)]2 afforded, as expected, a successful catalyst
for some of the most important palladium-catalysed reactions.
To a stirred suspension of LiAlH4 (3.8 g, 100 mmol) in anhydrous
THF (400 mL) at ꢁ20 ꢀC under argon atmosphere was added an-
hydride endo-2b (12.2 g, 50 mmol) in anhydrous THF (15 mL). After
one night of stirring at room temperature, the mixture was
refluxing for 3 h and then cooled at ꢁ20 ꢀC. Water (3.8 mL) fol-
lowed by 3.8 mL of 1 M solution of NaOH and 11.4 mL of water was
successively added. After 3 h of stirring, the suspension was filtered
and washed with diethyl ether. Filtrate was concentrated in vacuo
to give a white powder (11.0 g, 47 mmol, 94%) of 3b. Mp 121 ꢀC; 1H
4. Experimental part
4.1. General
NMR (CDCl3, 300 MHz)
3.28 (m, 2H), 1.92 (m, 2H), 1.84 (m, 2H), 1.41 (m, 6H); 13C NMR
(CDCl3, 75 MHz) 144.8 (s), 134.8 (d) (2C), 116.3 (s), 63.0 (t) (2C),
45.9 (d) (2C), 45.4 (d) (2C), 30.2 (t) (2C), 28.0 (t) (2C), 26.6 (t).
d 6.16 (m, 2H), 3.68 (m, 4H), 3.42 (m, 2H),
d
THF was freshly distilled from sodium-benzophenone; CH2Cl2,
triethylamine and pyridine from CaH2 under N2. Other reagents and
solvents were obtained from commercial sources and used as re-
ceived. Flash column chromatography (FC): Merck 230–400 Mesh
silica gel; EtOAc, Et2O and petroleum ether as eluents. Thin-layer
chromatography (TLC): Macherey–Nagel silica gel UV254 analytical
plates; detection either with UV, or by dipping in a solution of
KMnO4 (3 g), K2CO3 (20 g), KOH (0.3 g) in H2O (300 mL) and sub-
sequent heating. IR spectroscopy: Perkin–Elmer Paragon 1600 Four-
rier Transform. NMR spectroscopy: Bruker AC 300 (1H¼300 MHz,
4.5. (1S
*
,2R
*
,3S
*
,4R )-7-Cyclohexylidene-2,3-di(hydroxy-
*
methyl)bicyclo[2.2.1]hept-5-ene acetonide (4b)
To a stirred solution of 3b (23.4 g, 100 mmol) in CH2Cl2 (300 mL)
under argon atmosphere was added 2-methoxypropene (57 mL,
0.6 mol) and some crystals of camphorosulfonic acid. After 6 h of
stirring, small amounts of anhydrous K2CO3 were added. After 0.5 h
of stirring, the solution was filtered, concentrated in vacuo and flash
chromatographed on silica gel (PE/AcOEt 95:5) to give 4b as a yel-
low powder (26.3 g, 96 mmol, 96%). Mp 128 ꢀC; 1H NMR (CDCl3,
300 MHz)
2.54 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H), 1.49 (m, 4H), 1.35 (m, 2H),
1.30 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3, 75 MHz)
146.0 (s), 134.9
13C¼75 MHz); chemical shift
d in parts per million relative to CDCl3
(signals for residual CHCl3 in the CDCl3: 7.26 for ppm for 1H NMR and
d 6.22 (m, 2H), 3.68 (m, 2H), 3.42 (m, 2H), 3.18 (m, 2H),
77.00 (central) for 13C NMR); for the use of CD3OD as solvent,
d
¼3.34 ppm for 1H NMR and 49.0 ppm for 13C NMR. Carbon-proton
d
couplings were determined by DEPT sequence experiments. MS:
Applied Biosystems SCIEX QStar Elite. Mp: not corrected. Bu¨chi cap-
illary apparatus.
(d) (2C), 116.2 (s), 101.1 (s), 64.8 (t) (2C), 45.2 (d) (2C), 30.9 (d) (2C),
30.3 (t) (2C), 28.1 (t) (2C), 26.8 (t), 19.9 (q) (2C).
4.6. (cis,cis,cis)-1-Cyclohexylidene-2,3,4,5-tetra-
4.2. 5-Cyclohexylidene-1,3-cyclopentadiene (1b)
(hydroxymethyl)cyclopentane acetonide (5b)
To a stirred solution of cyclopentadiene (66 g, 1 mol) and cy-
clohexanone (42 mL, 0.40 mol) in methanol (1 L) under argon at-
mosphere was added dropwise pyrrolidine (51 mL, 0.60 mol) at
room temperature. After 1 h, acetic acid (37.6 mL, 0.64 mol) was
added and stirred for 0.15 h. The mixture was poured on cold water
and diethyl ether was added. Aqueous layer was extracted twice
with diethyl ether and the organic layer was washed with cold
water, dried over MgSO4, filtered and concentrated in vacuo to give
1 as a yellow oil (58.4 g, 0.40 mol), which was used for the following
Ozone in oxygen was bubbled through a stirred solution of 4b
(4.1 g, 15 mmol) in CH2Cl2 (120 mL) and pyridine (1.2 mL) contain-
ing two drops of a CH2Cl2 solution of sudan III (Eastman Kodak) at
ꢁ60 ꢀC until the red colour disappeared. The mixture was flushed
with argon and cooled to ꢁ80 ꢀC. A suspension of NaBH4 (1.70 g,
45 mmol) in EtOH was slowly added. After stirring at room tem-
perature overnight, brine and EtOAc were added. Aqueous layer was
extracted twice with EtOAc and the organic layer was dried over
MgSO4, filtered and concentrated in vacuo. The crude product was
recrystallised in CH2Cl2–Et2O to give 5b as a white powder (2.60 g,
step without further purification. 1H NMR (CDCl3, 300 MHz)
d 6.59
(m, 2H), 6.53 (m, 2H), 2.67 (t, J¼5.4 Hz, 4H), 1.72–1.55 (m, 6H); 13C
8.4 mmol, 56%). Mp 118 ꢀC; 1H NMR (CDCl3, 300 MHz)
4H), 3.61 (m, 4H), 2.10 (m, 4H), 1.42 (m, 10H), 1.36 (s, 6H); 13C NMR
(CDCl3, 75 MHz) 136.2 (s), 131.2 (s), 102.1 (s), 63.3 (t) (2C), 62.4 (t)
d 4.05 (m,
NMR (CDCl3, 75 MHz)
d 158.1 (s), 138.9 (s), 130.6 (d) (2C), 119.9 (d)
(2C), 33.7 (t) (2C), 28.6 (t) (2C), 26.4 (t).
d
(2C), 44.3 (d) (4C), 31.5 (t) (2C), 28.4 (t) (2C), 26.6 (t), 24.7 (q), 24.6
(q). C18H30O4 (310.21) C 69.64, H 9.74; found, C 69.59, H 9.71.
4.3. (1S ,2R ,6S ,7R )- and (1S ,2S ,6R ,7R )-10-
*
*
*
*
*
*
*
*
Cyclohexylidene-4-oxatricyclo[5.2.1.02.6]-
dec-8-ene-3,5-dione (2b)
4.7. (cis,cis,cis)-1-Cyclohexylidene-2,3,4,5-
tetra(hydroxymethyl)cyclopentane (6b)
To a stirred solution of 1b (14.6 g, 100 mmol) in CH2Cl2 (300 mL)
under argon atmosphere was added maleic anhydride (11.8 g,
120 mmol). After one night of stirring at room temperature, the
To a solution of 5b (1.55 g, 5 mmol) in THF (150 mL) and water
(15 mL) was added ion exchange resin Amberlite IRÒ 120 hydrogen

C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
7445
form (2.15 g). After refluxing and stirring for 1 h, the solution was
13C NMR (CDCl3, 75 MHz)
(d) (2C), 19.2 (q) (2C).
d
148.7 (s), 142.7 (s), 130.4 (d) (2C), 120.4
cooled to room temperature and filtrated. The solution was con-
centrated in vacuo. Residual water was removed by rotary distil-
lations in vacuo using toluene. This operation was repeated twice.
The crude product 6b appeared as a yellow oil (1.35 g, 5 mmol,
100%), which was used for the following step without further pu-
4.12. (1S ,2R
* *
,6S
*
,7R
*
)- and (1S
*
,2S
*
,6R
*
,7R )-10-iso-
*
Propylidene-4-oxatricyclo[5.2.1.02.6]dec-8-ene-3,5-dione (2a)
rification. 1H NMR (CD3OD, 300 MHz)
2H), 2.74 (m, 2H), 2.22–1.50 (m, 10H); 13C NMR (CD3OD, 75 MHz)
134.7 (s), 133.9 (s), 63.4 (t) (2C), 60.8 (t) (2C), 47.0 (d) (2C), 45.9 (d)
d 4.77–4.01 (m, 8H), 2.87 (m,
Following the procedure previously described for the synthesis
of 2b, from 1a (10.6 g, 100 mmol), crude 2a in ethyl acetate gave
crystals of exo isomer. Filtrate was purified by flash chromato-
graphy on silica gel (PE/AcOEt 80:20) to give endo and then exo-
isomers. Compound endo-2a, mp 112 ꢀC; 1H NMR (CDCl3, 300 MHz)
d
(2C), 31.7 (t) (2C), 28.6 (t) (2C), 26.8 (t).
d
6.41 (m, 2H), 3.90 (m, 2H), 3.51 (m, 2H), 1.56 (s, 6H); 13C NMR
170.8 (s) (2C), 145.9 (s), 135.8 (d) (2C), 112.6 (s),
46.5 (d) (2C), 45.2 (d) (2C), 19.6 (q) (2C). Compound exo-2a, mp
126 ꢀC; 1H NMR (CDCl3, 300 MHz)
6.43 (m, 2H), 3.85 (m, 2H), 3.03
(m, 2H), 1.57 (s, 6H); 13C NMR (CDCl3, 75 MHz)
171.1 (s) (2C), 139.6
(s), 137.8 (d) (2C), 116.9 (s), 49.0 (d) (2C), 46.6 (d) (2C), 19.5 (q) (2C).
4.8. (cis,cis,cis)-1-Cyclohexylidene-2,3,4,5-tetra-
(p-tosyloxymethyl)cyclopentane (7b)
(CDCl3, 75 MHz)
d
d
To a solution of p-tosyl chloride (63 g, 330 mmol) in CH2Cl2
(250 mL) and 30 mL of pyridine at ꢁ40 ꢀC was added a solution of
tetraol 6b (2.7 g, 10 mmol) in pyridine (60 mL). The solution was
stored at ꢁ20 ꢀC for 72 h. The mixture was poured on cold water
containing pyridine (60 mL) and CH2Cl2 (30 mL) and after stirring
for 0.5 h, the organic phase was washed with a cold solution of 1 M
HCl and with an aqueous solution of CuSO4, dried over MgSO4,
filtered, concentrated in vacuo and purified by flash chromatogra-
phy on silica gel (CH2Cl2/AcOEt 97.5:2.5) to give 7b as a white
d
4.13. (1S ,2R ,3S ,4R )-7-iso-Propylidene-2,3-di(hydroxy-
methyl)bicyclo[2.2.1]hept-5-ene (3a)
*
*
*
*
Following the procedure previously described for the synthesis
of 3b, from 2a (10.2 g, 50 mmol), 3a was obtained as a white
powder (9.7 g), which was used for the following step without
powder (5 g, 5.6 mmol, 56%). 1H NMR (CDCl3, 300 MHz)
d 7.10 (m,
further purification. 1H NMR (CDCl3, 300 MHz)
d
6.19 (m, 2H), 3.64
(m, 2H), 3.42 (m, 2H), 3.27 (m, 2H), 2.49 (m, 2H), 1.59 (s, 6H); 13C
NMR (CDCl3, 75 MHz) 147.7 (s), 134.9 (d) (2C), 134.8 (s), 63.1 (t)
(2C), 46.4 (d) (2C), 45.2 (d) (2C), 19.3 (q) (2C).
8H), 7.34 (m, 8H), 4.07 (m, 4H), 3.78 (m, 4H), 3.09 (m, 2H), 2.60 (m,
2H), 2.45 (s, 6H), 2.44 (s, 6H), 1.80 (m, 5H), 1.41 (m, 5H); 13C NMR
(CDCl3, 75 MHz)
d 145.1 (s), 145.0 (s), 139.9 (s), 132.3 (s), 132.0 (s),
d
130.0 (d), 129.9 (d), 129.8 (d), 127.9 (d), 127.8 (d), 126.7 (s), 69.1 (t)
(2C), 67.7 (t) (2C), 41.9 (d) (2C), 41.0 (d) (2C), 31.4 (t) (2C), 27.6 (t)
(2C), 26.2 (t), 21.6 (q) (2C), 21.5 (q) (2C).
4.14. (1S
*
,2R
*
,3S
*
,4R )-7-iso-Propylidene-2,3-di(hydroxy-
*
methyl)bicyclo[2.2.1]hept-5-ene acetonide (4a)
4.9. (cis,cis,cis)-1-Cyclohexylidene-2,3,4,5-
tetra[(boronatodiphenylphosphanyl)methyl]-
cyclopentane (8b)
Following the procedure previously described for the synthesis
of 4b, from 3a (19.4 g, 100 mmol), crude product was purified by
flash chromatography on silica gel (PE/AcOEt 95:5) to give 4a as
a white powder (17.1 g, 73 mmol, 73%). Compound 4a, mp 100 ꢀC;
To a solution of tetratosylate 7b (886 mg, 1 mmol) in anhydrous
THF (30 mL) at 0 ꢀC under argon atmosphere was added a solution
of LiPPh2 in THF (w0.8 M, 19 mL, 16 mmol). After 5 h of stirring at
room temperature, a 1 M solution of borane in THF (24 mL,
24 mmol) was added. After 1 h of stirring, the solution was poured
on cold water and extracted with CH2Cl2, dried over MgSO4, fil-
tered, concentrated in vacuo and purified by flash chromatography
on silica gel (PE/AcOEt 80:20) to give 8b as a white powder
(0.31 mmol, 310 mg, 31%). Mp 125 ꢀC; 1H NMR (CDCl3, 300 MHz)
1H NMR (CDCl3, 300 MHz)
d
6.30 (m, 2H), 3.71 (dd, J¼12.9, 4.2 Hz,
2H), 3.45 (m, 2H), 3.18 (m, 2H), 2.56 (m, 2H),1.52 (s, 6H),1.33 (s, 3H),
1.32 (s, 3H); 13C NMR (CDCl3, 75 MHz)
148.9 (s), 134.9 (d) (2C),
d
107.5 (s), 101.9 (s), 64.7 (t) (2C), 45.7 (d) (2C), 44.9 (d) (2C), 29.6 (q),
19.8 (q), 19.2 (q) (2C).
4.15. (cis,cis,cis)-1-iso-Propylidene-2,3,4,5-tetra-
(hydroxymethyl)cyclopentane acetonide (5a)
d
7.71–7.26 (m, 40H), 3.41 (m, 4H), 2.61 (m, 4H), 2.23 (m, 2H), 2.04
(s, 4H), 1.85 (m, 2H), 1.40 (m, 6H), 1.04 (m, 12H); 13C NMR (CDCl3,
75 MHz) 135.9–128.5 (50C), 38.7 (d) (2C), 37.7 (d) (2C), 31.4 (t)
(2C), 30.3 (t) (2C), 21.2 (t) (2C), 26.6 (t) (2C), 26.1 (t); 31P NMR
(121.5 MHz, CDCl3) 14.5 (major), 15.6, 16.6.
Following the procedure previously described for the synthesis
of 5b, from 4a (3.51 g, 15 mmol), crude product was purified by
flash chromatography on silica gel (PE/AcOEt 80:20) to give 5a
(2.43 g, 9 mmol, 60%). Compound 5a, 1H NMR (CDCl3, 300 MHz)
d
d
d
3.96 (m, 4H), 3.85 (m, 4H), 2.83 (m, 2H), 2.14 (m, 2H), 1.53 (s, 3H),
1.22 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
134.6 (s), 126.7 (s), 101.6 (s),
4.10. (cis,cis,cis)-1-Cyclohexylidene-2,3,4,5-tetra[(diphenyl-
phosphanyl)methyl]cyclopentane (9b)
62.1 (t) (2C), 61.6 (t) (br signal), 47.2 (d) (br signal) (2C), 44.0 (d)
(2C), 24.3 (q), 24.2 (q), 20.7 (q) (2C). C15H26O4 (270.18) C 66.64, H
9.69; found, C 66.55, H 9.75.
Compound 8b (50 mg, 0.05 mmol) was added to anhydrous
diethylamine (15 mL) and the solution was stirred at 60 ꢀC for 2 h.
The amine was removed in vacuo and the crude product was pu-
rified by flash chromatography on silica gel (PE/AcOEt 80:20) to
give 9b (34 mg, 0.036 mmol, 72%).
4.16. (cis,cis,cis)-2,3,4,5-Tetra(hydroxymethyl)cyclopentanone
acetonide (10)
Following the procedure previously described for the synthesis
of 5b but without pyridine, crude product was purified by flash
chromatography on silica gel (PE/AcOEt 95:5) to give 10 in 20% yield
4.11. 5-iso-Propylidene-1,3-cyclopentadiene (1a)
Following the procedure previously described for the synthesis
of 1b, from acetone (30 mL, 0.4 mol), 1a was obtained as a yellow
oil, which was used for the following step without further purifi-
as a yellow oil. Compound 10, 1H NMR (CDCl3, 300 MHz)
d 3.68 (m,
10H), 3.44 (m, 2H), 2.36 (m, 2H), 1.26 (dd, J¼10.2, 6.3 Hz, 6H); 13C
NMR (CDCl3, 75 MHz) d 207.2 (s), 102.0 (s), 61.1 (t) (2C), 61.0 (t) (2),
cation. 1H NMR (CDCl3, 300 MHz)
d
6.53–6.45 (m, 4H), 2.19 (s, 6H);
49.7 (d) (2C), 43.0 (d) (2C), 24.9 (q), 24.2 (q).

7446
C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
4.17. Ethyl 4-(2,4-cyclopentadien-1-ylidene)valerate (11)
After 6 h of stirring, small amounts of anhydrous K2CO3 were
added. After 1 h of stirring, the solution was filtered, concentrated
in vacuo, and purified by flash chromatography on silica gel
(CH2Cl2/PE 90:10) to give 14 as a yellow oil (3.28 g, 9. 37 mmol,
15%) and an 15 as an oil (7.26 g, 26.1 mmol, 41%). Compound 14, 1H
To a stirred solution of cyclopentadiene (115.8 g, 1.75 mol) and
ethyl levulinate (100 mL, 0.7 mol) in methanol (600 mL) under
argon atmosphere was added dropwise pyrrolidine (147 mL,
1.75 mol) at room temperature. After 1 h, acetic acid (65 mL,
1.14 mol) was added and stirred for 0.15 h. The mixture was
poured on cold water and diethyl ether was added. Aqueous layer
was extracted twice with diethyl ether and the organic layer was
washed with cold water, dried over MgSO4, filtered and concen-
trated in vacuo to give 11 as a yellow oil (134.4 g, 0.70 mol), which
was used for the following step without further purification. 1H
NMR (CDCl3, 300 MHz)
d 6.23 (m, 2H), 3.67 (m, 2H), 3.43 (m, 2H),
3.27 (t, J¼6.9 Hz, 2H), 3.15 (s, 3H), 3.08 (m, 2H), 2.55 (m, 2H), 1.92
(m, 2H), 1.57 (m, 2H), 1.51 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H), 1.30 (s,
6H); 13C NMR (CDCl3, 75 MHz)
d 149.9 (s), 134.9 (d), 134.8 (d), 110.9
(s), 101.1 (s), 99.7 (s), 64.6 (2C) (t), 60.2 (t), 48.3 (q), 45.8 (d), 45.5
(d), 45.1 (d), 44.8 (d), 30.1 (t), 29.5 (q), 28.6 (t), 24.4 (2C) (q), 19.8
(q), 16.8 (q). Compound 15, 1H NMR (CDCl3, 300 MHz)
d 6.24 (m,
NMR (CDCl3, 300 MHz)
(t, J¼7.6 Hz, 2H), 2.53 (t, J¼7.6 Hz, 2H), 2.19 (s, 3H), 1.24 (s, 3H);
13C NMR (CDCl3, 75 MHz)
172.4 (s), 150.2 (s), 143.2 (s), 131.3 (d),
d
6.48 (m, 4H), 4.12 (q, J¼7.1 Hz, 2H), 2.85
2H), 3.69 (m, 2H), 3.51 (t, J¼6.5 Hz, 2H), 3.43 (m, 2H), 3.18 (m, 2H),
2.56 (m, 2H), 1.97 (dt, J¼7.5, 3.6 Hz, 2H), 1.57 (t, J¼7 Hz, 2H), 1.51 (s,
d
3H), 1.32 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 150.1 (s),
131.1 (d), 120.6 (d), 120.2 (d), 60.5 (t), 33.6 (t), 31.8 (t), 20.4 (q),
14.1 (q).
134.9 (d), 134.8 (d), 110.8 (s), 101.1 (s), 64.59 (t), 64.58 (t), 62.3 (t),
45.7 (d), 45.5 (d), 45.0 (d), 44.7 (d), 30.6 (t), 29.7 (t), 29.6 (q), 19.7
(q), 16.7 (q). C17H26O3 (278.39) C 73.34, H 9.41; found, C 73.41, H
9.68.
4.18. (1S
*
,2R
*
,6S
*
,7R
*
)- and (1S ,2S
* *
,6R
*
,7R )-10-(4-
*
Ethoxycarbonylbut-2-ylidene)-4-oxatricyclo[5.2.1.02.6]-
non-8-ene-3,5-dione (12)
4.21. (cis,cis,cis)-1-(5-Hydroxypent-2-ylidene)-2,3,4,5-
tetra(hydroxymethyl)cyclopentane derivative (16)
To a stirred solution of 11 (10 g, 52.1 mmol) in CH2Cl2 (250 mL)
under argon atmosphere was added maleic anhydride (6.13 g,
62.55 mmol). After one night of stirring at room temperature, the
solution was filtered and concentrated in vacuo to give a mixture of
exo and endo isomers, which was purified by flash chromatography
on silica gel (petroleum ether (PE)/EtOAc 80:20) to give endo-12
(4.467 g, 16.07 mmol, 31%) and exo-12 (5.377 g, 19.34 mmol, 38%)
as a yellow oils. Compound endo-12, 1H NMR (CDCl3, 300 MHz)
Ozone in oxygen was bubbled through a stirred solution of 14
(3.3 g, 9.36 mmol) in CH2Cl2 (100 mL) and pyridine (1.2 mL) con-
taining two drops of a CH2Cl2 solution of sudan III (Eastman Kodak)
at ꢁ60 ꢀC until the red colour disappeared. The mixture was flushed
with argon and cooled to ꢁ80 ꢀC. A suspension of NaBH4 (1.06 g,
28 mmol) in EtOH was slowly added. After stirring at room tem-
perature overnight, brine and EtOAc were added. Aqueous layer
was extracted twice with EtOAc and the organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (PE/EtOAc
60:40) to give 16 as a yellow oil (1.62 g, 4.2 mmol, 45%). 1H NMR
d
6.39 (m, 2H), 4.04 (q, J¼7.1 Hz, 2H), 3.97 (m, 1H), 3.85 (m, 1H), 3.54
(m,1H), 3.45 (m,1H), 2.30 (m, 4H),1.55 (s, 3H),1.22 (t, J¼7.1 Hz, 3H);
13C NMR (CDCl3, 75 MHz)
172.6 (s), 170.7 (s), 170.6 (s), 147.9 (s),
d
135.8 (d), 135.5 (d), 115.3 (s), 60.4 (t), 46.4 (d), 46.2 (d), 45.2 (d), 45.1
(d), 32.1 (t), 28.9 (t), 16.7 (q), 14.1 (q). Compound exo-12, 1H NMR
(CDCl3, 300 MHz) d 3.97 (m, 4H), 3.53 (m, 4H), 3.28 (m, 2H), 3.09 (s,
(CDCl3, 300 MHz)
3.81 (m, 1H), 3.61 (m, 1H), 3.03 (m, 1H), 2.27 (m, 4H), 1.56 (s, 3H),
1.21 (s, 3H); 13C NMR (CDCl3, 75 MHz)
172.6 (s), 171.1 (s), 170.9 (s),
d
6.42 (m, 2H), 4.07 (q, J¼7.1 Hz, 2H), 3.89 (m,1H),
3H), 2.92 (m, 2H), 2.19 (m, 2H), 2.02 (t, J¼7.8 Hz, 2H), 1.60 (s, 3H),
1.50 (m, 2H), 1.29 (s, 6H), 1.24 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d
d 135.4 (s), 130.8 (s), 101.8 (s), 99.7 (s), 62.9 (t), 62.1 (t), 61.9 (t) (br
141.3 (s), 137.8 (d), 137.6 (d), 118.7 (s), 60.4 (t), 49.1 (d), 48.7 (d), 46.6
(d), 46.5 (d), 32.5 (t), 28.9 (t), 16.8 (q), 14.1 (q).
signal), 61.6 (t) (br signal), 60.1 (t), 48.2 (q), 47.4 (d) (br signal), 47.2
(d) (br signal), 44.3 (d), 44.0 (d), 31.4 (t), 28.6 (t), 24.5 (q), 24.4 (q),
24.2 (q) (2C), 18.0 (q).
4.19. (1S
*
,2R
*
,3S
*
,4R )-7-(5-Hydroxypent-2-ylidene)-2,3-
*
di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene (13)
4.22. (cis,cis,cis)-1-(5-Hydroxypent-2-ylidene)-2,3,4,5-
tetra(hydroxymethyl)cyclopentane (17)
To a stirred suspension of LiAlH4 (1.22 g, 32.2 mmol) in anhy-
drous THF (100 mL) at ꢁ20 ꢀC under argon atmosphere was added
endo-12 (4.47 g, 16.1 mmol) in anhydrous THF (15 mL). After one
night of stirring at room temperature, the mixture was refluxing for
3 h and then cooled at ꢁ20 ꢀC. Water (1.2 mL) followed by 1.2 mL of
1 M solution of NaOH and 3.6 mL of water were successively added.
After 3 h of stirring, the suspension was filtered and washed with
diethyl ether. Filtrate was concentrated in vacuo to give 13 as
a colourless oil (3.59 g, 15.1 mmol, 94%), which was used for the
following step without further purification. 1H NMR (CDCl3,
To a solution of 16 (638 mg, 1.65 mmol) in THF (28 mL) and
water (3 mL) was added ion exchange resin Amberlite IRÒ 120
hydrogen form (2.15 g). After refluxing and stirring for 1 h, the
solution was cooled to room temperature and filtrated. The solution
was concentrated in vacuo. Residual water was removed by rotary
distillations in vacuo using toluene. This operation was repeated
twice. The crude product 17 was obtained as a yellow oil (422 mg,
1.53 mmol, 93%), which was used for the following step without
further purification. 1H NMR (CD3OD, 300 MHz)
(m, 6H), 3.02 (m, 2H), 2.49 (m, 2H), 2.11 (m, 2H), 1.69 (s, 3H), 1.60
(m, 2H); 13C NMR (CD3OD, 75 MHz)
137.9 (s), 131.8 (s), 64.0 (t),
d 3.79 (m, 4H), 3.53
300 MHz)
2.05 (m, 2H), 1.93 (m, 2H), 1.52 (s, 3H); 13C NMR (CDCl3, 75 MHz)
149.0 (s), 134.83 (d), 134.76 (d), 110.8 (s), 62.6 (t), 62.5 (t), 61.9 (t),
46.3 (d), 46.0 (d), 45.1 (d), 44.9 (d), 30.5 (t), 29.6 (t), 16.7 (q).
d 6.17 (m, 2H), 3.50 (m, 4H), 3.39 (m, 2H), 3.26 (m, 4H),
d
d
63.3 (t), 62.8 (t), 61.6 (t), 61.4 (t), 48.4 (d), 47.9 (d), 46.8 (d), 46.1 (d),
32.4 (t), 32.2 (t), 18.6 (q).
4.20. (1S
*
,2R
*
,3S
*
,4R
*
)-7-(5-Hydroxypent-2-ylidene)-2,3-
4.23. (cis,cis,cis)-1-[5-(p-Tosyloxy)pent-2-ylidene]-2,3,4,5-
tetra(p-tosyloxymethyl)cyclopentane (18)
di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene acetonide
(14 and 15)
To a solution of p-tosyl chloride (4.94 g, 26 mmol) in CH2Cl2
(10 mL) at ꢁ40 ꢀC was added a solution of pentaol 17 (178 mg,
0.65 mmol) in pyridine (5 mL) and CH2Cl2 (5 mL). The solution was
stored at ꢁ20 ꢀC for 72 h. The mixture was poured on cold water
To a stirred solution of 13 (15.06 g, 63.3 mmol) in CH2Cl2
(200 mL) under argon atmosphere was added 2-methoxypropene
(12.2 mL, 126.6 mmol) and some crystals of camphorosulfonic acid.

C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
7447
containing pyridine (2 mL) and CH2Cl2 (10 mL) and after stirring for
4.27. (cis,cis,cis)-1-(5-Benzyloxypent-2-ylidene)-2,3,4,5-
0.5 h, the solution was acidified (pHw1) by addition of cold solution
of HCl followed by extraction with CH2Cl2. The organic phase was
washed with an aqueous solution of CuSO4, dried over MgSO4, fil-
tered, concentrated in vacuo and purified by flash chromatography
on silica gel (CH2Cl2/AcOEt 97.5:2.5) to give 18 as a white foam
tetra(hydroxymethyl)cyclopentane (22)
Following the procedure previously described for the hydrolysis
of 16, from 21 (113 mg, 0.28 mmol), 22 was obtained as a yellow oil
(102 mg, 0.28 mmol, 100%). 1H NMR (CDCl3, 300 MHz)
d 7.28 (m,
(292 mg, 0.28 mmol, 43%). 1H NMR (CDCl3, 300 MHz)
d
7.71 (m,
5H), 4.47 (s, 2H), 3.81 (m, 2H), 3.46 (m, 8H), 3.02 (m, 2H), 2.44 (m,
10H), 7.34 (m, 10H), 3.90 (m, 10H), 3.03 (m, 2H), 2.51 (m, 2H), 2.42
2H), 2.15 (m, 2H), 1.66 (m, 2H), 1.43 (s, 3H); 13C NMR (CDCl3,
(s, 15H), 2.35 (t, J¼6.5 Hz, 2H), 1.82 (m, 2H), 1.38 (s, 3H); 13C NMR
75 MHz) d 136.0 (s), 135.7 (s), 130.7 (s), 128.3 (d) (2C), 127.7 (d),
(CDCl3, 75 MHz)
d
145.1 (s), 145.0 (s), 144.8 (s), 134.0 (s), 132.7 (s),
127.6 (d), 72.8 (t), 70.0 (t), 62.8 (t) (br signal), 62.0 (t) (br signal),
60.5 (t) (2C), 46.8 (d), 46.4 (d), 45.3 (d), 44.4 (d), 31.2 (t), 27.9 (t),
20.9 (q).
132.3 (s), 132.1 (s), 131.9 (s), 131.7 (s), 130.0 (d), 129.9 (d), 129.8 (d),
127.71 (d), 127.65 (d), 127.6 (d), 69.7 (t), 68.9 (t), 68.3 (t), 67.5 (t),
67.4 (t), 42.8 (d), 42.3 (d), 41.0 (d), 40.6 (d), 30.7 (t), 26.8 (t), 21.5 (q),
21.46 (q), 21.40 (q), 18.0 (q).
4.28. (cis,cis,cis)-1-[5-(Benzyloxy)pent-2-ylidene]-2,3,4,5-
tetra(p-tosyloxymethyl)cyclopentane (23)
4.24. (cis,cis,cis)-1-[5-(Diphenylphosphanyl)pent-2-ylidene]-
2,3,4,5-tetra(diphenylphosphanylmethyl)cyclopentane (19)
Following the procedure previously described for the prepara-
tion of 18, from 22 (112 mg, 0.31 mmol), 23 was obtained as a col-
ourless oil (133 mg, 0.136 mmol, 45%). 1H NMR (CDCl3, 300 MHz)
To a solution of pentatosylate 18 (200 mg, 0.202 mmol) in an-
hydrous THF (10 mL) at 0 ꢀC under argon atmosphere was added
a solution of KPPh2 in THF (8.1 mL, 4.04 mmol) (Fluka). After 5 h of
stirring at room temperature, 2 mL of MeOH was added and the
solution was concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (PE then PE/Et2O 90:10)
(these eluents were previously degassed under argon atmosphere)
to give 19 as a wax (56 mg, 0.05 mmol, 25%). 1H NMR (CDCl3,
d
7.73 (m, 5H), 7.28 (m, 12H), 4.44 (s, 2H), 4.04 (m, 4H), 3.90 (m, 4H),
3.34 (t, J¼6.1 Hz, 2H), 3.10 (m, 2H), 2.52 (m, 2H), 2.44 (s, 9H), 2.42 (s,
3H), 2.37 (m, 2H), 1.90 (m, 2H), 1.45 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 145.1 (s), 145.1 (s), 145.0 (s), 138.3 (s), 135.5 (s), 132.4 (s),
132.2 (s), 132.13 (s), 132.11 (s), 130.7 (s), 130.04 (d), 130.01 (d), 129.9
(d),128.3 (d),127.8 (d),127.7 (d), 127.5 (d),127.4 (d), 72.8 (t), 69.4 (t),
69.1 (t), 68.5 (t), 67.7 (t) (2C), 42.9 (d), 42.4 (d), 41.4 (d), 40.8 (d), 31.4
(t), 27.8 (t), 21.6 (q), 21.5 (q), 18.2 (q).
300 MHz)
d 7.34 (m, 50H), 2.40 (m, 10H), 1.57 (m, 4H), 1.44 (s, 3H),
0.96 (m, 2H), 0.86 (m, 2H); 31P NMR (121.5 MHz, CDCl3)
d
ꢁ15 (3P),
4.29. (cis,cis,cis)-1-(5-Benzyloxypent-2-ylidene)-2,3,4,5-
tetra(diphenylphosphanylmethyl)cyclopentane (24)
ꢁ18 (2P).
4.25. (1S
*
,2R
*
,3S
*
,4R )-7-(5-Benzyloxypent-2-ylidene)-2,3-
*
Following the procedure previously described for the prepara-
tion of 19, from 23 (200 mg, 0.20 mmol), 24 was obtained as a col-
ourless wax (40 mg, 0.039 mmol, 19%). 1H NMR (CDCl3, 300 MHz)
di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene acetonide (20)
To a suspension of NaH (0.28 g, 7.05 mmol) in anhydrous THF
(30 mL) at 0 ꢀC under argon atmosphere was added a solution of
alcohol 15 (1.31 g, 4.70 mmol) and tetrabutylammonium iodide
(0.13 g, 0.47 mmol) in anhydrous THF (10 mL). The solution was
stirred for 1 h at room temperature and cooled to 0 ꢀC. Then, benzyl
bromide (1.12 mL, 9.40 mmol) was added. After stirring at room
temperature for 1 h, the solution was refluxed for 7 h. The solution
was poured on cold water and extracted with CH2Cl2. The organic
phase was washed with water, dried over MgSO4, filtered, con-
centrated in vacuo and purified by flash chromatography on silica
gel (PE/AcOEt 90:10) to give 20 (1.24 g, 3.38 mmol, 72%). 1H NMR
d
7.33 (m, 45H), 4.28 (br d, J¼2.4 Hz, 2H), 2.93 (t, J¼6.9 Hz, 2H), 2.37
(m, 8H),1.59 (m, 4H),1.43 (s, 3H),1.03 (s, 2H), 0.86 (m, 2H); 31P NMR
(121.5 MHz, CDCl3)
ꢁ14.3 (dd, J¼12.5, 8.0 Hz), ꢁ16.1 (dd, J¼10.2,
7.6 Hz), ꢁ18.4 (dd, J¼13.2, 3.5 Hz), ꢁ18.8 (dd, J¼10.5, 3.8 Hz).
d
4.30. (1S ,2R ,3S ,4R )-7-(5-tert-Butyldimethylsilyloxypent-2-
ylidene)-2,3-di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene
acetonide (24a)
*
*
*
*
To a solution of 14 (548 mg, 1.97 mmol) in anhydrous DMF
(20 mL) under argon atmosphere was added imidazole (0.271 g,
3.98 mmol) and tert-butyldimethylsilyl chloride (0.362 g,
2.39 mmol). After stirring for one night at room temperature, the
solution was poured on cold water and the mixture was extracted
with Et2O (three times) and the organic phase was washed with
water, dried over MgSO4, filtered and concentrated in vacuo to give
24a as a yellow oil (688 mg,1.76 mmol, 90%), which was used for the
following step without further purification. 1H NMR (CDCl3,
(CDCl3, 300 MHz) d 7.32 (m, 5H), 6.25 (m, 2H), 4.49 (s, 2H), 3.70 (m,
2H), 3.46 (m, 2H), 3.40 (t, J¼6.5 Hz, 2H), 3.19 (m, 2H), 2.58 (m, 2H),
1.99 (td, J¼7.6, 2.3 Hz, 2H), 1.65 (t, J¼7.2 Hz, 2H), 1.53 (s, 3H), 1.36 (s,
3H), 1.34 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 150.2 (s), 138.6 (s),
134.9 (d), 128.3 (d) (2C), 127.6 (d) (3C), 127.4 (d), 110.7 (s), 101.1 (s),
72.8 (t), 69.7 (t), 64.7 (t), 64.6 (t), 45.8 (d), 45.6 (d), 45.1 (d), 44.8 (d),
29.9 (t), 29.6 (q), 28.0 (t), 19.9 (q), 16.8 (q).
300 MHz)
d
6.23 (m, 2H), 3.68 (m, 2H), 3.53 (t, J¼6.5 Hz, 2H), 3.44 (m,
4.26. (cis,cis,cis)-9-(5-Benzyloxypent-2-ylidene)-8,10-
di(hydroxymethyl)-4,4-dimethyl-3,5-dioxa-
bicyclo[5.3.0]decane acetonide (21)
2H), 3.15 (m, 2H), 2.55 (m, 2H),1.90 (m, 2H),1.53 (m, 2H),1.52 (s, 3H),
1.32 (s, 3H), 1.31 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3,
75 MHz)d149.9(s),134.9 (d),134.8(d),110.9(s),101.1(s), 64.6(2C)(t),
62.5 (t), 45.8 (d), 45.5 (d), 45.1 (d), 44.8 (d), 31.3 (t), 29.6 (t), 29.5 (q),
Following the procedure previously described for the ozonolysis
25.9 (q) (3C), 19.8 (q), 18.2 (s), 16.9 (q), ꢁ5.33 (2C)(q).
of 14, from 19 (1 g, 2.72 mmol), 21 was obtained as a yellow oil
(540 mg, 1.48 mmol, 55%). 1H NMR (CDCl3, 300 MHz)
d
7.28 (m, 5H),
4.31. (1S ,2R
* *
,3S
*
,4R )-7-(5-Triphenylsilyloxypent-2-ylidene)-
*
4.46 (s, 2H), 4.02 (m, 4H), 3.55 (m, 4H), 3.41 (t, J¼6.2 Hz, 2H), 2.95
2,3-di(hydroxymethyl)bicyclo[2.2.1]hept-5-ene
acetonide (24b)
(m, 2H), 2.10 (m, 4H), 1.70 (m, 2H), 1.64 (s, 3H), 1.35 (s, 6H); 13C NMR
(CDCl3, 75 MHz)
d 138.2 (s), 135.6 (s), 130.8 (s), 128.2 (d)(2C), 127.5
(d), 127.4 (d), 101.8 (s), 72.8 (t), 69.9 (t), 63.0 (t), 62.1 (t), 62.0 (t), 61.6
(t), 47.3 (d)(2C), 44.3 (d), 44.0 (d), 31.3 (t), 28.2 (t), 24.4 (q) (2C), 18.0
(q). C24H36O5 (404.26) C 71.26, H 8.97; found, C 71.33, H 9.03.
Following the procedure previously described for the prepara-
tion of 24a, from 14, 24b was obtained, which was used for the
following step without further purification. 1H NMR (CDCl3,

7448
C. Reynaud et al. / Tetrahedron 65 (2009) 7440–7448
300 MHz)
d
7.68 (m, 6H), 7.41 (m, 9H), 6.24 (m, 1H), 6.17 (m, 1H),
Table 1) in the presence of the Cyclo-Tedicyp/palladium complex
under argon affords the corresponding coupling products 25–30
after addition of water, extraction with dichloromethane or ether,
separation, drying (MgSO4), evaporation and filtration on silica gel.
3.78 (t, J¼6.5 Hz, 2H), 3.68 (td, J¼12.1, 4.1 Hz, 2H), 3.43 (m, 2H), 3.13
(m, 2H), 2.53 (m, 2H), 2.00 (t, J¼7.5 Hz, 2H), 1.63 (m, 2H), 1.51 (s,
3H), 1.39 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 149.9 (s),
135.3 (d) (6C),134.2 (s) (3C), 134.8 (d), 134.4 (d), 129.9 (d) (3C), 127.8
(d) (6C), 110.9 (s), 101.3 (s), 64.7 (t), 64.6 (t), 63.6 (t), 45.7 (d), 45.5
(d), 45.0 (d), 44.7 (d), 31.0 (t), 29.7 (t), 29.6 (q), 19.8 (q), 16.8 (q).
Acknowledgements
C.R. thanks Dr. S. Goldstein for helpful comments and the Institut
de Recherche Servier (Suresnes, Fr 92150) for financial support. This
4.32. (cis,cis,cis)-9-(5-(tert-Butyldimethylsilyloxy)pent-2-
ylidene)-8,10-di(hydroxymethyl)-4,4-dimethyl-3,5-
dioxabicyclo[5.3.0]decane (25a)
`
work has been financially supported by the CNRS and the Ministere
´
de l’Enseignement Superieur et de la Recherche.
Following the procedure previously described for the ozonolysis
of 4, from 24a (1.46 g, 3.70 mmol), 25a was obtained as a yellow oil
(1.00 g, 2.33 mmol, 63%). 1H NMR (CDCl3, 300 MHz)
d 4.01 (m, 4H),
References and notes
3.54 (m, 6H), 2.93 (m, 2H), 2.02 (m, 2H), 1.62 (s, 3H), 1.51 (m, 2H),
1. Laurenti, D.; Feuerstein, M.; Pe`pe, G.; Doucet, H.; Santelli, M. J. Org. Chem. 2001,
66, 1633–1637.
1.33 (s, 6H), 1.25 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3,
75 MHz)
d
135.2 (s), 131.2 (s), 101.9 (s), 63.0 (t), 62.8 (2C) (t), 62.7 (t),
2. Tedicyp (CAS number: 333380-86-2) is commercially available at Advanced
Technology & Industrial Co., Ltd (product code¼3573040).
62.2 (t), 46.3 (d), 45.1 (d), 44.4 (d), 44.1 (d), 31.4 (t), 31.1 (t), 25.8 (q)
(3C), 24.6 (q), 24.5 (q), 18.2 (q), 14.6 (s), ꢁ5.4 (q) (2C).
3. Kondolff, I.; Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron 2007, 63, 9514–
9521.
4. (a) Feuerstein, M.; Doucet, H.; Santelli, M. J. Org. Chem. 2001, 66, 5923–5925;
(b) Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucet, H.; Santelli, M. Chem.
Commun. 2001, 325–326; (c) Doucet, H.; Santelli, M. Synlett 2006, 2001–2015;
(d) Kondolff, I.; Doucet, H.; Santelli, M. Organometallics 2006, 25, 5219–5222;
(e) Battace, A.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Adv. Synth. Catal.
2007, 349, 2507–2516; (f) Battace, A.; Lemhadri, M.; Zair, T.; Doucet, H.; San-
telli, M. Organometallics 2007, 26, 472–474; (g) Lemhadri, M.; Fall, Y.; Doucet,
H.; Santelli, M. Synthesis 2009, 1021–1035.
5. Laurenti, D.; Santelli, M. Org. Prep. Proced. Int. 1999, 31, 245–294.
6. Mayer, H. A.; Kaska, W. C. Chem. Rev. 1994, 94, 1239–1272.
7. Holz, J.; Bo¨rner, A. In Phosphorus Ligands in Asymmetric Catalysis; Bo¨rner, A., Ed.;
Wiley-VCH: Weinheim, Germany, Vol. 2, pp 822–827.
8. (a) King, R. B.; Kapoor, P. N. J. Am. Chem. Soc. 1969, 91, 5191–5192; (b) King, R. B.;
Kapoor, P. N. J. Am. Chem. Soc. 1971, 93, 4158–4166; (c) Schmidbaur, H.; Stu¨tzer,
A.; Bissinger, P. Z. Naturforsch. B 1992, 47, 640–644; (d) Mason, M. R.; Duff, C.
M.; Miller, L. L.; Jacobson, R. A.; Verkade, J. G. Inorg. Chem. 1992, 31, 2746–2755;
(e) Wang, P.-W.; Fox, M. A. Inorg. Chem. 1994, 33, 2938–2945; (f) Steenwinkel,
P.; Kolmschot, S.; Gossage, R. A.; Dani, P.; Veldman, N.; Spek, A. L.; van Koten,
G. Eur. J. Inorg. Chem. 1998, 477–483; (g) Oberhauser, W.; Stampfl, T.; Bach-
mann, C.; Haid, R.; Langes, C.; Kopacka, H.; Ongania, K.-H.; Bru¨ ggeller, P.
Polyhedron 2000, 19, 913–923; (h) Nair, P.; Anderson, G. K.; Rath, N. P. Inorg.
Chem. Commun. 2003, 6, 1307–1310; (i) Nair, P.; Anderson, G. K.; Rath, N. P.
Organometallics 2003, 22, 1494–1502; (j) Hierso, J.-C.; Fihri, A.; Amardeil, R.;
Meunier, P.; Doucet, H.; Santelli, M.; Donnadieu, B. Organometallics 2003, 22,
4490–4499; (k) Aikawa, K.; Mikami, K. Angew. Chem., Int. Ed. 2003, 42, 5458–
5461; (l) Imamoto, T.; Yashio, K.; Cre´py, K. V. L.; Katagiri, K.; Takahashi, H.;
Kouchi, M.; Gridnev, I. D. Organometallics 2006, 25, 908–914; (m) Nair, P.;
White, C. P.; Anderson, G. K.; Rath, N. P. J. Organomet. Chem. 2006, 691, 529–
537; (n) Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495–3524.
9. Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495–3524.
10. (a) Bayston, D. J.; Fraser, J. L.; Ashton, M. R.; Baxter, A. D.; Polywka, M. E. C.;
Moses, E. J. Org. Chem. 1998, 63, 3137–3140; (b) Nozaki, K.; Itoi, Y.; Shibahara, F.;
Shirakawa, E.; Otha, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998, 120, 4051–
4052; (c) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson, B. F. G.; Bell, R. G.;
Mantle, M. D. Chem. Commun. 2000, 1925–1926; (d) Uozumi, Y.; Shibatomi, K.
J. Am. Chem. Soc. 2001, 123, 2919–2920; (e) Ohkuma, T.; Takeno, H.; Honda, Y.;
Noyori, R. Adv. Synth. Catal. 2001, 343, 369–375; (f) Mansour, A.; Portnoy, M.
Tetrahedron Lett. 2003, 44, 2195–2198; (g) Aoki, K.; Shimada, T.; Hayashi, T.
Tetrahedron: Asymmetry 2004, 15, 1771–1777; (h) Leyva, A.; Garcı´a, H.; Corma,
A. Tetrahedron 2007, 63, 7097–7111; (i) Liu, H.; Wang, L.; Li, P. Synthesis 2008,
2405–2411.
4.33. (cis,cis,cis)-9-(5-(Triphenylsilyloxy)pent-2-ylidene)-
8,10-di(hydroxymethyl)-4,4-dimethyl-3,5-
dioxabicyclo[5.3.0]decane (25b)
Following the procedure previously described for the ozonolysis
of 4, from 24b (2.84 g, 5.30 mmol), 25b was obtained as a yellow
foam after a flash chromatography on silica gel (1.22 g, 2.12 mmol,
40%). 1H NMR (CDCl3, 300 MHz)
d 7.62 (m, 6H), 7.41 (m, 9H), 3.99
(m, 4H), 3.80 (td, J¼6.3, 1.2 Hz, 2H), 3.56 (m, 4H), 2.94 (m, 2H), 2.26
(m, 2H), 2.10 (m, 2H), 1.68 (m, 2H), 1.63 (s, 3H), 1.38 (s, 6H); 13C NMR
(CDCl3, 75 MHz)
d 135.4 (d) (6C), 135.3 (s), 134.2 (s) (3C), 131.2 (s),
130.0 (d) (3C), 101.9 (s), 63.6 (t) (2C), 63.1 (t), 62.4 (t), 61.8 (t), 47.0
(d) (2C), 44.3 (d) (2C), 31.2 (t), 31.1 (t), 24.7 (q), 24.6 (q), 18.3 (q).
4.34. Crystal data and structure refinement for Tedicyp–2
PdBr2 crystals
The complex co-crystallised together with three full occupancy
acetonitrile molecules and a fourth disordered one with a partial
occupancy of 0.25.
Crystallographic data: C63.5H63.75Br4N3.25P4Pd2, Mw¼1528.75,
monoclinic, yellow crystal (0.15ꢂ0.1ꢂ0.05 mm3), a¼17.4630(3) Å,
b¼22.4740(4) Å, c¼18.0690(3) Å,
b
¼117.3151(1)ꢀ, V¼6300.70(19) Å3,
space group P21/c, Z¼4,
r
¼1.612 g cmꢁ3
,
m
(Mo K
a
)¼3.25 cmꢁ1
,
14,723 unique reflections in the 1.31–29.0ꢀ
q range, 697 parameters
refined on F2 [Shelxl] to final indices R[F2>4
s
F2]¼0.05 (6965 re-
flections), wR[w¼1/[
s
2(Fo2)]¼0.1034 (all reflections). The last residual
Fourier positive and negative peaks were equal to 0.880 and ꢁ1.049,
respectively.
4.35. Preparation of the Pd/Cyclo-Tedicyp catalyst
11. Stone, K. J.; Little, R. D. J. Org. Chem. 1984, 49, 1849–1853.
12. Compound 2a: (a) Uebersax, B.; Meuenschwander, M.; Kellerhals, H.-P. Helv.
Chim. Acta 1982, 65, 74–88; (b) Graig, D.; Shipman, J. J.; Kiehl, J.; Widmer, F.;
Fowler, R.; Hawthorne, A. J. Am. Chem. Soc. 1954, 76, 4573–4575; (c) Erickson,
M. S.; Conan, J. M.; Gabriel Garcia, J.; McLaughlin, M. L. J. Org. Chem. 1992, 57,
2504–2508.
13. Compound 2b: Woodward, R. B.; Baer, H. J. Am. Chem. Soc. 1944, 66, 645–649.
14. Slomp, G., Jr.; Johnson, J. L. J. Am. Chem. Soc. 1958, 80, 915–921.
15. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807–810.
16. (a) Prelog, V.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1982, 21, 567–583;
(b) Prelog, V.; Thix, J.; Srikrishnan, T. Helv. Chim. Acta 1982, 65, 2622–2644.
17. (a) Bayston, D. J.; Fraser, J. L.; Ashton, M. R.; Baxter, A. D.; Polywka, M. E. C.;
Moses, E. J. Org. Chem. 1998, 63, 3137–3140; (b) Ohkuma, T.; Takeno, H.; Honda,
Y.; Noyori, R. Adv. Synth. Catal. 2001, 343, 369–375.
An over-dried 40-mL Schlenk tube equipped with a magnetic
stirring bar, under argon atmosphere, was charged with [Pd(h3
-
C3H5)Cl]2 (9.2 mg, 0.025 mmol) and Cyclo-Tedicyp (47.2 mg,
0.05 mmol). Anhydrous DMF (5 mL) was added, then the solution
was stirred at room temperature for 20 min. This solution was used
directly for the catalysed reactions.
4.36. General procedure for the coupling of n-butyl acrylate,
phenylacetylene or phenylboronic acid with aryl bromides
18. Hwu, J. R.; Chua, V.; Schroeder, J. E.; Barrans, R. E., Jr.; Khoudary, K. P.; Wang, N.;
Wetzel, J. M. J. Org. Chem. 1986, 51, 4731–4733.
19. Nozulak, J.; Scho¨llkopf, U. Synthesis 1982, 866–868.
20. Bo¨rner, A.; Ward, J.; Ruth, W.; Holz, J.; Kless, A.; Heller, D.; Kagan, H. B. Tetra-
hedron 1994, 50, 10419–10430.
The reaction of the aryl bromide (1 mmol), K2CO3 (2.76 g,
2 mmol) and n-butyl acrylate, phenylacetylene or phenylboronic
acid (2 mmol) at 130 ꢀC during 20 h in DMF or xylene (10 mL) (see