Heterogeneous metallo-organocatalysis for the selective one-pot synthesis of 2-benzylidene-indoxyl and 2-phenyl-4-quinolone

Article abstract of DOI:10.1016/j.tet.2010.11.112

One-pot tandem heterogeneously catalyzed procedures for the selective synthesis of 2-benzylidene-indoxyl and 2-phenyl-4-quinolone have been developed. For this purpose, heterogeneous palladium-, amine-, and phosphine-catalysts were prepared by post-synthe

Full text of DOI:10.1016/j.tet.2010.11.112

Tetrahedron 67 (2011) 976e981
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heterogeneous metallo-organocatalysis for the selective one-pot synthesis of
2-benzylidene-indoxyl and 2-phenyl-4-quinolone
,
b
,
y
,
z
b
, ,
,
Marie Genelot a
, Veronique Dufaud z, Laurent Djakovitch a
*
*
ꢀ
a
ꢀ
Universite de Lyon, CNRS, UMR 5256, IRCELYON, Institut de recherches sur la catalyse et l’environnement de Lyon, 2 avenue Albert Einstein, F-69626 Villeurbanne, France
Universite de Lyon, CNRS, UMR 5182, Laboratoire de Chimie, Ecole Normale Superieure de Lyon, 46 Allee d’Italie, F-69364 Lyon Cedex 07, France
b
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2010
Received in revised form 25 November 2010
Accepted 30 November 2010
Available online 7 December 2010
One-pot tandem heterogeneously catalyzed procedures for the selective synthesis of 2-benzylidene-
indoxyl and 2-phenyl-4-quinolone have been developed. For this purpose, heterogeneous palladium-,
amine-, and phosphine-catalysts were prepared by post-synthetic grafting onto SBA silica. The state of
the hybrid materials was characterized using a wide variety of molecular and solid-state techniques.
These materials exhibit high activities as 2-benzylidene-indoxyl was obtained in 81% yields through
{[Pd]@SBA-15þPPh3} catalysis while 2-phenyl-4-quinolone was prepared by a fully heterogeneous {[Pd]
@SBA-15þ[AMINE]@SBA-3} protocol in 61e75% isolated yield. For the later, we demonstrated that the
catalysts mixture could be reused up to three runs without strong deactivation.
Keywords:
Metallo-organocatalysis
Heterogeneous catalysis
One-pot synthesis
4-Quinolones
Ó 2010 Elsevier Ltd. All rights reserved.
Indoxyls
Mesoporous supports
1. Introduction
Catellani and co-workers22 involves the reaction of iodoaniline
with phenylacetylene under CO atmosphere.
Carbonyl containing N-heterocycles like 2-susbtituted-4-qui-
nolones or 2-arylmethylidene indoxyls represent an important
class of compounds in medicinal and pharmaceutical fields.
4-Quinolones exhibit various pharmaceutical activities as antibac-
terials,1,2 antifungals3 or anticancer substructures.4 Both stoichio-
metric strategies5e8 and palladium catalyzed procedures have been
reported for their synthesis.9e14 Among these methods, the palla-
dium catalyzed carbonylative coupling of 2-iodoanilines with ary-
lacetylenes initially reported by Torii and co-workers11,12 appears to
be the most versatile as it gives generally good yields toward the
expected compounds.
Therefore, under very similar conditions (2-iodoaniline, phe-
nylacetylene, CO, palladium based catalyst) either six-membered-
(4-quinolone, i.e., Torii11,12) or five-membered ring compounds
(indoxyl, i.e., Catellani22) can be obtained as they are issued from
the same non-cyclic intermediate (Scheme 1). However, these
methods tend to give amide containing side-products or mixture of
cyclized products along with the non-cyclic intermediate.
On the other hand, indoxyls represent important synthons for
the synthesis of either biologically active indole derivatives or
natural pigments (i.e., betanin, indigoid dyes.). Some indoxyls also
show by their own biological activities as anti-cancer drugs.15 These
compounds are either isolated from natural sources16e18 or gen-
erally prepared from indoles.19e21 Interestingly, when considering
the 2-arylmethylidene family, the most flexible method reported by
Scheme 1.
Interested in developing one-pot selective synthesis of
biologically relevant N-heterocycles we investigated these meth-
odologies and reported on the way to control carefully the selec-
tivity of the reaction in order to obtain either indoxyls or
4-quinolones from 2-iodoanilines and terminal alkynes.23 As a re-
sult of these studies, we were able to explain clearly the origin of
* Corresponding authors. Tel.: þ33 472445381; fax: þ33 472445399; e-mail
addresses: vdufaud@ens-lyon.fr (V. Dufaud), Laurent.Djakovitch@ircelyon.univ-lyon1.fr
(L. Djakovitch).
y
Tel.: þ33 472445381; fax: þ33 472445399.
z
Tel.: þ33 472728857; fax: þ33 472728860.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.112

M. Genelot et al. / Tetrahedron 67 (2011) 976e981
977
the selectivity toward the five- or six-membered ring compounds
as resulting from the respective role of the various catalytic species
involved (Fig. 1), whether they are organic or metallic. Thus, the
non-cyclic common intermediate 1 results from palladium catalysis
covalent bonding onto SBA type silica supports (Fig. 2). In order to
gain insight into the effect of chelation on catalyst performance and
stability (notably resistance to leaching) two different palladium
complexes bearing either monodentate phosphine or chelating
diphosphine linkers were considered (hybrid materials [PdP2]
@SBA-15 and [PdPNP]@SBA-15).
{[Pd]} while indoxyls
2 and 4-quinolones 3 are obtained,
respectively, through tandem {[Pd]/PR3} catalysis and two-step
multi-catalysis {[Pd]þHNEt2}.24
A silica supported phosphine catalyst, [P]@SBA-15, was
obtained through a multi-step tethering protocol (Supplementary
data, Scheme S2). The phosphine was protected as a phosphi-
neeborane complex prior to grafting. After the deactivation of the
surface and borane deprotection one obtains the desired diphe-
nylphosphine-based catalyst. In the case of the synthesis of ami-
nosilica derived solids, various mono and polyamines of the type
(EtO)3SiCH2CH2CH2(NHCH2CH2)nNH2 were anchored to a silica
material whose surface had been previously organically modified
with trimethylsilyl moieties to prevent undesirable interactions
between the amine-bound species and the surface silanols. Three
catalytic solids, which differ by the number of ethylene amino chain
P
Pd
N
Fig. 1. Involved catalytic species for the selective syntheses of 4-quinolones and
indoxyls.
Fig. 2. Targeted palladium, phosphine, and amine functionalized SBA silica materials.
While successful this methodology still suffers from drawbacks,
the main being related to the use of homogeneous catalysts that are
tedious to remove and could result in high palladium and ligand
(i.e., phosphine) contamination of final products, that is, not ac-
ceptable when dealing with human and animal health.25 With this
aim in mind, we underwent studies to develop full heterogeneous
catalyzed one-pot synthesis of indoxyls and 4-quinolones.
spacers (n¼0e2) and referred to as [N]@SBA-3, [NN]@SBA-3 and
[NNN]@SBA-3 were thus prepared. The resulting hybrids were
thoroughly characterized using several molecular and surface
techniques, which are gathered in Supplementary data: X-ray
powder diffraction (XRD) at small angles, elemental analysis,
thermogravimetric analysis, infrared spectroscopy, multi-nuclear
NMR spectroscopy, and nitrogen sorptions.
2. Results and discussions
2.1. Catalysts
2.2. Toward the selective synthesis of indoxyl
Previously, we described a one-pot homogeneous procedure for
the selective synthesis of 2-benzylidene-indoxyl 2. Thus, starting
from 2-iodoaniline and phenylacetylene and working under CO
atmosphere in presence of [Pd(PPh3)4] associated to free PPh3 the
2-benzylidene-indoxyl 2 was obtained in 74% isolated yield as the
(Z)-isomer.23 Changing the palladium catalyst for [Pd(PPh3)2Cl2]
allowed to achieve similar results (Table 1, entry 1).
As shown in Fig. 1, different types of catalytically active species,
used alone or in combination, were heterogenized in order to fulfill
the requirements for the one-pot synthesis of either indoxyls or
4-quinolones. Thus, palladium complexes, free phosphine, and free
amine (preferably primary or secondary) were immobilized by

978
M. Genelot et al. / Tetrahedron 67 (2011) 976e981
Table 1
Studies toward the heterogeneously catalyzed synthesis of 2-benzylidene-indoxyl
Entry
Method
Time (h)
GC analysisa
Yieldb
Pd contamination
1
2
4
1
A
B
C
24
24
24
48
72
96
0
2
81
66
56
20
99
98
11
19
23
24
0
0
2
11
21
53
d
94 ppmc
28 ppm
n.a.
2
81
n.a.
3d
4
5
6
Reaction conditions: method A: iodoaniline (3 mmol), phenylacetylene (1.2 equiv), [PdCl2(PPh3)2] (0.2 mol %), PPh3 (3.6 mol %), triethylamine (4 equiv), anisole (5 mL), CO
(20 bar), 80 ꢀC. Method B: iodoaniline (3 mmol), phenylacetylene (1.2 equiv), [PdP2]@SBA-15 (0.1 mol %), PPh3 (1 mol %), triethylamine (2.5 equiv), anisole (5 mL), CO (5 bar),
80 ꢀC. Method C: iodoaniline (3 mmol), phenylacetylene (1.2 equiv), [PdP2]@SBA-15 (0.1 mol %), [P]@SBA-15 (1 mol %), triethylamine (2.5 equiv), anisole (5 mL), CO (5 bar),
80 ꢀC.
a
GC-yields were determined with an external standard (biphenyl) (Δrel¼ꢁ5%).
b
When available isolated yields are reported.
c
Theoretical value, calculated from the amount of Pd introduced in the reaction.
Conversion of 2-iodoaniline (94%) was achieved.
d
Therefore, in order to address this selective synthesis in a het-
erogeneous fashion, [PdP2]@SBA-15 catalyst associated with
phosphine catalyst either as homogeneous PPh3 or heterogeneous
[P]@SBA-15 was used. The results are reported in Table 1, and
compared to those achieved using purely homogeneous catalysts.
As expected the use of heterogeneous palladium catalyst as
[PdP2]@SBA-15 did not influence strongly the results of the reaction
giving the expected 2-benzylidene-indoxyl 2 in 81% isolated yield.
However, as observed from elemental analysis, in spite of the use of
a heterogeneous source of palladium, metal contamination in crude
product remains high although reduced from 94 ppm to 28 ppm.
Encouraged by this interesting result, we evaluated next the
combination of heterogeneous [PdP2]@SBA-15 and [P]@SBA-15
Scheme 2. Proposed mechanism for the formation of 2-benzyl-1H-indole 4 from 2-
benzylidene-indoxyl 2.
catalysts in this reaction. As reported in Table 1, while the palladium
catalyzed step (i.e., toward 1) proceeds as likely giving >90% con-
version of 2-iodoaniline in 24 h, selective cyclization toward the
indoxyl 2 was not as efficient as expected as only 11% of 2-iodoa-
niline was effectively transformed in this target compound (Table 1,
entry 3). Prolonging the reaction up to 96 h did not allow to in-
crease the production of 2 (Table 1, entries 4e6); rather than that
a by-product was almost exclusively formed. Thus, the side-product
formation prevented further developments related to heteroge-
neously {Pd/P} catalyzed indoxyls synthesis.
This side-product 4 obtained from the reaction mixture (Table 1,
entry 6) is assumed to be 2-benzyl-1H-indole as deducted from 1H
NMR and GCeMS analyses.26 This product is probably issued from
palladium catalyzed hydride transfer on the indoxyl 2 as shown in
the proposed mechanism illustrated in Scheme 2. Reduction of
C]C bonds activated by carbonyl group through Pd-catalyzed hy-
dride transfer from triethylamine was previously reported. In our
case, such a mechanism reduced the indoxyl 2 to give the 3-oxo-
indole 5.27 While to our knowledge, no such reduction of carbonyl
group has been previously described it is highly reasonable to
propose that a second hydride transfer to carbonyl group affording
the palladacycle 6 occurs. Further steps to 4 would then involved
hydrolysis of 6 followed by dehydration. In such consecutive re-
actions, aromatization delivering indole nucleus is assumed to be
the driving force. Further studies to confirm this mechanism to-
ward 4 are currently under progress.
2.3. Toward the selective synthesis of 4-quinolone
To obtain selectively 4-quinolones, we demonstrated that the
best procedure corresponded to multi-catalysis {PdþAmine}.23
Thus, side-product formation and eventual negative mutual in-
teraction between metal and organo-catalyst were avoided.
However, when considering fully heterogeneously catalyzed
procedure it is not possible to add easily in the reaction media
further catalyst. Therefore to solve this difficulty, we first revisited
homogeneous protocol to develop tandem {Pd/Amine} catalysis.
Thus working with [PdCl2(dppp)] in presence of catalytic amount
of HNEt2 under the conditions previously optimized allowed to
obtain the target 2-phenyl-4-quinolone 3 in 47% yield, however
after 7 days (Table 2, entry 2), that is, close from the result achieved
using multi-catalysis procedure (Table 2, entry 1).
Encouraged by this result we then underwent studies in order to
develop further this procedure toward the exclusive use of het-
erogeneous catalysts (Table 2, entries 5e7). For this purpose,
a mechanical mixture of the [PdPNP]@SBA-15 and [AMINE]@SBA-
3 catalysts was used.
Initially, we evaluated the influence of using heterogeneous
palladium catalysts as [PdPNP]@SBA-15. Unexpectedly, replacing
the homogeneous [PdCl2(dppp)] by this heterogeneous one resul-
ted in better chemical yields whatever the procedure (i.e., multi-
catalysis or tandem catalysis) used. Thus >60% isolated yield toward
the expected compound was obtained (Table 2, entries 3e4).
In conclusion, the indoxyl 2 is formed during the reaction,
however the rate of formation is probably slower than that of hy-
dride transfers giving the indole 4.

M. Genelot et al. / Tetrahedron 67 (2011) 976e981
979
Table 2
Studies toward the heterogeneously catalyzed synthesis of 2-phenyl-4-quinolone
Entry
Method
Catalysts
Time (days)
Yield (%)
Pd contamination
1
2
Multi-catalysis
Tandem
[PdCl2(dppp)]þHNEt2
[PdCl2(dppp)]/HNEt2
7
7
57
47
n.d.
40 ppm
3
4
Multi-catalysis
Tandem
[PdPNP]@SBA-15þHNEt2
[PdPNP]@SBA-15/HNEt2
6
7
63
65
n.d.
5 ppm
5
6
7
Tandem
Tandem
Tandem
[PdPNP]@SBA-15/[N]@SBA-3
[PdPNP]@SBA-15/[NN]@SBA-3
[PdPNP]@SBA-15/[NNN]@SBA-3
3
3
4
61
68
75
5 ppm
3 ppm
3 ppm
Reaction conditions: 2-iodoaniline (3 mmol), phenylacetylene (1.2 equiv), [Pd] (0.1 mol %), HNEt2 or [AMINE]@SBA-3 (1 mol %), triethylamine (2.5 equiv), anisole (5 mL), CO
(5 bar), 80 ꢀC.
Developing further the procedure toward the exclusive use of
heterogeneous catalysts, we engaged the prepared [PdPNP]
@SBA-15 and [AMINE]@SBA-3 for the selective transformation of
2-iodoaniline and phenylacetylene toward 2-phenyl-4-quino-
lone. Surprisingly, using exclusively heterogeneous catalysts
allowed to achieve high chemical yields (>60% up to 75%) in
shorter reaction time (Table 2, entries 5e7). Therefore apparently,
grafted amines exhibited higher behavior in catalyzing the cy-
clization of 1 toward 3. This can be related to the higher nucle-
ophilicity of grafted ‘primary’ amine compared to the
homogeneous diethylamine.
These results indicate that the use of mesoporous silica to
support the catalytically active species (i.e., palladium and amines)
is well adapted to such synthesis as evidently no diffusion limit
occurred that is attested by the reduced reaction time observed to
full conversion toward the target molecule.
Additionally, the use of heterogeneous palladium catalyst
allowed to reduce considerably the palladium contamination of
crude product to few parts per million (Table 2, entries 4e7 vs 2).
Being confident with these results, we examined next recycling
the [PdPNP]@SBA-15/[N]@SBA-3 catalysts as follows: after a first
run, the catalytic material was separated by filtration, washed
successively with methylene chloride, methanol, and diethylether
in order to remove all organic materials and to allow drying of the
‘catalysts mixture’. The solid thus obtained was engaged in a new
run under the same reaction conditions.
evidenced by the longer reaction times required in the second cycle
to achieve full conversions toward 3.
In more details, our recycling experiments point out a relative
stability of the palladium catalyst as up to the third run no strong
deactivation was observed. This deactivation can stem from several
factors: (1) ineffective redeposition of leached palladium28,29 due to
the nature of the material unable to accommodate it,30 that is, cor-
related with determinations of palladium contamination in crude
products, which clearly indicate palladium leaching during the re-
action; however at low level (3e5 ppm); (2) the presence of salts
that can encapsulate leached palladium upon crystallization
resulting in the loss of metal during washing; (3) mechanical loss of
catalytic materialduring separation and washing. To date, wecannot
with certitude discard one or the other hypothesis.
Considering the amine-catalyzed step of the procedure, it seems
reasonable to suggest that deactivation is due to protonation of the
grafted amines during the reaction, that is, not completely counter-
balanced by the presence of triethylamine in the reaction medium.
Whatever the level of {[PdPNP]@SBA-15/[N]@SBA-3} catalysts
mixture deactivation, high isolated yields toward the target
2-phenyl-4-quinolone are achieved in all runs, given that longer
reaction time was used.
3. Conclusion
At this stage of our studies, it is interesting to compare the ho-
mogeneous versus the heterogeneous procedures (Fig. 3) for the
selective synthesis of 2-benzylidene-indoxyls and 2-phenyl-
The results reported in Table 3 reveal that while the catalytic
mixture is still active up to three runs, deactivation occurred as
Table 3
Recycling the {[PdPNP]@SBA-15/[N]@SBA-3} catalysts mixture for the synthesis of 2-phenyl-4-quinolone
Run
Time step 1 (days)
Time step 2 (days)
Yield (%)
1
2
3
1
1
2
3
5
9
60
62
72
Reaction conditions: run 1: 2-iodoaniline (6 mmol), phenylacetylene (1.2 equiv), [PdPNP]@SBA-15 (0.1 mol %), [N]@SBA-3 (1 mol %), triethylamine (2.5 equiv), anisole
(10 mL), CO (5 bar), 80 ꢀC, For the next runs: the same stoichiometry was used but the amount of reactants and solvent was adjusted according to the collected amount of
recovered catalysts mixture.

980
M. Genelot et al. / Tetrahedron 67 (2011) 976e981
chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad).
4.2. General procedures
4.2.1. Preparation of 2-benzylidene-indoxyl 2. A mixture of 2-iodoa-
niline (3 mmol), alkyne (1.2 equiv), [PdP2]@SBA-15 (0.1 mol %), PPh3
(1 mol %), and triethylamine (2.5 equiv) in anisole (5 mL) was placed
in a stainless autoclave, which was purged at 20 bar twice with Ar
and once with CO. The autoclave was charged with 5 bar CO. The
mixture was stirred at 80 ꢀC. At completion of the reaction, the au-
toclave was depressurized and purged twice at 20 bar with Ar. The
reaction media was taken up with CH2Cl2 (30 mL) and filtered on
sintered glass. The solid was washed several times with CH2Cl2. The
filtrate was washed with NaHCO3 (2ꢂ20 mL) then with brine
(1ꢂ20 mL). The organic layer was dried over MgSO4 and evaporated
under reduced pressure. The residue was then purified by chroma-
tography on silica gel to give pure indoxyl 2 as an orange solid (81%).
Fig. 3. Homogeneous and heterogeneous procedures for the one-pot syntheses of 2-
phenyl-4quinolone and 2-benzylidene-indoxyl.
4-quinolones. While using homogeneous systems, we were able to
propose two procedures for either the synthesis of indoxyls or that
of 4-quinolones;23 when using heterogeneous catalysts the for-
mation of the 2-benzyl-1H-indole 4 during the synthesis of
2-benzylidene-indoxyl 2 prevented further optimization toward
efficient protocols. Nevertheless, the fully heterogeneous approach
was successful for 2-phenyl-4-quinolone 3.
1H NMR (250 MHz, DMSO)
d 9.83 (s, 1H, NH), 7.78e7.69 (m, 2H,
C6H5), 7.63e7.56 (m, 1H, C6H4), 7.56e7.42 (m, 3H, C6H5), 7.40e7.32
(m, 1H, C6H4), 7.15 (dt, 3J¼8.1 Hz, 4J¼0.8 Hz, 1H, C6H4), 6.97e6.85
(m, 1H, C6H4), 6.65 (s, 1H, CH) in agreement with Ref. 23.
To conclude, a one-pot tandem {Pd/Amine} catalysis procedure
for the selective synthesis of 2-phenyl-4-quinolone through a car-
bonylative Sonogashira cross-coupling has been developed. Com-
pared to previously reported fully homogeneous protocols, the
present methodology based on the exclusive use of heterogeneous
catalytic materials resulted in noticeable improvement as it
allowed to reduce the overall reaction time from 7 to 3 days, to
decrease the palladium contamination in crude compound from
40 ppm to >5 ppm and to provide successful recycling of the
{[PdPNP]@SBA-15/[N]@SBA-3} catalysts mixture. Additionally, the
new protocol based on tandem catalysis allowed to introduce both
catalytic materials when setting-up the reaction, that is, apprecia-
ble since the initial reaction step is performed under CO pressure.
While the study revealed little deactivation of the system upon
recycling, prolonging the reaction time allowed to face with this
phenomenon giving high isolated yield in 4-quinolone.
4.2.2. Preparation of 2-phenyl-4-quinolone 3. A mixture of 2-iodoa-
niline (3 mmol), phenylacetylene (1.2 equiv), [PdPNP]@SBA-15
(0.1 mol %), [N]@SBA-3 (1 mol %), and triethylamine (2.5 equiv) in
anisole (5 mL) was placed in a stainless autoclave, which was purged
at 20 bar twice with Ar and once with CO. The autoclave was charged
with 5 bar CO. The mixture was stirred at 80 ꢀC. At completion of the
reaction, the autoclave was depressurized and purged twice at
20 bar with Ar. The reaction media was filtered over sintered glass
and the solid was washed with CH2Cl2. The collected solid was then
suspended in methanol in order to solubilize the 4-quinolone and
filtered. The methanol filtrate was then evaporated under reduced
pressure and dried under vacuum. The 2-phenyl-4-quinolone was
obtained pure without further refinement as a beige solid (62%).
1H NMR (250 MHz, DMSO)
d 11.73 (s, 1H, NH), 8.10 (dd,
3J¼8.0 Hz, 4J¼0.9 Hz, 1H, C6H4), 7.90e7.73 (m, 3H, C6H4, and C6H5),
7.73e7.63 (ddd, 3J¼8.3, 6.9 Hz, 4J¼0.9 Hz, 1H, C6H4), 7.63e7.54 (m,
3H, C6H5), 7.33 (ddd, 3J¼8.0, 6.9 Hz, 4J¼0.9 Hz, 1H, C6H4), 6.35 (s,1H,
CH) in agreement with Ref. 23.
4. Experimental
4.1. General
Acknowledgements
All commercial materials were used without further purifica-
tion. Analytical thin layer chromatography (TLC) was performed on
Fluka Silica Gel 60 F254. GC analyses were performed on a HP 4890
chromatograph equipped with a FID detector, a HP 6890 auto-
sampler and a HP-5 column (cross-linked 5% phenyl-methylsilox-
M.G. is grateful to the National Agency of Research for financial
support (No. ANR-07-BLAN-0167-01/02).
Supplementary data
ane, 30 mꢂ0.25 mm i.d.ꢂ0.25
mm film thickness) with nitrogen as
carrier gas. GCeMS analyses were obtained on a Shimadzu GCeMS-
Supplementary data related to this article can be found online
version at doi:10.1016/j.tet.2010.11.112. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
QP2010S equipped with a Supelco SLB-5MS column (95% methyl-
polysiloxaneþ5% phenylpolysiloxane, 30 mꢂ0.25 mmꢂ0.25
mm)
with Helium as carrier gas. Ionization was done by electronic im-
pact at 70 eV. Conversions were determined by GC based on the
relative area of GC-signals referred to an internal standard (bi-
phenyl) calibrated to the corresponding pure compounds. The ex-
perimental error was estimated to be Drel¼ꢁ5%. Chemical yields
refer to pure isolated substances. Purification of products was ac-
complished by flash chromatography performed at a pressure
slightly greater than atmospheric pressure using silica (Macher-
eyeNagel Silica Gel 60, 230e400 mesh) with the indicated solvent
system. Liquid NMR spectra were recorded on a BRUKER AC-250
spectrometer. All chemical shifts were measured relative to re-
sidual 1H or 13C NMR resonances in the deuterated solvents: DMSO,
References and notes
1. Grohe, H. Chem. Brit. 1992, 34e36.
2. Wentland, M. P.; Cornett, J. B. Annu. Rep. Med. Chem. 1985, 20, 145e154.
3. Ward, F. E.; Garling, D. L.; Bickler, R. T.; Lawer, D. M.; Cummings, D. P. J. Med.
Chem. 1981, 24, 1073e1077.
4. Aimi, A.; Nishimura, M.; Miwa, A.; Hoshino, H.; Sakai, S.; Higiniwa, J. Tetrahe-
dron Lett. 1989, 30, 4991e4994.
5. Leonard, N. J.; Herbrandson, F.-F.; van Heyningen, E. M. J. Am. Chem. Soc. 1946,
68, 1279e1281.
6. Reitsema, R. H. Chem. Rev. 1948, 43, 43e68.
7. Chen, B.; Huang, X.; Wang, J. Synthesis 1987, 482e483.
8. Kasahara, A.; Izumi, T.; Watabe, H.; Takahashi, S. Chem. Ind. 1981, 121.
9. Okuro, K.; Alper, H. J. Org. Chem. 1997, 62, 1566e1567.
d
2.50 ppm for 1H, 39.5 ppm for 13C. Data are reported as follows:

M. Genelot et al. / Tetrahedron 67 (2011) 976e981
981
10. Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Woodall, D. E.; Yoganathan, G. Tet-
rahedron Lett. 2000, 41, 7125e7128.
24. In TANDEM catalysis all catalysts are introduced in the reactor from the start of
the reaction; in MULTI-CATALYSIS, the catalysts are introduced in the reactor
step by step. See: Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248,
2365e2379.
25. Following the European Medicines Agency, in: E.M. Agency (Ed.) 2008 p. 34,
acceptable residual palladium content for drugs administered by oral and pa-
rental routes should be below 1 ppm and 10 ppm [often <5 ppm in drug
testing], respectively.
11. Torii, S.; Okumoto, H.; Xu, L. H. Tetrahedron Lett. 1991, 32, 237e240.
12. Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.; Shostakovsky, M. V.; Ponomar-
yov, A. B.; Kalinin, V. N. Tetrahedron 1993, 49, 6773e6784.
13. Kalinin, V. N.; Shostakovskii, M. V.; Ponomarev, A. B. Tetrahedron Lett. 1992, 33,
373e376.
14. Haddad, N.; Tan, J.; Farina, V. J. Org. Chem. 2006, 71, 5031e5034.
15. Gerby, B.; Boumendjel, A.; Blanc, M.; Bringuier, P. P.; Champelovier, P.; Fortune,
ꢀ
26. MS m/z (relative intensity): 207(49), 206 (30), 130 (100), 102 (16), 77 (15).1H
A.; Ronot, X.; Boutonnat, J. Bioorg. Med. Chem. Lett. 2007, 17, 208e213.
16. Abramovitch, R. A.; Marko, A. M. Can. J. Chem. 1960, 38, 131e135.
17. Dean, F. M.; Patamapongse, C. J. Chem. Soc., Perkin Trans. 1 1974, 952e955.
18. Wu, E.; Komolpis, K.; Wang, H. Y. Biotechnol. Tech. 1999, 13, 567e569.
19. Braudeau, E.; David, S.; Fischer, J. C. Tetrahedron 1974, 30, 1445e1455.
20. Hewitt, M. C.; Shao, L. ARKIVOC 2006, 37e46.
NMR (250 MHz, DMSO)
d
10.97 (s, 1H), 7.40 (d, J¼7.5 Hz, 1H), 7.33e7.11 (m, 6H),
6.95 (m, 2H), 6.13 (s, 1H), 4.05 (s, 2H) in agreement with Ambrogio, I.; Cacchi,
S.; Fabrizi, G.; Prastaro, A. Tetrahedron 2009, 65, 8916e8929.
27. Coquerel, Y.; Bremond, P.; Rodriguez, J. J. Organomet. Chem. 2007, 692, 4805e4808.
28. Djakovitch, L.; Koehler, K.; De Vries, J. G. In Nanoparticles and Catalysis; Astruc,
D., Ed.; Wiley-VCH: Weinheim, 2008; pp 303e348.
21. Hooper, M.; Pitkethly, W. N. J. Chem. Soc., Perkin Trans. 1 1972, 1607e1613.
22. An, Z. W.; Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1990, 397, C31eC32.
23. Genelot, M.; Bendjeriou, A.; Dufaud, V.; Djakovitch, L. Appl. Catal., A 2009, 369,
125e132.
29. Djakovitch, L.; Wagner, M.; Hartung, C. G.; Beller, M.; Koehler, K. J. Mol. Catal. A:
Chem. 2004, 219, 121e130.
30. Batail, N.; Bendjeriou, A.; Djakovitch, L.; Dufaud, V. Appl. Catal., A 2010, 388,
179e187.