A new gold-catalyzed domino cyclization and oxidative coupling reaction

Article abstract of DOI:10.1002/chem.200801848

Gold-catalyzed domino cyclization and oxidative coupling reaction for synthesis of dicoumarins was studied. Gold was thought to be an unreactive metal before its catalyzed reaction was discovered. HAuCl₄ was suspended in dry 1,2-dichloroethane (DCE), whereas protic solvent gave only monomer and UV absorption and fluorescence properties of dicoumarins were similar to those of monomers. The crude product was purified by flash column chromatography on silica and gold catalyst performed two different functions. Dicoumarins, scaffolds of natural products has interesting biological properties whereas, potential photostable UV-absorbent materials were accessed in two steps from commercially available starting materials. The reaction generally proceeded in moderate-to-good yields, tolerating a variety of substituents on the aromatic moiety.

Full text of DOI:10.1002/chem.200801848

DOI: 10.1002/chem.200801848
A New Gold-Catalyzed Domino Cyclization and Oxidative Coupling
Reaction
Hermann A. Wegner,* Sebastian Ahles, and Markus Neuburger[a]
Although gold was long thought to be an unreactive
metal, the first gold-catalyzed reactions were reported over
30 years ago.[1] Since then, especially in recent years, this
area of investigation has been growing rapidly.[2–4] The
unique properties of Au as a p Lewis acid enable the devel-
opment of novel routes to complex molecular structures.[5]
Herein, we report a new gold-catalyzed domino cyclization
and oxidative coupling reaction for the synthesis of dicou-
marins.
Metal-catalyzed cyclization of arylpropionic esters has
been used to form coumarins for a number of years.[6–10]
During our investigations into coumarin precursors, we dis-
covered a second product formed in the reaction, which ori-
ginated from a cyclization followed by an oxidative coupling
of two coumarin subunits (Scheme 1). Such homo-couplings
lines.[12b] Current syntheses of dicoumarins rely on oxidative
coupling,[13] Ullmann coupling[14a] or the Perkin reaction.[14b]
However, all of them suffer from low yields or low substrate
scope.
Different oxidants and Au-sources were screened with
compound 1 (Scheme 1) as test substrates to regenerate
AuIII, to allow for use of catalytic amounts of the gold spe-
cies. Anhydrous tert-butylhydroperoxide in combination
with HAuCl4 gave the best catalytic performance and af-
forded the desired dimer in good yields. The process was
highly solvent-dependent, and the best results were obtained
in 1,2-dichloroethane (DCE), whereas protic solvents, such
as ethanol, gave only the monomer (determined by
1H NMR spectroscopy).
The catalyst loading was lowered to 1 mol%, without loss
of yield or selectivity. However, reaction times for complete
conversion were considerably longer (1 h with 5 mol% cata-
lyst, compared to 24 h with 1 mol%). Variations in concen-
tration also altered results. The ratio of monomer to dimer
changed from 2:3 for
a
substrate concentration of
concentration of
50 mmolLÀ1in DCE, to 4:3 for
a
12 mmolLÀ1. If the reaction was performed at a higher con-
centration of 460 mmolLÀ1, the conversion (4%) and the
monomer/dimer ratio (9:10) both dropped dramatically. Ad-
dition of bases, such as Cs2CO3 or NaOMe, or water absorb-
ing materials, such as molecular sieves or MgSO4, did not
improve the results. Conversely, in most cases the reaction
failed completely. Not even a dimerization of the alkyne by
Glaser-type coupling was observed under basic conditions,
rendering a gold–acetylene species an unlikely intermedi-
ate.[15]
The reaction generally proceeded in moderate-to-good
yields, tolerating a variety of substituents on the aromatic
moiety. Even substitution in the ortho-position was tolerated
(Table 1, entries 3–5). Interestingly, in contrast to the simple
cyclization, high regioselectivity was detected in cases where
two possible regioisomers could be formed (Table 1, en-
tries 6 and 7).[16] The depicted isomers were the only ones
isolated. Substrates with an electron-rich aromatic group
gave the highest dimerization yields. Furthermore, the ester
Scheme 1. Formation of dicoumarins in the Au-catalyzed cyclization of
aryl propargylesters (DCE=1,2-dichloroethane).
of vinyl-Au species have been reported for reactions em-
ploying stoichiometric amounts of Au.[11]
This dicoumarin framework is present in a variety of natu-
ral products.[12] Some of them show moderate inhibitory ac-
tivity on cell growth of various leukemia and carcinoma cell
[a] Dr. H. A. Wegner, S. Ahles, Dr. M. Neuburger
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-09-76
E-mail: Hermann.wegner@unibas.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801848.
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COMMUNICATION
Table 1. Substrate scope of the domino cyclization/oxidative coupling re-
action.[a]
group also seems to be essential for cyclization to occur; a
precursor with an ether bridge gave no reaction (Table 1,
entry 10). Although the reaction conditions are mild, in
some cases, the presence of a strong oxidant, tBuOOH, led
to partial cleavage of the ester as well as oxidation, probably
to the quinone (Table 1, entries 6 and 8) .[17] Electron-with-
drawing groups on the aromatic moiety, such as CN, Cl, and
CO2Et, prohibit the reaction. In these cases, only starting
material was isolated, together with small amounts of the
corresponding phenol, resulting from ester cleavage. Inter-
estingly, it was even possible to isolate the dimer with a sub-
stituent on the alkyne (Table 1, entry 11). However, steric
hindrance appeared to hamper the dimerization process.
The first step of the domino cyclization/oxidative coupling
reaction has been studied by other groups[8,9,18] and has also
been investigated in our own laboratory, by using deutera-
tion experiments, which showed that the reaction proceeds
by an electrophilic Friedel–Crafts-type mechanism. This
finding explains why electron-rich aromatic rings are the
best substrates for such reactions.
Entry Starting material
Product
Yields [%][b]
D
M
SM
1
55 32
27 40
28 19
–
2
3
–
–
4
67 13
–
Based on these results, we propose the following mecha-
nism for the domino cyclization/oxidative coupling reaction
(Scheme 2): The Au catalyst coordinates to the alkyne 1 to
activate it for electrophilic substitution. Rearomatization
furnishes the s complex C, which in turn catalyzes a second
cyclization to form complex D. Protonation of complex C
terminates the cycle and results in the formation of the
monomeric coumarin 2. However, complex D undergoes an
oxidative coupling to the dimeric dicoumarin 3 and an AuI
species, which is subsequently reoxidized to AuIII, complet-
ing the catalytic cycle. An alternative rationale would be a
ligand exchange of two complexes C. A crossover experi-
ment, using a 1:1 mixture of naphthalen-1-yl propiolate 1d
(Table 1, entry 4) and 3-methoxyphenyl propiolate 1g
(Table 1, entry 7), was undertaken to test if the comparative
5
6
37 18 12
50[c] 30
–
7
8
40 23
–
–
34[c]
8
9
No reaction
No reaction
–
–
– 85
– 81
10
11
13 21 31
[a] Reaction conditions: HAuCl4 (5 mol%), tBuOOH (5 equiv), DCE,
608C, 24 h. [b] Yields of isolated product. D=dimer 3, M=monomer 2,
SM=starting material 1. [c] Inseparable mixture with oxidized products.
Scheme 2. Proposed mechanism for the Au-catalyzed domino cyclization/
oxidative coupling reaction.
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H. A. Wegner et al.
droperoxide (5.00 equiv, 80wt%) in cyclohexane was added and the aryl-
propionic ester (1.00 equiv) was dissolved in the solution. The mixture
was heated to 608C and was stirred for 24 h. If a precipitate was formed,
it was removed by filtration and recrystallized. Excess peroxide was re-
duced with Na2S2O3 (10% aq. solution). The mixture was diluted with di-
chloromethane (50 mL) and washed with H2O. The combined organic
layers were dried over Na2SO4, and the solvent removed under reduced
pressure. The crude product was purified by flash column chromatogra-
phy on silica.
reactivities of complex C influenced the outcome of the re-
action. However, only a mixture of the monomers, both ho-
modimers, and the heterodimer, in approximately stochastic
ratio, were obtained.
Reaction of the cyclized coumarin monomer under the
usual conditions for the domino cyclization/oxidative cou-
pling gave no dimerization product (Scheme 3), suggesting
Acknowledgements
HAW is indebted to the Fonds der Chemischen Industrie for a Liebig-
Fellowship. The authors thank Prof. E. Constable for fruitful discussions.
Scheme 3. Submission of the monomeric coumarin to the cyclization/oxi-
dative coupling conditions.
À
Keywords: C C coupling
homogeneous catalysis
· domino reactions · gold ·
À
that reinsertion of Au into the a C H of the coumarin does
not occur.
The UV absorption and the fluorescence properties of the
dicoumarins are very similar to those for the monomers.
This behavior is probably due to a twist of the two coumarin
units, which limits the conjugation of the p-electron system
to half of the molecule. A relative torsion angle of 38.48 can
be observed in the crystal structure (Figure 1). Preliminary
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investigations detected an interesting photostability of these
compounds, which makes them promising candidates for ap-
plication as UV-absorbent materials.
In summary, we have shown the first Au-catalyzed
domino cyclization/oxidative coupling reaction. In this pro-
cess the gold catalyst performed two different functions. Di-
coumarins, scaffold of natural products with interesting bio-
logical properties and potential photostable UV-absorbent
materials, were accessed in two steps from commercially
available starting materials. In the future, this method could
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Experimental Section
General procedure: HAuCl4 (0.05 equiv) was suspended in dry 1,2-di-
chloroethane (10 mL per 0.5 mmol substrate). A solution of tert-butylhy-
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Chem. Eur. J. 2008, 14, 11310 – 11313

Gold-Catalyzed Domino Reaction
COMMUNICATION
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From a total of 42256 reflections, 2655 were independent (merging
r=0.050). From these, 1815 were considered as observed (I>
2.0s(I)) and were used to refine 163 parameters. The structure was
solved by direct methods using the program SIR92.[20] Least-squares
refinement against F was carried out on all non-hydrogen atoms
using the program CRYSTALS[21] R=0.0459 (observed data), wR=
0.0891 (all data), GOF=1.2651. Minimal/maximal residual electron
density=À0.30/0.31 eꢄÀ3. Chebychev polynomial weights were used
to complete the refinement. Plots were produced using ORTEP3 for
Windows[22] CCDC 690486 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
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men-2,2’-dione 3a: C26H26O4, Mr =402.49, FACTHNUTRGENUG(N 000)=3852; colorless
¯
needle; crystal size 0.05ꢃ0.07ꢃ0.44 mm; trigonal; space group R3c,
a=25.3197(3), b=25.3197(3), c=18.7196(6) ꢄ; a=b=908, g=1208;
V=10393.1(4) ꢄ3; Z=18; 1calcd =1.157 MgmÀ3
.
The crystal was
measured on a Kappa APEX diffractometer at 173 K using graph-
ite-monochromated MoKa radiation with l=0.71073 ꢄ, Vmax
27.4718. Minimal/maximal transmission 0.99/1.00, m=0.077 mmÀ1
The APEX suite has been used for data collection and integration.
[22] L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
=
.
Received: September 8, 2008
Published online: November 12, 2008
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