Electrophilic carbon transfer in gold catalysis: Synthesis of substituted chromones

Article abstract of DOI:10.1016/j.tetlet.2011.03.018

Using easily accessible aromatic alkoxy-arylalkynones, we have investigated the gold-catalyzed intramolecular addition of ethers to alkynes, to give easy access to various substituted chromones. This reaction involves the transfer of the ether substituent via a carbodemetallation process. We also noticed a competing isomerization of several starting materials for which we propose a second gold catalyzed mechanism.

Full text of DOI:10.1016/j.tetlet.2011.03.018

Tetrahedron Letters 52 (2011) 2476–2479
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electrophilic carbon transfer in gold catalysis: synthesis of substituted
chromones
⇑
Jacques Renault, Zhao Qian, Philippe Uriac, Nicolas Gouault
Université de Rennes 1, UMR 6226 Sciences Chimiques de Rennes, Equipe PNSCM, UFR Sciences Biologiques et Pharmaceutiques, 2, Av., du Pr. Léon Bernard,
35043 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Using easily accessible aromatic alkoxy-arylalkynones, we have investigated the gold-catalyzed intramo-
lecular addition of ethers to alkynes, to give easy access to various substituted chromones. This reaction
involves the transfer of the ether substituent via a carbodemetallation process. We also noticed a com-
peting isomerization of several starting materials for which we propose a second gold catalyzed
mechanism.
Received 9 February 2011
Revised 25 February 2011
Accepted 2 March 2011
Available online 11 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chromones
Gold catalysis
Electrophilic transfer
Isomerisation
E
1. Introduction
R
[Au]
R
Over the past few years, transition metal-catalyzed reactions
have gained great importance as synthetic methods in heterocyclic
chemistry. Thus, gold-catalyzed addition of heteroatoms across
carbon–carbon unsaturated bonds -providing key structures of
natural products and organic materials- has attracted significant
interest.1 In a large number of gold-catalyzed reactions, the cata-
lytic cycle is completed by trapping of a vinyl–gold intermediate
with a proton, so-called protodemetallation. Recently, several
groups have disclosed that such intermediates can also be captured
by other electrophiles2 or used in carbon–carbon cross-coupling
strategies via transmetallation.3 In this context, one approach con-
sists of replacing the proton on the heteroatom (Y) responsible for
the cyclization process by another electrophilic group (E). Then the
reaction proceeds through a [1,3] shift of the migrating group
(Scheme 1).
The aim of the present work was to investigate the utility of
gold catalysts for the activation of alkynes toward the intramolec-
ular addition of ethers followed by carbodemetallation for the
synthesis of substituted chromone derivatives with potential bio-
logical activities.4 The use of an alkoxy group instead of hydroxyl
allows a carbon transfer during the catalytic heterocyclization
(Scheme 2).
Y
Y
E
[Au]
R
E
Y
Scheme 1. Electrophilic transfer in heterocyclization.
O
O
R2
R2
R1
[Au]
R3
O
R1
O
R3
Scheme 2. Gold catalyzed synthesis of chromones.
2. Results and discussion
The initial model for the optimization of this reaction was
allyloxyphenylpropynone 1 that was easily prepared in two steps
from the commercially available 2-(allyloxy)benzaldehyde.5 In
our initial attempts, in accordance with previous results,6 we used
triphenylphosphine gold chloride (PPh3AuCl, 10 mol %) associated
⇑
Corresponding author.
E-mail address: nicolas.gouault@univ-rennes1.fr (N. Gouault).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.018

J. Renault et al. / Tetrahedron Letters 52 (2011) 2476–2479
2477
O
O
O
O
O
[Cat]
OCH3
+
+
Solvent
Duration
O
O
O
OCH3
Temperature
3
4
1
2
OCH3
OCH3
Scheme 3. Reaction observed from 1.
Table 1
Influence of the catalytic system on the formation of compound 2
peared from the reaction medium and compound 4 with a better
stability remained visible (from 25% to 15% compared to the inter-
nal standard). The expected chromone 2 was present in a constant
amount of 57%. Complementary studies on solvents prompted us
to use DCE that was clearly found more efficient than dichloro-
methane, chlorobenzene or acetonitrile.
In order to investigate the role of water, three reactions were
carried out in the presence or absence of molecular sieves and with
the addition of 20 equiv of water in DCE. Comparable results
showed no obvious role of water in the reaction. Variation in the
percentage of the catalytic system (1 and 5 mol %) only delayed
the accomplishment of this reaction (8 h and 15 min, respectively).
The absence of reaction with PPh3AuCl or AgSbF6 attested the role
of the co-catalyst (entries 6–7).
Entry
Conditions
Yielda (%)
1
2
3
4
1
2
3
4
5
6
7
PPh3AuCl/AgOTf, 0.5 h, 50 °C
PPh3AuCl/AgBF4, 0.5 h, 50 °C
PPh3AuCl/AgSbF6, 0.5 h, 50 °C
PPh3AuCl/ AgSbF6, 0.5 h, rt
PPh3AuCl/ AgSbF6, 1 h, 50 °C
PPh3AuCl, 0.5 h, 50 °C
0
0
0
0
0
43
45
57
52
57
0
20
20
0
15
0
36
21
20
27
15
0
100
100
0
0
AgSbF6, 0.5 h, 50 °C
0
0
a
Estimated by 1H NMR using 1,4-dinitrobenzene as internal reference.
to a silver co-catalyst (AgOTf, 10 mol %) in 1,2-dichloroethane
(DCE) for 3 h. The first experiments were carried out at room
temperature in the presence of molecular sieves (4 Å) to limit a
possible harmful role of water. These conditions allowed a com-
plete conversion of the starting material but a low yield of com-
pound 2 (23%) was obtained (Scheme 3). Starting with this
model, we varied the catalytic system, duration and temperature.
In most cases, besides the expected chromone, two major com-
pounds were identified: the chromone 3—resulting from a simple
protodeauration- and the isomeric ketone 4 of the starting mate-
rial. This isomerization reaction is likely to be related to the
Meyer–Schuster rearrangement.7 The ratio of these compounds
could be evaluated by 1H NMR analysis of the crude material.
The influence of the catalytic system was studied and the re-
sults are presented in Table 1. In each case, the reaction was con-
ducted in DCE. Some differences could be noted in the formation
of the expected compound 2 with various silver sources (entries
1–3) with a slightly better conversion with AgSbF6 as a co-catalyst.
At room temperature (entry 4), the expected compound 2 was ob-
tained together with the chromone 3.
With these results in hand, we decided to investigate the scope
of the reaction on various analogous substrates. The compounds
5a–k were prepared either from salicylaldehydes or salicylic
acids.5 Salicylaldehydes were O-alkylated and reacted with ethy-
nyl-lithium salts to give the corresponding secondary alcohols.
These latter were then oxidized to give the final ketones 5a, 5c–
d, 5f–k. Salicylic acids were converted into their Weinreb amides
and were reacted with ethynyl-lithium salts to yield 5b and 5e.
The alkynones 5a–k were then reacted under ‘standard condi-
tions’.8 The results are presented in Table 2.
In most cases, the expected compounds 6a–k were obtained in
modest isolated yields.9 In many cases incomplete transfer of the
R1 group was observed. In the case of compound 5g, 7 (Fig. 1)
was obtained at the sole product (27%). A competing isomerization
of starting material was also observed and sometimes impaired the
chromone formation. Thus, 8 and 9 (Fig. 1) were the unique com-
pounds isolated in 65% and 48% yields, respectively, from 5j and
5k. In the case of the reaction of 5e, possessing an electron-rich
aromatic ring at the R3 position, in addition to the loss of R1 group,
we also observed the presence of 10a and 10b (8% and 12% isolated
yield, respectively).
A complementary study concerning the time of reaction (entry
5) exhibited product distribution differences. After 1 h, 3 disap-
Table 2
Results obtained from compounds 5a–k to 6a–k
O
PPh3AuCl 10 mol %
AgSbF6 10 mol %
O
O
R2
R2
R1
R3
R3
DCE
50°C, 0.5 h
O
R1
5a-k
6a-k
R1
R1
R2
R3
Product
Yielda (%)
R2
R3
Product
Yielda (%)
5a
5b
5c
5d
5e
5f
Ph-CH2–
Ph-CH2–
Ph-CH2–
Ph-CH2–
Ph-CH2–
4-Cl-Bn–
3-MeO-
H-
3,5-Br-
3-Allyl-
H-
n-Pr-
n-Pr-
n-Pr-
n-Pr-
4-MeOPh-
n-Pr-
6a
6b
6c
6d
6e
6f
45
31
40
38
25
40
5g
5h
5i
5j
5k
4-MeO-Bn-
Allyl-
Allyl-
Et-
H-
H-
H-
H-
H-
n-Pr-
Ph-
H-
n-Pr-
Ph-
6g
6h
6i
6j
6k
0b
38
35
0c
Et-
0d
H-
a
b
c
Isolated yield.
Only compound 7 was isolated (27%).
Isomer 8 was isolated (65%).
d
Isomer 9 was isolated (48%).

2478
J. Renault et al. / Tetrahedron Letters 52 (2011) 2476–2479
O
O
O
O
b
Ph
a
O
O
O
O
OCH3
7
10a-b
9
8
Figure 1. Structures of compounds 7, 8, 9, 10a and 10b.
We propose catalytic cycles for these reactions (Scheme 4). The
‘normal reaction’—resulting in a chromone formation—could pro-
ceed through a gold activation of the alkyne bond of the starting
material A. Attack of the oxygen lone pair of B to the activated al-
kyne can lead to the cyclic intermediate C. After the transfer of the
R1 substituent, gold(I) and cyclization product D are liberated. In
this reaction, the nature of the [1,3] migration has not been clearly
elucidated to date. The intramolecular nature of the rearrangement
was examined by the reaction of two mixed starting materials,
alkynones 1 and 5f (Scheme 5).
After 30 min under the standard experimental conditions, no
traces of possible ‘cross-reaction’ could be detected. We only iso-
lated the expected products 2 and 6f in usual yields together with
the usual by-products obtained in the individualized reactions. Yet,
when the reaction was performed in the presence of phenylethanol
in order to trap the carbocation intermediate—as studied by
Asao10—traces of the corresponding ether could be obtained. Fur-
thermore, the little isolation of 10b ([1,4] transfer) suggests a car-
bocation mechanism in this process instead of a [1,3] sigmatropic
rearrangement, as suggested by Yamamoto and co-workers11 in a
study of chirality transfer in a gold-catalyzed formation of benzo-
thiophenes. Finally, it seems that transfer of the carbon group is
governed by proximity effect, given that 10b is favored over 10a
despite the activating electronic effect of the methoxy group.
The unexpected isomerization of several starting materials was
also noticed and was especially favored when R1 was an alkyl group.
We propose the formation of an oxetenium intermediate E that
could explain the formation of isomerization product G. Such an
intermediate has been previously proposed by Yamamoto and co-
workers for the gold-catalyzed intramolecular carbocyclization of
alkynyl ketones12 and by Bégué and Malissard in the AgSbF6-pro-
moted dehalogenation of
a
-bromoketones to form b,c-unsaturated
O
O
R2
R3
R2
R3
O
R1
A
G
O
R1
O
O
R2
R1
R3
[Au]
[Au]
O
R3
R2
D
O
O
[Au]
R2
[Au]
O
O
R2
R3
R1
[Au]
R3
F
R3
B
O
R1
O
R1
R2
C
[Au]
O
R1
E
Scheme 4. Proposed catalytic cycles for the synthesis of substituted chromones versus isomerization.
O
O
O
OCH3
O
1
PPh3AuCl10 mol %
AgSbF6 10mol %
2
OCH3
Cl
O
O
+
+
O
DCE, 50°C, 30 min.
5f
Cl
O
6f
Scheme 5. Reaction observed for a mixture of 1 and 5f.

J. Renault et al. / Tetrahedron Letters 52 (2011) 2476–2479
2479
enones.13 To the best of our knowledge, no similar isomerization
reactions of alkynyl ketones have been reported to date.
In conclusion, we have developed a new gold catalyzed reaction
proceeding via activation of an alkyne group toward the intramo-
lecular addition of an ether functionality, followed by carbodemet-
Soc. 2009, 131, 3464–3465; (c) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y.
Org. Lett. 2007, 9, 4081–4083.
3. Garcia, P.; Malacria, M.; Aubert, C.; Gandon, V.; Fensterbank, L. ChemCatChem
2010, 2, 493–497.
4. (a) Bhat, A. S.; Whetstone, J. L.; Brueggermeier, R. W. Tetrahedron Lett. 1999, 40,
2469–2472; (b) Bauvois, B.; Puiffe, M.; Bongui, J. B.; Paillat, S.; Monneret, C.;
Dauzonne, D. J. Med. Chem. 2003, 46, 3900–3913; (c) Kim, H. P.; Son, K. H.;
Chang, H. W.; Kang, S. S. J. Pharmacol. Sci. 2004, 96, 229–245; (d) Benett, C. J.;
Caldwell, S. T.; McPhail, D. B.; Morrice, P. C.; Duthie, G. G.; Hartley, R. C. Bioorg.
Med. Chem. 2004, 12, 2079–2098.
5. For the syntheses of compounds 1, 5a–i, see Supplementary materials.
6. Jean, M.; Renault, J.; van de Weghe, P.; Asao, N. Tetrahedron Lett. 2010, 51, 378–
381.
allation to give
a substituted chromone derivative. Further
investigation of mechanistic details in the isomerization reaction
should render this reaction quite attractive in synthesis.
Supplementary data
7. Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. 1922, 55B, 819–823.
8. Representative synthesis of chromone 2: To a solution of alkynone 1 (0.1 mmol)
in 1,2-dichlorethane under argon were added PPh3AuCl (0.01 mmol) then
AgSbF6 (0.01 mmol). The suspension was stirred and heated at 50 °C for 30 min
under argon. After filtration over celite and concentration under vacuum,
compound 2 was purified using a flash chromatography. 1Y NMR 300 (CDCl3):
dH 3.34 (dt, J = 1.75 Hz, J = 5.60 Hz, 2H), 3.89 (s, 3H), 5.07 (m, 2H), 6.09 (m, 1H),
7.03 (m, 2H), 7.42 (m, 2H), 7.66 (m, 3H), 8.25 (dd, J = 7.95 Hz, J = 1.40 Hz, 1H).
13C NMR (CDCl3): dC 30.2, 55.4, 113.8, 115.3, 117.8, 118.8, 122.8, 124.7, 125.6,
126.0, 130.2, 133.3, 136.2, 156.1, 161.2, 162.3, 178.1. HRMS (EI): Calcd for
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.018.
References and notes
1. (a) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675–691; (b) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2010, 49, 5232–5241; (c) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180–3211; (d) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265; (e)
C
19H16O3Na: 315.0997. Found 315.0994, (57%).
ˇ
9. Spectral data of chromones or by-products are given in the Supplementary
materials.
10. Asao, N.; Aikawa, H.; Tago, S.; Umetsu, K. Org. Lett. 2007, 9, 4299–4302.
11. Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2008, 10, 2649–2651.
12. Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259–5262.
Jiménez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350; (f)
Muzart, J. Tetrahedron 2008, 64, 5815–5849; (g) Gorin, D. J.; Sherry, B. D.; Toste, F.
D. Chem. Rev. 2008, 108, 3351–3378; (h) Arcadi, A. Chem. Rev. 2008, 108, 3266–
3325; (i) Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449.
2. (a) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473–
4475; (b) Vermura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D. J. Am. Chem.
13. Bégué, J.-P.; Malissard, M. Tetrahedron 1978, 34, 2095–2103.