Palladium catalysed arylation of 6,8-dimethoxybenzofuranone

Article abstract of DOI:10.1016/j.tetlet.2005.09.062

6,8-Dimethoxybenzofuranone was arylated in the presence of a palladacycle catalyst and p-methoxyphenol to afford precursors of anti-cancer and anti-inflammatory drugs.

Full text of DOI:10.1016/j.tetlet.2005.09.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8017–8018
Palladium catalysed arylation of 6,8-dimethoxybenzofuranone
*
´
Abdelkarim Sani Souna Sido, Loıc Boulenger and Laurent Desaubry
¨
UMR 7175-LC1, Department of Medicinal Chemistry, Faculte´ de Pharmacie, 67401 Illkirch cedex, France
Received 26 July 2005; revised 9 September 2005; accepted 12 September 2005
Available online 3 October 2005
Abstract—6,8-Dimethoxybenzofuranone was arylated in the presence of a palladacycle catalyst and p-methoxyphenol to afford pre-
cursors of anti-cancer and anti-inflammatory drugs.
Ó 2005 Elsevier Ltd. All rights reserved.
Rocaglamide 2 and its related flavaglines isolated from
plants of the Aglaia species exhibit potent cytostatic
and proapoptotic activity in cancer cells, but are not
toxic to the organism.1–3 Recent findings have shown
that these compounds also display potent anti-inflam-
matory properties both in vitro and in vivo.4,5 Their cel-
lular target and mechanism of action are considered to
be distinct from those of known anti-inflammatory
and anti-cancer agents. The most straightforward
syntheses of flavaglines start from 1 (Fig. 1).6,7 However,
these approaches suffer from the difficulty to prepare
2-arylbenzofuranones: the synthesis of these com-
pounds by the Hoesch reaction is restricted to benzo-
furanones substituted by electron-donating groups.8
Moreover, this reaction displays a lack of reproducibil-
ity as reported by Taylor and co-workers, and verified
by us.6
concise and flexible synthesis of 2-arylbenzofuranones.
The recent development of palladium-catalysed a-aryla-
tion of ketones provides an opportunity to prepare these
compounds.9 To explore this reaction, we chose pallada-
cycle 4 as a catalyst, due to its efficiency, stability and
ease of preparation.10
First, we examined the reaction of dimethoxybenzofura-
none 3 with phenyl bromide in toluene under reflux. The
use of K3PO4 as a base led exclusively to the formation
of tar (Table 1, entry 1). Switching to a stronger base,
t-BuOK, afforded the expected adduct 5 in low yield
as well as O-phenyl ether 6 and diadduct 7 (entry 2).
Because the efficiency and the cleanliness of the reaction
were poor, we examined whether the addition of p-meth-
oxyphenol could improve this process as it has been ob-
served by Buchwald with the arylation of enolates
catalysed by Pd2(dba)3.11 We were pleased to observe
that this additive doubled the yield and suppressed
totally the formation of diadduct 7 (entry 3). As far as
we know, it is the first observation that a phenolate
increases the efficiency of a palladacycle catalyst.
In the course of our research on the structure–activity
relationship of rocaglamide, we needed to develop a
O
HO
HO
OMe
O
MeO
NMe2
Ph
Increasing the quantity of phenylbromide to 2 equiv
increased the yield up to 48% (entry 4). Only 10% of
the by-product 6 was formed. Lowering the amount of
t-BuOK to 2.5 equiv or replacing toluene by DMF
decreased both the yield of arylation (entries 5 and 6).
O
MeO
O
MeO
OMe
1
2
OMe
Figure 1. Rocaglamide 2 and its synthetic precursor 1.
As experience was gained with the previous example, we
successfully applied the a-arylation reaction to several
bromoarenes (Table 2).12 Arylated benzofuranones were
obtained in reasonable yields with a predominance of
the desired adducts 8.
Keywords: Arylation; Benzofuranone; Palladacycle.
*
Corresponding author. Tel.: +33 390 244 220; fax: +33 390 244
310; e-mail: desaubry@pharma.u-strasbg.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.062

8018
A. S. Souna Sido et al. / Tetrahedron Letters 46 (2005) 8017–8018
Table 1. a-Phenylation of benzofuranone 3
OH
OMe
O
Cl
Pd
NMe2
OMe
OMe
OMe
O
OPh
OPh
Ph
PCy3
base, 110 ºC
+
+
+
+
+ PhBr
O
Ph
MeO
O
O
O
MeO
MeO
MeO
OMe
4 (0.02 eq)
(0 or 0.2 eq)
3
5
6
7
Entry
PhBr (equiv)
Base (equiv)
Solvent
p-MeO-PhOH (equiv)
Isolated yield (%)
5
6
7
1
2
3
4
5
6
1
1
1.5
2
3
K3PO4 (1.5)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (2.5)
t-BuOK (3)
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
0
0
0.2
0.2
0.2
0.2
0
17
41
48
32
33
0
2
13
10
6
0
2
0
0
0
0
2
5
Table 2. a-Arylation of 3 by various aryl bromidesa
References and notes
OMe
OMe
O
OAr
1. Proksch, P.; Edrada, R.; Ebel, R.; Bohnenstengel, F. I.;
Nugroho, B. W. Curr. Org. Chem. 2001, 5, 923–938.
2. Lee, S. K.; Cui, B.; Mehta, R. R.; Kinghorn, A. D.;
Pezzuto, J. M. Chem. Biol. Interact. 1998, 115, 215–
228.
Ar
O
O
MeO
MeO
8
9
Entry
1
ArBr
Yield (%)
73
Ratio 8/9
3. Hausott, B.; Greger, H.; Marian, B. Int. J. Cancer 2004,
109, 933–940.
4. Proksch, P.; Giaisi, M.; Treiber, M. K.; Palfi, K.; Merling,
A.; Spring, H.; Krammer, P. H.; Li-Weber, M. J.
Immunol. 2005, 174, 7075–7084.
5. Fahrig, T.; Gerlach, I.; Horvath, E. Mol. Pharmacol. 2005,
67, 1544–1555.
6. Davey, A. E.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem.
Soc., Perkin Trans. 1 1992, 112, 2657–2666.
7. Dobler, M. R.; Bruce, I.; Cederbaum, F.; Cook, N. G.;
Diorazio, L. J.; Hall, R. G.; Irving, E. Tetrahedron Lett.
2001, 42, 8281–8284.
8. Katamna, C. Bull. Soc. Chim. Fr. 1970, 2309–2322.
9. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234–245.
Br
OMe
1.35/1
1.40/1
OMe
2
79
Br
Br
Br
OMe
3
4
87
92
1.65/1
1.42/1
Me
F
10. Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H.
Angew. Chem., Int. Ed. 2002, 41, 3668–3671.
11. Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 15168–15169.
5
61
1.44/1
Br
F
a All reactions were performed in toluene at 110 °C with 3 equiv of
t-BuOK, 0.2 equiv of p-MeO-PhOH and 0.2 equiv of 4.
12. Typical experimental procedure: A mixture of 3 (0.78 g,
4 mmol), 4-methoxyphenol (0.10 g, 0.8 mmol), t-BuOK
(1.35 g, 12 mmol), bromoarene (12 mmol) and 4 (0.10 g,
0.8 mmol) was degassed for 2 min at rt under vacuum and
stirred for 2 h at 110 °C under argon. After cooling
at room temperature, the mixture was quenched with
NH4Cl and extracted three times with EtOAc. The
combined organic layer was washed with brine, dried over
MgSO4, concentrated to dryness and purified by flash
chromatography.
In summary, the first a-arylation of benzofuranone
has been developed to prepare building blocks for the
synthesis of rocaglamide analogues. We have shown
that p-methoxyphenol increases dramatically the effi-
ciency of this reaction to afford a mixture of C- and
O-arylated regioisomers.