Palladium-catalyzed cascade allylation/carbopalladation/cross coupling: A novel three-component reaction for the synthesis of 3,3-disubstituted-2,3- dihydrobenzofurans

Article abstract of DOI:10.1016/j.tetlet.2003.09.169

A novel one-pot palladium-catalyzed cascade between 2-iodophenol, methyl bromomethylacrylate and an arylboronic acid provides an efficient access to heterocycles possessing the 3,3-disubstituted-2,3-dihydrobenzofuran skeleton via allylation/carbopalladati

Full text of DOI:10.1016/j.tetlet.2003.09.169

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8657–8659
Palladium-catalyzed cascade allylation/carbopalladation/cross
coupling: a novel three-component reaction for the synthesis of
3,3-disubstituted-2,3-dihydrobenzofurans
Magali Szlosek-Pinaud,a Philippe Diaz,b Jean Martineza and Fre´de´ric Lamatya,*
aLaboratoire des Aminoacides, Peptides et Prote´ines (LAPP), UMR 5810-CNRS-Universite´s Montpellier 1 et 2,
Place Euge`ne Bataillon, 34095 Montpellier Cedex 5, France
bGalderma R&D, 635, route des Lucioles, BP 87, 06902 Sophia Antipolis Cedex, France
Received 10 July 2003; revised 12 September 2003; accepted 19 September 2003
Abstract—A novel one-pot palladium-catalyzed cascade between 2-iodophenol, methyl bromomethylacrylate and an arylboronic
acid provides an efficient access to heterocycles possessing the 3,3-disubstituted-2,3-dihydrobenzofuran skeleton via allylation/car-
bopalladation/Suzuki cross-coupling.
© 2003 Elsevier Ltd. All rights reserved.
The search for new methods for the construction of
organic molecules from simple starting materials is an
ongoing challenge for the organic chemist. Domino
reactions are an attractive area since in one operation
many bonds can be successively created.1 Exploited in
their intermolecular version, these multi-component
reactions (MCR) are powerful methods for the efficient
synthesis of new compounds.2
When 2-iodophenol 1, methyl bromomethylacrylate 2
and phenylboronic acid 3 were reacted together in the
presence of Pd(OAc)2, K2CO3 and n-Bu4NCl in DMF
at 80°C, 3,3-disubstituted 2,3-dihydro benzofuran 4 was
obtained as the sole product in good yield (74% NMR
yield, 45% isolated).5
This reaction proceeded via allylic alkylation of 2-
iodophenol 1 followed by exo-trig cyclization via car-
bopalladation of the acrylate and then Suzuki
cross-coupling of the resulting alkylpalladium. Condi-
tions had to be adapted in order to design one catalytic
system which could catalyze the different processes.
Indeed most catalytic systems include the presence of
phosphines to perform a cyclization/Suzuki-coupling.6
In our case the reaction rate was dramatically reduced
when triphenylphosphine was used as a ligand.7 Fur-
thermore an aqueous medium, which is considered as a
standard condition for the Suzuki cross-coupling of
arylboronic acids,6 had to be avoided due to the poten-
tial hydrolysis of the methyl ester. We were finally
pleased to find out that a phosphine-free system but in
Palladium-catalyzed processes have come to the fore-
ground of transition metal-promoted multi-component
reactions because of the wide variety of processes which
can be mediated by this metal.3 Recently we have
published a new Pd-catalyzed multi-component reac-
tion involving a Pd-catalyzed allylation of methyl bro-
momethylacrylate 2 followed by a Heck reaction on the
substituted acrylate, demonstrating that 2 could partici-
pate in a one-pot substitution/carbopalladation reac-
tion.4 We now report a new three-component reaction
involving 2 and providing new molecules with a dihy-
drobenzofuran skeleton. The reaction is described in
Eq. (1).
(1)
Keywords: palladium; catalysis; cyclization; multicomponent reactions; oxygen heterocycles.
* Corresponding author. Tel.: +33-(0)4-6714-3847; fax: +33-(0)4-6714-4866; e-mail: frederic@univ-montp2.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.169

8658
M. Szlosek-Pinaud et al. / Tetrahedron Letters 44 (2003) 8657–8659
the presence of a tetraalkylammonium salt was efficient
in this reaction. This system has been previously
reported for the Heck reaction8 and for the Suzuki
coupling.9 It has been shown that the combination of
Pd(OAc)2 with n-Bu4NCl in the presence of a base
generated colloidal palladium nanoparticles which are
involved in the catalytic cycle.9 In the case described
herein the Pd particles also catalyzed the allylation of
phenol 1. While the alkylation does occur in the
absence of palladium, the reaction is much faster in the
presence of the catalyst.
phenylboronate (from reaction of phenylboronic acid 3
with the base and/or anions present in the reaction
medium) followed by reductive elimination generates
the final product 4 and recycles Pd(0).
To our knowledge, only a few examples of Pd-catalyzed
allylations combined with another Pd-catalyzed process
making use of a unique catalytic system are known in
the literature.4,13 The process has been categorized as
Pd-catalyzed pseudo-domino reaction (Pd-PDOM).13d
Recently allenes14 have been involved in a Pd-catalyzed
MCR complementary to the one described here: these
reactions require either sequential addition of the reac-
tant and/or do not give access to the structures
described herein.
Tsuji–Trost allylation10 and cyclisation–anion capture11
are well documented as separate processes. To the best
of our knowledge, we present herein the first example
of a palladium-catalyzed allylation/carbopalladation/
Suzuki-cross coupling MCR reaction. The palladium
participates in two different catalytic cycles (Scheme 1).
Initial reduction of Pd(OAc)2 with n-Bu4NCl in the
presence of K2CO3 generates the active Pd(0) species
denoted as Pd(0)Ln in Scheme 1. It is likely that the
reaction proceeds firstly via palladium activation of the
allylic bromide 2 followed by alkylation of the phenox-
ide,12 providing 5 and regenerating Pd(0) (catalytic
cycle A). The palladium complex is also expected to
participate in catalytic cycle B: oxidative addition of 5
to Pd(0) followed by cyclic carbopalladation of the
olefin provides alkylpalladium 6. Transmetallation with
Table 1 reports the yields of 3,3-disubstituted 2,3-dihy-
drobenzofurans obtained from five different aryl-
boronic acids ArB(OH)2. Electron donating and
withdrawing substituents can be present on the aro-
matic ring. However, substitution at the ortho position
led to lower yields.
In summary, we have described a novel three-compo-
nent reaction which gave access to new dihydrobenzo-
furan structures. Further development of this reaction
and related processes are underway in our laboratory.
Scheme 1.
Table 1. Palladium-catalyzed synthesis of dihydrobenzofurans
Ar-
Ph-
45
4-MeO-C6H4-
50
3-NO2-C6H4-
40
2-Me-C6H4-
28
4-Ph-C6H4-
57
Isolated yield (%)

M. Szlosek-Pinaud et al. / Tetrahedron Letters 44 (2003) 8657–8659
8659
Acknowledgements
127.51, 128.84, 129.99, 130.01, 136.59, 159.94, 173.28;
HRMS calculated for C17H16O3 (M+) 268.1099, observed
268.1081.
We thank Galderma S.A. (Sophia-Antipolis) and the
CNRS for financial support.
6. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
2483; (b) Suzuki, A. In Metal-Catalyzed Cross-coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp. 49–97; (c) Suzuki, A. In Handbook
of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley: New York, 2002; pp. 249–262.
7. (a) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59,
5034–5037; (b) Moreno-Man˜as, M.; Pajuelo, F.; Pleixats,
R. J. Org. Chem. 1995, 60, 2396–2397.
8. Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
9. Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed.
2000, 39, 165–168.
10. (a) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl.
1995, 34, 2589–2612; (b) Tsuji, J. Palladium Reagents and
Catalysts; John Wiley & Sons: Chichester, 1996; (c)
Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395–422.
References
1. Tietze, L. Chem. Rev. 1996, 96, 115–136.
2. Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210 and references cited therein.
3. (a) Negishi, E. Pure Appl. Chem. 1992, 64, 323–334; (b)
Heumann, A.; Re´glier, M. Tetrahedron 1996, 52, 9289–
9346; (c) Grigg, R.; Sridharan, V. J. Organomet. Chem.
1999, 576, 65–87; (d) de Meijere, A.; Bra¨se, S. J.
Organomet. Chem. 1999, 576, 88–110; (e) Bra¨se, S.; de
Meijere, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley: New
York, 2002; pp. 1369–1397.
4. Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J.
Tetrahedron 2001, 57, 9711–9718.
11. (a) Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridha-
ran, V.; Thangavelanthum, R.; Thornton-Pett, M.;
Wilson, D. Tetrahedron 1997, 53, 11803–11826; (b)
Brown, S.; Clarkson, S.; Grigg, R.; Thomas, W. A.;
Sridharan, V.; Wilson, D. M. Tetrahedron 2001, 57,
1347–1359.
5. To a solution of methyl-2-bromomethacrylate (48.9 mg,
0.274 mmol) in DMF (3 mL) were added K2CO3 (110.15
mg, 0.955 mmol), 2-iodophenol (50.2 mg, 0.228 mmol),
n-Bu4NCl (76 mg, 0.274 mmol), a solution of Pd(OAc)2
(5.12 mg, 0.0273 mmol) in DMF (1 mL) and PhB(OH)2
(30.54 mg, 0.25 mmol). The resulting mixture was stirred
for 15 h at 80°C, cooled to room temperature, filtered
over Celite and concentrated. Column chromatography
(silica gel, hexane/CH2Cl2: 1/1) afforded 27.5 mg (45%)
of the title compound. IR (neat) 3030 (w), 2953 (m), 2923
12. Roy, O.; Riahi, A.; He´nin, F.; Muzart, J. Tetrahedron
2000, 56, 8133–8140.
13. (a) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron
2000, 56, 5959–5989; (b) Poli, G.; Giambastiani, G.;
Pacini, B. Tetrahedron Lett. 2001, 42, 5179–5182; (c)
Gaudin, J.-M. Tetrahedron Lett. 1991, 32, 6113–6116; (d)
Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456–
9459.
14. (a) Huang, T.-H.; Chang, H.-M.; Wu, M.-Y.; Cheng,
C.-H. J. Org. Chem. 2002, 67, 99–105; (b) Grigg, R.;
Mariani, E.; Sridharan, V. Tetrahedron Lett. 2001, 42,
8677–8680.
(m), 1733 (s), 1480 (s), 1226 (s), 1022 (m), 701 (m) cm−1
;
1H NMR (Me4Si, CDCl3, 250 MHz) l 3.12 (d, 1H,
J=13.7 Hz), 3.50 (d, 1H, J=13.7 Hz), 3.76 (s, 3H, OMe),
4.53 (d, 1H, J=9.5 Hz), 4.91 (d, 1H, J=9.5 Hz), 6.81 (d,
1H, J=8 Hz.), 6.94 (td, 1H, J=7.5 Hz, J=0.9 Hz, H.),
7.03–7.07 (m, 2H.), 7.19–7.30 (m, 4H), 7.41 (dd, 1H,
J=7.5 Hz, J=1.2 Hz.); 13C NMR (Me4Si, CDCl3, 100
MHz) l 44.46, 52.93, 58.10, 77.01, 110.48, 121.09, 125.52,