Palladium assisted substitution of 3-benzo[b]furan triflates

Article abstract of DOI:10.1055/s-2002-20478

Triflates of 3-coumaranones were prepared, and experimented as coupling partners in palladium catalyzed Stille, Heck, Suzuki, and Sonogashira coupling reactions. The corresponding 3-substituted benzo[b]furans were obtained in excellent yields.

Full text of DOI:10.1055/s-2002-20478

LETTER
501
Palladium Assisted Substitution of 3-Benzo[b]furan Triflates
P
alladium Assiste
h
d
Substitutio
r
n
of 3-
B
i
enzo[
b
s
]fura
n
T
ri
t
f
lates ophe Morice, Fabrice Garrido, André Mann,* Jean Suffert
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081, Faculté de Pharmacie, 74, route du Rhin, BP 24 F-67401
Illkirch, France
E-mail: Andre.mann@pharma.u-strasbg.fr
Received 26 November 2001
In this Letter we present our results concerning the prepa-
Abstract: Triflates of 3-coumaranones were prepared, and experi-
ration of several 3-substituted benzofurans, based on the
mented as coupling partners in palladium catalyzed Stille, Heck,
conversion of 3-coumaranones into their corresponding
Suzuki, and Sonogashira coupling reactions. The corresponding 3-
triflates, followed by palladium assisted cross-coupling
reactions with various nucleophiles. Only one single re-
port can be found in the literature (a patent) about the
preparation and use of triflates of this type.7 It has to be
mentioned that the corresponding bromides did not react
under Stille or Sonogashira conditions.1a,8
substituted benzo[b]furans were obtained in excellent yields.
Key words: 3-coumaranone, triflate, benzofuran, palladium, catal-
ysis
The benzo[b]furan nucleus is present in large numbers of
natural products1 and becomes a suitable platform for
structure-activity studies in different areas of medicinal
chemistry. Reports are pointing out the bioisosterism of
the indole and benzofuran rings,2 and several groups have
described that properly substituted benzofurans are cross-
ing the blood brain barrier in producing comparable phar-
macological effects as the corresponding indoles on
serotonergic or dopaminergic receptors.3 A number of
routes are existing for the preparation of benzofurans sub-
stituted at the furan moiety on carbons C-2 or C-3.4 In-
tramolecular ring closures assisted by palladium on ortho-
substituted iodo-arylallyl ethers,5a,b or iodine assisted cy-
clization of o-alkynylphenols have been successfully ex-
perimented.5c But the substitution reactions on preformed
benzofurans appeared to us more attractive as the regiose-
lective introduction of substituents on the furan ring has
been recently demonstrated.6 In our current work we were
seeking for a practical route towards the preparation of
various C-3 substituted benzofurans, therefore we decided
to explore for this purpose the reactivity of the C-3 tri-
flates 3a–c, deriving from the corresponding coumara-
nones 2a–c.
In order to conduct efficiently our synthetic efforts, a con-
venient method for the preparation of 3-coumaranones
from readily available starting material was highly desir-
able. We decided to choose Jung’s strategy, relying on the
decomposition of an o-methoxy diazoketon9. In spite the
use of diazomethane, the procedure is suitable even for the
preparation of gram quantities of 2a–c. (Scheme 1).
In our hands this method gave the best results for the ob-
tention of 5-bromo- and 7-methoxy-3-coumaranone (2b,
2c)10 starting from the o-methoxybenzoic acids 1b, 1c.
The yields could be slightly improved in isolating the cor-
responding diazoketones, and running their decomposi-
tion in HOAc in presence of an excess of NaOAc at room
temperature. The preparation of the triflates 3a–c was
achieved under the usual conditions: triflic anhydride/
Hünig base in dichloromethane.11 The yields were excel-
lent and the triflates could be purified by column chroma-
tography.12 Then the palladium assisted Stille, Heck,
Suzuki or Sonogashira reactions were investigated on tri-
flates 3a–c. At first glance, if for 3a and 3c the substitution
at the C-3 was the only expected pathway, it was not se-
cured that for 3b, palladium insertion would occur regio-
selectively at C-3 in respect to C-5, indeed a competitive
insertion could take place at the bromine at C-5. But for
all the subsequent reactions performed on triflate 3b the
desired palladium oxydative insertion occurred chemose-
lectively at C-3, at the location of the triflate (Scheme 2).
Therefore triflates 3a–c are offering considerable poten-
tial for further transformations. For instance the prepara-
tion of 3-carboxylated benzofurans 4a,13 4b and 4c was
rather efficient as well as the direct preparation of the pi-
peridine-amide 5c, popular surrogates for aromatic acids
or amides. The former reported preparations of 3-vinyl
adducts 6a–c were troublesome,14 the now proposed Stille
approach not only produced high yields, but also opened
the way for Diels–Alder reactions. Interestingly the Sono-
gashira reaction with the propargylalcohol or -amine de-
livers the adducts 7a–c, 8a and 9a without initial
protection of the propargylic functions. The Heck adducts
OTf
O
Y
CO2H
OMe
Y
Y
i i
i
O
O
X
X
X
1a, 1b, 1c
2a, 2b, 2c
3a, 3b, 3c
a
(X = Y = H), b (X = H, Y = Br), c (X = OMe, Y = H)
Scheme 1 Reagents and conditions: (i) (COCl)2 then CH2N2; (ii)
NaOAc, HOAc, (71–84%); (iii) Hünig base and Tf2O, CH2Cl2 (87–
95%).
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0501,0503,ftx,en;G23201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

502
C. Morice et al.
LETTER
References
R
R2
(1) For recent examples see: (a) Inoue, M.; Carson, M. W.;
Frontier, A. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2001,
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references cited therein.
(2) Ohemeng, K. A.; Appollina, M. A.; Nguyen, V. N.;
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E. J. Med. Chem. 1992, 35, 2061. (b) Monte, A. P.; Marona-
Lewicka, D.; Parker, M. A.; Wainscott, D. B.; Nelson, D. L.;
Nichols, D. E. J. Med. Chem 1996, 39, 2953. (c) Parker, M.
A.; Marona-Lewicka, D.; Lucaites, V. L.; Nelson, D. L.;
Nichols, D. E. J. Med. Chem. 1998, 41, 5148.
COR1
Y
Y
Y
O
O
O
X
X
X
4a (R1 = OMe)
4b (R1 = OMe)
4c (R1 = OMe)
5c [R1 = N(CH2)5]
6a (R2 = H)
7a (R = SiMe3)
7b (R = CH2OH)
7c (R = CH2OH)
8a ( R = CH2OH)
6b (R2 = H)
6c (R2 = H)
9a ( R = CH2NH2)
(4) (a) For the construction of benzofuran rings see: Dell, C. P.
In Science of Synthesis (Houben-Weyl), Vol. 10; Thomas, E.
J., Ed.; Thieme: Stuttgart, 2001, 11. (b) For the
i i
i
i i i
OTf
Y
transformation of benzofuran rings see: Li, J. J.; Gribble, G.
W. Palladium in Heterocyclic Chemistry; Pergamon:
Oxford, 2000, 267.
O
(5) (a) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29,
4687. (b) Negishi, E.; Nguyen, T.; O’Connor, B.
X
Cl
i v
3a-c
v
Heterocycles 1989, 28, 55. (c) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432.
(6) (a) Bach, T.; Krüger, L. Tetrahedron Lett. 1998, 39, 1729.
(b) Bach, T.; Krüger, L. Eur. J. Org. Chem. 1999, 2045.
(7) Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D. UK Patent
2306471 A1, 1997; Chem. Abstr. 1997, 127, 149072.
(8) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1988, 36, 2248.
(9) Jung, M. E.; Abrecht, S. J. Org. Chem. 1988, 53, 423.
(10) Coumaranone 2a was purchased from Avocado.
(11) For a review on triflates see: Ritter, K. Synthesis 1993, 735.
(12) Preparation of Benzo[b]furan 3-yl Trifluoromethane
Sulfonate(2a)
N,N-diisopropylethylamine (1.1 g, 8.51 mmol, Hünig’s
base) was added dropwise to a stirred solution of 2a (1 g,
7.46 mmol) in dry CH2Cl2 under nitrogen at –10 °C.
Trifluoromethanesulfonic anhydride (2.5 g, 8.86 mmol) was
then added and the mixture was allowed to stand at r.t. for 16
h. The mixture was hydrolyzed with water (5 mL). The
organic layer was washed with water, dried over anhydrous
Na2SO4 and evaporated in vacuo. The residue was purified
by chromatography on silica gel eluenting with hexane–
Et2O: 80/20 to give 2a as a yellow oil (1.60 g, 81%). 1H
NMR (300 MHz, CDCl3, 25 °C): = 7.38 (td, J = 7.2 and 1.3
Hz, 1 H), 7.44 (td, J = 7.2 and 1.3 Hz, 1 H), 7.54 (dd, J = 7.2
and 1.3 Hz, 1 H), 7.65 (dd, J = 7.2 and 1.3 Hz, 1 H), 7.84 (s,
1 H); 13C (50 MHz, CDCl3, 25 °C): = 111.2, 118.1, 118.8
(q, J = 320 Hz), 120.2, 124.1, 126.2, 134.1, 135.3, 153.2.
(13) (a) Compound 4a (mp 52 °C) is reported by: Feinstein, A.;
Gore, P. H.; Reed, G. L. J. Chem. Soc. 1969, 205. (b)
Compound 10a is reported by: Fujiwara, Y.; Maruyama, O.;
Yoshidomi, M.; Taniguchi, H. J. Org. Chem. 1981, 46, 851.
(c) Compound 11a is reported by: Aurozo, A.; Faure, R.;
Mattioda, G.; Bonhomme, P.; Boufelle, C. Eur. J. Med.
Chem. 1975, 10, 82.
CN
Y
Y
O
O
X
X
11a , 11a, 11c
10a, 10b, 10c
Scheme 2 Reagents and conditions: (i) Pd(OAc)2 (5% mol), dppp
(5% mol), NEt3, MeOH, CO (1 atm, balloon), DMF, 80 °C, 2 h for
4a–c, and Pd(OAc)2 (5% mol), dppp (5% mol), NEt3, piperidine, CO
(1 atm, balloon), DMF, 80 °C, 2 h for 5c; (ii) vinyltributylstannane
(1.5 equiv), Pd(PPh3)4 (5% mol), DMF, 160 °C, 2 h; (iii) propargylal-
cohol or -amine (1.5 equiv), Pd(PPh3)2Cl2 (5% mol), CuI (5% mol),
NEt3 (5 equiv), THF, 50 °C, 4 h; (iv) acrylonitrile (2 equiv),
Pd(PPh3)2Cl2 (5% mol), NEt3, DMF, 100 °C, 4 h; (iii) propargylalco-
hol or -amine, Pd(PPh3)2Cl2 (5% mol), CuI (5% mol), NEt3, THF,
50 °C, 4 h; (v) p-Cl-phenylboronic acid (1 equiv), Pd(PPh3)4 (5%
mol), Na2CO3, DME, 90 °C, 3 h.
10a,13 10b and 10c are obtained easily and awaiting fur-
ther transformations. Some 3-phenyl benzofurans were
reported,15 but the easy preparation of 11a,13 11b and 11c
via the triflates suggest that the Suzuki reaction may
present a viable alternative.16
In conclusion, a new route to 3-substituted ben-
zo[b]furans, assisted by palladium is proposed, based on
the reactivity of the triflates derived from 3-coumara-
nones. This result represents an additional example of the
importance of triflates in forming efficiently C-C bounds.
(14) (a) Pearson, J. R.; Porter, N. P. Aust. J. Chem. 1991, 44, 907.
(b) Pearson, J. R.; Porter, N. P. Aust. J. Chem. 1991, 44,
1085.
(15) Haberman, J.; Ley, S. V.; Smits, R. J. Chem. Soc., Perkin
Trams. 1 1999, 2421.
Acknowledgement
(16) Selected Physical Data: 4b(oil);1H NMR (300 MHz,
CDCl3, 25 °C): =3.95 (s, 3 H), 7.38 (d, J = 8.7 Hz, 1 H),
7.45 (dd, J = 8.7 and 2.2 Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H),
8.24 (s, 1 H); 13C NMR (75 MHz, CDCl3, 25 °C): = 51.8,
113.1, 114.1, 117.6, 124.8, 126.4, 151.8, 154.3, 163.1,
We thank Bioprojet (Paris) for funding F. G.
Synlett 2002, No. 3, 501–503 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium Assisted Substitution of 3-Benzo[b]furan Triflates
503
178.6. HMRS: m/z calcd for C10H7BrO3: 253.9578; found:
253.9570.
H), 3.71 (s, 2 H), 7.23–7.46 (m, 2 H), 7.47–7.55 (m, 1 H),
7.60–7.72 (m, 1 H), 7.77 (s, 1 H); 13C NMR (75 MHz,
CDCl3, 25 °C): = 32.0, 71.5, 94.6, 104.0, 111.2, 120.0,
122.9, 124.8, 127.3, 147.1, 154.2.
6b(oil); 1H NMR (300 MHz, CDCl3, 25 °C): = 5.36–5.40
(dd, J = 11.2 and 1.2 Hz, 1 H), 5.66–5.74 (dd, J = 17.5 and
1.2 Hz, 1 H), 6.84–6.90 (dd, J = 17.5 and 11.2 Hz, 1 H),
7.37–7.40 (d, J = 8.7 Hz, 1 H), 7.44–7.47 (dd, J = 8.7 and 2.2
Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 8.24 (s, 1 H). HMRS:
m/z calcd for C10H7BrO: 221.9680; found: 221.9676.
7b(oil); 1H NMR (300 MHz, CDCl3, 25 °C): = 2.14 (brs, 1
H), 4.58 (s, 2 H), 7.35 (d, J = 8.7 Hz, 1 H), 7.43 (dd, J = 8.7
and 1.9 Hz), 7.78 (s, 1 H), 7.80 (d, J = 1.9 Hz, 1 H); 13C NMR
(75 MHz, CDCl3, 25 °C): = 51.6, 74.5, 92.5, 103.5, 113.1,
116.6, 123.1, 128.2, 129.3, 148.8, 153.2. HMRS: m/z calcd
for C11H7BrO2: 249.9629; found: 249.9621.
10c (mp 92 °C); 1H NMR (300 MHz, CDCl3, 25 °C):
=
4.02 (s, 3 H), 5.98 (d, J = 16.5 Hz, 1 H), 6.90–6.93 (dd, J =
6.2 and 2.5 Hz, 1 H), 7.23–7.29 (m, 2 H), 7.42–7.48 (d, J =
16.5 Hz, 1 H), 7.86 (s, 1 H). C12H9NO2 (199.02): calcd C,
72.35; H, 4.55; N, 7.03. Found: C, 72.40; H, 4.61; N, 6.91.
11c(oil); 1H NMR (300 MHz, CDCl3, 25 °C): = 4.08 (s, 3
H), 6.89–6.94 (dd, J = 7.8 and 1.2 Hz, 1 H), 7.24–7.32 (t, J
= 7.8 Hz, 1 H), 7.40–7.44 (dd, J = 7.8 and 1.2 Hz, 1 H), 7.46–
7.50 (d, J = 8.8 Hz, 2 H), 7.58–7.62 (d, J = 8.8 Hz, 2 H), 7.84
(s, 1 H). HMRS: m/z calcd for C15H11ClO: 258.0447; found:
258.0451.
9a(oil); 1H NMR (300 MHz, CDCl3, 25 °C): = 1.62 (brs, 2
Synlett 2002, No. 3, 501–503 ISSN 0936-5214 © Thieme Stuttgart · New York