New synthesis of benzo[b]furan and indole derivatives from 1,1-dibromo-1-alkenes using a tandem Pd-assisted cyclization-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2003.11.118

We report a new flexible method for the synthesis of 2-functionalized benzo[b]furans and indoles from readily available o-(2,2-dibromovinyl)-phenol, -aniline or -acetanilide using a tandem Pd-assisted cyclization-coupling reaction.

Full text of DOI:10.1016/j.tetlet.2003.11.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 907–910
New synthesis of benzo[b]furan and indole derivatives from
1,1-dibromo-1-alkenes using a tandem Pd-assisted
cyclization–coupling reaction
Sabine Thielges, Emilie Meddah, Philippe Bisseret* and Jacques Eustache
Laboratoire de Chimie Organique et Bioorganique associꢀe au CNRS, Universitꢀe de Haute-Alsace, Ecole Nationale Supꢀerieure
de Chimie de Mulhouse 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France
Received 21 October 2003; revised 17 November 2003; accepted 25 November 2003
Abstract—We report a new flexible method for the synthesis of 2-functionalized benzo[b]furans and indoles from readily available
o-(2,2-dibromovinyl)-phenol, -aniline or -acetanilide using a tandem Pd-assisted cyclization–coupling reaction.
Ó 2003 Elsevier Ltd. All rights reserved.
1,1-Dibromo-1-alkenes are versatile synthons in organo-
palladium chemistry. For example, using the soft ligand
tris(2-furyl)phosphine (TFP) in toluene or 1,4-dioxane,
they can be coupled with boronic acids (Suzuki reaction)
or organostannanes (Stille reaction) to afford (Z)-1-aryl-
1-bromo-alkenes with high stereoselectivity.1;2 In
dipolar solvents like DMF, they behave as equivalents
of 1-bromo-1-alkynes.2–4 1,1-Dibromo-1-alkenes have
also been used in a new high yield synthesis of iso-
coumarins involving a tandem Stille coupling/ring for-
mation that compared well with earlier preparations
starting from 2-alkenyl or 2-alkynyl benzoic acids.5 In
this report, we describe a similar but (to the best of our
knowledge) unprecedented synthesis of 2-substi-
tuted benzo[b]furans and indoles starting from suitable
1,1-dibromo-1-alkenes and involving a tandem Pd-
assisted coupling–annulation process.6
conditions run without zinc.8 A similar treatment was
successfully applied to the readily available benzalde-
hydes 3 and 6 leading to the new protected derivatives 4
and 79 as well as amine 5, which had been previously
prepared but in lower yield.8
In the course of a project dealing with the design of new
inhibitors of mycobacterial enzymes, we became inter-
ested in phosphonate preparation.10 The origin of the
present work is an attempt to prepare the new aromatic
alkynylphosphonates 8 and 9 by coupling the dibromi-
nated precursors 1 and 2 with diethylphosphite accord-
ing to the method recently described by Lera and
Hayes:11 Pd(OAc)2 as a catalyst, 1,10-bis(diphenyl-
phosphino)ferrocene (dppf) or TFP as
a ligand,
propylene oxide (PO) as a HBr scavenger and DMF as a
solvent. In this reaction, 1,1-dibromo-1-alkenes were
efficiently converted into alkynylphosphonates thus
acting as 1-bromoalkyne equivalents.3;4;11 Using Lera
and HayesÕs conditions, we found that, in addition to
the expected alkynes 8 and 9, significant amounts of
2-(diethylphosphonyl)-benzo[b]furan 10 was also
formed. From a preparative standpoint, this finding was
quite interesting and we decided to investigate further
this reaction, with the aim of maximizing benzofuran
formation. We first examined the effect of solvent and
base modification. Toluene was substituted for DMF
and propylene oxide was replaced by triethylamine as a
base (Table 1).
For our studies, 2-(2,2-dibromovinyl)-substituted phe-
nol 1 and aniline 5 as well as their respective MOM and
N-protected derivatives 2, 4 and 7 were prepared
(Scheme 1). Compound 1 was obtained in one step from
salicylaldehyde using the Corey–Fuchs procedure.7
Running the reaction in the presence of zinc powder, a
bromine scavenger, as originally reported,7 enabled us
to obtain a better yield than when using TopolskiÕs
Keywords: Benzofuran; Indole; Palladium chemistry; Tandem reaction;
Dibromo-alkenes.
Although the formation of alkynes could not be
avoided,12 the phosphonylated benzofuran 10 was
* Corresponding author. Tel.: +33-389336859; fax: +33-389336860;
e-mail: p.bisseret@uha.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.118

908
S. Thielges et al. / Tetrahedron Letters 45 (2004) 907–910
OH
O
O
O
O
a
b
Br
O
O
Br
H
H
b
2
OH
Br
Br
1
NH2
OH
NHBOC
NHBOC
NH2
e
c, d
b
Br
Br
Br
H
O
Br
4
5
3
f, d
g
NHAc
H
NHAc
b
Br
Br
O
6
7
Scheme 1. Reagents and conditions: (a) NaH, DMF then MOMCl, 12 h, rt, 40%; (b) CBr4, PPh3, Zn, CH2Cl2, 12 h, rt, 52% for 1, 70% for 2, 66% for
4, 35% for 7; (c) BOC2O, ClCH2CH2Cl, 2 h, reflux; (d) DMSO, Ac2O, 0 °C, 12 h, rt, 95% (two steps); (e) TFA, H2O, 1 h, rt, 84%; (f) AcCl, Et3N,
CH2Cl2, 12 h, rt, 94%.
Table 1. Palladium-assisted formation of alkynyl- and benzofuranyl(diethyl)phosphonates
OR
OR
O
P
O
H P
Pd(OAc)2, L
O
OEt
OEt
OEt
OEt
+
+
Br
Br
Base, solvent
OEt
OEt
P
O
10
8, R = H; 9, R = MOM
1, R = H; 2, R = MOM
Entry
Starting material
Base
Solvent, T
Ligand (L)
8 or 9/10a
Yield (%)b
1
2
3
4
5
6
1
1
2
2
2
2
Et3N
Et3N
None
PO
Toluene, 100 °C
DMF, 80 °C
DMF, 80 °C
DMF, 80 °C
Toluene, 100 °C
Toluene, 100 °C
dppf
dppf
dppf
dppf
dppf
TFP
1/1
1/1
91
60
Degradation
No reaction
2/1
1/1
65
75
PO
PO
a Ratio determined after TLC purification of individual compounds.
b Isolated yield.
obtained in satisfactory yield starting from phenol 1,
when the reaction was run in toluene in the presence of
triethylamine as base and dppf as the ligand. The TFP
ligand, which had been recommended for the Pd-
assisted coupling reaction of 1,1-dibromo-1-alkenes,1–3
was ineffective in our case. Remarkably, the formation
of 10 was also observed when using the protected
MOM-derivative 2 as coupling partner. The presence in
the medium of an excess of propylene oxide renders
MOM removal by HBr unlikely (formed in the Pd cat-
alytic cycle).13 The cleavage may result from the known
Lewis acidity of the Pd(II) species also formed in the
catalytic cycle.14
the reaction further and studied the coupling of phenol
derivative 1 with trimethyl(phenyl)tin (Stille coupling)
or p-methoxyphenylboronic acid as well as phenyl-
boronic anhydride (the Suzuki reaction) (Table 2). For
this purpose, the coupling experiments were conducted
with an increasing excess of the tin or boron reagents
relative to phenol 1. The results are reported in Table 2.
When the coupling partner was omitted (entry 1), the
starting material was efficiently converted to dibenzo-
furan 13. This compound subsequently proved to be the
only significant by-product in all Stille and Suzuki
coupling experiments and, remarkably, alkynyl deriva-
tives were never detected. Regarding benzofuran for-
mation, increasing the amount of coupling partner
generally leads to higher yields. The best conditions
Having selected the best conditions for the formation of
the benzo[b]furan 10, we decided to explore the scope of

S. Thielges et al. / Tetrahedron Letters 45 (2004) 907–910
Table 2. Tandem palladium-assisted coupling–annulation of phenol 1
909
OH
Pd(OAc)2, dppf
O
O
Et3N, toluene, 100 o
C
O
Br
Br
+
A
R
+
1
1
11, R = H; 12, R = OMe
3
Entry
A
11 or 12/13a
Yield (%)b
1
2
3
4
5
6
7
No reactant
PhSnMe3/1.2 equiv
0/1
1/1
4/1
3/2
1/0
1/1
1/0
82
70
75
91
80
78
82
PhSnMe3/3 equiv
(PhBO)3/1.2 equiv
(PhBO)3/3 equiv
p-MeOC6H4B(OH)2/1.2 equiv
p-MeOC6H4B(OH)2/3 equiv
a Ratio determined after TLC purification of individual compounds.
b Isolated yield.
H
N
NH2
O
H P
O
P
a
OEt
OEt
OEt
OEt
+
Br
Br
14
5
Ac
N
H
N
NHAc
Br
b
OH
OH
c
+
MeO
B
OMe
OMe
Br
16
6
15
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, dppf (3 equiv), Et3N, toluene, 100 °C, 12 h, 63%; (b) Pd2(dba)3, dppf (3 equiv), Et3N, toluene,
100 °C, 12 h, 52%; (c) 1 M NaOH, EtOH/H2O (4/1, v/v), 70 °C, 10 min, 100%.
involved the use of excess boronic acid or boronic
anhydride, resulting ultimately in the total suppression
of the formation of 13 and giving very good yields of the
known 2-(p-methoxyphenyl)-benzo[b]furan 1215 as well
as 2-phenylbenzo[b]furan 1116 (entries 5 and 7). A
positive but less impressive influence of reagent excess
was also observed in the Stille coupling experiments
(compare entries 2 and 3).
mixture of aromatic derivatives. In all other experi-
ments, 16 could not be isolated. This failure can be
attributed in part to the instability of this compound to
air, which rendered work-up and TLC purifications very
difficult.18 The answer to this problem was provided by
using acetanilide 6 instead of the free aniline 5 or the
BOC derivative 4. Using the typical reaction conditions
and preferably in the presence of tris(dibenzylidene-
acetone)dipalladium [Pd2(dba)3] instead of palladium
acetate19 we obtained a satisfactory yield of the new
product 15, a yellow solid that could be quantitatively
converted into 16 under basic conditions (Scheme 2).
We next turned our attention to the formation of indoles
starting from the dibrominated precursors 4 and 5.
Using the conditions selected for the formation of
phosphonylbenzofuran 10 from 2 (see Table 1, entry 5),
the BOC-derivative 4 yielded only complex mixtures. In
contrast, starting from the free aniline 5, the known
stable phosphonylated-2-indolyl derivative 1417 was
easily obtained using the conditions determined previ-
ously for coupling of the free dibromovinylphenol 1
(Table 1, entry 1). Remarkably, in this case no alkynyl
derivative was formed.
A possible simplified mechanism, which accounts for the
formation of the heteroaryl derivatives is shown in
Scheme 3. It is based on the known higher reactivity of
the trans C–Br bond relative to the cis C–Br bond
towards oxidative Pd(0) insertion1;2 and on the mecha-
nism advocated by Shen and co-workers for the related
formation of isocoumarin derivatives.5 Concurrent
simultaneous mechanisms implying the intervention of
alkynyl palladium species2 must be operative accounting
for the formation of alkynyl derivatives.
Suzuki or Stille coupling experiments run under the
conditions previously selected for the preparation of
2-arylbenzofurans were very disappointing. When
p-methoxyphenylboronic acid was used as a Suzuki
coupling partner, the expected compound 16 was
obtained in very low yield (<15%) along with a complex
In conclusion, we have developed a new, flexible, one-
pot procedure involving a tandem cyclization–coupling
process for the preparation of 2-functionalized indoles

910
S. Thielges et al. / Tetrahedron Letters 45 (2004) 907–910
3. Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857–2860.
XH
ꢀ
4. Zapata, J. A.; Ruız, J. Organomet. Chem. 1994, C6–C8.
Br
Ar
Suzuki or Stille
coupling
5. Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625–
7628.
+
Pd(0)L2
6. An alkynylbenzofuran derivative was observed as a by-
product on one occasion during a novel synthesis of
symmetrical diynes starting from dibromoalkenes (see Ref.
3). No comment on its formation was made.
XH
Br
Br
XH
PdL2Br
Ar
+
7. Corey, E.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
8. Topolski, M. J. Org. Chem. 1995, 60, 5588–5594.
9. All new compounds presented satisfactory analytical data.
10. (a) Bisseret, P.; Boiteau, J.-G.; Eustache, J. Tetrahedron
Lett. 2003, 44, 2351–2354; (b) Bosco, M.; Bisseret, P.;
Eustache, J. Tetrahedron Lett. 2003, 44, 2347–2349.
11. Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873–3875.
12. Attempts to enhance the production of benzofuran by
prolonging the reaction after further addition of Pd
catalyst was unsuccessful.
Pd(0)L2
HBr
X
PdL2
Ar
X
Ar
Scheme 3.
and benzo[b]furans starting from readily accessible 1,1-
dibromo-1-alkenylphenol or aniline derivatives. This
method competes well with the most efficient palladium-
based,15;20 or copper-based21 one-pot procedures
currently available for the preparation of similar hete-
roaryls, which involves alkynes instead of dibromoalk-
enes. Application of this method to the preparation of
structurally more complex indoles or benzofurans of
biological interest is in progress.
13. On the use of propylene oxide as an HBr scavenger see
Ref. 11 and: Abbas, S.; Hayes, C. J. Tetrahedron Lett.
2000, 41, 4513–4517.
14. For an example of a related Lewis acid catalysis see:
Bossharth, E.; Dessbordes, P.; Monteiro, N.; Balme, G.
Org. Lett. 2003, 5, 2441–2444.
15. Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron
2001, 57, 8017–8028.
16. Katritzky, A. R.; Zhang, Z.; Lan, X.; Lang, H. J. Org.
Chem. 1994, 59, 1901–1903.
17. Haelters, J. P.; Corbel, B.; Sturtz, G. Phosphorus Sulfur
1988, 37, 41–63.
Acknowledgements
18. Analytical data for the indole derivative 16 are in
agreement with the literature: Hughes, I. Tetrahedron
Lett. 1996, 37, 7595–7598, Although colourless once
isolated, we noticed that 16 degraded rapidly in air,
becoming pink.
19. With Pd(OAc)2 a more complex mixture was obtained
resulting in a difficult purification of 15 in a slightly lower
yield.
ꢁ
We thank the French Ministere de la Jeunesse, de
lÕEducation Nationale et de la Recherche and the CNRS
for financial support and for a fellowship to S.T. The
project is also supported through the ACI ÔMolecules et
ꢀ
ꢀ
Cibles TherapeutiquesÕ.
20. (a) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C.
J. Org. Chem. 1995, 60, 3270–3271; (b) Arcadi, A.; Cacchi,
S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280–9288; (c) Kamijo, S.; Yamamoto, Y. J. Org.
Chem. 2003, 68, 4764–4771, and references cited therein.
21. Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5,
3843–3846, and references cited therein.
References and notes
1. Shen, W. Synlett 2000, 737–739.
2. Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873–8879.