A multi-component coupling approach to benzo[b]furans and indoles

Article abstract of DOI:10.1039/b104624c

A single step access to multiply substituted benzo[b]furans and indoles has been developed.

Full text of DOI:10.1039/b104624c

A multi-component coupling approach to benzo[b]furans and indoles†
Jason H. Chaplin and Bernard L. Flynn*
Department of Chemistry, The Faculties, Australian National University, Canberra ACT, 0200,
Australia. E-mail: flynn@rsc.anu.edu.au
Received (in Cambridge, UK) 25th May 2001, Accepted 28th June 2001
First published as an Advance Article on the web 6th August 2001
A single step access to multiply substituted benzo[b]furans
This access to indoles 6 and 7 was generally quite efficient.
and indoles has been developed.
However, extending this approach to the synthesis of 2,3-di-
substituted benzo[b]furans from o-iodophenols proved prob-
lematic.6 The propensity of intermediate o-alkynylphenols 8 to
undergo cyclisation to simple 2-substituted benzo[b]furans 9,
particularly in the presence of palladium, required that the
phenolic hydroxy be protected during the initial coupling of the
alkyne to the o-iodophenol [eqn. (1)].6 Cyclisation of 8 to 9 was
Indoles, benzo[b]furans and benzo[b]thiophenes are structural
cores to a host of bioactive compounds in pharmaceutical use or
development. Recently, we described a novel, concise approach
to benzo[b]thiophenes.1 This synthesis was used to prepare the
tubulin polymerisation inhibitor (TPI) 1.1,2 TPIs are valued for
(1)
also a problem during deprotection and attempted hetero-
annulative coupling. As a result the overall yield of 2,3-di-
substituted benzo[b]furan obtained from this multi-step se-
quence was generally very low. The process was also quite
specific to the use of alkenyl triflates as substrates in the
heteroannulative coupling reaction and for electron with-
drawing groups in the o-alkynylphenol.6
We sought to improve this access to benzo[b]furans by
removing any possibility of cyclisation of the o-alkynylphenols
8 to 2-substituted benzo[b]furans 9 and by reducing the number
of steps required. This led to our development of a one-pot,
multi-component coupling procedure (Scheme 2). This involves
initial deprotonation of a mixture of o-iodophenol 10 and
terminal alkyne 4 with MeMgCl to give the corresponding
magnesium phenolate and magnesium acetylide respectively
(not shown). Addition of Pd(PPh3)2Cl2 (3 mol%) and heating
leads to a coupling to give o-alkynylphenoxy magnesium
chloride 12 (X = O). Dilution with an equal volume of DMSO
and addition of a suitable coupling partner R3Y (13) then gives
the heteroannulatively coupled product 14 (X = O) or 15 (X =
O) (under carbonylative conditions).
their capacity to inhibit the proliferation of cancer cells and to
target tumour vascular endothelial cells.2c Medarde et al.
recently described some cytotoxic 2,3-diarylindole systems,
e.g. 2, that were also believed to be TPIs.3 In our ongoing
examination of the structure–activity relationship (SAR) of
TPIs such as 1 and 2,1,4 we required a concise, flexible access to
2,3-diaryl (and aroyl) benzo[b]furans and indoles to comple-
ment our access to benzo[b]thiophenes. Here we describe a
palladium mediated, one-pot, multi-component coupling proc-
ess that gives direct access to 2,3-disubstituted benzo[b]furans
and indoles.
Cacchi and co-workers previously reported a two step
synthesis of 2,3-disubstituted indoles from o-iodotrifluoro-
acetanilides 3 (Scheme 1).5 This involves initial Sonogashira
coupling of 3 to a terminal alkyne 4 to give an o-alkynyltri-
fluoroacetanilide 5, which undergoes heteroannulative coupling
to aryl iodides and alkenyl triflates to give indoles 6 (R3 = aryl
or alkenyl respectively). The trifluoroacyl group is lost during
the coupling process. When performed under an atmosphere of
CO gas, heteroannulation proceeds in a carbonylative fashion to
provide the corresponding 3-acylindoles 7.
Alkenyl bromides, alkenyl iodides, and aryl iodides all
proved to be effective coupling partners in heteroannulation
(Table 1, entries 1–5).† The low yield of the product involving
Scheme 1
† Electronic supplementary information (ESI) available: experimental
procedures and spectroscopic data for 14a–h, 15a and 16. See http://
www.rsc.org/suppdata/cc/b1/b104624c/
Scheme 2
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Chem. Commun., 2001, 1594–1595
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104624c

Table 1 Multi-component coupling reaction for the formation of benzo[b]furans and indoles (see also Scheme 1)a
Components Components
Entry 10 Entry 10/11
4
13
Product (yield (%))
4
13
Product (yield (%))
1
2
6
10a
10a
7b
4a
3
4
10b
8c
10b
10c
4c
13c +
CO(g)
4b
4b
13c
13c
9c
4b
13b +
CO(g)
5
10
4c
13c
a All reactions were performed as follows (unless otherwise stated): (i) 10 (or 11), 4, 2 3 MeMgCl in THF, 0 °C; (ii) Pd(PPh3)2Cl2 3 mol%, 65 °C, 1–2 h;
(iii) cool to 18 °C, add 13, dilute with an equal volume of DMSO and heat to 80–95 °C, 4–19 h. b CH3CN was used as a solvent in place of DMSO and a
further 1.3 equiv. of 12e was added after 2 h. c CO (g) 1 atm was introduced upon addition of 13 and DMSO and the reaction heated to 80–95 °C for
20 h.
the styrenyl iodide 13b is expected to have resulted from the
instability of this iodide under the reaction conditions, that is, in
the presence of palladium at elevated temperatures. Good yields
were also obtained when allyl acetate 13d and propargyl
tosylate 13e (gives an allenic product) were used as coupling
partners (entries 6 and 7).
one-pot access to indoles as is exemplified by our efficient
preparation of 14h (entry 10).
The authors thank the Australian Research Council for
financial support including an ARC Australian Research
Fellowship to B. L. F.
When the coupling reaction that gave rise to 14c was
repeated, using a carbon monoxide atmosphere at the point of
introduction of 13c, the heteroannulative coupling proceeded in
a carbonylative fashion to give 15a in good yield (entry 8).
There were no signs of formation of significant quantities of
ester (esterification of the o-alkynylphenol) or the simple
2-substituted benzo[b]furan 9, which dominated under the
reaction conditions employed by Cacchi and co-workers.6
Heteroannulative coupling involving the styrenyl iodide 13b
under such carbonylative conditions gave rise to the 3-alkylide-
nebenzo[b]furan-2-one 16 as the major product (entry 9).
Benzo[b]furanone 16 has clearly resulted from an alternative
coupling pathway. Arcadi et al. recently described a similar
reaction involving vinyl triflates with o-ethynylphenols and
proposed a mechanism of formation of the benzo[b]fur-
anones.7
Notes and references
1 B. L. Flynn, P. Verdier-Pinard and E. Hamel, Org. Lett., 2001, 3, 651.
2 (a) K. G. Pinney, A. D. Bounds, K. M. Dingeman, V. P. Mocharla, G. R.
Pettit, R. Bai and E. Hamel, Bioorg. Med. Chem. Lett., 1999, 9, 108;
(b) K. G. Pinney, G. R. Pettit, V. P. Mocharla, P. M. M. Del and A.
Shirali, PCT Int. Appl. WO 9839323, 1998; Chem. Abstr., 1998, 129,
245 037; (c) Z. Chen, V. P. Mocharla, J. M. Farmer, G. R. Pettit, E. Hamel
and K. G. Pinney, J. Org. Chem., 2000, 65, 8811 and refs. therein.
3 M. Medarde, A. C. Ramos, E. Caballero, R. Pelaez-Lamamie de Clairac,
J. L. Lopez, D. G. Gravalos and A. San Feliciano, Bioorg. Med. Chem.
Lett., 1999, 9, 2303.
4 B. L. Flynn, G. P. Flynn, E. Hamel and M. K. Jung, Bioorg. Med. Chem.
Lett., in the press.
5 (a) A. Arcadi, S. Cacchi and F. Marinelli, Tetrahedron Lett., 1992, 33,
3915; (b) A. Arcadi, S. Cacchi, V. Carnicelli and F. Marinelli,
Tetrahedron, 1994, 50, 437.
6 A. Arcadi, S. Cacchi, M. Del Rosario, G. Fabrizi and F. Marinelli, J. Org.
Chem., 1996, 61, 9280.
7 A. Arcadi, S. Cacchi, G. Fabrizi and L. Moro, Eur. J. Org. Chem., 1999,
1137.
Although the two step process developed by Cacchi for the
synthesis of indoles was quite efficient we were gratified to find
that our approach to benzo[b]furans could also be extended to a
Chem. Commun., 2001, 1594–1595
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