Modular construction of 2-substituted benzo[b]furans from 1,2-Dichlorovinyl ethers

Article abstract of DOI:10.1021/ol902307m

"Chemical Equation Presented" (E)-1,2-Dichlorovinyl ethers and amides are easily accessible from trichloroethylene via nucleophilic addition across in situ synthesized dlchloroacetylene. A one-pot, sequential Suzukl-Miyaura coupling/intramolecular direct

Full text of DOI:10.1021/ol902307m

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5478-5481
Modular Construction of 2-Substituted
Benzo[b]furans from 1,2-Dichlorovinyl
Ethers
Laina M. Geary and Philip G. Hultin*
Department of Chemistry, UniVersity of Manitoba, Winnipeg,
Manitoba, Canada R3T 2N2
hultin@cc.umanitoba.ca
Received October 7, 2009
ABSTRACT
(E)-1,2-Dichlorovinyl ethers and amides are easily accessible from trichloroethylene via nucleophilic addition across in situ synthesized
dichloroacetylene. A one-pot, sequential Suzuki-Miyaura coupling/intramolecular direct arylation between dichlorovinyl ethers and organoboronic
acids provides easy access to a variety of benzofurans in only two steps from inexpensive commercially available compounds. The method
is extendable to the preparation of indoles from the analogous dichlorovinyl amides.
Benzo[b]furans and indoles are common motifs in natural
products, agrochemicals, and pharmaceuticals. The indole
structure is widely regarded as “privileged” in drug develop-
ment,1 while the benzo[b]furan nucleus shows promise of
attaining this status.2 Methods for the synthesis of benzo[b]-
furans and indoles have been reviewed,3 but substantial
activity continues because a broadly applicable strategy
remains elusive.
to a general strategy, but these methods suffer from either
regioselectivity issues or restrictive functional group require-
ments.
1,1-Dichloroalkenes undergo stepwise Pd-catalyzed reac-
tions with various organometallic reagents.7 Organ8 and
others9 have explored the use of a variety of 1,2-dihalo and
1,1,2-trihaloalkene derivatives including trichloroethylene
(TCE) as synthetic “linchpins” for convergent synthesis. We
thought that 1-aryloxy-1,2-dichloroethylenes (readily ob-
tained by addition of phenols to TCE10) might be regiose-
lectively functionalized by sequential cross-coupling and aryl
Direct routes from simple phenols and anilines could
minimize costs and reduce the number of manipulations prior
to the key assembly of the heterocycle nucleus. Recent work
by Glorius,4 Jung,5 and Zhao,6 among others, points the way
(7) (a) Negishi, E.-i.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.;
Hattori, H. Acc. Chem. Res. 2008, 41, 1474. (b) Tan, Z.; Negishi, E.-i.
Angew. Chem., Int. Ed. 2006, 45, 762. (c) Liron, F.; Fosse, C.; Pernolet,
A.; Roulland, E. J. Org. Chem. 2007, 72, 2220.
(1) de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. Mini ReV. Med.
Chem. 2009, 9, 782.
(2) De Luca, L.; Nieddu, G.; Porcheddu, A.; Giacomelli, G. Curr. Med.
Chem. 2009, 16, 1.
(8) (a) Organ, M. G.; Ghasemi, H.; Valente, C. Tetrahedron 2004, 60,
9453. (b) Ghasemi, H.; Antunes, L. M.; Organ, M. G. Org. Lett. 2004, 6,
2913. (c) Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh, F.;
Paul, T. J. Org. Chem. 2000, 65, 7959.
(3) (a) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2002, 56,
613. (b) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog.
Heterocycl. Chem. 2007, 18, 187. (c) Cacchi, S.; Fabrizi, G.; Goggiamani,
A. Curr. Org. Chem. 2006, 10, 1423. (d) Humphrey, G. R.; Kuethe, J. T.
Chem. ReV. 2006, 106, 2875. (e) Krueger, K.; Tillack, A.; Beller, M. AdV.
Synth. Catal. 2008, 350, 2153. (f) Patil, S. A.; Patil, R.; Miller, D. D. Curr.
Med. Chem. 2009, 16, 2531.
(9) (a) Pellegrini, S.; Castanet, Y.; Mortreux, A. J. Mol. Catal. A: Chem.
2007, 277, 21. (b) Anthony, J.; Boldi, A. M.; Rubin, Y.; Hobi, M.; Gramlich,
V.; Knobler, C. B.; Seiler, P.; Diederich, F. HelV. Chim. Acta 1995, 78, 13.
(c) Schmidt, B.; Ehlert, D. K.; Braun, H. A. Tetrahedron Lett. 2004, 45,
1751.
(4) Wuertz, S.; Rakshit, S.; Neumann, J. J.; Droege, T.; Glorius, F.
Angew. Chem., Int. Ed. 2008, 47, 7230.
(10) (a) Darses, B.; Milet, A.; Philouze, C.; Greene, A. E.; Poisson,
J.-F. Org. Lett. 2008, 10, 4445. (b) Kann, N.; Bernardes, V.; Greene, A. E.
Org. Synth. 1997, 74, 13. (c) Moyano, A.; Charbonnier, F.; Greene, A. E.
J. Org. Chem. 1987, 52, 2919.
(5) Jung, M. E.; Perez, F. Org. Lett. 2009, 11, 2165.
(6) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
10.1021/ol902307m CCC: $xxxx
Published on Web 11/11/2009
 2009 American Chemical Society

Table 1. Regioselective Cross-Coupling Reactions at C-1 in 1,2-Dichlorovinyl Ethers 1-3
a Preparation of 1-3 is described in the Supporting Information. b A: Aryl boronic acid (1.05 equiv), Pd(PPh3)4 (5 mol %), aq KOH, THF (0.4 M), 65
°C, 1-22 h. B: Arylboronic acid (1.05 equiv), Pd2dba3 (2.5 mol %), DPEphos (5 mol %), CsF (3 equiv), Cs2CO3 (3 equiv), THF (0.5 M), 65 °C, 6-24 h.
C: Terminal alkyne (1.1 equiv), Pd(PPh3)4 (5 mol %), CuI (10 mol %), THF, rt, overnight. c Yields of pure compounds after chromatography on silica gel
pretreated with triethylamine. See Supporting Information for details. d Gradually decomposed. e Based on recovered starting material (66% conversion).
TBDPS ) tert-butyldiphenylsilane.
C-H functionalization steps to form benzo[b]furan deriva-
tives (eq 1, X ) O). Similar processes involving dichlorovi-
nylaniline precursors might form indoles (eq 1, X ) NR).11
boronic acid, combating uncertain stoichiometry.13 In the Pd-
DPEphos-catalyzed reactions, the presence of both CsF and
Cs2CO3 afforded more consistent reaction times and higher
conversions compared with processes employing either of
these basic additives alone. Sonogashira alkynylation also
took place at the C-1 position in good yields (Table 1, entries
This would allow modular construction of benzofurans or
indoles from inexpensive phenols or anilines, trichloroeth-
ylene, and an organometallic R2 donor in as few as two steps,
with no need for specific functional groups or other structural
modifications.
Table 2. Cyclization of
(Z)-1-Substituted-1′-aryloxy-2-chloroethylenes
The 1,2-dichlorovinyl ethers 1-3 participated in repre-
sentative Pd-catalyzed cross-coupling reactions specifically
at the C-1 position. We found that Suzuki coupling in THF
at 65 °C catalyzed by either Pd(PPh3)4 or Pd2dba3/DPEphos12
could install aryl and heteroaryl groups (Table 1, entries 1-6)
or styryl (entry 7) quite satisfactorily using only 1.05 equiV
of the boronic acid. Many Suzuki reactions require excess
reactant
4-F-C6H4
4-MeO-6H4
(E)-C6H5-CHdCH-
-CC-C6H5
product
(yield)b
entry
R1
R2
1
2
3
4
5
6
7
4
10
11
5
H
H
H
H
16 (72%)
17 (86%)
18 (32%)
19 (80%)
20 (82%)
21 (74%)c
(11) Lautens has devised a related method for the synthesis of indoles
and benzofurans. See: (a) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008,
73, 538. (b) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203.
(c) Isono, N.; Lautens, M. Org. Lett. 2009, 11, 1329. (d) Nagamochi, M.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955.
4-MeO
3-MeO
4-MeO-C6H4
4-MeO-C6H4-
6
a Pd catalyst: Pd2dba3 (2.5 mol %), DPEphos (5 mol %). Base: 3 equiv
(12) Xantphos was an equally effective ligand in these reactions, but
we chose the less-expensive DPEphos for the bulk of our work.
(13) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 49.
of CsF and Cs2CO3. b Isolated yield. c A single regioisomer detected.
Org. Lett., Vol. 11, No. 23, 2009
5479

Table 3. One-Pot Suzuki Coupling/Direct Arylation Synthesis of 2-Substituted Benzofurans from 1,2-Dichlorovinyl Ethers
a Isolated yields. b Only one isomer could be detected. c Preparation of 24 and 26 is described in the Supporting Information.
8-12).14 In all cases, only one regio- and stereoisomer of
the product could be detected.
65 °C. The unsymmetrical derivatives 3 and 24 could react
by two different cyclization pathways; we were surprised to
find that the 3-methoxy compound 3 afforded only one
regioisomeric benzofuran product (21), while 3-nitro 24
cyclized to give a 6:1 mixture of isomeric benzofurans 25
and 25′.
We have not yet carried out detailed mechanistic studies
on the cyclization. Electrophilic aromatic substitution or
C-H activation are possible mechanisms consistent with our
observed reactivity.15 A concerted metalation-deprotonation
(CMD, also referred to as “proton abstraction”) mechanism
for direct aryl coupling processes has been proposed,16 most
recently by Fagnou17 and by Echavarren.18 The similar
reactivity of the 3- and 4-methoxy and 3-nitro enol ethers 2,
3, and 24 in our cyclizations might be consistent with a CMD
However, when Suzuki arylation of vinyl ether 1 was
allowed to proceed for extended periods of time, a byproduct
was observed in addition to 1-aryl vinyl ether 7. This was
identified as a benzo[b]furan, and when 7 was treated with
palladium, DPEphos, and the cesium bases, benzo[b]furan
16 became the sole product (72%). Benzo[b]furan formation
under these conditions proved successful with a range of
groups attached at C-1 (Table 2). The cyclization reactions
probably proceed via oxidative insertion of Pd into the
remaining vinylic C-Cl bond, followed by arylation and
reductive elimination.
While Suzuki couplings of vinyl ethers 1-3 were suc-
cessful in the presence of either CsF or Cs2CO3, the
cyclizations shown in Table 2 are much more dependent on
the bases. This reaction was moderately efficient with CsF
as the sole base but hardly proceeded at all when attempted
using only Cs2CO3, a notable difference from the Suzuki
couplings. Replacing either CsF by KF or Cs2CO3 by K2CO3
caused the cyclization to fail.
(15) (a) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C.
J. Am. Chem. Soc. 2003, 125, 11506. (b) Hennessy, E. J.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 12084.
(16) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754. (b) Biswas, B.; Sugimoto, M.; Sakaki, S. Organo-
metallics 2000, 19, 3895.
(17) (a) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64,
6015. (b) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
J. Org. Chem. 2008, 73, 5022. (c) Caron, L.; Campeau, L.-C.; Fagnou, K.
Org. Lett. 2008, 10, 4533. (d) Gorelsky, S. I.; Lapointe, D.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 10848.
Suzuki coupling and direct arylation could be combined
in a one-pot procedure (Table 3). The benzofuran products
were obtained in good to excellent yields after 12-24 h at
(18) (a) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (b) Garcia-
Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am.
Chem. Soc. 2006, 128, 1066.
(14) Schmidt et al. (ref 9c) have reported an analogous Pd-catalyzed
coupling to a 1,2-dichlorovinyl ether. Curiously, they obtained specific C-2
alkynylation.
5480
Org. Lett., Vol. 11, No. 23, 2009

mechanism. On the other hand, it may simply indicate that
oxidative insertion into the vinyl C-Cl bond is rate deter-
mining.
Scheme 4
.
One-Pot Access to 2-Aryl-N-tosyl Indoles from
1,2-Dichlorovinyl Amides
To extend our method to the synthesis of indoles, the
dichlorovinyl enamides 28-30 were prepared from the
corresponding anilines and TCE.19 The outcome of one-pot
Suzuki coupling/direct intramolecular cyclization of 28-30
to form 2-substituted indoles was dependent on the nitrogen
protecting group. N-Acetyl enamide 28 did not survive any
cross-coupling conditions, and the N-BOC derivatives 29a-c
were difficult to cyclize.20
in one pot.21 Among the benzofurans we have prepared are
the natural product Corsifuran C (20)22 and the core structure
(27) of the Ebenfuran family of estrogen receptor modula-
tors.23 We have also obtained promising initial results toward
extending this method to the synthesis of indoles. Further
studies to define the scope of this process, enhance its
efficiency, and understand its mechanism are ongoing.
Finally, N-tosyl enamides 30a,b underwent one-pot ary-
lation and cyclization to afford moderate yields of 2-arylin-
doles 31-32, after extended reaction times (Scheme 4). The
3-nitro enamide 30c underwent Suzuki coupling smoothly,
but even after 72 h of heating no evidence of the desired
nitroindole 33 could be detected either by TLC or 1H NMR
analysis of the crude reaction residue. The significance of
this poor reactivity is unclear but could support a mechanism
in which arylation is now rate determining.
Acknowledgment. This work was supported by a Dis-
covery Grant to PGH from the Natural Sciences and
Engineering Research Council of Canada and by NSERC
Postgraduate Fellowships to LMG. We thank Dr. Kirk Marat
(NMR), Mr. Xiao Feng (Dalhousie University, HRMS), and
Dr. Peter Budzelaar for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and full characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient modular
route to 2-substituted benzofurans from inexpensive phenols,
trichloroethylene, and a single equivalent of boronic acid in
only two steps. To our knowledge, this is only the second
report of sequential Suzuki cross coupling and direct arylation
OL902307M
(21) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054.
(22) von Reuss, S. H.; Koenig, W. A. Phytochemistry 2004, 65, 3113.
(23) (a) Halabalaki, M.; Alexi, X.; Aligiannis, N.; Alexis, M. N.;
Skaltsounis, A.-L. J. Nat. Prod. 2008, 71, 1934. (b) Halabalaki, M.;
Aligiannis, N.; Papoutsi, Z.; Mitakou, S.; Moutsatsou, P.; Sekeris, C.;
Skaltsounis, A.-L. J. Nat. Prod. 2000, 63, 1672. (c) Papoutsi, Z.; Kassi, E.;
Papaevangeliou, D.; Pratsinis, H.; Zoumpourlis, V.; Halabalaki, M.; Mitakou,
S.; Kalofoutis, A.; Moutsatsou, P. Steroids 2004, 69, 727.
(19) The preparation and characterization of 28-30 are described in
the Supporting Information.
(20) The N-BOC enamides underwent Suzuki coupling but failed to
cyclize under the one-pot conditions. When monoarylated N-BOC enamides
were separately subjected to Pd-catalyzed cyclization conditions, cyclization
did occur, but substantial loss of the BOC group was observed. See the
Supporting Information for experimental details.
Org. Lett., Vol. 11, No. 23, 2009
5481