Direct, one-step synthesis of condensed heterocycles: A palladium-catalyzed coupling approach

Article abstract of DOI:10.1021/ol061404k

A palladium-catalyzed one-step synthesis of fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes is reported. This method provides an efficient route to a wide variety of substituted polycyclic aromatic and heter

Full text of DOI:10.1021/ol061404k

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3601-3604
Direct, One-Step Synthesis of
Condensed Heterocycles: A
Palladium-Catalyzed Coupling Approach
Farnaz Jafarpour and Mark Lautens*
DaVenport Chemical Research Laboratories, Chemistry Department, UniVersity of
Toronto, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received June 8, 2006
ABSTRACT
A palladium-catalyzed one-step synthesis of fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes
is reported. This method provides an efficient route to a wide variety of substituted polycyclic aromatic and heteroaromatic compounds from
readily accessible starting materials.
Oxygen- and nitrogen-containing polycyclic compounds have
attracted considerable attention as a result of their biological
activity and their presence in a variety of natural and
unnatural products.1 For example, naphthofuran analogues,
which have been isolated from various natural sources such
as Fusarium oxysporum2 and Gossypium barbadense,3 are
known to exhibit antitumor, antifertility, mutagenic, growth
inhibitory, and oestrogenic activities.4 Thus, several ap-
proaches have been developed for their synthesis.5 One might
therefore expect that general and versatile synthetic methods
for the construction of these frameworks would find signifi-
cant utility in organic synthesis. In this area, we have recently
reported a practical and efficient route to annulated hetero-
cycles based on a tandem palladium-catalyzed alkylation/
arylation or alkenylation sequence.6
In the current study, we examine a different aspect of the
reaction with the goal of observing up to three C-H
functionalizations and two ring formations so as to quickly
assemble tri- and pentacyclic heteroatom-containing com-
pounds. Such a coupling is considerably more ambitious than
the examples previously described because both ortho
positions of the iodoarene are to be functionalized in the
two ring-closing steps and the timing of those processes is
important.
(1) (a) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58,
6795-6798 and references therein. (b) Szawkalo, J.; Zawadzka, A.;
Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetrahe-
dron: Asymmetry 2005, 16, 3619-3621.
(2) Stipanovic, R. D.; Bell, A. A.; Howell, C. R. Phytochemistry 1975,
14, 1809-1811.
(3) Tatum, J. H.; Baker, R. A.; Berry, R. E. Phytochemistry 1987, 26,
2499-2500.
(4) (a) Hagiwara, H.; Sato, K.; Suzuki, T.; Ando, M. Heterocycles 1999,
51, 497-500. (b) Weill-Thevenet, N.; Buisson, J.-P.; Royer, R.; Hofnung,
M. Mutat. Res. 1982, 104, 1-8. (c) Ribeiro-Rodrigues, R.; Dossantos, W.
G.; Oliveira, A. B.; Snieckus, V.; Romanha, A. Bioorg. Med. Chem. Lett.
1995, 5, 1509-1512. (d) Mehrotra, P. K.; Karkun, J. N.; Kar, A. B.
Contraception 1973, 7, 115-124.
Our initial attempts to test the feasibility of this reaction
employed iodoarene 1 and bromoenoate 2. Under the
optimized reaction conditions, 1a (0.20 mmol, 1 equiv), Pd-
(OAc)2 (10 mol %), triphenylphosphine (20 mol %), Cs2-
CO3 (6 equiv), norbornene (5 equiv), and 2 (5 equiv) in DME
(5) For a review, see: (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan,
P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955-
2020. (b) Ghera, E.; Maurya, R. Tetrahedron Lett. 1987, 28, 709-712. (c)
Naruta, Y.; Uno, H.; Maruyama, K. Tetrahedron Lett. 1981, 22, 5221-
5224. (d) Sestelo, J. P.; Real, M. D.; Mourino, A.; Sarandeses, L. A.
Tetrahedron Lett. 1999, 40, 985-988. (e) Park, K. K.; Jeong, J. Tetrahedron
2005, 61, 545-553.
(6) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127-8134. (c) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org.
Chem. 2002, 67, 3972-3974. (d) Pache, S.; Lautens, M. Org. Lett. 2003,
5, 4827-4830. (e) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148-13149.
10.1021/ol061404k CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/13/2006

(0.1 M) at 100 °C in a sealed tube for 48 h afforded the
fused tricyclic heterocycle 3 in 80% yield (Table 1, entry
halo alkyl ether chain (entries 2 and 3). Six- and seven-
membered annulated products, 5 and 7, were constructed in
51 and 44% yield, respectively, for a two-ring, three-bond
formation process. In both cases, use of an alkyl bromide
tether resulted in higher yield. Varying the bromoenoate
chain length was also explored, and modest yields were
obtained for the formation of 7,6,5-, 7,6,6-, and 7,6,7-
membered ring annulated compounds (entries 4-6). In the
case of bigger rings (entry 6), an increasing amount of the
ligand is needed for a better yield. Changing from an ester
(entry 1) to an amide (Scheme 1) diminished the yield to
50%.
Table 1. Synthesis of Tricyclic Oxygen-Containing
Heterocyclesa
Scheme 1
Tricyclic naphthalene derivatives are important constitu-
ents in pharmaceutical drug candidates.7 For instance,
compounds of type 14 have a high affinity and selectivity
for binding to melatonin receptors, resulting in either
melatonin receptor agonist or antagonist activity (Scheme
2).7 Furthermore, these compounds have been used in the
Scheme 2
a All reactions were run under the following conditions: iodoarene (0.20
mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (6 equiv),
norbornene (5 equiv), and bromoenoate (5 equiv) in DME (2 mL) were
heated in a sealed tube at 100 °C for 48 h. b Isolated yield. c PPh3 (30 mol
%) was used.
treatment of chronobiological disorders, glaucoma, cancer,
psychiatric disorders, and neurodegenerative diseases.7 Ac-
cordingly, tetrahydronaphtho[2,1-b]furan derivative 15 is a
key intermediate in the formation of one of these compounds,
1). The use of 1b with the iodoalkyl tether furnished the
same product in only 48% yield.
We next investigated the scope of the reaction using
aryliodides by varying the length and the substituents on the
(7) North, P. C.; Ladlow, M. Patent WO 9529173, 1995; Chem. Abstr.
124, 175833.
3602
Org. Lett., Vol. 8, No. 16, 2006

16, which can be readily prepared from compound 3 by acid-
mediated isomerization of the double bond in 50% yield
Scheme 3
Table 2. Synthesis of Annulated Indolesa
of iodoarene 1 and bromoalkylated indole 19 under the usual
conditions (Pd(OAc)2 as a catalyst, Cs2CO3 as a base, and
Scheme 4
a All reactions were run under the following conditions: iodoarene (0.20
mmol, 1 equiv), Pd(OAc)2 (10 mol %), tri-2-furylphosphine (22 mol %),
Cs2CO3 (2 equiv), norbornene (2 equiv), and bromoalkyl indole (2 equiv)
in acetonitrile (2 mL) were heated in a sealed tube at 90 °C for 24 h.
b Isolated yields.
accompanied by 50% of 3. Compound 15 has been converted
into 16 in three steps.7 Our method is also readily adapted
to making analogues of 14.
We next turned our attention to the synthesis of an
unsymmetrically substituted tricyclic heterocycle, containing
a benzoxepine moiety because these structural motifs have
received increasing interest because of their occurrence in
natural products,8 their biological activity, and their use as
natural herbicides.9 To this end, iodoarene 1 was reacted with
the ether-containing bifunctional acceptor 17 to provide the
desired tricyclic compound 18 in modest yield (Scheme 3).
We next sought to expand the scope of the palladium-
catalyzed annulation reaction to the construction of interest-
ing pentacyclic oxygen- and nitrogen-containing hetero-
cycles. However, our attempts to obtain 20 from the reaction
triphenylphosphine in DME at 100 °C) were unsuccessful.
We thus investigated the use of tri-2-furylphosphine (TFP)
as a ligand for Pd(OAc)2 in acetonitrile as a solvent. Good
results were obtained under these conditions (Table 2, entry
1). The low yield of the desired product was due to the
elimination of HBr from bromoalkyl indole 19 in the
presence of Cs2CO3. A bromoalkylated indole of longer chain
length was also studied. Iodoarene 1 was reacted with the
bromoalkylated indoles 21 and 23 using TFP to afford the
desired products 22 and 24 in 62% and 52% yield,
respectively (entries 2 and 3, Table 2).
(8) For recent examples, see: (a) Macias, F. A.; Varela, R. M.; Torres,
A.; Molinillon, J. M. G. Tetrahedron Lett. 1999, 40, 4725-4728 and
references therein. (b) Wijnberg, J. B. P. A.; van Veldhuizen, A.; Swarts,
H. J.; Frankland, J. C.; Field, J. A. Tetrahedron Lett. 1999, 40, 5767-
5770 and references therein. (c) Mericu¨li, F.; Mericu¨li, A. H.; Becker, H.;
Ulubelen, A. Phytochemistry 1996, 42, 1257-1258.
(9) (a) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G. Pure Appl.
Chem. 1999, 71, 2039-2046. (b) Kaupmann, W.; Ohlendorf, H. W.; Wolf,
K. U. Eur. J. Med. Chem. 1985, 20, 207-212. (c) Vyvyan, J. R.; Looper,
R. E. Tetrahedron Lett. 2000, 41, 1151-1154.
A possible mechanism for the formation of fused aromatic
carbocycle 3 is shown in Scheme 4 and follows a pathway
Org. Lett., Vol. 8, No. 16, 2006
3603

similar to that proposed by Catellani.10 Pd(0) inserts into the
Ar-I bond of 1 and then incorporates a norbornene and
inserts into the ortho C-H aryl bond, forming a palladacycle.
Elimination of HI by the base (here Cs2CO3) regenerates a
tetracoordinated Pd(II). Oxidative addition of the internal
alkyl halide leads to a cyclic Pd(IV) species. A reductive
elimination forms the five-membered oxacycle. An insertion
into the second ortho C-H aryl bond occurs, followed by
elimination of HX. Intermolecular oxidative addition of
bromoenoate takes place, followed by a reductive elimination
that puts the external alkyl group on the arene. Extrusion of
norbornene gives an aryl-Pd(II) species. This intermediate
undergoes a Heck reaction, leading to product 3.
It is possible to envisage an alternative mechanism leading
to 3, where the first ortho alkylation would occur with the
external alkyl halide and the second one would occur with
the internal alkyl halide. It seems difficult to distinguish
between the mechanisms, and both pathways may be
occurring simultaneously.
In summary, we have developed an efficient and straight-
forward one-step approach to fused heterocyclic compounds
based on a tandem palladium-catalyzed dialkylation/alkeny-
lation or arylation process which forms at least three new
C-C bonds, using readily accessible starting materials. The
application of this reaction toward the synthesis of natural
compounds is currently under investigation.
Acknowledgment. We thank Dr. Sandrine Pache (As-
traZeneca, Canada) for preliminary experiments and Dr. Dino
Alberico (University of Toronto) for helpful discussions and
practical help. We gratefully acknowledge the financial
support of the Natural Sciences and Engineering Research
Council (NSERC) of Canada, the Merck Frosst Centre for
Therapeutic Research for an Industrial Research Chair, and
the University of Toronto. F.J. thanks the Iranian Ministry
of Science and Technology for a research abroad fellowship
and Professor Hooshang Pirelahi (University of Tehran).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. 1997,
109, 142-145 and references therein; Angew. Chem., Int. Ed. Engl. 1997,
36, 119-122 and references therein. (b) Catellani, M.; Fagnola, M. C.
Angew. Chem. 1994, 106, 2559-2560; Angew. Chem., Int. Ed. Engl. 1994,
33, 2421-2422. (c) Catellani, M.; Cugini, F. Tetrahedron 1999, 55, 6595-
6602.
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