Palladium-catalyzed annulation of aryl heterocycles with strained alkenes

Article abstract of DOI:10.1021/ol070475w

An annulation reaction proceeding by the intermolecular addition of an arylpalladium(II) halide across a strained alkene, followed by an intramolecular C-H functionalization of a pendant heterocycle is described. A variety of polycyclic heterocycles have

Full text of DOI:10.1021/ol070475w

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1761-1764
Palladium-Catalyzed Annulation of Aryl
Heterocycles with Strained Alkenes
David G. Hulcoop and Mark Lautens*
DaVenport Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received February 23, 2007
ABSTRACT
An annulation reaction proceeding by the intermolecular addition of an arylpalladium(II) halide across a strained alkene, followed by an
intramolecular C H functionalization of a pendant heterocycle is described. A variety of polycyclic heterocycles have been prepared from
readily accessible haloaryl heterocycles by annulation with a range of strained alkene partners.
−
The catalytic activation of aromatic C-H bonds and direct
arylation processes are emerging as effective methods for
C-C bond formation.1 These methods do not require
stoichiometric organometallic reagents and as such can
shorten synthetic sequences and minimize waste. It has been
shown that the treatment of aryl halides 1 with norbornene
in the presence of catalytic amounts of palladium(0) can
produce cyclobutene products 2 via ortho C-H functional-
ization.2 Alternatively, annulation products 3 may arise if a
suitable functional group R is in place adjacent to the halide
(Scheme 1).3
to its presence in a wide variety of biologically active natural
products and drug molecules.4 Our group has previously
demonstrated that the norbornene-mediated palladium-
catalyzed domino ortho-alkylation reactions of aryl iodides
can be terminated by the direct arylation of a number of
different heterocyclic systems.5 We therefore began to
explore the idea that aryl halides substituted by N-containing
heterocycles would react with strained alkenes to provide
interesting annulation rather than cyclobutene products. The
annulation of biologically active heterocycles with nor-
bornene can provide new active compounds with improved
(2) (a) Catellani, M. Top. Organomet. Chem. 2005, 21-53. (b) Catellani,
M.; Ferioli, L. Synthesis 1996, 769-772.
(3) For annulation onto an alkene, see: (a) Grigg, R.; Kennewell, P.;
Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1993, 34, 153-156. For
annulation onto a nitrile, see: (b) Pletnev, A. A.; Tian, Q.; Larock, R. C.
J. Org. Chem. 2002, 67, 9276-9287. For annulation onto phenols and
anilines, see: (d) Catellani, M.; Del Rio, A. Russ. Chem. Bull. 1998, 47,
928-931. Saito, K.; Katsuhiko, O.; Sano, M.; Kiso, S.; Takeda, T.
Heterocycles 2002, 57, 1781-1786. Lautens, M.; Paquin, J.-F.; Piguel, S.;
Dahlma, M. J. Org. Chem. 2001, 66, 8217-8134.
Scheme 1. Reaction of Aryl Halides with Norbornene
(4) See: (a) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry
II; Katrizsky, A. R., Rees, C. W., Scriven, E. S. V., Eds.; Pergamon Press:
New York, 1996; Vol. 2, pp 207-257. (b) Le Quesne, P. W.; Dong, Y.;
Blythe, T. A. Alkaloids: Chem. Biol. Perspect. 1999, 13, 237-287. (c)
Janosik, T.; Bergman, J. In Progress in Heterocyclic Chemistry; Gribble,
G. W., Joule, J. A., Eds.; Pergamon: Amsterdam, 2003; Vol. 15, pp 140-
166.
(5) (a) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 13148-13149. (b) Blaszykowski, C.; Aktoudianakis, V.; Bressy, C.;
Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043-2045. (c) Martins, A.;
Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 4827-4829.
The synthesis and elaboration of nitrogen-containing
heterocycles is an active area of organic chemistry, among
which pyrrole occupies a prominent role. This is due in part
(1) For a recent review, see: Alberico, D.; Scott, M. E.; Lautens, M.
Chem. ReV. 2007, 107, 174-238.
10.1021/ol070475w CCC: $37.00
© 2007 American Chemical Society
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druglike properties such as lipophilicity.6 We initially
investigated the reaction of the pyrrole 6a with strained
alkenes based on a norbornene skeleton. Gratifyingly, treat-
ment of 6a with norbornene, in the presence of a Pd(OAc)2/
PPh3 catalyst system and using Cs2CO3 as a base, provided
the annulated product 7a (Table 1, entry 1) in quantitative
Scheme 2. Annulation of Biaryl Bromide 4
Table 1. Annulation of Pyrroles with Norbornene
(entry 8), and chloride (entry 4) moieties, which allow further
elaboration of the products. The aldehyde-containing sub-
strates 6e and 6g show excellent regioselectivity, providing
solely annulation products. However, upon substitution of
the C-3 of the pyrrole, regioselectivity became problematic,
as the annulation products were isolated as an inseparable,
nonstatistical mixture of compounds showing annulation at
the C-2 and C-5 positions (entry 6). Annulation of the 3,4-
disubstituted pyrrole 6h proceeded with excellent yield and
regioselectivity to deliver the annulation product 7i (entry
8). Annulation of the 3-substituted pyrrole 6i proceeded in
good yield onto the C-2 position of the pyrrole ring to provide
7j, and only trace amounts of the C-4 annulated product were
detected (entry 9). Interestingly, a reverse in regioselectivity
was observed when the biaryl bromide 4 was treated under
similar reaction conditions, with norbornadiene as the
strained alkene, providing solely the cyclobutene product 5
in quantitative yield (Scheme 2).7
Table 2. Annulation of 6a with Other Strained Alkenesa
a Isolated as an inseparable mixture.
yield. We next explored the effect of different functional
groups on both the pyrrole and the aryl rings (Table 1). The
annulation reaction was found to be tolerant of a variety of
functionalities, including aldehyde (entries 5 and 7), ester
a Reaction conditions: Pd(OAc)2 (10 mol %), PPh3 (22 mol %), Cs2CO3
(1 equiv), the alkene (3 equiv), and 6a (1 equiv) were heated in toluene at
110 °C in a sealed tube overnight.
(6) Leysk, R.; Zimenkovsky, B.; Atamanyuk, D.; Jensen, F.; Kiec-
Kononowicz, K.; Gzella, A. Bioorg. Med. Chem. 2006, 14, 5230-5240.
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Org. Lett., Vol. 9, No. 9, 2007

To extend the scope of this process, we next examined
the reaction of 6a with a range of strained alkene partners
(Table 2). Benzonorbornene 8 (entry 1) and the oxabicycles
10 (entry 2) and 12 (entry 3) reacted smoothly to generate
the corresponding annulated products in good to excellent
yields. No ring-opened products were detected with the
oxabicyclic substrates. The use of norbornadiene 14 (entry
4) provided an interesting result as both the annulated species
15a and the aromatic compound 16a were isolated.8 The
pyrroloquinoline 16a arises via an in situ retro-Diels-Alder
reaction and loss of cyclopentadiene from 15a.8 The use of
the less strained [2.2.2]-bridged bicycle 17 led only to
recovery of starting material (entry 5).
Table 4. Synthesis of Retro-Diels-Alder Products
We were able to selectively obtain either the norborna-
diene-annulated product or the annulation/retro Diels-Alder
product through careful control of the reaction temperature.
At a lower temperature, good yields of the annulated alkene
products were generated with a range of functional groups
on the aryl ring (Table 3). The regioselectivity in this case
Table 3. Annulation of Pyrroles with Norbornadienea
whereas the alkyl- or fluoro-substituted aryl substrates were
more selective (entries 1, 3, and 4).
a Reaction conditions: Pd(OAc)2 (10 mol %), PPh3 (22 mol %), Cs2CO3
(1 equiv), norbornadiene (4 equiv), and the substrate (1 equiv) were heated
in toluene at 80 °C in a sealed tube overnight.
At a higher reaction temperature, we were able to
synthesize a range of pyrroloquinoline and related hetero-
cyclic compounds. Bridgehead nitrogen heterocycles such
as these are an important class of natural products; many
exhibit interesting biological activity.9,10 For example, sub-
stituted pyrroloquinolines have been found to be activators
of caspases and inducers of apoptosis, while it has also been
shown that Birch reduction of these compounds can pro-
vide dihydroquinolines, showing activity against P388
leukemia.11-13 Pyrroloquinolines have also found utility in
seems dependent on the substitution pattern of the benzene
ring, as treatment of the unsubstituted substrate 6b provides
a 1:1 ratio of the isomeric products 15b and 18 (entry 2),
(7) For synthesis of biaryl analogues, see: (a) Albrecht, K.; Reiser, O.;
Weber, M.; Knieriem, B.; de Meijere, A. Tetrahedron 1994, 50, 383-401.
(b) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C. Org. Lett. 2006, 8, 5581-
5584.
(8) (a) For an example of an analogous Pd-catalyzed transformation in
the synthesis of coumarin, see: An, Z.; Catellani, M.; Chiusoli, G. P. J.
Organomet. Chem. 1989, 371, C51-C52. (b) For an analogous Pd-catalyzed
synthesis of cis-olefins, see: Masanori, K.; Kumara, T.; Oda, H.; Migita,
T. Bull. Chem. Soc. Jpn. 1993, 66, 3522-3524.
(9) Swinbourne, J. F.; Hunt, H. J.; Klinkert, G. AdV. Heterocycl. Chem.
1987, 23, 103.
(10) Hermecz, I.; Vasvari-Debreczy, L.; Matyus, P. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon Press: London, 1996; Vol. 8, Chapter 23, pp 563-595.
Org. Lett., Vol. 9, No. 9, 2007
1763

the annulated products such as 7b (Scheme 3). Functional-
ization of the pyrrole ring could be envisaged to occur by a
Heck process, electrophilic aromatic substitution by attack
of the pyrrole onto the palladium(II) species, or by direct
C-H insertion.
Scheme 3. Proposed Mechanism
In summary, we have developed a straightforward method
for the assembly of a variety of heterocyclic scaffolds. These
reactions are tolerant of a wide range of functional groups
and allow the rapid assembly of interesting structures
amenable to further elaboration. Studies toward the synthesis
of other heterocyclic species with interesting biological
activities and physical properties are underway and will be
reported in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National 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. D.G.H. thanks the
Leverhulme Trust for a postdoctoral fellowship.
organic electroluminescent devices.14 At the higher temper-
ature, the reaction is tolerant of a range of functionalities
(Table 4), although some loss of the formyl group was
observed with substrates 6e (entry 5) and 6g (entry 6).
Under these conditions, we found that annulation of the
indole substrate 6j (entry 9) occurred in good yield and
regioselectivity, in contrast to the use of norbornene with
this substrate under similar conditions.
Mechanistically, we propose that oxidative insertion of
palladium(0) into the aryl-bromine bond and subsequent
carbopalladation of the reactive alkene provides intermediate
20. Reaction of this intermediate with the aryl ring would
provide the known cyclobutene products;4 however, under
our conditions, the heterocycle reacts in preference to form
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.
OL070475W
(12) Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054-2059.
(13) (a) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J. Med.
Chem. 1998, 31, 2097-2102. (b) Anderson, W. K.; De Ruiter, J.; Heider,
A. R. J. Org. Chem. 1985, 50, 722-724.
(11) Cai, S. X.; Drewe, J. A.; Jiang, S.; Kasibhatla, S.; Kuemmerle, J.
D.; Sirisoma, N. S.; Zhang, H. Z. WO2004055163, 2004.
(14) Nakatsuka, M.; Shimamura, T. JP2000277263, 2000.
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