A palladium-catalyzed alkylation/direct arylation synthesis of nitrogen-containing heterocycles

Article abstract of DOI:10.1021/jo702052b

(Chemical Equation Presented) A norbornene-mediated palladium-catalyzed sequence is described in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one reaction vessel. The aryl-heteroaryl bond-forming step occurs via a direct arylation re

Full text of DOI:10.1021/jo702052b

A Palladium-Catalyzed Alkylation/Direct Arylation Synthesis of
Nitrogen-Containing Heterocycles
Christophe Blaszykowski,# Evangelos Aktoudianakis,† Dino Alberico,‡ Cyril Bressy,§
David G. Hulcoop, Farnaz Jafarpour, Arash Joushaghani, Benoˆıt Laleu, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6 Canada
mlautens@chem.utoronto.ca
ReceiVed September 19, 2007
A norbornene-mediated palladium-catalyzed sequence is described in which an alkyl-aryl bond and an
aryl-heteroaryl bond are formed in one reaction vessel. The aryl-heteroaryl bond-forming step occurs via
a direct arylation reaction. A number of six-, seven-, and eight-membered ring-annulated indoles, pyrroles,
pyrazoles, and azaindoles were synthesized from the corresponding bromoalkyl azole and an aryl iodide.
SCHEME 1. Aryl-N-Heteroaryl Bond Formation via
Cross-Coupling and Direct Arylation Reactions
Introduction
The aryl-N-heteroaryl bond is found in many bioactive
molecules, pharmaceuticals, and organic materials. Among the
various methods that exist for the synthesis of this bond, metal-
catalyzed cross-coupling reactions between aryl (or heteroaryl)
halides and heteroaryl (or aryl) organometallic compounds offer
the advantages of relatively mild reaction conditions and high
functional group tolerance (Scheme 1, eqs 1 and 2).1 More
recently, transition-metal-catalyzed direct arylation reactions
have emerged as an efficient alternative to traditional cross-
coupling reactions.2,3 This method generates a C-C bond from
an aryl halide and a heteroaryl C-H bond (Scheme 1, eq 3).
# Current address: Medmira Inc., Maple Biosciences, University of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6 Canada.
† Current address: Gilead, Department of Medicinal Chemistry, 333 Lakeside
Dr., Foster City, CA 94404.
‡ Current address: De´partement de Chimie, Universite´ de Montre´al, P.O. Box
6128, Station Downtown, Montre´al (Que´bec), H3C 3J7 Canada.
§ Current address: UMR CNRS 6178 Symbio, e´quipe Re´SO, Boˆıte 532,
Universite´ Paul Ce´zanne Aix Marseille III, Faculte´ des Sciences de St. Je´roˆme
13397 Marseille cedex 20, France.
Unlike cross-coupling reactions, direct arylation reactions avoid
the need for stoichiometric amounts of organometallic reagents,
resulting in fewer reaction steps and reduced waste. However,
due to the ubiquitous nature of C-H bonds, one of the
Current address: School of Chemistry, University College of Science,
University of Tehran, P.O. Box 13145-143, Tehran, Iran.
(1) (a) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651. (b) Hassan,
J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359. (c) Stanforth, S. P. Tetrahedron 1998, 54, 263. (d) Anastasia,
L.; Negishi, E.-I. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley: New York, 2002; pp 311-334. For
reviews on cross-coupling reactions involving nitrogen-containing hetero-
cycles, see: (e) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.;
Wong, D. J. Eur. J. Org. Chem. 2006, 3043. (f) Schnu¨rch, M.; Flasik, R.;
Farooq Khan, A.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org.
Chem. 2006, 3283. (g) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: New York, 2000.
(2) For reviews on direct arylation reactions, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (c) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (d) Satoh, T.; Miura,
M. Chem. Lett. 2007, 36, 200. (e) Godula, K.; Sames, D. Science 2006,
312, 67. (f) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55. (g)
Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. (h) Echavarren,
A. M.; Go´mez-Lor, B.; Gonza´lez, J. J.; de Frutos, OÄ . Synlett 2003, 585. (i)
Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (j) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1699.
10.1021/jo702052b CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/09/2008
1888
J. Org. Chem. 2008, 73, 1888-1897

Pd-Catalyzed Synthesis of N-Containing Heterocycles
SCHEME 2. Synthesis of Annulated Nitrogen-Containing Heterocycles via a Tandem Norbornene-Mediated
Palladium-Catalyzed Alkylation/Direct Arylation Reaction
challenges associated with direct arylation reactions is control-
ling chemoselectivity in terms of which C-H bond undergoes
the reaction. This obstacle can often be overcome by using a
tether to limit the degree of freedom in the system (intramo-
lecular direct arylation), exploiting the electronic nature of the
heterocycle (intermolecular), or employing a directing group
(semi-intermolecular).2a
Results and Discussion
Typical reaction conditions involve heating a solution of the
aryl iodide (1 equiv), N-bromoalkyl heterocycle (2 equiv),
palladium catalyst (Pd(OAc)2 or PdCl2, 10 mol %), tri-2-
furylphosphine (22 mol %), Cs2CO3 (2 equiv), and norbornene
(2 equiv) in acetonitrile (0.1 M) in a sealed tube at 90 °C for
16-24 h. In addition to the desired annulated products, a number
of side products were observed in some reactions, often in trace
amounts (Figure 1). For example, displacement of the bromide
of the N-bromoalkyl heterocycles with an iodide or acetate ion
afforded 1 and 2, respectively. Compound 2 was only observed
with Pd(OAc)2 and could be eliminated by using PdCl2. For
N-bromoalkyl heterocycles with n ) 1, the elimination alkene
product 3 was formed with some substrates. The ortho-alkylated/
ipso-reduced product 4 was also observed, especially for
N-bromoalkyl heterocycles with n ) 3. The ortho-insertion of
the N-bromoalkyl heterocycle followed by reduction, wherein
the alkyl halide is the hydride source (the desired final
cyclization being presumably much slower in that case), is
proposed to be responsible for formation of the product.10 This
observation is very important since it strongly suggests that the
ortho-alkylation precedes the final aryl-heteroaryl coupling.4b
Finally, in addition to the side products illustrated in Figure 1,
various norbornane-containing aromatic compounds are usually
formed in trace amounts.11
Our group has utilized direct arylation reactions to generate
annulated nitrogen-containing heterocycles.4 The method in-
volves a norbornene-mediated palladium-catalyzed intermo-
lecular ortho-alkylation of an aromatic C-H bond with an
N-bromoalkyl heterocycle, generating a tethered intermediate
(Scheme 2). The mechanism for the initial step is based upon
the findings of Catellani and involves a Pd(II)/Pd(IV)5 catalytic
cycle.6,7 The resulting species then undergoes an intramolecular
direct arylation reaction forming the aryl-N-heteroaryl bond at
the 2 position of the N-heteroaryl compound.8 Herein, we report
the details of our studies whereby functionalized annulated
indoles, pyrroles, pyrazoles, and azaindoles are generated from
readily available N-bromoalkyl heterocycles and ortho-substi-
tuted aryl iodides.9 In addition, we show that the annulated
products can be further functionalized via subsequent cross-
coupling methodologies.
(3) For recent papers on the direct arylation of nitrogen-containing
heterocycles, see: (a) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem.
2007, 72, 1476. (b) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
(c) Marcia de Figueiredo, R.; Thoret, S.; Huet, C.; Dubois, J. Synlett 2007,
529. (d) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron
2007, 63, 1970. (e) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2006, 45, 1589. (f) Leclerc, J.-P.; Fagnou, K. Angew.
Chem., Int. Ed. 2006, 45, 7781. (g) Cˇ ernˇa, I.; Pohl, R.; Klepeta´rˇova´, B.;
Hocek, M. Org. Lett. 2006, 8, 5389. (h) Djakovitch, L.; Dufaud, V.; Zaidi,
R. AdV. Synth. Catal. 2006, 348, 715. (i) Arai, N.; Takahashi, M.; Mitani,
M.; Mori, A. Synlett 2006, 3170. (j) Koubachi, J.; El Kazzouli, S.; Berteina-
Raboin, S.; Mouaddib, A.; Guillaumet, G. Synlett 2006, 3237. (k) Chupra-
kov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9,
2333.
(4) (a) Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.; Alberico, D.;
Lautens, M. Org. Lett. 2006, 8, 2043. (b) Bressy, C.; Alberico, D.; Lautens,
M. J. Am. Chem. Soc. 2005, 127, 13148. For the synthesis of annulated
furans and thiophenes, see: (c) Martins, A.; Alberico, D.; Lautens, M. Org.
Lett. 2006, 8, 4827.
(5) For a discussion on Pd(II)/Pd(IV) reactions, see: Deprez, N. R.;
Sanford, M. S. Inorg. Chem. 2007, 46, 1924 and references therein.
(6) For mechanistic studies and for related norbornene-mediated pal-
ladium-catalyzed reactions, see: (a) Catellani, M.; Frignani, F.; Rangoni,
A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. (b) Catellani, M.; Mealli,
C.; Motti, E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem.
Soc. 2002, 124, 4336. (c) Catellani, M. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; John
Wiley & Sons: Hoboken, NJ, 2002; pp 1479-1489. (d) Catellani, M. Synlett
2003, 298. (e) Tsuji, J. Palladium Reagents and Catalysis-New PerspectiVes
for the 21st Century; John Wiley & Sons: New York, 2004; pp 409-416.
(f) Catellani, M. Top. Organomet. Chem. 2005, 14, 21.
FIGURE 1. Various side products observed.
Synthesis of Annulated Indoles. We previously reported the
synthesis of six- and seven-membered ring-annulated indoles.4b,12
A number of bromoalkyl indoles with electron-donating or
electron-withdrawing substituents were prepared. These sub-
strates were reacted with both electron-rich and electron-poor
aryl iodides, affording a variety of annulated indoles in moderate
to good yields (Scheme 3). Various substituents are tolerated
under the reaction conditions including ester, amine, methyl,
methoxy, nitro, and chloride. The electronic nature of the
substituents seemed to have little effect on the product yields.
However, a N-methyl tosyl substituent at the meta-position of
the aryl iodide resulted in only 38% yield, presumably due to
steric interactions.4b
(10) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053.
(11) For examples, see ref 6d and: Motti, E.; Ippomei, C. P.; Deledda,
S.; Catellani, M. Synthesis 2003, 2671.
(7) For the proposed catalytic cycle as it relates to this reaction, see
ref 4.
(8) For a discussion on the possible mechanisms of the direct arylation
of heterocycles, see refs 2a and 2b and references therein.
(9) For preliminary studies, see refs 4a and 4b.
(12) For reviews on the synthesis and functionalization of indoles, see:
(a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (b) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
J. Org. Chem, Vol. 73, No. 5, 2008 1889

Blaszykowski et al.
SCHEME 3. Synthesis of Six- and Seven-Membered Ring-Annulated Indoles
SCHEME 4. Synthesis of Methoxy-Substituted Annulated Indole
SCHEME 5. Attempted Formation of Eight-Membered Ring-Annulated Indoles
TABLE 1. Synthesis of Eight-Membered Ring-Annulated Indolesa
a Unless otherwise specified, all reactions were run under the following conditions: aryl iodide (1 equiv), PdCl2 (10 mol %), tri-2-furylphosphine (22 mol
%), Cs2CO3 (2 equiv), and norbornene (2 equiv) in acetonitrile (0.1 M) were heated at 90 °C, and bromoalkyl indole (2 equiv, 0.07 M in MeCN) was added
dropwise via syringe pump over 12 h.
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Pd-Catalyzed Synthesis of N-Containing Heterocycles
SCHEME 6. Synthesis of Six- and Seven-Membered
Ring-Annulated Pyrroles
It should be noted that, when 2-iodoanisole was used as a
coupling partner in this reaction, lower yields of the products
were obtained (Scheme 4). It has been shown that aryl palladium
species with the palladium ortho to a methoxy group can
undergo C-H activation with the methoxy C-H bond to form
a stable five-membered palladacycle.13 This or other similar
reactions may be occurring, thereby preventing the desired steps
in the catalytic cycle.
The synthesis of eight-membered ring-annulated indoles
proved to be more difficult. When 10 was subjected to the
reaction conditions, no desired eight-membered ring compound
11b was isolated (Scheme 5).14 Rather, the acyclic ortho-inserted
product 11a was observed. Therefore, to promote the sluggish
cyclization step, we envisaged limiting the degrees of freedom
of the alkyl chain. Thus, 12a and 12b were prepared and
subjected to the standard reaction conditions, which involves
mixing all of the reagents and heating. Unfortunately, only low
yields (<20%) of product were isolated. Fortunately, we found
that the yield could be increased by adding the bromoalkyl
indole dropwise over 12 h. Ultimately, we could achieve the
formation of eight-membered ring compounds, albeit in modest
yields (Table 1). There are very few reports of ortho-alkylation
using benzylic halides, so the success in this instance is
noteworthy.
SCHEME 7. Synthesis of Functionalized Annulated
Pyrroles
Synthesis of Annulated Pyrroles. We also investigated the
synthesis of six- and seven-membered ring-annulated pyrroles
(Scheme 6).4a Reaction of unsubstituted bromoalkyl pyrroles
14 with a number of aryl iodides was conducted using PdCl2
as the catalyst. Good yields of product were generally obtained
with various electron-rich and electron-poor aryl iodides. Silyl-
protected aryl iodides are also compatible under the reaction
conditions and can be deprotected in situ to give the corre-
sponding alcohol product (Scheme 7, eq 1). Notably, aryl iodide
6f afforded an excellent yield of annulated pyrrole 18 (Scheme
7, eq 2). This compound is found in the core of biologically
active compounds including Lettowianthine and Lamellarin.15
More highly functionalized six-membered ring-annulated
pyrroles could be prepared using substituted bromoalkyl pyr-
roles. Pyrroles substituted with an ester in the 2 position
underwent cyclization with a number of aryl iodides (Table 2).
In order to simplify the purification process for certain
substrates, the ester moiety was converted to the corresponding
alcohol using lithium aluminum hydride (entries 4-7). The
scope of aryl iodides was expanded to include fluoride substit-
uents. 1-Fluoro-2-iodobenzene (6k) afforded the annulated
product 20f in 43% (entry 6), while the arene substituted with
a fluorine atom ortho to where the alkylation occurs (6i) resulted
in a lower yield of 21% (entry 4). Finally, pyrroles substituted
in the 3 position with an acetyl moiety furnished an 8:1 mixture
of annulated product, favoring the less sterically encumbered
4-substituted acetyl product (entry 8).
SCHEME 8. Synthesis of an Eight-Membered
Ring-Annulated Pyrrole
Synthesis of Annulated Azaindoles. Having successfully
generated annulated products from indoles and pyrroles, we next
investigated the effect of using heterocycles containing more
than one nitrogen atom.16 We initially examined the reaction
of 7-azaindole 23a with 2-iodotoluene (Table 3, entry 1).
Unfortunately 24a was isolated in only 32% yield, which may
be a result of the adjacent pyridyl nitrogen coordinating to one
of the palladium intermediates in the catalytic cycle. When
6-azaindole 23b, which contains the pyridyl nitrogen at a
position where chelation to palladium is impossible, is reacted,
the derived products 24b-j are generally isolated in higher
yields (Table 3). Azaindole 23b was prepared by reacting
commercially available 2-chloro-3-nitropyridine with vinylmag-
nesium bromide, followed by alkylation with 1,2-dibromoethane.
Larger ring sizes are also accessible for the pyrrole series.
An eight-membered ring compound was formed, albeit in low
yield (Scheme 8).
(13) (a) Dyker, G. J. Org. Chem. 1993, 58, 6426. (b) Dyker, G. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1023.
(14) In addition, no eight-membered ring product was observed by adding
the bromoalkyl indole dropwise over 12 h.
(15) Lettowianthine: (a) Nkunya, M. H. H.; Jonker, S. A.; Makangara,
J. J.; Waibel, R.; Achenbach, H. Phytochemistry 2000, 53, 1067. Lamellarin
D: (b) Facompre´, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.;
Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392. (c) Pla,
D.; Marchal, A.; Olsen, C. A.; Albericio, F.; AÄ lvarez, M. J. Org. Chem.
2005, 70, 8231.
(16) For a review on the synthesis and functionalization of azaindoles,
see: Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. Chem. Soc. ReV. 2007, 36, 1120.
J. Org. Chem, Vol. 73, No. 5, 2008 1891

Blaszykowski et al.
TABLE 2. Synthesis of Six-Membered Ring-Annulated Pyrroles from Functionalized Bromoalkyl Pyrrolesa
a Unless otherwise specified, all reactions were run under the following conditions: aryl iodide (1 equiv), PdCl2 (10 mol %), tri-2-furylphosphine (22 mol
%), Cs2CO3 (2 equiv), norbornene (2 equiv), and bromoalkyl pyrrole (2 equiv) in acetonitrile (0.1 M) were heated in a sealed tube at 90 °C for 24 h.
b Lithium aluminum hydride was added after 24 h.
Synthesis of Annulated Pyrazoles. We were also interested
in examining the reaction of pyrazoles because of the important
properties and uses of annulated pyrazoles as insecticides and
CB1 receptor antagonists17 and since, to the best of our knowl-
edge, there are no reported cases of direct arylations of pyra-
zoles. Initial studies were conducted with the unsubstituted
N-bromoalkyl pyrazole 25, which was easily prepared by the
alkylation of pyrazole with 1,2-dibromoethane. Under the typical
reaction conditions, which involve mixing all of the reagents
followed by heating the mixture, very low yields of products
were obtained. After exploring and altering various aspects of
the reaction conditions, we found that the dropwise addition of
the pyrazole substrate over 17 h significantly improved the yield
of the reaction. Once again, a variety of electron-rich and elec-
tron-poor aryl iodides were explored and generally gave moder-
ate to good yields of annulated pyrazoles in one step (Table 4).
(17) (a) Lamberth, C. Heterocycles 2007, 71, 1467. (b) Stoit, A. R.;
Lange, J. H. M.; den Hartog, A. P.; Ronken, E.; Tipker, K.; van Stuivenberg,
H. H.; Dijksman, J. A. R.; Wals, H. C.; Kruse, C. G. Chem. Pharm. Bull.
2002, 50, 1109.
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Pd-Catalyzed Synthesis of N-Containing Heterocycles
TABLE 3. Synthesis of Annulated Azaindolesa
a Unless otherwise specified, all reactions were run under the following conditions: aryl iodide (1 equiv), PdCl2 (10 mol %), tri-2-furylphosphine (22 mol
%), Cs2CO3 (2 equiv), norbornene (2 equiv), and bromoalkyl azaindole (2 equiv) in acetonitrile (0.1 M) were heated in a sealed tube at 90 °C for 24 h.
Functionalized N-bromoalkyl pyrazoles were also successful
partners in the reaction. Various substituents were introduced
at the 4 position of the pyrazole including nitro, iodo, and chloro.
These substrates were readily prepared by treating pyrazole 25
with HNO3 and H2SO4, I2 and CAN, and NaOCl, respectively.
Nitro-substituted pyrazole 27a gave comparable yields to the
unsubstituted pyrazole 25 (Table 5, entries 1-5), while halo-
substituted pyrazoles 27b and 27c gave slightly lower yields
(entries 6-8). We were delighted to see that both chloro- and
iodo-substituted pyrazoles were tolerated under the reaction
J. Org. Chem, Vol. 73, No. 5, 2008 1893

Blaszykowski et al.
TABLE 4. Synthesis of Six-Membered Ring-Annulated Pyrazolesa
a Unless otherwise specified, all reactions were run under the following conditions: aryl iodide (1.5 equiv), Pd(OAc)2 (10 mol %), tri-2-furylphosphine
(22 mol %), Cs2CO3 (2 equiv), and norbornene (2 equiv) in acetonitrile (0.3 M relative to the aryl iodide) were heated at 90 °C, and a 0.1 M acetonitrile
solution of bromoalkyl pyrazole (1 equiv) was added dropwise via syringe pump over 17 h and then heated for an additional 3 h.
1894 J. Org. Chem., Vol. 73, No. 5, 2008

Pd-Catalyzed Synthesis of N-Containing Heterocycles
TABLE 5. Synthesis of Six-Membered Ring-Annulated Pyrazoles from Functionalized Bromoalkyl Pyrazolesa
a Unless otherwise specified, all reactions were run under the following conditions: aryl iodide (1.5 equiv), Pd(OAc)2 (10 mol %), tri-2-furylphosphine
(22 mol %), Cs2CO3 (2 equiv), and norbornene (2 equiv) in acetonitrile (0.3 M relative to the aryl iodide) were heated at 90 °C, and a 0.1 M acetonitrile
solution of bromoalkyl pyrazole (1 equiv) was added dropwise via syringe pump over 17 h and then heated for an additional 3 h.
conditions and were not affected by the active palladium species
in solution.
catalyzed Sonogashira,18 Suzuki,19 and amine coupling reac-
tions,20 respectively (Scheme 9). Likewise, new functionality
can be efficiently added to the heterocyclic moiety of the
annulated product by subjecting chloro-substituted 28h to
One of the advantages of having halogen substituents on the
annulated heterocycles is that they can be easily converted into
other substituents via a number of metal-catalyzed coupling
reactions. For example alkyne, aryl, and amine substituents were
easily introduced onto the arene moiety of 26i via palladium-
(19) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685.
(20) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
(18) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
J. Org. Chem, Vol. 73, No. 5, 2008 1895

Blaszykowski et al.
SCHEME 9. Further Functionalization of the Arene Moiety of the Annulated Pyrazoles
SCHEME 10. Further Functionalization of the Pyrazole
Moiety of the Annulated Pyrazoles
Conclusion
We have developed a route to highly functionalized six-,
seven-, and eight-membered ring-annulated indoles, azaindoles,
pyrroles, and pyrazoles using a palladium-catalyzed norbornene-
mediated tandem process involving an intermolecular ortho-
alkylation of an aromatic C-H bond followed by an intramo-
lecular direct arylation reaction. The reaction tolerates a number
of substituents on both the N-bromoalkyl heterocycle and aryl
iodide including ester, nitro, amine, alkyl, methoxy, trifluorom-
ethyl, chloro, and fluoro. Furthermore, we showed that diverse
functionality can be introduced by treating the halo-containing
annulated products in palladium-catalyzed cross-coupling reac-
tions.
SCHEME 11. Iodination of the Annulated Pyrazoles and
Further Functionalization
Experimental Section
The following represents general experimental procedures toward
the synthesis of annulated products. Specific experimental details
and characterization data for the aforementioned compounds and
other new compounds can be found in the Supporting Information.
General Procedure for the Synthesis of Six- and Seven-
Membered Ring-Annulated Indoles, Azaindoles, and Pyrroles.
A vial equipped with a stir bar was charged with aryl iodide (1
equiv), Cs2CO3 (2 equiv), norbornene (2 equiv), palladium catalyst
(10 mol %; Pd(OAc)2 was used for indoles, and PdCl2 was used
for pyrroles and azaindoles), and tri-2-furylphosphine (22 mol %).
A solution of bromoalkyl indole, pyrrole, or azaindole (2 equiv) in
CH3CN (0.1 M) was then added, and the vial was capped and
purged with nitrogen. The resulting mixture was heated in an oil
bath at 90 °C for 16-24 h, cooled to room temperature, and then
filtered through a short plug of silica. Removal of the solvent gave
a crude product that was purified by flash chromatography.
General Procedure for the Synthesis of Eight-Membered
Ring-Annulated Indoles and Pyrroles. A solution of the appropri-
ate bromoalkyl indole or pyrrole (0.200 mmol, 2 equiv) in CH3CN
(6 mL) was added dropwise over 12 h to a solution of PdCl2 (10
mol %), tri-2-furylphosphine (22 mol %), Cs2CO3 (2 equiv),
norbornene (2 equiv), and the aryl iodide (1 equiv) in CH3CN (1
mL) at 80 °C. The reaction was then stirred at 80 °C for 3 h. Once
cooled to room temperature, the reaction was diluted with CH2Cl2,
filtered through Celite, and washed with CH2Cl2. Removal of the
solvent gave a crude product that was purified by flash chroma-
tography.
palladium-catalyzed coupling conditions (Scheme 10). Finally,
we showed an alternative route to similar products by introduc-
ing the halogen after the cyclization reaction by treating the
annulated product with I2 and CAN.21 These iodinated pyrazoles
were then subjected to Suzuki conditions22 and resulted in the
arylation of the pyrazole moiety in good yields (Scheme 11).
General Procedure for the Synthesis of Six-Membered Ring-
Annulated Pyrazoles. A 10 mL round-bottom flask equipped with
a reflux condenser was charged with aryl iodide (0.600 mmol, 1.5
equiv), tri-2-furylphosphine (22 mol %), norbornene (2 equiv), Cs2-
CO3 (2 equiv), Pd(OAc)2 (10 mol %), and CH3CN (2 mL). The
resulting mixture was heated to reflux, and then a solution of
(21) Rodr´ıguez-Franco, M. I.; Dorronsoro, I.; Herna´ndez-Higueras, A.
I.; Antequera, G. Tetrahedron Lett. 2001, 42, 863.
(22) Meegalla, S. K.; Doller, D.; Sha, D.; Soll, R.; Wisnewski, N.; Silver,
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1896 J. Org. Chem., Vol. 73, No. 5, 2008

Pd-Catalyzed Synthesis of N-Containing Heterocycles
bromoalkyl pyrazole (1.0 equiv) in CH3CN (2 mL) was added
dropwise (17 h syringe-pump addition). After the addition, the
resulting mixture was heated for an additional 3 h, allowed to cool
to room temperature, diluted with EtOAC, and filtered through a
short plug of silica (EtOAc washings). Removal of the solvent gave
a crude mixture that was purified by flash column chromatography.
University of Toronto. D.G.H. thanks the Leverhulme Trust for
a Post-Doctoral Fellowship. B.L. thanks the Swiss National
Science Foundation for a Post-Doctoral Fellowship. Cyril Bressy
thanks Le Ministe`re des Affaires Etrange`res Franc¸ais for a
Bourse Lavoisier Post-Doctoral Fellowship.
Supporting Information Available: Experimental details and
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. 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
JO702052B
J. Org. Chem, Vol. 73, No. 5, 2008 1897