Establishment of broadly applicable reaction conditions for the palladium-catalyzed direct arylation of heteroatom-containing aromatic compounds

Article abstract of DOI:10.1021/jo8026565

Conditions for the palladium-catalyzed direct arylation of a wide range of heterocycles with aryl bromides are reported. Those conditions employ a stoichiometric ratio of both coupling partners, as well as a substoiehiometric quantity of pivalic acid, which results in significantly faster reactions. An evaluation of the influence of the nature of the aryl halide has also been carried out.

Full text of DOI:10.1021/jo8026565

Establishment of Broadly Applicable Reaction Conditions for the
Palladium-Catalyzed Direct Arylation of Heteroatom-Containing
Aromatic Compounds
Benoˆıt Lie´gault, David Lapointe, Laurence Caron, Anna Vlassova, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, ON K1N 6N5, Canada
keith.fagnou@uottawa.ca
ReceiVed December 3, 2008
Conditions for the palladium-catalyzed direct arylation of a wide range of heterocycles with aryl bromides
are reported. Those conditions employ a stoichiometric ratio of both coupling partners, as well as a
substoichiometric quantity of pivalic acid, which results in significantly faster reactions. An evaluation
of the influence of the nature of the aryl halide has also been carried out.
SCHEME 1. Heteroatom-Containing Biaryls1-3
Introduction
Heteroatom-containing biaryls are common motifs in biologi-
cally active products,1 in organic materials2 and in ligands for
metal catalysis3 (Scheme 1). Over the past 30 years, the
preparation of these molecules has been dominated by the use
of transition-metal-catalyzed processes, where an organometallic
species can be cross-coupled with an aryl halide.4 Over the past
decade, however, alternatives are emerging where one of the
coupling partners (usually the organometallic component) is
(1) For selected examples, see: (a) Chimenti, F.; Maccioni, E.; Secci, D.;
Bolasco, A.; Chimenti, P.; Granese, A.; Carradori, S.; Alcaro, S.; Ortuso, F.;
Ya´n˜ez, M.; Orallo, F.; Cirilli, R.; Ferretti, R.; La Torre, F. J. Med. Chem. 2008,
51, 4874–4880. (b) Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J. M.;
Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis, R. T.; Stanley, J.; Smith, A. J.;
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Ronkin, S. M.; Saunders, J. O. WO9740028, 1997. (d) Dale, D. J.; Dunn, P. J.;
Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward,
G.; Wood, A. S. Org. Process Res. DeV. 2000, 4, 17–22. (e) Carpenter, A. J.;
Cooper, J. P.; Handlon, A. L.; Hertzog, D. L.; Hyman, C. E.; Guo, Y. C.; Speake,
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J.; Buchanan, J. L.; Buckner, W. H.; DiMauro, E. F.; Emkey, R.; Fremeau, R. T.;
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Martin, M. W.; Nguyen, H. Q.; Patel, V. F.; Tomlinson, S. A.; White, R. D.;
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1826 J. Org. Chem. 2009, 74, 1826–1834
10.1021/jo8026565 CCC: $40.75 2009 American Chemical Society
Published on Web 02/10/2009

Direct Arylation of Heteroatom-Containing Aromatic Compounds
replaced by a simple arene.5 Since the pioneering work more
than a quarter century ago,6 many research groups, including
ours, have been involved in the development of new methods
for the preparation of heteroatom-containing biaryl structures.7
A wide range of electron-rich heterocycles have been success-
fully employed in palladium-catalyzed cross-coupling reactions,
including (benzo)thiophenes,8 furans,9 (benz)oxazoles,10 in-
doles,11 pyrroles,12 (benz)imidazoles,13 (benzo)thiazoles,14 tria-
zoles,15 indolizines,16 purines,17 as well as imidazopyrimidine,
-pyrazine, and -triazine derivatives.18-21 Despite the growth,
challenges remain including the establishment of generally
applicable conditions that can enable the successful cross-
coupling of the broadest range of heterocyclic compounds
possible and the frequent need to use one of the coupling
partners in excess. Underlying the challenges is an inability to
point to a single predominant reaction pathway that may be used
as a starting point for a more rational approach to reaction
development. With a greater mechanistic understanding of these
processes should come the establishment of improved reaction
conditions and a greater acceptance of this approach in the
preparation of heterocycle containing biaryl molecules.
(4) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
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J. Org. Chem. Vol. 74, No. 5, 2009 1827

Lie´gault et al.
SCHEME 3. Evolution of Reaction Conditions for the
Direct Arylation of Electron-Deficient, Electron-Neutral, and
Electron-Rich (Hetero)arenes
SCHEME 2. Electrophilic Aromatic Substitution (SEAr) and
Concerted Metalation-Deprotonation (CMD) Pathways
Our research group has been involved in the development of
palladium-catalyzed direct arylation reactions with electron-deficient
arenes22,23 and heteroarenes.24 In these processes, the experimental
and computational data support the involvment of a concerted
metalation-deprotonation pathway (CMD)22a,23,25 that accurately
predicts both the relative rates as well as the regioselectivity
(Scheme 2). Recently, we questioned whether this mode of reaction
might also occur with some types of π-excessive aromatics that
are more commonly proposed to react via an electrophilic aromatic
substitution pathway (SEAr)6o,8b,11b,16,18a,26 and, upon evaluation
by computational analysis, found a remarkable parallel with the
computationally predicted and experimentally observed reaction
outcomes.27
SCHEME 4. Influence of Pivalic Acid in the Direct
Arylation of Benzene23
These studies prompted us to explore the use of the direct
arylation conditions developed for CMD-type aromatic coupling
partners to π-rich heteroaromatics, with a particular focus on
the use of pivalate additives. In this paper, we describe the
outcomes of these studies including the establishment of broadly
useful direct arylation reaction conditions that enable efficient
cross-coupling between a wide range of coupling partners with
a 1:1 substrate stoichiometry.
Results and Discussion
Previous work in our group has focused on the use of
palladium acetate in conjunction with sterically encumbered
alkylphosphine ligands and potassium carbonate as a stoichio-
metric base for use in direct arylation reactions with a wide
range of electron-deficient arenes and (predominantly) aryl
bromide coupling partners. While these conditions proved to
be successful for several aromatic substrates, extension to arenes
such as benzene23 and nitrobenzene22b relied on the use of
substoichiometric amounts of pivalate additives (Scheme 3). For
example, in the absence of pivalate, no reaction is observed
with benzene while the addition of 30 mol % pivalic acid to a
reaction run with an excess of potassium carbonate base
(generating potassium pivalate in situ) provides greater than 80%
yield of benzene direct arylation (Scheme 4).23 This increased
reactivity was initially rationalized by invoking the CMD
pathway where the pivalate was serving as a soluble proton
transfer agent from the arene and palladium catalyst to the
insoluble carbonate base and has been employed in other types
ofarene/alkanefunctionalizationreactions.10i,15c,17e,22b,24d,e,25c,d,27-29
With the finding that the CMD pathway may also apply to
heterocyclic aromatic compounds,27 similar conditions were
evaluated for their use. Three arenes were selected to evaluate
the impact of added pivalic acid (in situ becoming potassium
pivalate), benzothiophene 1, 4-methylthiazole 2, and the in-
(21) For copper-catalyzed direct arylation of heteroaromatics, see: (a) Do,
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L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081–
3084. (c) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 15185–15192. (d) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M.
Tetrahedron Lett. 2008, 49, 1598–1600.
(22) For palladium-catalyzed intermolecular direct arylation of perfluoroben-
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T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754–8756. (b) Caron, L.;
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derivatives, see: Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–
16497.
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Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020–18021. (b) Leclerc, J.-P.;
Fagnou, K. Angew., Chem. Int. Ed. 2006, 45, 7781–7786. (c) Campeau, L.-C.;
Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266–3267. (d)
Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.; Gorelsky,
S. I.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276–3277. (e) Campeau, L.-C.;
Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H.-Y.;
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Chem. Soc. 2008, 130, 52–54.
(25) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
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Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2007, 129, 6880–6886. (d) Pascual, S.; De Mendoza, P.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. Tetrahedron 2008, 64, 6021–
6029. (e) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299–
2302.
(28) (a) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 14570–14571. (b) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008,
64, 6015–6020. (c) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008,
10, 1759–1762. See also ref 25d.
(29) Similar effects have also been reported in ruthenium-catalyzed direct
arylation: (a) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2302. This benefit is likely due to the involvement of an analogous CMD-
type mechanism in these reactions; see: (b) Ozdemir, I.; Demir, S.; C¸ etinkaya,
B.; Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc.
2008, 130, 1156–1157.
(26) (a) Catellani, M.; Chiusoli, P. J. Organomet. Chem. 1992, 425, 151–
154. (b) Gonza´lez, J. J.; Garc´ıa, N.; Go´mez-Lor, B.; Echavarren, A. M. J. Org.
Chem. 1997, 62, 1286–1291. (c) Martin-Matute, B.; Mateo, C.; Cardenas, D. J.;
Echavarren, A. M. Chem.sEur. J. 2001, 7, 2341–2348.
(27) For mechanistic insights on palladium-catalyzed intermolecular direct
arylation of heteroaromatics, see: Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 10848–10849.
¨
1828 J. Org. Chem. Vol. 74, No. 5, 2009

Direct Arylation of Heteroatom-Containing Aromatic Compounds
dolizine 3. With the goal of establishing reaction conditions that
employ a 1:1 heteroarene/haloarene ratio, both the heterocycle
and the aryl bromide were employed in equimolar quantities.
For example, reactions of benzothiophene 1 and 4-bromotoluene
with palladium acetate (2 mol %), tricyclohexylphosphine (in
its bench-stable phosphonium tetrafluoroborate form,30
PCy3 ·HBF4) (4 mol %) and potassium carbonate as the base
(1.5 equiv) in N,N-dimethylacetamide (DMA, 0.3 M) at 100
°C are outlined in Figure 1. In the absence of pivalic acid, very
low conversion was observed (approximately 10% after 3 h).
On the other hand, addition of only 10 mol % of PivOH resulted
in a dramatic increase in reactivity, giving 65% conversion after
the same reaction time. The yield is further improved by
increasing the amount of pivalic acid to 30 mol %, which
generates greater than 80% GC yield after 3 h. A further increase
in the amount of pivalic acid above 30 mol % does not improve
the reactivity nor the yield beyond that observed with 30 mol
%. Very similar trends were also observed with 4-methylthiazole
2 (Figure 1b). In contrast, the effect of pivalic acid was less
pronounced for the highly nucleophilic indolizine 3 that exhibits
good reactivity even in the absence of added pivalate (Figure
1c). These trends may hold mechanistic significance and are a
focus of continued study. Nonetheless, the observation that the
use of a substoichiometric quantity of pivalic acid in conjunction
with a stoichiometric amount of insoluble carbonate base should
be of broad use in the establishment of generally applicable
direct arylation reaction conditions and in the establishment of
new reactions.
To evaluate the potential breadth of these reaction conditions,
a survey of heterocyclic cross-coupling partners was carried out
maintaining a strict 1:1 heteroarene/haloarene stoichiometry
(Table 1). Standard reaction conditions for these processes were
adopted to involve the use of the heterocycle (1 equiv), an aryl
bromide (1 equiv), Pd(OAc)2 (2 mol %), PCy3 ·HBF4 (4 mol
%), PivOH (30 mol %), and K2CO3 (1.5 equiv) in DMA (0.3
M) at 100 °C. The use of equimolar arene coupling partner ratios
and the use of 2 mol % catalyst (as opposed to 5 mol %, which
is more commonly employed when evaluating the scope of these
transformations) differentiates many of these entries from
previous reports and is more completely delineated for each
substrate class below.
C3-Substituted benzothiophenes have recently been employed
in direct arylation reactions using a slight excess of the aryl
halide substrate (1.1-1.5 equiv).8c,e Under the standard condi-
tions developed herein, unsubstituted benzothiophene 1 reacts
with numerous aryl bromides, providing the corresponding
2-arylbenzothiophenes 4a-i in synthetically useful yields after
4 h (entries 1-9). A reaction between 1 and 5-acetyl-2-
bromothiophene also furnished the heterocyclic biaryl product
4j, albeit in lower yield (entry 10). C2-Substituted thiophenes
are also good substrates for direct arylation. Previous reports
employing thiophene derivatives commonly necessitate the use
of small to moderate excesses of the thiophene cross-coupling
partner (between 1.2 and 3 equiv).8b,f,k Under the standard
conditions, thiophenes bearing C2 electron-withdrawing groups
(7 and 9) or electron-donating groups (11, 13 and 15) furnish
the 5-substituted products 8, 10, 12, 14, 16, and 18 in moderate
to very good yields (entries 12-24). With these substrates,
longer reaction times were required to reach high conversions
(typically 16 h).
FIGURE 1. Influence of pivalic acid in the direct arylation of
heteroaromatics with 4-bromotoluene. (a) GC yield in coupling product
overtime (min), using tetradecane as an internal standard. (b) Pd(OAc)2
(2 mol %), PCy3 ·HBF4 (4 mol %). (c) Pd(OAc)2 (1 mol %), PCy3 ·HBF4
(2 mol %).
Benzofurans have been more rarely examined in direct
arylation6g,j and were found to be more problematic substrates
under these conditions. For example, treatment of benzofuran
17 with 2-bromotoluene results in arylation at C2 in 29% yield
(entry 25). Other bromoarenes gave lower yields. On the other
(30) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295–4298.
J. Org. Chem. Vol. 74, No. 5, 2009 1829

Lie´gault et al.
TABLE 1. Scope of the Direct Arylation of Aromatic Heterocyclesa
1830 J. Org. Chem. Vol. 74, No. 5, 2009

Direct Arylation of Heteroatom-Containing Aromatic Compounds
TABLE 1. Continued
J. Org. Chem. Vol. 74, No. 5, 2009 1831

Lie´gault et al.
TABLE 1. Continued
a Conditions (unless otherwise specified): heterocycle (1 equiv), aryl bromide (1 equiv), Pd(OAc)2 (2 mol %), PCy3 ·HBF4 (4 mol %), PivOH (30 mol
%), K2CO3 (1.5 equiv), DMA (0.3 M), 100 °C. b Heterocycle (1.5 equiv). c Heterocycle (2 equiv). d Aryl bromide (1.5 equiv), K2CO3 (2 equiv). e Aryl
bromide (2 equiv), K2CO3 (2.5 equiv). f Pd(OAc)2 (4 mol %), PCy3 ·HBF4 (8 mol %). g K2CO3 (2.5 equiv).
hand, substituted furans 19 and 21 were found to participate in
these transformations with improved yield when employing a
1:1 or 2:1 furan/aryl bromide stoichiometryscomparing favor-
able to previous reports where 2-10 equiv of the furan have
been used.9 The yields with many of these reactions were
diminished due to the formation of furan/benzofuran arylation
regioisomers and to the presence of double arylation as a side
reaction. In cases where double arylation is problematic, the
use of more sterically hindered arylbromides results in increased
yield (entry 28 vs 27).
of aryl halide,11c can be accomplished under the standard
conditions to give arylated products 24, 26, and 28 in moderate
to good yields and with good regioselectivity (entries 29-32).
Similarly, substituted indolizines, first investigated by Gevor-
gyan,16 are excellent substrates for this transformation. For
example, indolizines 3 and 30 will react to give the biaryl
products 29 and 31 in very good yields, between 80% and 90%
(entries 33-37). When these substrates are reacted with electron-
deficient aryl bromides (bearing either an ester or a nitro group),
or with 2-acetyl-5-bromothiophene, longer reaction times of
16-24 h are required (entries 35, 36, and 37, respectively). This
is noteworthy since we have observed diminished reactivity
associated with electron-poor aryl bromide partners with other
Direct arylation of pyrrole substrates, which has previously
been achieved with a small excess of the pyrrole chlorozinc
anion,12 or as the SEM-protected pyrrole with a slight excess
1832 J. Org. Chem. Vol. 74, No. 5, 2009

Direct Arylation of Heteroatom-Containing Aromatic Compounds
SCHEME 5. Representative Unsuccessful Coupling
Products (Reactions Performed Using Standard Conditions;
Conversions Determined by GC-MS by Consumption of the
Limiting Starting Material)
coupling partners (vide infra). While the reason for this
diminished reactivity has not been established, it warrants
additional attention. We also determined that indolizine 29a can
undergo a second arylation to provide the corresponding
trisubstituted product 29d (entries 38-40).
Other heterocycles, such as imidazoles 32 and 34, triazoles
36, 38, and 40, and imidazopyrimidines 42 and 44 also react
efficiently with electron-rich and electron-deficient arylbromides
to give biaryls 33, 35, 37, 39, 41, 43, and 45 respectively (entries
41-54). In previous reports, these substrates have been suc-
cessfully coupled using a slight excess of the aryl halide
coupling partner (1.5-2 equiv).13a,f,15a,c,18a,c Finally, thiazole
46, 4- and 2-substituted thiazoles 2 and 49, 4,5-disubstituted
thiazoles 48b and 51, and oxazole 53 were also found to be
suitable components in the direct arylation reaction using our
optimized conditions, providing the corresponding products 47,
48, 50, 52, and 54 in good yields (entries 55-67), with a
regioselectivity in favor of the C5 position (when available,
entries 55-64). With thiazole, the use of some heterocyclic
arylbromides may also be used, such as in the reaction between
4-methylthiazole 2 and 3-bromopyridine which gives 48e in 56%
yield (entry 61).
All of the preceding reactions were performed with aryl
bromides since we had noted in previous studies superior
outcomes associated with these substrates. To probe the influ-
ence of the halide component under these conditions, 4-tolyl
chloride, bromide, iodide, and triflate were reacted with
heterocycles 1 and 49. With both substrates, optimal results are
achieved with the aryl bromide cross-coupling partner (entry
3). With benzothiophene 1, use of iodotoluene gave the
corresponding product 4a in 18% and 32% yields in the absence
or in the presence of silver carbonate,31 respectively (entries 1
and 2). We have previously observed an inhibitory effect of
iodide anions on direct arylation and a similar inhibition may
be occurring here.31 Despite the use of very electron-rich
phosphine ligands, which enable the use of aryl chloride
substrates in other types of cross coupling reactions,14e,15b,c the
use of a less reactive aryl chloride also gives inferior outcomes
(entry 4), as does the use of the aryl triflate (entry 5).
2-Isobutylthiazole 49 followed similar reactivity trends as 1,
with yields comprising between 33% and 46% using 4-iodo-
toluene or 4-tolyltriflate (entries 6, 7, and 10). No product was
observed with 4-chlorotoluene (entry 9). The mechanistic
reasons for the apparent difference in outcomes observed as the
nature of the halide cross-coupling partner is changed merits
further attention and is likely not unity for all species. Nonethe-
less, based on these results, we recommend the use of aryl
bromide substrates in direct arylation reaction when such a
choice is possible.
TABLE 2. Effect of the (Pseudo)halide on the Direct Arylation of
Aromatic Heterocyclesa
a Isolated yields. b 0.5 equiv of Ag2CO3 was added.
to traditional cross-coupling reactions, such limitations must
increasingly be identified and resolved. These limitations also
point to the continued need for further methodological develop-
ments to overcome these challenges.
While the conditions described in this report were found to
be broadly applicable, we also observed very low yields in
several cases (Scheme 5). For instance, some electron-deficient
haloarenes, bearing a cyano, nitro, or acetyl group, as well as
pyridines or their N-oxide counterparts, typically give rise to
low yields. We were also unable to couple several heterocycles,
such as unprotected imidazoles, 2-aminothiazole (unprotected
or acyl-protected), isoxazole, benzothiazole, and benzoxazole.
For direct arylation to continue to emerge as a viable alternative
Conclusion
In summary, we have established broadly applicable reaction
conditions for the palladium-catalyzed direct arylation of a very
wide variety of heteroatom-containing aromatic compounds with
arylbromides. These conditions highlight the utility associated
with the use of substoichiometric quantities of pivalic acid (in
situ generated potassium pivalate) in accelerating direct arylation
and improving reaction outcomes across a broad range of arene
classes. This establishment of these conditions should provide
a valuable starting point to those wishing to examine the use of
(31) It has been previously reported than silver salt additives could overcome
the poisoning effect resulting from the accumulation of iodide in the reaction
media: Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581–590.
J. Org. Chem. Vol. 74, No. 5, 2009 1833

Lie´gault et al.
δ 7.84 (br d, J ) 7.8 Hz, 1H), 7.75 (br d, J ) 7.6 Hz, 1H), 7.60
(d, J ) 8.0 Hz, 2H), 7.45 (d, J ) 0.5 Hz, 1H), 7.33 (ddd, J ) 8.1,
7.2 and 1.3 Hz, 1H), 7.29 (ddd, J ) 8.2, 7.2 and 1.4 Hz, 1H), 7.22
(d, J ) 8.0 Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
144.4, 140.8, 139.3, 138.3, 131.5, 129.6, 126.4, 124.4, 124.1, 123.4,
122.2, 118.8, 21.2.
direct arylation in biaryl synthesis and facilitate the discovery
of other novel cross-coupling partners in this type of chemistry.
Experimental Section
General Procedure for the Direct Arylation of Heter-
ocycles. K2CO3 (1.5 equiv), Pd(OAc)2 (2 mol %), PCy3 ·HBF4 (4
mol %), and PivOH (30 mol %) were weighed to air and placed in
a screw-cap vial equipped with a magnetic stir bar. The heterocycle
(1 equiv) and the aromatic halide (1 equiv) were added at this point
if solids. The vial was purged with argon, and DMA (0.3 M) was
added. The heterocycle (1 equiv) and the aromatic halide (1 equiv)
were added at this point if liquids. The reaction mixture was then
vigorously stirred at 100 °C over the indicated time. The solution
was then cooled to rt, diluted with EtOAc, washed with H2O (3
times), dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography to afford the corresponding product.
Acknowledgment. We thank NSERC, the University of
Ottawa, and the ACS (PRF Type AC) for support of this work.
The Research Corporation, Boehringer Ingelheim (Laval), Merck
Frosst Canada, Merck Inc., Eli Lilly, Amgen, and Astra Zeneca
Montreal are thanked for additional unrestricted financial
support. Elisia Villemure is kindly acknowledged for the loan
of pyrrole compounds.
Supporting Information Available: General considerations;
synthesis of starting materials 23, 25, and 27; characterization
of all compounds; copies of NMR spectra of all coupling
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
2-(p-Tolyl)benzothiophene 4a. Compound 4a was synthesized
according to the general procedure and exhibited identical spectral
data according to previous report:32 1H NMR (400 MHz, CDCl3)
(32) Baziard-Mouysset, G.; Tchani, G. W.; Stigliani, J. L.; Payard, M.;
Bonnafous, R.; Tisne-Versailles, J. Eur. J. Med. Chem. 1993, 28, 539–546.
JO8026565
1834 J. Org. Chem. Vol. 74, No. 5, 2009