Palladium-catalyzed decarboxylative cross-coupling reaction between heteroaromatic Carboxylic acids and Aryl halides

Article abstract of DOI:10.1021/jo9022793

"Chemical Equation Presented" A full overview of the decarboxylative cross-coupling reaction between heteroaromatic carboxylic acids and aryl halides is described. This transformation employs palladium catalysts with short reaction times providing facile synthesis of aryl-substituted heteroaromatics. The effect of each reaction parameter including solvent, base, and additive employed as well as the full substrate scope of this transformation are reported. Mechanistic evidence is also disclosed that sheds light on possible reaction pathways.

Full text of DOI:10.1021/jo9022793

pubs.acs.org/joc
Palladium-Catalyzed Decarboxylative Cross-Coupling Reaction Between
Heteroaromatic Carboxylic Acids and Aryl Halides
Franc-ois Bilodeau,* Marie-Christine Brochu, Nicolas Guimond, Kris H. Thesen, and
Pat Forgione*
ꢀ
Boehringer Ingelheim (Canada) Ltd. Research and Development, 2100 rue Cunard, Laval (Quebec),
Canada H7S 2G5
francois.bilodeau@boehringer-ingelheim.com
Received November 20, 2009
A full overview of the decarboxylative cross-coupling reaction between heteroaromatic carboxylic
acids and aryl halides is described. This transformation employs palladium catalysts with short
reaction times providing facile synthesis of aryl-substituted heteroaromatics. The effect of each
reaction parameter including solvent, base, and additive employed as well as the full substrate scope
of this transformation are reported. Mechanistic evidence is also disclosed that sheds light on possible
reaction pathways.
Introduction
alternative methods that attempt to address these issues
have begun to emerge. Direct functionalization through
C-H activation methods5 is an elegant example of atom
economy as well as synthetic efficiency since it precludes the
need of prefunctionalization. However, despite recent ad-
vances, a key challenge that persists is regioselective C-H
activation.
The metal-catalyzed decarboxylative cross-coupling strat-
egy has been recently highlighted6 as a new synthetically
useful tool. This stems from the observation that common
carboxylic acids can be employed as coupling partners in
palladium-catalyzed cross-coupling reactions. Pioneering
work in this field was reported by Myers7 which demon-
strated the use of a highly electrophilic palladium source to
generate, from electron-rich benzoic acids, the requisite Pd-
(II) species that subsequently underwent a Mirozoki-Heck
coupling reaction (Scheme 1).
Much effort has been devoted in the last decades toward
new methods to form carbon-carbon bonds. Notably,
metal-catalyzed cross-coupling reactions have found great
utility in synthetic chemistry and are now valuable tools that
are routinely employed.1 As a result, palladium-catalyzed
reactions,2 such as Suzuki-Miyaura3 or Stille-Migita4 cou-
plings, can often be found as common synthetic steps in
numerous total syntheses. However, drawbacks still exist,
including the limited commercial availability of some cou-
pling partners or their tedious preparation. In recent years,
(1) (a) Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998. (b) Transition Metals for Organic Synthesis,
2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004. (c) Handbook
of Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim,
2005; Vols. 1&2. (d) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
(e) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998. (f) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674.
(2) (a) Palladium Reagents in Organic Synthesis; Heck, R. F., Ed.; Academic
Press: New York, 1985. (b) Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Tsuji, J., Eds.; Wiley & Sons: New York, 1995. (c) Beller, M.;
Zapf, A. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; Wiley: New York, 2002; Vol. 1, p 1209. (d) Tamao, K.;
Hiyama, T.; Negishi, E.-I. J. Organomet. Chem. 2002, 653, 1.
(5) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Proch, S.; Kempe,
R. Angew. Chem., Int. Ed. 2007, 46, 3135. (c) Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 11904. (d) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. (e) Stuart, D. R.; Fagnou, K. Science 2007, 316,
1172. (f) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed.
2007, 46, 7996.
(6) (a) Baudoin, O. Angew. Chem., Int. Ed. 2007, 46, 2. (b) Goossen, L. J.;
Rodriguez, N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100. (c) Moon,
J.; Jang, M.; Lee, S. J. Org. Chem. 2009, 74, 1403.
(3) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Molander,
G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49.
(4) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(7) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc., 2005,
127, 10323 and references therein.
1550 J. Org. Chem. 2010, 75, 1550–1560
Published on Web 02/08/2010
DOI: 10.1021/jo9022793
r
2010 American Chemical Society

Bilodeau et al.
JOCArticle
SCHEME 1
TABLE 1. Pd-Catalyzed Arylation of Various Heteroaromatic Car-
boxylic Acids with PhBr
SCHEME 2
SCHEME 3
More recently, two groups have reported the use of the
decarboxylative coupling concept using benzoic acids
(Scheme 2). Employing copper(I) salts, Goossen et al.8 were
able to generate the nucleophilic partner from benzoic acids
for the synthesis of biaryl motifs using palladium catalysts.
Additionally, Becht et al.9 reported a strategy in which they
were able to perform a decarboxylative cross-coupling reac-
tion between a benzoic acid and an aryl halide using palla-
dium catalyst with silver carbonate as the additive
(Scheme 2). Steglich and co-workers reported an intramole-
cular Heck-like coupling between an aryl bromide and a
tetrasubstituted pyrrole carboxylic acid in their synthesis of
lamellarin L employing a stoichiometric amount of palla-
dium (Scheme 3).11 Subsequently, many reports have ap-
peared in the literature expanding the use of carboxylic acids
and related moieties in metal catalyzed cross-couplings.10
Previously, we reported the intermolecular coupling reac-
tion between heteroaromatic carboxylic acids and aryl ha-
lides employing catalytic palladium.12 This transformation
differs from both the Myers couplings and the Goosen/
Becht couplings of carboxylic acids. In the Myers case, the
aReaction conditions: heterocycle (0.80 mmol, 2.0 equiv), phenyl
bromide (0.40 mmol, 1 equiv), Pd[P(t-Bu)3]2 (5 mol %), n-Bu4NCl H2O
(0.40 mmol, 1 equiv), Cs2CO3 (0.60 mmol, 1.5 equiv), DMF (4 mL),
3
microwave, 170 °C, 8 min. bYield without additive (yield with n-
Bu4NCl H2O = 74% (contains 10 mol % of 1-methyl-2-pyrrole-n-
butylcarboxylic ester by 1H NMR)). cNo trace of product by HPLC.
3
carboxylic acid is employed to generate the electrophilic
coupling partner that undergoes subsequent coupling, in
an oxidative Heck-type mechanism, with a nucleophilic
alkene. In the Goosen/Becht examples, decarboxylation is
promoted by the presence of a second metal (Cu or Ag,
respectively) which generates the nucleophilic coupling part-
ner from the carboxylic acid, thus permitting the catalytic
cycle to be operative, in these cases with aryl halides as
coupling partners. In the present system, and similarly to
the known reactivity of 5-membered heteroaromatic, the
nucleophilicity of the heteroaromatic partner stems from
the delocalization of the lone pair of electrons of the hetero-
atom into the ring, which then undergoes reaction with the
electrophilic, in situ generated, Ar-Pd(X)(L) species. An-
other distinction to be made is that because of the different
intrinsic nature of the carboxylic acid partner (aryl vs
heteroaryl) it is likely that, although similar, such transfor-
mations would follow different mechanistic pathways. Re-
cently, seminal work by Liu shed light on Pd-catalyzed
decarboxylative coupling of carboxylic acids with olefins.13
(8) (a) Goossen, L. J.; Deng, G; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L.
M. J. Am. Chem. Soc. 2007, 127, 4824. (c) Goossen, L. J.; Rodriguez, N.;
Linder, C. J. Am. Chem. Soc. 2008, 130, 15248. (d) Goossen, L. J.;
Zimmermann, B.; Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103.
(9) Becht, J.-M.; Catala, C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9,
1781.
(10) (a) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008,
10, 1159. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 127, 3510. (c) Wang, C.;
Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (d) Miyasaka, M.;
Fukushima, A.; Satoh, T.; Hirano, K.; Miura, M. Chem.;Eur. J. 2009, 15,
3674. (e) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree, R. H.
Chem. Commun. 2008, 6312. (f) Use of silanolate was reported: Denmark, S.
E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440.
(11) Peschko, C.; Winklhofer, C.; Steglich, W. Chem.;Eur. J. 2000, 6,
1147.
(12) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M.
D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 126, 11350.
(13) Zhang, S.-L.; Fu, Y.; Shang, R.; Guo, Q.-X.; Liu, L. J. Am. Chem.
Soc. 2010, 132, 638 and references cited therein.
J. Org. Chem. Vol. 75, No. 5, 2010 1551

Bilodeau et al.
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SCHEME 4
considerations will be given later in this account; the first
section will provide an exhaustive study on the effect of various
reaction parameters as well as the scope of the reaction.
Results and Discussion
Base Effect. We first investigated the effect of the base on
the reaction outcome. Numerous bases were successfully
employed to promote the transformation (Table 2). Carbo-
nates (entries 1-3), fluorides (entries 5 and 6), and potassium
acetate (entry 8) all afforded the desired product in good
yields. However, the use of both lithium carbonate (entry 4)
and lithium fluoride as bases (entry 7) provided the desired
product in poor yields. This supports the hypothesis that a
precomplexation step between a carboxylate anion and a
Pd(II) species is pivotal to the reaction course. Both potas-
sium bicarbonate (entry 9) and potassium phosphate (entry
10) were found to give incomplete conversions (72% and
78%, respectively). Finally, complete conversion was ob-
served when triethylamine (entry 11) was used, but it was
found to be unsuitable for this transformation, giving a
complex mixture of products.
SCHEME 5. Postulated Mechanism
Solvent Effect. A similar study was undertaken to deter-
mine if solvent polarity played a significant role in the
reaction outcome (Table 3). We were pleased to observe that
the reaction could be efficiently conducted in a number of
solvents, ranging from highly polar (DMF, NMP and DMA,
entries 1-3) to nonpolar solvents such as xylenes (entry 8).
Moreover, the presence of protic solvents, such as water and
ethanol (entry 4 and 9), in DMF was tolerated and resulted in
only slightly lower yields (entries 4 and 9).
Catalyst Effect. Next, we examined the range of catalysts
that could be employed by evaluating different palladium
sources as well as varying the ligands and/or ligand stoichi-
ometry (Table 4). Rewardingly, only a minor difference was
observed when comparing reference conditions (entry 1) to
conditions where the catalyst is formed in situ (entry 2).
Further, since it has been previously demonstrated that the
active palladium species for this system could be a monopho-
sphine species,15 the experiment was conducted with a 1:1
ligand to catalyst ratio. Reduction of the ligand ratio led to
the desired product in comparable yield (entry 3 vs entry 2).
The use of a Pd(0) catalyst stabilized with an NHC ligand
was found not to be suitable for this transformation (entry
5). Lastly, other commercially available palladium catalysts
Additionally, in contrast to the intramolecular Heck-like
coupling of a pyrrole that is stoichiometric in palladium as
reported by Steglich, our communication demonstrated a
catalytic, intermolecular decarboxylative coupling in the
presence of reactive C-H groups for a variety of heteroaro-
matics to generate the desired products in modest to good
yields (Table 1). Despite the variety of examples demon-
strated in our initial report, some limitations were observed,
such as the effect on the yield of some substituents present on
the heteroaromatic partner (for example, entry 3 vs 4). We
demonstrated that the reduction in yield was in fact due to
the formation of 2,3-diarylated heteroaromatic products
(Scheme 4), which could be reduced by appropriate selection
of the additive. Despite this beneficial effect we still could
observe, in the case of entry 4, a 5:1 ratio of mono- and
diarylated product, respectively.
The reaction was also found to be limited by the specificity
of the position of the acid on the hereoaromatic ring (Table 1,
entry 9). In order to ensure that this reactivity was specific to
5-membered heteroaromatics, we also submitted benzoic
acid to the reaction conditions (entry 10) where, similarly
to 3-furoic acid, no coupling product was observed.
TABLE 2. Base Effect
In an attempt to provide a rationale for the formation of
the 2,3-diarylated side products, we presented in our initial
report a mechanism invoking C3 electrophilic palladation.
(Scheme 5, path C). Effectively, this mechanistic pathway
accounts for the production of both 2-arylated and 2,3-
diarylated products. Similar observations were reported by
Miura’s group for the palladium-catalyzed multiple aryla-
tion of thiophenes.14 Moreover, it highlights the difference
between our findings and those from the groups studying
couplings employing benzoic acids where additives and/or
cocatalystsarerequired topromotedecarboxylation. This last
point is important, since it explains why our method cannot
be extended to benzoic acids. More detailed mechanistic
entry
base
yield (%)
entry
base
LiF
KOAc
KHCO3
K3PO4
Et3N
yield (%)
1
2
3
4
5
6
Cs2CO3
K2CO3
Na2CO3
Li2CO3
CsF
88
81
88
14
81
75
7
8
9
10
11
4
84
50b
56b
36c
KF
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), 1-meth-
3
yl-2-pyrrolecarboxylic acid (0.80 mmol, 2.0 equiv), phenyl bromide
(0.40 mmol, 1 equiv), Pd[P(t-Bu)3]2 (5 mol %), base (0.60 mmol,
1.5 equiv), DMF (4 mL), microwave, 170 °C, 8 min bIncomplete
reaction. cComplex mixture was obtained
(14) Okazawa; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286.
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TABLE 3. Solvent Effect
TABLE 5. Pd-Catalyzed Arylation of N-Substituted Pyrrole-2-car-
boxylic Acid with PhBr
entry
solvent
DMF
NMP
yield (%) entry
solvent
THF
MeCN
xylenes
DMF/EtOHb
yield (%)
1
2
3
4
5
88
85
81
71
0
6
7
8
9
86
74
74
74
DMA
DMF/H2Ob
DMF/H2Oc
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), 1-meth-
3
yl-2-pyrrolecarboxylic acid (0.80 mmol, 2.0 equiv), phenyl bromide
(0.40 mmol, 1 equiv), Pd[P(t-Bu)3]2 (5 mol %), Cs2CO3 (0.60 mmol,
1.5 equiv), solvent (4 mL), microwave, 170 °C, 8 min. b19:1 mixture.
c1:1 mixture.
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), hetero-
3
cycle (0.80 mmol, 2.0 equiv), phenyl bromide (0.40 mmol, 1 equiv),
Pd[P(t-Bu)3]2 (5 mol %), Cs2CO3 (0.60 mmol, 1.5 equiv), DMF (4 mL),
microwave, 170 °C, 8 min.
TABLE 4. Catalyst Effect
TABLE 6. Intramolecular Pd-Catalyzed Arylation of N-Substituted
Pyrrole-2-carboxylic Acid
entry
catalyst
Pd[P(t-Bu)3]2
PdCl2 þ P(t-Bu)3 (10%)
PdCl2 þ P(t-Bu)3 (5%)
PdCl2 þ PMe(t-Bu)2-BF4 (5%)
PEPPSI-i-Prb
yield (%)
1
2
3
4
5
88
80
79
81
0c
entry
substrate
product
yield (%)
6
7
8
9
10
Pd[P(Ph)3]4
PdCl2[P(Ph)3]2
PdCl2 þ P(Ph)3 (10%)
Pd(OAc)2 þ P(Ph)3 (5%)
PdCl2[1,2-C2H4(P(Ph)2)2]
43
76
70
62
52
1
2
n = 1, 21a
n = 2, 22a
21b
22b
60
69
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), hetero-
cycle (0.80 mmol, 2.0 equiv), Pd[P(t-Bu)3]2 (5 mol %), cesium carbonate
(0.60 mmol, 1.5 equiv), DMF (4 mL), microwave, 170 °C, 8 min.
3
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), 1-meth-
3
yl-2-pyrrolecarboxylic acid (0.80 mmol, 2.0 equiv), phenyl bromide (0.40
mmol, 1 equiv), catalyst (5 mol %), Cs2CO3 (0.60 mmol, 1.5 equiv),
DMF (4 mL), microwave, 170 °C, 8 min. bPEPPSI-i-Pr = [1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)
dichloride. cA complex mixture was obtained.
observed and that the decarboxylative coupling product pre-
vailed over the C-H activation product.
Scope of the Reaction: Aryl Halide. In order to assess the
full scope of the aryl halide coupling partner, we undertook
a systematic study employing the pyrrole-2-carboxylic acid
scaffold to evaluate coupling with various aryl halides
(Table 7). Iodides, bromides, triflates, as well as chlorides
(entries 1-4) were all found to give the desired product in
good yields. The reaction is tolerant to substituents present
on the aryl ring, affording the desired product in good
yields, regardless of whether the substituents are electron-
donating (entries 5, 9, 11 and 12) or -withdrawing (entries 7,
8, 10, 13, and 14). In only one case, namely 2-bromoanisole
(entry 6), was the reactioncompletely shutdown; however, the
corresponding phenol (entry 9) and 4-bromoanisole (entry 12)
both produced the desired product in good yield.
Heteroaromatic bromides can also be employed as shown
in entries 15, 17, and 19. The low yield obtained with 2-
bromothiazole (entry 16) may be due to competing C5-H
activation as a side reaction. In addition, the 2,4-di-
methylthiazole (entry 17) undergoes the requisite transfor-
mation, but no desired products were obtained using the
more electron-deficient 5-bromo-4-trifluoromethyl-2-meth-
yl-1,3-thiazole (entry 18) as the coupling partner. However,
the examples from Table 7 exemplify this palladium-cata-
lyzed decarboxylative coupling employing heteroaromatic
carboxylic acids as an efficient transformation. Reward-
ingly, it is also clear that the reaction outcome is mostly
unaffected by steric and/or electronic effects.
(entries 6, 7, and 10) were also employed, and all gave modest
to good yields.
Reaction with N-Arylated Pyrroles. The decarboxylative
coupling was examined to determine whether the electronic
effects on the heteroaromatic acids would affect the reaction
course. Toward this aim, various N-substituted pyrroles
were prepared16 and submitted to the reaction conditions
(Table 5). Interestingly, all of the four analogues gave the
desired products in modest to good yields. Moreover, it
appears that a trend is observed where better yields are
obtained with more electron-rich heteroaromatics.
Intramolecular Arylation. Steglich and co-workers reported
previously an intramolecular decarboxylative coupling where
the C2- position on a pyrrole contained a carboxylic acid and all
other positions were substituted. In order to determine if
decarboxylative cross-coupling would occur preferentially over
competitive C-H activation, we examined an intramolecular
version of this transformation. Results from Table 6 show that
the yields obtained are lower than in the intermolecular case
(Table 1, entry 2, 88%). However, it is interesting that in both
cases no products resulting from intermolecular reaction were
(15) Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
6944.
(16) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578.
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TABLE 7. Pd-Catalyzed Arylation of 1-Methyl 2-Pyrrolecarboxylic Acid with Various Aryl Halides
aReaction conditions: 1-methyl-2-pyrrolecarboxylic acid (0.80 mmol, 2.0 equiv), aryl halide (0.40 mmol, 1 equiv), Pd[P(t-Bu)3]2 (5 mol %),
n-Bu4NCl H2O (0.40 mmol, 1 equiv), Cs2CO3 (0.60 mmol, 1.5 equiv), DMF (4 mL), microwave, 170 °C, 8 min. bMessy reaction. cNo reaction.
3
Thermal Conditions. All previous examples for this dec-
arboxylative cross-coupling reaction were performed by
microwave heating. As part of this extended study, we
wished to ensure this transformation could also be per-
formed under thermal conditions and evaluated the reaction
of pyrrole 2-carboxylic acid with phenyl bromide (Table 8).
We were pleased to observe that the reaction could be
performed under thermal conditions, although a decrease
in yields was observed (entries 1-4). The reaction time was
remarkably fast, however, as in most solvents the reaction
was complete within 2 h. A small quantity of water was again
tolerated (entry 4), although accompanied with a decrease in
yields (entry 1 vs 4). However, in contrast to microwave
heating, significantly lowered yields were observed when the
nonpolar solvent xylenes was employed (entry 5).
Mechanistic Considerations. In our initial communication,
we proposed a mechanism based on our preliminary empiri-
cal observations, namely that an important byproduct of this
process was C3-arylation. We also postulated that the car-
boxylate moiety could first attack the electrophilic
X-PdLAr complex formed from the oxidative addition
of the Pd(0) species into the C-X bond of the coupling
partner (Scheme 5). This postulated chelation is based on
Myers’ report and is supported by our observation that
lithium inorganic bases are not suitable for this trans-
formation, presumably due to the poor nucleophilicity of
the lithium carboxylate (see Table 2). Once this occurs, direct
decarboxylation, or potentially a concerted palladation-
decarboxylation, could occur to generate intermediate I (path
A) which, after reductive elimination, would provide the observed
product. However, this mechanistic pathway does not rationalize
the formation of the 2,3-diarylation products. Moreover, the
observation that there is no need for an additive specifically to
promote decarboxylation (i.e., Ag or Cu salts) in the case of
heteroaromatic carboxylic acids contradicts this proposal.
Due to these incongruities, we suggested in our earlier
communication that the reaction could follow a C3-electro-
philic palladation pathway (path C) to form the intermediate
III. Despite the fact that this type of reactivity has only
occasionally been invoked,17 it provided a rationale for most
(17) (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (b) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 4972. (c) Beck, E. M.; Grimster, N. P.; Hatley, R.;
Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528.
1554 J. Org. Chem. Vol. 75, No. 5, 2010

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TABLE 8. Pd-Catalyzed Arylation of 1-Methyl 2-Pyrrolecarboxylic
Acid with PhBr under Thermal Conditions
SCHEME 6. Molecular Orbital Analysis on Key Heteroaro-
matics
entry
solvent
DMF
NMP
DMA
DMF/H2Ob
xylenes
time (h)
yield (%)
1
2
3
4
5
1
1
1
2
5
57
66
63
45
23
aReaction conditions: n-Bu4NCl H2O (0.40 mmol, 1 equiv), 1-meth-
3
yl-2-pyrrolecarboxylic acid (0.80 mmol, 2.0 equiv), phenyl bromide (0.40
mmol, 1 equiv), Pd[P(t-Bu)3]2 (5 mol %), cesium carbonate (0.60 mmol,
1.5 equiv), solvent (4 mL), 140 °C, 8 min. b19:1 mixture.
of our key observations. Effectively, we hypothesized that
after the C3 electrophilic palladation a C3 to C2 palladium
migration18 could occur with concomitant or stepwise dec-
arboxylation to generate intermediate I. Our rationalization
of the formation of 2,3-diarylated compound was based on
the observation that intermediates such as III, when R = H,
could undergo a competing deprotonation reaction to gen-
erate intermediate IV. Reductive elimination of the latter
would give intermediate V that could re-enter the catalytic
cycle to ultimately yield the corresponding 2,3-diarylated
compound.
selectivity.21 Since π-nucleophilicity has been postulated to
contribute to reactivity and site selectivity,22 the HOMOs
were calculated for key heteroaromatics (Scheme 6).
Previously, we reported that C-H activation of 3-
methylthiophene produces a 3:1 mixture of C2:C5 arylation.
This is supported by the slight increase in the contribution to
the HOMO of C2 vs C5. Interestingly, the HOMO for 3-
methyl-2-thiophenecarboxylic acid is essentially identical to
3-methylthiophene; however, it yields exclusively the C2-
arylated product. This suggests the carboxylic acid group is
acting primarily as a directing group and does not signifi-
cantly change the π-character of the HOMO of the hetero-
aromatics.
Previously, we favored this mechanism since it provided a
rationale for the pivotal role of the carboxylic acid moiety
while accounting for the formation of 2,3-diarylated pro-
ducts through
a competing deprotonation pathway
Further, we designed competition experiments to shed
light on the mechanism. First, we reasoned that a competi-
tion experiment between 3-methyl-2-furoic acid and 3-
methylbenzofuran-2-carboxylic acid would provide infor-
mation on the comparative rates of C2 vs C3 electrophilic
palladation. Effectively, the C2-electrophilic palladation
should be of higher activation energy in the case of 3-
methylbenzofuran-2-carboxylic acid due to the fact that
the aromaticity of the phenyl group would be broken
(Scheme 7).
Since both substrates underwent the reaction with similar
yields, the rates were estimated through product distribution
after a competition experiment. We observed a 2.2:1 ratio
favoring the product resulting from the coupling with
3-methyl-2-furancarboxylic acid. This result seems to sup-
port the C2 electrophilic palladation pathway, since if the C3
pathway was favored, it could be expected that the product
resulting from the benzofuran analogue would have predo-
minated due to the lower aromatic character of the reacting
double bond.
Further, an additional competition experiment was de-
signed to evaluate electronic factors that could differentiate
between the proposed mechanisms. In this regard, two
analogues were synthesized and subjected to the reaction
conditions (Scheme 8). In the event, a 1.8:1 ratio in favor of
the electronic-rich substrate was obtained. This again lends
support to the C2 electrophilic palladation pathway (path B).
Namely, the electrophilicC3pathway followed bya migration
from C3 to C2 to yield the desired product should not be
affected by electronic factors at this position while the C2
electrophilic pathway should be affected.
(Scheme 5, III to IV). However, this proposal minimized
the propensity of 5-membered heteroaromatics to undergo
electrophilic aromatic substitution at the C2 position. This
behavior was nicely exemplified in the study of the electro-
philic iodination of pyrroles,19 as well as in the recent
publications reporting metal catalyzed C-H activation on
5- membered heteroaromatics. The Fagnou group has made
seminal contributions demonstrating such CMD-type me-
chanisms to account for these related transformations.20
These observations suggest that another plausible explana-
tion for the formation 2-arylated and 2,3-diarylated pro-
ducts could be a competition between C2 and C3 electro-
philic palladations (paths B and C). This implies that the
conversion of intermediate III to II may not occur, and thus,
the ratio of 2-arylated and 2,3-diarylated products could be
explained by the differences in the rates of C2 vs C3 electro-
philic palladations, respectively.
Acknowledging that these two pathways are plausible, we
attempted to gain additional knowledge to differentiate these
mechanistic possibilities. Toward this end, molecular orbital
analysis was performed to determine the role of the car-
boxylic acid on the π-bond reactivity as well as the C2/C5
(18) Hamel, P. J. Org. Chem. 2002, 67, 2854.
(19) Doak, K. W.; Corwin, A. H. J. Am. Chem. Soc. 1949, 71, 159.
ꢀ
(20) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826.
(21) DFT calculations of compounds 42 and 14a were performed to
obtain the equilibrium geometries from the ground states using the B3LYP-
(2) exchange correlation functional with the 6-311þþG** basis set for all
atoms.
(22) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.;
Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276.
J. Org. Chem. Vol. 75, No. 5, 2010 1555

Bilodeau et al.
JOCArticle
SCHEME 7. Pd-Catalyzed Arylation of Benzofuran-3-methyl-
carboxylic acid (0.80 mmol, 2 equiv), tetra-n-butylammonium
chloride hydrate (0.40 mmol, 1 equiv), base (0.60 mmol, 1.5
equiv), and catalyst (0.020 mmol, 0.05 equiv). Anhydrous DMF
(4 mL) was then added after which the mixture was stirred for
30 s and submitted to the microwave conditions (170 °C, 8 min,
high absorption level). The reaction mixture was then diluted
with ethyl acetate (50 mL), and the organic layer was washed
with brine (3ꢀ), saturated NaHCO3 solution (2ꢀ), water (1ꢀ),
and again with brine (1ꢀ). The organic layer was dried over
MgSO4 and filtered, and solvent evaporation over silica afforded
a solid residue that was purified using normal-phase silica gel.
2-(2-Tolyl)-1-methylpyrrole (7c; Table 7, Entry 5). Starting
from 1-methyl-2-pyrrolecarboxylic acid, the compound was
prepared and purified according to general procedure A to yield
the title compound as a colorless oil (52.1 mg, 0.304 mmol,
76%): HPLC (220 nm) 98.5%; 1H NMR (400 MHz, DMSO-d6)
δ 7.18-7.31 (m, 4H), 6.80 (s, 1H), 6.06 (s, 1H), 5.95 (s, 1H), 3.35
(s, 3H), 2.13 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 137.3,
132.7, 132.2, 130.8, 130.0, 127.8, 125.5, 108.2, 106.9, 33.8, 19.9;
HRMS (EI) calcd for C12H13N (Mþ•) 171.1048, found 171.1051.
2-(2-(Trifluoromethyl)phenyl)-1-methylpyrrole (7e; Table 7,
Entry 7). Starting from 1-methyl-2-pyrrolecarboxylic acid, the
compound was prepared and purified according to general
procedure A to yield the title compound as an off-yellow oil
(72.1 mg, 0.320 mmol, 80%): HPLC (220 nm) 97.8%; 1H NMR
(400 MHz, DMSO-d6) δ 7.83 (d, J = 7.8 Hz, 1H), 7.72 (t, J =
7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H),
2-carboxylic Acida
aConditions: 4-tolylBr, DMF, n-Bu4NCl hydrate, Pd[P(t-Bu)3]2, micro-
wave, 170 °C, 8 min.
SCHEME 8. Pd-Catalyzed Arylation of 5-Arylfuran-2-carboxy-
lic Acid Analoguesa
6.84 (br s, 1H), 6.06 (br s, 1H), 6.01 (br s, 1H) 3.33 (s, 3H); 13
C
aConditions: 4-tolylBr, DMF, n-Bu4NCl hydrate, Pd[P(t-Bu)3]2, micro-
wave, 170 °C, 8 min.
NMR (101 MHz, DMSO-d6) δ 133.4, 132.0, 128.8, 128.6, 126.1,
125.3, 122.8, 122.6, 109.7, 106.9, 33.9; HRMS (EI) calcd for
C12H10F3N (Mþ•) 225.0765, found 225.0767.
These results lead us to postulate that a mixed mechanism
is a distinct possibility depending on the structure of the
heteroaromatic scaffold employed (nature of substituents
and/or heteroatoms forming the ring). There is only the
formation of 2,3-diarylated products that constitutes an
unequivocal observation of one of the three pathways
(path C, Scheme 5); further studies are required that could
shed more light on the other mechanistic possibilities.
2-(2-Nitrophenyl)-1-methylpyrrole (7f; Table 7, Entry 8). Start-
ing from 1-methyl-2-pyrrolecarboxylic acid, the compound was
prepared and purified according to general procedure A to yield
the title compound as a brown oil (50.0 mg, 0.247 mmol, 62%):
HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 7.97
(d, J = 8.2 Hz, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.6 Hz,
1H), 7.57 (d, J = 7.5 Hz, 1H), 6.89 (br s, 1H), 6.05 (br s, 1H), 6.00
(br s, 1H) 3.43 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 149.8,
132.9, 132.5, 129.1, 127.2, 126.4, 124.2, 123.7, 109.2, 107.6, 34.0;
HRMS (EI) calcd for C11H10N2O2 (Mþ•) 202.0742, found
202.0745.23
Conclusion
We have demonstrated that the decarboxylative cross-
coupling reaction between heteroaromatic carboxylic acids
and aryl halides can be performed with a large range of aryl
halides. This is a valuable new route to compounds that are
commonly found in drug candidates. We have also shown
that the base and the solvent can be varied with only minor
impact on the reaction outcome. More importantly, the
transformation could be performed using catalysts that are
either preformed or formed in situ, both yielding similar
results. Efforts were also made to further understand the
operative mechanism for this intermolecular decarboxyla-
tive cross-coupling. Effectively, our observations lead us to
postulate that the electrophilic palladation pathways, over
direct decarboxylation, better accounts for the reactivity of
the 5-membered heteroaromatic carboxylic acids. This is in
contrast with what has been reported on related reactivity
using benzoic acids as metal surrogates.
2-(2-Hydroxyphenyl)-1-methylpyrrole (7g; Table 7, Entry 9).
Starting from 1-methyl-2-pyrrolecarboxylic acid, the compound
was prepared and purified according to general procedure A to
yield the title compound as a colorless oil (47.1 mg, 0.272 mmol,
68%): 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.12-7.16
(m, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H),
6.80-6.84 (m, 1H), 6.75-6.76 (m, 1H), 6.01 (d, J = 3.5, 1H),
5.93 (d, J = 3.5, 1H); 13C NMR (101 MHz, DMSO-d6) δ 155.1,
131.8, 131.2, 128.8, 122.3, 120.6, 118.9, 115.6, 108.3, 106.9, 34.2;
HRMS (EI) calcd for C11H12NO (Mþ•) 173.0843, found
173.0841.
2-(2-(Ethyl carboxylic ester)phenyl)-1-methylpyrrole (7h; Ta-
ble 7, Entry 10). Starting from 1-methyl-2-pyrrolecarboxylic
acid, the compound was prepared and purified according to
general procedure A to yield the title compound as a colorless oil
(65.4 mg, 0.285 mmol, 71%): HPLC (220 nm) >99%; 1H NMR
(400 MHz, DMSO-d6) δ 7.75 (d, J = 7.8 Hz, 1H), 7.58-7.62 (m,
1H), 7.49-7.53 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 6.79-6.81 (m,
1H), 6.01-6.03 (m, 1H), 5.89-5.90 (m, 1H), 4.04 (q, J = 7.0 Hz,
2H), 3.36 (s, 3H), 1.03 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz,
DMSO-d6) δ 167.7, 132.6, 131.8, 131.2, 129.0, 127.8, 122.6,
108.3, 107.0, 60.5, 33.8, 13.7; HRMS (EI) calcd for C14H15NO2
(Mþ•) 229.1109, found 229.1103.
Experimental Section
Preparation of Aryl-Substituted Heteroaromatic by Palla-
dium-Catalyzed Decarboxylative Coupling. General Procedure.
Unless otherwise noted, each reaction was performed using the
following procedure. In a microwave vial (2 to 5 mL), opened to
air, were added aryl halide (0.40 mmol, 1 equiv), heterocyclic
(23) Gryko, D. T.; Vakaliuk, O.; Gryko, D.; Beata, K. J. Org. Chem.
2009, 74, 9517.
1556 J. Org. Chem. Vol. 75, No. 5, 2010

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JOCArticle
2-(4-Tolyl)-1-methylpyrrole (7i; Table 7, Entry 11). Starting
from 1-methyl-2-pyrrolecarboxylic acid, the compound was
prepared and purified according to general procedure A to yield
the title compound as a colorless oil (53.6 mg, 0.313 mmol,
78%): HPLC (220 nm) 99%; 1H NMR (400 MHz, DMSO-d6) δ
7.31 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.80 (s, 1H),
6.09 (s, 1H), 6.03 (s, 1H), 3.61 (s, 3H), 2.32 (s, 3H); 13C NMR
(101 MHz, DMSO-d6) δ 135.7, 133.5, 130.2, 129.1, 127.9, 108.0,
2-(2,4-Dimethyl-5-thiazole)-1-methylpyrrole (7o; Table 7, En-
try 17). Starting from 1-methyl-2-pyrrolecarboxylic acid, the
compound was prepared and purified according to general
procedure A to yield the title compound as a colorless oil (52.6
mg, 0.274 mmol, 71%): HPLC (220 nm) >99%; 1H NMR (400
MHz, DMSO-d6) δ 6.89 (s, 1H), 6.13 (s, 1H), 6.08 (s, 1H), 3.48 (s,
3H), 2.61 (s, 3H), 2.20 (s, 3H); 13C NMR (101 MHz, DMSO-d6)
δ 163.7, 149.7, 124.2, 122.0, 121.3, 111.1, 107.5, 34.2, 18.8, 15.7;
HRMS (EI) calcd for C10H12N2S (Mþ•) 192.0721, found
192.0724.
107.3, 34.8, 20.7; HRMS (EI) calcd for C12H13N (Mþ•
171.1048, found 171.1051.24
)
2-(4-Methoxyphenyl)-1-methylpyrrole (7j; Table 7, Entry 12).
Starting from 1-methyl-2-pyrrolecarboxylic acid, the compound
was prepared and purified according to general procedure A to
yield the title compound as a very pale yellow oil (57.7 mg, 0.308
mmol, 77%): HPLC (220 nm) 99.4%; 1H NMR (400 MHz,
DMSO-d6) δ 7.34 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H),
6.77-6.78 (m, 1H), 6.01-6.05 (m, 2H), 3.78 (s, 3H), 3.59 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 158.1, 133.3, 129.3, 125.5,
123.4, 113.9, 107.6, 107.1, 55.1, 34.7.23
2-(5-Thiophene)-1-methylpyrrole (7q; Table 7, Entry 19).
Starting from 1-methyl-2-pyrrolecarboxylic acid, the compound
was prepared and purified according to general procedure A to
yield the title compound as an colorless oil (57.4 mg, 0.0.324
1
mmol, 78%): HPLC (220 nm) >99%; H NMR (400 MHz,
DMSO-d6) δ 6.90 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H),
6.01 (s, 1H), 3.66 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz,
DMSO-d6) δ 137.9, 132.3, 126.5, 126.0, 124.3, 124.2, 108.9,
107.4, 34.9, 14.8; HRMS (EI) calcd for C10H11NS (Mþ
177.0612, found 177.0609.26
)
3
2-(4-Trifluoromethyl)phenyl-1-methylpyrrole (7k; Table 7,
Entry 13). Starting from 1-methyl-2-pyrrolecarboxylic acid,
the compound was prepared and purified according to general
procedure A (Rf = 0.3 in 2:98 EtOAc/hexanes) to yield the title
compound as a white solid (70 mg, 0.312 mmol, 78%): HPLC
1-(4-Methoxyphenyl)-2-phenylpyrrole (17b; Table 5, Entry 1).
Starting from compound 17a, the compound was prepared
according to general procedure A and purified by preparative
HPLC to yield the title compound as a pale orange solid (66 mg,
0.265 mmol, 66%). HPLC (220 nm): 100%; 1H NMR (400
MHz, DMSO-d6) δ ppm 7.23 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.5
Hz, 1H), 7.09 (m, 4H), 6.98 (m, 1H), 6.94 (d, J = 8.8 Hz, 2H),
6.39 (m, 1H), 6.27 (m, 1H), 3.76 (s, 3H); 13C NMR (101 MHz,
DMSO-d6) δ ppm 157.9, 133.1, 132.9, 132.7, 128.2, 127.6, 126.9,
126.6, 125.0, 114.3, 110.2, 108.9, 55.3; HRMS (EI) calcd for
C17H15NO (Mþ•) 249.307 found 229.1159.28
1-Phenyl-2-phenylpyrrole (18b; Table 5, Entry 2). Starting
from compound 18a, the compound was prepared according
to general procedure A and purified by preparative HPLC to
yield the title compound as a white solid (51 mg, 0.233 mmol,
58%): HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6)
δ 7.39 (t, J = 7.5 Hz, 2H), 7.33 (m, 1H), 7.23 (t, J = 7.4 Hz, 2H),
7.17 (m, 3H), 7.08 (m, 3H), 6.42 (m, 1H), 6.31 (m, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 140.0, 132.6, 129.2, 128.2, 127.7, 126.8,
126.3, 125.5, 124.9, 110.8, 109.4; HRMS (EI) calcd for C16H13N
(Mþ•) 219.281, found 219.1052.28
1
(220 nm) >99%; H NMR (400 MHz, DMSO-d6) δ 7.74 (d,
J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 6.93 (m, 1H), 6.33
(m, 1H), 6.12 (m, 1H), 3.71 (s, 3H); 13C NMR (101 MHz,
DMSO-d6) δ 136.9, 131.9, 128.0, 125.9, 125.4, 110.1, 107.8,
35.2; HRMS (EI) calcd for C12H10F3N (Mþ•) 225.210, found
225.0760.25
2-(4-Nitrophenyl)-1-methylpyrrole (7l; Table 7, Entry 14).
Starting from 1-methyl-2-pyrrolecarboxylic acid, the compound
was prepared and purified according to general procedure A to
yield the title compound as a yellow solid (54 mg, 0.267 mmol,
66%): HPLC (220 nm) >99%; 1H NMR (400 MHz, DMSO-d6)
δ 8.23 (d, J = 9.1 Hz, 2H), 7.74 (d, J = 9.1 Hz, 2H), 6.99-7.01
(m, 1H), 6.47-6.49 (m, 1H), 6.14-6.16 (m, 1H), 3.76 (s, 3H); 13
C
NMR (101 MHz, DMSO-d6) δ 145.1, 139.4, 131.3, 127.7, 127.4,
123.9, 111.5, 108.3, 35.6.23,26
2-(3-Pyridyl)-1-methylpyrrole (7m; Table 7, Entry 15). Start-
ing from 1-methyl-2-pyrrolecarboxylic acid, the compound was
prepared and purified according to general procedure A to yield
the title compound as a pale yellow solid (53.5 mg, 0.338 mmol,
85%): HPLC (220 nm) 96.1%; 1H NMR (400 MHz, DMSO-d6)
δ 8.65-8.66 (m, 1H), 8.47-8.48 (m, 1H), 7.85-7.87 (m, 1H),
7.42-7.45 (m, 1H), 6.90-6.91 (m, 1H), 6.27-6.28 (m, 1H),
6.09-6.11 (m, 1H), 3.66 (s, 3H); 13C NMR (101 MHz, DMSO-d6)
δ148.4, 147.4, 135.0, 130.0, 129.0, 125.5, 123.7, 109.6, 107.8, 35.0.27
2-(2-Thiazolyl)-1-methylpyrrole (7n; Table 7, Entry 16). Start-
ing from 1-methyl-2-pyrrolecarboxylic acid, the compound
was prepared and purified according to general procedure A
(except that the temperature is 190 °C) to yield the title
compound as a yellow oil (12.1 mg, 0.074 mmol, 18%): HPLC
(220 nm) 96.6%; 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J =
4.0 Hz, 1H), 7.58 (d, J = 3.4 Hz, 1H), 6.97 (s, 1H), 6.64 (t, J =
1.7 Hz, 1H), 6.10 (t, J = 3.1 Hz, 1H), 3.94 (s, 3H); 13C NMR
(101 MHz, DMSO-d6) δ 160.3, 142.9, 127.1, 125.9, 117.6, 112.2,
108.1, 36.3; HRMS (EI) calcd for C8H8N2S (Mþ•) 164.0408,
found 164.0404.
1-(4-Trifluoromethylphenyl)-2-phenylpyrrole (19b; Table 5,
Entry 3). Starting from compound 19a, the compound was
prepared according to general procedure A and purified by
preparative HPLC to yield the title compound as a white solid
1
(50 mg, 0.174 mmol, 44%): HPLC (220 nm) 100%; H NMR
(400 MHz, DMSO-d6) δ 7.76 (d, J = 8.4 Hz, 2H), 7.37 (d, J =
8.4 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H),
7.10 (d, J = 7.1 Hz, 2H), 6.47 (m, 1H), 6.37 (m, 1H); 13C NMR
(101 MHz, DMSO-d6) δ 143.2, 132.9, 132.2, 128.5, 127.9, 126.7,
126.4, 125.8, 124.9, 111.9, 110.2; HRMS (EI) calcd for C17H12
F3N (Mþ•) 287.279, found 287.0927.
1-(4-Nitrophenyl)-2-phenylpyrrole (20b; Table 5, Entry 4).
Starting fom compound 20a, the compound was prepared
according to general procedure A and purified by preparative
HPLC to yield the title compound as a yellow solid (46 mg, 0.176
mmol, 44%): HPLC (220 nm) 100%; 1H NMR (400 MHz,
DMSO-d6) δ 8.24 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H),
7.28 (m, 4H), 7.12 (d, J = 7.1 Hz, 2H), 6.50 (m, 1H), 6.41 (m,
1H); 13C NMR (101 MHz, DMSO-d6) δ 145.1, 133.1, 132.0,
128.6, 128.0, 126.9, 125.8, 125.0, 124.8, 112.7, 110.7; HRMS (EI)
calcd for C17H12N2O2 (Mþ•) 264.279, found 264.0904.
(24) Drichkov, V. N.; Sobenina, L.; Vakul’skaya, T. I.; Ushakov, I.;
Mikhaleva, A. I.; Trofimov, B. A. Synthesis 2008, 16, 2631.
(25) Maekawa, T.; Kunitomo, J.; Odaka, H.; Kimura, H. PCT Int. Appl.
2003, 114 pp .
(26) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M.
D.; Bildeau, F. J. Am. Chem. Soc. 2006, 126, 11350.
Compound 21b (Table 6, Entry 1). Starting from compound
21a, the compound was prepared and purified according to
general procedure A (Rf = 0.35 in 5:95 EtOAc/hexanes) to yield
(27) Woodward, C. F.; Badgett, C. O.; Haines, P. G. Oxidation of
nicotine to 1-methyl-2-(3-pyridyl)pyrrole. US 2432642 19471216, 1947;
CAN 42:12012 AN 1948:12012 .
(28) Shibata, I.; Kato, H.; Yasuda, M.; Baba, A. J. Organomet. Chem.
2007, 16, 604.
J. Org. Chem. Vol. 75, No. 5, 2010 1557

Bilodeau et al.
JOCArticle
the title compound as an off-white solid (37 mg, 0.240 mmol,
60%): HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6)
δ 7.48 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.31 (t, J =
7.5 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.07 (m, 1H), 6.22 (m, 2H),
5.00 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 140.6, 137.3,
133.2, 127.8, 124.8, 123.5, 118.1, 117.1, 112.2, 98.0, 50.0.29
Compound 22b (Table 6, Entry 2). Starting from compound
22a (0.196 mmol) (quantity of other reagents adjusted
accordingly), the compound was prepared and purified accord-
ing to general procedure A (Rf = 0.34 in 5:95 EtOAc/hexanes)
to yield the title compound as a gray-blue solid (23 mg, 0.136
mmol, 69%): HPLC (220 nm): 100%; 1H NMR (400 MHz,
DMSO-d6) δ 7.51 (d, J = 7.4 Hz, 1H), 7.21 (m, 2H), 7.08 (t, J =
7.4 Hz, 1H), 6.82 (s, 1H), 6.49 (m, 1H), 6.09 (m, 1H), 4.05 (t, J =
6.5 Hz, 2H), 3.00 (t, J = 6.5 Hz, 2H); 13C NMR (101 MHz,
DMSO-d6) δ 130.4, 129.2, 128.7, 128.1, 126.9, 125.3, 121.9,
121.3, 108.2, 103.7, 43.3, 28.7.30
General Procedure for N-Alkylation of 1H-2-Pyrrole Methyl
Ester. Unless otherwise noted, each reaction was performed
using the following procedure. To a solution of the alkylating
agent (4.62 mmol) and 1H-2-pyrrole methyl ester (6.47 mmol,
1.4 equiv) in anhyd DMF (25 mL) at rt was added cesium
carbonate (18.47 mmol, 4 equiv). The mixture was stirred for 16
h, after which it was diluted with ethyl acetate (150 mL), the
organic layer was washed with brine (4ꢀ), dried over MgSO4,
and filtered, and solvent evaporation over silica afforded a solid
residue that was purified using normal-phase silica gel. Using 2-
bromobenzyl bromide as the alkylating agent, the compound
21a methyl ester was prepared and purified according to general
procedure B (Rf = 0.34 in 5:95 EtOAc/hexanes) to yield the N-
alkylated compound as a white solid (1.24 g, 4.23 mmol, 92%):
HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 7.65
(d, J = 7.8 Hz, 1H), 7.27 (m, 2H), 7.21 (td, J = 7.7 Hz and J =
1.3 Hz, 1H), 6.99 (m, 1H), 6.26 (m, 1H), 6.22 (d, J = 7.3 Hz, 1H),
5.59 (s, 2H), 3.64 (s, 3H).
50 °C for 4 h, after which time the solution was allowed to cool to
23 °C before being acidified using 1 N aqueous HCl. The
aqueous layer was extracted with EtOAc (3ꢀ ), and the organic
layer was dried over anhyd MgSO4. Filtration and solvent
evaporation afforded the desired products that were used with-
out further purification for the next step.
N-(2-Bromobenzyl)-2-pyrrolecarboxylic Acid (21a; Table 6,
Entry 1): pale brown solid (1.17 g, 4.177 mmol, 99%); HPLC
(220 nm) 98.8%; 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H),
7.62 (d, J = 7.0 Hz, 1H), 7.27 (m, 1H), 7.20 (m, 2H), 6.94 (m,
1H), 6.22 (m, 2H), 5.58 (s, 2H); 13C NMR (101 MHz, DMSO-d6)
δ 161.6, 138.6, 132.3, 129.9, 128.9, 128.1, 126.5, 122.4, 121.0,
118.1, 108.4, 51.7.
N-(2-Bromophenethyl)-2-pyrrolecarboxylicAcid(22a:Table6,
Entry 2): off-white solid (58 mg, 0.196, 96%); HPLC (220 nm)
96.6%; 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 7.58 (d,
J = 7.2 Hz, 1H), 7.28 (m, 1H), 7.16 (m, 2H), 6.87 (m, 1H), 6.80
(m, 1H), 6.01 (m, 1H), 4.51 (t, J = 7.2 Hz, 2H), 3.11 (t, J =
7.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 161.9, 137.6,
132.5, 130.9, 129.0, 128.7, 127.8, 124.0, 122, 117.8, 107.5, 47.9,
37.4.
General Procedure for N-Arylation of 1H-2-Pyrrole Methyl
Ester. Unless otherwise noted, each reaction was performed
using the following procedure. In a microwave vial (2 to 5 mL),
opened to air, were added 1-methyl-2-pyrrole methyl ester
(400 mg, 3.197 mmol), aryl halide (3.836 mmol, 1.2 equiv),
copper iodide (0.639 mmol, 0.2 equiv), potassium phosphate
tribasic (6.713 mmol, 2.1 equiv), and N,N-dimethylethylene-
diamine (1.279 mmol, 0.4 equiv). Anhydrous toluene (4 mL)
was then added, and the reaction mixture was put under argon
atmosphere, capped, and heated at 110 °C for 16 h. The
reaction mixture was cooled to 23 °C and diluted with ethyl
acetate (100 mL), and the organic layer was washed with water
(1ꢀ) and 1 N HCl (2ꢀ). The organic layer was dried over
MgSO4 and filtered, and solvent evaporation over silica
afforded a solid residue that was purified using normal-phase
silica gel.
Using 2-bromophenethyl bromide as the alkylating agent (see
below for preparation), the compound 22a methyl ester was
prepared and purified according to general procedure B (Rf =
0.24 in 5:95 EtOAc/hexanes) to yield the desired N-alkylated
compound as a yellow oil (66 mg, 0.214 mmol, 5%): HPLC (220
nm) 97.4%; 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.0
Hz, 1H), 7.27 (td, J = 7.7 Hz and J = 1.3 Hz, 1H), 7.15 (m, 2H),
6.94 (m, 1H), 6.85 (m, 1H), 6.06 (m, 1H), 4.52 (t, J = 7.1 Hz,
2H), 3.72 (s, 3H), 3.11 (t, J = 7.1 Hz, 2H).
1-(4-Nitrophenyl)-2-pyrrole Methyl Ester. Using 4-nitroiodo-
benzene as aryl halide, the compound was prepared and purified
according to general procedure D (Rf = 0.20 in 1:9 EtOAc/
hexanes) to yield the title compound as an off-white solid (354
mg, 1.436 mmol, 45%): HPLC (220 nm) 100%; 1H NMR (400
MHz, DMSO-d6) δ 8.30 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz,
2H), 7.40 (m, 1H), 7.13 (m, 1H), 6.41 (m, 1H), 3.66 (s, 3H); 13
C
Preparation of 2-Bromophenethyl Bromide. To a solution of 2-
bromophenethyl alcohol (1 g, 4.97 mmol) and triphenylpho-
sphine (5.97 mmol, 1.2 equiv) in anhydrous dichloromethane
(50 mL) at 23 °C was added carbon tetrabromide (5.97 mmol,
1.2 equiv). The resulting mixture was stirred at 23 °C for 16 h,
after which time silica gel was added. Solvent evaporation
afforded the mixture that was purified using normal-phase silica
gel (Rf = 0.54 in 2:98 EtOAc/hexanes) to afford the desired
product as a colorless oil (1.22 g, 4.62 mmol, 93%): HPLC (220
nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 7.8
Hz, 1H), 7.43 (dd, J = 7.5 Hz and J = 1.5 Hz, 1H), 7.36 (t, J =
7.5 Hz, 1H), 7.21 (td, J = 7.5 Hz and J = 1.5 Hz, 1H), 3.71 (t,
J = 7.4 Hz, 2H), 3.25 (t, J = 7.4 Hz, 2H).
NMR (101 MHz, DMSO-d6) δ 160.0, 146.2, 145.0, 130.6, 127.0,
124.0, 122.6, 120.2, 110.4, 51.3. 31
1-(4-Methoxyphenyl)-2-pyrrole Methyl Ester. Using 4-iodoa-
nisole as aryl halide, the compound was prepared and purified
according to general procedure D (Rf = 0.17 in 1:9 EtOAc/
hexanes) to yield the title compound as a white solid (665 mg,
2.877 mmol, 90%): HPLC (220 nm) 100%; 1H NMR
(400 MHz, DMSO-d6) δ 7.24 (d, J = 8.8 Hz, 2H), 7.16 (m,
1H), 7.00 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.28 (m, 1H), 3.80
(s, 3H), 3.61 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 160.0,
158.5, 132.9, 130.7, 127.3, 122.5, 118.5, 113.7, 109.0, 55.4,
50.9.32
1-(4-Trifluoromethylphenyl)-2-pyrrole Methyl Ester. Starting
with 200 mg (1.598 mmol) of the pyrrole ester and using
4-(trifluoromethyl)iodobenzene as aryl halide (quantity of other
reagents adjusted accordingly), the compound was prepared
and purified according to general procedure D (Rf = 0.39 in 1:9
EtOAc/hexanes) to yield the title compound as a white solid
(385 mg, 1.428 mmol, 89%). HPLC (220 nm): 99.5%; 1H NMR
General Procedure for Saponification of N-Alkylated-2-pyr-
role Methyl Esters. Unless otherwise noted, each reaction was
performed using the following procedure. To a solution of the
ester in THF (4 mL) and methanol (2 mL) at 23 °C was added 1
N aqueous NaOH solution. The resulting solution was stirred to
(29) Antonio, Y.; De la Cruz, M. E.; Galeazzi, E.; Guzman, A.; Bray, B.
L.; Greenhouse, R.; Kurz, L. J.; Lustig, D. A.; Maddox, M. L.; Muchowski,
J. M. Can. J. Chem. 1994, 72, 15.
(31) Auvin, S.; Harnett, J.; Bigg, D.; Chabrier De Lassauniere, P.-E.PCT
Int. Appl. 1998, 134 pp
(30) Crigg, R.; Myers, P.; Somasunderam, A.; Sridharan, V. Tetrahedron
1992, 48, 9735.
(32) Fogassy, K.; Kovacs, K.; Keseru, G. M.; Toke, L.; Faigl, F. J. Chem.
Soc., Perkin Trans. 1 2001, 9, 1039.
1558 J. Org. Chem. Vol. 75, No. 5, 2010

Bilodeau et al.
JOCArticle
(400 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 2H), 7.59 (d, J =
8.4 Hz, 2H), 7.35 (s, 1H), 7.09 (m, 1H), 6.38 (m, 1H), 3.65 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 160.0, 143.1, 130.6, 128.0,
126.9, 125.8, 125.4, 122.4, 119.6, 110.0, 51.2.33.33
1-Phenyl-2-pyrrole Methyl Ester. Using iodobenzene as aryl
halide, the compound was prepared and purified according to
general procedure D (Rf = 0.34 in 1:9 EtOAc/hexanes) to yield
the title compound as a white solid (596 mg, 2.963 mmol, 93%):
HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 7.43
(m, 3H), 7.38 (d, J = 6.8 Hz, 2H), 7.24 (m, 1H), 7.04 (m, 1H),
6.32 (m, 1H), 3.62 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ
160.0, 139.9, 130.6, 128.6, 127.6, 126.0, 122.4, 118.9, 109.3,
51.0.34
General Procedure for Saponification of N-Arylated 2-Pyrrole
Methyl Esters. Unless otherwise noted, each reaction was
performed using the following procedure. To a solution of the
ester in THF (4 mL) and methanol (2 mL) at 23 °C was added 1
N aqueous NaOH solution. The resulting solution was stirred to
50 °C for 4 h, after which time the solution was cooled to 23 °C
and acidified using 1 N aqueous HCl. The aqueous layer was
extracted with EtOAc (3ꢀ), and the combined organic layer was
dried over anhydrous MgSO4. Filtration and solvent evapora-
tion afforded the desired products that were used without
further purification.
1-(4-Methoxyphenyl)-2-pyrrolecarboxylic Acid (17a; Table 5,
Entry 1). Starting from the corresponding ester, the acid was
prepared according to general procedure E to yield the title
compound as a pale pink solid (614 mg, 2.828 mmol, 98%):
HPLC (220 nm) 99.5%; 1H NMR (400 MHz, DMSO-d6) δ 12.1
(s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.10 (m, 1H), 6.96 (d, J = 8.8
Hz, 2H), 6.94 (m, 1H), 6.25 (m, 1H), 3.79 (s, 3H); 13C NMR (101
MHz, DMSO-d6) δ 161.0, 158.3, 133.3, 130.2, 127.2, 123.6,
118.4, 113.6, 108.7, 55.4.
1-Phenyl-2-pyrrolecarboxylic Acid (18a; Table 5, Entry 2).
Starting from the corresponding ester, the acid was prepared
according to general procedure E to yield the title compound as
a white solid (514 mg, 2.745 mmol, 93%): HPLC (220 nm)
100%; 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 7.3 (m,
5H), 7.16 (s, 1H), 6.99 (s, 1H), 6.28 (s, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 161.0, 140.2, 130.1, 128.5, 127.4, 126.0, 123.6,
118.8, 109.0.
1-(4-Trifluoromethylphenyl)-2-pyrrolecarboxylic Acid (19a;
Table 5, Entry 3). Starting from the corresponding ester, the
acid was prepared according to general procedure E to yield the
title compound as a white solid (328 mg, 1.286 mmol, 90%):
HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 12.3
(s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.28
(s, 1H), 7.04 (m, 1H), 6.34 (m, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 161.1, 143.4, 130.2, 127.8, 127.5, 126.8, 125.7,
123.7, 119.6, 109.7.
1-(4-Nitrophenyl)-2-pyrrolecarboxylic Acid (20a; Table 5, En-
try 4). Starting from the corresponding ester, the acid was
prepared according to general procedure E to yield the title
compound as an off-white solid (320 mg, 1.379 mmol, 96%):
HPLC (220 nm) 100%; 1H NMR (400 MHz, DMSO-d6) δ 12.5
(s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.33
(s, 1H), 7.08 (m, 1H), 6.37 (m, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 161.0, 146.0, 145.3, 130.1, 126.9, 124.0, 120.1,
110.1.
Competition Experiments. 1. 3-Methylfuroic acid (10) vs 3-
methylbenzofurancarboxylic Acid (15a). Using general proce-
dure A (but using 4-bromotoluene as the aryl bromide), both
3-methyl-2-furoic acid (0.4 mmol, 1 equiv) and 3-methylbenzo-
furan-2-carboxylic acid (0.4 mmol, 1 equiv) were submitted to
the cross-coupling conditions. HPLC analysis of the crude
mixture revealed that both coupling products and n-butyl ester
products of the acids (through reaction with tetra-n-butyl
ammonium chloride hydrate) were formed. The crude mixture
was then submitted to the saponification conditions (see general
procedure E, stirred for 18 h), which after workup gave the
1
mixture of cross-coupling products. H NMR analysis of the
crude mixture demonstrated that the ratio of 2-arylated pro-
ducts was of 2.2:1 favoring the 2-(4-tolyl)-3-methylfuran.
2-(4-Tolyl)-3-methylfuran (10b). Starting from 3-methyl-2-
furoic acid and using the 4-bromotoluene as aryl bromide, the
compound was prepared and purified according to general
procedure A (Rf = 0.88 in 1:9 EtOAc/ hexanes) to yield the
title compound as a pale yellow oil (57 mg, 0.331 mmol, 83%):
HPLC (220 nm) 97.9%; 1H NMR (400 MHz, DMSO-d6) δ 7.59
(d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz,
2H), 6.44 (d, J = 1.8 Hz, 1H), 2.32 (s, 3H), 2.21 (s, 3H); 13C
NMR (101 MHz, DMSO-d6) δ 147.8, 141.1, 136.2, 129.3, 128.5,
124.8, 115.5, 115.4, 20.8, 11.5.
2-(4-Tolyl)-3-methylbenzofuran (15b). Starting from 3-meth-
yl-2-benzofurancarboxylic acid and using 4-bromotoluene as
the aryl bromide, the compound was prepared and purified
according to general procedure A (Rf = 0.71 in 5:95 EtOAcb/
hexanes) to yield the title compound as a white solid (76 mg,
0.341 mmol, 85%): HPLC (220 nm) 98.8%; 1H NMR (400
MHz, DMSO-d6) δ 7.71 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.1 Hz,
1H), 7.56 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.29 (m,
2H), 2.44 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, DMSO-d6)
δ 153.0, 150.1, 137.8, 130.7, 129.5, 127.8, 126.3, 124.5, 122.6,
119.5, 110.8, 110.6, 20.9, 9.1.
2. 5-(4-Methoxyphenyl)-2-furoic Acid (43a) vs 5-(4-Trifluoro-
methylphenyl)-2-furoic Acid (443a). Using general procedure
A (but using 4-bromotoluene as the aryl bromide), both 5-(4-
methoxyphenyl)-2-furoic acid (0.4 mmol, 1 equiv) and 5-(4-
trifluoromethylphenyl)-2-furoic acid (0.4 mmol, 1 equiv) (see
syntheses for both analogues below) were submitted to the
cross-coupling conditions. HPLC analysis of the crude mixture
revealed that both coupling products and n-butyl ester pro-
ducts of the acids (through reaction with tetra-n-butyl ammo-
nium chloride hydrate) were formed. The crude mixture was
then submitted to the saponification conditions (see general
procedure E, stirred for 18 h) which after workup gave the
1
mixture of cross-coupling products. H NMR analysis of the
crude mixture clearly demonstrated that the ratio of 2-arylated
products was of 1.8: 1 favoring the 2-(4-tolyl)-3-methylfuran.
5-(4-Methoxyphenyl)-2-(4-tolyl)furan (43b). Starting from
5-(4-methoxyphenyl)-2-furoic acid and using 4-bromotoluene
as the aryl bromide, the compound was prepared according to
general procedure A (purified using a semipreparative HPLC)
which yielded the desired product contaminated with n-butyl
ester derivative (resulting from the reaction with tetra-n-butyl
ammonium chloride hydrate). This mixture was then submitted
to the saponification conditions (see general procedure E) which
after appropriate workup gave the title compound as an off-
white solid (32 mg, 0.121 mmol, 30%): HPLC (220 nm) 96.7%;
1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.6 Hz, 2H), 7.67
(d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.6 Hz,
2H), 6.95 (d, J = 3.5 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H), 3.80 (s,
3H), 2.33 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 158.8,
152.4, 152.1, 136.6, 129.5, 127.6, 124.9, 123.2, 123.1, 114.4,
107.3, 106.3, 55.2, 20.8.35
Synthesis of 5-(4-Methoxyphenyl)-2-methylfuroic Acid (43a).
In a microwave vial (10-20 mL), opened to air, were added 2-
bromo-5-methylfuroate ester (4.88 mmol, 1 equiv), 4-methox-
yphenyl boronic acid (5.85 mmol, 1.2 equiv), potassium
(33) Faigl, F.; Fogassy, K.; Szucs, E.; Kovacs, K.; Keseru, G. M.;
Harmat, V.; Bocskeri, Z.; Toke, L. Tetrahedron 1999, 55, 7881.
(34) Cartoon, M. E. K.; Cheeseman, G. W. H. J. Organomet. Chem. 1982,
2, 123.
(35) Rees, C. W.; Yue, T.-Y, J. Chem. Soc., Perkin Trans. 1 1997, 15, 2247.
J. Org. Chem. Vol. 75, No. 5, 2010 1559

Bilodeau et al.
JOCArticle
carbonate (9.76 mmol, 2 equiv), and palladium(0) tetrakis-
triphenylphosphine (0.49 mmol, 0.10 equiv), and DMF (12 mL)
followed by water (3 mL), after which the mixture was stirred for
30 s and submitted to the microwave conditions (130 °C, 12 min,
high absorption level). The reaction mixture was then diluted
with ethyl acetate (100 mL), the organic layer was washed with
brine (3ꢀ), saturated NaHCO3 solution (2ꢀ), water (1ꢀ), and
again with brine (1ꢀ). The organic layer was finally dried over
MgSO4 and filtered, and solvent evaporation over silica afforded
a solid residue that was purified using normal-phase silica gel
(Rf = 0.23 in 1:9 EtOAc/hexanes) to yield the title compound as a
white crystalline solid (544 mg, 2.34 mmol, 48%). This is an
unoptimized yield; much saponification was observed (which
(12 mL) followed by water (3 mL), after which the mixture
was stirred for 30 s and submitted to the microwave conditions
(130 °C, 12 min, high absorption level). The reaction mixture was
then diluted with ethyl acetate (100 mL), and the organic layer
was washed with brine (3ꢀ), saturated NaHCO3 solution
(2ꢀ ), water (1ꢀ), and again with brine (1ꢀ). The organic
layer was dried over MgSO4 and filtered, and solvent evapora-
tion over silica afforded a solid residue that was purified using
normal-phase silica gel (Rf = 0.32 in 1:9 EtOAc/hexanes) to
yield the title compound as a white crystalline solid (214 mg,
0.792 mmol, 16%). This is an unoptimized yield, much saponi-
fication was observed (which material was not recovered):
1
HPLC (220 nm) 99.5%; H NMR (400 MHz, DMSO-d6) δ
1
material was not recovered): HPLC (220 nm) 98.7%; H NMR
8.03 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.47 (d, J =
3.5 Hz, 1H), 7.39 (d, J = 3.5 Hz, 1H), 3.86 (s, 3H); 13C NMR
(101 MHz, DMSO-d6) δ 158.2, 154.9, 143.9, 132.5, 126.1,
125.1, 120.5, 110.3, 52.0.
This intermediate was then submitted to the saponification
conditions (see general procedure E), which after appropriate
workup gave the title compound as a white solid (189 mg, 0.738
mmol, 93%) that was used without further purification for the
cross-coupling reaction: HPLC (220 nm) 99.3%; 1H NMR (400
MHz, DMSO-d6) δ 13.3 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.84
(d, J = 8.2 Hz, 2H), 7.36 (m, 2H); 13C NMR (101 MHz, DMSO-
d6) δ 159.2, 154.4, 145.1, 132.8, 126.1, 126.0, 124.9, 119.8,
110.2.38
(400 MHz, DMSO-d6) δ 7.76 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 3.8
Hz, 1H), 7.04 (m, 3H), 3.83 (s, 3H), 3.80 (s, 3H); 13C NMR (101
MHz, DMSO-d6) δ 160.0, 158.3, 157.1, 142.3, 126.2, 121.7, 120.8,
114.6, 106.5, 55.3, 51.7.
This intermediate was then submitted to the saponification
conditions (see general procedure E), which after appropriate
workup gave the title compound as an off-white solid (469 mg,
2.15 mmol, 97%) that was used without further purification:
HPLC (220 nm) 98.9%; 1H NMR (400 MHz, DMSO-d6) δ 13.0
(s, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 3.7 Hz, 1H), 7.05
(d, J = 9.0 Hz, 2H), 6.99 (d, J = 3.7 Hz, 1H), 3.81 (s, 3H); 13
C
NMR (101 MHz, DMSO-d6) δ 159.8, 159.3, 156.5, 143.4, 126.0,
122.0, 120.0, 114.5, 106.3, 55.3.36
5-(4-Trifluoromethylphenyl)-2-(4-tolyl)furan (44b). Starting
with 78 mg (0.304 mmol) of 5-(4-trifluoromethylphenyl)-2-
furoic acid and using 4-bromotoluene as the aryl bromide
(quantity of other reagents adjusted accordingly), the com-
pound was prepared according to general procedure A. The
crude mixture contained the desired product together with the
n-butyl ester derivative (resulting from the reaction with tetra-n-
butylammonium chloride hydrate). It was then submitted to the
saponifications conditions (see general procedure E) which after
appropriate workup gave the mixture that was purified accord-
ing to general procedure A to yield the title compound as a white
Acknowledgment. This paper is dedicated to the memory
of Professor Keith Fagnou, an inspiring scientist and won-
derful individual who provided valuable insights on this
work. We wish also to thank Professor A. B. Charette for
valuable discussions concerning this work and our collea-
gues, especially Dr. L. Morency, Dr. B. Moreau, and Dr. O.
Lepage, at Boehringer Ingelheim (Canada) Ltd., R&D, for
their support and useful suggestions during the preparation
of this manuscript. We also acknowledge Professor S. K.
Collins for suggestions concerning the manuscript and Pro-
fessor X. Ottenwaelder for his assistance with the molecular
orbital analysis.
1
solid (22 mg, 0.073 mmol, 48%): HPLC (220 nm) 99.1%; H
NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.3 Hz, 2H), 7.79 (d,
J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.29 (m, 3H), 7.08 (d, J
= 3.5 Hz, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ
154.0, 150.6, 137.5, 133.7, 129.5, 127.1, 125.9, 123.7, 110.8,
107.8, 20.9.37
Synthesis of 5-(4-Trifluoromethylphenyl)-2-methylfuroic Acid
(44a). In a microwave vial (10 to 20 mL), opened to air, were
added 2-bromo-5-methylfuroate ester (4.88 mmol, 1 equiv),
4-trifluoromethylphenyl boronic acid (5.85 mmol, 1.2 equiv),
potassium carbonate (9.76 mmol, 2 equiv), palladium(0) tetra-
kis-triphenylphosphine (0.49 mmol, 0.10 equiv), and DMF
Note Added after ASAP Publication. In the version pub-
lished ASAP on February 8, 2010, in the full paragraph under
Table 8, the expression SEAr-type was changed to CMD-type;
the corrected version posted on February 10, 2010.
Supporting Information Available: Experimental proce-
dures, NMR spectra, and HRMS data for compounds 7c,e-o,
q, 10b, 15b, 17-22, 43a,43b, 44a, and 44b and details on the
molecular orbital analysis of 42 and 14a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(36) Prasad, D. J.; Ashok, M.; Karegoudar, P.; Poojary, B.; Holla, B. S.;
Kumari, N. S. Eur. J. Med. Chem. 2009, 2, 551.
(37) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. am. Chem. Soc. 2009,
131, 6668.
(38) Carter, P. H.; Cherney, R. J.; Batt, D. G.; Dunica, J. V.; Gardner,
D. S.; Ko, S. S.; Srivastava, A. S.; Yang, M. G. PCT Int. Appl. 2005, 437 pp.
1560 J. Org. Chem. Vol. 75, No. 5, 2010