Palladium-catalyzed indole, pyrrole, and furan arylation by aryl chlorides

Article abstract of DOI:10.1021/jo1018969

The palladium-catalyzed direct arylation of indoles, pyrroles, and furans by aryl chlorides has been demonstrated. The method employs a palladium acetate catalyst, 2-(dicyclohexylphosphino)-biphenyl ligand, and an inorganic base. Electron-rich and electron-poor aryl chlorides as well as chloropyridine coupling partners can be used, and arylated heterocycles are obtained in moderate to good yields. Optimization of base, ligand, and solvent is required for achieving best results.

Full text of DOI:10.1021/jo1018969

pubs.acs.org/joc
Palladium-Catalyzed Indole, Pyrrole, and Furan Arylation
by Aryl Chlorides
Enrico T. Nadres, Anna Lazareva, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204, United States
olafs@uh.edu
Received September 29, 2010
The palladium-catalyzed direct arylation of indoles, pyrroles, and furans by aryl chlorides has been
demonstrated. The method employs a palladium acetate catalyst, 2-(dicyclohexylphosphino)-
biphenyl ligand, and an inorganic base. Electron-rich and electron-poor aryl chlorides as well as
chloropyridine coupling partners can be used, and arylated heterocycles are obtained in moderate to
good yields. Optimization of base, ligand, and solvent is required for achieving best results.
Introduction
research. Methods that have been developed for creation of
aryl-heteroaryl linkages are summarized in Scheme 1. One
can couple either the aryl halide with heteroaryl metal
reagent or aryl metal with heteroaryl halide (Pathway A).2
This is the classical route for creation of sp2-sp2 carbon-
carbon bonds. The advantages include excellent control of
regioselectivity as well as extensively investigated chemistry
that allows synthesis of nearly any structural motifs. A
disadvantage includes the necessity to prepare functionalized
starting materials, thus lengthening synthetic sequences.
Coupling of an aryl halide with a heterocycle C-H bond
or, rarely, arene with heteroaryl halide also can result in the
formation of an arylated heterocycle (Pathway B).3,4 In
this case, one can use readily available, stable heterocycles
and aryl halides, thus avoiding several synthetic steps and
shortening synthetic schemes. Regioselectivity issues are
The aryl-heteroaryl bond is common in organic materials,
bioactive molecules, and pharmaceuticals.1 Consequently,
formation of such bonds has been the focus of intensive
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DOI: 10.1021/jo1018969
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Published on Web 12/30/2010
J. Org. Chem. 2011, 76, 471–483 471
2010 American Chemical Society

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SCHEME 1. Methods for Heterocycle Arylation
manageable because most of heterocyclic C-H bond aryla-
tions are regioselective. The third possibility is the coupling
of arylmetal with heterocycle or, rarely, arene with a hetero-
aryl metal reagent (Pathway C).5 Carboxylates can be em-
ployed as arylmetal surrogates.5j Although this method
allows the use of stable and readily available heterocycles
as one of the coupling components, several disadvantages are
obvious compared with Pathway B. First, a stoichiometric
reoxidant, typically a copper or silver salt, is often required
for catalytic turnover generating heavy metal waste. Second,
aryl metal reagents are often prepared from aryl halides, thus
increasing total number of steps to the desired product. The
final possibility is the cross-coupling of heterocycle and
arene C-H bonds (Pathway D).6 Readily available arenes
and heterocycles are used as the coupling partners. Conse-
quently, Pathway D is the shortest route to the cross-coupled
product since no functionalized intermediates need to be
prepared. The potential problems include lack of regioselec-
tivity with respect to simple arene coupling partners such as
toluene and requirement for a stoichiometric oxidant. Ad-
ditionally, a large excess of the arene component is often
employed, decreasing the efficiency of the process. However,
this method appears to hold the most promise if the regios-
electivity problems are solved and environmentally friendly
oxidants such as oxygen7 could be employed.
The above analysis shows that methodology following
either Pathway B or Pathway D should result in the most
efficient arylation processes. At this point, it is not obvious
how to solve the regioselectivity issues for Pathway D,
although in special cases cross-coupling selectivity has been
obtained by employing tailored ligands on palladium.8 While
arylations according to pathway B are common, in most cases
aryl bromide or iodide reagents have been employed and the
methodology appears to be mature.3,4 In contrast, nonacti-
vated aryl chlorides rarely have been used.3d,e,4b,4c,4e Curiously,
a pioneering paper describing activated (electron-poor) aryl
chloride use in heterocycle arylation was published in 1985 and
is one of the first intermolecular direct heterocycle arylation
examples.3a Ohta showed that chloropyrazines regioselectively
arylate NH-indoles at the C-2 position if Pd(PPh3)4 catalyst is
employed. He also showed that a copper additive improves the
arylation yield, a modification that is now widely used for such
reactions. The use of nonactivated aryl chlorides for intermo-
lecular reactions was reported in 2004 when Sadighi disclosed a
method for the arylation of zincated pyrroles by aryl halides.3d
However, a general method for electron-rich heterocycle
arylation was not reported until 2007 when we showed that
electron-rich, bulky butyldi-1-adamantylphosphine in combi-
nation with Pd(OAc)2 effects the arylation of a wide variety of
five-membered ring heterocycles such as thiophene, benzothio-
phene, 1,2- and 1,3-oxazole derivatives, benzofuran, thiazoles,
benzothiazole, 1-alkylimidazoles, 1-alkyl-1,2,4-triazoles, and
caffeine. Electron-rich, electron-poor, and heteroaryl chlorides
can be used.3e However, indoles, furans, and pyrroles were not
arylated effectively. Low conversions and/or regioisomer mix-
tures were obtained. Several recent reports from other groups
describe use of nonactivated aryl chlorides in heterocycle C-H
bond arylations.4b,c,e However, N-substituted indole, pyrrole,
and furan arylation by nonactivated aryl chlorides has been
elusive. We report here a method for N-substituted indole and
pyrrole as well as furan arylation by aryl chlorides. A catalyst
system consisting of a combination of bulky Buchwald phos-
phine ligands with palladium(II) acetate and an inorganic base
is employed in most cases.
(5) (a) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428. (b)
Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2008, 47, 1473. (c) Liang, Z.; Yao, B.; Zhang, Y. Org. Lett.
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Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129. (f)Ban, I.;Sudo, T.;Taniguchi, T.;
Itami, K. Org. Lett. 2008, 10, 3607. (g) Hachiya, H.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202. (h) Xie, K.; Yang, Z.; Zhou, X.;
Li, X.; Wang, S.; Tan, Z.; An, X.; Guo, C.-G. Org. Lett. 2010, 12, 1564. (i)
Kasahara, A.; Izumi, T.; Yodono, M.; Saito, R.-i.; Takeda, T.; Sugawara, T.
Bull. Chem. Soc. Jpn. 1973, 46, 1220. (j) Zhang, F.; Greaney, M. F. Angew.
Chem., Int. Ed. 2010, 49, 2768. Reviews: (k) Bellina, F.; Rossi, R. Tetrahedron
2009, 65, 10269. (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 677.
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D. R.; Fagnou, K. Science 2007, 316, 1172. (c) Xi, P.; Yang, F.; Qin, S.; Zhao,
D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822. (d)
Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem.
Soc. 2009, 131, 1668. (e) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137.
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(7) (a) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
J. Org. Chem. 2008, 73, 5022. (b) Hagelin, H.; Oslob, J. D.; Akermark, B.
Results and Discussion
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Chem.;Eur. J. 1999, 5, 2413. (c) Brasche, G.; Garcıa-Fortanet, J.;
Buchwald, S. L. Org. Lett. 2008, 10, 2207. (d) Wang, D.-H.; Wasa, M.; Giri,
R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (e) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2009, 131, 17052. (f) Hamada, T.; Ye, X.; Stahl, S. S.
J. Am. Chem. Soc. 2008, 130, 833. (g) Basle, O.; Li, C.-J. Chem. Commun. 2009,
4124. (h) Ohashi, S.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2005, 486.
1. Indole Arylation. Aryl bromides and iodides have
been used extensively in palladium-catalyzed direct indole
(8) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072.
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SCHEME 2. Ligand Screening for Coupling of 1-Butyl-3-meth-
ylindole with Chlorobenzene
nylindole, and 3-cyclohexyl-1-methylindole can be arylated
in excellent yields (entries 2-6). It is known that activated
aryl chlorides are generally more reactive in heterocycle
arylation, and many examples have been described in
literature.3a,p,s,4l,4m However, in this case both electron-rich
and electron-poor aryl chlorides are reactive. Chloroben-
zene, 3-chloroanisole, 5-chloro-m-xylene, 3-chlorotoluene,
1-chloro-3,4-dimethylbenzene, 3-chloropyridine, and 1,4-di-
chlorobenzene are suitable coupling partners that afford
desired products in good to excellent yields. Substitution
on the phenyl ring of indole is tolerated (entries 16 and 17).
Previously unreactive 1,2-dimethylindole is arylated in the
3-position under the optimized conditions by employing
standard reaction conditions (entry 14). The major product
of the arylation of 1-methylindole is 1-methyl-2-phenylin-
dole in addition to minor amounts of 1-methyl-3-phenylin-
dole and 1-methyl-2,3-diphenylindole byproducts (entry 15).
However, this reaction requires slightly modified reaction
conditions. Butyldi-1-adamantylphosphine ligand in combi-
nation with K3PO4 base in NMP solvent afforded the best
results.
The method fails for the following substrates. Unpro-
tected indoles afford mostly N-arylated products under
these conditions.11 Arylation of indoles possessing electron-
withdrawing groups on the nitrogen result in either decom-
position of the starting material or low conversion to pro-
duct. Silicon-containing protecting groups on the indole
nitrogen are removed under these reaction conditions. Ar-
ylation of 1-tert-butyl-3-methylindole results in low conver-
sion, presumably due to steric bulk.
2. Pyrrole Arylation. Arylation of pyrroles by aryl iodides
and bromides has been extensively investigated.3k,s,t How-
ever, only a few examples of aryl chloride use have been
reported, most notably in the work by Sadighi where three
examples of N-zincated pyrrole arylation by aryl chlorides
were disclosed.3d A short ligand optimization was under-
taken for the arylation of N-methylpyrrole with chloroben-
zene (Scheme 3). Dicyclohexylphenyl- and tricyclohexyl-
phosphine afforded moderate conversions to the product,
whereas butyldi-1-adamantylphosphine was inefficient. A
bowl-shaped triarylphosphine12 afforded 69% conversion
to the monoarylated product. The best results were obtained
by employing 2-(dicyclohexylphosphino)biphenyl ligand
that was used for subsequent reactions.
The scope of the arylation is shown in Table 2. Excess of N-
methylpyrrole is used to avoid diarylation. Both electron-
rich (entries 5, 9, 11) and electron-poor (entries 2, 4, 6) aryl
chlorides are reactive. Introduction of two N-methylpyrrole
functionalities is possible if m-dichlorobenzene is employed
(entry 8), and 1,3-bis(1-methyl-1H-pyrrol-2-yl)benzene was
obtained in 72% yield. 1-Methyl-2-phenylpyrrole is also
reactive and can be para-tolylated in 63% yield (entry 9).
1-Methylpyrrole-2-carboxylic acid ethyl ester is arylated in
moderate yields (entries 10 and 11). 1-Phenylpyrrole can also
be arylated (entry 12). Functional groups such as ketone
(entry 2) and ester (entry 4) are tolerated. 2-Pyridyl chloride
is reactive (entry 13).
arylations.3g-o However, only a few examples of activated
aryl chloride use have been reported.3a Our previously
reported reaction conditions resulted in incomplete conver-
sions for substituted indole C-arylation.3e Consequently,
reaction conditions were optimized in the arylation of 1-butyl-
3-methylindole by chlorobenzene. A short screening with
respect to base and solvent showed that highest conversions
are obtained by employing dimethylacetamide in combina-
tion with sodium carbonate. During previous studies for the
coupling of electron-rich heterocycles with aryl chlorides
it was discovered that secondary phosphine oxides and
N-heterocyclic carbene (NHC) ligands are not effective in
promoting the desired reaction.3e Therefore, the present
evaluation mainly focused on electron-rich trialkyl phos-
phine ligands since they are known to promote oxidative
addition of aryl chlorides to Pd(0).9 Only commercially
available ligands were screened. Di-tert-butyl(methyl)-
phosphonium tetrafluoroborate afforded low conversion to
the desired product (Scheme 2). Surprisingly, structurally
similar ligands such as butyldi-1-adamantylphosphine and
benzyldi-1-adamantylphosphine demonstrated different re-
sults, with the former one being much more effective. Simi-
larly, structurally related Buchwald phosphines10 afforded
variable conversions depending on the substitution pattern.
Ligands containing two tert-butyl groups on the phosphorus
atom generally showed lower conversions to the arylated
product, in contrast with the report by Sadighi.3d Ligands
possessing two cyclohexyl substituents on the phosphorus
atom demonstrated good efficiency. Reasonable conversions
were also observed if tricyclohexylphosphine and tert-butyl-
dicyclohexylphosphine were used. Out of several ligands that
afforded high conversions in the arylation, 2-(dicyclo-
hexylphosphino)biphenyl was chosen for further investiga-
tion because of its air-stable nature and cost considerations.
A number of substituted indoles can be coupled with a
variety of aryl chlorides under these conditions (Table 1).
1,3-Dimethylindole reacts with aryl chlorides to give desired
products in good yields (entries 1, 11-13). Some steric bulk is
tolerated on indole species. 1-Butyl-3-methylindole, 3-butyl-
1-methylindole, 3-methyl-1-phenylindole, 1-methyl-3-phe-
(11) (a) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523. (b) Old, D. W.;
Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403.
(9) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(10) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(12) Iwasawa, T.; Kamei, T.; Watanabe, S.; Nishiuchi, M.; Kawamura,
Y. Tetrahedron Lett. 2008, 49, 7430.
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TABLE 1. Indole Arylation by Aryl Chloridesa
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TABLE 1. Continued
aConditions: 5 mol % Pd(OAc)2, 10 mol % Cy2P-o-biphenyl, Na2CO3 (2 equiv), indole (1 equiv), aryl chloride (5 equiv), DMA solvent, 24 h at 125 °C;
isolated yield. bConditions: 5 mol % Pd(OAc)2, 10 mol % BuAd2P, K3PO4 (2 equiv), indole (1 equiv), aryl chloride (5 equiv), NMP solvent; 24 h at 125
°C. 1-Methyl-3-phenylindole (7%) and 1-methyl-2,3-diphenylindole (8%) also isolated.
SCHEME 3. Ligand Optimization for Pyrrole Arylation
Furan arylation results are presented in Table 3. Furan
(entries 1-5, 11), furan-2-carboxylic acid ethyl ester (entries 6,
7), and 2-methylfuran (entries 8-10) can be arylated. Elec-
tron-rich (entries 1, 2) as well as electron-poor aryl chlorides
(entries 3-6, 8, 9) are reactive. Dichloroarenes can be reacted
with furan resulting in substances possessing several hetero-
cyclic moieties (entries 3, 4). 2-Chloropyridine is a competent
arylating reagent (entry 11). Yields range from moderate to
good. Several equivalents of furan are typically employed to
avoid diarylation. For monosubstituted furan arylation, an
excess of aryl chloride is used.
3. Furan Arylation. Many examples of furan arylation by
aryl bromides and iodides have been disclosed since the first
report by Catellani in 1985.3b,p,v,4a,4l However, use of unac-
tivated aryl chlorides in these reactions is rare. We have
reported the diarylation of benzofuran by chlorobenzene;
unfortunately, the arylation of other furan derivatives was
inefficient.3e A short ligand optimization revealed once more
that 2-(dicyclohexylphosphino)biphenyl affords the best
results (Scheme 4). Ligands such as dicyclohexylphenyl-,
tricyclohexyl-, and n-butyldi-1-adamantylphosphine were
not effective. Other Buchwald-type phosphines afford low
conversions.
Conclusions
We have demonstrated the arylation of indoles, pyrroles,
and furans by aryl chlorides. The method employs a palla-
dium acetate catalyst, 2-(dicyclohexylphosphino)biphenyl
ligand, and an inorganic base. Electron-rich, electron-poor,
and heterocyclic aryl chloride coupling partners can be used,
and arylated heterocycles are obtained in moderate to good
yields. Unfortunately, it appears that at this point arylation
by unactivated aryl chlorides requires extensive optimization
of reaction conditions for every substrate class to determine
optimal ligand, base, and solvent. N-Arylation of indoles
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TABLE 2. Pyrrole Arylationa
aConditions: 5 mol % Pd(OAc)2, 10 mol % Cy2P-o-biphenyl, 2 equiv of K3PO4, aryl chloride (1 equiv), pyrrole (5 equiv), NMP solvent, 24 h at 125 °C;
isolated yield. bDMPU solvent. cPyrrole (1 equiv), aryl chloride (3 equiv). Yields are the average of two runs.
476 J. Org. Chem. Vol. 76, No. 2, 2011

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SCHEME 4. Ligand Optimization for Furan Arylation
and pyrroles is preferred to C-arylation if unactivated aryl
chloride coupling partners are employed. Further investiga-
tions are required to solve these problems.
3-Butyl-2-(3-methoxyphenyl)-1-methylindole (Table 1, Entry 3).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexyl-
phosphino)biphenyl (17.5 mg, 0.05 mmol), sodium carbonate
(106 mg, 1.0 mmol), 3-butyl-1-methylindole (94 mg, 0.5 mmol),
3-chloroanisole (356 mg, 2.50 mmol), and anhydrous DMA (2 mL).
After column chromatography (hexanes/dichloromethane 5/1), 121
mg (82%) of a clear oil was obtained. Product darkens after several
hours on the bench. Rf = 0.60 (hexanes/dichloromethane 2/1;
Experimental Section
General Procedure for Coupling of Chloroarenes with 1,3-
Disubstituted Indoles and 1,2-Dimethylindole. Outside the glove-
box, a 2-dram vial equipped with a magnetic stir bar was
charged with Pd(OAc)2 (5 mol %), ligand (10 mol %), base
(2 equiv), indole (1 equiv), chloroarene (5 equiv), and anhydrous
solvent (4 mL). The vial was flushed with argon, capped, and
placed in a preheated oil bath (125 °C) for 24 h. The reaction
mixture was allowed to cool to room temperature and quenched
with water (40 mL). The resulting suspension was extracted with
hexanes (20 mL, then 2 Â 10 mL), and combined organic layers
were filtered through a pad of Celite. The filtrate was concen-
trated under vacuum. The crude product was purified by either
preparative TLC or flash column chromatography.
1
visualization by UV). H NMR (300 MHz, CDCl3, ppm) δ 0.84
(t, J = 7.2 Hz, 3H), 1.24-1.37 (m, 2H), 1.55-1.66 (m, 2H),
2.66-2.73 (m, 2H), 3.58 (s, 3H), 3.85 (s, 3H), 6.90-7.00 (m, 3H),
7.10-7.17 (m, 1H), 7.21-7.27 (m, 1H), 7.31-7.35 (m, 1H),
7.36-7.43 (m, 1H), 7.62-7.66 (m, 1H). 13C NMR (75 MHz,
CDCl3, ppm) δ 14.0, 22.8, 24.4, 30.8, 33.5, 55.3, 109.3, 113.4,
113.9, 116.2, 119.0, 119.2, 121.6, 123.1, 127.8, 129.3, 133.7, 137.2,
137.5, 159.4. FT-IR (neat, cm-1) υ 2954, 2857, 1609, 1578, 1486,
1468. Anal. Calcd for C20H23NO (293.40 g/mol): C, 81.87; H, 7.90;
N, 4.77. Found: C, 81.92; H, 7.95; N, 4.74.
2-(3-Methoxyphenyl)-3-methyl-1-phenylindole (Table 1, Entry 4).
Palladium acetate (10.3 mg, 0.046 mmol), 2-(dicyclohexyl-
phosphino)biphenyl (32.2 mg, 0.092 mmol), sodium carbonate
(195 mg, 1.84 mmol), 3-methyl-1-phenylindole (190 mg, 0.92 mmol),
3-chloroanisole (656 mg, 4.60 mmol), and anhydrous DMA (3.7 mL).
After column chromatography (hexanes/dichloromethane 7/2),
174 mg (60%) of a clear oil was obtained. Product darkens after
several hours on the bench. Rf = 0.50 (hexanes/dichloromethane 2/1;
visualization by UV). 1H NMR (300 MHz, CDCl3, ppm) δ 2.43 (s,
3H), 3.64 (s, 3H), 6.70-6.73 (m, 1H), 6.75-6.84 (m, 2H), 7.15-7.39
(m, 9H), 7.64-7.68 (m, 1H). 13C NMR (75 MHz, CDCl3, ppm) δ
9.6, 55.1, 110.3, 110.7, 113.1, 115.8, 118.9, 120.1, 122.5, 123.1, 126.6,
127.8, 128.9, 129.0, 133.3, 136.7, 137.6, 138.7, 159.0. Signal for one
carbon could not be located. FT-IR (neat, cm-1) υ 3059, 1598, 1499,
1460, 1451. Anal. Calcd for C22H19NO (313.39 g/mol): C, 84.31; H,
6.11; N, 4.47. Found: C, 84.28; H, 6.09; N, 4.34.
2-(3-Methoxyphenyl)-1-methyl-3-phenylindole (Table 1, Entry 5).
Palladium acetate (9.3 mg, 0.042 mmol), 2-(dicyclohexylphos-
phino)biphenyl (29.1 mg, 0.083 mmol), sodium carbonate (176 mg,
1.66 mmol), 1-methyl-3-phenylindole (172 mg, 0.83 mmol),
3-chloroanisole (596 mg, 4.10 mmol), and anhydrous DMA (3.3 mL).
After column chromatography (hexanes/dichloromethane 3/1),
a white solid was obtained. Product was recrystallized from 2,2,4-
trimethylpentane to give 165 mg (63%) of white crystals, mp =
95-97 °C. Rf = 0.40 (hexanes/dichloromethane 2/1; visualization
by UV). 1H NMR (300 MHz, CDCl3, ppm) δ 3.70 (s, 3H), 3.72
(s, 3H), 6.84-6.87 (m, 1H), 6.89-6.95 (m, 2H), 7.14-7.22 (m, 2H),
7.25-7.35 (m, 6H), 7.40-7.44 (m, 1H), 7.77-7.82 (m, 1H). 13C
NMR (75 MHz, CDCl3, ppm) δ 31.0, 55.2, 109.6, 113.8, 115.1,
116.6, 119.6, 120.2, 122.2, 123.5, 125.5, 126.9, 128.2, 129.4, 129.8,
133.1, 135.2, 137.3, 137.5, 159.3. FT-IR (neat, cm-1) υ 1600, 1550,
1496, 1468. Anal. Calcd for C22H19NO (313.39 g/mol): C, 84.31; H,
6.11; N, 4.47. Found: C, 84.21; H, 6.11; N, 4.42.
2-(3-Methoxyphenyl)-1,3-dimethylindole (Table 1, Entry 1).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexy-
lphosphino)biphenyl (17.5 mg, 0.05 mmol), sodium carbonate
(106 mg, 1.0 mmol), 1,3-dimethylindole (73 mg, 0.5 mmol),
3-chloroanisole (356 mg, 2.50 mmol), and anhydrous DMA
(2 mL). After column chromatography (hexanes/dichloro-
methane 5/1), 102 mg (81%) of a clear oil was obtained. Product
darkens after several hours on the bench. Rf = 0.50 (hexanes/
dichloromethane 2/1; visualization by UV). 1H NMR (300 MHz,
CDCl3, ppm) δ 2.30 (s, 3H), 3.63 (s, 3H), 3.86 (s, 3H), 6.93-7.01
(m, 3H), 7.12-7.19 (m, 1H), 7.22-7.29 (m, 1H), 7.31-7.44
(m, 2H), 7.58-7.63 (m, 1H). 13C NMR (75 MHz, CDCl3, ppm)
δ9.4, 31.0, 55.3, 108.6, 109.2, 113.2, 116.6, 118.8, 119.1, 121.8, 123.1,
128.4, 129.3, 133.5, 137.2, 137.4, 159.4. FT-IR (neat, cm-1) υ 3056,
2914, 1609, 1578, 1469. Anal. Calcd for C17H17NO (251.32 g/mol):
C, 81.24; H, 6.82; N, 5.57. Found: C, 80.88; H, 6.90; N, 5.33.
1-Butyl-2-(3-methoxyphenyl)-3-methylindole (Table 1, Entry 2).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexyl-
phosphino)biphenyl (17.5 mg, 0.05 mmol), sodium carbonate
(106 mg, 1.0 mmol), 1-butyl-3-methylindole (94 mg, 0.5 mmol),
3-chloroanisole (356 mg, 2.50 mmol), and anhydrous DMA (2 mL).
After column chromatography (hexanes/dichloromethane 7/1), 108
mg (73%) of a clear oil was obtained. Product darkens after several
hours on the bench. Rf = 0.60 (hexanes/dichloromethane 2/1;
1
visualization by UV). H NMR (300 MHz, CDCl3, ppm) δ 0.77
(t, J = 7.4 Hz, 3H), 1.08-1.21 (m, 2H), 1.55-1.65 (m, 2H), 2.24 (s,
3H), 3.85 (s, 3H), 4.00-4.07 (m, 2H), 6.91-7.00 (m, 3H),
7.10-7.16 (m, 1H), 7.19-7.24 (m, 1H), 7.32-7.43 (m, 2H),
7.57-7.61 (m, 1H). 13C NMR (75 MHz, CDCl3, ppm) δ 9.3,
13.7, 20.1, 32.2, 43.7, 55.3, 108.7, 109.7, 113.3, 116.2, 118.9, 119.0,
121.6, 123.1, 128.6, 129.4, 133.9, 136.3, 137.3, 159.5. FT-IR (neat,
cm-1) υ 2958, 2932, 1608, 1578, 1488, 1465. Anal. Calcd for
C20H23NO (293.40 g/mol): C, 81.87; H, 7.90; N, 4.77. Found: C,
82.03; H, 8.01; N, 4.73.
3-Cyclohexyl-2-(3-methoxyphenyl)-1-methylindole (Table 1,
Entry 6). Palladium acetate (6.0 mg, 0.025 mmol),
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TABLE 3. Furan Arylationa
aConditions: 5 mol % Pd(OAc)2, 10 mol % Cy2P-o-biphenyl, K3PO4 (2 equiv), furan (5 equiv), aryl chloride (1 equiv), NMP solvent, 24 h at 100 °C;
isolated yield. bFuran (1 equiv), aryl chloride (5 equiv). Yields are the average of two runs.
2-(dicyclohexylphosphino)biphenyl (17.5 mg, 0.05 mmol), sodium
carbonate (106 mg, 1.0 mmol), 3-cyclohexyl-1-methylindole
(107 mg, 0.50 mmol), 3-chloroanisole (356 mg, 2.50 mmol), and
anhydrous DMA (2 mL). After column chromatography
(hexanes/dichloromethane 4/1), 99 mg (62%) of a clear oil was
obtained. Product darkens after several hours on the bench. Rf =
0.60 (hexanes/dichloromethane 2/1; visualization by UV). 1H
NMR (300 MHz, CDCl3, ppm) δ 1.23-1.34 (m, 3H), 1.69-1.83
(m, 5H), 1.87-2.03 (m, 2H), 2.62-2.75 (m, 1H), 3.53 (s, 3H),
3.86 (s, 3H), 6.87-7.01 (m, 3H), 7.07-7.14 (m, 1H), 7.19-7.23
(m, 1H), 7.30-7.35 (m, 1H), 7.36-7.43 (m, 1H), 7.81-7.86
(m, 1H). 13C NMR (75 MHz, CDCl3, ppm) δ 26.3, 27.1, 30.7,
33.5, 36.7, 55.3, 109.5, 113.5, 116.4, 118.6, 118.7, 120.7, 121.3,
123.3, 126.3, 129.2, 133.9, 136.6, 137.3, 159.3. FT-IR (neat, cm-1
)
υ 2926, 2850, 1610, 1578, 1466. Anal. Calcd for C22H25NO (319.44
g/mol): C, 82.72; H, 7.89; N, 4.38. Found: C, 83.19; H, 8.00; N,
4.17.
1-Butyl-3-methyl-2-phenylindole (Table 1, Entry 7). Palladium
acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-
biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106 mg,
478 J. Org. Chem. Vol. 76, No. 2, 2011

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1.0 mmol), 1-butyl-3-methylindole (94 mg, 0.5 mmol), chloro-
benzene (0.25 mL, 2.50 mmol), and anhydrous DMA (2 mL).
After column chromatography (hexanes, then hexanes/diethyl
ether 10/1), 89 mg (67%) of a clear oil was obtained. Product
darkens after several hours on the bench. Rf = 0.20 (hexanes).
1H NMR (300 MHz, CDCl3, ppm) δ 0.75 (t, J = 7.4 Hz, 3H),
1.06-1.20 (m, 2H), 1.52-1.63 (m, 2H), 2.24 (s, 3H), 3.98-4.06
(m, 2H), 7.10-7.17 (m, 1H), 7.19-7.26 (m, 1H), 7.33-7.52 (m,
6H), 7.57-7.62 (m, 1H). 13C NMR (75 MHz, CDCl3, ppm) δ
9.2, 13.6, 20.0, 32.1, 43.6, 108.6, 109.6, 118.8, 118.9, 121.4, 127.7,
128.3, 128.6, 130.6, 132.5, 136.3, 137.4. FT-IR (neat, cm-1) υ
3051, 2957, 2931, 1606, 1464. Anal. Calcd for C19H21N (263.38
g/mol): C, 86.65; H, 8.04; N, 5.32. Found: C, 86.62; H, 7.95; N,
5.11.
(0.25 mL, 2.50 mmol), and anhydrous DMA (2 mL). After
column chromatography (hexanes (600 mL), then hexanes/
diethyl ether 20/1), an impure product was obtained. After
purification by preparative TLC (elution 4 times in hexanes),
81 mg (73%) of a clear oil was obtained. Product darkens after
several hours on the bench. This compound is known.3n 1
H
NMR (300 MHz, CDCl3, ppm) δ 2.29 (s, 3H), 3.62 (s, 3H),
7.12-7.19 (m, 1H), 7.23-7.29 (m, 1H), 7.32-7.36 (m, 1H),
7.38-7.45 (m, 3H), 7.46-7.53 (m, 2H), 7.59-7.63 (m, 1H).
1,3-Dimethyl-2-(pyridin-3-yl)indole (Table 1, Entry 12). Palla-
dium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-
biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106 mg, 1.0
mmol), 1,3-dimethylindole (73 mg, 0.5 mmol), 3-chloropyridine
(284 mg, 2.50 mmol), and anhydrous DMA (2 mL). After
column chromatography (hexanes/ethyl acetate 2/1), 71 mg
(64%) of a white solid was obtained, mp = 62-64 °C (2,2,4-
trimethylpentane). Rf = 0.50 (hexanes/dichloromethane 2/1;
visualization by UV). 1H NMR (300 MHz, CDCl3, ppm) δ 2.29
(s, 3H), 3.63 (s, 3H), 7.14-7.21 (m, 1H), 7.25-7.32 (m, 1H),
7.33-7.37 (m, 1H), 7.41-7.47 (m, 1H), 7.59-7.64 (m, 1H),
7.70-7.75 (m, 1H), 8.63-8.71 (m, 2H). 13C NMR (75 MHz,
CDCl3, ppm) δ 9.3, 31.0, 109.4, 110.1, 119.1, 119.4, 122.4, 123.3,
128.3, 133.9, 137.5, 137.8, 148.9, 151.2. Signal for one carbon
could not be located. FT-IR (neat, cm-1) υ 3052, 1571, 1467.
Anal. Calcd for C15H14N2 (222.29 g/mol): C, 81.05; H, 6.35; N,
12.60. Found: C, 81.07; H, 6.50; N, 12.57.
1-Butyl-3-methyl-2-m-tolylindole (Table 1, Entry 8). Palla-
dium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-
biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106 mg, 1.0
mmol), 1-butyl-3-methylindole (94 mg, 0.5 mmol), 3-chloroto-
luene (316 mg, 2.50 mmol), and anhydrous DMA (2 mL). After
preparative TLC plate was eluted 4 times (hexanes), 90 mg
(65%) of a clear oil was obtained. Product darkens after several
hours on the bench. Rf = 0.20 (hexanes). 1H NMR (300 MHz,
CDCl3, ppm) δ 0.78 (t, J = 7.3 Hz, 3H), 1.08-1.22 (m, 2H),
1.54-1.66 (m, 2H), 2.25 (s, 3H), 2.44 (s, 3H), 3.99-4.06 (m, 2H),
7.11-7.27 (m, 5H), 7.33-7.41 (m, 2H), 7.58-7.62 (m, 1H). 13
C
NMR (75 MHz, CDCl3, ppm) δ 9.3, 13.6, 20.0, 21.5, 32.1, 43.6,
108.5, 109.6, 118.8, 118.9, 121.4, 127.7, 128.2, 128.5, 128.6,
131.2, 132.5, 136.3, 137.6, 137.9. FT-IR (neat, cm-1) υ 2958,
2873, 1608, 1464. Anal. Calcd for C20H23N (277.40 g/mol): C,
86.59; H, 8.36; N, 5.05. Found: C, 86.45; H, 8.37; N, 5.06.
1-Butyl-2-(3,5-dimethylphenyl)-3-methylindole (Table 1, Entry 9).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexy-
lphosphino)biphenyl (17.5 mg, 0.05 mmol), sodium carbonate
(106 mg, 1.0 mmol), 1-butyl-3-methylindole (94 mg, 0.5 mmol),
5-chloro-m-xylene (351 mg, 2.50 mmol), and anhydrous DMA
(2 mL). After preparative TLC plate was eluted 4 times (hexanes),
88 mg (60%) of a clear oil was obtained. Product darkens after
several hours on the bench. Rf = 0.30 (hexanes). 1H NMR (300
MHz, CDCl3, ppm) δ 0.79 (t, J = 7.3 Hz, 3H), 1.10-1.24 (m, 2H),
1.55-1.67 (m, 2H), 2.25 (s, 3H), 2.40 (s, 6H), 3.99-4.06 (m, 2H),
7.00 (bs, 2H), 7.06 (bs, 1H), 7.11-7.17 (m, 1H), 7.20-7.26
(m, 1H), 7.33-7.38 (m, 1H), 7.58-7.62 (m, 1H). 13C NMR
(75 MHz, CDCl3, ppm) δ 9.3, 13.6, 20.0, 21.4, 32.1, 43.6, 108.3,
109.6, 118.7, 118.8, 121.2, 128.3, 128.6, 129.4, 132.3, 136.2, 137.7,
137.8. FT-IR (neat, cm-1) υ 2958, 2929, 2872, 1602, 1465. Anal.
Calcd for C21H25N (291.43 g/mol): C, 86.55; H, 8.65; N, 4.81.
Found: C, 86.32; H, 8.74; N, 4.69.
1-Butyl-2-(3,4-dimethylphenyl)-3-methylindole (Table 1, Entry 10).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-
biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106 mg,
1.0 mmol), 1-butyl-3-methylindole (94 mg, 0.5 mmol), 1-chloro-
3,4-dimethylbenzene (351 mg, 2.50 mmol), and anhydrous
DMA (2 mL). After preparative TLC plate was eluted 4 times
(hexanes), 76 mg (52%) of a clear oil was obtained. Product
darkens after several hours on the bench. Rf = 0.20 (hexanes).
1H NMR (300 MHz, CDCl3, ppm) δ 0.79 (t, J = 7.3 Hz, 3H),
1.09-1.23 (m, 2H), 1.54-1.66 (m, 2H), 2.24 (s, 3H), 2.34
(s, 3H), 2.35 (s, 3H), 3.99-4.06 (m, 2H), 7.09-7.16 (m, 3H),
7.18-7.26 (m, 2H), 7.32-7.37 (m, 1H), 7.58-7.61 (m, 1H). 13C
NMR (75 MHz, CDCl3, ppm) δ 9.3, 13.7, 19.7, 19.9, 20.1, 32.2,
43.6, 108.3, 109.6, 118.7, 118.8, 121.2, 128.1, 128.6, 129.6,
129.9, 131.7, 136.2, 136.5, 137.7. Signal for one carbon could
not be located. FT-IR (neat, cm-1) υ 2957, 2931, 2872, 1655,
1610, 1501, 1465.
2-(4-Chlorophenyl)-1,3-dimethylindole (Table 1, Entry 13).
Palladium acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphos-
phino)biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106
mg, 1.0 mmol), 1,3-dimethylindole (73 mg, 0.5 mmol), 1,4-
dichlorobenzene (368 mg, 2.50 mmol), and anhydrous DMA
(2 mL). After preparative TLC plate was eluted 4 times
(hexanes), 98 mg (77%) of a white solid was obtained, mp =
122-124 °C (2,2,4-trimethylpentane). Rf = 0.20 (hexanes). 1H
NMR (300 MHz, CDCl3, ppm) δ 2.26 (s, 3H), 3.60 (s, 3H),
7.12-7.19 (m, 1H), 7.23-7.29 (m, 1H), 7.30-7.35 (m, 3H),
7.44-7.49 (m, 2H), 7.58-7.62 (m, 1H). 13C NMR (75 MHz,
CDCl3, ppm) δ 9.3, 30.9, 109.0, 109.3, 118.9, 119.3, 122.0, 128.3,
128.7, 130.6, 131.8, 133.8, 136.3, 137.3. FT-IR (neat, cm-1) υ
1491, 1469. Anal. Calcd for C16H14ClN (255.74 g/mol): C,
75.14; H, 5.52; N, 5.48. Found: C, 75.18; H, 5.54; N, 5.43.
1,2-Dimethyl-3-phenylindole (Table 1, Entry 14). Palladium
acetate (11 mg, 0.05 mmol), 2-(dicyclohexylphosphino)biphenyl
(35 mg, 0.1 mmol), sodium carbonate (212 mg, 2.0 mmol), 1,2-
dimethylindole (145 mg, 1.0 mmol), chlorobenzene (0.5 mL, 5.0
mmol), and anhydrous DMA (4 mL). After preparative TLC
plate was eluted 4 times (hexanes), 144 mg (65%) of a white solid
was obtained. Product darkens after several hours on the bench.
This compound is known.14a 1H NMR (300 MHz, CDCl3,
ppm) δ 2.50 (s, 3H), 3.75 (s, 3H), 7.08-7.15 (m, 1H), 7.19-
7.26 (m, 1H), 7.27-7.36 (m, 2H), 7.44-7.53 (m, 4H), 7.65-7.70
(m, 1H).
1-Methyl-2-phenylindole, 1-Methyl-3-phenylindole, and 1-Methyl-
2,3-diphenylindole (Table 1, Entry 15). Palladium acetate (11 mg,
0.05 mmol), butyldi-1-adamantylphosphine (38 mg, 0.1 mmol),
potassium phosphate (425 mg, 2.0 mmol), 1-methylindole (131
mg, 1.0 mmol), chlorobenzene (0.5 mL, 5.0 mmol), and anhydrous
NMP (4 mL). After preparative TLC plate was eluted 5 times
(hexanes), 116 mg (56%) of 1-methyl-2-phenylindole was obtained
as a yellow solid. Also, 36 mg of the 2:3 mixture of 1-methyl-3-
phenylindole and 1-methyl-2,3-diphenylindole was obtained as a
clear oil. Calculations based on the ratios from NMR spectrum
showed that 14.4 mg (7%) of 1-methyl-3-phenylindole and 21.6 mg
of 1-methyl-2,3-diphenylindole (8%) were present in the mixture.
Products darken after several hours on the bench. These compounds
are known.3h,14b,14c 1-Methyl-2-phenylindole: 1H NMR (300 MHz,
CDCl3, ppm) δ 3.75 (s, 3H), 6.56 (s, 1H), 7.11-7.17 (m, 1H), 7.22-
7.28 (m, 1H), 7.35-7.54 (m, 6H), 7.62-7.66 (m, 1H). A mixture of
1,3-Dimethyl-2-phenylindole (Table 1, Entry 11). Palladium
acetate (6.0 mg, 0.025 mmol), 2-(dicyclohexylphosphino)-
biphenyl (17.5 mg, 0.05 mmol), sodium carbonate (106 mg,
1.0 mmol), 1,3-dimethylindole (73 mg, 0.5 mmol), chlorobenzene
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1-methyl-3-phenylindole and 1-methyl-2,3-diphenylindole: 1H
NMR (300 MHz, CDCl3, ppm) δ 3.69 (s, 3H), 3.85 (s, 3H),
7.14-7.48 (m), 7.64-7.69 (m), 7.78-7.83 (m), 7.93-7.98 (m).
Ethyl 4-(5-Fluoro-1,2-dimethyl-1H-indol-3-yl)benzoate (Table 1,
Entry 17). Palladium acetate (6 mg, 0.025 mmol), 2-(dicyclo-
hexylphosphino)biphenyl (17 mg, 0.05 mmol), sodium carbonate
(106 mg, 1.0 mmol), 5-fluoro-1,2-dimethyl-1H-indole (88.7 mg,
0.5 mmol), ethyl 4-iodobenzoate (0.46 g, 2.5 mmol), and anhydrous
DMA (2 mL). After column chromatography (hexanes/diethyl
ether 80/20), 155 mg (92%) of white crystals were obtained,
mp = 149-150 °C (hexanes), Rf = 0.21 (hexanes/diethyl ether 80/
20). 1H NMR (500 MHz, CDCl3, ppm) δ 8.13 (d, J = 8.2 Hz, 2H),
7.51 (d, J = 8.2 Hz, 2H), 7.32-7.30 (m, 1H), 7.23-7.21 (m, 1H),
6.98-6.94 (m, 1H), 4.40 (q, J = 6.9, 2H), 3.72 (s, 3H), 2.49 (s, 3H),
1.42 (t, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3, ppm) 166.8,
158.5 (d, JC-F = 233.9 Hz), 140.4, 135.9, 133.4, 130.0, 129.1, 127.8,
127.0 (d, JC-F = 10.3 Hz), 113.5, 109.6 (d, JC-F = 20.3 Hz), 109.5
(d, JC-F = 15.5 Hz), 103.7 (d, JC-F = 24.0 Hz), 61.0, 30.1, 14.5,
11.5. FT-IR (neat, cm-1) υ 1705, 1606, 1482, 1272, 1175, 1145,
1127, 1104, 973. Anal. Calcd for C17H17NO (251.32 g/mol): C,
73.29; H, 5.83; N, 4.50. Found: C, 73.46; H, 5.80; N, 4.48.
Ethyl 4-(5-Methoxy-1,2-dimethyl-1H-indol-3-yl)benzoate (Table 1,
Entry 16). Palladium acetate (6 mg, 0.025 mmol), 2-(dicyclohexyl-
phosphino)biphenyl (17 mg, 0.05 mmol), sodium carbonate (106 mg,
1.0 mmol), 5-methoxy-1,2-dimethyl-1H-indole (88.4 mg, 0.5 mmol),
ethyl 4-iodobenzoate (0.46 g, 2.5 mmol), and anhydrous DMA
(2 mL). After column chromatography (hexanes/diethyl ether 80/20),
112 mg (69%) of white crystals were obtained, mp = 103-104 °C
(hexanes), Rf = 0.36 (hexanes/diethyl ether 80/20). 1H NMR (500
MHz, CDCl3, ppm) δ 8.17-8.14 (m, 2H), 7.57-7.54 (m, 2H), 7.23
(d, J = 9.0 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 9.0, 2.3
Hz, 1H), 4.40 (q, J = 7.3 Hz, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 2.46
(s, 3H), 1.42(t, J=7.3Hz, 3H). 13C NMR (125 MHz, CDCl3, ppm)
δ 166.9, 154.8, 141.1, 134.9, 132.1, 130.0, 129.2, 127.5, 127.0,
113.1, 111.3, 109.8, 100.7, 60.9, 56.1, 29.9, 14.5, 11.4. FT-IR (neat,
cm-1) υ 1706, 1488, 1270, 1103, 720. Anal. Calcd for C17H17NO
(251.32 g/mol): C, 74.28; H, 6.55; N, 4.33. Found: C, 74.42; H, 6.58;
N, 4.37.
General Procedure for Pyrrole Arylation. Outside the glove-
box, a 4-dram vial equipped with a magnetic stir bar was charged
with pyrrole and chloroarene. The vial was flushed with argon,
capped, and placed inside a glovebox. To this mixture were added
2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (2.0 mmol, 425 mg), and anhydrous N-methylpyrrolidone
(2 mL). The mixture was shaken, and Pd(OAc)2 (0.05 mmol, 11 mg,
5 mol %) was added. The sealed vial was taken out of the glovebox,
stirred at room temperature for 15 min, placed in a heating block
(125 °C), and stirred vigorously for 24 h. The reaction mixture was
allowed to cool to room temperature and then diluted with ethyl
acetate (50 mL). The resulting suspension was filtered. The filtrate
was concentrated under vacuum to a volume of about 2 mL. The
mixture was absorbed on silica gel and subjected to column
chromatography. After concentration of the fractions containing
the product, the residue was dried under reduced pressure (40 °C) to
yield a pure arylated pyrrole. The yields listed in the table are the
average of two runs.
2-(Biphenyl-4-yl)-1-methyl-1H-pyrrole (Table 2, Entry 1). Pal-
ladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-pyrrole
(5.0 mmol, 0.40 g, 0.44 mL), 4-chlorobiphenyl (192 mg, 1.0 mmol),
2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
After column chromatography (hexanes/ethyl acetate 95/5),
pure fractions were combined and solvent was evaporated
leaving white crystals. The impure fractions were combined,
concentrated and subjected to another column chromatography
step (hexanes/ethyl acetate 95/5). The pure fractions were
combined and the solvent was evaporated. A total of 136 mg
(57% yield) of white crystalline product was obtained. A second
experiment under the same conditions gave 54% yield. The
compound is known.14d Rf = 0.51 (hexanes/ethyl acetate 95/5).
1H NMR (500 MHz, C6D6, ppm) δ 7.52-7.45 (m, 4H),
7.34-7.32 (m, 2H), 7.25-7.22 (m, 1H), 7.15-7.14 (m, 2H),
6.49-6.46 (m, 2H), 6.38 (dd, J = 6.3 Hz, 3.5 Hz, 1H), 2.94
(s, 3H).
(4-(1-Methyl-1H-pyrrol-2-yl)phenyl)(phenyl)methanone (Table 2,
Entry 2). Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-
pyrrole (5.0 mmol, 0.40 g, 0.44 mL), (4-chlorophenyl)(phenyl)-
methanone (192 mg, 1.0 mmol), 2-(dicyclohexylphosphino)- bi-
phenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0 mmol),
and anhydrous NMP (2.0 mL). After column chromatography
(hexanes/ethyl acetate 95/5), fractions containing the desired com-
pound were combined and the solvent was evaporated affording
186 mg of crude product. The crude compound was recrystallized
from hexanes giving 96 mg (55%) of a yellowish powder. A second
experiment under the same conditions gave 47% yield. Rf = 0.15
(hexanes/ethyl acetate 95/5), mp = 75-76 °C (hexanes). 1H NMR
(500 MHz, C6D 6, ppm) δ 7.79-7.76 (m, 4H), 7.20-7.18 (m, 2H),
7.14-7.13 (m, 1H), 7.09-7.06 (m, 2H), 6.45-6.44 (m, 1H),
6.41-6.39 (m, 1H), 6.32-6.31 (m, 1H), 2.94 (s, 3H). 13C NMR
(125 MHz, C6D6, ppm) δ 195.2, 138.5, 137.7, 135.8, 133.6, 132.0,
130.7, 130.2, 128.4, 128.3, 125.3, 110.8, 108.9, 34.7. FT-IR (neat,
cm-1) υ 1653, 1602, 1475, 1446, 1319, 1310,1277, 1186, 1059. Anal.
Calcd for C18H15NO (261.32 g/mol): C, 82.73; H, 5.79; N, 5.36.
Found: C, 82.60; H, 5.88.
2-(3,5-Dimethoxyphenyl)-1-methyl-1H-pyrrole (Table 2, En-
try 3). Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-
pyrrole (5.0 mmol, 0.40 g, 0.44 mL), 1-chloro-3,5-dimethoxy-
benzene (185 mg, 1.0 mmol), 2-(dicyclohexylphosphino)-
biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0
mmol), and anhydrous NMP (2.0 mL). After column chroma-
tography (hexanes/ethyl acetate 90/10), fractions containing the
desired compound were combined and the solvent was evapo-
rated. The crude compound was subjected to preparative TLC
(2 plates, hexanes/ethyl acetate 90/10, Rf = 0.30) giving 120 mg
(52% yield) of a viscous yellow oil. A second experiment under
the same conditions gave 48% yield. 1H NMR (400 MHz, C6D6,
ppm) δ 6.64 (d, J = 2.3 Hz, 2H), 6.54-6.52 (m, 1H), 6.49-6.47
(m, 1H), 6.45-6.43 (m, 1H), 6.34-6.32 (m, 1H), 1.66 (s, 6H),
1.54 (s, 3H). 13C NMR (125 Mz, C6D6, ppm) 161.3, 136.0, 134.7,
123.8, 109.4, 108.3, 107.2, 99.5, 54.8, 34.5. FT-IR (neat, cm-1) υ
1592, 1465, 1421, 1279, 1204, 1154, 1065. Anal. Calcd for
C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.89; H,
6.79; N, 6.48.
Ethyl 4-(1-Methyl-1H-pyrrol-2-yl)benzoate (Table 2, Entry 4).
Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-pyrrole
(5.0 mmol, 0.40 g, 0.44 mL), ethyl-4-chlorobenzoate (188 mg,
1.0 mmol), 2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10
mmol, 10 mol %), K3PO4 (425 mg, 2.0 mmol), and anhydrous
NMP (2.0 mL). The reaction mixture was directly adsorbed
onto the silica column. After two successive column chromato-
graphies (both hexanes/ethyl acetate 95/5 eluent) 180 mg (78%
yield) of a white powder was obtained. A second experiment
under the same conditions gave 78% yield. Rf = 0.19 (hexanes/
ethyl acetate 95/5). This compound is known.14e 1H NMR
(400 MHz, CDCl3, ppm) δ 8.08-8.06 (m, 2H), 7.49-7.46
(m, 2H), 6.77-6.76 (m, 1H), 6.34-6.33 (m, 1H), 6.22-6.23
(m, 1H), 4. 39 (q, J = 7.4 Hz, 2H), 3.71 (s, 3H), 1.41 (t, J =
7.4 Hz, 3H).
2-(4-Methoxyphenyl)-1-methyl-1H-pyrrole (Table 2, Entry 5).
Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-pyrrole
(5.0 mmol, 0.40 g, 0.44 mL), 4-chloroanisole (131 mg, 1.0
mmol), 2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol,
10 mol %), K3PO4 (425 mg, 2.0 mmol), and anhydrous DMPU
(2.0 mL). After column chromatography (hexanes/ethyl acetate
95/5), 131 mg (71% yield) of a white powder was obtained. Rf =
0.38 (hexanes/ethyl acetate 95/5). A second experiment under
480 J. Org. Chem. Vol. 76, No. 2, 2011

Nadres et al.
JOCArticle
the same conditions gave 69% yield. This compound is known.13
1H NMR (500 MHz, C6D6, ppm) δ 7.22-7.19 (m, 2H), 6.79-
6.76 (m, 2H), 6.46 (dd, J = 3.5 Hz, 1.7 Hz, 1H), 6.42-6.41
(m, 1H), 6.40-6.38 (m, 1H), 3.31 (s, 3H), 3.03 (s, 3H).
10 mol %), K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP
(2.0 mL). After column chromatography (hexanes/ethyl acetate
95/5), fractions containing the desired compound were com-
bined and solvent was evaporated. The crude compound was
recrystallized (hexanes/ethyl acetate 99/1) giving 140 mg (63%)
of white crystals. A second experiment under the same condi-
tions gave 63% yield. Rf = 0.27 (hexanes/ethyl acetate 95/5), mp
= 154-155 °C. 1H NMR (500 MHz, C6D6, ppm) δ 7.40-7.37
(m, 2H), 7.32-7.30 (m, 2H), 7.23-7.19 (m, 2H), 7.11-7.09 (m,
1H), 7.03 (d, J = 8.2, 2H), 6.51 (s, 2H), 3.15 (s, 3H), 2.16 (s, 3H).
13C NMR (125 MHz, C6D6, ppm) δ 137.0, 136.6, 136.1, 134.2,
131.3, 129.1, 128.8, 128.7, 128.4, 126.5, 109.3, 109.0, 33.6, 20.8.
FT-IR (neat, cm-1) υ 1548,1490, 1468, 1331. Anal. Calcd for
C18H17N (217.26 g/mol): C, 87.41; H, 6.93; N, 5.66. Found: C,
87.25; H, 7.26; N, 5.61.
1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-pyrrole (Table 2,
Entry 6). Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-
1H-pyrrole (5.0 mmol, 0.40 g, 0.44 mL), 4-chlorobenzotrifluor-
ide (201 mg, 1.0 mmol), 2-(dicyclohexylphosphino)biphenyl
(35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0 mmol),
and anhydrous NMP (2.0 mL). After column chromatography
(hexanes), fractions containing the desired compound were
combined and the solvent was evaporated. The crude compound
was subjected to another column chromatography (hexanes/
ethyl acetate 99/1). The fractions with the product were com-
bined and the solvent was evaporated giving 165 mg (60%) of a
viscous yellow oil. A second experiment under the same condi-
tions gave 61% yield. This compound is known.14f Rf = 0.23
(hexanes). 1H NMR (400 MHz, C6D6, ppm) δ 7.32 (d, J = 8.2
Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 6.38-6.36 (m, 1H), 6.33-6.32
(m, 1H), 6.29-6.27 (m, 1H), 2.86 (s, H).
1-Methyl-2-phenyl-1H-pyrrole (Table 2, Entry 7). Palladium
acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-pyrrole (5.0 mmol,
0.40 g, 0.44 mL), chlorobenzene (136 mg, 1.0 mmol), 2-(dicyclo-
hexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
After column chromatography (hexanes/ethyl acetate 99/1), 113
mg (62%) of white powder was obtained. A second experiment
under the same conditions gave 58% yield. This compound is
known.14f Rf = 0.28 (hexanes/ethyl acetate 95/5). 1H NMR (400
MHz, CDCl3, ppm) δ 7.42-7.38 (m, 4H), 7.32-7.25 (m, 1H),
6.73 (dd, J = 4.6, 2.8 Hz, 1H), 6.25-6.23 (m, 1H), 6.22-6.20 (m,
1H), 3.67 (s, 3H).
1,3-Bis(1-methyl-1H-pyrrol-2-yl)benzene (Table 2, Entry 8).
Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-2-phenyl-1H-
pyrrole (1.0 mL, 10.0 mmol), m-dichlorobenzene (175 mg, 1.0
mmol), 2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol,
10 mol %), K3PO4 (850 mg, 2.0 mmol), and anhydrous NMP
(3.0 mL). After column chromatography (hexanes/ethyl acetate
96/4), fractions containing the desired compound were com-
bined and the solvent was evaporated. The crude compound was
subjected to another column chromatography (hexanes/ethyl
acetate 96/4) giving 140 mg (73%) of a yellowish oil. A second
experiment under the same conditions gave 70% yield. Rf =
0.16 (hexanes/ethyl acetate 96/4). 1H NMR (500 MHz, CDCl3,
ppm) δ 7.52-7.51 (m, 1H), 7.49-7.46 (m, 2H), 7.41-7.39
(m, 1H), 6.80-6.79 (m, 2H), 6.34-6.33 (m, 2H), 6.29-6.28
(m, 2H), 3.76 (s, 6H). 13C NMR (125 MHz, CDCl3, ppm) δ
134.5, 133.6, 128.9, 128.5, 127.1, 123.0, 109.0, 108.0 35.3. FT-IR
(neat, cm-1) υ 1604, 1490, 1091. Anal. Calcd for C16H16N2 (236.3 g/
mol): C, 81.32; H, 6.82; N, 11.85. Found: C, 81.16; H, 6.81; N, 11.69.
1-Methyl-2-phenyl-5-p-tolyl-1H-pyrrole (Table 2, Entry 9).
Palladium acetate (11.4 mg, 0.05 mmol), 1-methyl-2-phenyl-
1H-pyrrole (1.0 mmol, 141 mg), 4-chlorotoluene (380 mg, 3.0
mmol), 2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol,
Ethyl 1-Methyl-5-phenyl-1H-pyrrole-2-carboxylate (Table 2,
Entry 10). Palladium acetate (11.4 mg, 0.05 mmol), ethyl
1-methyl-1H-pyrrole-2-carboxylate (1.0 mmol, 159 mg), chloro-
benzene (0.30 mL, 3.0 mmol), 2-(dicyclohexylphosphino)-
biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg,
2.0 mmol), and anhydrous NMP (2.0 mL). The reaction mixture
was directly adsorbed onto the silica column. After column
chromatography (hexanes/ethyl acetate 95/5), 119 mg (51%
yield) of a colorless oil was obtained. A second experiment under
the same conditions gave 55% yield. This compound is known.14g
1
Rf = 0.38 (hexanes/ethyl acetate 95/5). H NMR (500 MHz,
CDCl3, ppm) δ 7.45-7.38 (m, 5H), 7.04 (d, J = 4.0 Hz, 1H),
6.21 (d, J = 4.0, 1H), 4.30 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.37
(t, J = 7.0 Hz, 3H).
Ethyl 5-(4-Methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxy-
late (Table 2, Entry 11). Palladium acetate (11.4 mg, 0.05 mmol),
ethyl 1-methyl-1H-pyrrole-2-carboxylate (1.0 mmol, 160 mg),
1-chloro-4-methoxybenzene (0.37 mL, 3.0 mmol), 2-(dicyclo-
hexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
The reaction mixture was directly adsorbed onto the silica
column. After column chromatography (hexanes/ethyl acetate
95/5), 145 mg (52%) of a white powder was obtained. A second
experiment under the same conditions gave 54% yield. This
compound is known.14h Rf = 0.14 (hexanes/ethyl acetate 95/5).
1H NMR (500 MHz, CDCl3, ppm) δ 7.31 (d, J = 8.9 Hz, 2H),
7.02 (d, J = 4.0, 1H), 6.96 (d, J = 8.9 Hz, 2H), 6.15 (d, J = 4.0
Hz, 1H), 4.29 (q, J = 6.9 Hz, 2H), 3.85 (s, 6H), 1.36 (t, J = 6.9
Hz, 3H).
1,2-Diphenyl-1H-pyrrole (Table 2, Entry 12). Palladium acet-
ate (11.4 mg, 0.05 mmol), 1-phenyl-1H-pyrrole (1.0 mmol, 141 mg),
chlorobenzene (0.37 mL, 3.0 mmol), 2-(dicyclohexylphosphino)-
biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg,
2.0 mmol), and anhydrous NMP (2.0 mL). The reaction mix-
ture was directly adsorbed onto the silica column. After column
chromatography (hexanes), 95 mg (44%) of a white powder was
obtained. A second experiment under the same conditions gave
40% yield. This compound is known.14f Rf = 0.22 (hexanes).
1H NMR (500 MHz, CDCl3, ppm) δ 7.35-7.15 (m, 10H), 6.97
(dd, J = 2.8, 1.8 Hz, 1H), 6.47 (dd, J = 3.4, 1.8 Hz, 1H), 6.39
(dd, J = 3.4, 2.8 Hz, 1H).
2-(1-Methyl-1H-pyrrol-2-yl)pyridine (Table 2, Entry 13). Pal-
ladium acetate (11.4 mg, 0.05 mmol), 1-methyl-1H-pyrrole (5.0
mmol, 0.45 mL), 2-chloropyridine (119.6 mg, 1.0 mmol), 2--
(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol
%), K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
The reaction mixture was directly adsorbed onto the silica
column. After column chromatography (hexanes/ethyl acetate
95/5), 88 mg (54%) of a colorless oil was obtained. A second
experiment under the same conditions gave 51% yield. This
compound is known.14g Rf = 0.15 (hexanes/ethyl acetate 95/5).
1H NMR (400 MHz, CDCl3, ppm) δ 8.56-8.54 (m, 1H),
7.64-7.60 (m, 1H), 7.52-7.50 (m, 1H), 7.07-7.04 (m, 1H),
(13) Forgione, P. J.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(14) (a) Tillack, A.; Jiao, H.; Castro, I. G.; Hartung, C. G.; Beller,
M. Chem.;Eur. J. 2004, 10, 2409. (b) Rodrıguez, J. G.; Lafuente, A.;
€
Garcia-Almaraz, P. J. Heterocycl. Chem. 2000, 37, 1281. (c) Furstner, A.;
Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215. (d) Deng,
J. Z.; Paone, D. V.; Ginetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman,
S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11, 345. (e) Gavryushin,
A.; Kofink, C.; Manolikakes, G.; Knochel, P. Tetrahedron 2006, 62, 7521.
(f) Bilodeau, F.; Brochu, M. -C.; Guimond, N.; Thesen, K. H.; Forgione, P.
J. Org. Chem. 2010, 75, 1550. (g) Gupton, J. T.; Krolikowski, D. A.; Yu,
R. H.; Phong, V.; Sikorski, J. A.; Dahl, M. L.; Jones, C. R. J. Org. Chem.
1992, 57, 5480. (h) Pelter, A.; Rowlands, M.; Clements, G. Synthesis 1987, 1,
51. (i) Wang, L.; Wang, Z. -X. Org. Lett. 2007, 9, 4335. (j) Avery, T. D.;
Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2000, 65, 5531. (k) Molander,
G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74, 973.
J. Org. Chem. Vol. 76, No. 2, 2011 481

Nadres et al.
JOCArticle
6.73-6.72 (m, 1H), 6.57-6.55 (m, 1H), 6.18-6.17 (m, 1H), 3.99
(s, 3H).
were combined and the solvent was evaporated affording white
powder (103 mg, 72%). A second experiment under the same
conditions gave 76% yield. Rf = 0.28 (hexanes). This compound
is known.14i 1H NMR (500 MHz, CDCl3, ppm) δ 7.69 (s, 4H),
7.48 (dd, J = 1.8, 0.9 Hz, 2H), 6.67 (dd, J = 3.4, 0.9 Hz, 1H), 6.48
(dd, J = 3.4, 1.8 Hz, 1H).
General Procedure for Furan Arylation. Outside the glovebox,
a 4-dram vial equipped with a magnetic stir bar was charged
with furan and chloroarene. The vial was flushed with argon,
capped, and placed inside a glovebox. To this mixture were
added 2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol,
10 mol %), K3PO4 (2.0 mmol, 425 mg), and anhydrous NMP
(2 mL). The mixture was shaken, and Pd(OAc)2 (0.05 mmol, 11
mg, 5 mol %) was added. The sealed vial was taken out of the
glovebox, stirred at room temperature for 15 min and placed in
heating block (100 °C) for 24 h. The reaction mixture was
allowed to cool to room temperature and diluted with ethyl
acetate (50 mL). Resulting suspension was filtered. The filtrate
was concentrated under vacuum to a volume of about 2 mL. The
mixture was absorbed on silica gel and subjected to column
chromatography. After concentration of the fractions contain-
ing the product, the residue was dried under reduced pressure
(40 °C) to yield a pure arylated furan. The yields listed in the
table are the average of two runs.
(4-(Furan-2-yl)phenyl)(phenyl)methanone (Table 3, Entry 5).
Palladium acetate (11.4 mg, 0.05 mmol), furan (0.47 mL, 5.0
mmol), (4-chlorophenyl)(phenyl)methanone (238 mg, 1.0 mmol),
2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL). After
column chromatography (hexanes), pure fractions were combined
and the solvent was evaporated. The impure fractions were com-
bined, solvent was evaporated, and the impure product was
recrystallized from hexanes. A total of 205 mg (75% yield) of pale
yellow crystalline product was obtained. A second experiment
under the same conditions gave 80% yield. Rf = 0.07 (hexanes).
This compound is known.14i 1H NMR (500 MHz, C6D6, ppm) δ
7.77-7.69 (m, 2H), 7.73-7.72 (m, 2H), 7.53-7.51 (m, 2H),
7.14-7.12 (m, 1H), 7.27-7.04 (m, 3H), 6.39-6.37 (m, 1H),
6.12-6.10 (m, 1H).
Ethyl 5-(4-(Ethoxycarbonyl)phenyl)furan-2-carboxylate (Table 3,
Entry 6). Palladium acetate (11.4 mg, 0.05 mmol), ethyl 2-furoate
(143 mg, 1.0 mmol), ethyl 4-chlorobenzoate (800 mg, 5.0 mmol),
2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL),
reaction temperature 125 °C. The reaction mixture was loaded
directly onto the column. After column chromatography (hexanes/
ethyl acetate 95/5), fractions containing the desired compound were
combined and the solvent was evaporated leaving a white powder
(178 mg, 61% yield). A second experiment under the same condi-
tions gave 64% yield. Rf = 0.10 (hexanes/ethyl acetate 95/5), mp
48-49 °C (hexanes). 1H NMR (500 MHz, CDCl3, ppm) δ 8.05 (d,
J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 3.7 Hz, 1H),
6.82 (d, J = 3.7 Hz, 1H), 4.38-4.34 (m, 4H), 1.39-1.36 (m, 6H).
13C NMR (100 MHz, CDCl3, ppm) 166.0, 158.7, 156.1, 144.7, 133.3
130.4, 130.1, 124.5, 119.8, 108.7, 61.1, 61.2, 14.4, 14.3. FT-IR (neat,
cm-1) υ1718, 1708, 1301, 1265, 1177, 1141, 1100, 1021. Anal. Calcd
for C16H16O5 (288.3 g/mol): C, 66.66; H, 5.59. Found: C, 67.14; H,
5.26.
Ethyl 5-(Biphenyl-4-yl)furan-2-carboxylate (Table 3, Entry 7).
Palladium acetate (11.4 mg, 0.05 mmol), ethyl 2-furoate (143
mg, 1.0 mmol), 4-chlorobiphenyl (508 mg, 3.0 mmol), 2-
(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol
%), K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
The reaction mixture was loaded directly onto the column. After
column chromatography (hexanes/ethyl acetate 95/5), fractions
containing the desired compound were combined and the
solvent was evaporated leaving yellowish powder (282 mg).
The impure product was recrystallized from hexanes giving
155 mg (52%) of a beige powder. A second experiment under
the same conditions gave 55% yield. Rf = 0.13 (hexanes/ethyl
acetate 95/5), mp = 95-96 °C (pentane). 1H NMR (500 MHz,
C6D6, ppm) δ 7.68-7.65 (m, 2H), 7.41-7.37 (m, 4H), 7.22-7.19
(m, 2H), 7.15-7.13-7.11 (m, 2H), 6.26 (d, J = 3.4 Hz, 1H), 4.14
(q, J = 7.5 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H). 13C NMR (125
MHz, C6D6, ppm) δ 158.3, 157.1, 144.5, 141.5, 140.4, 128.8,
128.6, 128.0, 127.5, 127.0, 125.2, 119.6, 106.8, 60.4, 14.1. FT-IR
(neat, cm-1) υ 1722, 1479, 1302, 1284, 1271, 1218, 1153, 1022.
Anal. Calcd for C19H16O3 (292.33 g/mol): C, 78.06; H, 5.52.
Found: C, 78.14; H, 5.54.
2-(3-Methoxyphenyl)furan (Table 3, Entry 1). Palladium acet-
ate (11.4 mg, 0.05 mmol), furan (0.47 mL, 5.0 mmol), 3-chlor-
oanisole (147 mg, 1.0 mmol), 2-(dicyclohexylphosphino)bi-
phenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0
mmol), and anhydrous NMP (2.0 mL). After column chroma-
tography (hexanes/ethyl acetate 95/5), 167 mg (93% yield) of a
light yellow oil was obtained. A second experiment under the
same conditions gave 90% yield. This compound is known.14h
1
Rf = 0.23 (hexanes/ethyl acetate 95/5). H NMR (400 MHz,
C6D6, ppm) δ 7.39 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.11-7.07
(m, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.41 (s, 1H), 6.15-6.13
(m, 1H), 3.31 (s, 3H).
2-(4-Methoxyphenyl)furan (Table 3, Entry 2). Palladium acet-
ate (11.4 mg, 0.05 mmol), furan (0.47 mL, 5.0 mmol), 4-chlor-
oanisole (165 mg, 1.0 mmol), 2-(dicyclohexylphosphino)-
biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg,
2.0 mmol), and anhydrous NMP(2.0 mL). After column chroma-
tography (hexanes) 149 mg (73%) of white powder were ob-
tained. A second experiment under the same conditionsgave 68%
yield. This compound is known.14h Rf = 0.24 (hexanes). 1H
NMR (500 MHz, C6D6, ppm) δ 7.61-7.58 (m, 2H), 7.15-7.13
(m, 1H), 6.77-6.75 (m, 2H), 6,34 (d, J = 4.0 Hz), 6.18-6.16 (m,
1H), 3.25 (s, 3H).
1,3-Di(furan-2-yl)benzene (Table 3, Entry 3). Palladium acet-
ate (11.4 mg, 0.05 mmol), furan (0.94 mL, 10.0 mmol), 1,3-
dichlorobenzene (159 mg, 1.0 mmol), 2-(dicyclohexylphos-
phino)biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425
mg, 2.0 mmol), and anhydrous NMP (2.0 mL). After column
chromatography (hexanes), pure fractions were combined and
the solvent was evaporated. The impure fractions were com-
bined, concentrated, and subjected to another column chroma-
tography step (hexanes). The pure fractions were combined and
after evaporation of the solvent more product was obtained. A
total of 184 mg (80% yield) of a pale yellow oil was obtained. A
second experiment under the same conditions gave 83% yield.
Rf =0.48 (hexanes). 1H NMR (500 MHz, CDCl3, ppm) δ
7.99-7.98 (m, 1 H), 7.55 (dd, J = 7.4 Hz, 1.7 Hz, 2 H), 7.48
(d, J = 1.7 Hz, 1H), 7.39-7.37 (m, 2H), 6.70 (d, J = 3.4 Hz, 2H),
6.49-6.47 (m, 2H). 13C NMR (125 MHz, CDCl3, ppm) δ 153.7,
142.2, 131.3, 129.0, 122.7, 119.1, 111.7, 105.4. FT-IR (neat,
cm-1) υ 1614, 1503, 1220, 1156, 1012. Anal. Calcd for C14H10O2
(210.23 g/mol): C, 79.98; H, 4.79. Found: C, 79.80; H, 4.79.
1,4-Di(furan-2-yl)benzene (Table 3, Entry 4). Palladium acet-
ate (11.4 mg, 0.05 mmol), furan (0.47 mL, 5.0 mmol), 1,4-
dichlorobenzene (72 mg, 0.5 mmol), 2-(dicyclohexylphosphino)-
biphenyl (35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0
mmol), and anhydrous NMP (2.0 mL). After column chroma-
tography (hexanes), fractions containing the desired compound
2-Methyl-5-(4-(trifluoromethyl)phenyl)furan (Table 3, Entry 8).
Palladium acetate (11.4 mg, 0.05 mmol), 2-methylfuran (0.47 mL,
5.0 mmol), 4-chlorobenzotrifluoride (199 mg, 1.0 mmol), 2-
(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
After column chromatography (hexanes), 189 mg (76%) of
a white powder was obtained. A second experiment under the
482 J. Org. Chem. Vol. 76, No. 2, 2011

Nadres et al.
JOCArticle
same conditions gave 76% yield. Rf = 0.62 (hexanes). This
compound is known.14j 1H NMR (500 MHz, C6D6, ppm) δ
7.39-7.32 (m, 4H), 6.31 (d, J = 3.4 Hz, 1H), 5.79 (m, 1H), 1.98
(s, 3H).
gave 52% yield. Rf = 0.09 (hexane/ethyl acetate 98/2). 1H NMR
(400 MHz, CDCl3, ppm) δ 6.79 (d, J = 2.3 Hz, 2H), 6.52 (d, J =
3.2 Hz, 1H), 6.35-6.33 (m, 1H), 6.04-6.03 (m, 1H), 3.8
(s, 6H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm) δ
161.1, 152.1, 133.0, 107.8, 106.6, 101.5, 99.4, 55.5, 31.0, 13.9.
FT-IR (neat, cm-1) υ 1592, 1551, 1485, 1426, 1336,1227, 1203,
1155, 1023. Anal. Calcd for C13H14O3 (218.25 g/mol): C, 71.54;
H, 6.47. Found: C, 71.79; H, 6.29.
2-(Furan-2-yl)pyridine (Table 3, Entry 11). Palladium acetate
(11.4 mg, 0.05 mmol), furan (5.0 mmol, 0.47 mL), 2-chloropyr-
idine (124.7 mg, 1.0 mmol), 2-(dicyclohexylphosphino)biphenyl
(35 mg, 0.10 mmol, 10 mol %), K3PO4 (425 mg, 2.0 mmol), and
anhydrous NMP (2.0 mL). The reaction mixture was directly
adsorbed onto the silica column. After column chromatography
(pentane/diethyl ether 95/5), 82 mg (52%) of a colorless oil was
obtained. A second experiment under the same conditions gave
53% yield. This compound is known.14k Rf = 0.15 (pentane/
diethyl ether 95/5). 1H NMR (400 MHz, CDCl3, ppm) δ 8.60-
8.56 (m, 1H), 7.73-7.67 (m, 2H), 7.54-7.53 (m, 1H), 7.16-7.13
(m, 1H), 7.06-7.05 (m, 1H), 6.54-6.52 (m, 1H).
Ethyl 4-(5-Methylfuran-2-yl)benzoate (Table 3, Entry 9). Pal-
ladium acetate (11.4 mg, 0.05 mmol), 2-methylfuran (0.5 mL,
5.0 mmol), ethyl 4-chlorobenzoate (159 mg, 1.0 mmol), 2-
(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol
%), K3PO4 (425 mg, 2.0 mmol), and anhydrous NMP (2.0 mL).
After column chromatography (hexanes/ethyl acetate 98/2),
fractions containing the desired compound were combined
and the solvent was evaporated affording white powder (107
mg, 50% yield). A second experiment under the same conditions
gave 50% yield. Rf = 0.14 (hexanes/ethyl acetate 98/2), mp =
52-53 °C. 1H NMR (500 MHz, CDCl3, ppm) δ 8.03-8.01 (m,
2H), 7.67-7.65 (m, 2H), 6.67-6.65 (m, 1H), 6.09-6.08 (m, 1H),
4.37 (q, J = 6.9 Hz, 2H), 2.38 (s, 3 H), 1.40 (t, J = 6.9 Hz, 3H).
13C NMR (125 MHz, CDCl3, ppm) δ 166.5, 153.4, 151.4, 135.1,
130.1, 128.3, 122.9, 108.4, 108.3, 61.0, 14.5, 13.9. FT-IR (neat,
cm-1) υ 1699, 1610, 1274, 1178, 1103, 1024. Anal. Calcd for
C14H14O3 (230.09 g/mol): C, 73.03; H, 6.13. Found: C, 72.95; H,
6.12.
2-(3,5-Dimethoxyphenyl)-5-methylfuran (Table 3, Entry 10).
Palladium acetate (11.4 mg, 0.05 mmol), 2-methylfuran (0.5 mL,
5.0 mmol), 1-chloro-3,5-dimethoxybenzene (172 mg, 1.0 mmol),
2-(dicyclohexylphosphino)biphenyl (35 mg, 0.10 mmol, 10 mol %),
K3PO4 (425 mg, 2.0 mmol), and anhydrous DMPU (2.0 mL).
After column chromatography (hexane/ethyl acetate 98/2),
fractions containing the desired compound were combined and
the solvent was evaporated affording 282 mg (56% yield) of a
yellowish oil. A second experiment under the same conditions
Acknowledgment. We thank the Welch Foundation (Grant
E-1571), NIGMS (Grant R01GM077635), the A. P. Sloan
Foundation, and the Camille and Henry Dreyfus Foundation
for supporting this research.
Supporting Information Available: Detailed experimental
procedures and characterization data for starting materials and
reaction optimization tables. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 483