Efficient Suzuki-Miyaura coupling of (hetero)aryl chlorides with thiophene- and furanboronic acids in aqueous n-butanol

Article abstract of DOI:10.1021/jo8001886

(Chemical Equation Presented) An efficient Suzuki cross-coupling protocol enables the reaction of N-hetero and normal aryl chlorides with thiophene- and furanboronic acids. Coupling is effected in aqueous n-butanol as the solvent in near quantitative yield with a catalyst loading of 0.1-1 mol %. For heterocyclic substrates aqueous catalysis is found to be more efficient than Suzuki coupling under anhydrous conditions. The developed Suzuki coupling procedure utilizes biodegradable solvents and is useful for large scale reactions, as it includes the facile product separation from a biphasic solvent mixture without the need for additional organic solvents during workup.

Full text of DOI:10.1021/jo8001886

Efficient Suzuki-Miyaura Coupling of (Hetero)aryl Chlorides with
Thiophene- and Furanboronic Acids in Aqueous n-Butanol
Christoph A. Fleckenstein and Herbert Plenio*
Anorganische Chemie im Zintl-Institut, TU Darmstadt, Petersenstrasse 18, 64287 Darmstadt, Germany
plenio@tu-darmstadt.de
ReceiVed January 24, 2008
An efficient Suzuki cross-coupling protocol enables the reaction of N-hetero and normal aryl chlorides
with thiophene- and furanboronic acids. Coupling is effected in aqueous n-butanol as the solvent in near
quantitative yield with a catalyst loading of 0.1-1 mol %. For heterocyclic substrates aqueous catalysis
is found to be more efficient than Suzuki coupling under anhydrous conditions. The developed Suzuki
coupling procedure utilizes biodegradable solvents and is useful for large scale reactions, as it includes
the facile product separation from a biphasic solvent mixture without the need for additional organic
solvents during workup.
Introduction
numerous natural products,14 flavors, and fragrances;15,16 mol-
ecules bearing a furan moiety often display pharmacological
activity.13,17-21 (N-Hetero)arylthiophenes and -furans such as
thiophenylpyridines,11,22 furanylpyridines,17 or furanylquino-
lines,18 are ubiquitous in drugs.19
Thiophenes are common in natural products and constitute
attractive targets in pharmaceutical and fine chemistry because
of their potential biological activity,1-13 furans are found in
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10.1021/jo8001886 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/21/2008
3236
J. Org. Chem. 2008, 73, 3236-3244

Suzuki-Miyaura Coupling of (Hetero)aryl Chlorides
SCHEME 1. Ligands Tested in Suzuki Cross-Coupling of
Thiopheneboronic Acids
2-Arylated furans and thiophenes are accessible via conven-
tional electrophilic substitution reactions20 or CH-activation,21
while the 3-position in thiophenes and furans is less easily
accessible.20,22 The Suzuki coupling23,24 can be very useful for
the synthesis of arylthiophenes or -furans. Such coupling
reactions proceed smoothly only when halogenothiophenes or
-furans are reacted with the respective aryl boronic acids.
Typically catalyst loadings of 0.05-2.0 mol % tend to be
sufficient for the quantitative coupling of chlorothiophenes or
chlorofurans with sterically hindered boronic acids,25,26 pyridyl-
boronic acid,27,28 or phenylboronic acid.29 Quite in contrast, the
use of thiophene- or furanboronic acids in Suzuki reactions is
fraught with problems, because of the facile decomposition of
such metalloids in polar protic reaction media via protode-
boronation.30-33 This was studied in detail by Roques et al. for
furanboronic acids34 and by Brown et al. for thiopheneboronic
acids.35 Consequently, the general application of such thiophene
and furan metalloids is limited to the use of aryl iodides/
bromides or activated aryl chlorides as coupling partners.36-39
With thiopheneboronic acid, the more challenging 2-chloropy-
ridine or related compounds are problematic40 and require high
catalyst loadings (1-10 mol %) for activated N-heterocyclic
aryl chlorides.25,41,42 The Suzuki coupling of furanboronic acid
has primarily been explored in combination with iodo- and
bromo(hetero)aryl halides;18,39,43,44 only few examples are known
for the conversion of activated N-heteroaryl chlorides.45,46
Notable exceptions are efficient catalysts recently reported by
Buchwald and Billingsley; the Suzuki protocol developed by
Buchwald proved to be efficient for the coupling of various
furanboronic acids with activated aryl chlorides but failed with
N-heterocyclic chlorides.27 Only a few examples are known for
the coupling of less activated47-49 or (hetero)aryl chlorides50
with furanboronic acids. Trifluoroborates can be alternatives to
the classical boronic acids. However the corresponding thiophene-
and furan metalloids also suffer from low stability; thus, efficient
Suzuki reactions are facile only with aryl bromides. Only few
transformations of aryl chlorides were reported.51
The limitations in Suzuki couplings with thiophene- and
furanboronic acids result from the dichotomy that polar protic
solvents are known to facilitate this kind of catalytic reaction,
while boronic acids tend to be unstable in these solvents. Hence,
in order to improve the efficiency of Suzuki couplings with these
heteroarylboronic acids, coupling catalysts need to be developed,
which accelerate the respective cross-coupling reactions such
that it turns out to be significantly faster than the competitive
protodeboronation in polar protic solvents.
On the basis of our recent development of the cataCXium F
family of fluorenylphosphines,52-54 we report here on Pd-
phosphine complex catalysts, which enable the efficient coupling
of thiophene- and furanboronic acids in anhydrous and in
aqueous media.
(22) Nanayakkara, P.; Alper, H. AdV. Synth. Catal. 2006, 348, 545-
550.
(23) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(24) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419-2440.
(25) Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.;
Martinelli, M. J. J. Org. Chem. 2007, 72, 5104-5112.
(26) Dhudshia, B.; Thadani, A. N. Chem. Commun. 2006, 668-670.
(27) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358-3366.
Results and Discussion
Suzuki Coupling, with Thiopheneboronic Acids under
Anhydrous Conditions. Pd complexes of fluorenyldialkylphos-
phines constitute highly active catalysts for Suzuki coupling,
especially for N-heterocyclic compounds.28,55 The ligands
depicted in Scheme 1 were the most useful ones in various cross-
coupling reactions. Consequently, we decided to first evaluate
these ligands in the anhydrous Suzuki coupling with thiophene-
and furanboronic acids. In a preliminary study we tested three
fluorenylphosphines (1-3) and Cp*PCy2 (4). 2-Chloropyridine
(28) Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2008, 14, DOI:
10.1002/chem200701877.
(29) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.;
Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun.
2004, 38-39.
(30) Gronowitz, S.; Roos, C. Acta Chem. Scand. 1975, B29, 990-998.
(31) Gronowitz, S.; Malm, J.; Hoernfeldt, A. B. Collect. Czech. Chem.
Commun. 1991, 56, 2340-51.
(32) Gronowitz, S.; Peters, D. Heterocycles 1990, 30, 645-658.
(33) Klingensmith, L. M.; Bio, M. M.; Moniz, G. A. Tetrahedron Lett.
2007, 48, 8242-8245.
(34) Florentin, D.; Fournie-Zaluski, M. C.; Callanquin, M.; Roques, B.
P. J. Heterocycl. Chem. 1976, 13, 1265-1272.
(35) Brown, R. D.; Buchanan, A. S.; Humffray, A. Aust. J. Chem. 1965,
18, 1521-1525.
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Szczepankiewicz, B. G.; Wang, S.; Clampit, J. E.; Gum, R. J.; Haasch, D.
L.; Trevillyan, J. M.; Sham, H. L. Bioorg. Med. Chem. Lett. 2006, 16, 5723-
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Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304 -4308.
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1319.
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12130.
(39) Kondolff, I.; Doucet, H.; Santelli, M. J. Mol. Catal. A 2007, 269,
110-118.
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10895.
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N.; Duceppe, J.-S.; Hache, B.; Jakalian, A.; Lagace, L.; LaPlante, S.;
McKercher, G.; Moreau, E.; Perreault, S.; Stammers, T.; Thauvette, L.;
Warrington, J.; Kukolj, G. Bioorg. Med. Chem. Lett. 2006, 16, 4987-4993.
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(51) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302 -4314.
(52) Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2007, 13, 2701-2716.
(53) Fleckenstein, C. A.; Plenio, H. Organometallics 2007, 26, 2758-
2767.
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2008, 12, DOI: 10.1021/op700149.
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J. Org. Chem, Vol. 73, No. 8, 2008 3237

Fleckenstein and Plenio
TABLE 1. Catalytic Activity of Various Pd-Phosphine Complexes
in the Suzuki Cross-Coupling of Thiopheneboronic Acids
was reacted with 3-thiopheneboronic acid using anhydrous
n-butanol as the solvent and a 1 mol % catalyst loading.
Of these phosphines the in situ formed [Pd/2] complex (2 )
9-(9′-ethylfluorenyl)dicyclohexylphosphine) was the most ef-
fective one in the coupling of 2-chloropyridine with 3-thiophene-
boronic acid (Table 1).
Consequently we studied complex [Pd/2] in more detail for
Suzuki cross-coupling of 2- and 3-thiopheneboronic acids.
Because of its higher stability, 3-thiopheneboronic acid allows
lower catalyst loadings for quantitative Suzuki cross-coupling.
Applying 0.1 mol % [Pd/2]-complex as catalyst, 2-chloropyri-
dine was successfully cross-coupled with 3-thiopheneboronic
acid in pure n-butanol at 100 °C using K2CO3 as base with an
89% conversion. Quantitative conversion was accomplished at
0.5 mol % catalyst loading (Table 2, entry 1). In the same
manner 2-chloro-4-picoline and 2-chloro-isonicotinamide were
reacted with 3-thiopheneboronic acid affording near quantitative
entry
ligand L
yielda (%)
1
2
3
4
1
2
3
4
66
g99
68
86
a Average of two runs, determined by GC using heptadecane as internal
standard.
TABLE 2. Suzuki Reaction with 3- and 2-Thiopheneboronic Acid Utilizing Anhydrous n-Butanol Reaction Mediaa
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boronic acid, 3.2 equiv of K2CO3, 100 °C, 14 h, cat.: the respective volume of catalyst stock
solution (in n-butanol) (cPd ) 0.01 mol/L, Na2PdCl4/ligand 2 L/Pd ) 2:1). Reaction times and temperature were not optimized. b Average of two runs,
determined by GC using heptadecane as internal standard. c Average of two runs, products were isolated via column chromatography (silica (20 × 3 cm),
cyclohexane:EtOAc:NEt3 (10:1:1) as eluent). d Degassed tert-amyl alcohol (5 mL mmol-1) in addition to 0.25 g of molecular sieves 4 Å was used instead
n-butanol of as reaction solvent and for in situ preparation of the precatalyst. e Product not isolated.
3238 J. Org. Chem., Vol. 73, No. 8, 2008

Suzuki-Miyaura Coupling of (Hetero)aryl Chlorides
TABLE 3. Suzuki Reaction with 3-Thiopheneboronic Acid Using n-Butanol/Water as Solventa
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boronic acid, 3.2 equiv of K2CO3, degassed n-butanol (5 mL mmol-1), degassed water (2
mL‚mmol-1), 100 °C, 12 h, cat.: the respective volume of catalyst stock solution (in n-butanol) (cPd ) 0.005 mol/L, Na2PdCl4/ligand 5 L/Pd ) 2:1).
Reaction times and temperature were not optimized. b Average of two runs, determined by GC using heptadecane as internal standard. c Average of two
runs, products were isolated via column chromatography (silica (20 × 3 cm), cyclohexane:EtOAc:NEt3 (10:1:1) as eluent).
yield (89%, 91%) at 0.5 mol % catalyst loading (Table 2, entries
2 + 3). 4-Chlorotoluene is coupled with the same metalloid
quantitatively using 1 mol % catalyst (Table 2, entry 5).
Interestingly, when n-butanol was used as a solvent, the highly
active 2-chloropyrimidine preferably underwent an SNAr-
mechanism instead of the slower Suzuki cross-coupling reaction
to form the undesired product 2-butoxypyrimidine in 79% yield
(Table 2, entry 4).56 Consequently, we switched to tert-amyl
alcohol under anhydrous conditions (in combination with
molecular sieves) as solvent with the more labile 2-thiophenebo-
ronic acid. Then the activated 2-chloropyrimidine reacted
smoothly and selectively with 2-thiopheneboronic acid in tert-
amyl alcohol as solvent, affording 89% isolated yield with 0.5
mol % catalyst loading (Table 2, entry 10). Under these
conditions, formation of the respective ether was not detected.
When 1 mol % catalyst loading was applied, 2-chloropyridine
was quantitatively cross-coupled with 2-thiopheneboronic acid
using tert-amyl alcohol as solvent (Table 2, entry 6). However
more deactivated N-heterocyclic aryl chlorides like 2-chlorol-
epidine or 2-chloro-6-methoxypyridine were not quantitatively
Suzuki cross-coupled using 1 mol % [Pd/2]-complex as catalyst
(Table 2, entries 7 + 8, 73% and 17% conversion, respectively).
Unfortunately, the catalyst failed with the most challenging
substrate combination of 4-amino-2-chloropyridine and 2-thio-
pheneboronic acid (Table 2, entry 9).
In conclusion, the fluorenylphosphine-based catalysts show
activity comparable to the best systems reported so far for
Suzuki coupling of aryl chlorides with thiopheneboronic acids.27
Suzuki Coupling Using an Aqueous Reaction Protocol.
Very recently we reported that water as a (co)solvent drastically
enhances the Suzuki coupling of N-heterocyclic substrates.28,55,57,58
In this context, the use of Pd complexes with highly water
soluble disulfonated fluorenyldialkylphosphine 5 (Scheme 2)59
led to unprecedented activities in the Suzuki coupling of
heteroaryl chlorides. According to our hypothesis, the nitrogen
moieties of the applied substrates preferentially engage in
hydrogen bonding60 with water rather than coordinating to the
Pd-center of the active catalyst. In this manner poisoning of
the catalyst by the heterocyclic substrates39 is minimized.
We were interested to learn whether enhanced Suzuki
(57) Fleckenstein, C. A.; Roy, S.; Leutha¨usser, S.; Plenio, H. Chem.
Commun. 2007, 2870-2872.
(58) an der Heiden, M. R.; Plenio, H. Chem. Eur. J. 2004, 10, 1789-
1797.
(59) This ligand is commercially available from Strem and Aldrich under
the trade name cataCXium F Sulf.
(60) Plenio, H.; Diodone, R. Chem. Ber. 1997, 130, 633-640.
(56) 2-Butoxypyrimidine is also formed in the absence of catalyst under
otherwise identical reaction conditions.
J. Org. Chem, Vol. 73, No. 8, 2008 3239

Fleckenstein and Plenio
TABLE 4. Suzuki Reaction with 2-Thiopheneboronic Acid Using n-Butanol/Water as Solventa
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boronic acid, 3.2 equiv of K2CO3, degassed n-butanol (5 mL mmol-1), degassed water (2
mL‚mmol-1), 100 °C, 12 h, cat.: the respective volume of catalyst stock solution (in n-butanol) (cPd ) 0.005 mol/L, Na2PdCl4/ligand 5 L/Pd ) 2:1).
Reaction times and temperature were not optimized. b Average of two runs, determined by GC using heptadecane as internal standard. c Average of two
runs, products were isolated via column-chromatography (silica (20 × 3 cm), cyclohexane:EtOAc:NEt3 (10:1:1) as eluent). d Product not isolated.
SCHEME 2. High Water Soluble Disulfonated
substantiate the robustness of the aqueous cross-coupling
protocol, we coupled a variety of N-heterocyclic and normal
aryl chlorides with 2-thiophene- and 3-thiopheneboronic acids.
Dicyclohexyfluorenylphosphine Ligand 5‚3H+
Suzuki Coupling of 3-Thiopheneboronic Acid. Utilizing a
catalyst loading of 0.25 mol % a number of activated and
deactivated chloropyridines and chloroquinolines were quanti-
tatively Suzuki coupled with 3-thiopheneboronic acid in water/
n-butanol as solvent (Table 3, entries 2-6). This reaction
protocol enables efficient coupling of 4-chlorotoluene with
3-thiopheneboronic acid affording 83% conversion at a catalyst
loading of 0.5 mol % and quantitative coupling applying 1 mol
% catalyst, respectively (Table 3, entry 8). The reaction of
2-chloropyrimidine with 3-thiopheneboronic acid using 0.1 mol
% catalyst selectively and quantitatively affords the desired
Suzuki biaryl in water/n-butanol as solvent. The formation of
2-n-butoxypyrimidine, which was isolated as main product when
working under anhydrous conditions, was not observed. Obvi-
ously, the use of water effectively inhibits the undesired ether
formation.
reactivity in water/n-butanol mixtures can be realized with labile
thiophene- and furanboronic acids. This approach boldly ignores
the fact that the decomposition of the thiophene- and furanbo-
ronic acids in water is drastically accelerated. On the other hand,
the chosen aqueous/organic reaction medium is convenient as
it is cheap, safe, and biodegradable. We were pleased to see,
that in a preliminary test with Pd/5 as catalyst (formed in situ
from Na2PdCl4 and the phosphonium salt of 5), 2-chloropyridine
was smoothly coupled with 3-thiopheneboronic acid in water/
n-butanol (2:5) as solvent and K2CO3 as base at 100 °C utilizing
only 0.1 mol % catalyst (Table 3, entry 1). This indicates that
the aqueous reaction protocol is superior to the anhydrous one,
which requires a fivefold higher catalyst loading to achieve full
conversion (see Table 2, entry 1; 0.5 mol %). In order to
Suzuki Coupling of 2-Thiopheneboronic Acid. Suzuki
coupling of 2-thiopheneboronic acids required higher catalyst
loadings because of the increased propensity of this metalloid
toward protodeboronation, which is about 120 times faster than
that of 3-thiopheneboronic acid.35 When 1 mol % of Pd/5 was
applied, the substrates 2-chloropyridine, 2-chloroquinoline, and
2-chlorolepidine were smoothly coupled with this heteroboronic
3240 J. Org. Chem., Vol. 73, No. 8, 2008

Suzuki-Miyaura Coupling of (Hetero)aryl Chlorides
TABLE 5. Suzuki Reaction with Furanboronic Acids Using n-Butanol/Water as Solventa
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boronic acid, 3.2 equiv of K2CO3, degassed n-butanol (5 mL mmol-1), degassed water (2
mL‚mmol-1), 100 °C, 12 h, cat.: the respective volume of catalyst stock solution (in n-butanol) (cPd ) 0.005 mol/L, Na2PdCl4/ligand 5 L/Pd ) 2:1).
Reaction times and temperature were not optimized. b Average of two runs, determined by GC using heptadecane as internal standard. c Average of two
runs, products were isolated via column chromatography (silica (20 × 3 cm), cyclohexane:EtOAc:NEt3 (10:1:1) as eluent). d Product not isolated.
acid (Table 4, entries 1-3). Again the aqueous coupling protocol
demonstrates its superiority over the anhydrous protocol where
full conversion of 2-chlorolepidine with 2-thiopheneboronic acid
was not feasible using Pd/2 at the same catalyst-loading (Table
2, entry 7, 73% conversion); such limitations in the conversion
of N-heteroaryl chlorides were also reported in the Buchwald
protocol.27 Nonetheless, deactivated N-heterocyclic aryl chlo-
rides did not undergo full conversion under aqueous conditions
but still performed significantly better than under anhydrous
conditions (Table 4, entries 4, 5). Pharmaceutically interesting
chloroazines like 2-chloropyrimidine and 2-chloro-3,5-dimethox-
ytriazine (another biological active moiety)61,62 are smoothly
coupled with 2-thiopheneboronic acid using the aqueous reaction
conditions, affording 94% and 89% isolated yield, respectively,
with 0.5 mol % catalyst loading (Table 4, entries 6 + 7).
Formation of undesired N-arylbutoxide byproducts was not
observed.
of the more labile furanboronic acids. We were pleased to
observe the smooth coupling of 3-furanboronic acid with a large
variety of activated and deactivated 2-chloropyridines and
2-chloroquinolines and 2-chloropyrimidine including the notori-
ous 4-amino-2-chloropyridine (typically 92-97% yield, 1 mol
% Pd/5) (Table 5, entries 1-5). Suzuki coupling with 3-furan-
boronic acid is not limited to N-heteroaryl chlorides: p-
chloroacetophenone or 6-chloro-5-methylbenzothiazole are ary-
lated using the same conditions as for the heteroaryl chlorides
(Table 5, entries 7 and 8). Thus, the reactivity of this catalytic
system is significantly higher than that of other protocols which
are limited to activated (N-hetero)aryl chlorides.27 Our aqueous
reaction protocol enables Suzuki coupling of electron-deficient
and thus more labile 2-furanboronic acids. Unfortunately, the
rapid decomposition of 2-furanboronic acids still prevents
coupling of nonactivated aryl chlorides.
Other than providing high Suzuki reactivity, the developed
reaction protocol is very convenient in many respects: (a) the
water/n-butanol mixture is cheap and nontoxic, and the organic
component is biodegradable; (b) anhydrous conditions are not
required; (c) a convenient base (K2CO3) is used. When working
on larger scale, product separation is simple since additional
organic solvents such as ethers or alkanes are not required.
Suzuki Coupling of Furanboronic Acids. Next we studied
the applicability of our aqueous reaction protocol to the coupling
(61) Dianzani, C.; Collino, M.; Gallicchio, M.; Samaritani, S.; Signore,
G.; Menicagli, R.; Fantozzi, R. J. Pharm. Pharmacol. 2006, 58, 219-226.
(62) Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Via, L. D.
J. Med. Chem. 2004, 47, 4649-4652.
J. Org. Chem, Vol. 73, No. 8, 2008 3241

Fleckenstein and Plenio
temperature: 270 °C, detector temperature: 350 °C. Temperature
program: isotherm 150 °C for 5 min, heating to 300 °C with 25
°C/min, isotherm for 15 min.
Instead, addition of more water to the reaction mixture ensures
an effective separation of the product-containing n-butanol layer
from the water layer containing salts as well as excess of boronic
acid. In cases of quantitative conversion of the aryl chloride,
simple phase separation, drying of the alcoholic solution, and
solvent removal afforded the desired product in excellent isolated
yield and high purity (>95% judged by GC and NMR) without
additional chromatographic purification.
General Procedures for the Suzuki Cross-Coupling Reactions.
Preparation of Catalyst Stock Solution for Suzuki Coupling in
Anhydrous Alcohols. [Na2PdCl4] (11.8 mg, 0.04 mmol), the
respective phosphine (1-4) (0.08 mmol), and K2CO3 (69 mg, 0.5
mmol) were placed in a 10 mL Schlenk tube, evacuated, and
backfilled with Ar thrice. Degassed dry n-butanol (4 mL) was added
and the mixture stirred at 55 °C for 3 h to obtain a yellow
suspension. cPd of this catalyst stock solution is 0.01 mmol‚mL-1
.
Summary and Conclusion
When the cross-coupling reaction was performed in tert-amyl
In summary, we have developed a highly efficient Suzuki
cross-coupling protocol enabling conversion of N-hetero- and
normal aryl chlorides with thiophene- and furanboronic acids
in aqueous n-butanol as the solvent. The facile coupling
reactions are based on the Pd complex of the highly water
soluble disulfonated fluorenylphosphine 5, obtained in situ from
Na2PdCl4 and the respective phosphonium salt of 5. For
heterocyclic substrates, aqueous catalysis was found to be
significantly more efficient than Suzuki coupling under anhy-
drous conditions. Using the aqueous catalysis protocol, a variety
of different N-heterocyclic and nonheterocyclic aryl chlorides
was Suzuki coupled with 2- and 3-thiopheneboronic acids as
well as furanboronic acids in near quantitative yield at catalyst
loadings of 0.1-1 mol %. The undesired ether formation
observed for some substrate combinations in anhydrous n-
butanol as the solvent is suppressed in the presence of water.
Furthermore, on a large scale the developed system enables
efficient and sustainable Suzuki coupling including the facile
product separation without the need for additional organic
solvents during workup.
alcohol as solvent, this alcohol was used for the stock solution.
Cross-Coupling Reaction in Anhydrous Alcohols (n-butanol
or tert-amyl alcohol) as Solvent. Boronic acid (1.2 mmol) and
K2CO3 (440 mg, 3.2 mmol) were placed in a 25 mL Schlenk tube,
evacuated, and backfilled with Ar thrice. For cross-coupling
reactions with 2-thiopheneboronic acids more molecular sieve (0.25,
g 4 Å) was added prior to the degassing sequence. Then degassed
n-butanol (or tert-amyl alcohol, respectively) (5 mL), the aryl halide
(1 mmol), and the respective volume of catalyst stock solution were
added. The reaction mixture was stirred for 12 h at 100 °C and
then cooled to room temperature. Water (5 mL) was added, and
the product was extracted with methyl tert-butyl ether (2 × 5 mL).
The organic layer was concentrated in Vacuo and the residue
purified via column chromatography (silica (20 × 3 cm), cyclo-
hexane:EtOAc:NEt3 (10:1:1)), to afford the pure cross-coupling
product in 51-93% yield, respectively.
Preparation of Catalyst Stock Solution for Suzuki Coupling
in Aqueous n-Butanol. [Na2PdCl4] (5.9 mg, 0.02 mmol), phosphine
5 (30 mg, 0.04 mmol), and K2CO3 (33 mg, 0.24 mmol) were placed
in a 25 mL Schlenk tube, evacuated, and backfilled with Ar thrice.
Degassed water (4 mL) was added and the mixture stirred at 55 °C
for 3 h to obtain a clear, nearly colorless solution. cPd of this catalyst
stock solution is 0.005 mmol‚mL-1
.
Experimental Section
Cross-Coupling Reaction in Water/n-Butanol (screening
experiments). Boronic acid (1.2 mmol) and K2CO3 (440 mg, 3.2
mmol) were placed in a 25 mL Schlenk tube, evacuated, and
backfilled with Ar thrice. Then degassed n-butanol (5 mL) was
added as well as the aryl halide (1 mmol) and the respective volume
of catalyst stock solution. The amount of water in the reaction
mixture was adjusted to 2 mL total volume. The reaction mixture
was stirred for 12 h at 100 °C and then cooled to room temperature.
Water (5 mL) was added, and the product was extracted with methyl
tert-butyl ether (2 × 5 mL). The organic layer was concentrated in
Vacuo and the residue purified via column chromatography (silica
(20 × 3 cm), cyclohexane:EtOAc:NEt3 (10:1:1)) to afford the pure
respective cross-coupling product in 89-97% yield.
All chemicals were purchased as reagent grade from commercial
suppliers and used without further purification, unless otherwise
noted. Used solvents (water, n-butanol were all technical grade)
were deaerated via freeze and thaw technique (2×). For cross-
coupling reactions under anhydrous conditions, n-butanol (technical
grade, dried over molecular sieves, 4 Å) was used. Potassium
carbonate, used in cross-coupling reactions, was technical grade.
The phosphine ligands were prepared according to published
procedures: 1,54 2,52 3,54 4,53 5;28 these ligands are also com-
mercially available under the trade name cataCXium F from Evonik-
Degussa GmbH. All “phosphines” mentioned in this publication
were used in the form of their air stable phosphonium salts and
deprotonated in situ during the catalyst preparation. All experiments
were carried out under an argon atmosphere, unless otherwise noted.
Proton (1H NMR), carbon (13C NMR), phosphorus (31P NMR), and
nitrogen (15N NMR) nuclear magnetic resonance spectra were
recorded on Bruker DRX 500 at 500 MHz, 125.75, 202.46, and
50.69 MHz, respectively, at 293 K. The chemical shifts are given
in parts per million (ppm) on the delta scale (δ) and are referenced
to tetramethylsilane (δ ) 0 ppm), 1H NMR, 65% aq H3PO4. (δ )
0 ppm), 31P NMR and nitromethane (δ ) 0 ppm), 15N NMR.
Abbreviations for NMR data: s ) singlet; d ) doublet; t ) triplet;
q ) quartet; qi ) quintet; dd ) doublet of doublets; dt ) doublet
of triplets; dq ) doublet of quartets; tt ) triplet of triplets; m )
multiplet. Mass spectra were recorded on a Finnigan MAT 95
magnetic sector spectrometer. Thin layer chromatography (TLC)
was performed using Fluka silica gel 60 F 254 (0.2 mm) on
aluminum plates. Silica gel columns for chromatography were
prepared with E. Merck silica gel 60 (0.063-0.20 mesh ASTM).
GC experiments were run on a Clarus 500 GC with autosampler
and FID detector. Column: Varian CP-Sil 8 CB (l ) 15 m, diam
) 0.25 mm, dF ) 1.0 µm), N2 (flow: 17 cm/s; split 1:50); injector
Preparative Scale Cross-Coupling Reaction in Water/n-
Butanol. 3-Thiopheneboronic acid (1.66 g, 13 mmol), 2-chloro-
quinoline (1.66 g, 10 mmol), and K2CO3(4.14 g, 30 mmol) were
placed in a 50 mL Schlenk flask, evacuated, and backfilled with
Ar thrice. Then degassed n-butanol (25 mL) was added as well as
the catalyst stock solution (0.5 mol % catalyst loading). After the
reaction mixture was stirred for 12 h at 100 °C, quantitative
conversion was observed via GC chromatography. The reaction
mixture was then cooled to room temperature, water (10 mL) was
added, and the organic layer separated, dried over MgSO4, and
filtered. Removal of the volatiles in Vacuo afforded the crude
product 2-thiophen-3-ylquinoline (1.92 g, 91%) as an off white solid
1
(purity checked by GC and H NMR: >95%).
2-Thiophen-3-ylpyridine (Table 2, entry 1/Table 3, entry 1).
1H NMR (500 MHz, CDCl3) δ 8.61 (dq, 3J ) 4.7 Hz, J ) 1.0 Hz,
3
1 H, CH, ar), 7.89 (dd, J ) 3.2 Hz, J ) 1.3 Hz, 1 H, CH, ar),
3
7.69-7.64 (m, 2 H, CH, ar), 7.59 (dt, J ) 8.0 Hz, J ) 1.0 Hz, 1
H, CH, ar), 7.38 (dd, 3J ) 5.0 Hz, J ) 3.0 Hz, 1 H, CH, ar), 7.14
(ddd, 3J ) 7.6 Hz, J ) 4.6 Hz, J ) 1.2 Hz, 1 H, CH, ar); 13C{1H}
3242 J. Org. Chem., Vol. 73, No. 8, 2008

Suzuki-Miyaura Coupling of (Hetero)aryl Chlorides
NMR (125.77 MHz, CDCl3) δ 154.0, 150.0, 142.6, 137.1, 126.7,
126.6, 123.9, 122.2, 120.7; HRMS calcd for C9H7NS: 161.03, found
161.02985.
3-pTolylthiophene (Table 2, entry 5/Table 3 entry 8). 1H NMR
(500 MHz, CDCl3) δ 7.41 (d, J ) 8.0 Hz, 2 H, CH, ar), 7.32 (t,
J ) 2.0 Hz, 1 H, CH, ar), 7.29 (s, 1 H, CH, ar), 7.29 (t, J ) 1.0
Hz, 1 H, CH, ar), 7.29 (d, 3J ) 8.0 Hz, 2 H, CH, ar), 2.29 (s, 3 H,
CH3); 13C{1H} NMR (125.77 MHz, CDCl3) δ 141.3, 135.8, 132.1,
128.5 (2x), 125.3, 125.0, 118.6, 20.1; HRMS calcd for C11H10S:
174.0504, found 174.04988.
3
1
2-Thiophen-3-ylquinoline (Table 3, entry 2). H NMR (500
3
3
MHz, CDCl3) δ 8.13 (d, J ) 8.5 Hz, 1 H, CH, ar), 8.11 (d, J )
8.8 Hz, 1 H, CH, ar), 8.03 (dd, J ) 3.0 Hz, J ) 1.3 Hz, 1 H, CH,
3
3
ar), 7.87 (dd, J ) 5.1 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.77 (dd, J
3
2-Thiophen-2-ylpyridine (Table 2, entry 6/Table 4, entry 1).
) 8.0 Hz, J ) 1.0 Hz, 1 H, CH, ar), 7.75 (d, J ) 8.6 Hz, 1 H,
1H NMR (500 MHz, CDCl3) δ 8.56 (dt, 3J ) 4.5 Hz, J ) 1.2 Hz,
3
3
CH, ar), 7.69 (ddd, J ) 8.5 Hz, J ) 7.0 Hz, J ) 1.5 Hz, 1 H,
3
3
3
1 H, CH, ar), 7.68-7.62 (m, 2 H, CH, ar), 7.56 (dd, J ) 3.8 Hz,
CH, ar), 7.49 (ddd, J ) 8.2 Hz, J ) 7.0 Hz, J ) 1.3 Hz, 1 H,
CH, ar), 7.43 (dd, 3J ) 5.0 Hz, J ) 3.0 Hz, 1 H, CH, ar); 13C{1H}
NMR (125.77 MHz, CDCl3) δ 153.7, 148.7, 143.1, 137.1, 130.1,
129.9, 127.9, 127.5, 127.3, 126.8, 126.5, 125.0, 119.4; HRMS calcd
for C13H9NS: 211.0456, found 211.04371.
J ) 1.2 Hz, 1 H, CH, ar), 7.38 (dd, 3J ) 5.0 Hz, J ) 1.0 Hz, 1 H,
CH, ar), 7.14-7.09 (m, 2 H, CH, ar); 13C{1H} NMR (125.77 MHz,
CDCl3) δ 151.6, 148.5, 143.8, 135.6, 127.0, 127.5, 123.5, 120.9,
117.8; HRMS calcd for C9H7NS: 161.03, found 161.02942.
1
2-Thiophen-2-ylquinoline (Table 4, entry 2). H NMR (500
4-Methyl-2-thiophen-3-ylpyridine (Table 2, entry 2/Table 3,
entry 3). 1H NMR (500 MHz, CDCl3) δ 8.46 (d, 3J ) 5.0 Hz, 1 H,
CH, ar), 7.87 (dd, 3J ) 2.9 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.64 (dd,
3J ) 5.0 Hz, J ) 1.2 Hz, 1 H, CH, ar), 7.43-7.41 (m, 1 H, CH,
3
3
MHz, CDCl3) δ 8.11 (d, J ) 8.6 Hz, 1 H, CH, ar), 8.08 (d, J )
8.5 Hz, 1 H, CH, ar), 7.78 (d, 3J ) 8.5 Hz, 1 H, CH, ar), 7.75 (dd,
3J ) 8.2 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.72 (dd, J ) 3.8 Hz, J )
1.2 Hz, 1 H, CH, ar), 7.68 (ddd, 3J ) 8.5 Hz, 3J ) 7.0 Hz, J ) 1.5
Hz, 1 H, CH, ar), 7.47 (ddd, 3J ) 8.0 Hz, 3J ) 6.7 Hz, J ) 1.0 Hz,
1 H, CH, ar), 7.46 (dd, 3J ) 5.0 Hz, J ) 1.0 Hz, 1 H, CH, ar), 7.15
(dd, 3J ) 5.0 Hz, J ) 3.8 Hz, 1 H, CH, ar); 13C{1H} NMR (125.77
MHz, CDCl3) δ 151.3, 147.1, 144.4, 135.6, 128.8, 128.3, 127.5,
127.0, 126.4, 126.2, 125.1, 124.8, 116.6; HRMS calcd for C13H9-
NS: 211.0456, found 211.04476.
3
3
ar), 7.37 (dd, J ) 5.0 Hz, J ) 2.8 Hz, 1 H, CH, ar), 6.97 (dq, J
) 5.0 Hz, J ) 0.8 Hz, 1 H, CH, ar), 2.36 (s, 3 H, CH3); 13C{1H}
NMR (125.77 MHz, CDCl3) δ 153.4, 149.4, 147.7, 142.3, 126.2,
126.2, 123.3, 122.9, 121.2, 21.1; HRMS calcd for C10H9NS:
175.0456, found 175.04453.
4-Methyl-2-thiophen-3-ylquinoline (Table 3, entry 4). 1H NMR
(500 MHz, CDCl3) δ 8.10 (dq, 3J ) 8.5 Hz, J ) 0.6 Hz, 1 H, CH,
4-Methyl-2-thiophen-2-ylquinoline (Table 2, entry 7/Table 4,
entry 3). 1H NMR (500 MHz, CDCl3) δ 8.05 (d, 3J ) 8.2 Hz, 1 H,
CH, ar), 7.81 (dd, 3J ) 8.2 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.63 (dd,
3J ) 3.5 Hz, J ) 1.0 Hz, 1 H, CH, ar), 7.61 (ddd, 3J ) 8.6 Hz, 3J
) 7.0 Hz, J ) 1.6 Hz, 1 H, CH, ar), 7.51 (s, 1 H, CH, ar), 7.40
(ddd, 3J ) 8.3 Hz, 3J ) 7.0 Hz, J ) 1.3 Hz, 1 H, CH, ar),7.39 (dd,
3J ) 5.0 Hz, J ) 1.3 Hz, 1 H, CH, ar), 2.59 (s, 3 H, CH3); 13C-
{1H} NMR (125.77 MHz, CDCl3) δ 152.4, 148.4, 146.0, 145.1,
130.2, 129.8, 128.7, 128.4, 127.7, 126.2, 126.1, 124.0, 118.6, 19.2;
HRMS calcd for C14H11NS: 225.0613, found 225.05936.
3
ar), 7.99 (dd, J ) 1.2 Hz, J ) 3.0 Hz, 1 H, CH, ar), 7.90 (dd, J
) 8.5 Hz, J ) 1.2 Hz, 1 H, CH, ar), 7.84 (dd, 3J ) 5.1 Hz, J ) 1.3
Hz, 1 H, CH, ar), 7.66 (ddd, 3J ) 8.5 Hz, 3J ) 7.0 Hz, J ) 1.5 Hz,
3
1 H, CH, ar), 7.55 (d, J ) 1.0 Hz, 1 H, CH, ar), 7.47 (ddd, J )
8.5 Hz, 3J ) 7.0 Hz, J ) 1.2 Hz, 1 H, CH, ar), 7.39 (dd, 3J ) 5.0
Hz, J ) 3.0 Hz, 1 H, CH, ar), 2.67 (d, J ) 1.0 Hz, 3 H, CH3);
13C{1H} NMR (125.77 MHz, CDCl3) δ 153.4, 148.5, 145.1, 143.2,
130.5, 129.7, 127.6, 127.3, 126.6, 126.2, 124.8, 124.0, 120.1, 19.3;
HRMS calcd for C14H11NS: 225.0613, found 225.05940.
2-Thiophen-3-ylisonicotinamide (Table 2, entry 3/Table 3,
entry 5). 1H NMR (500 MHz, DMSOd6) δ 8.71 (dd, 3J ) 5.0 Hz,
J ) 0.6 Hz, 1 H, CH, ar), 8.28 (s (br), 1 H, NH2), 8.25-8.23 (m,
2 H, CH, ar), 7.80 (dd, 3J ) 5.0 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.76
2-Thiophen-2-ylpyrimidine (Table 2, entry 10/Table 4, entry
6). 1H NMR (500 MHz, CDCl3) δ 8.62 (d, 3J ) 5.0 Hz, 2 H, CH,
3
3
ar), 7.94 (dd, J ) 3.8 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.41 (dd, J
) 5.0 Hz, J ) 1.3 Hz, 1 H, CH, ar), 7.08 (dd, 3J ) 5.0 Hz, J ) 3.7
3
(s (br), 1 H, NH2), 7.67 (dd, J ) 5.0 Hz, J ) 3.2 Hz, 1 H, CH,
Hz, 1 H, CH, ar), 7.02 (t, J ) 5.0 Hz, 1 H, CH, ar); 13C{1H}
3
3
ar), 7.65 (dd, J ) 5.0 Hz, J ) 1.6 Hz, 1 H, CH, ar); 13C{1H}
NMR (125.77 MHz, CDCl3) δ 160.6, 156.2, 142.2, 128.9, 128.0,
127.3, 117.5; HRMS calcd for C8H6N2S: 162.0253, found 162.02788.
2,4-Dimethoxy-6-thiophen-2-yl-[1,3,5]triazine (Table 4, entry
NMR (125.77 MHz, DMSOd6) δ 166.7, 153.8, 150.5, 142.7, 141.9,
127.6, 126.6, 125.0, 120.1, 118.1; 15N NMR (50.69 MHz, DMSOd6)
δ -275.1 (NH2), -66.5 (pyridyl); HRMS calcd for C10H8N2OS:
204.0358, found 204.03597.
1
3
7). H NMR (500 MHz, CDCl3) δ 8.15 (dd, J ) 3.8 Hz, J ) 1.3
Hz, 1 H, CH, ar), 7.59 (dd, 3J ) 5.0 Hz, J ) 1.3 Hz, 1 H, CH, ar),
2-Methoxy-6-thiophen-3-ylpyridine (Table 3, entry 6). 1H
NMR (500 MHz, CDCl3) δ 7.90 (dd, J ) 3.0 Hz, J ) 1.2 Hz, 1 H,
CH, ar), 7.63 (dd, 3J ) 5.0 Hz, J ) 1.2 Hz, 1 H, CH, ar), 7.55 (dd,
3
3
7.16 (dd, J ) 5.0 Hz, J ) 3.8 Hz, 1 H, CH, ar), 4.09 (s, 6 H,
OCH3); 13C{1H} NMR (125.77 MHz, CDCl3) δ 171.6, 169.7, 139.7,
131.5, 130.9, 127.3, 54.2; HRMS calcd for C9H9N3O2S: 223.0416,
found 223.03932.
3
3
3J ) 8.2 Hz, J ) 7.4 Hz, 1 H, CH, ar), 7.35 (dd, J ) 5.0 Hz, J
3
2-Furan-3-ylpyridine (Table 5, entry 1). 1H NMR (500 MHz,
) 3.0 Hz, 1 H, CH, ar), 7.17 (dd, J ) 7.5 Hz, J ) 0.5 Hz, 1 H,
CH, ar), 6.62 (dd, 3J ) 8.0 Hz, J ) 0.5 Hz, 1 H, CH, ar), 4.00 (s,
3 H, OCH3); 13C{1H} NMR (125.77 MHz, CDCl3) δ 164.1, 151.4,
142.6, 139.5, 126.6, 126.4, 123.7, 113.0, 109.3, 53.6; HRMS calcd
for C10H9NOS: 191.0405, found 191.04062.
3
CDCl3) δ 8.58 (dq, J ) 4.8 Hz, J ) 0.9 Hz, 1 H, CH, ar), 8.02
(dd, J ) 1.5 Hz, J ) 0.9 Hz, 1 H, CH, ar), 7.65 (dt, J ) 7.8 Hz,
3
J ) 1.8 Hz, 1 H, CH, ar), 7.49 (t, J ) 1.8 Hz, 1 H, CH, ar), 7.44
(dt, 3J ) 7.9 Hz, J ) 1.0 Hz, 1 H, CH, ar), 7.12 (ddd, 3J ) 7.6 Hz,
J ) 4.8 Hz, J ) 1.1 Hz, 1 H, CH, ar), 6.89 (dd, J ) 1.8 Hz, J )
0.8 Hz, 1 H, CH, ar); 13C{1H} NMR (125.77 MHz, CDCl3) δ 152.2,
150.1, 144.2, 141.6, 136.9, 127.5, 122.1, 120.5, 109.0; 15N NMR
(50.69 MHz, CDCl3) δ -76.7; HRMS calcd for C9H7NO: 145.0528,
2-Thiophen-3-ylpyrimidine (Table 3, entry 7). 1H NMR (500
MHz, CDCl3) δ 8.73 (d, 3J ) 5.0 Hz, 2 H, CH, ar), 8.30 (dd, J )
3
3.1 Hz, J ) 1.2 Hz, 1 H, CH, ar), 7.90 (dd, J ) 5.0 Hz, J ) 1.2
Hz, 1 H, CH, ar), 7.38 (dd, 3J ) 5.0 Hz, J ) 3.1 Hz, 1 H, CH, ar),
7.10 (t, J ) 4.9 Hz, 1 H, CH, ar); 13C{1H} NMR (125.77 MHz,
found 145.05257. The H NMR spectrum was identical to that in
3
1
CDCl3) δ 160.9, 156.2, 140.6, 127.0, 126.3, 125.1, 117.6; 15N
NMR (50.69 MHz, CDCl3) δ -95.4; HRMS calcd for C8H6N2S:
162.0253, found 162.02548.
the literature.63
2-Furan-3-ylquinoline-3-carbaldehyde (Table 5, entry 2). 1H
NMR (500 MHz, CDCl3) δ 10.41 (s, 1 H, CHO), 8.74 (s, 1 H,
CH, ar), 8.13 (dq, 3J ) 8.5 Hz, J ) 0.8 Hz, 1 H, CH, ar), 7.95 (d,
3J ) 8.3 Hz, 1 H, CH, ar), 7.90-7.89 (m, 1 H, CH, ar), 7.83 (ddd,
1
2-Butoxypyrimidine (Table 2, entry 4). H NMR (500 MHz,
CDCl3) δ 8.43 (d, 3J ) 4.8 Hz, 2 H, CH, ar), 6.83 (t, 3J ) 4.8 Hz,
3
3J ) 8.5 Hz, J ) 6.9 Hz, J ) 1.4 Hz, 1 H, CH, ar), 7.61 (t, J )
3
1 H, CH, ar), 4.28 (t, J ) 6.8 Hz, 2 H, OCH2), 1.76-1.70 (m, 2
1.7 Hz, 1 H, CH, ar), 7.59 (ddd, 3J ) 8.1 Hz, 3J ) 7.1 Hz, J ) 1.2
Hz, 1 H, CH, ar), 6.95 (q, J ) 0.9 Hz, 1 H, CH, ar); 13C{1H}
3
3
H, CH2), 1.44 (qui, J ) 7.4 Hz, 2 H, CH2), 0.90 (t, J ) 7.5 Hz,
2 H, CH3); 13C{1H} NMR (125.77 MHz, CDCl3) δ 164.35, 158,2,
113.7, 66.4, 29.9, 18.1, 12.8; HRMS calcd for C8H12N2O: 152.0949,
found 152.06218.
(63) Ribereau, P.; Queguiner, G. Can. J. Chem. 1983, 61, 334-342.
J. Org. Chem, Vol. 73, No. 8, 2008 3243

Fleckenstein and Plenio
NMR (125.77 MHz, CDCl3) δ 190.2, 151.3, 148.9, 142.7, 142.5,
137.5, 131.6, 128.4, 128.3, 126.8, 126.4, 125.1, 123.3, 110.7; 15N
NMR (50.69 MHz, CDCl3) δ -71.2; HRMS calcd for C14H9NO2:
223.0633, found 223.06263.
{1H} NMR (125.77 MHz, CDCl3) δ 176.7, 157.3, 151.6, 149.0,
146.8, 135.9, 122.8, 121.9, 119.1, 109.7; 15N NMR (50.69 MHz,
CDCl3) δ -76.3; HRMS calcd for C10H7NO2: 173.0477, found
173.04588.
2-Furan-3-yl-6-methoxypyridine (Table 5, entry 3). 1H NMR
(500 MHz, CDCl3) δ 8.00 (dd, J ) 1.6 Hz, J ) 0.9 Hz, 1 H, CH,
ar), 7.53 (dd, 3J ) 8.2 Hz, 3J ) 7.4 Hz, 1 H, CH, ar), 7.46 (t, J )
1.7 Hz, 1 H, CH, ar), 7.01 (dd, 3J ) 7.4 Hz, J ) 0.6 Hz, 1 H, CH,
1-(4-Furan-3-ylphenyl)ethanone (Table 5, entry 7). 1H NMR
3
(500 MHz, CDCl3) δ 7.96 (d, J ) 8.2 Hz, 2 H, CH, ar), 7.82-
3
7.81 (m, 1 H, CH, ar), 7.56 (d, J ) 8.2 Hz, 2 H, CH, ar), 7.51-
7.50 (m, 1 H, CH, ar), 6.74-6.73 (m, 1 H, CH, ar), 2.60 (s, 3 H,
CH3); 13C{1H} NMR (125.77 MHz, CDCl3) δ 196.4, 143.1, 138.6,
136.2, 134.6, 128.0, 124.7, 124.6, 107.6, 25.5; HRMS calcd for
C12H10O2: 186.068, found 186.06642. The NMR spectra were
identical to those in the literature.22
3
ar), 6.85 (dd, J ) 1.9 Hz, J ) 0.9 Hz, 1 H, CH, ar), 7.59 (dd, J
) 8.2 Hz, J ) 0.6 Hz, 1 H, CH, ar), 3.96 (s, 3 H, OCH3); 13C{1H}
NMR (125.77 MHz, CDCl3) δ 162.7, 148.2, 142.6, 140.2, 137.9,
126.0, 111.4, 107.7, 107.6, 52.1; 15N NMR (50.69 MHz, CDCl3) δ
-120.8; HRMS calcd for C10H9NO2: 175.0633, found 175.06154.
5-Furan-3-yl-2-methylbenzothiazole (Table 5, entry 8). 1H
NMR (500 MHz, CDCl3) δ 8.06 (d, J ) 1.6 Hz, 1 H, CH, ar), 7.80
(dd, 3J ) 8.2 Hz, J ) 0.6 Hz, 1 H, CH, ar), 7.80 (dd, J ) 1.6 Hz,
J ) 0.9 Hz, 1 H, CH, ar), 7.51 (t, J ) 1.7 Hz, 1 H, CH, ar), 7.49
(dd, 3J ) 8.3 Hz, J ) 1.7 Hz, 1 H, CH, ar), 6.77 (dd, J ) 1.8 Hz,
J ) 0.9 Hz, 1 H, CH, ar), 2.84 (s, 3 H, CH3); 13C{1H} NMR (125.77
MHz, CDCl3) δ 166.7, 153.1, 142.8, 137.7, 133.1, 129.7, 125.2,
121.9, 120.6, 118.4, 108.0, 19.2; 15N NMR (50.69 MHz, CDCl3) δ
-73.9; HRMS calcd for C12H9NOS: 215.0405, found 215.03914.
1
2-Furan-3-ylpyridin-4-ylamine (Table 5, entry 4). H NMR
(500 MHz, CDCl3) δ 8.17 (dd, 3J ) 5.7 Hz 1 H, CH, ar), 7.94 (s,
1 H, CH, ar), 7.45-7.43 (m, 1 H, CH, ar), 6.81-6.78 (m, 1 H,
CH, ar), 6.67 (d, J ) 2.0 Hz, 1 H, CH, ar), 6.38 (dd, 3J ) 5.6 Hz,
J ) 2.1 Hz, 1 H, CH, ar), 4.44 (s (br), 1 H, NH2); 13C{1H} NMR
(125.77 MHz, CDCl3) δ 152.6, 151.2, 149.0, 142.6, 140.0, 126.2,
107.6, 107.1, 104.8; 15N NMR (50.69 MHz, CDCl3) δ -317.6
(NH2); HRMS calcd for C9H8N2O: 116.00637, found 160.06261.
2-Furan-3-ylpyrimidine (Table 5, entry 5). 1H NMR (500
MHz, CDCl3) δ 8.69 (d, 3J ) 4.8 Hz, 2 H, CH, ar), 8.27-8.26 (m,
Acknowledgment. This work was supported by the DFG
and the Evonik Degussa GmbH, Provadis Partner fu¨r Bildung
und Beratung GmbH, C. A. F. by the Fonds der Chemischen
Industrie and the Studienstiftung des Deutschen Volkes with a
fellowship.
3
1 H, CH, ar), 7.50 (t, J ) 1.7 Hz, 1 H, CH, ar), 7.08 (t, J ) 4.9
Hz, 1 H, CH, ar), 7.07-7.06 (m, 1 H, CH, ar); 13C{1H} NMR
(125.77 MHz, CDCl3) δ 160.4, 156.1, 143.8, 142.9, 126.0, 117.5,
108.4; 15N NMR (50.69 MHz, CDCl3) δ -95.4; HRMS calcd for
C8H6N2O: 146.048, found 146.04496.
5-Pyridin-2-ylfuran-2-carbaldehyde (Table 5, entry 6). 1H
NMR (500 MHz, CDCl3) δ 9.72 (s, 1 H, CHO), 8.66 (dq, 3J ) 4.7
Supporting Information Available: Contains the full set
1
of H, 13C and 15N NMR spectra of all compounds synthesized.
3
Hz, J ) 0.9 Hz, 1 H, CH, ar), 7.92 (dt, J ) 7.9 Hz, J ) 0.9 Hz,
This material is available free of charge via the Internet at
http://pubs.acs.org.
1 H, CH, ar), 7.79 (dt, 3J ) 7.8 Hz, J ) 1.8 Hz, 1 H, CH, ar), 7.36
(d, J ) 3.8 Hz, 1 H, CH, ar), 7.29 (ddd, 3J ) 7.6 Hz, J ) 4.7 Hz,
J ) 1.2 Hz, 1 H, CH, ar), 7.26 (d, J ) 3.8 Hz, 1 H, CH, ar); 13C-
JO8001886
3244 J. Org. Chem., Vol. 73, No. 8, 2008