Highly efficient suzuki-miyaura coupling of heterocyclic substrates through rational reaction design

Article abstract of DOI:10.1002/chem.200701877

A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl) phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na₂PdCl₄] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridineor indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol% of Pd catalyst at 100°C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol% of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

Full text of DOI:10.1002/chem.200701877

FULL PAPER
DOI: 10.1002/chem.200701877
Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates
through Rational Reaction Design
Christoph A. Fleckenstein and Herbert Plenio*[a]
Abstract: A dicyclohexyl(2-sulfo-9-(3-
(4-sulfophenyl)propyl)-9H-fluoren-9-
yl)phosphonium salt was synthesized in
64% overall yield in three steps from
simple commercially available starting
materials. The highly water-soluble cat-
alyst obtained from the corresponding
phosphine and [Na2PdCl4] enabled the
Suzuki coupling of a broad variety of
N- and S-heterocyclic substrates. Chlor-
opyridines (-quinolines) and aryl chlor-
ides were coupled with aryl-, pyridine-
or indoleboronic acids in quantitative
dylboronic
acids
required
0.01–
yields in water/n-butanol solvent mix-
tures in the presence of 0.005–
0.05 mol% of Pd catalyst at 1008C,
0.05 mol% Pd catalyst for full conver-
sion. The key to the high activity of the
Pd-phosphine catalyst is the rational
design of the reaction parameters (i.e.,
the presence of water in the reaction
mixture, good solubility of reactants
and catalyst in n-butanol/water (3:1),
and the electron-rich and sterically de-
manding nature of the phosphine
ligand).
chloropurines
were
quantitatively
Suzuki coupled in the presence of
0.5 mol% of catalyst, and S-heterocy-
clic aryl chlorides and aryl- or 3-pyri-
Keywords: cross-coupling · indoles ·
palladium · purines · thiophenes
Introduction
secondary amino groups have been masked by protective
groups to allow the coupling of such substrates, while with-
out N-protection the Suzuki coupling was less efficient.[39]
Lacking general and efficient cross-coupling protocols, syn-
thetic chemists resort to heteroaryl bromides as coupling
substrates[40,41] instead of the cheaper and more easily avail-
able aryl chlorides, which require at least 1 mol% of catalyst
for quantitative conversion.[42–44] Recently, significant im-
provements in the coupling of heteroaryl chlorides have
been reported by Guram et al.,[45,46] Buchwald et al.[35] and
Fu et al.[33] Interestingly, some of the more efficient coupling
reactions involving heterocyclic substrates were performed
in water[25,47–60] or in water-containing solvent mixtures (with
toluene, dioxane, CH3CN or n-butanol).
We have recently demonstrated that water in combination
with water-soluble, sulfonated fluorenylphosphine Pd com-
plexes is a very useful solvent for Suzuki coupling reactions
of N-heterocycles.[61] Our working hypothesis is that basic ni-
trogen atoms in pyridines, indoles or primary amines prefer
to engage in hydrogen-bonding interactions with water
rather than to inhibit the catalytically active metal centre.
Apart from being a cheap, safe and benign solvent,[62–64]
water has the additional advantage that the organic products
of the coupling reactions are often poorly soluble and can
thus easily be separated from the reaction mixture. This ad-
vantage, though, also turns out to be a drawback, as the aryl
halide reactants tend to be poorly soluble in water, leading
The biological activity associated with numerous nitrogen-
and sulfur-containing heterocycles explains their wide use as
active pharmaceutical ingredients.[1–6] Consequently, a siza-
ble portion of recent US patents reports on organic process
development of aromatic heterocycles.[7,8] A useful synthetic
tool for the modification of such compounds is the Suzuki–
Miyaura coupling,[9,10] which has been applied for the prepa-
ration of arylpyridines,[11,12] bipyridines,[11–15] arylpyrimi-
dines,[16–18] pyridopyridines[11,12,19–21] and aryltriazines,[22,23] the
synthesis of nucleosides[24,25] or the introduction of thio-
phene,[26,27] benzothiazole[28] or indolyl[29–32] moieties.
Nonetheless, the cross-coupling chemistry of heterocyclic
substrates suffers from limitations. In particular, N-heterocy-
cles or compounds bearing free amino moieties are regarded
as challenging substrates.[11,33–37] Problems include the inhibi-
tion of the catalytically active centre by N-coordination, the
trimerization of boronic acids[38] and the poor reactivities of
electron-deficient boronic acids. In some cases primary or
[a] Dipl.-Ing. C. A. Fleckenstein, Prof. Dr. H. Plenio
Anorganische Chemie im Zintl-Institut, TU Darmstadt
Petersenstrasse 18, 64287 Darmstadt (Germany)
E-mail: plenio@tu-darmstadt.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 4267 – 4279
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4267

to a decrease in the overall rate of the coupling reaction due
to mass transfer limitations. In order to improve the efficien-
cy of Suzuki reactions further, we reasoned that increasing
the solubility of the reactants in water by addition of a co-
solvent should lead to even faster Suzuki coupling reactions.
However, this must be achieved without compromising the
previously mentioned advantages. The cosolvent should be
benign: it should form a biphasic mixture with water at
room temperature and a single solvent phase at elevated
temperatures to avoid mass transfer limitations.[65] n-Butanol
fulfils the criteria defined above: it has a large phase separa-
tion region with water at room temperature,[66] but forms
monophasic mixtures at elevated temperatures, does not in-
terfere with the Suzuki reaction, has a satisfactory boiling
point and proves to represent a good trade-off between eco-
nomical, safety and ecological aspects.[67,68]
We wish to report here on highly efficient Suzuki coupling
reactions of various N- and S-heterocyclic substrates in the
presence of a highly water-soluble catalyst, based on a disul-
fonated phosphine, in an optimized water/n-butanol mix-
ture.
Scheme 2. Synthesis of the disulfonated fluorenyldialkylphosphine 4. a) 3-
phenylpropan-1-ol, 3-phenylpropanal, KOH, 1508C; b) nBuLi, Cy2PCl,
MTBE, À308C, aq. HBF4; c) CH2Cl2, H2SO4, 508C; d) NaOH.
through the use of simple commercially available starting
materials.[71] Following our report on the large-scale synthe-
sis of various fluorenylphosphines (including 3·H+),[70] we
now routinely perform the double sulfonation of 3·H+ on a
50 g scale using sulfuric acid, completely avoiding the forma-
tion of undesired phosphine oxides—even when the reaction
is carried out in the presence of oxygen.
Results and Discussion
Synthesis of a highly water-soluble disulfonated fluorenyl-
dialkylphosphine: We have recently reported the synthesis
of fluorenylphosphines whose Pd complexes are excellent
catalysts for various cross-coupling reactions.[61,69,70] Some of
these phosphines are easily monosulfonated by treating
their respective phosphonium salts with sulfuric acid
(Scheme 1).[61] Nonetheless, the water solubilities of the cor-
responding Pd–phosphine complexes remain modest.
Optimizing the water/n-butanol system: As pointed out
before, the poor solubility of aryl halides in pure water ap-
pears to be a drawback for coupling reactions in this solvent.
We first wanted to test whether the addition of n-butanol as
a co-solvent would enhance the catalytic activity of the [Pd/
4] complex in Suzuki cross-coupling reactions. The catalyst
was formed in situ by treatment of two equivalents of phos-
phonium salt 4·3H+ with [Na2PdCl4] in the presence of six
equivalents of base and the reactants. We chose the coupling
of 4-amino-2-chloropyridine and 3-pyridylboronic acid as
the test reaction, and obtained quantitative conversion
(93%) in water/n-butanol (1:1) solvent with the [Pd/4] com-
plex as formed in situ as catalyst.
Scheme 1. Monosulfonation of a 9-ethylfluorenyldicyclohexylphosphoni-
um salt.
In pure water significantly lower conversion (44%) was
observed under the same conditions (Table 1), while in n-bu-
tanol no coupling (<1%) occurred. This result confirms our
initial idea that the reaction rate can be enhanced by provid-
ing better substrate solubility, while on the other hand a sig-
nificant amount of water in the n-butanol is required to
allow highly effective cross-coupling reactions.
We next studied the impact of the n-butanol/water ratio
in Suzuki reactions of heterocycles to optimize the solvent
composition in a more systematic manner. With the same
catalyst as before, 2-chloro-4-picoline was coupled with p-
tolylboronic acid in pure water, pure n-butanol or various
mixtures of the two solvents (Figure 1).
Disulfonation of 9-ethylfluoren-9-yldicyclohexylphospho-
nium salt 1·H+ was not successful. The use of more reactive
sulfonating reagents (oleum, ClSO3H) on phosphine 1 led to
the quantitative oxidation of PIII during aqueous workup,
while less forcing reaction conditions afforded only the mon-
osulfonated product. Consequently, we introduced another
phenyl ring at the periphery of the ligand to serve as an
anchor for a second sulfonato group (Scheme 2). The corre-
sponding dicyclohexylfluorenylphosphonium salt 3 is readily
sulfonated on treatment with sulfuric acid, affording the di-
sulfonated fluorenylphosphonium salt 4·3H+. Treatment of
this reaction mixture with dilute NaOH and subsequent
methanolic workup afforded the free phosphine 4 as the cor-
responding sodium salt in 65% overall yield from fluorene,
At 808C and 0.01 mol% [Pd] loading in pure water 59%
conversion was observed, increasing on addition of n-buta-
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Chem. Eur. J. 2008, 14, 4267 – 4279

Suzuki–Miyaura Coupling of Heterocyclic Substrates
FULL PAPER
Table 1. Influence of solvent on catalytic activity: water versus water/n-
butanol.
in cross-coupling reactions. Further increasing the amount
of n-butanol results in drastically lowered yields—obviously
a certain amount of water is very important. Consequently,
the 1:3 water/n-butanol ratio represents a good trade-off be-
tween good substrate solubility, a monophasic reaction at
elevated temperatures and biphasic behavior at ambient
conditions, combined with maximum water content.
We next compared the catalytic activities of Pd complexes
formed in situ with the doubly sulfonated phosphine 4, the
monosulfonated phosphine 1 and the phosphine 3. Those
three ligands are electron-rich and sterically demanding
phosphines, which is essential for the formation of high-ac-
tivity Pd complexes.[73,74] This was done to demonstrate the
superiority of highly polar Pd complexes over their medium-
polar and lipophilic counterparts. On treatment of 2-chloro-
4-picoline with p-tolylboronic acid at 1008C in the water/n-
butanol (1:3) mixture, Pd complexes with the doubly sulfo-
nated phosphine 4·3H+ showed significantly higher catalytic
activity than their mono- and non-sulfonated relatives
(Table 2). Under the same set of conditions, the palladium
salt alone (i.e., in the absence of phosphine) does not afford
any detectable cross-coupling product (Table 2, entry 3).
Entry
1
Aryl chloride
Boronic acid
Product
Conv. [%][a]
44[b]
93[c]
<1[d]
[a] Average of two runs, determined by GC with heptadecane as internal
standard. [b] In pure water as solvent. [c] In H2O/n-butanol 1:1 as sol-
vent. [d] In n-butanol.
Table 2. Catalytic activity of water-soluble and water-insoluble catalysts.
Entry
Ligand L
Cat. loading [mol%]
Yield [%][a]
1
2
3
4
5
6
7
4
4
–
1
1
3
3
0.01
0.005
0.01[b]
0.01
0.005
0.01
>99
>99
0
>99
73
79
59
0.005
[a] Average of two runs, determined by GC with heptadecane as internal
standard. [b] Control experiment: 0.01 mol% [Na2PdCl4], no phosphine
ligand.
Figure 1. Effect of water/n-butanol ratio on catalytic activity. Reaction
*
*
temperature: : 808C. : 608C.
nol to reach 100% conversion over a wide range of water/n-
butanol compositions of 1:1 to 1:9. With a further increase
in the alcohol content, the conversion drops drastically to
only 19% conversion in pure n-butanol (technical grade).
To identify the best solvent composition the screen was re-
peated at a lower reaction temperature (608C). Under these
conditions a catalytic optimum was found at approximately
75% (v/v) n-butanol. Almost the same water/n-butanol com-
position was used by Billingsley and Buchwald for the
Suzuki coupling of 2-bromothiophene and pyrrole boronate
esters.[72]
Suzuki cross-coupling of N-heterocycles: We next wanted to
demonstrate the generality of the optimized reaction condi-
tions for Suzuki reactions of N-heterocyclic substrates by
coupling a number of different 2-chloropyridines and 2-
chloroquinolines in Suzuki reactions with various boronic
acids (mainly tolyl- and naphthylboronic acid) (Table 3).
Coupling reactions of 2-chloropyridines with sterically un-
hindered boronic acids (p-tolyl-, m-tolyl-) or electron-defi-
cient m-(trifluoromethyl)phenylboronic acid were carried
out at 1008C in n-butanol/water (3:1) over 12 h with K2CO3
as the base and in the presence of 0.005 mol% of Pd cata-
lyst[75] (Table 1, entries 1–12). Even with the sterically hin-
dered 1-naphthylboronic acid, quantitative conversion was
achieved in the presence of 0.01 mol% of Pd catalyst
(Table 3, entries 13–19). Difficult substrates such as the
highly basic 4-amino-2-chloropyridine reacted with p-tolyl-
From the water/n-butanol phase diagram,[66] we believe
that a water/n-butanol 1:3 solvent mixture provides the high-
est possible water content in a homogeneous solution at
1008C. At higher water contents the water/n-butanol mix-
ture turns biphasic, leading to significantly diminished yields
Chem. Eur. J. 2008, 14, 4267 – 4279
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4269

H. Plenio and C. A. Fleckenstein
Table 3. Suzuki reactions with 2-chloropyridines and 2-chloroquinolines with arylboronic acids in water/n-bu-
boronic acid or 1-naphthylbor-
onic acid to afford quantitative
conversions at 0.01 mol% cata-
lyst loading (Table 3, entries 8,
16). For these substrates the
tanol (1:3)[a]
Pd-phosphine complex
4 is
Entry
1
Aryl chloride
Boronic acid
Product
Pd [mol%]
0.005
Conv. [%][b]
Yield[c]
95
about four times more active
in water/n-butanol than in pure
water and 10 to 100 times
more active than other recent-
ly reported catalysts.[33,35,76]
ꢀ99
2
3
0.005
0.005
ꢀ99
ꢀ99
92
91
Suzuki coupling of N-heterocy-
clic boronic acids: More chal-
lenging Suzuki substrate com-
binations are those in which
both coupling partners contain
a pyridyl or an amino moiety.
In order to probe the activity
of our catalytic system we
screened reactions of various
2-chloropyridines and 2-chloro-
quinolines with 3-pyridylbor-
onic acid. With 0.01 mol% cat-
alyst loading, 2-chloropyridines
and 2-chloroquinolines reacted
smoothly with 3-pyridylboronic
acid to afford near quantitative
conversion (Table 4, entries 1–
5). The highly basic 4-amino-2-
chloropyridine was coupled in
near quantitative yield with 3-
pyridylboronic acid (Table 4,
entry 7) or with 2,4-dimethoxy-
3-pyridylboronic acid (Table 4,
entry 9) when 0.05 mol% cata-
lyst were applied.
4
0.005
ꢀ99
95
5
6
0.005
0.005
0.005
ꢀ99
ꢀ99
ꢀ99
94
96
7
8
94
92
0.01
0.005
ꢀ99
78
9
0.005
0.005
ꢀ99
ꢀ99
96
96
10
Our optimized reaction pro-
tocol is not limited to 2-chloro-
pyridines as coupling partners.
Both 4-chloropyridine and the
less activated 3-chloropyridine
coupled quantitatively with p-
tolylboronic acid (Table 5, en-
tries 1 and 2) in the presence
of as little as 0.05 mol% of cat-
alyst. Sterically hindered bor-
onic acids such as 2,6-dimethyl-
boronic acid (Table 5, entry 3)
reacted smoothly in the same
manner with 4-chloropyridine.
3-Pyridylboronic acid—an elec-
tron-deficient metalloid—gave
quantitative conversion with
either 3-chloropyridine or 4-
chloropyridine (Table 5, en-
tries 4 and 5).
11
12
0.005
0.005
ꢀ99
ꢀ99
94
95
13
14
15
0.01
0.01
0.01
ꢀ99
ꢀ99
ꢀ99
92
96
95
4270
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Chem. Eur. J. 2008, 14, 4267 – 4279

Suzuki–Miyaura Coupling of Heterocyclic Substrates
FULL PAPER
couple indole-6-boronic acid
with N-heterocyclic aryl chlor-
ides such as 2-chloro-6-me-
Table 3. (Continued)
Product
Entry
16
Aryl chloride
Boronic acid
Pd [mol%]
0.01
Conv. [%][b]
Yield[c]
91
thoxypyridine
(Table 4,
entry 11) in 95% yield. Even
deactivated and sterically hin-
dered aryl chlorides such as 2-
chlorotoluene were coupled
under the same conditions in
91% yield (Table 4, entry 12).
In the absence of N-protecting
groups, the Suzuki pathway is
the preferred one.
ꢀ99
17
0.01
ꢀ99
94
18
19
0.01
0.01
ꢀ99
ꢀ99
91
95
Suzuki coupling of purines: Pu-
rines, the core bases of the
DNA and RNA nucleotide
building blocks adenine and
guanine, represent an impor-
tant class of biologically active
compounds and are used as an-
[a] Reaction conditions: 1.0 equiv aryl halide, 1.2 equiv boronic acid, 3.2 equiv K2CO3, degassed water
(1.5 mLmmolÀ1), degassed n-butanol (4.5 mLmmolÀ1), 1008C, cat.: the corresponding volume of aqueous cata-
lyst stock solution (cPd =0.001 molLÀ1, Na2PdCl4/ligand (4·3H+) L/Pd 2:1. Reaction times and temperature
were not optimized. [b] Average of two runs, determined by GC with heptadecane as internal standard.
[c] Average of two runs; products were isolated by column chromatography (silica gel), cyclohexene/EtOAc/
NEt3 10:1:1.
tiviral[83–87]
or
anticancer
agents.[85,88–93] Suzuki couplings
have been used to introduce
various substituted aryl groups
into purine systems.[89,94] How-
ever, unprotected halo-9H-
purine bases proved to be un-
Application of the standard coupling protocol to deacti-
vated 4-chloroanisole with the sterically hindered and elec-
tron-deficient 2,4-dimethoxy-3-pyridylboronic acid led to
quantitative product formation (Table 4, entry 8). The same
outcome was observed when the deactivated 1-(4-chloro-
phenyl)-1H-pyrrole was coupled with 3-anisylboronic acid
(Table 5, entry 6) or N-heterocyclic boronic acids (3-pyridyl-
boronic acid; Table 5, entry 7).
Because of its ubiquitous appearance in natural products,
compounds bearing an indole ring are of importance for
pharmaceutical chemistry[77] as, for example, antitumor
agents.[78,79] Suzuki couplings of aryl halides with the corre-
sponding indoleboronic acids should thus represent a con-
venient approach for the introduction of this heterocycle. In
a comprehensive study of the reactivity of haloindoles and
indoleboronic acids in Suzuki cross-couplings, Giralt et al.[30]
noted that unprotected indoleboronic acid is not well suited
for Suzuki reactions. It is thus not surprising that most of
the known cross-coupling protocols either utilize N-protect-
ed indoleboronic acids,[80] accepting the need for a protec-
tion/deprotection sequence, or otherwise are restricted to
the use of the more active aryl bromides as coupling part-
ners.[29,34,41,81,82] Recently, the use of improved catalysts and
modified reaction protocols has allowed the coupling of aryl
chlorides with unprotected indoleboronic acids—unfortu-
nately, though, this requires catalyst loadings of 2–
5 mol%.[33,35,72]
reactive in common cross-coupling protocols, due to remov-
al of the N9 proton.[44,95] Cross-coupling proceeded only
when N9 was decorated with a protective group, although
high Pd catalyst loadings (at least 5 mol%) combined with
elevated reaction temperatures were still required.[88,89,94,96–98]
Recently, Shaughnessy and co-workers reported improved
Suzuki arylations of unprotected bromonucleosides in the
presence of water-soluble arylphosphine Pd complexes in
aqueous media, eliminating the need for protection/depro-
tection steps.[25,60] An extension of this method for cross-cou-
pling of free chloropurine bases offering high-yielding cross-
couplings was reported by Hocek, but again excessive
amounts of catalyst (5–10 mol%) combined with microwave
irradiation were required.[59] Interestingly, the use of highly
water-soluble ligands is essential for the reported protocols.
Shaughnessy and Hocek independently demonstrated that
highly water-soluble ligands—such as triphenylphosphine-
trissulfonate (TPPTS)—have a significant higher catalytic
activity in Suzuki couplings of halopurines than poorly solu-
ble phosphine ligands.[25,60,99] Hence, excellent water solubili-
ty of the catalyst seems to be essential for coupling of halo-
purines in aqueous media.
In contrast to previous work, the Pd complex of our
doubly sulfonated phosphine 4·3H+ allows Suzuki couplings
of unprotected chloropurines in the presence of only
0.5 mol% catalyst. 6-Chloro-9H-purine was successfully
Suzuki-coupled with p-tolylboronic acid and m-anisylboron-
ic acid in 91 and 86% yields, respectively, in water/n-butanol
as solvent (Table 6).
With our newly developed reaction protocol (Table 4),
catalyst loadings of only 0.05 mol% [Pd/4] are sufficient to
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4271

H. Plenio and C. A. Fleckenstein
Table 4. Suzuki reactions with 2-chloropyridines, 2-chloroquinolines and deactivated aryl chlorides with N-het-
erocyclic boronic acids in water/n-butanol 1:3.[a]
Suzuki couplings of S-hetero-
cyclic aryl chlorides: Thio-
phenes and N,S-heterocyclic
thiazoles are abundant in natu-
ral products, and many com-
pounds bearing thiophene moi-
eties are of interest in pharma-
ceutical and fine chemistry,
due to their biological activi-
ties.[20,100,101,102–110] Aryl deriva-
tives of benzothiazole have at-
tracted interest due to their
biological activities as gluta-
mate receptor antagonists.[28]
There are a few reports on
Suzuki couplings of chlorothio-
phenes in the presence of cata-
Entry
1
Aryl chloride
Boronic acid
Product
Pd [mol%]
0.01
Conv.[b] [%]
Yield[c] [%]
91
ꢀ99
2
3
0.01
0.01
ꢀ99
ꢀ99
93
93
lyst
loadings
of
1–
4
5
0.01
0.01
0.05
ꢀ99
ꢀ99
ꢀ99
89
92
2 mol%.[72,111,112]
We were interested to know
whether the catalyst formula-
tion successfully applied in the
synthesis of N-heterocycles
would also be useful in the
synthesis of S-heterocyclic biar-
yls. 3-Chlorothiophene was
quantitatively coupled with p-
tolylboronic acid (Table 7,
entry 1) in water/n-butanol at
1008C in the presence of
0.05 mol% of [Pd/4] complex
generated in situ as catalyst.
Quantitative conversion was
achieved in the reactions of 2-
chlorothiophene with the elec-
tron-deficient 3-pyridylboronic
acid (Table 7, entry 2) and of
5-chloro-2-methylbenzothia-
6
7
93
90
0.05
0.02
ꢀ99
63
8
9
0.05
0.05
0.05
ꢀ99
97
92
90
92
zole with p-tolylboronic acid
(Table 7, entry 3). When 3-pyr-
idylboronic acid was used as
an electron-deficient metalloid
10
ꢀ99
a
catalyst
loading
of
0.05 mol% gave 95% yield.
The reaction protocol used
for the N-heterocycles can thus
also be applied to the S-het-
erocycles with use of between
0.01–0.05 mol% of catalyst
with quantitative conversion of
the substrates.
11
12
0.05
0.05
ꢀ99
ꢀ99
95
91
[a]–[c] Same conditions as reported in Table 3.
Summary and Conclusions
A disulfonated sterically de-
manding and electron-rich flu-
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Chem. Eur. J. 2008, 14, 4267 – 4279

Suzuki–Miyaura Coupling of Heterocyclic Substrates
FULL PAPER
Table 5. Suzuki reactions with several activated and deactivated N-heterocyclic aryl chlorides in water/n-buta-
pyridine- or indoleboronic
acids in quantitative yields in
water/n-butanol solvent, in the
presence of between 0.005–
0.05 mol% of this Pd catalyst
at 1008C. Chloropurines are
quantitatively Suzuki-coupled
in the presence of 0.5 mol% of
catalyst. S-Heterocyclic aryl
chlorides and aryl- or 3-pyri-
dylboronic acids require 0.01–
0.05 mol% Pd catalyst for full
conversion.
nol 1:3.[a]
Entry
1
Aryl chloride
Boronic acid
Product
Conv. [%][b]
Yield [%][c]
95
ꢀ99
2
3
ꢀ99
ꢀ99
93
93
Essential for the superior
performance of the disulfonat-
ed fluorenylphosphine in the
Suzuki coupling of heterocyclic
substrates is the rational reac-
tion design, based on the excel-
lent water solubility of the Pd
catalyst, the electron-rich and
sterically demanding nature of
the phosphine ligand, the good
solubility of all reactants in the
n-butanol/water (3:1) solvent
mixture, the presence of a sig-
nificant amount of water in the
reaction solvent and the mono-
phasic nature of the reaction
mixture at the reaction temper-
atures.
4
5
ꢀ99
ꢀ99
94
95
6
7
ꢀ99
ꢀ99
94
90
[a]–[c] Same conditions as reported in Table 3.
Table 6. Suzuki reactions with 6-chloropurine in water/n-butanol 1:3.[a]
All of these properties com-
bined furnish a catalyst of un-
precedented activity for Suzuki
couplings of a broad range of
N- and S-heterocyclic sub-
strates.
Entry
1
Aryl chloride
Boronic acid
Product
Conv. [%][b]
97
Yield [%][c]
91
Experimental Section
All chemicals were purchased as re-
agent grade from commercial suppli-
ers and were used without further pu-
rification, unless otherwise noted.
Solvents used (water, n-butanol, all
technical grade) were deaerated by
the freeze and thaw technique (2”).
Potassium carbonate used in cross-
coupling reactions was technical
grade. The phosphine ligands Phen-
2
94
86
[a], [b] Same conditions as reported in Table 3. [c] Average of two runs; products were isolated by column
chromatography (silica gel), CH2Cl2/MeOH/NEt3 5:1:1.
orenylphosphine (4) was synthesized in three steps from
PropFluPCy2·HBF4 (3) and PropPhenFluPCy2DS (4·3H+) are also com-
mercially available under the trade name cataCXium F and cataCXium F
sulf from Evonik–Degussa GmbH. All experiments were carried out
under argon unless otherwise noted. Proton (1H NMR), carbon
(13C NMR), phosphorus (31P NMR) and nitrogen (15N NMR) nuclear
magnetic resonance spectra were recorded on a Bruker DRX 500 instru-
ment at 500 MHz, 125.75 MHz, 202.46 MHz and 50.69 MHz, respectively
at 293 K. The chemical shifts are given in parts per million (ppm) on the
delta scale (d) and are referenced to tetramethylsilane (d=0 ppm,
simple commercially available starting materials in 64%
overall yield on a 50 g scale. The corresponding air-stable
phosphonium salt (4·3H+) is readily deprotonated under
cross-coupling conditions and forms a highly water-soluble
Pd complex with [Na2PdCl4]. We have demonstrated for var-
ious substrate combinations that chloropyridines (-quino-
lines) and aryl chlorides can be Suzuki-coupled with aryl-,
Chem. Eur. J. 2008, 14, 4267 – 4279
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4273

H. Plenio and C. A. Fleckenstein
Table 7. Suzuki reactions of S-heterocyclic chlorides in n-butanol/water 1:3.[a]
CH2), 0.93–0.84 ppm (m, 2H; CH2-
CH2-CH2); 13C{1H} NMR (125.8 MHz,
CDCl3): d=141.4 (d,
JP,C =4.3 Hz),
141.1, 139.9 (d, JP,C =1.8 Hz), 130.3,
129.2, 128.4, 128.3, 126.0, 125.0, (d,
J
P, C =1.8 Hz), 121.1, 52.3 (d, JP, C
=
34.2 Hz), 34.9, 32.9, 31.2 (d, JP, C
=
34.1 Hz), 29.4 (d, JP, C =3.6 Hz), 28.0
(d, JP, C =3.5 Hz), 26.8, 26.7, 26.6, 26.5,
24.9, 24.3, 24.2 ppm; 31P{1H} NMR
(202.5 MHz, CDCl3): d=35.6 ppm;
31P NMR (202.5 MHz, CDCl3): d=
35.6 ppm (d, JP, H =477.5 Hz); elemen-
tal analysis calcd (%) for C34H42BF4P:
C 71.83, H 7.45; found: C 71.54, H
7.40.
Entry
1
Aryl chloride
Boronic acid
Product
Pd [mol%]
0.05
Conv. [%][b]
Yield%[c]
93
ꢀ99
2
3
0.05
0.01
ꢀ99
90
89
ꢀ99
PropPhenFluPCy2DS disodium salt
(4): 9-(3-Phenylpropyl)FluCy2·HBF4
(3·H+, 400 mg, 0.70 mmol) was dis-
solved in CH2Cl2 (2 mL) in a 25 mL
Schlenk tube. After addition of conc.
H2SO4 (1 mL, 18.8 mmol) the solution
was stirred overnight at 508C. The so-
lution was added dropwise to ice; in
the end a clear colorless solution was
obtained. After degassing of this solu-
tion, it was neutralised with NaOH
(20% solution in degassed water), in
4
0.05
ꢀ99
95
[a]–[c] Same conditions as reported in Table 3.
1H NMR), 65% aq. H3PO4 (d=0 ppm, 31P NMR) and nitromethane (d=
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,
br=broad. Selected NMR spectra are given in the Supporting Informa-
tion. Mass spectra were recorded on a Finnegan MAT 95 magnetic sector
spectrometer. Thin layer chromatography (TLC) was performed on
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). Quantitative elemental analyses were performed on a
Vavio Micro instrument (Elementar Analysensysteme, GmbH, Germa-
ny). GC experiments were run on a Clarus 500 GC with autosampler and
FID detector. Column: Varian CP-Sil 8 CB (l=15 m, di=0.25 mm, dF=
1.0 mm), N2 (flow: 17 cmsecÀ1; split 1:50). Injector temperature: 2708C,
detector temperature: 3508C. Temperature program: isotherm 1508C for
5 min, heating to 3008C at 258CminÀ1, isotherm for 15 min. 9-(3-Phenyl-
propyl)-9H-fluorene (2) was prepared by a published procedure.[70]
the presence of degassed phenolphthaleine solution as an indicator. The
water was removed in vacuo until Na2SO4 started to precipitate. De-
gassed MeOH (10 mL) was then added to precipitate most of the
Na2SO4, which was removed by filtration to give a clear filtrate. Removal
of the volatiles in vacuo afforded 4 (412 mg, 86%) as a white solid.
1H NMR (500 MHz, CD3OD): d=7.97 (s, 1H; CH, ar), 7.89–7.85 (m,
3H; CH, ar), 7.66–7.61 (m, 2H; CH, ar), 7.43–7.30 (m, 3H; CH, ar), 7.97
(d, 3J=8.0 Hz, 2H; CH, ar), 2.53–2.29 (m, 4H; CH2), 2.00–0.73 ppm (m,
24H; CH+CH2); 13C{1H} NMR (125.77 MHz, CD3OD): d=151.2, 150.2,
146.3, 145.3, 144.4, 144.0, 141.5, 129.6, 129.3, 128.6, 127.3, 126.4, 125.5 (d,
J
P, C =5.1 Hz), 123.2 (d, JP, C =3.3 Hz), 121.8, 121.0, 57.1 (d, JP,C =28.5 Hz),
38.8 (d, JP, C =22.7 Hz), 36.8, 35.2, 35.0, 34.9, 34.7, 34.7, 34.6, 34.5, 31.6 (d,
P, C =10.4 Hz), 31.1 (d, JP, C =7.5 Hz), 29.2 (d, JP, C =13.1 Hz), 28.9, 28.8,
J
28.8, 28.5 (d, JP, C =7.03 Hz), 27.8, 27.6, 27.4, 27.2, 26.9 (d, JP,C =10.4 Hz),
26.2 ppm; 31P{1H} NMR (202.46 MHz, CD3OD): d=33.6 ppm; MS
(70 eV): m/z: 700 [M+O]+, 684 [M]+, 601 [MÀCy]+.
PropPhenFluPCy2DS·H2SO4
A
(270 mL, 5 mol) was added at 08C under argon to a solution of 9-(3-phe-
nylpropyl)FluPCy2·HBF4 (3·H+, 50 g, 0.88 mol) in CH2Cl2 (100 mL, tech-
nical grade). The reaction mixture was warmed up to 508C with stirring.
After removal of the CHCl2, the reaction mixture was stirred at 508C
overnight. The clear, slightly yellow solution was poured onto ice
(1500 g). The white precipitate was separated by suction filtration and
washed with ice water (2”100 mL). The precipitate was dissolved in
MeOH (300 mL) and filtered, and the clear, colorless filtrate was added
dropwise to MTBE (1600 mL, vigorously stirred) to precipitate the prod-
uct. Decantation of the solvent and removal of the volatiles in vacuo af-
9-(3-Phenylpropyl)FluPCy2·HBF4
A
rene (2, 117 g, 0.410 mol) was suspended in dry methyl tert-butyl ether
(MTBE, 2.7 L) under argon in a 6 L three-necked round-bottomed flask.
nBuLi (2.5m in hexane, 162 mL, 0.406 mol) was added at 08C over
10 min. The reaction mixture was warmed to 208C, forming a deep red,
clear solution that was stirred for an additional 2 h at ambient tempera-
ture. The mixture was then cooled to À308C, and Cy2PCl (92.75 g, 0.399
mol) was added over 10 min. The red color disappeared to form a yellow
clear solution, which was stirred for an additional 1 h at 208C (precipita-
tion of LiCl started after about 20 min). The suspension was extracted
with degassed water (1”750 mL) to remove the LiCl. The clear, slightly
yellowish organic layer was treated with aqueous HBF4 (48%, 59 mL,
0.451 mol) with vigorous stirring over 2 min to precipitate the title com-
pound as white crystals. More HBF4 (25 mL, 2m in water) was added, the
suspension was stirred for another 10 min, and the precipitate was then
separated by suction filtration (glass frit G3) and washed with MTBE
(2”100 mL). Drying of the product at 608C in vacuo afforded 3·H+
(208 g, 92%) as white crystals. 1H NMR (500 MHz, CDCl3): d=7.85 (d,
3J=7.5 Hz, 2H; CH, ar), 7.69 (d, 3J=7.5 Hz, 2H; CH, ar), 7.56 (t, 3J=
7.0 Hz, 2H; CH, ar), 7.48 (t, 3J=7.5 Hz, 2H; CH, ar), 7.20–7.14 (m, 2H;
CH, ar), 7.14–7.01 (m, 1H; CH, ar), 6.92 (d, 3J=7.5 Hz, 2H; CH, ar),
1
forded the pure product (4·3H+) (50.3 g, 77%) as a white solid. H NMR
(500 MHz, CD3OD): d=8.26 (s, 1H; CH, ar), 8.13–8.08 (m, 3H; CH, ar),
3
3
7.73 (d, J=8.0 Hz, 1H; CH, ar), 7.69–7.64 (m, 1H; CH, ar), 7.67 (d, J=
8.5 Hz, 2H; CH, ar), 7.57 (dt, 5J=0.5, 7.0 Hz, 1H; CH, ar), 7.04 (d, 3J=
8.5 Hz, 2H; CH, ar), 2.89–2.80 (m, 1H; CH), 2.74–2.62 (m, 2H; CH and
CH2), 2.59–2.45 (m, 2H; CH2), 2.44–2.33 (m, 1H; CH2), 1.92–1.83 (m,
1H; CH2), 1.80–0.93 (m, 20H; CH2), 0.87–0.76 ppm (m, 1H; CH2);
13C NMR (125.77 MHz, CD3OD): d=147.6, 145.6, 145.1 (d, JP, C =4.4 Hz),
144.2, 142.5 (d, JP, C =4.8 Hz), 142.4 (d, JP, C =2.8 Hz), 141.7 (d, JP,C
=
4.2 Hz), 132.2, 131.2, 129.8, 129.7, 127.6, 126.8 (d, JP, C =3.9 Hz), 124.4 (d,
J
P, C =3.9 Hz), 123.6, 122.9, 53.7 (d, JP, C =33.5 Hz), 35.8, 34.5, 32.7 (d, JP, C
=
=
3.8 Hz), 32.5 (d, P,C =4.0 Hz), 31.2 (d, P, C =3.9 Hz), 30.6 (d, JP, C
J
J
1
6.47 (d, J=479.5 Hz, 1H; PH), 2.75–2.67 (m, 2H; Flu-CH2), 2.47 (t, J=
7.5 Hz, 2H; Ph-CH2), 2.23–2.11 (m, 2H; CH), 1.87–1.01 (m, 20H; Cy-
3.5 Hz), 30.0 (d, JP, C =3.3 Hz), 29.8 (d, JP, C =3.3 Hz), 28.1, 28.0, 28.0, 27.9,
27.9, 27.8, 27.8, 27.7, 26.4 (d, JP, C =1.5 Hz), 25.4, 25.3 ppm; 31P {1H} NMR
4274
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4267 – 4279

Suzuki–Miyaura Coupling of Heterocyclic Substrates
FULL PAPER
(202.46 MHz, CD3OD): d=34.2 ppm; MS (70 eV): m/z: 641
[MÀHSO4À]+, 639 [MÀH2SO4ÀH]À, 442 [MÀH2SO4ÀPCy2ÀH]À.
2.44 ppm (s, 3H; CH3); 13C{1H} NMR (125.77 MHz, CD3CN): d=156.2,
147.6, 144.9, 139.1, 138.1, 129.7, 129.5, 129.0, 128.3, 127.6, 126.9, 125.7,
124.1, 123.6, 119.0, 20.3, 17.7 ppm; HRMS: m/z: calcd for C17H15N:
233.1205; found: 233.12109.
General procedure for Suzuki cross-coupling reactions in aqueous n-bu-
tanol
4-Methyl-2-(3-trifluoromethyl-phenyl)-quinoline
(Table 3,
entry 10):
Preparation of catalyst stock solution: [Na2PdCl4] (5.9 mg, 0.02 mmol),
PropPhenFluPCy2DS·H2SO4 (4·3H+, 30 mg, 0.04 mmol) and K2CO3
(33 mg, 0.24 mmol) were placed in a 25 mL Schlenk tube and evacuated
and backfilled with Ar thrice. Degassed water (20 mL) was added, and
the mixture was stirred at 558C for 3 h to provide a clear, nearly colorless
1H NMR (500 MHz, CD3CN): d=8.54 (s, 1H; CH, ar), 8.41 (d, 3J=
7.0 Hz, 1H; CH, ar), 8.08–8.02 (m, 2H; CH, ar), 7.87–7.85 (m, 1H; CH,
ar), 7.78–7.71 (m, 2H; CH, ar), 7.68 (t, 3J=7.5 Hz, 1H; CH, ar), 7.60–
7.56 (m, 1H; CH, ar), 2.73–2.72 ppm (m, 3H; CH3); 13C{1H} NMR
(125.77 MHz, CD3CN): d=154.2, 147.5, 145.6, 140.0, 130.5, 130.1 (q, 2J=
31.8 Hz, CCF3), 129.6, 129.3, 129.3, 127.1, 126.2, 125.4 (q, 3J=4.4 Hz,
CHCCF3), 123.7, 124.2 (q, 1J=271.8 Hz, CF3), 123.5 (q, 3J=2.9 Hz,
CHCCF3), 118.7, 17.7 ppm; HRMS: m/z: calcd for C17H12NF3: 287.0922;
found: 287.09206.
solution. The c[Pd] of this catalyst stock solution is 0.001 mmolmLÀ1
.
Cross-coupling reaction: The boronic acid (1.2 mmol) and K2CO3
(440 mg, 3.2 mmol) were placed in a 25 mL Schlenk tube and evacuated
and backfilled with Ar thrice. Degassed water (1 mL) and degassed n-bu-
tanol (3 mL) were then added together with the aryl halide (1 mmol) and
the appropriate volume of catalyst stock solution (e.g., 1 mL of the solu-
2-m-Tolylquinoline-3-carbaldehyde
(Table 3,
entry 11):
1H NMR
(500 MHz, CD3CN): d=10.10 (s, 1H; CHO), 8.83 (s, 1H; CH, ar), 8.12–
8.08 (m, 2H; CH, ar), 7.90 (ddd, 5J=1.5, 3J=7.0, 9.0 Hz, 1H; CH, ar),
7.67 (ddd, 5J=1.0, 3J=7.0, 8.0 Hz, 1H; CH, ar), 7.53–7.50 (m, 1H; CH,
ar), 7.46–7.43 (m, 2H; CH, ar), 7.40–7.35 (m, 1H; CH, ar), 2.45 ppm (s,
3H; CH3); 13C{1H} NMR (125.77 MHz, CD3CN): d=191.0, 159.8, 149.0,
138.1, 137.9, 137.8, 132.3, 130.4, 129.5, 129.3, 128.8, 128.0, 127.6, 127.2,
127.1, 126.0, 20.2 ppm; HRMS: m/z: calcd for C17H13NO: 247.0997;
found: 247.09813.
tion prepared above was added to obtain
a catalyst loading of
0.1 mol%). The reaction mixture was stirred for 12 h at 1008C 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 was purified by column chro-
matography (silica (20”3 cm), cyclohexene/EtOAc/NEt3 (10:1:1) as
eluent) to afford the pure corresponding cross-coupling product in 86–
96% yield.
2-(3-Trifluoromethyl-phenyl)-quinoline-3-carbaldehyde
(Table 3,
Analytical data forthe Suzuki products
entry 12): 1H NMR (500 MHz, CD3CN): d=10.10 (s, 1H; CHO), 8.87 (s,
1H; CH, ar), 8.15–8.10 (m, 2H; CH, ar), 8.03 (s, 1H; CH, ar), 7.93 (ddd,
5J=1.5, 3J=7.0, 8.5 Hz, 1H; CH, ar), 7.91–7.84 (m, 2H; CH, ar), 7.76–
7.68 ppm (m, 2H; CH, ar); 13C{1H} NMR (125.77 MHz, CD3CN): d=
190.6, 157.7, 148.9, 139.3, 139.2, 133.6, 132.6, 129. (q, 2J=32.3 Hz, CCF3),
129.2, 128.9, 128.9, 127.6, 127.5, 126.3 (q, 3J=3.9 Hz, CHCCF3), 126.2,
125.3 (q, 3J=3.8 Hz, CHCCF3), 124.0 ppm (q, 1J=272.4 Hz, CF3);
HRMS: m/z: calcd for C17H10NOF3: 301.0714; found: 301.06928.
2-p-Tolylpyridine (Table 3, entry 1): The NMR spectra were identical to
those in the literature.[113]
2-p-Tolylisonicotinonitrile (Table 3, entry 2): 1H NMR (500 MHz,
5
3
CDCl3): d=8.75 (dd, J=0.5, J=5.0 Hz, 1H; CH, ar), 7.84–7.80 (m, 3H;
CH, ar), 7.32 (dd, 4J=1.0, 3J=5.0 Hz, 1H; CH, ar), 7.24 (d, 3J=8.0 Hz,
2H; CH, ar), 2.35 ppm (s, 3H; CH3); 13C{1H} NMR (125.77 MHz,
CDCl3): d=157.7, 149.5, 139.5, 133.5, 128.8, 125.8, 121.8, 120.7, 120.1,
115.8, 20.3 ppm; HRMS: m/z: calcd for C13H10N2: 194.0844; found:
194.08414.
2-Naphthalen-1-yl-quinoline-3-carbaldehyde (Table 3, entry 13): 1H NMR
(500 MHz, CD3CN): d=9.74 (s, 1H; CHO), 8.96 (s, 1H; CH, ar), 8.22 (d,
3J=8.0 Hz, 1H; CH, ar), 8.13 (dd, 5J=0.5, 3J=8.5 Hz, 1H; CH, ar), 8.09
(d, 3J=8.0 Hz, 1H; CH, ar), 8.04 (d, 3J=8.0 Hz, 1H; CH, ar), 7.96 (ddd,
5J=1.0, 3J=6.5, 8.5 Hz, 1H; CH, ar), 7.75 (ddd, 5J=1.5, 3J=7.0, 8.5 Hz,
1H; CH, ar), 7.67 (dd, 3J=7.0, 8.0 Hz, 1H; CH, ar), 7.62–7.52 (m, 3H;
CH, ar), 7.44 ppm (ddd, 5J=1.5, 3J=7.0, 8.5 Hz, 1H; CH, ar);
13C{1H} NMR (125.77 MHz, CD3CN): d=190.6, 159.2, 149.3, 137.8, 135.6,
133.2, 132.5, 131.8, 129.5, 128.9, 128.8, 128.8, 128.1, 127.9, 127.5, 126.6,
126.4, 126.0, 125.0, 125.0 ppm; HRMS: m/z: calcd for C20H13NO:
283.0997; found: 283.09811.
2-p-Tolylquinoline-3-carbaldehyde (Table 3, entry 3): 1H NMR (500 MHz,
CD3CN): d=10.12 (s, 1H; CHO), 8.85 (s, 1H; CH, ar), 8.14–8.09 (m,
3H; CH, ar), 7.91 (ddd, 5J=1.5, 3J=7.0, 8.5 Hz, 1H; CH, ar), 7.76 (ddd,
5J=1.5, 3J=7.0, 8.5 Hz, 1H; CH, ar), 7.59 (td, 4J=2.0, 3J=8.0 Hz, 2H;
CH, ar), 7.41–7.38 (m, 2H; CH, ar), 2.45 ppm (s, 3H; CH3);
13C{1H} NMR (125.77 MHz, CD3CN): d=191.1, 159.6, 149.1, 139.2, 137.9,
135.1, 132.3, 130.0, 129.3, 128.8, 128.8, 127.7, 127.1, 126.0, 20.1 ppm;
HRMS: m/z: calcd for C17H13NO: 247.0997; found: 247.09700.
4-Methyl-2-p-tolylquinoline (Table 3, entry 4): The NMR spectra were
identical to those in the literature.[114]
2-Naphthalen-1-ylpyridine (Table 3, entry 14): The NMR spectra were
identical to those in the literature.[116]
4-Methyl-2-p-tolylpyridine (Table 3, entry 5): The NMR spectra were
identical to those in the literature.[115]
2-Naphthalen-1-ylquinoline (Table 3, entry 15): The NMR spectra were
identical to those in the literature.[117]
2-p-Tolylquinoline (Table 3, entry 6): The NMR spectra were identical to
those in the literature.[115]
2-Naphthalen-1-ylpyridin-4-ylamine
(Table 3,
entry 16):
1H NMR
(500 MHz, CDCl3): d=8.20 (d, 3J=5.5 Hz, 1H; ar), 8.01 (d, 3J=8.0 Hz,
1H; ar), 7.76 (t, 3J=9.5 Hz, 2H; ar), 7.43–7.33 (m, 4H; ar), 6.47 (d, 4J=
2.0 Hz, 1H; ar), 6.27 (dd, 3J=5.5, 4J=2.5 Hz, 1H; ar), 4.37 ppm (brs,
2H; NH2); 13C{1H} NMR (125.77 MHz, CDCl3): d=158.5, 152.4, 148.5,
138.0, 132.7, 130.2, 127.4, 127.1, 125.8, 125.1, 124.9, 124.7, 124.1, 109.6,
107.1 ppm; HRMS: m/z: calcd for C15H12N2: 220.1001; found: 220.09869.
2-Methoxy-6-p-tolylpyridine (Table 3, entry 7): 1H NMR (500 MHz,
CDCl3): d=7.93 (d, 3J=8.5 Hz, 2H; CH, ar), 7.58 (dd, 3J=7.5, 8.0 Hz,
5
3
5
1H; CH, ar), 7.29 (dd, J=0.5, J=7.5 Hz, 1H; CH, ar), 7.24 (dd, J=0.5,
3J=8.5 Hz, 2H; CH, ar), 6.64 (d, 3J=8.0 Hz, 1H; CH, ar), 4.02 (s, 3H;
OCH3), 2.39 ppm (s, 3H; CH3); 13C{1H} NMR (125.77 MHz, CDCl3): d=
164.1, 155.2, 139.5, 139.2, 136.8, 129.7, 127.0, 112.8, 109.2, 53.5, 21.7 ppm;
HRMS: m/z: calcd for C13H13NO: 199.0997; found: 199.09999.
4-Methyl-2-naphthalen-1-ylquinoline (Table 3, entry 17): The NMR spec-
tra were identical to those in the literature.[118]
2-p-Tolylpyridin-4-ylamine (Table 3, entry 8): 1H NMR (500 MHz,
CDCl3): d=8.25 (d, 3J=5.5 Hz, 1H; ar), 7.78 (d, 3J=8.0 Hz, 2H; ar),
7.21 (d, 3J=8.0 Hz, 2H; ar), 6.85 (s, 1H; ar), 6.39 (dd, 3J=5.5, 4J=
2.5 Hz, 1H; ar), 4.35 (brs, 2H; NH2), 2.36 ppm (s, 3H; CH3);
13C{1H} NMR (125.77 MHz, CDCl3): d=157.2, 152.6, 159.0, 137.6, 136.0,
128.2, 125.7, 107.2, 105.1, 20.2 ppm; HRMS: m/z: calcd for C12H12N2:
184.1001; found: 184.09808.
4-Methyl-2-m-tolylquinoline (Table 3, entry 9): 1H NMR (500 MHz,
CD3CN): d=8.06–8.01 (m, 3H; CH, ar), 7.99–7.96 (m, 1H; CH, ar), 7.82
(d, 5J=0.5 Hz, 1H; CH, ar), 7.71 (ddd, 5J=1.5, 3J=6.5, 8.5 Hz, 1H; CH,
ar), 7.55 (ddd, 5J=1.0, 3J=6.5, 8.5 Hz, 1H; CH, ar), 7.40 (t, 3J=8.0 Hz,
1H; CH, ar), 7.30–7.27 (m, 1H; CH, ar), 2.71 (d, 5J=0.5 Hz, 3H; CH3),
1-Naphthylisonicotinonitrile (Table 3, entry 18): 1H NMR (500 MHz,
5
3
4
CD3CN): d=8.75 (dd, J=0.5 Hz, J=5.0 Hz, 1H; CH, ar), 8.75 (dd, J=
2.5 Hz, 3J=6.5 Hz, 1H; CH, ar), 7.82–7.81 (m, 1H; CH, ar), 7.81–7.79
5
3
(m, 2H; CH, ar), 7.58 (dd, J=1.5 Hz, J=5.5 Hz, 1H; CH, ar), 7.45–7.42
(m, 2H; CH, ar), 7.38 (ddd, 5J=1.0 Hz, 3J=7.0 Hz, 3J=7.5 Hz, 1H; CH,
ar), 7.34 ppm (ddd, 5J=1.0 Hz, 3J=6.5 Hz, 3J=8.0 Hz, 1H; CH, ar);
13C{1H} NMR (125.77 MHz, CD3CN): d=159.2, 149.6, 135.6, 133.5, 130.3,
129.6, 128.2, 127.8, 127.0, 126.7, 126.1, 125.1, 124.7, 124.0, 121.2,
116.3 ppm; HRMS: m/z: calcd for C16H10N2: 230.0844; found: 230.08168.
2-Methoxy-6-naphthalen-1-ylpyridine (Table 3, entry 19): The NMR spec-
tra were identical to those in the literature.[119]
Chem. Eur. J. 2008, 14, 4267 – 4279
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4275

H. Plenio and C. A. Fleckenstein
2-Pyridin-3-ylquinoline-3-carbaldehyde (Table 4, entry 1): 1H NMR
(500 MHz, CD3CN): d=10.15 (s, 1H; CHO), 8.93 (s, 1H; CH, ar), 8.87
(d, 5J=1.5 Hz, 1H; CH, ar), 8.73 (dd, 5J=1.5 Hz, 3J=4.5 Hz, 1H; CH,
ar), 8.19–8.14 (m, 2H; CH, ar), 8.07–8.04 (m, 1H; CH, ar), 7.96 (ddd,
5J=1.0 Hz, 3J=6.5 Hz, 3J=8.5 Hz, 1H; CH, ar), 7.73 (ddd, 5J=1.0 Hz,
3J=7.0 Hz, 3J=8.0 Hz, 1H; CH, ar), 7.54 ppm (ddd, 5J=0.5 Hz, 3J=
4.5 Hz, 3J=8.0 Hz, 1H; CH, ar); 13C{1H} NMR (125.77 MHz, CD3CN):
d=190.7, 156.5, 150.1, 149.6, 149.0, 139.6, 137.1, 132.7, 129.3, 128.9, 127.7,
127.7, 126.2, 123.9, 122.9 ppm; HRMS: m/z: calcd for C15H10N2O:
234.0793; found: 234.07699.
134.6, 129.2 (2”), 125.8, 125.5, 124.6, 123.5, 120.7, 119.0, 110.5, 101.3,
19.6 ppm; HRMS: m/z: calcd for C15H13N: 207.1048; found: 207.10515.
1
4-p-Tolylpyridine (Table 5, entry 1): H NMR (500 MHz, CDCl3): d=8.62
(dd, 3J=4.8, J=1.7 Hz, 2H; CH, ar), 7.53 (d, 3J=8.0 Hz, 2H; CH, ar),
7.45 (dd, 3J=4.5, J=1.7 Hz, 2H; CH, ar), 7.28 (d, 3J=8.0 Hz, 2H; CH,
ar), 2.40 ppm (s, 3H; CH3); 13C{1H} NMR (125.8 MHz, CDCl3): d=150.6,
148.6, 139.6, 135.6, 130.2, 127.2, 121.8, 21.6 ppm; 15N NMR (50.7 MHz,
CDCl3): d=À74.2 ppm; HRMS: m/z: calcd for C12H11N: 169.0892;
found: 169.08774.
1
3-p-Tolylpyridine (Table 5, entry 2): H NMR (500 MHz, CDCl3): d=8.83
(dd, 3J=2.4, J=0.6 Hz, 1H; CH, ar), 8.56 (dd, 3J=4.9, J=1.6 Hz, 1H;
CH, ar), 7.83 (ddd, 3J=7.9, J=2.4, 1.6 Hz, 1H; CH, ar), 7.47 (d, 3J=
A
those in the literature.[120]
3
2-Pyridin-3-ylquinoline (Table 4, entry 3): The NMR spectra were identi-
8.2 Hz, 2H; CH, ar), 7.32 (ddd, J=7.9, J=4.9, 0.7 Hz, 1H; CH, ar), 7.27
cal to those in the literature.[121,122]
(d, 3J=7.9 Hz, 2H; CH, ar), 2.40 ppm (s, 3H; CH3); 13C{1H} NMR
(125.8 MHz, CDCl3): d=147.2 (2 x), 137.0, 135.5, 133.9, 133.1, 128.8,
125.9, 122.4, 20.1 ppm; 15N NMR (50.7 MHz, CDCl3): d=À68.1 ppm;
HRMS: m/z: calcd for C12H11N1: 169. 0892; found: 169.08751.
4-Methyl-[2,3’]bipyridinyl (Table 4, entry 4): The NMR spectra were
identical to those in the literature.[20]
4-Methyl-2-pyridin-3-ylquinoline (Table 4, entry 5): The NMR spectra
4-(2,6-Dimethylphenyl)pyridine (Table 5, entry 3): 1H NMR (500 MHz,
CDCl3): d=8.67 (dd, 3J=4.4, J=1.7 Hz, 2H; CH, ar), 7.20 (dd, 3J=8.2,
7.0 Hz, 1H; CH, ar), 7.12 (d, 3J=7.0 Hz, 2H; CH, ar), 7.11 (dd, 3J=4.4,
J=1.7 Hz, 2H; CH, ar), 2.02 ppm (s, 6H; CH3); 13C{1H} NMR
(125.8 MHz, CDCl3): d=149.1, 148.4, 138.0, 134.1, 126.8, 126.6, 123.4,
19.6 ppm; 15N NMR (50.7 MHz, CDCl3): d=À72.8 ppm; HRMS: m/z:
calcd for C13H13N1: 183.1048; found: 183.10352.
were identical to those in the literature.[123]
6-Methoxy-[2,3’]bipyridinyl (Table 4, entry 6): The NMR spectra were
identical to those in the literature.[124]
N
CDCl3): d=9.01 (d, J=1.5 Hz, 1H; ar), 8.53 (dd, J=5.0 Hz, J=1.5 Hz,
1H; ar), 8.22 (d, 3J=6.0 Hz, 1H; ar), 8.16 (dt, 3J=8.0 Hz, 4J=2.0 Hz,
4
3
1H; ar), 6.29–6.26 (m, 1H; ar), 6.87 (d, J=2.0 Hz, 1H; ar), 6.44 (dd, J=
6.0 Hz, 4J=2.5 Hz, 1H; ar), 4.53 ppm (s, 2H; NH2); 13C{1H} NMR
(125.77 MHz, CDCl3): d=154.5, 152.8, 149.5, 148.6, 147.1, 134.4, 133.4,
122.5, 107.9, 105.5 ppm; HRMS: m/z: calcd for C10H9N3: 171.0797; found:
171.07820.
A
(dd, 3J=2.5, J=1.0 Hz, 2H; CH, ar), 8.66 (dd, 3J=4.8, J=1.5 Hz, 2H;
CH, ar), 7.89 (ddd, 3J=8.0, J=2.5, 1.8 Hz, 2H; CH, ar), 7.42 ppm (ddd,
3J=8.0, J=4.8, J=1.0 Hz, 2H; CH, ar); 13C{1H} NMR (125.8 MHz,
CDCl3): d=149.4, 148.2, 134.4, 133.5, 123.8 ppm; 15N NMR (50.7 MHz,
CDCl3) d=À66.4 ppm; HRMS: m/z: calcd for C10H8N2: 156.0688; found:
156.06957.
2,6-Dimethoxy-3-(4-methoxyphenyl)pyridine (Table 4, entry 8): 1H NMR
(500 MHz, CDCl3): d=7.52 (d, 3J=8.0 Hz, 1H; CH, ar), 7.45 (d, 3J=
9.0 Hz, 2H; CH, ar), 6.93 (d, 3J=9.0 Hz, 2H; CH, ar), 6.36 (d, 3J=
8.0 Hz, 1H; CH, ar), 3.96 (s, 3H; OCH3 Pyr), 3.95 (s, 3H; OCH3 Pyr),
3.82 ppm (s, 3H; OCH3 (Anis)); 13C{1H} NMR (125.77 MHz, CDCl3): d=
162.3, 159.6, 159.0, 141.6, 130.4, 129.7, 115.9, 114.1, 101.3, 55.7, 54.0,
53.8 ppm; HRMS: m/z: calcd for C14H15NO3: 245.1052; found: 245.10379.
A
(d, 3J=2.0 Hz, 1H; CH, ar), 8.72 (dd, 3J=4.5, J=1.7 Hz, 2H; CH, ar),
8.69 (dd, 3J=4.9, J=1.5 Hz, 1H; CH, ar), 7.93 (ddd, 3J=8.0, J=2.4,
1.7 Hz, 1H; CH, ar), 7.51 (dd, 3J=4.5, J=1.7 Hz, 2H; CH, ar), 7.43 ppm
(ddd, 3J=8.0, 4.9, J=0.7 Hz, 1H; CH, ar); 13C{1H} NMR (125.8 MHz,
CDCl3): d=150.6, 150.2, 148.2, 145.2, 134.3, 133.8, 123.8, 121.6 ppm;
15N NMR (50.7 MHz, CDCl3): d=À66.5, À69.8 ppm; HRMS: m/z: calcd
for C10H8N2: 156.0688; found: 156.0679.
1-(3’-Methoxybiphenyl-4-yl)-1H-pyrrole (Table 5, entry 6): 1H NMR
(500 MHz, CDCl3): d=7.62 (d, 3J=8.6 Hz, 2H; CH, ar), 7.43 (d, 3J=
8.6 Hz, 2H; CH, ar), 7.35 (t, 3J=7.9 Hz, 1H; CH, ar), 7.17 (ddd, 3J=7.6,
J=1.6, 0.9 Hz, 1H; CH, ar), 7.13–7.10 (m, 3H; CH, ar), 6.90 (ddd, 3J=
8.2, J=2.6, 0.9 Hz, 1H; CH, ar), 6.36 (t, 3J=2.2 Hz, 2H; CH, ar),
3.85 ppm (s, 3H; OCH3); 13C{1H} NMR (125.8 MHz, CDCl3): d=160.1,
141.7, 140.0, 138.4, 129.9, 128.2, 120.6, 119.4, 119.3, 112.8, 112.7, 110.6,
55.3 ppm; 15N NMR (50.7 MHz, CDCl3): d=À 206.7 ppm; HRMS: m/z:
calcd for C17H15N1O1: 249.1154; found: 249.11369.
2’,6’-Dimethoxy-[2,3’]bipyridinyl-4-ylamine (Table 4, entry 9): 1H NMR
3
(500 MHz, CDCl3): d=8.27 (dd, J=5.7, J=0.6 Hz, 1H; CH, ar), 8.20 (d,
3J=8.2 Hz, 1H; CH, ar), 7.21 (dd, J=2.5, 0.6 Hz, 1H; CH, ar), 6.43–6.40
(m, 2H; CH, ar), 4.18 (brs, 2H; NH2), 4.02 (s, 3H; OCH3), 3.96 ppm (s,
3H; OCH3); 13C{1H} NMR (125.77 MHz, CDCl3): d=161.8, 158.7, 153.8,
151.3, 148.7, 141.3, 113.5, 108.9, 106.8, 100.5, 52.6, 52.4 ppm; HRMS: m/z:
calcd for C12H13N3O2: 231.1008; found: 231.10084.
2-(1H-Indol-6-yl)-4-methylquinoline
(Table 4,
entry 10):
1H NMR
(500 MHz, CDCl3): d=9.54 (brs, 1H; NH), 8.49–8.48 (m, 1H; CH, ar),
8.21 (dq, 3J=8.5, J=0.6 Hz, 1H; CH, ar), 7.99 (dd, 3J=8.5, J=1.3 Hz,
1H; CH, ar), 7.84 (dd, 3J=8.2, J=1.6 Hz, 1H; CH, ar), 7.80–7.79 (m,
3
3
3
1H; CH, ar), 7.73 (d, J=8.2 Hz, 1H; CH, ar), 7.68 (ddd, J=8.2 Hz, J=
7.0, J=1.5 Hz, 1H; CH, ar), 7.51 (ddd, 3J=8.2 Hz, 3J=7.0, J=1.3 Hz,
1H; CH, ar), 7.16 (t, J=2.8 Hz, 1H; CH, ar), 6.54–6.52 (m, 1H; CH, ar),
2.76 ppm (s, 3H; CH3); 13C{1H} NMR (125.77 MHz, CDCl3): d=158.3,
148.2, 144.7, 136.5, 133.4, 129.6, 129.4, 129.1, 127.2, 126.2, 125.6, 123.7,
120.7, 120.3, 119.3, 110.9, 102.2, 19.0 ppm; 15N{1H} NMR (50.69 MHz,
CDCl3) d=À250.3, À90.3 ppm; HRMS: m/z: calcd for C18H14N2:
258.1157; found: 258.11354.
3-(4-Pyrrol-1-ylphenyl)pyridine (Table 5, entry 7): 1H NMR (500 MHz,
CDCl3): d=8.86 (dd, 3J=2.5, J=0.6 Hz, 1H; CH, ar), 8.60 (dd, 3J=4.8,
J=1.6 Hz, 1H; CH, ar), 7.86 (ddd, 3J=7.9, J=2.5, 1.6 Hz, 1H; CH, ar),
7.62 (d, 3J=8.6 Hz, 2H; CH, ar), 7.49 (d, 3J=8.6 Hz, 2H; CH, ar), 7.36
(ddd, 3J=7.9, J=4.9, J=0.7 Hz, 1H; CH, ar), 7.13 (t, 3J=2.2 Hz, 2H;
3
CH, ar), 6.38 ppm (t, J=2.2 Hz, 2H; CH, ar); 13C{1H} NMR (125.8 MHz,
6-(6-Methoxypyridin-2-yl)-1H-indole (Table 4, entry 11): 1H NMR
(500 MHz, CDCl3): d=8.25 (brs, 1H; NH), 8.12–8.11 (m, 1H; CH, ar),
7.80 (dd, 3J=8.5, J=1.6 Hz, 1H; CH, ar), 7.68 (dt, 3J=8.5, J=0.7 Hz,
1H; CH, ar), 7.59 (dd, J=8.2, 7.6 Hz, 1H; CH, ar), 7.35 (dd, J=7.6, J=
0.6 Hz, 1H; CH, ar), 7.20 (dd, J=3.1, J=2.2 Hz, 1H; CH, ar), 6.64 (dd,
3J=8.2, J=0.6 Hz, 1H; CH, ar), 6.56–6.54 (m, 1H; CH, ar), 4.06 ppm (s,
3H; OCH3 Pyr); 13C{1H} NMR (125.77 MHz, CDCl3): d=163.7, 155.8,
139.2, 136.3, 133.3, 128.6, 125.6, 120.6, 118.9, 112.7, 109.6, 108.2, 102.6,
53.2 ppm; HRMS: m/z: calcd for C14H12N2O: 224.095; found: 224.09509.
6-o-Tolyl-1H-indole (Table 4, entry 12): 1H NMR (500 MHz, CDCl3): d=
8.01 (brs, 1H; NH), 7.63 (d, 3J=8.2 Hz, 1H; CH, ar), 7.29–7.19 (m, 5H;
CH, ar), 7.10–7.06 (m, 2H; CH, ar), 6.55–6.52 (m, 1H; CH, ar), 2.28 ppm
(s, 3H; CH3); 13C{1H} NMR (125.77 MHz, CDCl3): d=141.9, 134.9, 134.7,
CDCl3): d=147.6, 147.1, 139.6, 134.6, 134.0, 133.0, 127.2, 122.6, 119.8,
118.2, 109.8 ppm; 15N NMR (50.7 MHz, CDCl3): d=À 66.8, À206.9 ppm;
HRMS m/z calcd for C15H11N2: 220.1001; found: 220.10105.
6-p-Tolyl-9H-purine (Table 6, entry 1): 1H NMR (500 MHz, [D6]DMSO):
d=13.59 (brs, 1H; NH), 8.92 (s, 1H; ar (pos. 2)), 8.83–8.70 (brm, 2H; ar
(o-tol)), 8.61 (s, 1H; ar (pos. 8)), 7.39 (d, 3J=8.0 Hz, 2H; ar (m-tol)),
2.40 ppm (s, 3H; CH3); 13C{1H} NMR (125.75 MHz, [D6]DMSO): d=
153.7 (br), 152.5 (br), 152.2, 144.9 (br), 141.1, 133.3, 129.9 (br), 129.6 (4”
), 21.4 ppm; 15N NMR (50.69 MHz, [D6]DMSO): d=À223.1, À137.9,
À130.3, À112.3 ppm; HRMS: m/z: calcd for C12H10N4: 210.0906; found:
210.08788.
3
3
6-(3-Methoxyphenyl)-9H-purine (Table 6, entry 2): 1H NMR (500 MHz,
[D6]DMSO): d=13.40 (brs, 1H; NH), 8.96 (s, 1H; ar (pos. 2)), 8.65 (s,
4276
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4267 – 4279

Suzuki–Miyaura Coupling of Heterocyclic Substrates
FULL PAPER
3
1H; ar (pos. 8)), 8.52–8.35 (brm, 2H; (o-anis), 7.50 (t, J=8.2 Hz, 1H; ar
[12] C. B. Madsen-Duggan, J. S. Debenham, T. F. Walsh, R. B. Tou-
pence, S. X. Huang, J. Wang, X. Tong, J. Lao, T. M. Fong, M.-T.
Schaeffer, J. C. Xiao, C. R.-R. C. Huang, C.-P. Shen, D. S. Stribling,
L. P. Shearman, A. M. Strack, D. E. MacIntyre, L. H. T. van der
Ploeg, M. T. Goulet, Bioorg. Med. Chem. Lett. 2007, 17, 2031.
[13] B. L. Hodous, S. D. Geuns-Meyer, P. E. Hughes, B. K. Albrecht, S.
Bellon, J. Bready, S. Caenepeel, V. J. Cee, S. C. Chaffee, A. Coxon,
M. Emery, J. Fretland, P. Gallant, Y. Gu, D. Hoffman, R. E. John-
son, R. Kendall, J. L. Kim, A. M. Long, M. Morrison, P. R. Olivieri,
V. F. Patel, A. Polverino, P. Rose, P. Tempest, L. Wang, D. A. Whit-
tington, H. Zhao, J. Med. Chem. 2007, 50, 611.
3
(m-anis)), 7.14 (ddd, J=8.2, J=2.5, 0.9 Hz, 1H; ar (p-anis)), 3.87 ppm (s,
3H; OCH3); 13C{1H} NMR (125.75 MHz, [D6]DMSO): d=159.8, 154.1
(br), 152.1, 152.0 (br), 145.4 (br), 137.4, 130.2 (br), 130.0, 122.1, 117.0,
114.5, 55.5 ppm; 15N NMR (50.69 MHz, [D6]DMSO): d=À222.8, À138.0,
À128.3, À111.1 ppm; HRMS: m/z: calcd for C12H10N4O: 226.0855; found:
226.08501.
3-Thiophen-2-ylpyridine (Table 7, entry 2): 1H NMR (500 MHz, CDCl3):
d=8.89 (s, 1H; CH, ar), 8.52 (d, J=3.5 Hz, 1H; CH, ar), 7.86 (dt, 3J=
8.0, J=1.6 Hz, 1H; CH, ar), 7.36 (s, 1H; CH, ar), 7.35 (q, J=1.3 Hz, 1H;
CH, ar), 7.30 (dd, J=7.6, J=4.8 Hz, 1H; CH, ar), 7.12 ppm (dd, J=5.0,
J=3.8 Hz, 1H; CH, ar); 13C{1H} NMR (125.77 MHz, CDCl3): d=147.4,
146.0, 139.3, 132.1, 129.5, 127.3, 125.1, 123.2, 122.6 ppm; HRMS: m/z:
calcd for C9H7NS: 161.03; found: 161.02992.
3
3
[14] S. Gamsey, A. Miller, M. M. Olmstead, C. M. Beavers, L. C. Hir-
ayama, S. Pradhan, R. A. Wessling, B. Singaram, J. Am. Chem. Soc.
2007, 129, 1278.
[15] N. Leclerc, S. Sanaur, L. Galmiche, F. Mathevet, A.-J. Attias, J.-L.
Fave, J. Roussel, P. Hapiot, N. Lemaitre, B. Geffroy, Chem. Mater.
2005, 17, 502.
[16] L.-D. Cantin, S. Liang, H. Ogutu, C. I. Iwuagwu, K. Boakye, W. H.
Bullock, M. Burns, R. Clark, T. Claus, F. E. dela Cruz, M. Daly,
F. J. Ehrgott, J. S. Johnson, C. Keiper, J. N. Livingston, R. W.
Schoenleber, J. Shapiro, C. Town, L. Yang, M. Tsutsumi, X. Ma,
Bioorg. Med. Chem. Lett. 2007, 17, 1056.
[17] J. V. Wade, C. A. Krueger, J. Comb. Chem. 2003, 5, 267.
[18] W. Maes, W. Dehaen, Synlett 2003, 79.
[19] J. M. Large, M. Clarke, D. M. Williamson, E. McDonald, I. Collins,
Synlett 2006, 6, 861.
[20] T. T. Denton, X. Zhang, J. R. Cashman, J. Med. Chem. 2005, 48,
224.
[21] A. Tikad, S. Routier, M. Akssira, J.-M. Leger, C. Jarry, G. Guillau-
met, Org. Lett. 2007, 9, 4673.
[22] Z. Pei, X. Li, T. W. Von Geldern, K. Longenecker, D. Pireh, K. D.
Stewart, B. J. Backes, C. Lai, T. H. Lubben, S. J. Ballaron, D. W. A.
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Chem. 2007, 50, 1983.
2-Methyl-5-p-tolylbenzothiazole (Table 7, entry 3): 1H NMR (500 MHz,
CDCl3): d=8.15 (d, J=1.6 Hz, 1H; CH, ar), 7.84 (dd, J=8.2, J=0.6 Hz,
3
1H; CH, ar), 7.56 (ddd, 3J=10.0, 8.2, J=1.7 Hz, 1H; CH, ar), 7.55 (d,
3J=8.0 Hz, 2H; CH, ar), 7.28 (dt, 3J=7.9, J=0.6 Hz, 2H; CH, ar), 2.85
(s, 3H; SCCH3), 2.41 ppm (s, 3H; CH3-tolyl); 13C{1H} NMR
(125.77 MHz, CDCl3) d=166.5, 153.1, 138.5, 136.9, 136.2, 133.3, 128.6,
126.2, 123.0, 120.4, 119.5, 20.1, 19.2 ppm; 15N{1H} NMR (50.69 MHz,
CDCl3): d=À73.5 ppm; HRMS: m/z: calcd for C15H13NS: 239.0769;
found: 239.07605.
2-Methyl-5-pyridin-3-ylbenzothiazole
(Table 7,
entry 4):
1H NMR
3
(500 MHz, CDCl3): d=8.93 (d, J=2.2 Hz, 1H; CH, ar), 8.62 (dd, J=4.8,
J=1.6 Hz, 1H; CH, ar), 8.16 (d, J=1.6 Hz, 1H; CH, ar), 7.94 (ddd, 3J=
7.9, J=2.2, J=1.6 Hz, 1H; CH, ar), 7.92 (d, 3J=8.4 Hz, 1H; CH, ar),
7.57 (dd, 3J=8.4, J=1.9 Hz, 1H; CH, ar), 7.40 (ddd, 3J=7.9, J=4.8, J=
0.8 Hz, 1H; CH, ar), 2.87 ppm (s, 3H; SCCH3); 13C{1H} NMR
(125.77 MHz, CDCl3): d=167.1, 153.2, 147.6, 147.5, 135.3, 135.0, 134.5,
133.5, 122.9, 122.6, 121.0, 119.8, 19.2 ppm; 15N{1H} NMR (50.69 MHz,
CDCl3): d=À73.6, À67.2 ppm; HRMS: m/z: calcd for C13H10N2S:
226.0566; found: 226.05647.
[23] Q.-S. Guo, B. Liu, Y.-N. Lu, F.-Y. Jiang, H.-B. Song, J.-S. Li, Tetra-
hedron: Asymmetry 2005, 16, 3667.
´
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Acknowledgement
This work was supported by the DFG and Evonik Degussa, GmbH, Pro-
vadis Partner für Bildung und Beratung, GmbH, and C.A.F. by the Fonds
der Chemischen Industrie and the Studienstiftung des Deutschen Volkes
with a fellowship. Sabine Kraus and Walter Weigand of Elementar Ana-
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Published online: March 25, 2008
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