Three-component synthesis of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyridine derivatives and their palladium-catalyzed coupling reactions

Article abstract of DOI:10.1021/jo9022183

(Chemical Equation Presented) A three-component reaction with lithiated alkoxyallenes, nitriles, and perfluorinated carboxylic acids as precursors led to a series of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyridine derivatives. These compoun

Full text of DOI:10.1021/jo9022183

pubs.acs.org/joc
Three-Component Synthesis of Perfluoroalkyl- or
Perfluoroaryl-Substituted 4-Hydroxypyridine Derivatives
and Their Palladium-Catalyzed Coupling Reactions
Tilman Lechel,† Jyotirmayee Dash,†,‡ Paul Hommes,† Dieter Lentz,† and
Hans-Ulrich Reissig*,†
†
€
Institut fu€r Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany, and
‡Indian Institute of Science, Education and Research Kolkata, Mohanpur Campus, Mohanpur 741252,
Nadia, West Bengal, India
hans.reissig@chemie.fu-berlin.de
Received October 16, 2009
A three-component reaction with lithiated alkoxyallenes, nitriles, and perfluorinated carboxylic
acids as precursors led to a series of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyr-
idine derivatives. These compounds were converted into 4-pyridyl nonaflates which can be
employed as versatile building blocks for the synthesis of π-conjugated compounds with use of
palladium-catalyzed couplings. Suzuki reactions at C-4 and C-3 of the pyridine ring proceeded
with moderate to high yields. In addition, Suzuki-Miyaura, Stille, or Buchwald-Hartwig
coupling reactions have also been studied and afforded the corresponding highly substituted
pyridine derivatives. Starting from an arylated propargylic ether the three-component reac-
tion led to a pentasubstituted 4-hydroxypyridine derivative that could also be employed in
palladium-catalyzed processes at C-4 and at C-3 of the pyridine core. With this simple approach
the sterically highly crowded 3,4,5-triphenyl-substituted pyridine derivative 37a could be
prepared and studied by an X-ray analysis. With acetonitrile as precursor a different reaction
pathway was found when this component was used in excess resulting in a pyridine derivative with
a new substitution pattern. In summary, the methods described here allow a flexible and fairly
efficient entry to a variety of highly substituted pyridine derivatives bearing perfluorinated alkyl
or aryl groups.
Introduction
science, agrochemicals, and pharmaceuticals.1,2 We have
recently discovered a novel and efficient three-component
reaction for the preparation of highly substituted 4-hydroxy-
6-(trifluoromethyl)pyridines 3 (Scheme 1).3 The addition of
an excess of lithiated alkoxyallenes 1 to nitriles, followed by
quenching with an excess of trifluoroacetic acid (TFA)
furnished enamides 2 together with 4-hydroxypyridines 3.
Full conversion to the desired pyridine derivatives 3 can
be accomplished by subjecting the enamide intermediates
2 to an intramolecular aldol-type condensation with
The development of efficient methods for the synthesis of
fluorinated compounds is an area of strong interest because
of the great importance of these products in bioorganic,
medicinal, and synthetic chemistry.1,2 The incorporation of
perfluoroalkyl groups into organic molecules often induces a
dramatic influence on the physical, chemical, and biological
properties. For this reason an increasing number of organo-
fluorine compounds find diverse applications in material
726 J. Org. Chem. 2010, 75, 726–732
Published on Web 12/23/2009
DOI: 10.1021/jo9022183
r
2009 American Chemical Society

Lechel et al.
JOCArticle
SCHEME 1. General Route to 4-Hydroxy-6-(trifluoromethyl)-
pyridine Derivatives 3
as the reagent to incorporate the CF3 group and lithiated
alkoxyallenes are employed as crucial C-3 building
blocks.6,7
The unique mechanism of this three-component reac-
tion is depicted in an abbreviated version in Scheme 2; it
has already been described in earlier publications in more
detail.3,7a The first step is the formation of an allenyl
imine 4 resulting from the addition of lithiated alkoxyal-
lene 1 to the nitrile carbon. Upon treatment with an ex-
cess of trifluoroacetic acid the protonated species of 4
is attacked by the carboxylate at the central allene
carbon to form intermediate 5. A subsequent acyl transfer
gives the enamide 2. A partial acid-catalyzed aldol-type
condensation of enamide 2 affords pyridin-4-one 6,
which is in equilibrium with its tautomeric 4-hydroxpyri-
dine 3. In most cases of this report the 4-hydroxypyridine
tautomer is the predominant form (in CDCl3 at room
temperature).
trimethylsilyl triflate and triethylamine as reagents.
Although they constitute an important class of ring systems
found in numerous drugs and pharmaceuticals there are only
a restricted number of reports concerning the synthesis of
trifluoromethylated heteroaromatic compounds.4,5 Signifi-
cantly, synthetic methods efficiently leading to trifluoro-
methyl-substituted pyridines2,4 commence from pyridyl
precursors and approaches from nonpyridine precursors
are inherently limited. In this regard, our method offers
a new and significant application wherein TFA is used
SCHEME 2. Proposed Mechanism for the Formation of En-
amide 2 and 4-Hydroxypyridine 3
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Eds.; John Wiley & Sons: New York, 1991. (b) Biochemical Frontiers of
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The 4-hydroxy and the 3-alkoxy group of pyridine deri-
vatives 3 offer a range of opportunities for subsequent syn-
thetic manipulation and diverse functionalizations. Pyridine
derivatives such as 8 should be accessible by palladium-
catalyzed coupling reactions of the corresponding nonaflates
7 (Scheme 3).
€
€
(3) (a) Flogel, O.; Dash, J.; Brudgam, I.; Hartl, H.; Reissig, H.-U.
SCHEME 3. Subsequent Palladium-Catalyzed Coupling Reac-
tions of 4-Pyridyl Nonaflates 7
€
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5544. (d) Lechel, T.; Dash, J.; Reissig, H.-U. Eur. J. Org. Chem. 2008, 3647–
3655. (e) Synthesis of chiral pyridine derivatives: Eidamshaus, C.; Reissig, H.-U.
Adv. Synth. Catal. 2009, 351, 1162–1166.
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(a) Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem.
2003, 1559–1568. (b) Usachev, B.; Sizov, A. Y.; Vorontsov, I. I.; Shkiyaev, Y.
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Krotko, D. G.; Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531–1540. (d) Sandford, G.; Wilson, I.; Timperley, C. M. J.
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€
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(a) Zimmer, R. Synthesis 1993, 165–178. (b) Zimmer, R.; Khan, F. A. J.
Prakt. Chem. 1996, 338, 92–94. (c) Reissig, H.-U.; Schade, W.; Okala
Amombo, M. G.; Pulz, R.; Hausherr, A. Pure Appl. Chem. 2002, 74, 175–
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45–56. (e) Pfrengle, F.; Reissig, H.-U. Chem. Soc. Rev. 2010, 38, DOI 10.1039/
b914356. (f) Lechel, T.; Reissig, H.-U. Pure Appl. Chem. 2010, in print. For
selected recent applications developed by our group see: (g) Kaden, S.; Reissig,
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H.; Figuera-Perez, S.; Thutewohl, M.; Paulsen, H.; Kroh, W.; Klewer, D.
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15, 6811-6814 and references cited therein.
(5) (a) Donohue, B. A.; Michelotti, E. L.; Reader, J. C.; Reader, V.;
Stirling, M.; Tice, C. M. J. Comb. Chem. 2002, 4, 23–32. (b) Sosnovskikh, V.
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Int. Ed. 2005, 44, 214-231.
€
H.-U. Org. Lett. 2006, 8, 4763–4766. (h) Sorgel, S.; Azap, C.; Reissig, H.-U.
Org. Lett. 2006, 8, 4875–4878. (i) Pfrengle, F.; Lentz, D.; Reissig, H.-U. Angew.
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(7) For recent applications of enamides in the synthesis of highly func-
€
tionalized pyrimidines or oxazoles, see: (a) Lechel, T.; Mohl, S.; Reissig, H.-
U. Synlett 2009, 1059–1062. (b) Lechel, T.; Lentz, D.; Reissig, H.-U. Chem.;
Eur. J. 2009, 15, 5432–5435.
J. Org. Chem. Vol. 75, No. 3, 2010 727

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JOCArticle
The generality of heteroaryl nonaflates8,9 as halide or
triflate equivalents in cross coupling reactions has been
scarcely studied compared to alkenyl or aryl fluoroalkylsul-
fonates.10,11 As a first demonstration of this option we have
recently reported that the 4-pyridyl nonaflates 19a-c could
efficiently be employed in palladium-catalyzed Sonogashira
reactions with alkynes and Suzuki couplings with arylboro-
nic acids.3 In continuation of our interest in nonaflate
chemistry,11 we now describe our results with substituted
4-pyridyl nonaflate derivatives9 and the reactivity of these
pseudohalide electrophiles in Suzuki reactions12 and related
processes. Moreover, recent advances in polymer and
organic-based electrooptic devices, such as light-emitting
diodes13 and field-effect transistors,14 encouraged us to
exploit these derivatives as possible precursors in the synth-
esis of novel π-conjugated heteroaromatic compounds.
There are reports on electronic systems based on hetero-
cycles with a (trifluoromethyl)aryl group.15 It is also known
that an enhancement of photophysical properties16 of com-
pounds may occur upon introduction of fluorine. Therefore,
we envisioned that extended π-systems equipped with tri-
fluoromethylated pyridine groups would also be interesting
building blocks for the synthesis of functional materials.
In this report we describe for the first time the scope
and limitations of the three-component synthesis of 6-per-
fluoroalkyl- or 6-perfluoroaryl-substituted 4-hydroxypyri-
dines and 4-pyridyl nonaflates in full detail. We also
demonstrate that our approach allows the preparation of
pentasubstituted pyridine derivatives. Representative palla-
dium-catalyzed couplings either at 4- or 3-position, including
examples under formation of C-S or C-N bonds, lead to a
variety of new fluorinated heterocycles.
Results and Discussion
Following the reaction conditions briefly described in the
Introduction a variety of 4-hydroxypyridine derivatives
could be prepared. Table 1 demonstrates that different
alkoxyallenes such as benzyloxyallene, methoxyallene, or
even the acid labile (2-trimethylsilyl)ethoxyallene are suita-
ble precursors for the synthesis of highly substituted
4-hydroxypyridines 9a-j. A broad range of nitriles
(aliphatic, functionalized aliphatic, aromatic, or hetero-
aromatic) can successfully be used in this reaction introdu-
cing different substituents R2. With respect to carboxylic
acids, trifluoroacetic acid, perfluorooctanoic acid, and
perfluorobenzoic acid were employed to provide perfluori-
nated substituents R3. With this standard procedure the
yields of the corresponding 4-hydroxypyridines are often
only moderate after two steps, but the simplicity of the
procedure compensates for the moderate efficacy in many
examples.
TABLE 1. Synthesis of 6-Perfluoroalkyl- and 6-Perfluorophenyl-Sub-
stituted 4-Hydroxypyridines 9
(8) For cross coupling reactions of heteroaryl perfluoroalkylsulfonates,
see: (a) Oxazole and thiazole triflates: Langille, N. F.; Dakin, L. A.; Panek, J.
S. Org. Lett. 2002, 4, 2485–2488. (b) Pyrazole triflates: Bourrain, S.; Ridgill,
M.; Collins, I. Synlett 2004, 795–798. (c) Dvorak, C. A.; Rudolph, D. A.; Ma,
S.; Carruthers, N. I. J. Org. Chem. 2005, 70, 4188–4190.
entry
R1
R2
R3
9, yield [%]
(9) For rare examples of applications of pyridyl triflate or nonaflate, see:
(a) Khatyr, A.; Ziessel, R. J. Org. Chem. 2000, 65, 3126–31234. (b) Seganish,
W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137–1143. (c) Tundel, R. E.;
Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2006, 71, 430–433.
(10) (a) For a review on triflates see: Ritter, K. Synthesis 1993, 735–762.
(b) For palladium-catalyzed cross coupling reactions of aryl and alkenyl
nonaflates or related perfluoroalkylsulfonates, see: Chen, Q.-U.; Yang,
1
2
3
4
5
6
7
8
9
10
Bn
TMSE
3-MeOC6H4CH2
Bn
Me
Me
Me
Me
Me
Me
tBu
tBu
tBu
Me
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C6F5
C7F15
9a, 50
9b, 42
9c, 37
9d, 43
9e, 37
9f, 32
9g, 67
9h, 23
9i, 43
9j, 27
(CH2)3CHdCH2
2-Thienyl
CMe2OH
tBu
€
Z.-Y. Tetrahedron Lett. 1986, 27, 1171–1174. (c) Brase, S.; de Meijere, A.
Angew. Chem. 1995, 107, 2741–2743. Angew. Chem., Int. Ed. Engl. 1995, 34,
2545-2547. (d) Voigt, K.; Zezschwitz, P.; Rosauer, K.; Lansky, A.; Adams,
A.; Reiser, O.; de Meijere, A. Eur. J. Org. Chem. 1998, 1521–1534. (e)
€
€
Rottlander, M.; Knochel, P. J. Org. Chem. 1998, 63, 203–208. (f) Brase, S.
Synlett 1999, 1654–1656. (g) Kwong, F. Y.; Lai, C. W.; Chan, K. S. J. Am.
Chem. Soc. 2001, 123, 8864–8865. (h) Denmark, S. E.; Sweis, R. F. Org. Lett.
2002, 4, 3771–3774. (i) Anderson, K. W.; Mendez-Perez, M.; Priego, J.;
Buchwald, S. L. J. Org. Chem. 2003, 68, 9563–9573. (j) Zhang, W.; Chen, C.
H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473–1476.
tBu
In general, this method can also be performed with only
1 equiv of lithiated alkoxyallene and an excess of nitrile.
In most cases the yields do not dramatically differ between
these two protocols. However, for R-acidic nitriles such
as acetonitrile a surprising outcome was observed as
illustrated in Scheme 4 (for the “normal” conditions see
Table 1, entries 4 and 5). Here the modified reaction condi-
tions did not lead to the desired mixture of enamide 11 and
4-hydroxypyridine 9d but to a completely different pyridine
(11) Alkenyl nonaflates as partners in palladium-catalyzed reactions: (a)
€
Webel, M.; Reissig, H.-U. Synlett 1997, 1141–1142. (b) Hogermeier, J.;
Reissig, H.-U. Chem.;Eur. J. 2007, 13, 2410–2420. (c) Recent review:
€
Hogermeier, J.; Reissig, H.-U. Adv. Synth. Catal. Accepted for publication.
(12) (a) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457–2483. (b)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2. (c) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147–168.
(13) For reviews on light emitting organic materials, see: (a) Kim, D. Y.;
Cho, H. N.; Kim, C. Y. Prog. Polym. Sci. 2000, 25, 1089–1139. (b) Chen,
C.-T. Chem. Mater. 2004, 16, 4389–4400. (c) Tang, C. W.; VanSlyke, S. A.
Appl. Phys. Lett. 1987, 51, 913–915. (d) Kraft, A.; Grimsdale, A. C.; Holmes,
A. B. Angew. Chem. 1998, 110, 416–443. Angew. Chem., Int. Ed. 1998, 37,
402-428.
SCHEME 4. Formation of Pyridine Derivative 12 with an Ex-
cess of Acetonitrile
(14) For reviews on organic field-effect transistors, see: (a) Dimitrako-
poulos, C. D.; Malenfant, P. R. L. Adv. Mater. 2002, 14, 99–117. (b) Qiu, Y.;
Hu, Y.; Dong, G.; Wang, L.; Xie, J.; Ma, Y. Appl. Phys. Lett. 2003, 83, 1644–
1646. (c) Pannemann, Ch.; Diekmann, T.; Hilleringmann, U. J. Mater. Res.
2004, 19, 1999–2002.
(15) Ando, S.; Nishida, J.-i.; Tada, H.; Inoue, Y.; Tokito, S.; Yamashita,
Y. J. Am. Chem. Soc. 2005, 127, 5336–5337.
(16) Krebs, F. C.; Spanggaard, H. J. Org. Chem. 2002, 67, 7185–7192.
728 J. Org. Chem. Vol. 75, No. 3, 2010

Lechel et al.
JOCArticle
SCHEME 5. Proposed Mechanism of the Formation of Pyridine Derivative 12
derivative 12 and only 5% of 11. The X-ray analysis
of pyridine derivative 12 proves its constitution (see the
Supporting Information).17 Regarding the substitution
pattern it is obvious that 12 consists of one alkoxyallene unit
and three acetonitrile moieties without incorporation of the
carboxylic acid (Scheme 4).18
TABLE 2. Direct Synthesis of Perfluoroalkyl- and Perfluorophenyl-
Substituted 4-Pyridyl Nonaflates 19
A plausible mechanism of this newly detected transforma-
tion is depicted in Scheme 5. As for the standard pathway,
acetonitrile acts as an electrophile and adds to the lithiated
alkoxyallene to furnish lithiated allenyl imine 13 (Scheme 5).
Due to the present excess of acetonitrile this species
then attacks again an acetonitrile molecule to give inter-
mediate 14, which may subsequently deprotonate a third
acetonitrile molecule. Alternatively, lithiated alkoxyallene
may also directly deprotonate acetonitrile. The generated
acetonitrile anion then adds to the central carbon of the
allenyl system to give anion 15, which can also be represented
by its mesomeric formula 150. After proton migration to
intermediate 16 and cyclization to 17 a protonation by
TFA occurs under the release of ammonia leading to the
aromatic heterocycle 12. The moderate yields for 4-hydro-
xypyridines 9, in particular for nitriles with small and/or
R-acidic substituents (Table 1), may be due to similar side
reactions as involved in the multistep mechanism leading to
compound 12.
entry
R1
Bn
R2
R3
19, yield [%]a
1
2
3
4
5
6
7
8
tBu
tBu
tBu
cPr
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CHF2
C6F5
19a, 37
19b, 30
19c, 623a
19d, 38
19e, 48
19f, 51
19g, 26
19h, 41
TMSE
Me
Me
Me
Me
nOct
tBu
tBu
Me
Me
aOverall yields for three steps.
TABLE 3. Suzuki Couplings of 4-Pyridyl Nonaflates 19 with Different
Arylboronic Acids Leading to 4-Arylpyridine Derivatives 20
For the planned palladium-catalyzed reactions the re-
quired 4-pyridyl nonaflates were prepared in high yields by
subjecting the 4-hydroxypyridine derivatives 9 to sodium
hydride in the presence of commercially available nonafluoro-
butanesulfonyl fluoride (NfF).11 Owing to their numerous
potential applications we tried to simplify the preparation of
the fairly stable 4-pyridyl nonaflates (Table 2). The crude
reaction mixture at the 4-hydroxypyridine stage was directly
used for the next step and gratifyingly nonaflates 19a-h were
isolated after column chromatography on silica gel in gram
scale with moderate to good overall yields (26-62%, based on
the corresponding alkoxyallenes 1 or nitriles).
entry
R1
Me
R2
R3
t [h]
20, yield [%]
1
2
3
4
5
6
tBu
Ph
4-NC-C6H4
4-MeO-C6H4
Ph
8
4
4
2
2
8
20a, 81
20b, 74
20c, 69
20d, 99
20e, 60
20f, 88
Me
TMSE
Bn
Bn
tBu
tBu
tBu
tBu
Ph
4-MeO-C6H4
trans-2-styryl
Me
The Suzuki couplings12 of nonaflates 19a-c with aryl
boronic acids were carried out with use of a catalytic system
consisting of Pd(OAc)2/PPh3 and K2CO3 in DMF at 70 °C to
provide heterobiaryl scaffolds. The corresponding 4-aryl-
substituted pyridine derivatives 20a-f were obtained in good
to excellent yields (60-99%, Table 3).
We also examined the applicability of the 4-pyridyl non-
aflates as coupling partners in other palladium-catalyzed
processes such as Stille,19 Buchwald-Hartwig,20 and
(17) CCDC-750423 (for 12) and CCDC-750424 (for 37a) contain the
supplementary crystallographic data. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
(18) For a related process with incorporation of two arylnitrile units
leading to pyrimidines, see: Blangetti, M.; Deagostino, A.; Prandi, C.;
Zavattaro, C.; Venturello, P. Chem. Commun. 2008, 1689–1691.
J. Org. Chem. Vol. 75, No. 3, 2010 729

Lechel et al.
JOCArticle
SCHEME 6. Palladium-Catalyzed C-C, C-S, and C-N Couplings of 4-Pyridyl Nonaflates 19b,c
SCHEME 7. Three-Component Synthesis of 5-Substituted Pyridine Derivatives 28, 29, and 30 Starting from γ-Substituted Propargylic Ether 25
Miyaura21 reactions (Scheme 6). The Stille coupling
was performed by treating nonaflate 19c and tributyl(trifluoro-
vinyl)stannane22 with Pd(OAc)2, PPh3 in DMF at 50 °C
for 1 day to furnish compound 21 bearing two perfluori-
nated substituents. A C-S cross coupling with nonaflate 19c
and thiophenol was achieved to give compound 22 with
microwave conditions developed by Zhang.23 The C-N
cross coupling with aniline to 23 was performed under slightly
modified conditions as reported by Buchwald.9c In this
case a weaker base such as triethylamine has been used
instead of DBU. The homocoupling of 19c with bis-
(pinacolato)diborane21 gave the desired highly substituted
symmetric 4,40-bipyridine derivative 24. All products 21-24
could be obtained in good to high yields (73-93%).
The examples of Table 3 and Scheme 6 demonstrate that
the 4-pyridyl nonaflates introduced in this study are very
suitable coupling partners and that a variety of interestingly
substituted heterocyclic compounds should be available
with these methods.
To extend the aromatic π-system at C-5 of the result-
ing pyridine core we developed a simple route starting
from a terminally substituted propargylic ether such as 25
(Scheme 7). The corresponding enamide 27 was obtained
under standard conditions via base induced isomerization of
alkyne 25 to lithiated allene 26. Enamide 27 was then
subjected to the general cyclization-nonaflation conditions
to give 4-pyridyl nonaflate 29. Finally, the Suzuki coupling
reaction with phenylboronic acid afforded the pentasubsti-
tuted pyridine derivative 30.
The alkoxy group at C-3 of 4-hydroxypyridine derivatives
or their subsequent products constitutes an ideal tool for
additional modifications at the pyridine ring. A third exten-
sion of the π-system could be easily achieved by deprotection
of the 3-alkoxy group followed by nonaflation of the free
hydroxy group and subsequent palladium-catalyzed cou-
plings (Scheme 8). The benzyl group of 20d could be cleaved
by using a mixture of TFA and 1,2-dichloroethane at 80 °C. The
deprotection of methoxy-substituted pyridine 30 was carried
out by treatment with trimethylsilyl iodide in 1,2-dichloro-
ethane at 80 °C. The corresponding 3-hydroxypyridines 31
and 32 were subsequently converted into nonaflates 33 and 34
(19) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 1636–1638.
(b) Milstein, D.; Stille, J. K. J. Org. Chem. 1979, 44, 1613–1616.
(20) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805–818. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31,
852–860.
(21) (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447–3450. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura,
N. J. Am. Chem. Soc. 2002, 124, 8001–8006.
(22) Akkermann, F. A.; Kickbusch, R.; Lentz, D. Chem. Asian J. 2008, 3,
719–731.
(23) Lu, Y.; Chen, C. H.-T.; Zhang, W. Mol. Diversity 2003, 7, 199–202.
730 J. Org. Chem. Vol. 75, No. 3, 2010

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JOCArticle
SCHEME 8. Modifications at C-3 of Pyridines: Synthesis of Di-
Experimental Section
and Triphenyl-Substituted Pyridine Derivatives 35, 36, and 37aa
Typical Procedure for Preparation of 4-Hydroxypyridines: 3-
Methoxy-2-(thiophen-2-yl)-6-(trifluoromethyl)pyridin-4-ol (9g).
Methoxyallene (0.69 mL, 8.30 mmol) was dissolved in diethyl
ether (17 mL) and n-butyllithium (2.76 mL, 6.90 mmol, 2.5 M in
hexanes) was added at -40 °C. After 25 min at -50 to -40 °C
the solution was cooled to -78 °C and thiophene-2-carbonitrile
(0.235 mL, 2.50 mmol) was added. After the solution was stirred
for 4 h at this temperature trifluoroacetic acid (1.21 mL, 16.4
mmol) was added and the mixture was warmed overnight to
room temperature. Then the reaction mixture was quenched
with satd aq NaHCO3 solution (15 mL) and extracted with
dichloromethane (3 ꢀ 15 mL). The combined organic phases
were dried with Na2SO4 and then evaporated. The residue was
dissolved in dichloromethane (25 mL) and treated at 0 °C with
triethylamine (1.05 mL, 7.50 mmol) and trimethylsilyl triflate
(1.45 mL, 7.50 mmol). The mixture was heated under reflux for 3
d and then quenched at room temperature with satd aq NH4Cl
solution (15 mL) and extracted with dichloromethane (3 ꢀ 10
mL), then the combined organic phases were evaporated to
provide the crude product. The resulting crude product was
dissolved again in dichloromethane (20 mL) and treated first
with TFA (0.08 mL, 1 mmol) and then with water (20 mL). Next
it was extracted with dichloromethane (3 ꢀ 5 mL) and the
combined organic extracts were dried with Na2SO4 and con-
centrated to dryness. The residue was purified by chromato-
graphy on silica gel (hexane/ethyl acetate = 1:1) to afford
aReagents and conditinos: (a) TFA, 1,2-C2H4Cl2, 80 °C, sealed tube; (b)
TMSI, 1,2-C2H4Cl2, 80 °C, sealed tube; (c) Suzuki reaction: PhB(OH)2,
Pd(OAc)2, PPh3, iPr2NH, DMF, 70 °C; (d) Sonogashira reaction:
phenylacetylene, Pd(OAc)2, PPh3, CuI, DMF, 70 °C.
under standard conditions, which were then subjected to the
final palladium-catalyzed couplings. Suzuki and Sonogashira
reactions of nonaflate 33 gave the expected products 35 and 36
in moderate to good yields. Applying Suzuki cross coupling to
34 with phenyl boronic acid gave the desired 3,4,5-triphenyl-
substituted pyridine 37a together with reduction product 37b.
The X-ray analysis of pyridine derivative 37a proves the con-
stitution and shows interesting structural features (see the
Supporting Information).17 Quite remarkably, the C-4 phenyl
group is arranged almost perpendicular to the pyridine core,
while in a compound like hexaphenylbenzene (HPB)24a inter-
planar angles between 62° and 71° only are observed. Further-
more, the 1H NMR spectra of 37a show a high field shift of two
phenyl protons to 6.62 ppm, which is slightly stronger than in
HPB24b that only shows a signal at 6.84 ppm. This observation
might be directly traced back to a higher shielding effect of the
perpendicularly arranged C-4 phenyl group to its neighbor
phenyl groups.
1
460 mg (67%) of 9g as a brownish viscous liquid. H NMR
(CDCl3, 500 MHz): δ 3.83 (s, 3 H, OMe), 7.13 (s, 1 H, 5-H), 7.14
(dd, J = 5.1, 3.7 Hz, 1 H, 40-H), 7.46 (dd, J = 5.0, 1.1 Hz, 1 H, 30-
H), 7.93 (dd, J = 3.7, 1.1 Hz, 1 H, 50-H) ppm. OH could not be
detected. 13C NMR (CDCl3, 126 MHz): δ 60.6, 107.7 (q, 3JCF
=
2.7 Hz), 122.2 (q, JCF = 274 Hz), 127.9, 128.9, 129.2, 139.0,
1
2
142.1, 144.1 (q, JCF = 34.1 Hz), 146.8, 157.4 ppm. IR (film):
ν 3440-3400 (O;H), 3100 (dC;H), 2940, 2840 (C-H),
1600-1580 (CdC) cm-1. MS (EI): m/z (%) 275 (1) [M]þ, 232
(100), 77 (52), 43 (13). HRMS (EI): calcd for C11H8F3NO2S
275.02280, found 275.02355.
Typical Procedure for One-Pot Preparation of 4-Pyridinyl
Nonaflates: 2-Cyclopropyl-3-methoxy-6-(trifluoromethyl)pyri-
din-4-yl nonaflate (19d). Methoxyallene (900 mg, 12.9 mmol) was
dissolved in diethyl ether (25 mL) and n-butyllithium (4.63 mL,
11.6 mmol, 2.5 M in hexanes) was added at -40 °C. After 25 min
at -50 to -40 °C the solution was cooled to -78 °C and
cyclopropylnitrile (0.32 mL, 4.29 mmol) was added. After the
solution was stirred for 4 h at this temperature trifluoroacetic acid
(1.98 mL, 25.7 mmol) was added and the mixture was warmed
overnight to room temperature. The reaction mixture was then
quenched with satd aq NaHCO3 solution (20 mL) and extracted
with dichloromethane (3 ꢀ 25 mL). The combined organic phases
were dried with Na2SO4 and then evaporated. The residue was
dissolved in dichloromethane (25 mL) and treated at 0 °C with
triethylamine (1.80 mL, 12.9 mmol) and trimethylsilyl triflate
(2.48 mL, 12.9 mmol). The mixture was heated under reflux for
3 d and then quenched at room temperature with satd aq NH4Cl
solution (20 mL), extracted with dichloromethane (3 ꢀ 25 mL),
dried with Na2SO4, and evaporated to provide the crude product.
The resulting crude product was dissolved in THF (25 mL) and
NaH (514 mg, 60% in mineral oil, 12.9 mmol) was added under an
argon atmosphere. Nonafluorobutanesulfonyl fluoride (2.31 mL,
12.9 mmol) was added dropwise at room temperature. The mixture
was stirred at room temperature overnight and quenched by slow
addition of methanol and water. It was then extracted with ethyl
acetate (3 ꢀ 25 mL), dried with Na2SO4, and concentrated to
dryness. The residue was purified by chromatography on silica gel
(hexane/ethyl acetate = 10:1) to afford 832 mg (38%) of 19d as a
light yellow oil. 1H NMR (CDCl3, 500 MHz): δ 1.11-1.14,
Conclusions
In summary, highly flexible synthetic routes leading to
various tetra- or penta-substituted 6-perfluoroalkyl- or
6-perfluorophenyl-substituted 4-hydroxypyridine deriva-
tives have been developed. The three-component synthesis
employing fluorinated carboxylic acids as one key compo-
nent combined with palladium-catalyzed processes allows
the introduction of a broad range of substituents at the
pyridine ring. If acetonitrile is used as electrophile an excess
of this component leads to a different mechanism and the
predominating formation of a 3-cyanopyridine derivative
was observed. Trifluoromethyl-substituted 4-pyridyl nona-
fluorobutanesulfonates were found to be excellent substrates
for diverse palladium-catalyzed coupling reactions. We have
hence established a rapid, flexible, and efficient access to 3,4-
di- and 3,4,5-triaryl-substituted pyridines bearing perfluor-
oalkyl or perfluoraryl groups at C-6.
(24) (a) Bart, J. C. Acta Crystallogr. 1968, B24, 1277–1287. (b) Komber,
H.; Stumpe, K.; Voit, B. Macromol. Chem. Phys. 2006, 207, 1814–1824.
J. Org. Chem. Vol. 75, No. 3, 2010 731

Lechel et al.
JOCArticle
1.19-1.23 (2 m, 2 H each, 20-H, 30-H), 2.45 (mc, 1 H, 10-H), 4.01 (s,
3 H, OMe), 7.28 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3, 126 MHz):
δ 11.4, 11.8, 62.2, 111.2 (q, 3JCF = 2.8 Hz), 120.6 (q, 1JCF = 274
Hz), 144.1 (q, 2JCF = 36.2 Hz), 148.1, 148.5, 162.1 ppm. 19F NMR
(CDCl3, 470 MHz): δ -68.0 (s, CF3), -80.6, -109.0, -120.6,
-125.6 (4 m, ONf) ppm. IR (film): ν 3095-3005 (dC;H),
2950-2840 (C-H), 1745-1595 (CdC) cm-1. HRMS (ESI-TOF):
calcd for C14H10F12NO4S [MH]þ 516.0134, found 516.0135.
Typical Procedure for Suzuki Coupling Reaction: 2-tert-Butyl-
3-(benzyloxy)-4-phenyl-6-(trifluoromethyl)pyridine (20d). A mix-
ture of 4-pyridyl nonaflate 19a (120 mg, 0.198 mmol), phenyl
boronic acid (35 mg, 0.287 mmol), Pd(OAc)2 (2.2 mg, 0.010
mmol), PPh3 (10 mg, 0.039 mmol), and K2CO3 (27 mg, 0.195
mmol) in DMF (2 mL) was heatedto 70 °C for 2 h under anargon
atmosphere. The mixture was allowed to cool to room tempera-
ture and diluted with water (5 mL) and extracted with diethyl
ether (3 ꢀ 5 mL). The combined organic phase was dried with
Na2SO4 and concentrated to dryness. The residue was purified by
chromatography on silica gel (hexane/ethyl acetate = 40:1) to
give 76 mg (99%) of 20d as a colorless solid. Mp 57 °C. 1H NMR
(CDCl3, 500 MHz): δ 1.48 (s, 9 H, t-Bu), 4.48 (s, 2 H, 10-H),
7.08-7.62 (m, 10 H, Ph), 7.52 (s, 1 H, 5-H) ppm. 13C NMR
(CDCl3, 126 MHz): δ 29.4, 38.6, 74.5, 121.0 (q, 3JCF = 2.9 Hz),
121.8 (q, 1JCF = 274 Hz), 127.7, 128.0, 128.3, 128.5, 128.9, 129.0,
136.2, 136.4, 141.0 (q, 2JCF = 34.4 Hz), 143.2, 153.6, 163.2 ppm.
2 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ 28.9, 39.1, 62.0,
113.1 (q, 3JCF = 2.8 Hz), 120.7 (q, 1JCF = 274 Hz), 127.1, 127.5,
129.1, 130.2, 137.0, 142.1 (q, 2JCF = 35.9 Hz), 149.5, 166.3 ppm.
IR (KBr):
1590-1570 (CdC) cm-1
ν 3070-3050 (dC;H), 2960-2870 (C;H),
. HRMS (ESI-TOF): calcd for
C17H18F3NOS [MH]þ 342.1134, found 342.1147.
Preparation of 2-tert-Butyl-N-phenyl-6-(trifluoromethyl)-
3-[2-(trimethylsilyl)ethoxy]pyridin-4-amine (23). A mixture of
4-pyridyl nonaflate 19b (227 mg, 0.368 mmol), Pd2(dba)3 (6.7
mg, 0.007 mmol), XPhos (14 mg, 0.029 mmol), aniline (0.47 mL,
0.478 mmol), and Et3N (0.13 mL, 1.01 mmol) in toluene (1.4
mL) was heated in an ACE-sealed tube to 140 °C for 10 min
under an argon atmosphere. The mixture was allowed to cool to
room temperature, diluted with brine (3 mL), and extracted with
diethyl ether (3 ꢀ 5 mL). The combined organic phase was dried
with Na2SO4 and concentrated to dryness. The residue
was purified by chromatography on silica gel (hexane/ethyl
acetate = 10:1) to give 124 mg (82%) of 23 as a colorless oil.
1H NMR (CDCl3, 700 MHz): δ 0.05 (s, 9 H, TMS), 1.26 (mc, 2
H, 20-H), 1.45 (s, 9 H, t-Bu), 4.00 (mc, 2 H, 10-H), 6.34 (sbr, 1 H,
NH), 7.28 (s, 1 H, 5-H), 7.15-7.19, 7.39-7.42 (2 m, 3 H, 2 H, Ph)
ppm. 13C NMR (CDCl3, 176 MHz): δ -1.4, 19.1, 29.8, 38.2,
70.5, 103.6 (q, 3JCF = 2.5 Hz), 121.7 (q, 1JCF = 274 Hz), 121.7,
2
124.4, 129.8, 143.4, 139.5, 142.1 (q, JCF = 33.9 Hz), 145.6,
161.0 ppm. IR (film): ν 3410 (N;H), 3060-2870 (dC;H, C;
H), 1590-1580 (CdC) cm-1. HRMS (ESI-TOF): calcd for
C21H29F3N2OSi [MH]þ 411.2074, found 411.2092.
IR (KBr):
ν 3090-3040 (dC;H), 3000-2875 (C;H),
1600-1550 (CdC) cm-1. MS (EI): m/z (%) 385 (11) [M]þ, 91
(100). C23H22F3NO (385.4) calcd for C 71.67, H 5.75, N 3.63,
found C 71.73, H 5.59, N 3.68.
Preparation of 2,20-Di-tert-butyl-3,30-dimethoxy-6,60-bis-
(trifluoromethyl)-4,40-bipyridine (24). A mixture of 4-pyridyl
nonaflate 19c (245 mg, 0.461 mmol), PdCl2(dppf) (30 mg,
0.026 mmol), B2Pin2 (59 mg, 0.232 mmol), and K2CO3 (191
mg, 1.38 mmol) in dioxane (3 mL) was heated to 80 °C for 1 d
under an argon atmosphere. The mixture was allowed to cool to
room temperature, diluted with brine (4 mL), and extracted with
dichloromethane (3 ꢀ 5 mL). The combined organic phase was
dried with Na2SO4 and concentrated to dryness. The residue was
purified by chromatography on silica gel (hexane/ethyl
acetate = 40:1) to give 100 mg (93%) of 24 as a colorless solid.
Mp 118-120 °C. 1H NMR (CDCl3, 500 MHz): δ 1.46 (s, 18 H,
t-Bu), 3.41 (s, 6 H, OMe), 7.59 (s, 2 H, 5-H) ppm. 13C NMR
(CDCl3, 176 MHz): δ 29.1, 38.8, 60.6, 120.6 (q, 3JCF = 2.9 Hz),
122.6 (q, 1JCF = 274 Hz), 136.7, 140.9 (q, 2JCF = 35.1 Hz), 154.8,
163.7 ppm. IR (KBr): ν 3005-2850 (dC;H, C;H), 1595-1540
(CdC) cm-1. MS (EI): m/z (%) 464 (14) [M]þ, 449 (60), 433 (100),
403 (20), 69 (10), 57 (92). HRMS (EI): calcd for C22H26F6N2O2
[M]þ 464.18985, found 464.18876. C22H26F6N2O2 (464.4) calcd
for C 56.89, H 5.64, N 6.03, found C 56.45, H 5.14, N 5.89.
Preparation of 2-tert-Butyl-3-methoxy-6-(trifluoromethyl)-
4-(trifluorovinyl)pyridine (21). A mixture of 4-pyridyl nonaflate
19c (261 mg, 0.491 mmol), Pd(OAc)2 (5.5 mg, 0.025 mmol), PPh3
(26 mg, 0.098 mmol), and tributyl(1,2,2-trifluorovinyl)stannane
(292 mg, 0.786 mmol) in DMF (2.3 mL) was heated to 50 °C for 1
d under an argon atmosphere. The mixture was allowed to cool
to room temperature, diluted with brine (3 mL), and extracted
with diethyl ether (3 ꢀ 3 mL). The combined organic phase was
dried with Na2SO4 and concentrated to dryness. The residue
was purified by chromatography on silica gel (hexane/ethyl
acetate = 40:1) to give 112 mg (73%) of 21 as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ 1.42 (s, 9 H, t-Bu), 3.89 (s, 3 H,
OMe), 7.49 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3, 126 MHz):
δ 29.0, 38.7, 60.6 (qd, 5JCF = 3.1 Hz), 119.1, 121.6 (q, 1JCF
=
273 Hz), 124.4 (ddd, JCF = 233, 51.1, 21.9 Hz), 126.6 (ddd,
J
J
CF = 21.9, 5.7, 0.9 Hz), 140.4 (q, 2JCF = 35.3 Hz), 153.2 (ddd,
CF = 294, 283, 51.1 Hz), 155.1, 164.0 ppm. 19F NMR (CDCl3,
470 MHz): δ -67.6 (s, CF3), -96.9 (dd, J = 59.7, 32.2 Hz, 10-F),
-111.0 (dd, J = 115.0, 59.7 Hz, 20-Fb), -170.1 (dd, J = 115.0,
32.2 Hz, 20-Fa) ppm. IR (film): ν 2965-2870 (dC;H, C;H),
1770 (CdC) cm-1. HRMS (ESI-TOF): calcd for C13H13F6NO
[MH]þ 314.0974, found 314.0966.
Acknowledgment. Generous support of this work by the
Alexander von Humboldt foundation (research fellowship
for J. D.), the Deutsche Forschungsgemeinschaft (GRK
1582/1), the Fonds der Chemischen Industrie, and the Bayer
Schering Pharma AG is most gratefully acknowledged. We
Preparation of 2-tert-Butyl-3-methoxy-4-(phenylthio)-6-
(trifluoromethyl)pyridine (22). 4-Pyridyl nonaflate 19c (267 mg,
0.503 mmol), PdCl2(dppf) (41 mg, 0.050 mmol), thiophenol
(62 μL, 0.60 mmol), and K2CO3 (139 mg, 1.01 mmol) were
dissolved in a 4:4:1 mixture of acetone, toluene, and H2O
(4.5 mL) and heated to 70 °C for 1 h under an argon atmosphere
in a microwave reactor. The mixture was allowed to cool to
room temperature, diluted with brine (5 mL), and extracted with
ethyl acetate (3 ꢀ 5 mL). The combined organic phase was dried
with Na2SO4 and concentrated to dryness. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate
= 40:1) to give 156 mg (91%) of 22 as a colorless solid. Mp
52 °C. 1H NMR (CDCl3, 500 MHz): δ 1.45 (s, 9 H, t-Bu), 4.00 (s,
3 H, OMe), 7.47 (s, 1 H, 5-H), 7.23-7.30, 7.48-7.52 (2 m, 3 H,
€
also thank Dr. R. Zimmer (Freie Universitat Berlin) for his
help during preparation of this manuscript.
Supporting Information Available: Characterization data
for all compounds, including copies of 1H and 13C NMR spectra
for all compounds and X-ray crystallographic data for 12 and
37a in CIF format.25,26 This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467–473.
(26) Sheldrick, G. M. A program for refining crystal structures, Uni-
€
versitat Gottingen, Germany, 1997.
€
732 J. Org. Chem. Vol. 75, No. 3, 2010