A new color of the synthetic chameleon methoxyallene: Synthesis of trifluoromethyl-substituted pyridinol derivatives: An unusual reaction mechanism, a remarkable crystal packing, and first palladium-catalyzed coupling reactions

Article abstract of DOI:10.1002/chem.200400322

Addition of lithiated methoxyallene to pivalonitrile afforded after aqueous workup the expected iminoallene 1 in excellent yield. Treatment of this intermediate with silver nitrate accomplished the desired cyclization to the electron-rich pyrrole derivati

Full text of DOI:10.1002/chem.200400322

FULL PAPER
A New Color of the Synthetic Chameleon Methoxyallene: Synthesis of
Trifluoromethyl-Substituted Pyridinol Derivatives: An Unusual Reaction
Mechanism, a Remarkable Crystal Packing, and First Palladium-Catalyzed
Coupling Reactions
Oliver Flˆgel, Jyotirmayee Dash, Irene Br¸dgam, Hans Hartl, and Hans-Ulrich Rei˚ig*[a]
Abstract:
Addition
of
lithiated
allene carbon atom of an allenyl imini-
um intermediate as crucial step. Enam-
ide 3 is converted to pyridinol 4 by an
intramolecular aldol-type process. A
practical direct synthesis of trifluoro-
methyl-substituted pyridinols 4, 10, 11,
and 12 starting from typical nitriles and
methoxyallene was established. Pyridi-
nol 10 shows an interesting crystal
packing with three molecules in the el-
ementary cell and a remarkable helical
supramolecular arrangement. Trifluoro-
methyl-substituted pyridinol 4 was con-
verted to the corresponding pyridyl
nonaflate 13, which is an excellent pre-
cursor for palladium-catalyzed reac-
tions leading to pyridine derivatives
14 16 in good to excellent yields. The
new synthesis of trifluoromethyl-substi-
tuted pyridines disclosed here demon-
strates a novel reactivity pattern of
lithiated methoxyallene which is incor-
porated into the products as the unusu-
al tripolar synthon B.
methoxyallene to pivalonitrile afforded
after aqueous workup the expected
iminoallene 1 in excellent yield. Treat-
ment of this intermediate with silver ni-
trate accomplished the desired cycliza-
tion to the electron-rich pyrrole deriva-
tive 2 in moderate yield. Surprisingly,
trifluoroacetic acid converted iminoal-
lene 1 to a mixture of enamide 3 and
trifluoromethyl-substituted pyridinol 4
(together with its tautomer 5). A plau-
sible mechanism proposed for this in-
triguing transformation involves addi-
tion of trifluoroacetate to the central
Keywords: allenes
palladium
¥
cyclization
¥
¥
¥
pyridines
supramolecular chemistry
Introduction
adducts which, after cyclization, could directly furnish elec-
tron-rich pyrroles (Scheme 1) that are potentially interesting
aromatic p systems.[6] This turned out to be feasible, but syn-
thetically not very useful. However, during the search for a
suitable cyclization protocol we detected an entirely unex-
pected and mechanistically intriguing formation of new
highly functionalized trifluoromethyl-substituted pyridine
derivatives. These results impressively demonstrate the cha-
meleon-like character of lithiated alkoxyallenes as versatile
We recently reported that the addition of lithiated alkoxyal-
lenes to various imines is a very smooth and highly flexible
route towards many dihydropyrrole derivatives.[1] This [3+2]
cyclization path to functionalized pyrroles was applied to a
relatively short and perfectly stereoselective synthesis of the
uncommon g-amino acid (À)-detoxinine,[2] to a synthesis of
the pyrrolidinol derivative anisomycin,[3] and (by use of 3-
alkyl-substituted 1-alkoxyallene derivatives) to a synthesis
of (À)-preussin.[4] In addition, a variety of other highly sub-
stituted pyrrole derivatives have been synthesized.[5] In-
spired by this broad scope of the allene/imine combination,
we tried to extend the alkoxyallene methodology to the cor-
À
responding C N triple-bond systems. Nitriles as electrophil-
ic partners of lithiated alkoxyallenes should provide primary
[a] Dr. O. Flˆgel, Dr. J. Dash, I. Br¸dgam, Prof. Dr. H. Hartl,
Prof. Dr. H.-U. Rei˚ig
Institut f¸r Chemie, Freie Universit‰t Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax (+49)30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
Scheme 1.
Chem. Eur. J. 2004, 10, 4283 4290
DOI: 10.1002/chem.200400322
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4283

FULL PAPER
synthetic building blocks, which has again led us in a new di-
rection.[7]
was formed as one of the possible two diastereomers, where-
as pyridinol 4 exists in solution together with its pyridinone
tautomer 5 (ratio in CDCl3 ca. 60:40); in CD3OD only the
signals of pyridinol 4 were detected.
Results
A mechanism to explain these puzzling results is present-
ed in Scheme 4. Although we do not have real proof of any
Formation and reactions of iminoallene derivatives: As an-
ticipated lithiated methoxyallene added to a nitrile such as
pivalonitrile, and after aqueous workup followed by careful
distillation, iminoallene 1 was obtained analytically pure in
excellent yield (Scheme 2). Similar adducts could be isolated
Scheme 2.
in modest yields and purities from other nitriles; however,
these compounds proved to be considerably more sensitive
to hydrolysis or oxidation than tert-butyl-substituted 1.[5a]
The desired cyclization of 1 could be achieved by catalysis
with silver nitrate in the presence of potassium carbonate,
which is often the method of choice for cyclizations of allen-
yl amines and alcohols,[8] and it provided the expected 2-tert-
butyl-3-methoxypyrrole (2) in moderate yield. This electron-
rich pyrrole is sensitive to oxygen and decomposes rather
rapidly. Other nitrile allene adducts delivered the corre-
sponding pyrroles only in much inferior yields and with
lower purity.[5a]
We also observed that 1 was completely converted to 2 on
storing a sample in deuterochloroform for seven days. After
distillation 2 was obtained in 64% yield. Since we suspected
that this process occurred by proton/deuteron catalysis, we
studied the reaction of 1 in the presence of acid. Quite un-
expectedly, treatment of iminoallene 1 with trifluoroacetic
acid in deuterochloroform provided two new compounds.
After 20 min at 08C we could already observe enamide 3 to-
gether with pyridinol 4 (Scheme 3). These two products
were isolated after stirring the solution for 16 h at room
temperature in 27 and 15% yield, respectively. Enamide 3
Scheme 4.
of these steps, the overall mechanism seems plausible. In the
first step iminoallene 1 is protonated to give iminium ion 6,
which can also be represented by mesomer 6’. Protonation
therefore results in electrophilic character of the central
carbon atom of the allene moiety. Apparently, even a weak
nucleophile such as trifluoroacetate is able to add (in equili-
brium?) to this center to generate the next intermediate 7
with an alkenyl trifluoroacetate as key functional group.
This unit is a fairly strong acylating agent, and it transfers
the trifluoroacetyl group to the geometrically well posi-
tioned amino group to finally lead to the isolated enamide
3.[9] The formation of the second product, pyridinol 4, is
easily explained by an acid-catalyzed formation of enol 8
and its intramolecular aldol condensation, which furnishes
pyridinone 5 and its tautomer 4. We are not aware of pyri-
dine syntheses which employ three components in a similar
manner.[10]
Having found these surprising transformations of iminoal-
lene 1 we checked the possibility of forming enamide and
pyridine derivatives without isolation of the imine inter-
mediate. Treatment of benzonitrile with lithiated methoxyal-
lene and subsequent addition of an excess of trifluoroacetic
acid led to a mixture of the expected enamide 9 and its con-
densation product, pyridinol 10 (Scheme 5). The two com-
pounds could easily be separated by column chromatogra-
phy and were isolated in good overall yield. For 10 we did
not observe its pyridinone tautomer in the NMR spectrum.
Scheme 3.
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Synthesis of Trifluoromethyl-Substituted Pyridinols
4283 4290
Crystal structure of 10: From pyridinol derivative 10 we
were able to obtain suitable single crystals for an X-ray crys-
tal structure analysis, which not only proved the constitution
of the compound but also showed an interesting arrange-
ment of the molecules in the unit cell. The compound crys-
≈
tallizes triclinic in the centrosymmetric space group P1. The
crystal structure is built up by three crystallographically in-
dependent molecules A, B, and C with almost identical
bond lengths and angles (Figure 1, Table 1). These molecules
À
are connected by strong O H¥¥¥N hydrogen bonds with
Scheme 5.
À
O N distances of 2.787(2), 2.667(2), and 2.756(2) ä to form
With these compounds we could also establish a method for
complete conversion of enamide 9 to pyridine derivative 10.
Treatment of 9 with trimethylsilyl triflate in the presence of
triethylamine under reflux in dichloromethane provided the
desired pyridinol 10 in 52% yield.[11]
The question now arises why enamides 3 and 9 did not
completely undergo cyclization in the presence of trifluoro-
acetic acid. Possibly, the enamides isolated are actually the
Z isomers and not the E isomers depicted in the schemes
above. However, only the E isomers can directly undergo
aldol condensation to give pyridine derivatives, whereas the
Z enamides must change configuration before cyclization.
Perhaps this latter process is too slow with trifluoroacetic
acid, but induced under forcing conditions with trimethylsil-
yl triflate and triethylamine.
Direct synthesis of trifluoromethyl-substituted pyridine de-
rivatives: The next task was the development of a direct
protocol for conversion of nitriles to trifluoromethyl-substi-
tuted pyridinols which combines all reactions described
above. For this purpose the nitriles were treated with lithiat-
ed methoxyallene and then with trifluoroacetic acid. The
crude product obtained was subsequently refluxed with tri-
methylsilyl triflate in the presence of triethylamine and,
after acidic workup, pyridine derivatives 4, 10, 11, and 12
were obtained in moderate to very good yields (Scheme 6).
Figure 1. Structure of 10 (ORTEP plot; 50% probability level).
Table 1. Bond lengths [ä] for the three crystallographically independent
molecules of 10.
Bond
Molecule A
Molecule B
Molecule C
À
N1 C6
1.3363(19)
1.3559(19)
1.393(2)
1.483(2)
1.3732(18)
1.397(2)
1.3376(18)
1.400(2)
1.376(2)
0.955(17)
1.504(2)
1.321(2)
1.328(2)
1.329(2)
1.424(2)
1.340(2)
1.358(2)
1.392(2)
1.488(2)
1.3675(19)
1.403(2)
1.3358(19)
1.396(2)
1.370(2)
0.958(17)
1.505(2)
1.324(2)
1.325(2)
1.328(2)
1.402(3)
1.334(2)
1.3523(19)
1.397(2)
1.490(2)
1.3620(19)
1.393(2)
1.3422(18)
1.392(2)
1.371(2)
0.953(17)
1.506(2)
1.335(2)
1.336(2)
1.339(2)
1.454(3)
À
N1 C2
À
C2 C3
À
C2 C9
À
C3 O1
À
C3 C4
À
C4 O2
À
C4 C5
À
C5 C6
À
C5 H5
À
C6 C7
À
C7 F3
À
C7 F1
À
C7 F2
À
C8 O1
À
C8 H820.97(3)
0.97(3)
0.96(3)
À
C8 H81
1.03(3)
0.98(3)
1.391(2)
1.394(2)
1.379(2)
0.943(18)
1.04(3)
0.88(3)
1.389(2)
1.392(2)
1.383(3)
0.967(18)
1.01(3)
1.15(5)
1.389(2)
1.394(2)
1.384(3)
0.946(19)
À
C8 H83
À
C9 C10
À
C9 C14
Scheme 6.
À
C10 C11
À
C10 H10
À
C11 C121.379(3)
1.377(3)
1.381(3)
À
C11 H11
0.95(2)
1.379(3)
0.96(2)
1.380(3)
0.956(19)
0.953(19)
0.93(2)
0.95(2)
1.382(3)
0.96(2)
1.381(2)
0.96(2)
0.985(18)
0.90(2)
0.98(2)
1.373(3)
0.98(2)
1.381(3)
1.02(2)
0.94(2)
0.87(3)
These first examples demonstrate that nitriles with alkyl
groups (primary, secondary, tertiary) and with aryl substitu-
ents are suitable substrates for this three-component multi-
step process.[12] We are currently exploring the scope and
limitations of this unique reaction leading to pyridine deriv-
atives with so far unknown substitution patterns.[13]
À
C12 C13
À
C12 H12
À
C13 C14
À
C13 H13
À
C14 H14
À
O2 H2
Chem. Eur. J. 2004, 10, 4283 4290
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H.-U. Rei˚ig et al.
FULL PAPER
helical chains with the approximate symmetry of a threefold
pyridyl nonaflate 13 in good yield (Scheme 7).[17] Reductive
removal of this excellent leaving group occurred under stan-
dard conditions with hydrogen in the presence of Pd/C to
À
screw axis in the direction of the c axis. The O H¥¥¥N hydro-
gen bonds are almost linear, with bond angles of 173(2),
173(2), and 176(2)8 (Figure 1), whereby the hydrogen atoms
are clearly located at the oxygen atoms. The only significant
differences between the three molecules are the dihedral
À
À
À
angles of the C CF3 and C OCH3 moieties and the C C
bond linking the phenyl and the pyridyl rings. The interpla-
nar angles between the best planes of the pyridyl and
phenyl rings are 58.05(6)8 in molecule A, 69.17(5)8 in B, and
46.76(8)8 in C. The helical chains are arranged as pairs of
enantiomers with left- and right-hand screw in an approxi-
mately hexagonal rod packing parallel to the
(Figure 2).
c axis
Scheme 7.
smoothly furnish 2-tert-butyl-3-methoxy-6-trifluoromethyl-
pyridine (15).[18] As expected 13 is an excellent substrate for
À
palladium-catalyzed C C bond forming processes. Suzuki
coupling[19] with para-methoxyphenylboronic acid in the
presence of 5 mol% of palladium(ii) acetate afforded the
desired 4-anisyl-substituted pyridine derivative 14 in 84%
yield. With phenylacetylene in the presence of palladium(ii)
acetate, nonaflate 13 provided the Sonogashira coupling[20]
product 16 in 72% yield. These first examples demonstrate
that a broad range of subsequent transformations, in particu-
lar, palladium-catalyzed reactions, are possible with our ser-
endipitously discovered trifluoromethyl-substituted pyridinol
derivatives. Many interesting pyridine derivatives with ex-
tended p systems are conceivable, for example, new donor
acceptor-substituted p systems, but the palladium chemistry
may also be very suitable for introducing these trifluoro-
methyl-substituted pyridinyl substituents into targets which
should be studied for their biological activity.
Figure 2. Packing of 10 along the c axis.
Palladium-catalyzed coupling reactions: Heterocycles bear-
ing trifluoromethyl (or perfluoroalkyl) groups are of interest
as substituents of biologically active compounds for use as
pharmaceuticals or as crop-protection agents.[14] Although
methods leading to 2- or 6-trifluoromethyl-substituted pyri-
dine derivatives have been reported[15] the pyridinols pre-
sented here should offer many and unique possibilities for
subsequent synthetic manipulation. The 4-hydroxy group
allows alkylation or arylation, and demethylation at the 3-
methoxy substituent should provide brenzcatechin-analo-
gous pyridine derivatives.[16] These building blocks are not
only of interest because they may be connected as substitu-
ents for potential biologically active compounds, but they
may also serve as novel elements of supramolecular con-
structions. Here we present our first results employing typi-
cal palladium-catalyzed reactions which replace the 4-hy-
droxy group of 4 by different substituents.
Conclusion
We have demonstrated that the reaction of lithiated alkoxy-
allenes with nitriles does not only lead to the expected elec-
tron-rich pyrrole derivatives (Scheme 2) but it also opens
the way to a completely unexpected and unique pyridine
synthesis. By subsequent treatment of the intermediates
with trifluoroacetic acid and then with trimethylsilyl triflate,
6-trifluoromethyl-substituted pyridinols 4, 10, 11, and 12
were obtained in good overall yield. Compound 10 shows an
interesting helical arrangement of the molecules in the crys-
tal (Figure 2). A practical direct synthesis of these unusually
substituted pyridine derivatives from nitriles and the me-
For this purpose pyridinol 4 was deprotonated with
sodium hydride in THF and then quenched with nonafluoro-
butane-1-sulfonyl fluoride (NfF), which provided the desired
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Synthesis of Trifluoromethyl-Substituted Pyridinols
4283 4290
Table 2. Crystal data and structure refinement for 10.
thoxyallene could be established (Scheme 6). The resulting
pyridinols are very versatile building blocks that are of inter-
est for introduction into potentially biological active com-
pounds and also as construction elements of supramolecular
arrangements. As first examples of their subsequent trans-
formations a few typical palladium-catalyzed transforma-
tions were performed and led to coupling products such as
14 and 16. The synthetic chameleon methoxyallene has
again presented a new color: whereas the equivalence of
lithiated methoxyallene with 1,3-zwitterions A is well estab-
lished[7] the introduction of this C3 building block into the
trifluoromethyl-substituted pyridines in a unique three-com-
ponent reaction demonstrates its equivalence to the new tri-
polar synthon B. As illustrated in Scheme 8 the methoxyal-
lene unit is attacked by an electrophile at C-1, a nucleophile
at C-2, and a second electrophile at C-3, which involves a
formal umpolung of reactivity at all three carbon atoms.[21]
recrystallized from
empirical formula
formula weight
hexane/ethyl acetate
C13H10F3NO2
269.2
T [K]
173(2)
l [ä]
0.71073
triclinic, P1
≈
crystal system, space group
a [ä]
b [ä]
c [ä]
a [8]
b [8]
g [8]
V [ä3]
Z
10.009(3)
14.057(4)
15.292(5)
113.61(1)
100.61(1)
99.67(1)
1866.6(10)
6
1calcd [MgmÀ3
absorption coefficient [mmÀ1
]
1.437
0.127
]
effective transmission min./max. 5.82
F(000)
828
crystal size [mm]
q range for data collection [8]
limiting indices
collected/unique reflections
completeness to q=30.568 [%]
refinement method
0.3î0.1î0.03
1.64 30.56
À14ꢀhꢀ14, À19ꢀkꢀ16, À20ꢀlꢀ21
23138/11194 [R(int)=0.0291]
97.8
full-matrix least-squares on F2
11194/0/634
data/restraints/parameters
goodness-of-fit on F2
final R indices [I>2 s(I)]
R indices (all data)
1.014
R1=0.0463, wR2=0.1105
R1=0.0911, wR2=0.1281
0.463/À0.353
largest diff. peak/hole [eAÀ3
]
Scheme 8.
1H NMR (250 MHz, CDCl3): d=5.77 (s, 2H, 6-H), 3.47 (s, 3H, OMe),
1.27 ppm (s, 9H, C(CH3)3), the signal for NH could not be detected;
13C NMR (62.9 MHz, CDCl3): d=202.7 (s, C-5), 177.3 (s, C-3), 127.5 (s,
C-4), 93.3 (t, C-6), 55.2(q, OMe), 38.5, 28.3 ppm (s, q, C(CH 3)3), the in-
tensity of the C-4 signal at 127.5 ppm is extremely low; its presence was
confirmed by addition of chromium(iii) tris(acetylacetonate);[26] IR
Experimental Section
General methods: Unless otherwise stated all reactions were performed
under argon atmosphere in flame-dried flasks by adding the components
by syringe. All solvents were dried by standard procedures. IR spectra
were measured with a Perkin Elmer FT-IR spectrometer Nicolet 5 SXC
À
À
(neat): n˜ =3270 (=N H), 2955 2835 (C H), 1940 (C=C=C), 1685 (C=N),
1600 cmÀ1 (C=C); MS (80 eV, EI): m/z (%): 153 (56) [M]+, 138 (97)
[MÀCH3]+, 123 (20) [MÀC2H6]+, 96 (28) [MÀC4H9]+, 57 (100) [C4H9]+;
HRMS (80 eV): calcd for C9H15NO 153.11536; found 153.11578.
or Nicolet 205. H and 13C NMR spectra were recorded on Bruker instru-
1
ments (WH 270, AC 250, AC 500). Proton chemical shifts are reported in
ppm relative to TMS (d=0.00 ppm) or CHCl3 (d=7.26 ppm). Higher
order NMR spectra were approximately interpreted as first-order spectra
if possible. 13C chemical shifts are reported relative to CDCl3 (d=
77.0 ppm). Neutral aluminum oxide (activity III, Fluka/Merck) or silica
gel (0.040 0.063 mm, Fluka) were used for column chromatography. Nu-
cleosil 50-5 (Macherey & Nagel) was used for HPLC. Melting points are
uncorrected.
2-tert-Butyl-3-methoxypyrrole (2): Iminoallene 1 was prepared from piva-
lonitrile (166 mg, 2.00 mmol) as described above, but not purified. The
crude addition product (285 mg, max. 2.00 mmol) was dissolved in aceto-
nitrile (10 mL), and silver nitrate (68 mg, 0.40 mmol) and potassium car-
bonate (550 mg, 3.98 mmol) were added. The resulting mixture was stir-
red with exclusion of light for 17 h at room temperature, then filtered
through a short pad of celite (elution with ethyl acetate), and the filtrate
was concentrated by evaporation. Purification of the residue by chroma-
tography on aluminum oxide (n-hexane/ethyl acetate 10/1, 1% triethyl-
amine added) provided 2 (172mg; 56%) as a yellow oil. 1H NMR
(500 MHz, CDCl3): d=7.66 (sbr, 1H, NH), 6.38, 5.97 (2t, J=3.0 Hz, 1 H
X-ray crystallography: Single-crystal X-ray data were collected on a
Brooker-XPS diffractometer (CCD area detector, MoKa radiation, l=
0.71073 ä, graphite monochromator), empirical absorption correction
using symmetry-equivalent reflections (SADABS),[22] structure solution
and refinement by SHELXS-97[23] and SHELXL-97[24] in the WINGX
system (Table 2).[25] The hydrogen atoms were located by difference Four-
ier syntheses. CCDC-234635 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12Union Road, Cambridge CB21EZ, UK;
fax: (+44)1223-336-033; or deposit@ccdc.cam.uk).
each, 5-H, 4-H), 3.72(s, 3H, OMe), 1.31 ppm (s, 9H, C(CH )3); 13C NMR
3
(125.8 MHz, CDCl3): d=154.4, 123.3 (2 s, C-3, C-2), 111.5, 98.1 (2d, C-5,
C-4), 59.0 (q, OMe), 31.3, 29.4 ppm (s, q, C(CH3)3); IR (neat): n˜ =3400
À1
À
À
À
(N H), 3130 3000 (=C H), 2955 2825 (C H), 1575 cm (C=C); MS
(80 eV, EI): m/z (%): 153 (31) [M]+, 138 (100) [MÀCH3]+, 123 (26)
[MÀC2H6]+, 108 (7) [MÀC3H9]+; HRMS (80 eV) calcd for C9H15NO:
153.11536; found: 153.11488.
Cyclization of 1 to 2 in deuterochloroform: Crude iminoallene 1 (294 mg,
max. 1.81 mmol) was dissolved in CDCl3 (1 mL) and stored for seven
days at room temperature. The solvent was evaporated, and the resulting
pyrrole 2 purified by distillation (608C, 0.05 mbar). Yield: 178 mg (64%)
of 2 as a yellow oil.
4-Methoxy-2,2-dimethyl-4,5-hexadien-3-imine (1): A solution of methoxy-
allene (0.50 mL, 420 mg, 6.00 mmol) in diethyl ether (8 mL) was treated
at À408C with n-butyllithium (2.00 mL, 2.5m in hexane, 5.00 mmol) and
the mixture was stirred for 15 min. At À788C pivalonitrile (0.20 mL,
150 mg, 1.81 mmol) was added, and the mixture was stirred for 4 h at this
temperature and then quenched with water (60 mL). After extraction
with diethyl ether (3î10 mL), drying with MgSO4, and evaporation of
the solvent the crude product was purified by careful distillation at room
temperature/0.04 mbar. In the dry ice trap of a B¸chi kugelrohr oven 1
(262 mg, 95%, purity >95%) was condensed as pale yellow liquid.
Treatment of iminoallene 1 with TFA: Compound 1 (273 mg, max.
1.81 mmol, crude product) was dissolved in CDCl3 (2mL) under an
argon atmosphere. At 08C trifluoroacetic acid (0.15 mL, 222 mg,
1.95 mmol) was added and the solution was stirred for 15 min. After 16 h
at room temperature the solvent was evaporated and the reddish residue
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H.-U. Rei˚ig et al.
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was treated with n-hexane (50 mL), stirred for 1 h, and filtered, and the
filtrate was again evaporated. Purification by HPLC (silica gel, n-hexane/
iPrOH 95/5) provided 3 (131 mg; 27%) as a colorless solid (m.p. 104
1088C), and 4 (67 mg; 15%) as a yellowish oil.
1H NMR (500 MHz, CD3OD): d=7.86 7.82, 7.45 7.37 (2 m, 5H, Ph),
7.21 (s, 1H, 5-H), 3.60 ppm (s, 3H, OMe); 13C NMR (125.8 MHz,
2
CD3OD): d=160.2, 154.1, 146.1 (3 s, C-2, C-3, C-4), 144.7 (q, JC,F
=
34 Hz, C-6), 135.7 (s, ipso-Ph), 130.1, 130.0, 129.1 (3d, Ph), 122.9 (q,
1JCF =273 Hz, CF3), 109.8 (d, C-5), 60.8 ppm (q, OMe); IR (neat): n˜ =
N-[1-(tert-Butyl)-2-methoxy-3-oxo-1-buten-1-yl]-2,2,2-trifluoroacetamide
(3): 1H NMR (250 MHz, CDCl3): d=8.06 (sbr, 1H, NH), 3.56 (s, 3H,
OMe), 2.30 (s, 3H, 4’-H), 1.25 ppm (s, 9H, C(CH3)3); 13C NMR
(62.9 MHz, CDCl3): d=200.4 (s, C-3’), 156.6 (q, 2JC,F =37 Hz, C-1), 151.9
À1
À
À
À
3410 (O H), 3065 3015 (=C H), 2940 2845 (C H), 1605 cm (C=C);
MS (80 eV, EI): m/z (%): 269 (100) [M]+, 250 (27) [MÀF]+, 77 (16)
[C6H5]+, 69 (3) [CF3]+; elemental analysis calcd (%) for C13H10F3NO2
(269.2): C 58.00, H 3.74, N 5.20; found: C 58.01, H 3.72, N 5.08.
1
(s, C-2’), 130.1 (s, C-1’), 115.8 (q, JC,F =288 Hz, C-2), 58.9 (q, OMe), 36.4,
À
28.2 (s, q, C(CH3)3), 27.2 ppm (q, C-4’); IR (KBr): n˜ =3285 (N H), 2975
Conversion of enamide
9 to pyridinol 10: Enamide 9 (112mg,
À1
À
2945 (C H), 1725, 1700 (C=O), 1630 cm (C=C); MS (80 eV, EI): m/z
0.39 mmol) was dissolved in dichloromethane (15 mL) and treated at
À788C with triethylamine (0.72mL, 518 mg, 5.09 mmol) and trimethylsil-
yl triflate (1.08 mL, 1.32g, 5.97 mmol). After 30 min the cooling bath was
removed and the solution allowed to warm to room temperature over
16 h. The mixture was heated under reflux for three days and then
quenched at room temperature with saturated NH4Cl solution (20 mL).
Extraction with dichloromethane (3î20 mL), drying with MgSO4, and
evaporation provided the crude product. Purification by column chroma-
tography (silica gel, n-hexane/ethyl acetate 8/1) furnished 10 (55 mg;
52%) as a pale yellow solid. For analytical details, see above.
(%): 267 (2) [M]+, 252 (1) [MÀCH3]+, 224 (100) [MÀC2H3O]+, 210 (2)
[MÀC4H9]+, 194 (11) [MÀC3H5O2]+, 69 (11) [CF3]+, 57 (10) [C4H9]+, 43
(14) [C2H3O]+; elemental analysis calcd (%) for C11H16F3NO3 (267.3): C
49.44, H 6.03, N 5.24; found: C 49.44, H 5.94, N 5.16.
2-tert-Butyl-3-methoxy-6-(trifluoromethyl)-4-pyridinol (4) and 2-tert-
butyl-3-methoxy-6-(trifluoromethyl)-4(1H)-pyridone (5): In CDCl3 at
243 K a ratio of 4:5 of approximately 60:40 was observed.
Signals of pyridinol 4: 1H NMR (500 MHz, CDCl3, 243 K): d=10.9 (sbr,
1H, OH), 7.23 (s, 1H, 5-H), 3.95 (s, 3H, OMe), 1.40 ppm (s, 9H,
C(CH3)3); 13C NMR (125.8 MHz, CDCl3, 243 K): d=162.1 (s, C-2), 157.1
Direct synthesis of pyridines from nitriles, general procedure: Methoxyal-
lene was dissolved in diethyl ether (10 mL), and n-butyllithium (BuLi)
was added at À408C. After 15 min at À50 to À408C the solution was
cooled to À788C, and the corresponding nitrile, dissolved in diethyl ether
(2.5 mL/1.00 mmol), was added. After stirring for 4 h at this temperature
trifluoroacetic acid (TFA, for amounts see individual experiments) was
added and the mixture was warmed overnight to room temperature.
Then saturated aqueous NaHCO3 solution (10 mL/1.00 mmol of nitrile)
was added, and the mixture was extracted with dichloromethane (3î
10 mL/1.00 mmol). The combined organic phases were dried with MgSO4
and then evaporated. The resulting crude product mixture was dissolved
in dichloromethane (7.5 mL/1.00 mmol), and at À788C triethylamine and
trimethylsilyl triflate (TMS triflate) were added. After 30 min the cooling
bath was removed, and the reaction flask was allowed to warm to room
temperature overnight. Then it was heated under reflux for 3 d and
quenched with saturated NH4Cl solution (10 mL/1.00 mmol). After ex-
traction with dichloromethane (3î25 mL/1.00 mmol) the combined or-
ganic phases were dried with MgSO4 and evaporated. The resulting crude
product was dissolved in dichloromethane (20 mL/1.00 mmol) and treated
first with TFA (ca. 1 equivalent) and then with water (20 mL/1.00 mmol).
Extraction with dichloromethane (3î20 mL/1.00 mmol), drying with
MgSO4, and evaporation provided the corresponding pyridine.
(s, C-4), 145.2(s, C-3), 140.9 (q, 2JC,F =34 Hz, C-6), 121.4 (q, JC,F
=
1
273 Hz, CF3), 114.9 (d, C-5), 60.0 (q, OMe), 37.8, 28.9 ppm (s, q,
C(CH3)3).
Signals of pyridone 5: 1H NMR (500 MHz, CDCl3, 243 K): d=8.73 (sbr,
1H, NH), 7.01 (s, 1H, 5-H), 4.04 (s, 3H, OMe), 1.52ppm (s, 9H,
C(CH3)3); 13C NMR (125.8 MHz, CDCl3): d=174.7 (s, C-4), 150.2(s, C-
2), 148.9 (s, C-3), 133.4 (q, 2JC,F =36 Hz, C-6), 120.4 (q, 1JC,F =273 Hz,
CF3), 59.2(q, OMe), 35.7, 27.5 ppm (s, q, C(CH 3)3).
In CD3OD at room temperature we observed only the signals of 4:
1H NMR (500 MHz, CD3OD): d=7.08 (s, 1H, 5-H), 3.87 (s, 3H, OMe),
1.34 ppm (s, 9H, C(CH3)3); 13C NMR (125.8 MHz, CD3OD): d=163.2(s,
C-2), 158.7 (s, C-4), 146.7 (s, C-3), 142.5 (q, 2JC,F =34 Hz, C-6), 122.9 (q,
1JC,F =273 Hz, CF3), 109.1 (d, C-5), 60.4 (q, OMe), 38.9, 29.7 ppm (s, q,
C(CH3)3).
À1
À
À
À
IR (neat): n˜ =3405 (O H), 3285 (N H), 2990 2900 (C H), 1610 cm
(C=O); MS (80 eV, EI): m/z (%): 249 (39) [M]+, 234 (100) [MÀCH3]+,
218 (22) [MÀOMe]+, 192(8) [ MÀC4H9]+, 69 (2) [CF3]+, 57 (5) [C4H9]+;
elemental analysis calcd (%) for C11H14F3NO2 (249.2): C 53.01, H 5.66, N
5.62; found: C 53.09, H 5.57, N 5.37.
Reaction of benzonitrile followed by treatment with trifluoroacetic acid:
Methoxyallene (0.55 mL, 462mg, 6.60 mmol) was dissolved in diethyl
ether (10 mL) and treated at À408C with n-butyllithium (2.20 mL, 2.5m
in hexane, 5.50 mmol). After 15 min of stirring at À50 to À408C the solu-
tion was cooled to À788C and a solution of benzonitrile (0.20 mL,
202 mg, 1.96 mmol) in diethyl ether (5 mL) was added. After 4 h at
À788C trifluoroacetic acid (1.00 mL, 1.48 g, 13.0 mmol) was added and
the solution was allowed to warm to room temperature over 16 h and
then quenched with saturated NaHCO3 solution (20 mL). Extraction with
diethyl ether (3î20 mL), drying with MgSO4, and evaporation provided
the crude products. Purification by column chromatography (silica gel, n-
hexane/ethyl acetate 8/1) afforded 9 (158 mg; 30%) as a yellowish solid
(m.p. 132 1338C) and 10 (159 mg; 28%) as a yellow oil.
2-tert-Butyl-3-methoxy-6-(trifluoromethyl)-4-pyridinol (4): According to
the general procedure, pivalonitrile (0.22 mL, 165 mg, 1.99 mmol), me-
thoxyallene (0.55 mL, 462mg, 6.60 mmol), nBuLi (2.20 mL, 2.5m in
hexane, 5.50 mmol), TFA (1.00 mL, 1.48 g, 13.0 mmol), TEA (1.12mL,
806 mg, 7.97 mmol), TMS triflate (1.93 mL, 2.22 g, 9.99 mmol), and TFA
(0.15 mL, 222 mg, 1.95 mmol) provided crude 4, which was purified by
HPLC (silica, hexane/iPrOH 95/5) to yield 4 (410 mg; 83%) as a pale
yellow oil.
3-Methoxy-2-phenyl-6-(trifluoromethyl)-4-pyridinol (10): According to
the general procedure, benzonitrile (0.20 mL, 202 mg, 1.96 mmol), me-
thoxyallene (0.55 mL, 462mg, 6.60 mmol), nBuLi (2.20 mL, 2.5m in
hexane, 5.50 mmol), TFA (1.00 mL, 1.48 g, 13.0 mmol), TEA (1.12mL,
806 mg, 7.97 mmol), TMS triflate (1.93 mL, 2.22 g, 9.99 mmol), and TFA
(0.15 mL, 222 mg, 1.95 mmol) provided crude 10, which was purified by
column chromatography with silica gel (gradient elution: n-hexane/ethyl
acetate 8/1 to 4/1) to yield 10 (323 mg; 60%) as a yellowish solid (m.p.
132 1338C).
N-[2-Methoxy-3-oxo-1-phenyl-1-buten-1-yl]-2,2,2-trifluoroacetamide (9):
1H NMR (250 MHz, CDCl3): d=12.19 (sbr, 1H, NH), 7.43 (mc, 5H, Ph),
3.23 (s, 3H, OMe), 2.41 ppm (s, 3H, 4’-H); 13C NMR (62.9 MHz, CDCl3):
d=203.0 (s, C-3’), 155.3 (q, 2JC,F =38 Hz, C-1), 140.4, 138.8 (2s, ipso-Ph,
C-2’), 129.6, 128.3, 128.2 (3d, Ph), 115.3 (q, 1JC,F =289 Hz, C-2), 60.5 (q,
OMe), 27.4 ppm (q, C-4’), the C-1’ signal was hidden by the signals of the
À
À
aryl group; IR (neat): n˜ =3250 (N H), 3060 3000 (=C H), 2940 2840
2-Ethyl-3-methoxy-6-trifluoromethyl-4-pyridinol (11): According to the
general procedure, propionitrile (0.14 mL, 108 mg, 1.96 mmol), methoxy-
allene (0.55 mL, 462mg, 6.60 mmol), nBuLi (2.20 mL, 2.5m in hexane,
5.50 mmol), TFA (1.00 mL, 1.48 g, 13.0 mmol), TEA (1.12mL, 806 mg,
7.97 mmol), TMS triflate (1.93 mL, 2.22 g, 9.99 mmol), and TFA
(0.15 mL, 222 mg, 1.95 mmol) provided crude 11, which was purified by
column chromatography on silica gel (hexane/ethyl acetate 4/1). Yield:
273 mg (63%) of 11 as a colorless solid (m.p. 102 1038C). 1H NMR
(500 MHz, CD3OD): d=7.06 (s, 1H, 5-H), 3.85 (s, 3H, OMe), 2.79,
1.21 ppm (q, t, J=7.5 Hz, 2H, 3H, CH2CH3); 13C NMR (125.8 MHz,
CD3OD): d=159.5, 145.8 (2s, C-2, C-3, C-4)*, 143.7 (q, 2JC,F =36 Hz,
À1
À
(C H), 1750 (C=O), 1610, 1590 cm (C=C); MS (80 eV, EI): m/z (%):
287 (37) [M]+, 268 (1) [MÀF]+, 244 (100) [MÀC2H3O]+, 229 (17)
[MÀC3H6O]+, 77 (19) [C6H5]+; HRMS (80 eV) calcd for C13H12F3NO3:
287.07693; found 287.07744.
3-Methoxy-2-phenyl-6-(trifluoromethyl)-4-pyridinol
(10):
1H NMR
(250 MHz, CDCl3): d=7.95 7.88, 7.50 7.40 (2m, 5H, Ph), 7.22(s, 1H, 5-
H), 3.55 ppm (s, 3H, OMe), the OH signal could not be detected;
13C NMR (62.9 MHz, CDCl3): d=158.0, 151.6, 144.4 (3 s, C-2, C-3, C-4),
143.5 (q, 2JC,F =34 Hz, C-6), 135.7 (s, ipso-Ph), 129.3, 128.8, 128.4 (3 d,
Ph), 121.2 (q, 1JC,F =274 Hz, CF3), 108.5 (d, C-5), 60.6 ppm (q, OMe);
4288
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4283 4290

Synthesis of Trifluoromethyl-Substituted Pyridinols
4283 4290
C-6), 122.8 (q, 1JC,F =273 Hz, CF3), 109.6 (d, C-5), 61.1 (q, OMe), 26.0 (t,
CH2), 13.7 ppm (q, CH3), * only two signals could be unambiguously de-
13C NMR (125.8 MHz, CDCl3): d=158.2, 156.3 (2 s, C-2, C-3), 137.8 (q,
1
2JC,F =35 Hz, C-6), 122.1 (q, JC,F =273 Hz, CF3), 119.1, 117.2(2d, C-4, C-
À
5), 55.2 (q, OMe), 38.2, 28.3 ppm (s, q, C(CH3)3); IR (neat): n˜ =3090,
tected for three carbon atoms; IR (KBr): n˜ =3395 (br, O H), 2980 2885
À
À1
À1
(C H), 1610 cm (C=C); MS (80 eV, EI): m/z (%): 221 (100) [M]+, 2 06
À
2955 2850 (C H), 1665 1590 cm (C=C); MS (80 eV, EI): m/z (%): 233
(29) [M]+, 218 (100) [MÀCH3]+, 214 (5) [MÀF]+, 202 (4) [MÀOCH3]+,
198 (24) [MÀCH3ÀHF]+, 57 (44) [C4H9]+; HRMS calcd for C11H14F3NO:
233.10344; found: 233.10275.
(58) [MÀCH3]+, 203 (55) [MÀH2O]+, 191 (31) [MÀC2H6]+, 69 (9)
[CF3]+; elemental analysis calcd (%) for C9H10F3NO2 (221.2): C 48.87, H
4.56, N 6.33; found: C 48.60, H 4.54, N 6.13.
2-tert-Butyl-3-methoxy-4-phenylethynyl-6-trifluoromethylpyridine (16): A
reaction flask containing nonaflate 13 (100 mg, 0.188 mmol), Pd(OAc)2
(2.1 mg, 0.0094 mmol), PPh3 (9.9 mg, 0.038 mmol), and CuI (1.8 mg,
0.0094 mmol) was degassed and filled with argon. DMF (0.86 mL) and
diisopropylamine (0.43 mL) were added followed by phenylacetylene
(23 mg, 0.23 mmol). After stirring at room temperature under an argon
atmosphere for 17 h, the mixture was diluted with water (2mL) and ex-
tracted with diethyl ether (3î5 mL). The combined organic solution was
washed with water and brine, dried with Na2SO4 and concentrated to dry-
ness. The residue was purified by chromatography on silica gel (pentane)
to afford 16 (45 mg; 72%) as a colorless solid (m.p. 72 73 8C). 1H NMR
(500 MHz, CDCl3): d=7.61 (s, 1H, 5-H), 7.58 7.56, 7.43 7.37 (2m, 2H,
3-Methoxy-2-isopropyl-6-(trifluoromethyl)-4-pyridinol (12): According to
the general procedure, isobutyronitrile (0.18 mL, 137 mg, 1.98 mmol),
methoxyallene (0.55 mL, 462mg, 6.60 mmol), nBuLi (2.20 mL, 2.5m in
hexane, 5.50 mmol), TFA (1.00 mL, 1.48 g, 13.0 mmol), TEA (1.12mL,
806 mg, 7.97 mmol), TMS triflate (1.93 mL, 2.22 g, 9.99 mmol), and TFA
(0.15 mL, 222 mg, 1.95 mmol) provided crude 12, which was purified by
HPLC (silica gel, n-hexane/iPrOH 95/5) to yield 12 (252 mg; 54%) as a
colorless oil.
1H NMR (250 MHz, CD3OD): d=7.04 (s, 1H, 5-H), 3.83 (s, 3H, OMe),
3.42, 1.21 ppm (sept, d, J=6.8 Hz, 1H, 6H, CH(CH3)2); 13C NMR
(62.9 MHz, CD3OD): d=162.8, 158.8, 144.8 (3 s, C-2, C-3, C-4), 144.3 (q,
2JC,F =34 Hz, C-6), 123.0 (q, 1JC,F =273 Hz, CF3), 108.8 (d, C-5), 61.2(q,
3H, Ph), 4.19 (s, 3H, OMe), 1.43 ppm (s, 9H, C(CH3)3); 13C NMR
À
OMe), 30.3, 21.9 ppm (d, q, CH(CH3)2); IR (neat): n˜ =3360 (br, O H),
2
(125.8 MHz, CDCl3): d=162.7 (s, C-2), 157.8 (s, C-3), 140.2 (q, JC,F
=
À1
À
À
3090 (=C H), 2970 2840 (C H), 1610 cm (C=C); MS (80 eV, EI): m/z
(%): 235 (70) [M]+, 220 (100) [MÀCH3]+, 204 (23) [MÀOMe]+, 192(9)
[MÀC3H7]+, 69 (21) [CF3]+, 43 (32) [C3H7]+; HRMS (80 eV) calcd for
C10H12F3NO2: 235.08202; found: 235.08355.
35 Hz, C-6), 131.6 (d, Ph), 129.6 (d, C-5), 128.7 (d, Ph), 124.3 (s, C-4),
122.8 (d, Ph), 122.1 (s, ipso-Ph), 121.6 (q, 1JC,F =274 Hz, CF3), 99.3, 83.7
(2s, CꢁC), 61.1 (q, OMe), 38.5, 29.1 ppm (s, q, (C(CH3)3); IR (KBr): n˜ =
À
À
3010 2990 (=C H), 2960 (C H), 2225 2205 (CꢁC), 1600, 1590,
1580 cmÀ1 (C=C); MS (80 eV, EI): m/z (%): 333 (42) [M]+, 332(19)
[MÀH]+, 318 (28) [MÀCH3]+, 302(8) [ MÀOCH3]+; elemental analysis
calcd (%) for C19H18F3NO (333.3): C 68.46, H 5.44, N 4.20; found: C
68.16, H 5.22, N 4.12.
2-tert-Butyl-3-methoxy-6-trifluoromethylpyridin-4-yl nonaflate (13): NaH
(128 mg, 60% in mineral oil, 3.2 mmol) was added to a solution of pyridi-
nol 4 (400 mg, 1.60 mmol) in THF (10 mL) under an argon atmosphere.
Nonafluorobutanesulfonyl fluoride (0.83 mL, 4.8 mmol) was added drop-
wise at room temperature. The mixture was stirred for 3 h and quenched
by slow addition of water (15 mL). It was extracted with ethyl acetate
(3î10 mL), dried with Na2SO4 and concentrated to dryness. The residue
was purified by chromatography on silica gel (n-hexane) to afford 13
1
Acknowledgment
(663 mg; 78%) as a colorless oil. H NMR (500 MHz, CDCl3): d=7.42(s,
1H, 5-H), 3.98 (s, 3H, OMe), 1.41 ppm (s, 9H, C(CH3)3); 13C NMR
(125.8 MHz, CDCl3): d=166.4 (s, C-2), 149.5, 149.4 (2 s, C-3, C-4), 142.0
(q, 2JC,F =37 Hz, C-6), 120.6 (q, 1JC,F =275 Hz, CF3), 113.1 (d, C-5), 62.0
(q, OMe), 39.1, 28.8 ppm (s, q, C(CH3)3); 19F NMR (470.6 MHz, CDCl3):
d=À67.8 (s, 3 F, CF3), À80.5 (s, 3 F, F-4), À109.1 (s, 2F, F-3), À120.6 (s,
Support of this work by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie and Schering AG is most gratefully appreciat-
ed. We thank Mr. T. Lechel for experimental assistance, Dr. Khandavalli
P. Chary for preliminary experiments with nonaflate 13 and Dr. R.
Zimmer for help during preparation of this manuscript.
À
2F, F-2), À125.7 ppm (s, 2 F, F-1); IR (neat): n˜ =2960 2870 (C H), 1590,
1575 (C=C), 1435, 1350 cmÀ1 (SO); elemental analysis calcd (%) for
C15H13F12NSO4 (531.3): C 33.91, H 2.47, N 2.64; found: C 34.06, H 2.57,
N 2.63.
[1] a) G. M. Okala Amombo, A. Hausherr, H.-U. Rei˚ig, Synlett 1999,
1871 1874; b) G. M. Okala Amombo, Dissertation, Technische Uni-
versit‰t Dresden, Germany, 2000; c) for related reactions of lithiated
methoxyallene with chiral hydrazones derived from SAMP or
RAMP, see: V. Breuil-Desvergnes, P. Compain, J.-M. Vatÿle, J.
Gorÿ, Tetrahedron Lett. 1999, 40, 5009 5012; V. Breuil-Desvergnes,
J. Gorÿ, Tetrahedron 2001, 57, 1939 1950; V. Breuil-Desvergnes, J.
Gorÿ, Tetrahedron 2001, 57, 1951 1960.
2-tert-Butyl-3-methoxy-4-(4-methoxyphenyl)-6-trifluoromethylpyridine
(14): A mixture of nonaflate 13 (200 mg, 0.376 mmol), 4-methoxyphenyl-
boronic acid (68 mg, 0.45 mmol), Pd(OAc)2 (4.2mg, 0.019 mmol), PPh 3
(19.7 mg, 0.075 mmol), and K2CO3 (51 mg, 0.38 mmol) in DMF (2.8 mL)
was heated to 708C for 5 h under an argon atmosphere. The mixture was
allowed to cool to room temperature, diluted with water (4 mL), and ex-
tracted with diethyl ether (3î5 mL). The combined organic phase was
washed with water and brine, dried with Na2SO4 and concentrated to dry-
ness. The residue was purified by chromatography on silica gel (pentane/
ethyl acetate 10/1) to afford 14 (107 mg; 84%) as a colorless solid (m.p.
93 958C). 1H NMR (500 MHz, CDCl3): d=7.53 7.51 (m, 2H, Ar), 7.45
(s, 1H, 5-H), 7.02 6.98 (m, 2H, 4-Ar), 3.87, 3.36 (2 s, 3 H each, OMe),
1.46 ppm (s, 9H, C(CH3)3); 13C NMR (125.8 MHz, CDCl3): d=162.8,
160.1, 155.2(3 s, C-2, C-3, ipso-Ar), 142.1 (s, C-4), 140.8 (q, 2JCF =35 Hz,
C-6), 129.8 (d, Ar), 128.6 (s, ipso-Ar), 120.8 (d, C-5), 114.4 (d, Ar), 60.3,
55.4 (2q, OMe), 38.4, 29.4 ppm (s, q, C(CH 3)3), the CF3 signal could not
[2] O. Flˆgel, G. M. Okala Amombo, H.-U. Rei˚ig, G. Zahn, I. Br¸d-
gam, H. Hartl, Chem. Eur. J. 2003, 9, 1405 1415.
[3] S. Kaden, M. Kratzert, H.-U. Rei˚ig, unpublished results.
[4] A. Hausherr, Dissertation, Freie Universit‰t Berlin, Germany, 2002.
[5] a) O. Flˆgel, Dissertation, Freie Universit‰t Berlin, Germany, 2003,
and references [1b] and [4]; b) O. Flˆgel, H.-U. Rei˚ig, Synlett 2004,
895 897.
[6] For syntheses of electron-rich pyrroles, see: A. Merz, T. Meyer, Syn-
thesis 1999, 94 99; A. Merz, S. Annikin, B. Lieser, H. Heinze, H.
John, Chem. Eur. J. 2003, 9, 449 455, and references therein. For
general reviews on pyrrole syntheses, see: a) A. Gossauer in Meth-
oden der Organischen Chemie (Houben-Weyl), Vol. E6a/1, 4th ed.,
1994, pp. 556 798; b) Comprehensive Heterocyclic Chemistry, Vol. 2
(Eds.: A. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press,
Oxford, 1996, pp. 1 257. For selected examples of recent pyrrole
syntheses, see: c) W. von der Saal, R. Reinhardt, J. Stawitz, H.
Quast, Eur. J. Org. Chem. 1998, 1645 1652; d) R. K. Dieter, H. Yu,
Org. Lett. 2000, 2, 2283 2286; e) R. Grigg, V. Savic, Chem.
Commun. 2000, 873 874; f) L. Ghosez, C. Franc, F. Denonne, C.
Cuisinier, R. Touillaux, Can. J. Chem. 2001, 79, 1827 1839; g) F.-A.
Marcotte, W. D. Lubell, Org. Lett. 2002, 4, 2601 2603; h) M. Frie-
drich, A. W‰chtler, A. de Meijere, Synlett 2002, 619 621.
À
À
unambiguously be assigned; IR (KBr): n˜ =3000 (=C H), 2980 2835 (C
H), 1610, 1515 cmÀ1 (C=C); MS (80 eV, EI): m/z (%): 339 (53) [M]+, 338
(100) [MÀH]+, 324 (69) [MÀCH3]+, 308 (19) [MÀOCH3]+; elemental
analysis calcd (%) for C18H20F3NO2 (339.4): C 63.71, H 5.94, N 4.13;
found: C 63.29, H 5.49, N 3.60.
2-tert-Butyl-3-methoxy-6-trifluoromethylpyridine (15): A mixture of non-
aflate 13 (100 mg, 0.188 mmol) and palladium (ca. 10 mg, 10% on char-
coal) in ethyl acetate (1 mL) was stirred for two days under an atmos-
phere of hydrogen. Filtration of the reaction mixture through a short pad
of silical gel with pentane/ethyl acetate (10/1) afforded 15 (39 mg; 89%)
as a colorless oil. 1H NMR (500 MHz, CDCl3): d=7.48, 7.15 (2d, J=
8.4 Hz, 2H, 4-H, 5-H), 3.89 (s, 3H, OMe), 1.40 ppm (s, 9H, C(CH3)3);
Chem. Eur. J. 2004, 10, 4283 4290
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4289

H.-U. Rei˚ig et al.
FULL PAPER
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Received: April 1, 2004
Published online: July 19, 2004
4290
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www.chemeurj.org
Chem. Eur. J. 2004, 10, 4283 4290