Practical routes to 2,6-disubstituted pyridine derivatives

Article abstract of DOI:10.1002/ejoc.200701200

We report the synthesis of a series of 2,6-disubstituted pyridines in a straightforward manner starting from readily available 2-substituted pyridines. The main sequence involves a selective ?-lithiation reaction with halogen functionalization followed by

Full text of DOI:10.1002/ejoc.200701200

FULL PAPER
DOI: 10.1002/ejoc.200701200
Practical Routes to 2,6-Disubstituted Pyridine Derivatives
Lucie Vandromme,[a] Hans-Ulrich Reißig,*[a] Susie Gröper,[b] and Jürgen P. Rabe[b]
Keywords: C–C coupling / Nitrogen heterocycles / Lithiation / Halogenation / Scanning tunnelling microscopy
We report the synthesis of a series of 2,6-disubstituted
pyridines in a straightforward manner starting from readily
available 2-substituted pyridines. The main sequence in-
volves a selective α-lithiation reaction with halogen function-
alization followed by a Grignard reaction catalyzed by Fe-
(acac)3. After demonstration of the easy feasibility of this
strategy by synthesizing 2,6-disubstituted pyridines 1, the
route was applied to obtain pyridine derivatives bearing
electron-donating or electron-withdrawing groups. Thus, a
series of pyridines bearing an aryl moiety in the 6-position
and an alkyl chain in the 2-position was obtained. The pyr-
idines were studied for their self-assembly abilities at the
interface between an organic solution and the basal plane
of graphite. Preliminary STM results for one compound are
reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
which have up to now never been combined. Whereas the
preparation of 2,6-diaryl- or 2,6-dialkylpyridines has been
described previously,[5] the syntheses of mixed alkyl/aryl
pyridines have been rarely achieved.[5c,5k,6] 2-Alkylpyridine
derivatives 3 are easily accessible from 2-chloropyridine (2)
by using an iron-catalyzed coupling reaction[5g,7] with a
freshly prepared solution of an alkyl Grignard reagent and
Fe(acac)3 as a catalyst (Scheme 1). The iron-catalyzed coup-
ling proved to be the best choice in this case, as it is an
efficient method when an aromatic moiety and an alkyl
chain are involved. In an initial set of experiments we found
that the presence of N-methylpyrrolidone (NMP) as a co-
solvent greatly accelerated the reaction:[8] completion of the
coupling after 15 min was observed with NMP, whereas a
2:1 mixture of product and starting material was obtained
after 1 h in the absence of NMP.
Introduction
The pyridine ring is one of the most common heterocy-
clic scaffolds in pharmaceuticals, including antibiotics,[1] as
well as in many natural products.[2] It also finds frequent
applications in physical organic chemistry and in supramo-
lecular chemistry to study ion recognition. Two-dimen-
sional supramolecular chemistry is often studied by scan-
ning tunnelling microscopy (STM).[3] As part of an ongoing
project, we were interested in the development of a rapid
and highly flexible route to functionalized pyridine deriva-
tives, whose behaviour at the interface between an organic
solution and highly oriented pyrolytic graphite (HOPG)
should be studied.[4] Herein, we describe a convenient and
straightforward approach to 2,6-disubstituted pyridine de-
rivatives 1 bearing an aryl moiety to facilitate π-stacking
interactions with the graphite surface and a suitable alkyl-
chain moiety to favour the subsequent autoassembly of the
molecules (Figure 1).
Scheme 1. Fe(acac)3 catalyzed coupling of 2-chloropyridine (2)
with an alkyl Grignard reagent to pyridine 3.
Figure 1. Target compounds 1 required for STM studies.
Among the several methods available to halogenate the
pyridine core,[5a,9] the α-lithiation route described by Gros
and Fort, which employs the nBuLi–Me2N(CH2)2OLi su-
perbase (hereafter described as nBuLi–LiDMAE), is very
efficient and convenient, as it is highly regioselective. This
regioselectivity is attributed to the complexation of the in-
termediate aggregate with the pyridine nitrogen atom.[10]
Interestingly, 2-alkylpyridine derivatives 3, when subjected
to the lithiation reaction with nBuLi-LiDMAE, afforded a
Results and Discussion
The synthesis of 2,6-disubstituted pyridine derivatives 1
was attempted by using different reported methods, but
[a] Institut für Chemie und Biochemie, Freie Universität Berlin
Takustrasse 3, 14195 Berlin, Germany
Fax: +49 -30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Institut für Physik, Humboldt Universität zu Berlin
Newtonstrasse 15, 12489 Berlin, Germany
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L. Vandromme, H.-U. Reißig, S. Gröper, J. P. Rabe
FULL PAPER
complex mixture consisting of the expected 2-halogenated iron-catalyzed Grignard reaction smoothly proceeded to
pyridines 4, along with the product of halogenation in the furnish products 13 and 14 (Scheme 4). Deprotection of
alkyl chain 5 and dihalogenated pyridine 6 (Scheme 2).
acetal 14 with TFA afforded required aldehyde 15.
Scheme 2. Initial attempts at chlorination of 2-decylpyridine (3).
Because of this lack of selectivity in the presence of an
alkyl chain, we investigated a new route to 2,6-disubstituted
pyridines 1 starting from 2-phenylpyridine (7). The lithi-
ation reaction occurred selectively at the 6-position under
the conditions described by Gros and Fort to afford haloge-
nated pyridines 8a and 8b in excellent yields. The Grignard
reactions were attempted with both halogenated pyridines,
but only chloropyridine derivative 8a afforded the expected
pyridines 1 in moderate to good yields (Scheme 3). Unex-
pectedly, the use of bromopyridine 8b either led to loss of
the bromine or to complete recovery of unchanged starting
material.
Scheme 4. Syntheses of arylpyridine derivatives 13–15.
Aldehyde 15 was either smoothly oxidized to carboxylic
acid 16 with sodium chlorite by using 2-methyl-2-butene as
a chlorine scavenger[14] Ϫ a method which tolerates a large
range of functionalities Ϫ or transformed into oxime 17,
which was subsequently converted into nitrile 18 by treat-
ment with thionyl chloride (Scheme 5).[12]
Scheme 3. Halogenation of 2-phenylpyridine (7) followed by Fe-
(acac)3 catalyzed reactions with alkyl Grignard reagents.
Having demonstrated the feasibility of this new strategy
in a straightforward route, we went on to investigate the
effect of substituents on the aryl ring that should have an
influence on the self-assembly of the resulting pyridine de-
rivatives. We therefore introduced electron-withdrawing
Scheme 5. Conversion of aldehyde 15 into arylpyridine derivatives
16–18.
It is well known that fluorinated substituents induce cru-
groups (CN or COOH) or an electron-donating substituent cial but not always well understood properties.[15] It was
(OMe) on the aryl ring. Thus, Suzuki coupling[11] of 2-bro- therefore interesting to develop a method that could pro-
mopyridine (9) with the corresponding arylboronic acids af- vide asymmetrically substituted pyridine derivatives bearing
forded 2-arylpyridines 10 and 11. The aldehyde group was a fluorinated side chain, as we were unable to form the re-
selected because of its versatility of transformations; for ex- quired Grignard reagent with our chosen fluorous iodide
ample, the aldehyde functionality could be easily trans- 20. However, we could prepare the mixed aryl/fluoroalk-
formed into either a carboxylic acid or a nitrile group in ylpyridine 19 by employing a Negishi coupling, as reported
good yields under mild conditions.[12] Therefore, aldehyde by Gladysz and coworkers.[16] In situ formation of the fluo-
11 was first converted into dimethylacetal 12 by using tri- rinated alkyliodozinc derivative and subsequent reaction
methylorthoformate under acidic conditions (catalytic with bromopyridine 8b in the presence of catalytic amounts
amount of PTSA).[13] Both pyridines 10 and 12 were halo- of trans-Cl2Pd(PPh3)2 furnished the desired pyridine deriva-
genated in moderate to good yields, and the subsequent tive 19 in 76% yield (Scheme 6).
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Practical Routes to 2,6-Disubstituted Pyridine Derivatives
added by syringe. Solvents were dried by standard procedures. TLC
was performed with precoated silica gel plates (Sil G-60 F254) and
detected under UV light at 254 nm. Products were purified by flash
chromatography on silica gel (230–400 mesh, Merck). Unless stated
1
otherwise, H and 13C NMR spectra were determined with Bruker
DRX 500 or Jeol Eclipse 500 instruments. Chemical shifts (in δ
units, ppm) are referenced to TMS by using CHCl3 (δ = 7.26 ppm)
and CDCl3 (δ = 77.0 ppm) as the internal standards for 1H and
13C NMR spectra, respectively. IR spectra were measured with a
Nicolet 205 FTIR spectrometer. MS and HRMS analyses were per-
formed with Finnigan MAT 711 (EI = 80 eV, 8 kV), MAT 95 (EI
= 70 eV) or MAT CH7A (EI = 80 eV, 3 kV) instruments. ESI-TOF
MS were measured with an Agilent 6210 ESI-TOF (solvent flow
rate was adjusted to 4 µL/min, spray voltage set to 4.000 V; drying
gas flow rate was set to 15 psi). Elemental analyses were carried
out with a Vario EL instrument. Melting points were measured
with a Büchi 510 apparatus and are uncorrected.
Scheme 6. Negishi coupling reaction of bromopyridine 8b to the
fluoroalkyl-substituted arylpyridine derivative 19.
These straightforward methods allowed the preparation
of a series of disubstituted pyridine derivatives. Preliminary
STM experiments of 2,6-disubstituted pyridines at the
interface between an organic solution and the basal plane
of highly oriented pyrolytic graphite (HOPG) demonstrated
that carboxylic acid derivative 16 can self-assemble into epi-
taxial two-dimensional crystals with one hydrogen-bonded
dimer per unit cell (Figure 2).
Scanning Tunnelling Microscopy: STM imaging was carried out at
room temperature at the interface between a freshly cleaved highly
oriented pyrolytic graphite (HOPG) substrate and an almost-satu-
rated solution in 1,2,4-trichlorobenzene (Aldrich) by employing a
home-made set-up at a scan speed between 10 and 50 lines/s. After
visualization of the HOPG lattice, a drop of an almost-saturated
solution was applied to the basal plane of HOPG. The STM images
were corrected with respect to the hexagonal HOPG lattice under-
neath by exploiting SPIP software. In this way, the unit cell of the
adsorbate crystal could be defined with a high degree of precision.
Typical Procedure for Suzuki Coupling Reaction (Procedure A):
Pd(PPh3)4 (5 mol-%) was added to a degassed solution of haloge-
nated pyridine, K2CO3 (3 equiv.) and boronic acid (1.5 equiv.) in
dioxane/H2O (4:1 mL/0.4 mmol). The resulting mixture was heated
at reflux until completion as shown by TLC. After cooling to room
temperature, water was added, and the mixture was extracted with
CH2Cl2. The combined organic layer was dried with MgSO4, fil-
tered and concentrated. The crude product was purified by
chromatography (silica gel, hexane/EtOAc).
Figure 2. STM current image of pyridine derivative 16 at the inter-
face between an organic solution and the basal plane of HOPG.
Bright areas correspond to high current, indicating that the car-
boxyl groups dimerize and that the lamellae are formed by interdi-
gitating dimers (see implemented molecular model of 4ϫ16).[3c]
Between the lined-up head groups contrast due to the methylene
groups and the underlying graphite lattice can be recognized. Unit
cell size: a = 2.65 nm, b = 1.01 nm, α = 92.4°, A = 2.67 nm2.
Typical Procedure for Halogenation (Procedure B): A solution of
nBuLi (2.5  in hexane, 6 equiv.) was added dropwise at 0 °C to a
solution of 2-(dimethylamino)ethanol (3 equiv.) in hexane (1 mL/
mmol). After 30 min stirring at 0 °C, a solution of the correspond-
ing pyridine derivative in hexane (1 mL/mmol) was added dropwise.
The mixture was stirred at 0 °C for 1 h and then cooled to –78 °C
before the addition of a solution of the halogen source (3.5 equiv.,
tetrabromomethane or hexachloroethane) in hexane (1 mL/mmol).
The reaction mixture was stirred at –78 °C for 1 h before it was
allowed to warm to room temperature overnight. The hydrolysis
was then performed at 0 °C by the addition of water. The organic
layer was extracted with Et2O, dried with MgSO4 and concen-
trated. The crude oil was purified by chromatography (silica gel,
hexane/EtOAc).
Conclusions
We have developed a simple and efficient route to pyr-
idine derivatives by employing a combination of reported
cross-coupling methodologies, including Suzuki, Grignard
and Negishi reactions. The regioselective functionalization
of the pyridine core is induced by using the superbase
nBuLi–LiDMAE, as described by Gros and Fort, and this
base plays a crucial role in our sequences. By this way, a
broad range of unsymmetrically substituted and function-
alized pyridine derivatives can be prepared within a few
steps in high yields and excellent regioselectivities. Prelimi-
nary investigations of the properties of these derivatives on
HOPG are encouraging and further studies will be pub-
lished in due course.
Typical Procedure for Grignard Coupling Reaction (Procedure C):
The bromoalkane (2.5 equiv.) was added dropwise to a suspension
of magnesium turnings (10 equiv.) and iodine (few crystals) in dry
diethyl ether (1 mmol/mL). The reaction mixture was heated at re-
flux for 1 h and then added to a solution of the corresponding
chloropyridine derivative and Fe(acac)3 (10 mol-%) in THF/NMP
(10 mL/1 mL/mmol) cooled to 0 °C. The reaction mixture was
stirred at 0 °C for 15 min and then quenched with brine. After ex-
traction with CH2Cl2, the combined organic layer was dried with
MgSO4, filtered and concentrated. The resulting crude product was
purified by chromatography (silica gel, hexane/ethyl acetate).
Experimental Section
General Information: Reactions were performed under an atmo-
sphere of argon in flame-dried flasks; solvents and reagents were
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2-Chloro-6-phenylpyridine (8a): According to general procedure B,
2-DMAE (2.0 mL, 19 mmol) in hexane (15 mL), nBuLi (2.5  in
hexane, 15.6 mL, 39 mmol), 2-phenylpyridine (7) (1.00 g,
13C NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7 (t, CH2),
29.4–29.8 (br. signal, CH2), 31.9, 38.6 (2t, CH2), 117.6 (d, C-5),
120.9 (d, C-3), 127.0 (d, Ar), 128.6 (d*, Ar), 136.7 (d, C-4), 139.9
6.40 mmol) in hexane (10 mL) and C2Cl6 (5.34 g, 22.6 mmol) in (s, Ar), 156.7 (s, C-6), 162.4 (s, C-2) ppm. *Higher intensity. IR
hexane (15 mL) provided the crude product, which was purified by
chromatography with silica gel (hexane/EtOAc, 1:0 to 95:5) to af-
ford 8a as a slightly yellow oil (1.22 g, quant.). 1H NMR
(KBr): ν = 3090–2850 (CH), 1595–1445 (C=C) cm–1. MS (ESI-
˜
TOF): m/z (%) = 379 (35) [M]+·, 196 (34) [M – C13H27]+, 182 (46) [M –
C14H29]+, 169 (100) [M – C15H31]+. C27H41N (379.6): calcd. C
(500 MHz, CDCl3): δ = 7.25 (dd, J = 0.8, 7.8 Hz, 1 H, 5-H), 7.35 85.42, H 10.89, N 3.69; found C 85.32, H 11.27, N 3.62.
(dd, J = 0.8, 7.8 Hz, 1 H, 3-H), 7.40–7.49 (m, 3 H, Ar), 7.69 (t, J
= 7.8 Hz, 1 H, 4-H), 7.99 (br. d, J = 7.3 Hz, 2 H, Ar) ppm. 13C
NMR (126 MHz, CDCl3): δ = 118.8 (d, C-5), 122.6 (d, C-3), 127.1,
128.9, 129.7, 137.8 (3 d, s, Ar), 139.4 (d, C-4), 151.4 (s, C-2), 158.2
(s, C-6) ppm. MS (ESI): m/z (%) = 189 (100) [M + H]+, 154 (40)
[M – Cl]+. Spectroscopic data are consistent with data reported in
the literature.[6a]
2-Decylpyridine (3): According to general procedure C, Mg (2.14 g,
88.1 mmol), bromodecane (5.0 mL, 22 mmol) in dry Et2O (20 mL),
2-chloropyridine (2) (1.00 g, 8.81 mmol) and Fe(acac)3 (311 mg,
0.88 mmol) in dry THF/NMP (40 mL/4 mL) afforded the crude
product, which was purified by chromatography with silica gel
(hexane/EtOAc, 95:5) to give pyridine 3 as a colourless oil (1.51 g,
1
78%). H NMR (500 MHz, CDCl3): δ = 0.86 (t, J = 7.0 Hz, 3 H,
CH3), 1.23–1.35 (m, 14 H, 7 CH2), 1.70 (quint., J = 7.7 Hz, 2 H,
CH2), 2.76 (t, J = 7.7 Hz, 2 H, CH2), 7.06 (m, 1 H, 5-H), 7.11 (d,
J = 7.7 Hz, 1 H, 3-H), 7.55 (td, J = 1.8, 7.7 Hz, 1 H, 4-H), 8.50
(m, 1 H, 6-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.2 (q,
CH3), 22.7, 29.4, 29.5, 29.6, 29.6, 29.7, 30.0, 32.0, 38.6 (9t, CH2),
120.1 (d, C-5), 122.7 (d, C-3), 136.2 (d, C-4), 149.3 (d, C-6), 162.6
(s, C-2) ppm. MS (ESI-TOF): m/z (%) = 220 (100) [M + H]+.
HRMS (ESI-TOF): calcd. for C15H26N [M + H]+ 220.2060; found
220.2060. C15H25N (219.4): calcd. C 82.13, H 11.49, N 6.39; found
C 81.80, H 11.45, N 6.50.
2-Bromo-6-phenylpyridine (8b): According to general procedure B,
2-DMAE (2.0 mL, 19 mmol) in hexane (15 mL), nBuLi (2.5  in
hexane, 15.5 mL, 38.7 mmol), 2-phenylpyridine (7) (1.00 g,
6.40 mmol) in hexane (10 mL) and CBr4 (7.48 g, 22.6 mmol) in hex-
ane (15 mL) afforded the crude product, which was purified by
chromatography with silica gel (hexane/EtOAc, 1:0 to 95:5) to pro-
vide 8b as a yellow solid (1.51 g, quant.). M.p. 44–46 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.38 (dd, J = 1.3, 7.7 Hz, 1 H, 5-H), 7.39–
7.50 (m, 3 H, Ar), 7.65 (t, J = 7.7 Hz, 1 H, 4-H), 7.65 (dd, J = 1.3,
7.7 Hz, 1 H, 3-H), 7.97 (br. dd, J = 1.3, 7.7 Hz, 2 H, Ar) ppm. 13C
NMR (126 MHz, CDCl3): δ = 119.1 (d, C-5), 126.4 (d, C-3), 127.1,
128.9, 129.8, 137.7 (3 d, s, Ar), 139.1 (d, C-4), 142.2 (s, C-2), 158.6
(s, C-6) ppm. MS (ESI): m/z (%) = 233 (65) [M]+·, 235 (64) [M +
H]+, 154 (100) [M – Br]+. Spectroscopic data are consistent with
data reported in the literature.[6a]
2-(4-Methoxyphenyl)pyridine (10): According to general procedure
A, 2-bromopyridine (9) (180 mg, 1.14 mmol), K2CO3 (472 mg,
3.42 mmol) and p-methoxybenzeneboronic acid (260 mg,
1.71 mmol) in degassed dioxane/H2O (12 mL/3 mL) and Pd(PPh3)4
(66 mg, 0.06 mmol) were heated at reflux for 8 h to afford the crude
product, which was purified by chromatography with silica gel
(hexane/EtOAc, 9:1) to give 10 as a slightly yellow solid (200 mg,
2-Decyl-6-phenylpyridine (1a): According to general procedure C,
Mg (256 mg, 10.5 mmol), I2 (few crystals), bromodecane (0.60 mL,
2.64 mmol) in dry Et2O (3 mL), 8a (200 mg, 1.05 mmol) and Fe-
(acac)3 (37 mg, 0.10 mmol) in dry THF/NMP (10 mL/1 mL) pro-
vided the crude product, which was purified by chromatography
with silica gel (hexane/EtOAc, 95:5) to afford 1a (265 mg, 85%) as
a colourless oil. 1H NMR (500 MHz, CDCl3): δ = 0.91 (t, J =
7.0 Hz, 3 H, CH3), 1.28–1.43 (m, 14 H, 7 CH2), 1.82 (quint., J =
7.7 Hz, 2 H, CH2), 2.87 (t, J = 7.7 Hz, 2 H, CH2), 7.08 (d, J =
7.7 Hz, 1 H, 3-H), 7.38–7.43 (br. t, J = 7.5 Hz, 1 H, Ar), 7.47 (t, J
= 7.5 Hz, 2 H, Ar), 7.53 (d, J = 7.7 Hz, 1 H, 5-H), 7.64 (t, J =
7.7 Hz, 1 H, 4-H), 8.02 (dd, J = 1.0, 7.5 Hz, 2 H, Ar) ppm. 13C
NMR (126 MHz, CDCl3): δ = 14.2 (q, CH3), 22.8, 29.9, 29.8, 29.7,
29.6, 29.5, 29.4, 32.0, 38.7 (9t, CH2), 117.7 (d, C-5), 121.0 (d, C-
3), 127.1 (d, Ar), 128.7 (d*, Ar), 136.8 (d, C-4), 140.0 (s, Ar), 156.9
1
95%). M.p. 52–53 °C. H NMR (500 MHz, CDCl3): δ = 3.83 (s, 3
H, CH3O), 6.98 (dt, J = 2.6, 9.4 Hz, 2 H, Ar), 7.14 (m, 1 H, 5-H),
7.62–7.69 (m, 2 H, 3-H, 4-H), 7.94 (dt, J = 2.6, 9.4 Hz, 2 H, Ar),
8.64 (m, 1 H, 6-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 55.4
(q, CH3O), 114.2 (d, Ar), 119.9 (d, C-3), 121.5 (d, C-5), 128.2,
132.1 (d, s, Ar), 136.8 (d, C-4), 149.6 (d, C-6), 157.2 (s, C-2), 160.5
(s, Ar) ppm. IR (KBr): ν = 3100–2835 (CH), 1610–1405 (C=C,
˜
CN) cm–1. MS (ESI-TOF): m/z (%) = 186 (100) [M + H]+. HRMS
(ESI-TOF): calcd. for C12H12NO [M + H]+ 186.0919; found
186.0925. C12H11NO (185.2): calcd. C 77.81, H 5.99, N 7.56; found
C 77.39, H 5.81, N 7.55. Spectroscopic data are consistent with
data reported in the literature.[17]
4-(Pyridin-2-yl)benzaldehyde (11): According to general procedure
A, 2-bromopyridine (9) (500 mg, 3.16 mmol), K2CO3 (1.31 g,
9.49 mmol) and p-formylphenylboronic acid (712 mg, 4.75 mmol)
in degassed dioxane/H2O (40 mL/10 mL) and Pd(PPh3)4 (183 mg,
0.16 mmol) were heated at reflux for 8 h to afford the crude prod-
uct. This was purified by chromatography with silica gel (hexane/
EtOAc, 9:1 to 8:2) to give 11 (580 mg, quant.) as a pale-yellow
(s, C-6), 162.5 (s, C-2) ppm. *Higher intensity. IR (film): ν = 3085–
˜
2850 (CH), 1590–1445 (C=C) cm–1. MS (ESI-TOF): m/z (%) = 296
(100) [M + H]+. HRMS (ESI-TOF): calcd. for C21H30N [M +
H]+ 296.2378; found 296.2379. C21H29N (295.5): calcd. C 85.37, H
9.89, N 4.74; found C 85.00, H 10.25, N 4.07.
1
solid. M.p. 50–51 °C. H NMR (500 MHz, CDCl3): δ = 7.20–7.25
2-Hexadecyl-6-phenylpyridine (1b): According to general procedure
C, Mg (640 mg, 26.4 mmol), bromohexadecane (2.0 mL, 6.6 mmol)
in dry Et2O (6 mL), 2-chloropyridine (8a) (500 mg, 2.64 mmol) and
Fe(acac)3 (93 mg, 0.26 mmol) in dry THF/NMP (15 mL/1 mL) af-
forded the crude product, which was purified by chromatography
with silica gel (hexane/EtOAc, 1:0 to 95:5) to give 1b as a colourless
solid (543 mg, 54%). M.p. 33–34 °C. 1H NMR (500 MHz, CDCl3):
δ = 0.91 (t, J = 6.9 Hz, 3 H, CH3), 1.25–1.45 (m, 26 H, 13 CH2),
1.82 (quint., J = 7.7 Hz, 2 H, CH2), 2.87 (t, J = 7.7 Hz, 2 H, CH2),
7.08 (d, J = 7.7 Hz, 1 H, 3-H), 7.41 (br. t, J = 7.2 Hz, 1 H, Ar),
(m, 1 H, 5-H), 7.72 (m, 2 H, 3-H, 4-H), 7.90 (d, J = 8.4 Hz, 2 H,
Ar), 8.10 (d, J = 8.4 Hz, 2 H, Ar), 8.67 (dt, J = 1.4, 5.0 Hz, 1 H,
6-H), 10.00 (s, 1 H, CHO) ppm. 13C NMR (126 MHz, CDCl3): δ
= 121.2 (d, C-3), 123.2 (d, C-5), 127.5, 130.2, 136.4 (2d, s, Ar),
137.0 (d, C-4), 144.9 (s, Ar), 150.0 (d, C-6), 155.8 (s, C-2), 192.0
(d, CHO) ppm. MS (ESI-TOF): m/z (%) = 184 (100) [M + H]+.
HRMS (ESI-TOF): calcd. for C12H9NO [M + H]+ 184.0762; found
184.0768. Spectroscopic data are consistent with data reported in
the literature.[18]
7.47 (t, J = 7.2 Hz, 2 H, Ar), 7.53 (d, J = 7.7 Hz, 1 H, 5-H), 7.64 2-(4-Dimethoxymethylphenyl)pyridine (12): A solution of aldehyde
(t, J = 7.7 Hz, 1 H, 4-H), 8.03 (br. d, J = 7.2 Hz, 2 H, Ar) ppm. 11 (790 mg, 4.31 mmol), trimethyl orthoformate (2.1 mL, 19 mmol)
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Practical Routes to 2,6-Disubstituted Pyridine Derivatives
and p-toluenesulfonic acid (40 mg) in MeOH (40 mL) was stirred
at 50 °C for 3 h. After cooling to room temperature, the reaction
mixture was diluted with Et2O (300 mL) and washed with a solu-
tion of NaHCO3 (1 , 3ϫ). The combined organic layer was dried
with MgSO4, filtered and concentrated. The crude product was
purified by chromatography with silica gel (hexane/EtOAc, 8:2) to
afford pyridine 12 (835 mg, 84%) as a colourless oil. 1H NMR
(500 MHz, CDCl3): δ = 3.32 (s, 6 H, 2 CH3O), 5.44 (s, 1 H,
OCHO), 7.18 (sext., J = 5.0 Hz, 1 H, 5-H), 7.54 (br. d, J = 8.5 Hz,
2 H, Ar), 7.69 (m, 2 H, 3-H, 4-H), 7.98 (dt, J = 1.9, 8.5 Hz, 2 H,
Ar), 8.66 (br. d, J = 5.0 Hz, 1 H, 6-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 52.7 (q, CH3O), 102.8 (d, OCHO), 120.6 (d, C-3),
122.2 (d, C-5), 126.8, 127.2 (2d, Ar), 136.8 (d, C-4), 138.8, 139.6 (2
s, Ar), 149.8 (d, C-6), 157.1 (s, C-2) ppm. MS (ESI-TOF): m/z (%)
= 252 (5) [M + Na]+, 230 (100) [M + H]+. MS (ESI-TOF): calcd.
for C14H15NO2 [M + H]+ 230.1176; found 230.1172.
1.0, 7.6 Hz, 1 H, 3-H), 7.66 (t, J = 7.6 Hz, 1 H, 4-H), 7.98 (br. d,
J = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 52.7
(q, CH3O), 102.7 (d, OCHO), 118.8 (d, C-5), 122.7 (d, C-3), 126.9,
127.3, 137.9 (2 d, s, Ar), 139.4 (d, C-4), 139.6 (s, Ar), 151.4 (s, C-
2), 157.8 (s, C-6) ppm. MS (ESI-TOF): m/z (%) = 286 (7) [M +
Na]+, 266 (34), 264 (100) [M + H]+, 232 (18) [M – CH3O]+. HRMS
(ESI-TOF): calcd. for C14H14ClNO2 [M + H]+ 264.0791; found
264.0798.
Grignard Reaction: According to general procedure C, Mg (276 mg,
11.4 mmol), bromodecane (0.60 mL, 2.84 mmol) in dry Et2O
(3 mL), the 2-chloropyridine derivative (300 mg, 1.14 mmol) and Fe-
(acac)3 (40 mg, 0.11 mmol) in dry THF/NMP (10 mL/1 mL) af-
forded after work up the crude product, which was purified by
chromatography with silica gel (hexane/EtOAc, 95:5) to give 14
1
(357 mg, 85%) as a colourless oil. H NMR (500 MHz, CDCl3): δ
= 0.86 (mc, 3 H, CH3), 1.20–1.40 (m, 14 H, 7 CH2), 1.78 (m, 2 H,
CH2), 2.85 (t, J = 7.7 Hz, 2 H, CH2), 3.34 (s, 6 H, 2 CH3O), 5.46
(s, 1 H, OCHO), 7.07 (d, J = 7.3 Hz, 1 H, 5-H), 7.52 (br. d, J ≈
7.4 Hz, 1 H, 3-H), 7.54 (br. d, J ≈ 8.3 Hz, 2 H, Ar), 7.63 (t, J =
7.7 Hz, 1 H, 4-H), 8.00 (br. d, J = 8.4 Hz, 2 H, Ar) ppm. 13C NMR
(126 MHz, CDCl3): δ = 14.2 (q, CH3), 22.7, 29.4, 29.5, 29.6, 29.7,
29.8, 29.9, 32.0, 38.6 (9 t, CH2), 52.6 (q, CH3O), 102.9 (d, OCHO),
117.7 (d, C-5), 121.1 (d, C-3), 126.9, 127.2 (2 d, Ar), 136.8 (d, C-
4), 138.5, 140.1 ( 2s, Ar), 156.5 (s, C-6), 162.6 (s, C-2) ppm. MS
(ESI-TOF): m/z (%) = 370 (100) [M + H]+. HRMS (ESI-TOF):
calcd. for C24H35NO2 [M + H]+ 370.2746; found 370.2760.
2-Dodecyl-6-(4-methoxyphenyl)pyridine (13)
Chlorination: According to general procedure B, 2-DMAE
(0.50 mL, 5.40 mmol) in hexane (5 mL), nBuLi (2.5  in hexane,
2.6 mL, 6.5 mmol), pyridine derivative 10 (200 mg, 1.08 mmol) and
C2Cl6 (895 mg, 3.78 mmol) in hexane (5 mL) afforded the crude
product, which was purified by chromatography with silica gel
(hexane/EtOAc, 95:5) to give the 2-chloropyridine derivative as a
colourless solid (123 mg, 52%). M.p. 98–100 °C. 1H NMR
(500 MHz, CDCl3): δ = 3.85 (s, 3 H, CH3O), 6.97 (br. d, J = 9.0 Hz,
2 H, Ar), 7.17 (dd, J = 0.8, 7.8 Hz, 1 H, 5-H), 7.56 (dd, J = 0.8,
7.8 Hz, 1 H, 3-H), 7.63 (t, J = 7.8 Hz, 1 H, 4-H), 7.95 (br. d, J =
9.0 Hz, 2 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 55.4 (q,
CH3O), 114.2 (d, Ar), 117.9 (d, C-5), 121.7 (d, C-3), 128.4, 130.4
(d, s, Ar), 139.3 (d, C-4), 151.3 (s, C-2), 157.8 (s, C-6), 161.0 (s, Ar)
ppm. MS (ESI-TOF): m/z (%) = 220 (100) [M + H]+. HRMS (ESI-
TOF): calcd. for C12H10ClNO [M + H]+ 220.0524; found 220.0523.
4-(6-Decylpyridin-2-yl)benzaldehyde
(15):
TFA
(10.6 mL,
138 mmol) was added at room temperature to a solution of 14
(850 mg, 2.30 mmol) in CH2Cl2 (50 mL). The resulting orange
solution was stirred at room temperature for 45 min (TLC control)
and neutralized with saturated aqueous NaHCO3 solution. After
washing with saturated NaHCO3 solution and extraction with
CH2Cl2, the combined organic layer was dried with MgSO4, fil-
tered and concentrated to afford 15 (716 mg, 96%) as a colourless
solid, which was analytically pure. M.p. 37–39 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H, CH3), 1.25–1.41
(m, 14 H, 7 CH2), 1.79 (quint., J = 7.7 Hz, 2 H, CH2), 2.86 (t, J =
7.7 Hz, 2 H, CH2), 7.15 (d, J = 7.7 Hz, 1 H, 3-H), 7.59 (d, J =
7.7 Hz, 1 H, 5-H), 7.69 (t, J = 7.7 Hz, 1 H, 4-H), 7.97 (br. d, J =
8.4 Hz, 2 H, Ar), 8.18 (br. d, J = 8.4 Hz, 2 H, Ar), 10.05 (s, 1 H,
CHO) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7,
29.3, 29.4, 29.5, 29.6, 29.6, 29.7, 31.9, 38.4 (9 t, CH2), 118.4 (d, C-
3), 122.1 (d, C-5), 127.5, 130.1, 136.2 (2 d, s, Ar), 137.1 (d, C-4),
145.3 (s, Ar), 155.1 (s, C-2), 162.9 (s, C-6), 192.0 (d, CHO) ppm.
Grignard Reaction: According to general procedure C, Mg (111 mg,
4.55 mmol), bromododecane (0.30 mL, 1.14 mmol) in dry Et2O
(1 mL), the 2-chloropyridine derivative (100 mg, 0.46 mmol) and
Fe(acac)3 (16 mg, 0.05 mmol) in dry THF/NMP (10 mL/1 mL)
gave the crude product. which was purified by chromatography
with silica gel (hexane/EtOAc, 95:5) to afford 13 (159 mg, 99%) as
a colourless oil. 1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J =
7.0 Hz, 3 H, CH3), 1.20–1.43 (m, 18 H, 9 CH2), 1.80 (quint., J =
7.7 Hz, 2 H, CH2), 2.84 (t, J = 7.7 Hz, 2 H, CH2), 3.85 (s, 3 H,
CH3O), 6.99 (br. d, J = 9.0 Hz, 2 H, Ar), 7.02 (d, J = 7.7 Hz, 1 H,
5-H), 7.46 (d, J = 7.7 Hz, 1 H, 3-H), 7.59 (t, J = 7.7 Hz, 1 H, 4-
H), 7.97 (dt, J = 2.6, 9.0 Hz, 2 H, Ar) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.2 (q, CH3), 22.8, 29.4, 29.5, 29.6, 29.7, 29.7, 29.8,
29.8, 29.9, 32.0, 38.7 (11t, CH2), 55.4 (q, CH3O), 114.1 (d, Ar),
116.9 (d, C-5), 120.3 (d, C-3), 128.3 (d, Ar), 132.7 (s, Ar), 136.7 (d,
IR (KBr): ν = 3060–2725 (CH), 1700 (C=O), 1610–1570 (C=C)
˜
cm–1. MS (ESI-TOF): m/z (%) = 324 (100) [M + H]+, 197 (11)
[M – C9H19]+. HRMS (ESI-TOF): calcd. for C22H30NO [M + H]+
324.2322; found 324.2317. C22H29NO (323.5): calcd. C 81.69, H
9.04, N 4.33; found C 81.48, H 9.21, N 4.35.
C-4), 156.5 (s, C-6), 160.3 (s, Ar), 162.3 (s, C-2) ppm. IR (film): ν
˜
= 3065–2850 (CH), 1610–1440 (C=C) cm–1. MS (ESI-TOF): m/z
(%) = 354 (100) [M + H]+. HRMS (ESI-TOF): calcd. for
C24H35NO [M + H]+ 354.2797; found 354.2811. C24H35NO (353.5):
calcd. C 81.53, H 9.98, N 3.96; found C 81.55, H 9.64, N 3.90.
4-(6-Decylpyridin-2-yl)benzoic Acid (16): A solution of NaClO2
(36 mg, 0.40 mmol) in pH 3.5 buffer (3 mL NaH2PO4) was added
dropwise to a rapidly stirred solution of aldehyde 15 (100 mg,
0.31 mmol) and 2-methyl-2-butene (0.30 mL, 3.10 mmol) in tBuOH
2-Decyl-6-[(4-dimethoxymethyl)phenyl]pyridine (14)
Halogenation: According to general procedure B, 2-DMAE (15 mL). The solution was stirred at room temperature overnight,
(0.70 mL, 7.56 mmol) in hexane (5 mL), nBuLi (2.5  in hexane,
4.4 mL, 11 mmol), acetal 12 (500 mg, 2.18 mmol) in hexane (5 mL)
and C2Cl6 (1.81 g, 7.63 mmol) in hexane (10 mL) provided the
crude product, which was purified by chromatography with silica
gel (hexane/EtOAc, 95:5) to give the 2-chloropyridine derivative as
a colourless oil (460 mg, 80%). H NMR (500 MHz, CDCl3): δ =
3.32 (s, 6 H, 2 CH3O), 5.43 (s, 1 H, OCHO), 7.22 (dd, J = 1.0,
7.6 Hz, 1 H, 5-H), 7.53 (br. d, J = 8.4 Hz, 2 H, Ar), 7.61 (dd, J =
basified with NaOH (1 , to pH 10) and tBuOH was removed un-
der vacuum. After addition of water, the solution was extracted
with hexane, the aqueous layer was acidified with HCl (2%, to pH
4) and extracted with Et2O. The combined organic layer was dried
with MgSO4, filtered and concentrated to afford 16 as a colourless
solid, which was washed with pentane (80 mg, 76%). M.p. 146–
148 °C. 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H,
CH3), 1.26–1.42 (m, 14 H, 7 CH2), 1.81 (quint., J = 7.7 Hz, 2 H,
1
Eur. J. Org. Chem. 2008, 2049–2055
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2053

L. Vandromme, H.-U. Reißig, S. Gröper, J. P. Rabe
CH2), 2.87 (t, J = 7.7 Hz, 2 H, CH2), 7.15 (d, J = 7.7 Hz, 1 H, 3- mixture was stirred for 15 min and then added to a mixture of
FULL PAPER
H), 7.60 (d, J = 7.7 Hz, 1 H, 5-H), 7.69 (t, J = 7.7 Hz, 1 H, 4-H),
8.12, 8.20 (2 d, J = 8.4 Hz, 2 H each, Ar) ppm. No signal detected
for CO2H. 13C NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7,
29.3, 29.4, 29.5, 29.6*, 29.7, 31.9, 38.5 (8 t, CH2), 118.2 (d, C-3),
122.0 (d, C-5), 127.0, 129.1, 130.6 (d, s, d, Ar), 137.0 (d, C-4), 144.8
(s, Ar), 155.4 (s, C-2), 162.8 (s, C-6), 171.0 (s, CO2H) ppm. *Higher
bromopyridine derivative 8b (82 mg, 0.35 mmol) and trans-
PdCl2(PPh3)2 (12 mg, 0.02 mmol). The resulting mixture was
stirred at 65 °C for 5 h and after cooling to room temperature Et2O
was added. After washing with saturated aqueous NH4Cl solution,
the organic layer was dried with MgSO4, filtered and concentrated.
The crude oil was purified by chromatography with silica gel (hex-
ane/EtOAc: 98:2) to give 19 (160 mg, 76%) as a yellow solid. M.p.
intensity. IR (KBr): ν = 3065–2845 (CH), 2720–2550 (O–H), 1675
˜
(C=O), 1610–1510 (C=C), 1290 (C–O) cm–1. MS (ESI-TOF): m/z
(%) = 340 (100) [M + H]+. HRMS (ESI-TOF): calcd. for
C22H30NO2 [M + H]+ 340.2277; found 340.2269. C22H29NO2
(339.5) + 1/2 H2O: calcd. C 75.83, H 8.68, N 4.02; found C 75.76,
H 8.53, N 4.04.
54–55 °C. H NMR (500 MHz, CDCl3): δ = 2.73 (mc, 2 H, CH2),
1
3.15 (mc, 2 H, CH2), 7.12 (d, J = 7.6 Hz, 1 H, 3-H), 7.42 (tt, J =
1.6, 7.3 Hz, 1 H, Ar), 7.48 (br. t, J = 7.3 Hz, 2 H, Ar), 7.60 (d, J
= 7.7 Hz, 1 H, 5-H), 7.68 (t, J = 7.7 Hz, 1 H, 4-H), 8.02 (dt, J =
1.6, 7.3 Hz, 2 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 28.7
(t, CH2), 30.3 (t, JC,F = 22 Hz, CH2), 118.4 (d, C-5), 121.3 (d, C-
3), 126.9, 128.8, 129.1 (3 d, Ar), 137.3 (d, C-4), 139.3 (s, Ar), 157.0
4-(6-Decylpyridin-2-yl)benzaldehyde Oxime (17): Hydroxylamine
hydrochloride (172 mg, 2.47 mmol) was added to a solution of al-
dehyde 15 (400 mg, 1.24 mmol) and K2CO3 (171 mg, 1.24 mmol)
in a mixture of MeOH/H2O (15 mL/1.5 mL). The resulting solution
was heated at reflux for 2 h. At room temperature H2O was added,
and the aqueous layer was extracted with Et2O. The combined or-
ganic layer was dried with MgSO4, filtered and concentrated to
give oxime 17 as a colourless solid (402 mg, 96%), which was used
without any further purification. M.p. 69–71 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.87 (t, J = 7.0 Hz, 3 H, CH3), 1.25–1.42
(m, 14 H, 7 CH2), 1.79 (quint., J = 7.7 Hz, 2 H, CH2), 2.86 (t, J =
7.7 Hz, 2 H, CH2), 7.11 (d, J = 7.7 Hz, 1 H, 3-H), 7.54 (d, J =
7.7 Hz, 1 H, 5-H), 7.64–7.68 (m, 3 H, 4-H, Ar), 8.02 (br. d, J =
8.4 Hz, 2 H, Ar), 8.19 (s, 1 H, CHN), 8.20 (br. s, 1 H, OH) ppm.
13C NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7, 29.3, 29.4,
29.5, 29.6, 29.6, 29.8, 31.9, 38.5 (9 t, CH2), 117.8 (d, C-3), 121.4
(d, C-5), 127.3, 127.4, 132.3 (2 d, s, Ar), 136.9 (d, C-4), 141.2 (s,
Ar), 150.0 (d, CHN), 155.9 (s, C-2), 162.7 (s, C-6) ppm. MS (ESI-
TOF): m/z (%) = 339 (100) [M + H]+. HRMS (ESI-TOF): calcd.
for C22H30N2O [M + H]+ 339.2436; found 339.2433.
(s, C-6), 158.4 (s, C-2) ppm. IR (KBr): ν = 3095–2870 (CH), 1595–
˜
1575 (C=C), 1315–1090 (C–F) cm–1. MS (EI): m/z (%) = 601 (100)
[M]+·, 231 (62) [M – C7F15]+, 181 (27) [M – C8F17]+. HRMS: calcd.
for C21H12F17N [M]+· 601.06928; found: 601.06929. C21H12F17N
(601.3): calcd. C 41.95, H 2.01, N 2.33, F 53.71; found C 42.37, H
2.13, N 2.36, F 53.0.
Acknowledgments
Support of this work by the Deutsche Forschungsgemeinschaft
(SFB 765), the Fonds der Chemischen Industrie and the Bayer
Schering Pharma AG is most gratefully acknowledged. We also
thank Dr. R. Zimmer and Dr. J. N. Martin for help during prepara-
tion of the manuscript.
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4-(6-Decylpyridin-2-yl)benzonitrile (18): To a solution of oxime 17
(380 mg, 1.12 mmol) in CH2Cl2 (15 mL) was added SOCl2
(1.00 mL, 11.3 mmol). The mixture was stirred at room tempera-
ture overnight. After evaporation of the solvent, the residue was
dissolved in EtOAc and washed with saturated aqueous NaHCO3
solution. The combined organic layer was dried with MgSO4, fil-
tered and concentrated. The crude oil was then purified by
chromatography with silica gel (hexane/EtOAc, 95:5) to give 18
(345 mg, 96%) as a colourless solid. M.p. 39–40 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H, CH3), 1.20–1.40
(m, 14 H, 7 CH2), 1.79 (quint., J = 7.7 Hz, 2 H, CH2), 2.85 (t, J =
7.7 Hz, 2 H, CH2), 7.16 (d, J = 7.7 Hz, 1 H, 3-H), 7.56 (d, J =
7.7 Hz, 1 H, 5-H), 7.69 (t, J = 7.7 Hz, 1 H, 4-H), 7.74, 8.13 (2 dt,
J = 1.8, 8.6 Hz, 2 H each, Ar) ppm. 13C NMR (126 MHz, CDCl3):
δ = 14.1 (q, CH3), 22.7, 29.3, 29.4, 29.5, 29.5, 29.6, 29.7, 31.9, 38.5
(9 t, CH2), 112.1 (s, Ar), 118.0 (s, CN), 118.9 (d, C-3), 122.3 (d, C-
5), 127.5, 132.4 (2 d, Ar), 137.1 (d, C-4), 143.9 (s, Ar), 154.4 (s, C-
2), 163.0 (s, C-6) ppm. IR (KBr): ν = 3080–2850 (CH), 2230
˜
(CϵN), 1610–1570 (C=C) cm–1. MS (ESI-TOF): m/z (%) = 321
(100) [M + H]+. HRMS (ESI-TOF): calcd. for C22H29N2 [M +
H]+ 321.2325; found 321.2327. C22H28N2 (320.5): calcd. C 82.45,
H 8.81, N 8.74; found C 82.17, H 8.64, N 8.61.
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in dry THF (1 mL) was added 1,2-dibromoethane (0.02 mL,
0.18 mmol). The mixture was heated at reflux to initiate the reac-
tion and cooled to room temperature. Then, Me3SiCl (0.01 mL,
0.07 mmol) was added. After 10 min, a solution of ICH2CH2C8F17
20 (500 mg, 0.88 mmol) in THF (1 mL) was added dropwise. The
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: December 18, 2007
Published Online: March 3, 2008
Eur. J. Org. Chem. 2008, 2049–2055
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