In search of oligo(2-thienyl)-substituted pyridine derivatives: A modular approach to di-, tri- and tetra(2-thienyl)pyridines

Article abstract of DOI:10.1002/chem.201101739

Herein, we describe our attempts to systematically prepare a series of oligo(2-thienyl)-substituted pyridine derivatives. The crucial starting material, a β-alkoxy-β-ketoenamide, is easily available on a large scale by the reaction of lithiated methoxyallene with thiophene-2-carbonitrile and thiophene-2-carboxylic acid. This three-component reaction is followed by intramolecular cyclization to yield the suitably functionalized 2,6-di(2-thienyl)-substituted pyridine derivates. The two oxygen atoms allow the programmed activation of positions C-3, C-4, or C-5 of the pyridine ring to perform palladium-catalyzed coupling reactions with thiophene-2-boronic acid or 2-(tributylstannyl)thiophene, and alternatively, reductive removal of groups. With this concept, we were able to prepare five pyridine derivatives with 2-thienyl substituents in the 2,6-, 2,3,6-, 2,4,6-, 2,3,4,6-, and 2,3,5,6-positions. 2,3,4,5,6-Penta(2-thienyl)pyridine was not available with our methods. The UV/Vis and fluorescence spectra of all pyridines were recorded and showed a dependence on the substitution pattern and protonation state. For the protonated 2,3,5,6-tetra(2-thienyl)-substituted pyridine, a Stokes shift of about 180 nm with an emission at 515 nm was observed.

Full text of DOI:10.1002/chem.201101739

DOI: 10.1002/chem.201101739
In Search of Oligo(2-thienyl)-Substituted Pyridine Derivatives: A Modular
Approach to Di-, Tri- and Tetra(2-thienyl)pyridines
Mrinal K. Bera, Paul Hommes, and Hans-Ulrich Reissig*[a]
Dedicated to Professor Siegfried Hꢀnig on the occasion of his 90th birthday
Abstract: Herein, we describe our at-
tempts to systematically prepare
series of oligo(2-thienyl)-substituted
pyridine derivatives. The crucial start-
derivates. The two oxygen atoms allow
the programmed activation of positions
C-3, C-4, or C-5 of the pyridine ring to
perform palladium-catalyzed coupling
reactions with thiophene-2-boronic
acid or 2-(tributylstannyl)thiophene,
and alternatively, reductive removal of
groups. With this concept, we were
able to prepare five pyridine deriva-
tives with 2-thienyl substituents in the
2,6-, 2,3,6-, 2,4,6-, 2,3,4,6-, and 2,3,5,6-
positions. 2,3,4,5,6-Penta(2-thienyl)pyri-
dine was not available with our meth-
ods. The UV/Vis and fluorescence
spectra of all pyridines were recorded
and showed a dependence on the sub-
stitution pattern and protonation state.
a
ing material,
a
b-alkoxy-b-ketoen-
ACHTUNGTRENNUNG
scale by the reaction of lithiated me-
thoxyallene with thiophene-2-carboni-
trile and thiophene-2-carboxylic acid.
This three-component reaction is fol-
lowed by intramolecular cyclization to
yield the suitably functionalized
For the protonated 2,3,5,6-tetraACHTUNGTRENNUNG(2-
Keywords: allenes · fluorescence ·
nonaflates · palladium · pyridines ·
thiophenes
thienyl)-substituted pyridine, a Stokes
shift of about 180 nm with an emission
at 515 nm was observed.
2,6-di(2-thienyl)-substituted
pyridine
Introduction
the introduction of a broad range of new substituents at the
pyridine ring by palladium-catalyzed couplings leading to
products with general structure D.[12] To demonstrate the ro-
bustness, scope, and limitation of our methods, we tackled
the problem of preparing all types of oligo(2-thienyl)-substi-
tuted pyridine derivatives.[13] The absorption and emission
behavior of the resulting compounds were also investigated.
Thiophenes[1] and pyridines[2] are among the most important
five- and six-membered heterocycles. Whereas thiophene
units are present in many compounds of interest in materials
science,[3] in particular, as organic electronic materials,[4] the
pyridine substructure is very common in biologically active
and pharmaceutically relevant compounds,[5] as well as in
building blocks used in supramolecular chemistry.[6] Surpris-
ingly, no systematic combinations of these two important
classes of heterocycles have been attempted,[7,8] for example,
compounds with a pyridine core surrounded by a definite
number of 2-thienyl substituents such as A. Compounds of
this type should be of considerable interest with regard to
their optical and electronic properties.[9,10] Our group has re-
cently discovered an extremely flexible method to prepare
highly functionalized pyridine derivatives of type B,[11] which
allows the introduction of a broad range of substituents in
all five positions of the heterocycle. The 3-, 4- and 5-posi-
tions of B can be modified to selectively generate com-
pounds of type C containing functional groups that allow
Results and Discussion
Our reaction sequence starts with the addition of lithiated
methoxyallene 2 (generated in situ from methoxyallene 1 by
treatment with n-butyllithium)[14] to thiophene-2-carbonitrile
(3) and subsequent treatment with an excess of thiophene-2-
carboxylic acid (4) (Scheme 1). The desired b-alkoxy-b-ke-
toenamide 5 was isolated in 70% yield in multigram quanti-
ties.[15] The mechanism of this reaction has been described
earlier in detail[11a] and is not presented here again. The in-
tramolecular aldol-type condensation of the methyl ketone
moiety of 5 with its amide carbonyl group is promoted by
TMSOTf and triethylamine providing 71% of tetrasubstitut-
ed pyridine derivative 6. This key compound was subse-
quently converted into nonaflate 7 by deprotonation with
[a] Dr. M. K. Bera, P. Hommes, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie
Freie Universitꢁt Berlin, Takustr. 3
14195 Berlin (Germany)
Fax : (+49)30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101739.
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FULL PAPER
Next, we planned to synthesize a symmetrically substitut-
ed tri(2-thienyl)- and two tetra(2-thienyl)pyridine deriva-
tives. The thiophene moiety was introduced into the 4-posi-
tion of the pyridine core by performing a Suzuki coupling of
nonaflate 7 with boronic acid 11 to give intermediate 14 in
excellent yield (Scheme 3). Subsequent deprotection with
Scheme 1. Synthesis of b-alkoxy-b-ketoenamide 5 and subsequent trans-
formations into pyridine derivatives 6, 7, 8, and 9. Reagents and condi-
tions: a) nBuLi, Et2O, À708C, 4 h; then thiophene-2-carboxylic acid (4),
À708C to RT, 12 h; b) Et3N, trimethylsilyl triflate (TMSOTf), 1,2-di-
chloroethane, sealed tube, 1008C, 5 d; c) NaH, nonaflyl fluoride (NfF),
THF, RT, 6 h; d) PdACHTUNGTRENNUNG(OAc)2, 1,3-bis(diphenylphosphino)propane (DPPP),
Et3N, HCO2H, DMF, sealed tube, 908C, 2 h; e) BBr3 (1m in CH2Cl2),
CH2Cl2, 08C to RT, 12 h.
sodium hydride and the addition of NfF.[16] Subsequent re-
ductive removal of the nonaflate unit[17] gave trisubstituted
pyridine derivative 8, which was transformed into 3-hy-
droxy-2,6-di(2-thienyl)pyridine (9) by treatment with boron
tribromide in good overall yield. Compounds 6, 7, 8, and 9
are crucial precursors in our efforts to prepare the desired
oligo(2-thienyl)-substituted pyridine derivatives A.
Compound 9 was converted into the corresponding pyrid-
3-yl nonaflate 10 under standard conditions in very good
yield. This intermediate served as a precursor for the synthe-
sis of 2,6-di(2-thienyl)pyridine (13) and of 2,3,6-tri(2-thie-
nyl)pyridine (12) (Scheme 2). The trisubstituted compound
12 was formed in moderate yield by Suzuki coupling with
11, whereas the disubstituted pyridine derivative 13 was ob-
tained by reductive removal of the nonafloxy substituent
under palladium catalysis. The first two compounds of our
series have hence been prepared in fairly short sequences
without any problems.
Scheme 3. Suzuki coupling of pyrid-4-yl nonaflate 7, deprotection of 14
to 15, and subsequent syntheses of tri- and tetrasubstituted pyridine de-
rivatives 17 and 18. Reagents and conditions: a) 11, [Pd
DMF, 708C, 8 h; b) NaSEt, DMF, 908C, sealed tube, 2 h; c) NaH, NfF,
THF, RT, 12 h; d) Pd(OAc)2, DPPP, Et3N, HCO2H, DMF, sealed tube,
908C, 2 h; e) 11, [Pd(PPh3)4], K2CO3, DMF, 808C, 24 h.
ACHTNUGERTN(NUGN PPh3)4], K2CO3,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
sodium ethanethiolate efficiently afforded 3-hydroxy-2,4,6-
tri(2-thienyl)pyridine (15), which was converted into nona-
flate 16 in excellent yield. This nonaflate was then reductive-
ly converted into the desired symmetrically substituted pyri-
dine derivative 17 with 2-thienyl groups in the 2-, 4-, and
6-positions. Our first attempt to prepare tetrasubstituted
compound 18 employed a Suzuki coupling of nonaflate 16
with boronic acid 11. This resulted in a mixture of the de-
sired product 18 (45%) together with the desulfonylated
compound 15 (30%). It is known that aryl triflates and non-
aflates can undergo this reaction under basic conditions,[18]
and is very likely to be due to attack of a nucleophilic spe-
cies present to the sulfur atom of the leaving group.
Alternatively, we prepared bisACTHNUTRGNEUGN(triflate) 20 by deprotection
of compound 6 and treatment of the resulting 3,4-dihydroxy-
pyridine derivative 19 with Tf2O and base (Scheme 4). Bis-
AHCTUNGTRENNUNG
Scheme 2. Preparation and conversion of pyrid-3-yl nonaflate 10 into di-
and trisubstituted pyridine derivatives 13 and 12. Reagents and condi-
tions: a) NaH, NfF, THF, RT, 6 h; b) thiophene-2-boronic acid (11),
AHCTUNGTRENNUNG
was also subjected to reductive removal of the trifloxy
PdACHTUNGTRENNUNG(OAc)2, K2CO3, PPh3, DMF, 708C, 12 h; c) PdAHCTUNGTREN(NUGN OAc)2, DPPP, Et3N,
HCO2H, DMF, sealed tube, 908C, 2 h.
groups, which again provided 13 (70% yield).
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H.-U. Reissig et al.
cates that the Suzuki coupling of 22 probably proceeds
faster at the 5-iodo than at the 4-triflate position.
With the aim of synthesizing 28, we tried to achieve the
missing transformations with 23. Deprotection to 25 fol-
lowed by nonaflation to 26 or by triflation to 27, respective-
ly, proceeded without any particular problems and in good
to excellent yields (Scheme 6). The two activated com-
Scheme 4. Synthesis of bisACTHNUTRGNEUG(N triflate) 20 as a precursor of di- and tetrasub-
stituted pyridine derivatives 13 and 18. Reagents and conditions: a) 1m
ionic liquid consisting of 2AlCl3/Me3NHCl in CH2Cl2, RT, 2 h;
b) trifluoro
ACHTUNGTRENNUNG
pyridine (DMAP), CH2Cl2, 08C to RT, 12 h; c) 11, PdAHCTUNGTRENNUNG
PPh3, DMF, 808C, 24 h; d) Pd
tube, 908C, 2 h.
ACHTUNGTRENNUNG
Finally, we tried to prepare the penta(2-thienyl)-substitut-
ed pyridine derivative 28. To make our intermediates ready
for this target, an additional activating group had to be in-
stalled, allowing coupling reactions in the as yet unsubstitut-
ed 5-position of the pyridine core. Compound 6 was again
an ideal precursor for this plan because iodination under
basic conditions[11c] converted this pyridinol derivative into
pentasubstituted product 21 offering three potential activat-
ing groups in good yield (Scheme 5). Transformation of the
free hydroxyl group into a triflate gave compound 22 under
standard conditions in excellent yield. The twofold Stille
coupling of this intermediate with 2-(tributylstannyl)thio-
phene smoothly gave the desired tetra(2-thienyl)-substituted
pyridine derivative 23 in 75% yield, whereas the Suzuki
coupling of 22 with 11 gave a mixture of 23 (45%) together
with the desulfonylated compound 24. This experiment indi-
Scheme 6. Preparation of nonaflate 26 and triflate 27 and attempted cou-
pling reactions to synthesize pentasubstituted pyridine derivative 28. Re-
agents and conditions: a) NaSEt, DMF, sealed tube, 908C, 2 h; b) NaH,
NfF, THF, RT, 12 h; c) Tf2O, Et3N, DMAP, CH2Cl2, 08C to RT, 8 h; d) 11,
[Pd
[Pd
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
pounds 26 and 27 were ready for subsequent coupling reac-
tions, however, the attempted Suzuki reactions with 11
failed to generate the desired product 28. In both cases, in-
stead of 28 only the unsymmetrical tetrasubstituted pyridine
derivative 18 was isolated in moderate yields as a result of
reductive removal of the trifloxy or nonafloxy group. Similar
events during attempted Suzuki couplings have been report-
ed in the literature, for example, for calix[4]arene triflates,
halopyrimidine, and halopyrrole derivatives.[19] The reducing
agent in this side reaction is most likely to be DMF.[19b] As
an alternative, we also tried to perform Stille couplings with
26 and 27, but these attempts also failed and gave unidenti-
fiable mixtures of products. These negative results indicate
the limitations of our modular approach to highly substitut-
ed pyridine derivatives.
The final palladium-catalyzed couplings of compounds
such as 26 and 27 are apparently hampered by steric hin-
drance or by electronic deactivation. The oxidative addition
of palladium(0) probably occurs (as indicated by the isola-
tion of the reduction product 18; Scheme 6), but subsequent
transmetallation with the boron (or tin) species seems to be
unfavorable in this case. We cannot rule out that the pres-
ence of two neighboring thiophene substituents displays an
“electronic” effect on the intermediate palladium(II) spe-
cies, possibly in a pincer-type position between two sulfur
atoms. Additional studies should reveal whether less bulky
Scheme 5. Synthesis of 5-iodo-substituted pyridinol derivative 21 and sub-
sequent functionalization leading to pyridine derivatives 22, 23, and 24.
Reagents and conditions: a) I2, Na2CO3, THF/H2O (1:1), RT, 24 h;
b) Tf2O, pyridine (Py), DMAP, CH2Cl2, RT, 4 h; c) 2-(tributylstannyl)-
ACHTUNGTRENNUNGthiophene, [PdACHTUNGTRENNUNG(PPh3)4], DMF, 1208C, 2 h.
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Oligo(2-thienyl)-Substituted Pyridine Derivatives
FULL PAPER
substituents are more suitable for coupling to the “small
gap” offered in molecules such as 26 or 27 as opposed to
2-thienyl groups. It has to be mentioned here that a pyrid-3-
yl nonaflate (with substituents different from 2-thienyl) was
able to undergo a Suzuki coupling to a pentasubstituted pyr-
idine derivative in low yield, with reductive removal of the
nonafloxy group as a competing reaction.[11e]
Starting with semi-protected pentasubstituted pyridine de-
rivative 24, we could also prepare the symmetrical tetra(2-
thienyl)-substituted pyridine 33 and the unsymmetrical tri(2-
thienyl)-substituted pyridine 12 (Scheme 7). The required
steps follow the methods described above and consist of
nonaflation to intermediate 29, reductive removal of the
nonafloxy group to give 30, and subsequent deprotection
and triflation of 31 to give key compound 32. All transfor-
mations proceeded in good to excellent yields. Finally,
2,3,5,6-tetra(2-thienyl)pyridine (33) was obtained in moder-
ate yield by the standard Suzuki procedure employing 11 as
a component, whereas trisubstituted compound 12 was ob-
tained by this route through reduction of 32 in good yield.
fluence of the substitution pattern, whereas with increasing
number of 2-thienyl substituents the shoulder of these ab-
sorptions are systematically redshifted from about 330 to
355 nm. The 3-methoxy group as present in compounds 8
and 23 displays a stronger effect, shifting this shoulder to
about 355 nm.
The emission is more dependent on the substitution pat-
tern, resulting in smaller Stokes shifts for compounds with
2-thienyl substituents in 2,6- or 2,4,6-positions (ca. 90 nm for
compounds 13 and 17). Pyridine derivatives with 2-thienyl
groups in the 2,3-positions (12 and 18) show higher Stokes
shifts of about 105 nm, whereas the emission of the symmet-
rical tetrasubstituted pyridine 33 results in the strongest
Stokes shift of 172 nm. Methoxy groups cause emissions at
longer wavelengths than those of the pyridine derivatives
without these substituents (compare 8 with 13 and 23 with
18, Table 1). The UV/Vis and fluorescence spectra of 33 are
depicted in Figure 1.
Figure 1. UV (dashed lines) and fluorescence spectra (solid lines) of 33 in
CHCl3 (lines 1) and in CHCl3 with 1% TFA (lines 2).
A mixture of chloroform/TFA (99:1) should be sufficient
to fully protonate the pyridine derivatives dissolved. The ab-
sorption and emission data of the resulting pyridinium salts
are also included in Table 1, but are not discussed in detail.
All absorptions are shifted to longer wavelengths, but there
seems to be no general pattern if just the lmax values are
considered. The fluorescence of the protonated species leads
to emissions in the range of 445 to 515 nm. Tetrasubstituted
compound 33 shows the highest Stokes shift of 182 nm in
the protonated form. The fluorescence spectrum of proton-
ated 33 is also integrated into Figure 1.
Scheme 7. Synthesis of 3-trifloxy pyridine derivative 32 and subsequent
transformations into tetra- and trisubstituted pyridines 33 and 12. Re-
agents and conditions: a) NaH, NfF, THF, RT, 8 h; b) PdACTHUNRGTNEUNG(OAc)2, DPPP,
Et3N, HCO2H, DMF, sealed tube, 908C, 2 h; c) BBr3 (1m in CH2Cl2), 08C
to RT, 12 h; d) Tf2O, Et3N, DMAP, CH2Cl2, 08C to RT, 4 h; e) 11, [Pd-
A
ACHTUGNTRENNUN(G OAc)2, DPPP, Et3N, HCO2H,
Absorption and fluorescence spectra: With symmetrical and
unsymmetrical oligo(2-thienyl)-substituted pyridine deri-
vates in hand, we started to study their photophysical prop-
erties. The data of the absorption and emission in chloro-
form are collected in Table 1 and compared with the corre-
sponding spectra of the protonated compounds obtained by
using a solution in chloroform containing 1% of trifluoro-
acetic acid (TFA). The neutral pyridine derivatives generally
show the strongest absorption at 290 to 305 nm with little in-
Conclusion
Our building block system allowed the modular synthesis of
a series of 2-thienyl-substituted pyridine derivatives. Starting
from 1, 3, and 4, a suitably functionalized 2,6-di(2-thienyl)-
substituted pyridine derivative was obtained. Compound 11,
as additional thiophene component, and standard operations
led to the simple preparation of di-, tri- and tetra-substituted
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H.-U. Reissig et al.
Table 1. Absorption and emission data of 2-thienyl-substituted pyridine derivatives.
2-Thienyl
pyridine
In CHCl3
emission[b,c]
In CHCl3/TFA (99:1)
absorption[a]
lmax [nm], (log e)
Stokes shift
[nm]
absorption[a]
lmax [nm], (log e)
emission[b,c]
Stokes shift
[nm]
lmax [nm]
lmax [nm]
290 (4.27), 329 (sh) (4.12)
294 (4.29), 352 (sh) (4.18)
377
87
383 (4.34), 279 (sh) (4.14)
403 (4.35), 299 (sh) (4.17)
445
476
62
73
402
108
300 (4.29), 332 (sh) (4.25)
299 (4.60), 348 (sh) (3.97)
303 (4.28), 340 (sh) (4.28)
301 (4.51), 343 (sh) (4.11)
402, 422 (sh)
102
93
392 (4.23), 329 (sh) (4.16)
362 (4.51), 283 (sh) (4.26)
333 (4.28), 389 (sh) (4.17)
378 (4.26), 292 (sh) (4.10)
486
452
515
474
94
100
182
96
392
475, 451 (sh)
172
107
408
300 (4.35), 355 (sh) (4.04)
418
118
326 (4.09), 404 (sh) (4.08)
506
180
[a] Recorded at c=10À5 molLÀ1 in 1 cm cuvettes. [b] Excitation at maximum absorption wavelength. [c] Recorded at c=10À5–10À6 molLÀ1 in 1 cm cuv-
ettes.
pyridine derivatives. The desired compound 28 was not
available due to severe steric hindrance (or specific elec-
tronic effects) in the attempted final coupling step, hence
showing the limitation of our approach to this class of com-
pounds. The resulting oligo-2-thienyl-substituted pyridine
derivatives show interesting photophysical properties, as
demonstrated by their absorption and qualitatively studied
fluorescence. Absorption and emission are strongly influ-
enced by the number and position of 2-thienyl substituents.
Symmetrically substituted 33 not only showed the strongest
Stokes shift in the neutral form, but also as a protonated
species with an emission at 515 nm. These results demon-
strate that oligo(2-thienyl)-substituted pyridines are interest-
ing compounds, the properties of which should be studied in
more detail. The redox properties of these heterocycles and
related compounds, including pyridine derivatives with
2,2’-di-5-thienyl substituents, will be reported in due course.
Experimental Section
The Experimental Section can be found in the Supporting Information
and includes full compound characterization.
Acknowledgements
Support of this work by the Alexander von Humboldt Foundation (fel-
lowship for M.K.B.), the Deutsche Forschungsgemeinschaft, the Center
for Supramolecular Interactions of the Freie Universitꢁt Berlin (fellow-
11842
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Chem. Eur. J. 2011, 17, 11838 – 11843

Oligo(2-thienyl)-Substituted Pyridine Derivatives
FULL PAPER
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knowledged. We thank Dr. R. Zimmer for his help during preparation of
this manuscript.
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Received: June 7, 2011
Published online: September 6, 2011
Chem. Eur. J. 2011, 17, 11838 – 11843
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11843