Synthesis of planar chiral N-heterocyclic-substituted pyridinophanes

Article abstract of DOI:10.1002/ejoc.201201286

Four new planar chiral N-heterocyclic-substituted [2](1,4)benzene[2](2,5) pyridinophanes have been synthesized. With the attached pyrazole, triazole, tetrazole, and pyrimidine moieties, different N,N-chelating ligands that vary in the number of enclosed nitrogen atoms, ring size, and electronic properties were added to a mostly neglected class of pyridinophanes. Additionally, the known synthesis of the pyridinophane scaffold was simplified considerably. With the acetyl, amino, and amido pyridinophane, various useful intermediates for new pyridinophane ligands were synthesized, which would allow for further investigations of this ligand system. New planar chiral bis(heterocyclic) N-donors based on the rarely investigated class of [2](1,4)-benzene[2](2,5) pyridinophanes were synthesized. The synthesis of the pyridinophane scaffold was simplified, and a pyrazole, triazole, tetrazole, and pyrimidine heterocycle were successfully attached to the planar chiral backbone. Copyright

Full text of DOI:10.1002/ejoc.201201286

FULL PAPER
DOI: 10.1002/ejoc.201201286
Synthesis of Planar Chiral N-Heterocyclic-Substituted Pyridinophanes
Joshua J. P. Kramer,[a] Martin Nieger,[b] and Stefan Bräse*[a]
Keywords: Nitrogen heterocycles / Cyclophanes / N ligands / Chirality
Four new planar chiral N-heterocyclic-substituted [2](1,4)-
benzene[2](2,5)pyridinophanes have been synthesized. With
the attached pyrazole, triazole, tetrazole, and pyrimidine
moieties, different N,N-chelating ligands that vary in the
number of enclosed nitrogen atoms, ring size, and electronic
properties were added to a mostly neglected class of pyrid-
inophanes. Additionally, the known synthesis of the pyrid-
inophane scaffold was simplified considerably. With the
acetyl, amino, and amido pyridinophane, various useful in-
termediates for new pyridinophane ligands were synthe-
sized, which would allow for further investigations of this li-
gand system.
ure 1).[7] In the last decade, the [2.2]paracyclophane scaffold
2 with its rigidity in combination with its high steric de-
Introduction
The design and development of new ligand systems and mand has been successfully explored for its use in different
the controlled modification and improvement of existing li- ligands, and not only for asymmetric catalysis.[8] However,
gands play a pivotal role in synthetic organic chemistry. in the development of new ligands, the use of the aza-[2.2]-
One of the most important nitrogen-containing ligand sys- paracyclophane backbone as in [2](1,4)benzene[2](2,5)pyr-
tems is 2,2Ј-bipyridine with its manifold applications in ca- idinophane (3) has been mostly neglected, although it pro-
talysis and supra-, nano-, and macromolecular chemistry as vides an additional donor site with the nitrogen embedded
well as photochemistry.[1]
directly in the ligand backbone. Hence, we focused on this
Other N,N-chelating pyridine (Py) ligands that are struc- class of rarely investigated ligands that has already been
turally and electronically closely related to 2,2Ј-bipyridines known for approximately 40 years, but has only been men-
such as pyrazolyl-Py [2-(pyrazol-3-yl)pyridine],[2] triazolyl- tioned in the publications cited herein.
Py [2-(1,2,4-triazol-3-yl)pyridine],[3] tetrazolyl-Py [2-(1H-
tetrazol-5-yl)pyridine],[4] and pyrimidinyl-Py [2-([2-amino]-
pyrimidine-4-yl)pyridine][5] have not been extensively inves-
tigated. However, by combining the pyridine core with
other N-containing heterocycles, a broad range of different
and interesting ligands are available, in which the steric and
electronic properties can be specifically tuned by varying
the attached heterocycle and its substitution pattern.
For new chiral N-heterocyclic ligands, the use of a planar
chiral scaffold is a promising opportunity. The combination
of the coordinating properties of 2,2Ј-bipyridines with the
Figure 1. Combination of planar chiral para-bridged cyclophanes
and 2,2Ј-bipyridines.
planar chirality of para-bridged cyclophanes was first inves-
The synthesis of [2](1,4)benzene[2](2,5)pyridinophane (3)
tigated by Vögtle et al. in the syntheses of pyrid-2-yl[2]-
was first mentioned in the literature by Bruhin and Jenny,
(1,4)benzene[2](5,8)quinolinophane (1)[6] and 13-pyrid-
but the compound was obtained only in poor yield, and the
inyl[2](1,4)benzene-[2](2,5)pyridinophane (4, see Fig-
experimental details as well as the synthesis of the precur-
sors were not given.[9] After a successful synthesis, photo-
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology (KIT), Campus South,
electron spectra were recorded to obtain the ionization en-
ergies[10] as well as the UV spectra, which in combination
with the theoretical calculations provided a deeper under-
standing of the electronic structure and type of electronic
transitions for pyridinophane 3.[11] Theoretical examination
of the pyridinophane was expanded by determining the en-
thalpy of formation, the binding energy, and the locations
of the HOMO und LUMO through quantum mechanical
calculations.[12]
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-48581
E-mail: braese@kit.edu
Homepage: http://www.ioc.kit.edu/braese/
[b] Laboratory of Inorganic Chemistry, Department of Chemistry,
P. O. Box 55 (A. I. Virtasen aukio 1), 00014 University of Hel-
sinki, Finland
E-mail: nieger@mappi.helsinki.fi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201286.
Eur. J. Org. Chem. 2013, 541–549
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. J. P. Kramer, M. Nieger, S. Bräse
FULL PAPER
The first substituted pyridinophane was presented as a clophane formation.[7] The latter compound was commer-
model of vitamin B6 by Iwata, who had used previously cially available, but rather expensive for multigram use. On
functionalized building blocks for the synthesis.[13] Thus, no the other hand, it was easily obtained in an excellent yield
general synthetic route to the pyridinophane scaffold was from 1,4-bis(bromomethyl)benzene (see Scheme 1).[18]
available until Vögtle published the complete synthesis of
scaffold 3 from commercially available precursors.[7] How-
ever, the constraint of this route, designed for a larger scale
synthesis, was the time-consuming isolation of diol precur-
sor 13, which was only possible through the extensive use
of a cation-exchange resin. Therefore, we modified and op-
timized the synthesis of the pyridinophane scaffold with re-
gard to less laborious reaction procedures to give easier ac-
cess to the scaffold and allow for further investigations with
this class of ligand.
Scheme 1. Synthesis of dithiol building block 10 from commercially
available 1,4-bis(bromomethyl)benzene (9).[18]
The first and so far only known direct functionalization
of pyridinophane scaffold 3 is the conversion of its N-oxide
The synthesis of 2,5-bis(bromomethyl)pyridine (14) from
into nitrile 5 through a modified Reissert–Henze reac- a commercially available precursor is more elaborate.
tion.[7,14] Consequently, this nitrile is the precursor of all Vögtle proceeded by starting from 2,5-pyridinedicarboxylic
known pyridinophane derivatives (see Figure 2), that is, bi- acid, which underwent an esterification to give the diethyl
pyridine 6,[7] oxazolinyl pyridine 7,[15] and the imidazole ester, followed by an intricate reduction upon treatment
pyridine 8,[16] the first two of which gave promising results with sodium borohydride to afford diol 13.[7] This reaction
in asymmetric catalysis and the latter was used for studying included multiple centrifugation steps, and the isolation of
the donor properties of planar chiral N-heterocyclic carb- the diol was reported as only possible through the use of
enes and their application in gold catalysis.[17]
a strongly acidic cation-exchange resin, which required the
subsequent evaporation of large amounts of diluted NH3
solution and provided the diol as only the crude product in
67% yield. Furthermore, the yield was not mentioned for
the following time-consuming bromination step with a 6 d
reaction time, and the dibromide decomposed at room tem-
perature to a red solid.
Therefore, we first investigated an alternative synthetic
route and then looked to optimize the previously described
reaction procedures. Attempts for the direct access to the
dibromide through a radical bromination of 2,5-lutidine
with N-bromosuccinimide yielded different brominated
products, and the desired dibromide 14 was only isolated in
poor yield, because of its decomposition during purifica-
tion.
Instead of a direct synthesis for dibromide 14, we had
to vary the demanding reduction procedure. Therefore, we
modified a different known reduction of dimethyl ester 12,
which was synthesized by esterification of the 2,5-pyridine-
dicarboxylic acid (11, see Scheme 2).[19] The optimized re-
duction protocol tremendously simplified the synthesis of
the highly hygroscopic diol by heating the alkoxyborate spe-
cies at reflux in a mixture of saturated aqueous potassium
carbonate solution and acetone. The K2CO3 was used as a
base for the faster hydrolysis of the alkoxyborate species,
and the acetone transferred the highly water soluble diol 13
into the organic phase. After purification, this route yielded
diol 13 as a pure product in 74% yield.
Figure 2. The only pyridinophane scaffold containing ligands
known in the literature.
Herein, in addition to the optimization of the synthesis
of the pyridinophane scaffold, we present the syntheses of
four new N-heterocyclic-substituted pyridinophanes as well
as interesting synthetic intermediates, which offer versatile
possibilities for the syntheses of further pyridinophane de-
rivatives.
Results and Discussion
The following steps were conducted as reported by
Improved Synthesis of Pyridinophane Scaffold 3
Vögtle[7] with slightly better yields, and the optimized syn-
The preparation of new pyridinophane ligands requires thesis afforded pyridinophane scaffold 3 in 19% overall
a reproducible synthesis for scaffold 3 that can be done on yield in five steps from commercially available starting ma-
a multigram scale. The known synthetic route from Vögtle terial 11. The crystal structure analysis of dithia pyrid-
used 2,5-bis(bromomethyl)pyridine (14) and 1,4-bis(mer- inophane 15 showed disorder of the nitrogen through a cen-
captomethyl)benzene (10) as building blocks for the cy- ter of symmetry (see Figure 3). Also, single crystals of scaf-
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Planar Chiral N-Heterocyclic-Substituted Pyridinophanes
Scheme 2. Optimized synthesis of pyridinophane scaffold 3 from commercially available 2,5-pyridinedicarboxylic acid (11).
fold 3 were obtained (two polymorphs), but the X-ray struc- was obtained from pyridinophane 3 through its correspond-
ture analysis showed a disordered arrangement of the nitro- ing N-oxide by following a reported procedure[7,16a] (see
gen.[20]
Scheme 3), and its structure was additionally proven by X-
ray crystal structure analysis.[7,16a,20]
The most straightforward method for the synthesis of a
nitrogen heterocycle starting from nitrile 5 is through a
[2+3] cycloaddition with an azide. The conversion of the
nitrile with sodium azide and ammonium chloride yielded
tetrazolyl-substituted pyridinophane 17 in modest yield,
along with the recovery of starting material (see Scheme 4).
The observed incomplete conversion could be a conse-
quence of the high steric demand of the pyridinophane scaf-
fold attached to the nitrile. This new planar chiral 2-(1H-
tetrazol-5-yl)pyridine ligand 17 possesses five electron-do-
nating nitrogen atoms and, therefore, should be able to par-
ticipate in mono-, bi-, and multidentate coordination modes
with different metal ions.
Another N-heterocyclic ligand, structurally and electron-
ically closely related to 2,2Ј-bipyridine, is 2-(3-pyrazolyl)-
pyridine. A common and efficient route for the synthesis of
3-substituted pyrazoles occurs through the ring closure of
a β-diketone, or a derivative of comparable reactivity, by
treatment with hydrazine.[2f] For the synthesis of the planar
chiral analogue, we prepared dimethylaminopropenone 19
as a “masked” β-keto aldehyde, which could offer good re-
activity and access to different N-heterocycles. Starting
from nitrile 5, this was achieved in very good yields by
treatment with MeLi, followed by a subsequent condensa-
tion of acetyl derivative 18 with N,N-dimethylformamide
dimethyl acetal (DMFDMA, see Scheme 5).
Figure 3. Molecular structure of dithia pyridinophane 15. (One dis-
ordered part is shown, and displacement parameters are drawn at
50% probability level.)
The enantiomeric resolution of racemic scaffold 3 could
be undertaken, as reported, by HPLC with a semiprepar-
ative column carrying a chiral stationary phase.[7] For the
sake of simplicity, all further investigations towards new N-
heterocyclic substituted pyridinophanes were carried out
with racemic pyridinophane 3.
Overall, we modified and optimized the synthesis of the
scaffold on a multigram scale, not only slightly in yield, but
also significantly in time, effort, and practicability, to sim-
plify access to this ligand system.
Acetyl pyridinophane 18 (see Figure 4) is also a suitable
precursor for further functionalizations of the pyrid-
Synthesis of the N-Heterocyclic-Substituted Pyridinophanes
For the synthesis of different N-heterocycles, we used inophane ligand system (e.g., the synthesis of planar chiral
pyridinophane nitrile 5 as the precursor. This compound pyridine imines). We also synthesized the pyridinophane al-
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J. J. P. Kramer, M. Nieger, S. Bräse
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Scheme 3. Synthesis of pyridinophane nitrile 5.[7,16a]
amount of hydrazine hydrate (see Scheme 6). This N,N-che-
late ligand can bidentately coordinate to a metal center
through the formation of a favorable five-membered chelate
ring. Furthermore, the 1H-pyrazole moiety can bridge with
metal centers after deprotonation as a pyrazolide anion.
Through versatile functionalization possibilities at different
positions of the pyrazoles by aromatic substitution, N-alk-
ylation, and N-arylation reactions, a whole panoply of
tailor-made chelating ligands could be synthesized. An ad-
vantage of the chosen synthetic method is that N-alkylated
and N-arylated pyrazole derivatives should be accessible by
simply using N-alkyl- or N-arylhydrazines for the ring
closure.[21]
Scheme 4. Synthesis of planar chiral 2-(1H-tetrazol-5-yl)pyridine
ligand 17 (brsm = based on recovered starting material).
Additionally, the use of the enaminone 19 as a precursor
allowed for easy access to other heterocycles such as the six
membered N-heterocyclic pyrimidines.[5b,21b,22] For exam-
ple, the synthesis of planar chiral 2-[2-(amino)-pyrimidine-
4-yl]pyridine 21 was accomplished in excellent yield by the
condensation of 19 with guanidine nitrate in the presence
of sodium ethoxide (see Scheme 6). The structure of com-
pound 21 was proven by X-ray structure analysis (see Fig-
ure 5). This pyrimidine pyridine is a polydentate ligand that
offers multiple coordination modes. As an outlook for the
future, the 2-substituent of the pyrimidines could vary from
hydrogen to the sterically more demanding alkyl or aryl
substituents by replacing guanidine nitrate with an appro-
priate amidine such as formamidine acetate or carboxamid-
ines.[5,23]
Scheme 5. Synthesis of (dimethylamino)propenone 19.
dehyde, a useful intermediate for new pyridinophane li-
gands, through the reduction of nitrile 5 with DIBAL (di-
isobutylaluminum hydride).[20]
Another interesting polyaza heterocycle that completes
this small collection of 2,2Ј-bipyridine analogues is 2-(1,2,4-
triazol-3-yl)pyridine. The triazole moiety could be synthe-
sized from the corresponding carboxamide.[24] By con-
verting nitrile 5 with hydrogen peroxide and potassium
carbonate, we obtained pyridinophane carboxamide 22 in
good yield based on the reisolation of small amounts of the
starting material (see Scheme 7).
The crystal structure of amide 22 shows inter- and intra-
molecular hydrogen bonding (see Figure 6). The intramo-
lecular hydrogen bond is formed between the carboxamide
H atom and the pyridine N atom, whereas the intermo-
lecular hydrogen bond is located between the two carbox-
amide units. Also, the hydrogen bonding of amide 22 in
solution could be observed by the large separation of the
two H atoms of the NH2 group and the significant down-
field shift in the NMR spectrum.[20]
Figure 4. Molecular structure (displacement parameters are drawn
at 50% probability level) of acetyl pyridinophane 18.
The synthesis of planar chiral 2-(pyrazol-3-yl)pyridine 20
was then accomplished in good yield through the ring clo-
Carboxamide 22 was then used as a precursor for the
sure of enaminone precursor 19 by treatment with an excess triazole synthesis. Corresponding to the pyrazole precursor
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Planar Chiral N-Heterocyclic-Substituted Pyridinophanes
Scheme 6. Synthesis of planar chiral 2-(pyrazol-3-yl)pyridine 20 and 2-[2-(amino)pyrimidine-4-yl]pyridine 21.
excess amount of hydrazine in acetic acid, after the evapora-
tion of the excess DMFDMA, yielded planar chiral 2-
(1,2,4-triazol-3-yl)pyridine 24 in good yield (see Scheme 8).
Figure 5. Molecular structure (displacement parameters are drawn
at 50% probability level) of planar chiral pyrimidine pyridine 21.
Scheme 8. Synthesis of the planar chiral 2-(1,2,4-triazol-3-yl)pyr-
idine 24.
The triazole moiety has an acidic NH group and could
coordinate as a strong σ-donor at either the N-2 or N-4. In
combination with the π-acceptor properties of the pyridine,
a new chelating ligand with complementary properties was
available.
Scheme 7. Synthesis of amido pyridinophane 22.
Carboxamide 22 was also a good precursor for further
functionalization at the pyridinophane ligand system. For
example, we carried out a Hofmann rearrangement[25] by
treatment with bromine and potassium hydroxide that
yielded amine 26 in good yield based on the recovery of
starting material (see Scheme 9). This amine was a N,N-
chelating ligand and could be used in further functionaliza-
tions such as imine formation or heterocyclic synthesis. In
addition, isocyanate 25, which was formed as an intermedi-
ate in the Hofmann rearrangement, could also undergo a
hydrolysis reaction with alcohols or amines, instead of
water, in a one-pot procedure starting from pyridinophane
amide 22 to yield the corresponding planar chiral carb-
amate or urea pyridinophane ligands.
Figure 6. Molecular structure (displacement parameters are drawn
at 50% probability level) of the dimer of pyridinophane carboxam-
ide 22.
synthesis, carboxamide 22 was heated at reflux in
DMFDMA, resulting in the formation of the NЈ-acylpyrid-
inophanyl-N,N-dimethylformamidine 23. This N-acyl-
formamidine could not be isolated because of its high reac-
tivity. However, its direct conversion by treatment with an Scheme 9. Hofmann rearrangement of carboxamide 22.
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J. J. P. Kramer, M. Nieger, S. Bräse
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13 (11.3 g, 81.2 mmol, 74%) as a yellow, hygroscopic oil; Rf = 0.27
(CH2Cl2/MeOH, 7:1). 1H NMR (250 MHz, [D4]methanol): δ =
4.65 (s, 2 H, CH2OH), 4.69 (s, 2 H, CH2OH), 7.54 (d, 3J = 8.0 Hz,
Conclusions
In summary, we established the modification and optimi-
zation, especially in regard to practicability, of a known
synthetic route to pyridinophane scaffold 3. We further ex-
panded the rare number of pyridinophane derivatives
through the synthesis of four new planar chiral pyrid-
inophanes substituted with a pyrazole, triazole, tetrazole,
and pyrimidine moiety. These polyaza heterocyclic ligands
with different attached heterocycles, which vary in the
number of enclosed nitrogen atoms, ring size, and electronic
properties, are an ideal complement to planar chiral bipyr-
idine 4. With their bis(heterocyclic) design, the synthesized
N,N-donors offer rich coordination modes with different
metals and can provide access to mono-, bi-, and multimet-
allic complexes. Through the chosen synthetic approach
with enaminone 19 and N-acylformamidine 23 as precur-
sors, the pyrazole-, pyrimidine-, and triazole-containing
pyridinophanes can easily be synthesized in good to very
good yields. Furthermore the ligands should be simple to
modify, in terms of steric and electronic features, through
the use of appropriate organic hydrazines, which is an ap-
parent advantage to planar chiral bipyridine. Besides the
detailed description of all of the steps in the synthesis and
the complete characterization of the ligands, we also syn-
thesized different intermediates that offer versatile down-
stream chemistry to prepare new pyridinophane ligands.
Nevertheless, to assess the new planar chiral ligands,
studies of their coordination and complexation to different
metals as well as their application in asymmetric catalysis
are under investigation in our laboratories. In cooperation,
we are also studying how the photochemical properties are
influenced by the cyclophane embodied in the ligands.
3
4
1 H, Py-H3), 7.83 (dd, J = 8.0, J = 2.2 Hz, 1 H, Py-H4), 8.44 (d,
4J = 2.2 Hz, 1 H, Py-H6) ppm. IR (KBr): ν = 3319 (br.) [O–H],
˜
2868 (m), 1606 (m), 1575 (m), 1493 (m), 1451 (m), 1401 (m), 1364
(w), 1216 (w), 1132 (vw), 1026 (m), 832 (m), 756 (m), 650 (m), 406
(vw) cm–1. MS (70 eV, EI): m/z (%) = 139 (67) [M]+, 138 (100) [M –
H]+, 122 (10) [M
–
OH]+, 110 (40) [C6H8NO]+, 109 (19)
[C6H7NO]+, 108 (18) [C6H6NO]+, 93 (12) [C6H7N]+, 92 (6)
[C6H6N]+, 80 (13) [C5H6N]+, 78 (11) [C5H4N]+, 77 (8) [C5H3N]+.
HRMS: calcd. for C7H9NO2 139.0633; found 139.0634. Its analyti-
cal and spectral properties match those reported in the literature.[7].
rac-13-(1H-Tetrazol-5-yl)[2](1,4)benzeno[2](2,5)pyridinophane (17):
Into
a sealed vial, rac-13-cyano[2](1,4)benzene-[2](2,5)pyrid-
inophane (5, 100 mg, 0.427 mmol, 1.00 equiv.), sodium azide
(85.8 mg, 1.28 mmol, 3.00 equiv.), and ammonium chloride
(68.5 mg, 1.28 mmol, 3.00 equiv.) were suspended in dry DMF
(3 mL), and the resulting mixture was stirred at 150 °C for 22 h.
The reaction mixture was cooled and diluted with EtOAc (20 mL),
and the resulting solution was washed with HCl (5 m aqueous solu-
tion, 8 mL). The aqueous phase was extracted with EtOAc
(2ϫ15 mL), and the combined organic phases were washed with
brine (20 mL) and dried with MgSO4. The solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (CH2Cl2/MeOH, 10:1) to yield the recovered start-
ing material 5 (35.6 mg, 0.152 mmol) and tetrazole 17 (38.5 mg,
0.139 mmol, 33%, 51% brsm) as a colorless solid (decomposition
1
at 166 °C); Rf = 0.26 (CH2Cl2/MeOH, 10:1). H NMR (400 MHz,
[D4]methanol): δ = 2.85–3.30 (m, 7 H, HPyp), 4.15–4.21 (m, 1 H,
3
4
3
HPyp), 6.09 (dd, J = 7.9, J = 1.2 Hz, 1 H, Ar-H), 6.50 (dd, J =
4
3
4
8.0, J = 1.4 Hz, 1 H, Ar-H), 6.53 (dd, J = 8.0, J = 1.4 Hz, 1 H,
3
4
Ar-H), 6.63 (dd, J = 7.9, J = 1.2 Hz, 1 H, Ar-H), 6.70 (d, 3J =
7.8 Hz, 1 H, Py-H3), 7.12 (d, J = 7.8 Hz, 1 H, Py-H4) ppm. 13C
3
NMR (100 MHz, CDCl3): δ = 33.90 (–, CH2), 34.81 (–, CH2), 34.97
(–, CH2), 36.98 (–, CH2), 126.95 (+, C3-Py), 130.52 (+, C-Ar),
133.25 (+, C-Ar), 134.70 (+, 2 C-Ar), 135.04 (Cq, C5-Py), 139.64
(Cq, C-Ar), 141.03 (Cq, C-Ar), 144.21 (Cq, C6-Py), 144.92 (+, C4-
Py), 157.34 (Cq, C2-Py), 161.02 (Cq, CN4 H) ppm. IR [ATR (atten-
Experimental Section
uated total reflection)]: ν = 2923 (w), 2852 (w), 1909 (vw), 1653
˜
General Remarks: General information about the analytical equip-
ment, all detailed synthetic procedures, the complete characteriza-
tions of all of the compounds including the 1H and 13C NMR
spectra, and the crystallographic data can be found in the Support-
ing Information.
(vw), 1578 (w), 1537 (w), 1501 (vw), 1465 (w), 1413 (w), 1373 (vw),
1351 (vw), 1322 (vw), 1241 (vw), 1145 (vw), 1090 (w), 1025 (w),
943 (w), 916 (w), 894 (w), 852 (w), 820 (w), 797 (w), 740 (vw), 721
(w), 694 (vw), 672 (w), 646 (w), 590 (vw), 541 (vw), 522 (w), 482
(vw), 465 (vw) cm–1. HRMS: calcd. for C16H15N5 277.1327; found
277.1325.
CCDC-892233 (for 15), -892234 (for 18), -892235 (for 21), -892236
(for 22), and -892237 (for 5) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
rac-13-Acetyl[2](1,4)benzeno[2](2,5)pyridinophane (18): To a solu-
tion of rac-13-cyano[2](1,4)benzene-[2](2,5)pyridinophane (5,
353 mg, 1.51 mmol, 1.00 equiv.) in dry Et2O (30 mL) cooled to
–50 °C was slowly added MeLi (1.60 m in Et2O, 1.32 g, 1.89 mL,
3.02 mmol, 2.00 equiv.), and the resulting mixture was stirred, as it
was warmed to room temperature for 3 h. The reaction mixture
was quenched with a saturated aqueous solution of NH4Cl (15 mL)
and HCl (2 m aqueous solution, 15 mL), and the aqueous phase
was extracted with Et2O (3ϫ30 mL). The combined organic phases
were washed with brine (30 mL) and dried with MgSO4, and the
solvent was removed under reduced pressure to yield ketone 18
(355 mg, 1.41 mmol, 94%) as a yellow solid without further purifi-
cation. Rf = 0.46 [cHex (cyclohexane)]/EtOAc, 7:1); m.p. 92 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.55 (s, 3 H, COCH3), 2.74–2.80 (m,
1 H, HPyp), 2.96–3.02 (m, 1 H, HPyp), 3.15–3.34 (m, 5 H, HPyp),
2,5-Bis(hydroxymethyl)pyridine (13): To a suspension of dimethyl
2,5-pyridinedicarboxylate (12, 21.5 g, 110 mmol, 1.00 equiv.) in dry
ethanol (300 mL) cooled to 0 °C was added NaBH4 (16.7 g,
441 mmol, 4.00 equiv.) portionwise. After stirring at 0 °C for 1 h,
the reaction mixture was stirred at room temperature for 3 h and
then was heated at reflux for 14 h. The solvent was removed under
reduced pressure, and the residue was dissolved in a mixture of
acetone (300 mL) and a saturated aqueous solution of K2CO3
(300 mL). After stirring and heating at reflux for 1 h, the reaction
mixture was separated into an aqueous colorless layer and a yellow-
ish organic phase, and the latter was separated. The solvent was
removed under reduced pressure, and the crude product was puri-
fied by column chromatography (CH2Cl2/MeOH, 7:1) to yield diol
4
4.04–4.12 (m, 1 H, HPyp), 6.43 (dd, 3J = 7.8, J = 1.4 Hz, 1 H, Ar-
3
H), 6.46–6.50 (m, 2 H, Ar-H), 6.55 (d, J = 7.6 Hz, 1 H, Py-H3),
546
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 541–549

Planar Chiral N-Heterocyclic-Substituted Pyridinophanes
3
4
3
6.61 (dd, J = 7.8, J = 1.4 Hz, 1 H, Ar-H), 6.85 (d, J = 7.6 Hz,
umn chromatography (cHex/EtOAc, 1:2) to yield pyrazole 20
1 H, Py-H4) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.12 (+, (72.6 mg, 0.264 mmol, 90%) as a colorless solid. Rf = 0.30 (cHex/
COCH3), 34.24 (–, CH2), 34.27 (–, CH2), 34.53 (–, CH2), 36.99 EtOAc, 1:2); m.p. 187 °C. H NMR (400 MHz, CDCl3): δ = 2.84–
1
3
(–, CH2), 126.05 (+, C3-Py), 130.51 (+, C-Ar), 131.76 (+, C-Ar),
3.25 (m, 7 H, HPyp), 3.76–3.82 (m, 1 H, HPyp), 6.37 (dd, J = 7.8,
132.27 (+, C-Ar), 133.64 (+, C-Ar), 133.98 (Cq, C5-Py), 138.37 (Cq, 4J = 1.6 Hz, 1 H, Ar-H), 6.46 (d, J = 7.7 Hz, 1 H, Py-H3), 6.47
3
C-Ar), 140.28 (Cq, C-Ar), 142.82 (+, C4-Py), 151.46 (Cq, C6-Py),
158.96 (Cq, C2-Py), 201.68 (Cq, COCH3) ppm. IR [DRIFT (dif-
fused reflectance infrared Fourier transform-spectroscopy)]: ν =
(dd, 3J = 7.9, 4J = 1.7 Hz, 1 H, Ar-H), 6.51 (dd, 3J = 7.9, 4J =
1.7 Hz, 1 H, Ar-H), 6.64 (dd, 3J = 7.8, 3J = 1.7 Hz, 1 H, Ar-H),
4
3
6.71 (d, J = 1.9 Hz, 1 H, pyrazole-H), 6.86 (d, J = 7.7 Hz, 1 H,
˜
3
3352 (vw), 3035 (w), 3010 (w), 2965 (m), 2933 (m), 2855 (w), 2362 Py-H4), 7.70 (d, J = 1.9 Hz, 1 H, pyrazole-H), 11.20 (br. s, 1 H,
(vw), 1891 (vw), 1685 (s) [C=O], 1596 (w), 1567 (m), 1540 (m), NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.83 (–, CH2), 34.25
1504 (w), 1452 (m), 1435 (w), 1413 (m), 1384 (w), 1352 (m), 1327
(w), 1287 (m), 1224 (w), 1180 (w), 1160 (w), 1128 (w), 1072 (m),
(–, CH2), 34.34 (–, CH2), 36.85 (–, CH2), 105.20 (+, pyrazole-C4),
123.11 (+, C3-Py), 129.43 (Cq, C5-Py), 129.68 (+, C-Ar), 132.02
1014 (w), 948 (m), 926 (w), 898 (w), 863 (w), 826 (w), 797 (m), 750 (+, pyrazole-C5), 132.09 (+, 2 C-Ar), 133.13 (+, C-Ar), 138.51 (Cq,
(w), 723 (m), 687 (vw), 662 (w), 613 (m), 600 (m), 558 (w), 520 (m), C-Ar), 139.41 (Cq, C-Ar), 140.01 (Cq, pyrazole-C3), 142.58 (+, C4-
442 (w), 424 (vw) cm–1. MS (70 eV, EI): m/z (%) = 251 (100) [M]+,
250 (43) [M – H]+, 222 (5) [M – C2H5]+, 208 (7) [M – COCH3]+,
182 (7) [M – C3H3NO]+, 180 (5) [M – C3H5NO]+, 147 (34) [M –
Py), 147.18 (C , C6-Py), 158.93 (C , C2-Py) ppm. IR (ATR): ν =
˜
q q
3122 (w), 3017 (w), 2928 (w), 2890 (w), 1722 (w), 1598 (w), 1557
(w), 1532 (w), 1487 (w), 1450 (w), 1429 (w), 1412 (w), 1385 (w),
C8H10]+, 105 (19) [C7H7N]+, 104 (79) [C8H8]+, 103 (22) [C8H7]+, 78 1341 (w), 1238 (w), 1194 (w), 1173 (w), 1145 (w), 1087 (w), 1064
(23) [C5H4N]+, 77 (12) [C5H3N]+, 43 (26) [COCH3]+. HRMS:
calcd. for C17H17NO 251.1312; found 251.1310.
(w), 1035 (w), 986 (w), 958 (w), 933 (w), 921 (w), 895 (w), 844 (w),
826 (w), 792 (w), 772 (m), 755 (m), 717 (m), 674 (w), 650 (w), 618
(m), 594 (w), 548 (w), 522 (m), 489 (w) cm–1. MS (70 eV, EI): m/z
(%) = 275 (60) [M]+, 274 (13) [M – H]+, 171 (21) [M – C8H8]+, 153
(11), 104 (31) [C8H8]+, 89 (12), 77 (21) [C5H3N]+, 58 (25), 43 (100)
[NC2H5]+. HRMS: calcd. for C18H17N3 275.1422; found 275.1425.
rac-13-(3-Dimethylamino-2-propene-1-on-1-yl)[2](1,4)benzeno[2]-
(2,5)pyridinophane (19): Into a vial, rac-13-acetyl[2](1,4)benzene-
[2](2,5)pyridinophane (18, 135 mg, 0.537 mmol, 1.00 equiv.) was
dissolved in N,N-dimethylformamide dimethyl acetal (0.714 mL,
0.640 mg, 5.37 mmol, 10.0 equiv.), and the resulting mixture was
stirred at 130 °C for 15 h. After the DMFDMA was removed under
reduced pressure, the crude product was purified by column
chromatography (CH2Cl2/MeOH, 30:1) to yield aminopropenone
19 (153 mg, 0.499 mmol, 93%) as a yellow solid. Rf = 0.33
(CH2Cl2/MeOH, 30:1); m.p. 189 °C. 1H NMR (400 MHz, CDCl3):
δ = 2.75–3.31 [m, 13 H, HPyp, N(CH3)2], 3.99–4.04 (m, 1 H, HPyp),
5.96 (d, 3J = 11.6 Hz, 1 H, COCHCHNMe2), 6.44 (d, 3J = 7.6 Hz,
1 H, Py-H3), 6.45–6.49 (m, 2 H, Ar-H), 6.63 (dd, 3J = 7.9, 4J =
1.4 Hz, 1 H, Ar-H), 6.72 (dd, 3J = 7.9, 4J = 1.4 Hz, 1 H, Ar-H),
6.79 (d, 3J = 7.6 Hz, 1 H, Py-H4), 7.69 (d, 3J = 11.6 Hz, 1 H,
COCHCHNMe2) ppm. 13C NMR (100 MHz, CDCl3): δ = 34.00
(–, CH2), 34.37 (–, CH2), 34.94 (–, CH2), 37.03 (–, CH2), 37.23 (+,
NCH3), 44.88 (+, NCH3), 93.98 (+, COCHCHNMe2), 124.63 (+,
C3-Py), 131.12 (+, C-Ar), 131.48 (+, C-Ar), 132.45 (+, C-Ar),
133.04 (+, C-Ar), 133.10 (Cq, C5-Py), 138.23 (Cq, C-Ar), 140.38
(Cq, C-Ar), 142.43 (+, C4-Py), 153.78 (+, COCHCHNMe2), 154.29
(Cq, C6-Py), 158.19 (Cq, C2-Py), 189.46 (Cq, CO) ppm. IR (ATR):
rac-13-(2-Aminopyrimidin-4-yl)[2](1,4)benzeno[2](2,5)pyridinophane
(21): Into a vial, a solution of guanidine nitrate (50.1 mg,
0.411 mmol, 1.25 equiv.) in dry ethanol (3 mL) was added to a
warm solution of rac-13-(3-dimethylamino-2-propene-1-on-1-
yl)[2](1,4)benzene[2](2,5)pyridinophane (19, 100 mg, 0.329 mmol,
1.00 equiv.) in ethanol (2 mL), and the reaction mixture was heated
at reflux for 1 h. A solution of sodium ethoxide [Na (15.1 mg) in
EtOH (2 mL), 0.657 mmol, 2.00 equiv.) was added, and the reac-
tion mixture was heated at reflux for 24 h. The solvent was removed
under reduced pressure. The residue was dissolved in CH2Cl2
(20 mL), and H2O (10 mL) was added. The organic phase was sep-
arated, and the aqueous phase was extracted with CH2Cl2
(3ϫ10 mL). The combined organic phases were dried with MgSO4,
and the solvent was removed under reduced pressure to yield pyr-
imidine 21 (96.3 mg, 0.318 mmol, 97%) as a colorless solid without
further purification. Rf = 0.35 (CH2Cl2/MeOH, 30:1); m.p. 217 °C.
1H NMR (400 MHz, CDCl3): δ = 2.86–2.95 (m, 2 H, HPyp), 3.00–
3.06 (m, 2 H, HPyp), 3.24–3.29 (m, 3 H, HPyp), 4.05–4.12 (m, 1 H,
HPyp), 5.30 (br. s, 2 H, NH2), 6.47–6.51 (m, 3 H, Ar-H and Py-
H3), 6.54 (dd, 3J = 7.8, 4J = 1.4 Hz, 1 H, Ar-H), 6.70 (dd, 3J =
7.8, 4J = 1.4 Hz, 1 H, Ar-H), 6.91 (d, 3J = 7.6 Hz, 1 H, Py-H4),
7.47 (d, 3J = 5.1 Hz, 1 H, pyrimidine-H), 8.50 (d, 3J = 5.1 Hz, 1
H, pyrimidine-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.78
(–, CH2), 34.37 (–, CH2), 34.82 (–, CH2), 37.01 (–, CH2), 110.72
(+, pyrimidine-C5), 124.39 (+, C3-Py), 129.96 (+, C-Ar), 131.90
(+, C-Ar), 132.22 (+, C-Ar), 132.79 (Cq, C5-Py), 133.08 (+, C-Ar),
138.53 (Cq, C-Ar), 139.92 (Cq, C-Ar), 142.92 (+, C4-Py), 153.47
(Cq, pyrimidine-C2), 158.74 (Cq, pyrimidine-C4), 159.08 (+, pyrim-
idine-C6), 162.74 (Cq, C5-Py), 166.37 (Cq, C2-Py) ppm. IR (ATR):
ν = 2922 (vw), 1639 (w), 1554 (m) [C=O], 1488 (w), 1445 (w), 1419
˜
(w), 1381 (w), 1347 (w), 1278 (w), 1252 (w), 1148 (vw), 1127 (vw),
1106 (w), 1035 (w), 996 (w), 970 (vw), 937 (w), 893 (w), 861 (vw),
814 (vw), 791 (w), 771 (w), 719 (w), 671 (vw), 654 (w), 635 (w), 585
(vw), 524 (w), 464 (vw) cm–1. MS (70 eV, EI): m/z (%) = 306 (62)
[M]+, 305 (8) [M – H]+, 263 (20) [M – NC2H5]+, 262 (13) [M –
NC2H6]+, 203 (14) [M – C8H7]+, 202 (100) [M – C8H8]+, 201 (13)
[M – C8H9]+, 159 (21) [M – C8H8 – NC2H5]+, 158 (7) [M – C8H8
– NC2H6]+, 131 (10) [C10H11]+, 130 (9) [C10H10]+, 107 (22)
[C8H11]+, 106 (12) [C8H10]+, 105 (23) [C7H7N]+, 104 (31) [C8H8]+,
103 (18) [C8H7]+, 98 (71) [C5H8NO]+, 89 (19), 79 (11) [C5H5N]+,
78 (22) [C5H4N]+, 77 (54) [C5H3N]+, 69 (19) [NC4H7]+, 57 (20)
[NC3H7]+, 43 (65) [NC2H5]+. HRMS: calcd. for C20H22N2O
306.1732; found 306.1734.
ν = 3311 (w), 3162 (w), 2958 (vw), 2922 (w), 2850 (vw), 1646 (w),
˜
1566 (w), 1540 (w), 1477 (w), 1443 (w), 1341 (w), 1229 (w), 1142
(w), 1072 (w), 1003 (vw), 973 (vw), 950 (vw), 928 (vw), 894 (vw),
852 (vw), 826 (w), 813 (w), 795 (w), 763 (vw), 717 (w), 701 (w), 645
(w), 634 (w), 592 (w), 575 (w), 520 (w), 469 (w), 434 (w) cm–1. MS
(70 eV, EI): m/z (%) = 302 (46) [M]+, 199 (12) [M – C8H7]+, 198
(100) [M – C8H8]+, 197 (29) [M – C8H9]+, 77 (12) [C4H1N2]+, 69
(11) [C2H3N3]+, 59 (12) [N2C2H7]+, 58 (23) [N2C2H6]+, 57 (11)
[N2C2H5]+, 43 (63) [NC2H5]+. HRMS: calcd. for C18H17N3
302.1531; found 302.1531.
rac-13-(Pyrazol-3-yl)[2](1,4)benzeno[2](2,5)pyridinophane (20): Into
a
vial, hydrazine hydrate (0.143 mL, 147 mg, 2.94 mmol,
10.0 equiv.) was added to a solution of rac-13-(3-dimethylamino-
2-propene-1-on-1-yl)[2](1,4)benzene-[2](2,5)pyridinophane (19,
90.0 mg, 0.294 mmol, 1.00 equiv.) in EtOH (10 mL), and the reac-
tion mixture was heated at reflux for 14 h. The solvent was removed
under reduced pressure, and the crude product was purified by col-
Eur. J. Org. Chem. 2013, 541–549
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
547

J. J. P. Kramer, M. Nieger, S. Bräse
FULL PAPER
rac-[2](1,4)Benzeno[2](2,5)pyridinophane-13-carboxamide (22): To a
solution of rac-13-cyano[2](1,4)benzene-[2](2,5)pyridinophane (5,
160 mg, 0.683 mmol, 1.00 equiv.) in DMSO (dimethyl sulfoxide,
1 mL) cooled to 0 °C was slowly added H2O2 (35%, 250 μL,
282 mg, 2.90 mmol, 4.25 equiv.) followed by K2CO3 (32.0 mg,
0.232 mmol, 0.34 equiv.). The reaction mixture was warmed to
room temperature, as it was stirred for 1.5 h, and then diluted with
H2O (5 mL). The resulting mixture was extracted with CH2Cl2
(3ϫ20 mL). The combined organic phases were dried with MgSO4,
and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography (cHex/EtOAc,
2:1) to yield the recovered starting material (23.3 mg, 99.4 μmol)
and amide 22 (141 mg, 0.560 mmol, 82%, 96% brsm) as a colorless
solid. Rf = 0.23 (cHex/EtOAc, 2:1); m.p. 217 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.77–2.83 (m, 1 H, HPyp), 2.96–3.05 (m, 1
H, HPyp), 3.13–3.31 (m, 5 H, HPyp), 4.40–4.45 (m, 1 H, HPyp), 5.52
3363 (w), 3019 (vw), 2928 (vw), 2850 (vw), 1573 (vw), 1533 (vw),
1503 (vw), 1477 (vw), 1433 (vw), 1410 (vw), 1344 (vw), 1259 (vw),
1233 (vw), 1177 (vw), 1145 (vw), 1091 (w), 1077 (vw), 1011 (w),
964 (vw), 913 (vw), 893 (vw), 857 (vw), 811 (vw), 742 (vw), 722
(w), 706 (w), 695 (w), 677 (w), 666 (vw), 655 (vw), 642 (vw), 594
(vw), 542 (vw), 523 (w), 480 (vw), 451 (vw) cm–1. MS (70 eV, EI):
m/z (%) = 276 (100) [M]+, 275 (24) [M – H]+, 172 (85) [M –
C8H8]+, 105 (13) [C7H7N]+, 104 (44) [C8H8]+, 103 (14) [C8H7]+,
78 (10) [C5H4N]+. HRMS: calcd. for C17H16N4 276.1375; found
276.1377.
Supporting Information (see footnote on the first page of this arti-
cle): General methods including explanation of abbreviations and
symbols used in characterization data, experimental procedures,
1
characterization data, H and 13C NMR spectra, crystal structure
analyses, and references are provided.
4
(br. s, 1 H, NH2), 6.44 (dd, 3J = 7.9, J = 1.2 Hz, 1 H, Ar-H), 6.48
3
4
3
(dd, J = 7.9, J = 1.2 Hz, 1 H, Ar-H), 6.56 (d, J = 7.7 Hz, 1 H,
Acknowledgments
3
Py-H3), 6.64–6.68 (m, 2 H, Ar-H), 6.90 (d, J = 7.7 Hz, 1 H, Py-
H4), 7.81 (br. s, 1 H, NH2) ppm. 13C NMR (125 MHz, CDCl3): δ
= 34.37 (–, CH2), 34.42 (–, CH2), 34.53 (–, CH2), 36.92 (–, CH2),
126.08 (+, C3-Py), 130.73 (+, C-Ar), 131.90 (+, C-Ar), 132.28 (+,
C-Ar), 133.60 (+, C-Ar), 135.37 (Cq, C5-Py), 138.15 (Cq, C-Ar),
140.58 (Cq, C-Ar), 143.49 (+, C4-Py), 147.86 (Cq, C6-Py), 158.36
This work has been supported by the Karlsruhe Institute of Tech-
nology (KIT) and the Landesgraduiertenförderung (fellowship to
J. K.). Also, financial support by the Deutsche Forschungsgemein-
schaft (DFG) through SFB/TRR 88 “3MET” is gratefully ac-
knowledged.
(C , C2-Py), 167.79 (C , CONH ) ppm. IR (ATR): ν = 3407 (vw)
˜
q
q
2
[N–H], 3180 (vw) [N–H], 2926 (vw), 2349 (vw), 2321 (vw), 2162
(vw), 2042 (vw), 2017 (vw), 1993 (vw), 1674 (vw) [C=O], 1568 (vw),
1498 (vw), 1400 (vw), 1363 (vw), 1220 (vw), 1093 (vw), 1073 (vw),
967 (vw), 943 (vw), 896 (vw), 867 (vw), 829 (vw), 799 (vw), 721
(vw), 671 (vw), 665 (vw), 610 (vw), 579 (vw), 525 (vw), 447 (vw),
426 (vw), 412 (vw) cm–1. MS (70 eV, EI): m/z (%) = 252 (100)
[M]+, 251 (6) [M – H]+, 208 (16) [M – CONH2]+, 207 (20) [M –
CONH3]+, 206 (11) [M – CONH4]+, 180 (6) [M – C2ONH4]+, 149
(7) [M – C8H7]+, 148 (80) [M – C8H8]+, 105 (7) [C7H7N]+, 104 (57)
[C8H8]+, 103 (20) [C8H7]+, 78 (19) [C5H4N]+, 77 (10) [C5H3N]+.
HRMS: calcd. for C16H16N2O 252.1263; found 252.1261.
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rac-13-(1,2,4-Triazol-3-yl)[2](1,4)benzeno[2](2,5)pyridinophane (24):
Into a vial, rac-13-amido[2](1,4)benzene-[2](2,5)pyridinophane (22,
61.5 mg, 0.244 mmol, 1.00 equiv.) was dissolved in DMFDMA
(1.94 mL, 1.74 g, 14.6 mmol, 60.0 equiv.), and the reaction mixture
was stirred at 130 °C for 7 h. After the DMFDMA was removed
under reduced pressure through a cannula, the residue in the vial
was dissolved in concentrated AcOH (2 mL), and hydrazine hy-
drate (59.2 μL, 61.1 mg, 1.22 mmol, 5.00 equiv.) was added drop-
wise. After stirring at 80 °C for 6 h, the reaction mixture was di-
luted with H2O (5 mL) and CH2Cl2 (5 mL), and the resulting solu-
tion was washed with a diluted aqueous solution of NaHCO3
(2ϫ15 mL). The aqueous phase was extracted with CH2Cl2
(3ϫ10 mL), and the combined organic phases were washed with
brine (20 mL) and dried with MgSO4. The solvent was removed
under reduced pressure, and the crude product was purified by col-
umn chromatography (CH2Cl2/MeOH, 50:1) to yield triazole 24
(59.0 mg, 0.214 mmol, 88%) as a colorless solid. Rf = 0.34 (CH2Cl2/
MeOH, 50:1); m.p. 255 °C. 1H NMR (400 MHz, CDCl3): δ = 2.87–
2.94 (m, 1 H, HPyp), 3.01–3.29 (m, 6 H, HPyp), 4.49–4.56 (m, 1 H,
3
HPyp), 6.21 (d, J = 7.9 Hz, 1 H, Py-H3), 6.47–6.52 (m, 2 H, Ar-
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3
H), 6.55–6.60 (m, 2 H, Ar-H), 6.95 (d, J = 7.9 Hz, 1 H, Py-H4),
8.15 (s, 1 H, triazole-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
33.45 (–, CH2), 34.21 (–, CH2), 34.35 (–, CH2), 36.82 (–, CH2),
125.07 (+, C3-Py), 129.78 (+, triazole-C5), 132.20 (+, C-Ar), 132.28
(+, 2 C-Ar), 132.64 (Cq, C5-Py), 133.45 (+, C-Ar), 138.28 (Cq, C-
Ar), 140.25 (Cq, C-Ar), 143.08 (+, C4-Py), 144.60 (Cq, C6-Py),
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˜
q
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