Derivatives of pyrazinecarboxylic acid: 1H, 13C and 15N NMR spectroscopic investigations

Article abstract of DOI:10.1002/mrc.2437

NMR spectroscopic studies are undertaken with derivatives of 2-pyrazinecarboxylic acid. Complete and unambiguous assignment of chemical shifts (1H, 13C, 15N) and coupling constants (1H,1H; 13C,1H; 15N,1H) is achieved by combined application of various 1D and 2D NMR spectroscopic techniques. Unequivocal mapping of13C,1H spin coupling constants is accomplished by 2D (S,J) long-range INEPT spectra with selective excitation. Phenomena such as the tautomerism of 3-hydroxy-2-pyrazinecarboxylic acid are discussed.

Full text of DOI:10.1002/mrc.2437

Spectral Assignments and Reference Data
Received: 21 January 2009
Revised: 13 March 2009
Accepted: 14 March 2009
Published online in Wiley Interscience: 28 April 2009
(
www.interscience.com) DOI 10.1002/mrc.2437
1
13
Derivatives of pyrazinecarboxylic acid: H, C
15
and N NMR spectroscopic investigations
∗
∗
Wolfgang Holzer, Gernot A. Eller, Barbara Datterl and Daniela Habicht
NMR spectroscopic studies are undertaken with derivatives of 2-pyrazinecarboxylic acid. Complete and unambiguous
1
13 15
1
1
13
1
15
1
assignmentofchemicalshifts( H, C, N)andcouplingconstants( H, H; C, H; N, H)isachievedbycombinedapplicationof
1
3
1
various1Dand2DNMRspectroscopictechniques.Unequivocalmappingof C, Hspincouplingconstantsisaccomplishedby2D
δ,J)long-rangeINEPTspectrawithselectiveexcitation. Phenomenasuch asthetautomerismof3-hydroxy-2-pyrazinecarboxylic
(
acid are discussed. Copyright ꢀc 2009 John Wiley & Sons, Ltd.
Keywords: NMR; H NMR; 13C NMR; 15N NMR; pyrazines
1
Introduction
Results and Discussion
1H NMR
In the course of a program devoted to the synthesis of
1
The H NMR data of compounds 1–14 are collected in Table 1.
[
1–6]
new heterocyclic scaffolds,
we recently presented the syn-
1
Assignmentofsignalsinthe HNMRspectraof 2-monosubstituted
ꢁ
ꢁ
thesis of pyrazolo[4 ,3 :5,6]pyrano[2,3-b]pyrazin-4(1H)-ones of
type 16 via reaction of 1-substituted or 1,3-disubstituted 2-
pyrazolin-5-ones (15) and 3-chloro-2-pyrazinecarbonyl chloride
pyrazines 1–4 is facile considering the known characteris-
1
1
tic H, H coupling behaviour in monosubstituted pyrazines:
3
5
4
J(H5,H6) > J(H3,H6) > J(H3,H5); the latter coupling constant
(13), the latter being available from the corresponding 3-chloro-
approximating 0 Hz. Thus, for instance, for ester 2 in DMSO-d6
2
(
-pyrazinecarboxylic acid (12) by treatment with thionyl chloride
values of 2.43 (5,6), 1.49 (3,6) and 0.30 Hz (3,5) are given in the
Scheme 1).[
7]
[10]
literature. For 1–4, we found coupling constants of 2.2–2.7 Hz
3
5
4
As convenient approaches regarding the synthesis of acid
2 – the key educt of the described synthesis – are not well
for J(H5,H6) and 1.5 Hz for J(H3,H6), whereas J(H3,H5) was not
resolved. This leads to doublets for the signals due to H-3 (1.5 Hz)
and H-5 (∼2.4 Hz) and a double doublet for the H-6 resonance. In-
troduction of an additional substituent into the 3-position results
in the reduction of the pyrazine-H spectrum into two doublets
1
documented in the literature, we tested different pathways
for the synthesis of 12 as given in Scheme 2. Except for 8,
which was obtained upon attempted transformation of nitrile
(
or an AB-system) of H-5 and H-6; however, an assignment on
7
into 12, all other compounds represented in Scheme 2 are
basis of the splitting pattern is not possible by now. From Ta-
ble 1 it emerges that the order of signals due to H-5 and H-6 is
strongly dependent on the substituents attached to positions 2
and 3 and also from the solvent (compare compound 12). The
difficulty in the unambiguous distinction between the signals of
H-5 and H-6 on basis of chemical shift considerations may be the
main reason that in the relevant literature assignments are not
given with 2,3-disubstituted pyrazines in nearly all cases. Never-
theless, reliable and unequivocal assignments can be achieved
known compounds, some of them being also commercially
available. Since the quoted reaction types are well known, the
synthetic details will not be discussed here. Nevertheless, in the
present paper we want to present the results of the extensive
1
13
15
NMR ( H, C, N) studies undertaken with compounds 1–14
Scheme 2), which – except for chloropyrazine (3) – can be all
(
considered as derivatives of pyrazinecarboxylic acid (1). Although,
from most of these essential pyrazine derivatives more or less,
NMR data are available (selected references are specified in
Tables 1–3), particularly with 2,3-disubstituted pyrazines almost
persistently no assignments of chemical shifts and spin coupling
13
1
15
1
considering the C, H and N, H spin coupling constants of the
mentioned protons (see below). In compound 10, the magnitude
of the vicinal J(H5,H6) coupling (3.7 Hz) is considerably larger
than those of all other compounds, thus giving a hint for its spe-
cial status (presence as 3-oxo-3,4-dihydropyrazine rather than as
6
1
3
constants are given and the lack of reliable C NMR data
is noticeable. However, the availability of such unambiguously
assigned chemical shift data is crucial, as reference material for
3-hydroxypyrazine tautomer in DMSO-d solution) (Scheme 3).
[
8]
databases used in NMR prediction programs such as CSEARCH
[
9]
or ACD/C + H Predictor, programs that have become more
and more popular in the last years, especially for the prediction
∗
Correspondence to: Wolfgang Holzer and Gernot A. Eller, Department of Drug
1
3
of C NMR chemical shifts. Nevertheless, the quality of such
predictions is considerably dependent on the availability of
authentic reference data of related structures, a criterion which
is frequently not fulfilled for heteroaromatic systems such as
pyrazine.
andNatural Product Synthesis, Faculty of LifeSciences, University ofVienna, Al-
thanstrasse 14, A-1090 Vienna, Austria. E-mail: wolfgang.holzer@univie.ac.at;
gernot.eller@univie.ac.at
Department of Drug and Natural Product Synthesis, University of Vienna,
Althanstrasse 14, A-1090 Vienna, Austria
Magn. Reson. Chem. 2009, 47, 617–624
Copyright ꢀc 2009 John Wiley & Sons, Ltd.

W. Holzer et al.
O
O
O
R3
R3
N
N
N
N
N
N
OH
Cl
N
N
R1
+
N
O
Cl
Cl
N
R1
O
12
13
15
16
Scheme 1. Synthesis of tricycles 16.
N
CN
N
CN
N
CONH2
OEt
6
5
1
2
SO Cl2
6
5
1
NaOH/H O/EtOH
2
6
5
1
2
3
2
3
2
3
4
4
4
N
N
Cl
N
4
7
8
1
2
) NaNO /HCl
POCl3
pyridine
2
N
N
COCl
Cl
COOH
NH2
+
N
COOH
OH
N
COOH
Cl
) H /H O
1
6
5
1
2
6
5
1
6
5
1
SOCl2
6
5
2
3
2
3
2
3
2
3
4
4
4
4
N
N
N
N
9
10
12
13
Na CO3
2
H O/MeOH
2
1
) NaNO /HCl
2
N
COOMe
NH2
N
COOMe
N
COOEt
Cl
1
2) CuCl
1
6
5
1
6
5
6
2
3
2
3
2
3
5
4
4
4
N
N
Cl
N
6
ethyl pyruvate
H O
5
11
2
2
FeSO ·7 H O
4
2
SO Cl2
2
N
COOH
MeOH/H+
N
COOMe
N
COOMe
N
1
1
1
4
6
5
6
5
6
5
6
2
3
2
3
2
3
3
2
4
4
5
4
1
N
N
Cl
N
N
Cl
1
2
14
3
Scheme 2. Compounds investigated (with atom numbering).
–
31.9 ppm
COOH
can be unequivocally discriminated employing 2D (δ,J) long-range
INEPT spectra with selective excitation[11] of the resonances due to
H-6 and H-3, respectively. Besides, unequivocal assignment of C-3
N
COOH
OH
N
1
6
5
1
1
6
5
and C-6 in 1–4 can also be easily achieved by consulting the J(C-
2
3
2
3
4
4
H) correlations from the HSQC spectra, as H-3 and H-6 can be easily
identified as described above. A characteristic attribute observed
N
H
N
O
5
5
with pyrazines 1, 2 and 4 is the J(CO,H5) or J(CN,H5) coupling
H
–
190.9 ppm
constant of 1.0–1.5 Hz, which was unambiguously assigned via
NOE
2
D long-range INEPT experiments with selective excitation. In
OH-form
10
NH-form
4
contrast, a J coupling of H-6 to CO or CN could not be observed.
With 2,3-disubstituted pyrazines, the situation is a little bit more
tricky. The quaternary carbon atoms C-2 and C-3 show very similar
coupling patterns and similarly this is the case for C-5 and C-6.
With compounds 8, 9 and 11 the substituent in 3-position (OEt,
NH2) is characterized by a pronounced −I but +M effect, thus
enabling a smooth distinction between C-2 and C-3 on basis of
chemical shift considerations (δ C-3 ꢂ δ C-2) and also between
C-5 and C-6 (δ C-5 > δ C-6). However, these differences in chemical
shifts are less pronounced in compounds 5, 6, 12 and 13 with
a chloro atom linked to pyrazine C-3. Here, a safe identification
of H-5 and thus the starting point for unambiguous assignments
of all carbon atoms can be accomplished by 2D (δ,J) long-range
Scheme 3. Tautomeric forms of compound 10.
13C NMR
In Table 2, the 13C NMR data of the investigated compounds are
summarized. In monosubstituted pyrazines 1–4, the signal of C-5
can be smoothly distinguished from those of C-3 and C-6 on
1
basis of the splitting patterns in the H-coupled spectra. Whereas
the signals of C-3 and C-6 in each case exhibit one larger and
one smaller long-range coupling (for instance, C-3 in 1 gives a
1
0.2 Hz and a 1.4 Hz splitting, the C-6 signal is split with 10.8
and 1.3 Hz), the C-5 resonance shows two larger splittings [1:
2
3
J(C5,H6) = 10.8 Hz and J(C5,H3) = 9.6 Hz]. The latter couplings
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Copyright ꢀc 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 617–624

Derivatives of Pyrazinecarboxylic Acid
Table 1. 1H NMR data of 1–14 (δ in ppm, J in Hz)
Compound
Solvent
δ (H-3)
δ (H-5)
δ (H-6)
δ other H
3J(5,6)
Other J
1
2
DMSO-d6
CDCl3
9.16
9.17
9.16
8.55
8.76
8.91
9.20
–
8.82
8.65
8.86
8.43
8.63
8.79
8.95
8.50
8.72
8.51
8.77
8.59
8.79
8.32
8.50
8.71
8.85
8.56
8.75
8.57
10–14 (OH)
2.4
2.4
2.4
2.5
2.5
2.5
2.5
2.4
2.4
2.3
1.5 J(3,6)
1.5 J(3,6)
1.5 J(3,6)
1.5 J(3,6)
1.4 J(3,6)
1.5 J(3,6)
1.5 J(3,6)
–
3.90 (OMe)
DMSO-d6
CDCl3
3.90 (OMe)
3
4
5
6
7
8
9
–
DMSO-d6
CDCl3
–
–
DMSO-d6
CDCl3
–
4.01 (OMe)
3.93 (OMe)
4.49 (OCH2),
DMSO-d6
CDCl3
–
–
–
7.2 (CH2,CH3)
1
.43 (Me)
CDCl3
–
–
8.61
8.83
8.23
8.28
8.19
7.80
8.14
8.23
8.70
8.65
8.62
–
8.65
8.85
8.22
8.17
7.86
7.65
7.94
7.87
8.69
8.71
8.68
8.63
8.91
–
–
2.4
2.4
2.4
2.7
2.3
3.7
2.3
2.0
2.2
2.3
2.2
–
–
DMSO-d6
CDCl3
–
–
7.62, 6.90 (CONH2), 4.53 (OCH2), 1.45 (Me)
7.1 (CH2,CH3)
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
–
7.88, 7.61 (CONH2), 4.38 (OCH2), 1.32 (Me)
7.38 (NH2), 5.50 (OH)
8–15 (OH, NH)
7.1 (CH2,CH3)
–
–
1
1
0
1
–
–
–
3.93 (OMe), 6.56 (NH2)
3.82 (OMe), 7.29 (NH2)
9.21 (OH)
–
DMSO-d6
CDCl3
–
–
1
2
–
–
DMSO-d6
CDCl3
–
10–16 (OH)
–
1
1
3
4
–
–
–
CDCl3
9.01
9.01
3.97 (OMe)
1.3 J(3,6)
1.3 J(3,6)
DMSO-d6
–
3.91 (OMe)
–
selected references: 1,[20] 2,[21] 3,[22,23,24] 4,[23,25] 5,[26,27] 6,[28] 7,[29] 9,[30] 10,[31] 11,[32] 12,[33] 14,[27]
INEPT experiments with selective excitation considering the above
mentioned characteristic J(CO,H5) coupling.
FromTable 2itisapparentthat, for5–9and11–13theabsolute
F2
ppm)
5
3J (C5, H3) = 9.5 Hz
(
140
2
2
value of J(C5,H6) is slightly larger than J(C6,H5); however, the re-
141
142
C-5
C-2
3
3
lationship J(C3,H5) > J(C2,H6) is not true stringentin every case.
The excellent utility of 2D (δ,J) long-range INEPT spectra with
selective excitation for the definitive mapping of 1 C, H coupling
constants is demonstrated in Fig. 1. In chloropyrazine 3, the signal
ofC-5issplittedby185.6, 10.3and9.5 Hz. Discriminationofthetwo
latter – quite similar – couplings on basis of the known values for
143
3
1
144
1
1
1
1
45
46
47
48
8 6 4
-0
-4
Hz
2J (C2, H3) = 7.8 Hz
2
3
theparentpyrazinemolecule – J(C2,H3) = +10.4 Hz, J(C2,H6) =
149
150
+
9.8 Hz[ – seems to be less trustable. However, upon selective
12]
151
excitation of the H-3 resonance, in the 2D (δ,J) INEPT spectrum the
signal of C-5 is split by 9.5 Hz, thus assigning J(C5,H3) to be 9.5 Hz
and – indirectly – J(C5,H6) must be 10.3 Hz (Fig. 1). Moreover,
from this experiment the magnitude of J(C2,H3) is unequivocally
assigned with 7.8 Hz, thus, J(C2,H6) must be 11.3 Hz. In the same
way, all long-range C, H coupling constants given in Table 2
were unequivocally allocated by corresponding experiments.
2
152
2
8
6 4
-0
-4
-8
8 6 4
-0
-4 Hz
2
F1 (Hz)
3
1
3
1
Figure 1. Longe-range 2D (δ,J) INEPT spectrum of 3 obtained upon
selective irradiation of the H-3 resonance.
15N NMR
couplings of N-1 and N-4 are very congruent and cover the range
of 10.4–11.6 Hz (absolute value), being characteristic for pyridine-
type nitrogen atoms with the axis of the nitrogens lone-pair being
Table 3 comprises the 15N NMR data of 1–14. The values we
found for monosubstituted pyrazines 1–4 are in nearly perfect
agreement with those published by G u¨ nther and coworkers
[
13]
[13,15]
coplanarwiththeN-C-Hsystem.
Thelargedifferencebetween
[
14]
15
1
(but not with those given by Jovanovic ). Compounds 1–3
the geminal (∼11 Hz) and the vicinal (∼1.5 Hz) N, H coupling
constants also affects the form and intensity of the corresponding
signals in the HMBC spectra, which helps to identify the N–H
connectivities. The N-4 signal of monosubstituted pyrazines 1–4
can be easily identified due to its characteristic triplet structure (dt)
exhibit somewhat larger chemical shifts for N-4 when compared
with those of N-1, whereas in disubstituted compounds 5–14
the situation is reverted due to the more or less pronounced
π-donating properties of the chloro, amino or ethoxy substituent
2
1
15
[13]
in position 3 affecting the ortho located N-4 atom. The J(N,H)
inthe H-coupled NNMRspectra(twogeminalN,Hcouplings).
Magn. Reson. Chem. 2009, 47, 617–624
Copyright ꢀc 2009 John Wiley & Sons, Ltd.
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W. Holzer et al.
www.interscience.wiley.com/journal/mrc
Copyright ꢀc 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 617–624

Derivatives of Pyrazinecarboxylic Acid
Magn. Reson. Chem. 2009, 47, 617–624
Copyright ꢀc 2009 John Wiley & Sons, Ltd.
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W. Holzer et al.
The exceptional position of compound 10 is best reflected by
its 15N NMR spectrum: The chemical shift of −190.9 ppm for N-4
definitely rules out an ‘aromatic’ pyrazine system (Scheme 3). The
predominanceoftheNH-formisfurtherconfirmedbythedistinctly
smaller chemical shifts for H-5 (7.90 ppm) and H-6 (7.65 ppm)
compared to the corresponding shifts in all other compounds
were recorded either on a Varian UnityPlus NMR spectrometer
1
13
(300 MHz for H, 75 MHz for C) or on a Bruker Avance 500
instrument (500 MHz for 1H, 125 MHz for 13C) at 25 C from
approximately 0.5 M solutions using 5 mm direct detection
broadband probes and deuterium lock. The center of the solvent
signal was used as an internal standard which was related to
◦
1
13
(
>8.17 ppm), furthermore by the larger H5,H6 coupling (3.7 Hz
tetramethylsilane with δ 2.49 ppm ( H) and δ 39.5 ppm ( C).
2
instead of ∼2.4 Hz, see above), by the markedly smaller J(C6,H5)
of 5.5 Hz (instead of 10.2–11.7 Hz) and by an obvious NOE on
H-5 upon irradiation of the (broad) NH resonance (Scheme 3).
In contrast, the corresponding 3-amino-2-pyrazinecarboxylic acid
1
The recording conditions were the following: H NMR: pulse
angle 30 , acquisition time 5 s, digital resolution 0.2 Hz/data point,
◦
spectral width 20 ppm, 16 transients, relaxation delay 5 s; broad-
13
◦
band decoupled C-NMR spectra: pulse angle 30 , acquisition
time 2 s, digital resolution 0.5 Hz/data point, spectral width
9
, which in principle is capable of prototropic tautomerism as
well, does not show such behaviour and thus can be considered
to be existent in the amino form in DMSO-d6 solution. These
findings are in full agreement with those published for related
compounds.[
2
20 ppm, 256–2048 transients, relaxation delay 2 s, exponential
multiplication with 1.0 Hz line broadening factor before FT;
gated decoupled C-NMR spectra: as above but acquisition time
2
13
16]
.5 s, digital resolution 0.4 Hz/data point, 512–8192 transients,
An interesting phenomenon was observed with 3-chloro-2-
pyrazinecarboxylic acid 12. In this compound, obvious differences
were evident between spectra observed in DMSO-d6 and those
relaxation delay 2.5 s, resolution enhancement by Gaussian
weighting (Varian: lb = −0.15, gf = 0.7; Bruker: lb = −0.6,
gb = 0.2) before FT. Full and unambiguous assignments were
1
5
in CDCl3 solution (Fig. 2). The situation in the N NMR spectra
seemstobeespeciallystriking whereas, inDMSO-d6 δ(N-1)islarger
than δ(N-4) (−44.2 vs −51.5 ppm) – as observed in all other 2,3-
disubstituted pyrazines 5–11 and 13 – a reverse situation appears
for 12 in CDCl3, namely δ(N-1) < δ(N-4) (−51.7 vs −46.6 ppm).
Moreover, in CDCl3 a significantly smaller absolute value for
1
13
achieved by consequent application of fully H-coupled C-NMR
[
37]
spectra (gated decoupling), gs-HSQC (1024 × 256 data matrix,
0 ppm for H, 160 ppm for C, four transients accumulated
per t1 increment; optimized for J = 160 Hz, qsine multiplication
in both dimensions) and gs-HMBC
1
13
1
[
38]
(1024 × 256 data matrix,
1
13
2
10 ppm for H, 180 ppm for C, 16 transients accumulated
per t1 increment; optimized for J = 8 Hz, sine multiplication in
both dimensions) techniques to all compounds. The unequivocal
mapping of C, H coupling constants was performed via 2D
long-range INEPT (δ,J) spectra with selective excitation (DANTE)
J(N1,H6) (10.0 Hz) was determined compared to that in DMSO-d6
2
(
11.5 Hz), whereas, J(N4,H5) remained almost unaffected by the
change of the solvent (11.3 Hz in DMSO-d6, 11.2 Hz in CDCl3). A
possible explanation for the mentioned effects can be given by the
assumption that, in CDCl3 the pyrazine N-1 atom of 12 is involved
in an intramolecular hydrogen bond (Fig. 2). The so-caused stress
of the nitrogen’s lone-pair leads to a decrease in the magnitude
1
3
1
[
11]
of pyrazine-H resonances (12 Hz excitation width, optimized for
J = 8 Hz, 64 increments for 20 Hz width in F1, 128 transients
2
[15,17,18]
accumulated per t increment; zero-filling to 128 data points in
of J(N1,H6) and also to a decrease of δ(N-1).
It is well
1
the F1 dimension, shifted sine multiplication in F1). The 15N-
known from the literature that, lone-pair effects can drastically
influence a large variety of different spin coupling constants.
Additionally, the involvement of pyridine-type nitrogen atoms
in hydrogen bonding, complexation or protonation is known to
NMR spectra were obtained on a Bruker Avance 500 instrument
(50.69 MHz) equipped with a 5 mm broadband observe probe at
◦
2
5 C and were referenced against external, neat nitromethane.
1
5
1
decrease the magnitude of the corresponding geminal N, H
Chemical shifts of pyrazine nitrogen atoms were determined
employing refocused, H-decoupled INEPT spectra optimized for
an N, H coupling of 11 Hz (acquisition time 1 s, digital resolution
1 Hz/data point, spectral width 400 ppm, 512–4K transients),
nitrile N-atoms were covered by inverse gated decoupled
NMR spectra (pulse width 7 µs (50 ), relaxation delay 10 s, 8 K
transients). The N, H coupling constants were determined either
from H-coupled N-NMR spectra (30 pulse angle, 10 s relaxation
delay) of from DEPT experiments without H-decoupling [both:
acquisitiontime3s,digitalresolution0.33 Hz/datapoint,resolution
coupling constant.[
17,18]
Furthermore, it is well documented that,
1
1
5
1
the involvement of pyridine-type nitrogen atoms in hydrogen
bonding or – more drastically – in protonation causes an upfield
1
5
[19]
15
shift of the corresponding N resonance.
In DMSO-d6, which
N
◦
exhibits strong acceptor properties, intramolecular hydrogen
bonds are usually broken and such distinctive features can not
be observed. In contrast, esters 2 and 5 having no capability for
hydrogen bonding exhibit only small differences between the
concerning chemical shifts and coupling constants in DMSO-
d6 and CDCl3 solution. Investigations with regard to similar
phenomena in other pyrazinecarboxylic acids (1, 9) were not
possible owing to the very low solubility of the latter compounds
in CDCl3.
1
5
1
1
15
◦
1
enhancement by Lorentz-to-Gauss transformation (lb = −0.6,
1
15
gb = 0.2)]. For the assignment of pyrazine N-signals H, N gs-
[38]
HMBC experiments (Bruker standard program ‘inv4gplplrndqf’,
048 × 128 data matrix, 10 ppm for H, 200 ppm for 15N, 32
1
2
In conclusion, we have presented full and unambiguous
transients accumulated per t1 increment; 65 (45) ms delay for
1
13
15
assignments of H, C and N NMR chemical shifts of a variety of
-substitutedand2,3-disubstitutedpyrazinesaswellasacomplete
15
1
the evolution of the N, H long-range coupling, optimized
for J = 8 (11) Hz, zero-filling to 1K data points in the
F1 dimension, sine multiplication in both dimensions) were
undertaken.
The melting point was determined on a Reichert–Kofler hot-
stage microscope and is uncorrected. The mass spectrum was
obtained on a Shimadzu QP 1000 instrument (EI, 70 eV), the IR
spectrum on a Perkin-Elmer FTIR 1605 spectrophotometer. The
elemental analysis (C, H, N) was performed at the Microanalytical
Laboratory, University of Vienna.
2
1
1
analysis of the connected scalar spin coupling constants ( H, H;
1
3
1
15
1
C, H; N, H) employing an extensive combination of different
D and 2D NMR spectroscopic techniques.
1
Experimental
All NMR experiments were performed using standard NMR
[
36]
1
13
spectroscopic techniques.
The H NMR and C NMR spectra
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Copyright ꢀc 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 617–624

Derivatives of Pyrazinecarboxylic Acid
Table 3. 15N NMR data of 1–14 (δ in ppm, J in Hz)
Compound
Solvent
δ (N-1)
−47.3
δ (N-4)
−45.2
δ other N
2J(N1,H6)
3J(N1,H5)
2J(N4,H5)
3J(N4,H6)
1
DMSO-d6
–
11.0
1.5
10.6
1.3
J(N1,H3) = 1.0
J(N4,H3) = 10.6
2
3
4
5
CDCl3
−51.2
−47.8
−57.8
−57.0
−44.5
−46.6
−46.0
−45.0
−40.2
−37.1
−44.7
−44.5
–
10.9
1.6
10.4
1.1
J(N1,H3) = 0.9
J(N4,H3) = 10.4
DMSO-d6
CDCl3
–
11.1
1.5
10.7
1.4
J(N1,H3) = 0.8
J(N4,H3) = 10.7
–
11.0
1.7
10.6
1.6
J(N1,H3) = 0.9
J(N4,H3) = 10.6
DMSO-d6
CDCl3
–
11.2
1.7
10.7
1.4
J(N1,H3) = 0.9
J(N4,H3) = 10.7
−118.9 (CN)
−119.5 (CN)
11.2
1.4
10.5
1.4
J(N1,H3) = 0.7
J(N4,H3) = 10.5
DMSO-d6
11.3
1.3
10.7
1.1
J(N1,H3) = 0.7
J(N4,H3) = 10.2
CDCl3
−43.8
−42.6
−44.1
−35.5
−38.2
−42.2
−45.2
−43.2
−31.9
−47.3
−50.3
−50.8
−50.7
−52.1
−53.9
−92.7
−95.8
−92.3
−190.9
−93.6
–
11.3
11.5
11.3
11.7
11.6
1.2
1.4
1.4
1.5
1.5
11.2
11.3
11.2
11.3
11.3
1.3
1.5
1.6
1.6
1.6
DMSO-d6
CDCl3
–
6
7
–
−112.7 (CN)
−114.0 (CN)
−279.6 (NH2)
−271.6 (NH2) J = 88.3, 89.5
−300.3 (NH2)
–
CDCl3
DMSO-d6
CDCl3
8
not determined due to low solubility
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
11.1
11.1
10.8
11.0
1.6
1.5
2.4
1.5
11.2
11.2
1.7
1.4
9
1
1
0
1
not found
11.0
not found
1.3
−305.5
(
NH2)
J(N4,NH2) = 4.0
DMSO-d6
−41.9
−91.0
−300.0
11.4
1.5
11.3
1.3
(
NH2, J = 90.4)
1
2
CDCl3
−51.7
−44.2
−39.5
−42.8
−46.6
−51.5
−47.8
−55.2
–
–
–
–
10.0
11.5
11.6
11.0
1.6
1.4
1.4
–
11.2
11.3
11.3
–
1.6
1.6
1.6
0.9
DMSO-d6
CDCl3
1
1
3
4
CDCl3
J(N1,H3) = 0.9
J(N4,H3) = 11.3
DMSO-d6
−39.2
−55.9
–
11.1
–
–
0.8
J(N1,H3) = 0.9
J(N4,H3) = 11.1
selected references: 1,[13,35] 2,[13] 3,[13] 4,[13]
–
44.2 ppm
164.9 ppm
H
51.7 ppm
–
162.8 ppm
O
H
N
COOH
H
N
1
1
2J (N1, H6) = 11.5 Hz
6
5
2J (N1, H6) = 10.0 Hz
6
5
O
2
3
2
3
4
4
N
Cl
N
Cl
–
51.5 ppm
–46.6 ppm
DMSO-d6
12
CDCl3
Figure 2. Differences in the NMR spectra of 12 recorded from DMSO-d6 and CDCl3 solution.
3
-Ethoxypyrazine-2-carboxamide (8)
was formed, which was filtered off, and washed with H2O;
◦
−1
Yield: 3.62 g (29%); M.p.: 165–166 C; IR (KBr): ν = 1639 cm
;
Compound 7 (10.4 g, 75 mmol) was suspended in EtOH (150 mL)
and a solution of NaOH (10%, 30 mL) was added. The reaction
mixture was heated 2 h under reflux. Then H2O (30 mL) was
added and the EtOH was evaporated under reduced pressure.
Upon adjusting the pH to 2–3 with 2N HCl a precipitate
+
MS (70 eV): m/z (%) = 167 (M , 19), 150 (76), 123 (37), 96
(
45), 80 (45), 68 (100), 44 (76). Anal. Calculated for C7H9N3O2:
C, 50.29; H, 5.43; N, 25.14. Found: C, 50.51; H, 5.36; N,
24.92.
Magn. Reson. Chem. 2009, 47, 617–624
Copyright ꢀc 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

W. Holzer et al.
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Copyright ꢀc 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 617–624