Structural characterisation of 2,3-disubstituted pyrazines: NMR and X-ray crystallography

Article abstract of DOI:10.1016/j.molstruc.2005.01.061

2-Formyl-3-aminopyrazine (1), 2-acetyl-3-aminopyrazine (2) and 2-benzoyl-3-aminopyrazine (3) have been studied by multinuclear magnetic resonance spectroscopy in solution and in solid state. Amino-imine tautomerism in such derivatives has been discussed on the basis of the calculated stabilities of the different tautomers by the hybrid B3LYP/6-31G** method. The crystalline structure of compound 3 has been solved, it belongs to the monoclinic P2₁/n space group, and shows supramolecular architectures involving N-H?O and N-H?N-pyrazine intermolecular hydrogen bonds.

Full text of DOI:10.1016/j.molstruc.2005.01.061

Journal of Molecular Structure 741 (2005) 67–75
www.elsevier.com/locate/molstruc
Structural characterisation of 2,3-disubstituted pyrazines:
NMR and X-ray crystallography
a,
a
a,
b
´
M. Angeles Farr a´ n
, Rosa M. Claramunt , Concepci o´ n L o´ pez
* *
, Elena Pinilla ,
c
b
M. Rosario Torres , Jos e´ Elguero
a
Departamento de Qu ´ı mica Org a´ nica y Bio-Org a´ nica, Universidad Nacional de Educaci o´ n a Distancia (UNED),
Facultad de Ciencias, Senda del Rey 9, 28040 Madrid, Spain
Departamento de Qu ´ı mica Inorg a´ nica I, Facultad de Ciencias Qu ´ı micas, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
b
c
Instituto de Qu ´ı mica M e´ dica, Consejo Superior de Investigaciones Cient ´ı ficas (CSIC), Juan de la Cierva 3, 28006, Madrid, Spain
Received 10 December 2004; revised 27 January 2005; accepted 31 January 2005
Available online 9 March 2005
Dedicated to Professor Pedro Molina on his 60th anniversary.
Abstract
2-Formyl-3-aminopyrazine (1), 2-acetyl-3-aminopyrazine (2) and 2-benzoyl-3-aminopyrazine (3) have been studied by multinuclear
magnetic resonance spectroscopy in solution and in solid state. Amino-imine tautomerism in such derivatives has been discussed on the basis
of the calculated stabilities of the different tautomers by the hybrid B3LYP/6-31G** method. The crystalline structure of compound 3 has
been solved, it belongs to the monoclinic P2 /n space group, and shows supramolecular architectures involving N–H/O and N–H/N-
1
pyrazine intermolecular hydrogen bonds.
q 2005 Elsevier B.V. All rights reserved.
Keywords: Solid state; Amino-imine tautomerism; Intermolecular hydrogen bonds
1
. Introduction
route to prepare them starting from the commercially
available 3-aminopyrazine-2-carboxylic acid (4) which was
first converted into methyl 3-aminopyrazine-2-carboxylate
(5) and after reduction [6] with DIBAL-H afforded 2-
formyl-3-aminopyrazine (1). On the other hand, 2-acetyl-3-
aminopyrazine (2) and 2-benzoyl-3-aminopyrazine (3) were
prepared from 2-methyl(or 2-phenyl)-4H-pyrazino[2,3-
Pyrazines are well known nitrogen heterocycles that are
used in the flavour [1] as well as in the pharmaceutical
industries [2]. We have been interested in the synthesis and
characterisation of a family of 3-amino-2-carbonylpyra-
zines (Fig. 1a) as a model of the amino-imine
tautomerism of alloxazine ring, main structural feature of
the prosthetic groups of the naturally occurring flavoen-
zymes (Fig. 1b) [3].
d][1,3]oxazin-4-ones (6a-b) [7] by reaction with CH Li or
3
PhMgBr to give 2-substituted-3-amidopyrazines (7a-b) that
upon hydrolysis yielded the final compounds 2 and 3. Full
details are given in Scheme 1 and in Section 4.
Some NMR data on pyrazines [8–13] were found in the
literature, but to our knowledge the characterisation of the
present compounds has not been reported, neither in
solution nor in the solid state.
2
. Results and discussion
Even if the synthesis of the three pyrazines had been
reported in the literature [4,5], we have used an alternative
1
13
15
The H, C, and N NMR chemical shift data in
solution for pyrazines 1-3 are summarised in Tables 1 and 2
and the assignments were made on the basis of a detailed
1
7
*
Corresponding authors. Tel.: C34 913987327; fax: C34 913986697.
E-mail address: clopez@ccia.uned.es (C. L o´ pez).
NMR study for compound 1. The O NMR spectra has only
been obtained for this latter compound from a sample of
80 mg of 1 in 0.7 mL of CDCl , the –CHO chemical shift
appearing at 547 ppm.
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.01.061
3

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
68
pyridine-like nitrogens at around K38 ppm for N-1 and
K88 ppm for N-4, and one amino group with an average
chemical shift of about K297 ppm. In the remaining solvents
(
a)
b)
N
NH2
N
NH2
CH3
N
NH2
O
H
N
N
N
1
15
(save 1 in CDCl ) only the H- N gs-HMBC spectra were
3
1
2
3
O
O
recorded, so the amino group was not detected and the
pyrazineringnitrogenschemicalshiftswereofthesameorder.
(
H
N
1
15
N
N
O
Moreover, Fig. 3 shows the H- N 2D inverse proton
detection heteronuclear shift correlation experiments for
compound 1 obtained in DMSO-d , where the amino
N
H
6
group appears at K297.7 ppm allowing us to determine
2
O
1
the J(
Z82.2 Hz and J(N–H)Z10.4 Hz.
N–H)
Fig. 1. (a) 3-Amino-2-carbonylpyrazines (1-3); (b) alloxazine ring.
According to all the NMR data it clearly appears that, the
amino form is the predominant one in solution for all these
disubstituted pyrazines 1-3.
The resonances of the carbon atoms were assigned first,
using as reference the reported values for 2-aminopyrazine
and 2-acetylpyrazine [13], and then using the results of 2D
inverse proton detection heteronuclear shift correlation
15
Finally, Table 3 displays the resonance values of N and
C obtained in the solid state, and a similar conclusion
13
arises when examining the chemical shift values: the 2-
carbonyl-3-amino tautomer is the only one present in the
solid compounds 1-3.
1
13
1
spectra ( H - C gs-HMQC, gs-HMBC), the H NMR
signals could be attributed.
1
As seen in the gs-HMQC spectrum of Fig. 2a, the J
correlations of C-5 and C-6 indicate that the signals at 8.20
and 8.05 ppm correspond to H-5 and H-6. The gs-HMBC
spectrum (Fig. 2b) corroborates the assignments.
2.1. Theoretical calculations of tautomeric equilibrium
1
5
Using the Inverse Gated technique, in DMSO-d three
N
NMR signals were observed for each compound, two
We began a systematic exploration of the structure,
tautomerism and NMR properties of flavine (Fig. 4).
6
N
NH2
OH
N
NH2
OCH3
N
NH2
i
ii
H
N
N
N
4
O
5
O
1
O
o
i) MeSO H, 16 h, NaCO H(aq) pH=7-8; ii) DIBAL-H, -78 C, 2h
4
3
O
O
CH3
N
N
N
CH3
N
N
N
v
H
O
O
CH3
6
a
7a
7b
N
N
NH2
iii
iv
O
N
O
N
OH
Ph
N
N
Ph
O
vi
N
N
4
H
6
b
Ph
O
O
N
NH2
vii
7
a
2
CH3
N
N
O
NH2
viii
7b
3
Ph
N
O
o
iii) Ac O reflux, 3 h; iv) PhCOCl, Et N 24 h, RT; v) CH Li(1.6 M in Et O)1 eq, -78 C, 15 min;
2
3
3
2
o
vi) PhMgBr (1 M in THF),1.5 eq, -78 C, 2 h; vii) HCl/MeOH, 2 eq, reflux 5 h;
viii) NaOH/MeOH, 2 eq, reflux 3 h
Scheme 1. Synthesis of 3-amino-2-carbonylpyrazines (1-3).

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
69
Table 1
The suppression of the methyl groups at positions 7 and 8
and, more important for tautomerism, the R substituent at
position 10, led to isoalloxazine that exists in the alloxazine
tautomeric form [14a]. If the fused benzene ring is then
formally deleted, lumazines are obtained, which exist in the
framed tautomeric form [14b,15]. There are three possible
disconnections of the pyrimidindione ring, which result in
three structures 8, 9 and 10. Further simplifications led first
13
C NMR chemical shifts (d in ppm) of 3-amino-2-R-pyrazines in CDCl
3
Compound C-2
C-3
C-5
C-6
CO
R
1
2
3
130.6
154.6
154.6
156.6
148.0
147.3
147.6
134.6
132.8
133.3
195.0
202.7
196.0
–
130.4
131.0
25.8
138.4
1
1
1
32.1
30.6
28.4
Table 2
15 1
N and H NMR chemical shifts (d in ppm) of 3-amino-2-R-pyrazines
Compound
Solvent
CDCl
DMSO-d
THF-d
CDCl
DMSO-d
THF-d
CDCl
DMSO-d
THF-d
N-1
N-4
NH
2
H-5
H-6
NH
2
(H)R
1
3
K38.2
K36.2
K39.1
K91.9
K87.5
K90.1
K304.1
K297.7
8.20
8.30
8.15
8.05
8.01
7.93
6.49
7.66
7.36
10.04
9.89
9.91
6
6
6
a
8
a
2
3
3
K41.3
K41.7
K43.3
K92.6
K87.4
K89.7
8.17
8.27
8.14
7.94
7.92
7.83
5.73
7.68
6.91
2.68
2.56
2.58
K293.9
a
8
a
3
K38.7
K37.7
K38.1
K91.1
K88.4
K89.2
8.19
8.29
8.16
7.99
7.92
7.87
6.91
7.74
7.49
7.94, 7.54, 7.45
7.82, 7.58, 7.48
7.98, 7.49, 7.40
K298.4
a
8
a
Not determined.
1
1
2
00
50
00
(
a)
(b)
1
1
1
1
1
1
1
1
1
10
20
30
40
50
60
70
80
90
ppm (t1)
ppm (f1)
1
0.00
9.50
9.00
8.50
8.00
10.00 9.50 9.00 8.50 8.00 7.50 7.00
ppm (t2)
ppm (f2)
4
H
H
N
NH2
1
13
3
H- C HMBC correlations
5
6
C-2
C-3
H-6
H-5
CHO
CHO
2
H
N
1
O
1
1
13
1
13
3
Fig. 2. (a) H- C gs-HMQC; (b) H- C gs-HMBC for compound 1 in CDCl .

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
70
(a)
(b)
–
–
–
–
–
–
–
–
–
90
80
70
60
50
40
30
20
10
–
–
–
–
310.0
305.0
300.0
295.0
–290.0
ppm (t1)
ppm (t1)
8.30
8.20
8.10
8.00
7.900 7.850 7.800 7.750 7.700 7.650 7.600
ppm (t2)
ppm (t2)
4
H
H
N
NH2
1
15
3
H- N HMBC correlations
5
6
N-1
N-4
H-6
H-5
2
H
N
1
O
1
15
1
15
6
Fig. 3. (a) H- N gs-HMBC; (b) H - N gs-HMQC of compound 1 in DMSO-d .
to compounds 11 and 7 and then to the pyrazines of the
present study, 1-3.
ethanol. All attempts to get appropriate crystals of 1 and 2
were unsuccessful. As shown in Fig. 6, the molecular structure
of 2-benzoyl-3-aminopyrazine (3) presents an internal
hydrogen bond between the carbonyl group of the phenyl
ketone and the amino group in position 3 of the pyrazine.
Additionally these molecules are bonded through inter-
molecular hydrogen bonds to give chains in the [101] as
shown in Fig. 7. Bond distances and angles have values in
the expected range and the geometry of the hydrogen bonds
is gathered in Table 5.
We approached the tautomerism of compounds 1-3 by
means of theoretical calculations carried out at the hybrid
Becke 3LYP/6-31G** level. Tautomers a, b and c for each
pyrazine derivative are represented in Fig. 5.
In all cases, the stable tautomer is the a form and the
other two have much higher energy values of about
K1
K1
8
5 kJ mol
(b form) and 170 kJ mol
(c form). These
results, summarised in Table 4, account for the fact that they
are not observed.
3
. Conclusions
2
.2. X-Ray crystallography
Non functional aminopyrazines exist as amines [14c],
but the presence of an ortho-acyl group to the amino
function should stabilise the imino tautomers. However this
For compound 3, single crystals suitable for X-ray
diffraction structural determination were obtained from
Table 3
15 13
N and C CPMAS NMR chemical shifts (d in ppm)
Compound N-1
N-4
NH
2
C-2
C-3
C-5
C-6
CO
R
1
2
3
K35.2
a
K98.2 K294.6
K90.9 K294.1
K96.9, K100.4 K289.0
129.8
128.6
128.7
155.2
153.5
154.9
149.1
146.9
147.3
132.9
133.0
132.2
195.0
202.3
196.8
–
28.0
K33.2
141.1, 130.7, 128.7 126.7, 124.7
a
Not detected after an acquisition time of 26 h.

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
71
R
H
N
H
N
H
3
C
8
7
N
N
4
2
O
H
N
O
O
H
N
N
O
H
1
0
N
N
N
H C
N
N
3
O
O
Flavine: FMN or FAD
Isoalloxazine
Alloxazine
H
N
H
N
a
N
O
O
N
O
H
b
N
H
N
N
N
c
O
Pteridine-2,4-dione:
lumazine
a
c
b
H
O
H
R
O
N
H
H
N
N
N
N
N
N
N
N
N
R
H
O
H
O
H
O
N
8
9
10
N
R
H
H
O
O
R
H
N
N
N
N
N
N
R
H
O
H
O
1
1
7
N
H
H
H
N
N
H
O
1
-3
N
R
Fig. 4. Retrosynthetic analysis starting from flavine to pyrazines 1-3.
stabilisation is not sufficient, as our experimental and
theoretical calculations on compounds 1-3 have proved.
a Model SSC5200H Disk Station and for the other
compounds a ThermoGalen hot stage microscope was
used. Thermograms (sample size 0.003–0.0010 g) were
In going upwards, the two derivatives 7a (RZCH ) and
3
K1
7
data show that they also are amino tautomers. Therefore is
b (RZC H ) of Fig. 4 have been prepared and the NMR
recorded at the scanning rate of 2.0 8C min . Column
chromatography was performed on silica gel (Merck 60,
6
5
our purpose to explore more complex structures like 10 and
1
7
0-230 mesh) and the Rf values were measured on
aluminum baked TLC plates of silica gel 60 F254 (Merck,
.2 mm) with the indicated eluent. Elemental analyses for
1 to provide new insights on the problem.
0
4
. Experimental
carbon, hydrogen, and nitrogen were carried out by the
Microanalytical Service of the Complutense University on
a Perkin–Elmer 240 analyser. Mass spectra were obtained
on a Shimadzu QP-5000 mass spectrometer with an
electron impact (EI) ion source using a 60 eV ionization
energy.
4
.1. General
Melting points for pyrazines 1, 2 and 3 were
determined by DSC on a Seiko DSC 220C connected to

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M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
72
WB-400 spectrometer at 300 K with a wide-bore 4-mm
DVT probehead at rotational frequencies of ca. 5–10 kHz.
Samples were carefully packed in ZrO rotors, and the
H
N
H
N
N
N
NH
N
N
NH
OH
H
O
O
2
C
H
N
C
H
C
standard CPMAS with the TPPM decoupling pulse
sequence and NQS technique (Non Quaternary Suppression
to observe only the quaternary C-atoms) were employed
H
1
2
a
a
1b
2b
1c
1
3
[16]. C spectra were originally referenced to a glycine
sample and then the chemical shifts were recalculated to the
H
N
H
N
N
N
NH
N
N
NH
H
O
Me Si [for the carbonyl atom d(glycine)Z176.1 ppm] and
4
O
OH
1
5
15
C
N
C
C
N spectra to NH Cl and then converted to nitromethane
4
1
5
15
CH3
CH3
CH3
scale using the relationship: d N (MeNO )Zd N(NH Cl)
2 4
K338.1 ppm.
.3. Computational details
The optimisation of the structures of all compounds
2c
H
N
H
N
4
N
N
NH
N
N
NH
OH
H
O
O
C
N
C
C
discussed in this paper was carried out at the hybrid
B3LYP/6-31G** level [17,18] with basis sets of Gaussian
type functions using Spartan ’02 for Windows [19].
3
a
3b
3c
4
.4. Syntheses
-Aminopyrazine-2-carboxylic acid (4) was purchased
Fig. 5. Tautomeric forms for pyrazines 1, 2 and 3.
3
4
.2. NMR parameters
Spectra were recorded in a Bruker DRX 400 (9.4T,
from Aldrich (O99%).
4.4.1. Methyl 3-aminopyrazine-2-carboxylate (5)
1
00.13 MHz for H, 100.62 MHz for C, 40.56 MHz for
13
4
To 2 g (14.37 mmol) of 3-aminopyrazine-2-carboxylic
acid (4) suspended in 5 mL of methanol, a previously
prepared solution of 4 mL of methanol and 3.8 mL of
1
5
17
N and 50.26 MHz for O NMR) spectrometer. Chemical
shifts (d in ppm) are given from internal solvents, CDCl3
7.26 ppm), THF-d (3.58 ppm) and DMSO-d (2.49 ppm)
(
for H NMR; CDCl (77.0 ppm), THF-d (67.4 ppm) and
ClSO H was added. The mixture was let to stir for 16 h at
3
8
6
1
13
room temperature. Then, 25 mL of water were added and the
reaction mixture was neutralized with sodium bicarbonate
until the pH reached a value of 7–8. A yellowish precipitate
appeared that was filtered, dried under vacuum and crystal-
lised from ethanol to give 2.3 g of 5 (80% yield), m.p. 172 8C.
3
8
1
3
DMSO-d (39.5 ppm) for C NMR; external nitromethane
6
5
1
0.0) for N NMR and external D O (K3.00 ppm) for
17
(
NMR spectroscopy. Coupling constants (J in Hz) are
O
2
1
13
15
accurate to G0.2 Hz for H and C and G0.6 Hz for N.
The acquisition parameters for inverse gated spectra were:
spectral width (14 kHz), relaxation delay (30 s), pulse width
C
1
MS m/z (relative intensity): 153 (M , 60), 28 (100). H NMR
3
3
(CDCl
(bs, NH
(COOCH
): 8.20 (d, H-5, JZ2.2), 8.00 (d, H-6, JZ2.2), 6.46
3
1
3
9
proton detected heteronuclear shift correlation spectra,
08 (28,5 ms) and number of scans (4.000–7000). 2D inverse
2
), 3.99 (s, COOCH
). C NMR (CDCl ): 166.8
3 3
1
), 155.5 (C-3), 147.5 (C-5, JZ170.0), 133.6 (C-6,
JZ180.1), 124.3 (C-2), 52.7 (COOCH
3
1
13
1
13
1
15
H- C gs-HMQC, H- C gs-HMBC, H- N gs-HMBC
1
1
JZ128.5).
3
1
15
and H- N gs-HMQC, were carried out with the standard
pulse sequences [16].
4.4.2. 2-Formyl-3-aminopyrazine (1)
3.3 g (21 mmol) of 5 were dissolved in 180 mL of dry
dichloromethane in a three-necked flask. The reaction
1
3
15
Solid-state C (100.73 MHz) and N (40.59 MHz)
CPMAS-NMR spectra have been obtained with a Bruker
Table 4
K1
Experimental and calculated relative stabilities in kJ mol of the different tautomers (in parentheses, dipole moments in Debye)
Compound
Absolute value for tautomer
Tautomer a
Tautomer b
Tautomer c
a
1
2
3
K433.0264
0 (1.94)
0
83.8 (5.15)
84.5
175.8 (2.47)
175.8
(
CZPE) K431.9230
K472.3539
CZPE) K472.2227
K664.0913
CZPE) K663.9065
0 (1.24)
0
85.8 (4.76)
86.8
174.0 (3.34)
173.6
(
0 (0.99)
0
85.6 (4.56)
86.2
169.2 (4.22)
168.6
(
Absolute energies of the most stable tautomer in Hartrees.

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
73
1
3
1
C NMR (CDCl ): 195.0 (CHO, JZ181.7) 154.6 (s, C-3),
3
1
3
1
1
3
48.0 (C-5, JZ180.7, JZ12.1), 134.6 (C-6, JZ185.1,
JZ10.7), 130.6 (C-2).
4
.4.3. 2-Methyl-4H-pyrazino[2,3-d][1,3]oxazin-4-one (6a)
Two grams (14.37 mmol) of 3-aminopyrazine-2-car-
boxylic acid (4) were suspended in 20 mL of acetic
anhydride and heated to reflux for 3 h until all the starting
material was in solution. Then, acetic anhydride was
evaporated under reduced pressure and the remaining
solid (6a) was dried under vacuum and kept away from
air and moisture due to its high instability. This compound
1
was used without further purification. H NMR (CDCl ):
3
3
3
8
.95 (d, H-7, JZ2.2), 8.82 (d, H-6, JZ2.2), 2.56 (s, CH ).
3
1
3
C (CDCl ): 165.6 (C-4), 156.2 (C-2), 151.1 (C-7), 149.7
3
(C-8a), 145.7 (C-6), 126.1 (C-4a), 21.6 (CH3).
8
N
1
Fig. 6. X-Ray molecular structure of 2-benzoyl-3-aminopyrazine (3).
8
a
N
2
R
7
6
mixture was cooled to K78 8C by immersing it in a Dewar
flask bath filled with liquid nitrogen. Then, 21 mL
3
O
N
5
4a
4
(
21 mmol) of DIBAL-H (1 M solution in dichloromethane)
were slowly added. The reaction was let to stir for 1 h, then
6 mL of a saturated solution of ammonium chloride were
O
3
added and the mixture was let to warm up to room
temperature. The remaining solids were filtered and the
organic phase was evaporated under reduced pressure and
purified by column chromatography using as eluent a 2:1
hexane-ethyl acetate mixture. 0.7 g of 1 (30% yield) were
obtained as a yellow solid, which was further purified by
4
.4.4. 2-Phenyl-4H-pyrazino[2,3-d][1,3]oxazin-4-one (6b)
.4 g (10 mmol) of 3-aminopyrazine-2-carboxylic acid
4) were dissolved in 50 mL of dry DMF, then 4.13 mL of
1
(
benzoyl chloride (20 mmol) and 3.06 mL (22 mmol) of
triethylamine were added. The reaction mixture was stirred
for 24 h at room temperature, then the solvent was
evaporated under reduced pressure and the solid obtained
was purified by column chromatography using hexane-ethyl
acetate (1:1). 0.7 g (30% yield) of 6b were obtained as a
white solid, m.p. 199 8C, Lit. [20] 183 8C. MS m/z (relative
sublimation, m.p. 118.9 8C, Lit. [4] 98–100 8C. MS m/z
C
relative intensity): 123 (M , 60), 28 (100). Anal. Calcd. for
(
C H N O, C 48.78, H 4.09, N 34.13; found, C 48.82, H
5
5 3
1
4
.21, N 34.27. H NMR (CDCl ):10.04 (s, CHO), 8.20 (d,
3
3
3
C
1
H-5, JZ2.2), 8.05 (d, H-6, JZ2.2), 6.49 (bs, NH2).
intensity): 225 (M , 20), 28 (100). H NMR (CDCl ): 9.00
3
Fig. 7. A sheet of hydrogen bonded molecules of 3 viewed through b.

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
74
C
(M K105, 10), 105 (100).
Table 5
˚
Hydrogen bonds for 2-benzoyl-3-aminopyrazine (3), distances in A, angles
in degrees
3´´
4
´´
2´´
1´´
D–H/A
d(D–H)
d(H/A)
d(D/A)
!(DHA)
5
´´
O
N(7)–H(7A)/O(1)
N(7)–H(7A)/O(1)
N(7)–H(7B)/N(4)
0.92(2)
0.92(2)
0.95(2)
2.05(2)
2.31(2)
2.11(2)
2.717(2)
3.037(3)
3.053(3)
129(2)
135(2)
177(2)
a
6
´´
b
3'
4
N
2'HN
1'
3
2
a
Symmetry transformations used to generate equivalent atoms: (KxC1,
b
Ky,KzC1). (Kx,Ky,Kz).
4'
5
6
5
'
N1
3
3
0 0
0 0
6'
(
d, H-7, JZ2.2), 8.86 (d, H-6, JZ2.2), 8.44 (d, ArH-2 6 ,
3
0
3
3
JZ8.0), 7.68 (t, ArH-4 , JZ JZ7.0), 7.58 (t, ArH-3 5 ,
JZ JZ7.0). C NMR (CDCl ): 161.2 (C-4), 157.1 (C-2),
O
3
3
13
3
1
3
H NMR (CDCl ): 11.4 (s, NH), 8.69 (d, H-5, JZ2.2),
0
3
1
54.7 (C-8a), 151.4 (C-7), 145.5 (C-6), 134.1 (C-4 ), 130.3
0 0 0 0 0
3
0 0
3
3
8.46 (d, H-6, JZ2.2), 8.08 (d, ArH-2 6 , JZ8.4), 8.03
(
C-4a), 129.3 (C-3 5 ), 128.9 (C-2 6 ), 128.7 (C-1 ).
00 00 00
3
3
(
d, ArH-2 6 , JZ8.4), 7.64 (t, ArH-4 , JZ JZ7.0), 7.61
0
3
3
0
0
0
0
3
3
(
t, ArH-4 , JZ JZ7.0), 7.54 (t, ArH-3 5 , JZ JZ7.0),
4
.4.5. N-(3-Acetylpyrazin-2-yl)acetamide (7a)
In a three necked flask 1.5 g (9.2 mmol) of 6a were
dissolved in 70 mL of dry dichloromethane. The reaction
mixture was cooled to K78 8C by immersing it in a Dewar
flask bath filled with liquid nitrogen and 1 equivalent
0 0
.52 (t, ArH-3 5 , JZ JZ7.0). C NMR (CDCl ): 195.4
3
3
3
13
7
(
CO), 164.9 (CONH), 149.3 (C-3), 145.9 (C-5), 137.8 (C-6),
0 00 0 00
1
36.4 (C-1 ), 133.8 (C-1 ), 133.4 (C-4 ), 132.7 (C-4 ), 131.0
0 0 0 0 00 00
(
(
C-2 6 ), 129.4 (C-2), 129.0 (C-3 5 ), 128.2 (C-3 5 ), 127.7
0
0 00
C-2 6 ).
(
9.2 mmol) of CH Li (1.6 M solution in diethyl ether) were
3
added. The reaction was stirred at low temperature for
5 min and after addition of 10 mL of a saturated
1
4.4.7. 2-Acetyl-3-aminopyrazine (2)
ammonium chloride solution the mixture was let to warm
up at room temperature. The dichloromethane solution was
extracted twice with 20 mL of water. The organic phase was
dried over anhydrous sodium sulphate and the solvent
evaporated under reduced pressure. The residue was
purified by column chromatography using hexane-ethyl
acetate (1:1) as eluent. The tertiary alcohol as the main
product as well as 350 mg (20% yield) of a brown solid 7a
were obtained, m.p. 137 8C. MS (EI) m/z (relative intensity):
Fifty milligrams (0.28 mmol) of 7a were suspended in
1.5 mL of methanol and to it 12 mL of a solution of 10%
HCl in methanol were added. After the reaction was
refluxed for 5 h, 10 mL of water were added and a yellow
precipitate was formed that was filtered, dried and
Table 6
Crystal data and structure refinement for 2-benzoyl-3-aminopyrazine (3)
Identification code
Empirical formula
Formula weight
Temperature
CCDC-257606
C11H N O
C
1
9
3
1
65 (M C1, 10), 28 (100). H NMR (CDCl ): 11.2 (s,
3
199.21
3
3
NH), 8.51 (d, H-5, JZ2.2), 8.29 (d, H-6, JZ2.2), 2.72 (s,
CH -CO), 2.36 (s, CH -CONH). C NMR (CDCl ): 203.5
293(2) K
1
3
˚
3
3
3
Wavelength
0.71073 A
Monoclinic
P2(1)/n
(
(
CO-CH ), 169.5 (CONH), 148.0 (C-3), 146.6 (C-5), 137.5
3
Crystal system
Space group
C-6), 132.7 (C-2), 26.9 (CH CONH), 25.9 (CH CO).
3
3
˚
Unit cell dimensions
aZ5.890(3) A,
˚
bZ22.425(10) A, bZ101.644(9)8
4
.4.6. N-(3-Benzoylpyrazin-2-yl)benzamide (7b)
In a three necked flask 1.032 g (4.58 mmol) of 6b were
˚
cZ7.413(3) A,
3
˚
959.0(7) A
Volume
dissolved in 50 mL of dry dichloromethane. The reaction
mixture was cooled to K78 8C by immersing it in a Dewar
flask bath filled with liquid nitrogen and 1.5 eq (6.87 mmol,
Z
4
3
Density (calculated)
Absorption coefficient
F(000)
1.380 Mg/m
K1
0.093 mm
416
6
.87 mL) of PhMgBr (1.0 M solution in THF) were added.
The reaction stirred at low temperature for 2 h and then
0 mL of a saturated ammonium chloride solution were
3
Crystal size
0.07!0.15!0.17 mm
1.82–24.998
Theta range for data
collection
1
Index ranges
K7%h%6, K26%k%26, K8%l%7
4929
added and the mixture was let to warm up at room
temperature. The dichloromethane solution was extracted
twice with 20 mL of water. The organic phase was dried
with sodium sulphate and the solvent evaporated under
reduced pressure. The residue was purified by column
chromatography and hexane-ethyl acetate (1:1) used as
eluent. The tertiary alcohol as main product together with
Reflections collected
Independent reflections
Data/restraints/par-
ameters
1674 [R(int)Z0.0439]
1674/0/142
2
G.o.f. (F )
0.940
a
R
R
1
2
[IO2sigma(I)]
(all data)
0.0386 (ref. Obs. 1025)
0.1026
b
P
P
a
4
00 mg (30% yield) of a white solid 7b were obtained.
½jF jKjF jŠ= jF j:
P P
2 2 2
o
c
o
b
2
2
1=2
m.p.Z165.5 8C. MS m/z (relative intensity): 198
f
½wðFo KFc Þ Š= ½wðFo Þ Šg
:

´
M.A Farr a´ n et al. / Journal of Molecular Structure 741 (2005) 67–75
75
crystallised from hexane to give 2 (35 mg, 90% yield) as a
pale yellow solid. m.p.Z125.4 8C, Lit. [5b] 124 8C. MS m/z
12 union Road, Cambridge CB2 1EZ, UK; fax: (C44)
1223-336033; or deposit@ccdc.cam.uk.
C
relative intensity): 137 (M , 40), 28 (100). Anal. Calcd. for
(
C H N O, C 52.55, H 5.14, N 30.64; found C 52.62, H 5.16,
6
7 3
1
3
N 30.83. H NMR (CDCl ): 8.17 (d, H , JZ2.2), 7.94 (d,
3
5
1
H-6), 5.73 (bs, NH ), 2.68 (s, CH CO). C NMR (CDCl ):
3
Acknowledgements
2
3
2
3
3
1
2
02.7 (CO, JZ6.0), 154.6 (C-3, JZ9.2), 147.3 (C-5, JZ
68.7, JZ12.2), 132.8 (C-6, JZ180.4, JZ10.7), 130.4
C-2), 25.8 (CH , JZ128.5).
3
2
1
2
1
This work has been financed by the MCyT/DGI of Spain
(BQU2003-00976) and UNED (2003I/PUNED/21). One of
us (M.A.F.) thanks the MCyT for a ‘Ramon y Cajal’
fellowship.
1
(
4
.4.8. 2-Benzoyl-3-aminopyrazine (3)
Hundred-and-ten milligrams (0.4 mmol) of 7b were
suspended in 5 mL of methanol with 80 mL of 12 M
NaOH solution (0.8 mmol) and refluxed for 3 h. Then, 5 mL
of water were added to the solution, a bright yellow
precipitate formed that was filtered, dried and crystallised
from ethanol to give 3 (65 mg, 85% yield) as bright yellow
crystals, m.p. 161.3 8C, Lit [5b] 160 8C MS m/z (relative
References
[
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1
1 9 3
1
3
4
.66, N 21.11. H NMR (CDCl ): 8.19 (d, H-5, JZ2.2),
.99 (d, H-6, JZ2.2), 7.94 (d, ArH-2 6 , JZ8.0), 7.54 (t,
ArH-4 , JZ JZ7.0), 7.45 (t, ArH-3 5 , JZ JZ7.0),
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2 3
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3
6
2
(
1
2
0
JZ10.7), 147.6 (C-5, JZ173.3, JZ10.7), 138.4 (C-1 ,
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61.0, JZ7.5), 131.0 (C-2, JZ10.7), 130.6 (C-3 5 , JZ
61.0, JZ7.5), 128.4 (C-2 6 , JZ160.0, JZ7.5).
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[
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[
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CCD diffractometer using graphite-monochromated Mo Ka
[
[
13] G.S. Marx, P.E. Spoerri, J. Org. Chem. 37 (1972) 111.
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˚
radiation (lZ0.71073 A) operating at 50 kV and 30 mA.
(
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Data were collected over a hemisphere of the reciprocal
space by combination of three exposure sets. Each exposure
of 30 s covered 0.3 in u. Reflection ranges for the data
collection were 1.82!q! 24.998. Structure was solved by
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(
[
[
[
15] W. Pfleiderer, In Comprehensive Heterocyclic Chemistry, 3, Perga-
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2
16] S. Braun, H.-O. Kalinowski, S. Berger, 150 and More Basic NMR
Experiments, Wiley-VCH, Weinheim, 1998.
square procedures on F for all reflections (SHELXL-97) [21].
All non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were located on a difference Fourier map
and fixed, save the hydrogens bonded to nitrogen atom (N7)
where only coordinates were refined. Crystal data and other
structure determination details are presented in Table 6.
CCDC-257606 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
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(
(
b) C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785;
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(
[
[
[
[
18] P.A. Hariharan, J.A. Pople, Theor. Chim. Acta 28 (1973) 213.
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(
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