Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline

Article abstract of DOI:10.1016/j.molstruc.2020.128826

Monoxide and dioxide of animo quinoxaline were synthesized and characterized by ¹H NMR, ¹³C NMR and HRMS. The result shows that monoxide is main product. ¹H NMR analysis, quantum calculation and crystal structure all indicate that the monoxide is 4-oxide structure but not 1-oxide structure. The subsequent discussions of electronic effect and steric effect of 1-oxide and 4-oxide support the conclusion that 4-oxide is dominant product, which is consistent with ¹H NMR analysis and crystal structure. At last, the calculated structure is in good agreement with the crystal structure in this paper, which indicates that the calculation result in this paper is credible.

Full text of DOI:10.1016/j.molstruc.2020.128826

Journal Pre-proof
Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl
quinoxaline
Rui Wang, Min Zhang, Wenfeng Wang, Xucheng Wang, Yaofeng Yuan, Junjian Li
PII:
S0022-2860(20)31151-0
DOI:
https://doi.org/10.1016/j.molstruc.2020.128826
MOLSTR 128826
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 January 2020
Revised Date: 21 June 2020
Accepted Date: 2 July 2020
Please cite this article as: R. Wang, M. Zhang, W. Wang, X. Wang, Y. Yuan, J. Li, Synthesis, crystal
structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline, Journal of Molecular
Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.128826.
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CRediT author statement
Rui Wang: Conceptualization, Methodology
Min Zhang: Formal analysis, Investigation
Wenfeng Wang: Conceptualization, Supervision
Xucheng Wang: Investigation
Yaofeng Yuan: Project administration
Junjian Li: Software

Synthesis, crystal structure and calculation of oxides of
-methylamino-3-methyl quinoxaline
2
Rui Wang, Min Zhang, Wenfeng Wang *, Xucheng Wang, Yaofeng Yuan, Junjian Li
College of Chemistry, Fuzhou University, 350116, P. R. China
Abstract: Monoxide and dioxide of animo quinoxaline were synthesized and
1
13
characterized by H NMR, C NMR and HRMS. The result shows that
1
monoxide is main product. H NMR analysis, quantum calculation and
crystal structure all indicate that the monoxide is 4-oxide structure but not
1
-oxide structure. The subsequent discussions of electronic effect and steric
effect of 1-oxide and 4-oxide support the conclusion that 4-oxide is dominant
1
product, which is consistent with H NMR analysis and crystal structure. At
last, the calculated structure is in good agreement with the crystal structure
in this paper, which indicates that the calculation result in this paper is
credible.
Keyword: Oxide of quinoxaline, calculation, crystal structure, electronic effect, steric
effect.
1
. Introduction
Quinoxaline derivatives are pharmacologically important compounds possessing various
[
1-3]
biological activities
. Thereinto, 2-amino quinoxaline dioxide is isoelectronic with
Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide, TPZ) which has become an
anticancer drug in clinical treatment. TPZ is a good chemo- and radio-sensitizer because it
selectively causes DNA breakage in hypoxic tumor cells via a one-electron bioreductive
1
/ 18

[
4]
activation . Like TPZ, quinoxaline dioxides can also undergo a one-electron bioreductive
[
5]
activation to generate OH radical , which is shown in Fig. 1. It is well known that OH
radical can break DNA double helix, so it is worthy of designing and synthesizing amino
quinoxaline 1,4-dioxide derivative.
Fig. 1 The generation of OH radical by the bioreductive activation of quinoxaline dioxide
There is hardly any report about the synthesis of oxides of amino quinoxaline. Gates reported the
[6]
oxidation of 3-amino-1,2,4-benzotriazine in 2001 , which gave a mixture of three mono-N-oxides and one
1
,4-di-N-oxides, as shown in Fig. 2.
Fig. 2 The synthetic route of oxides of 3-amino-1,2,4-benzotriazine
[7]
There are many reports on the synthesis of quinoxaline oxides. Elina reported that the oxidation of A
[8]
and B afforded 1,4-di-N-oxides and mono-N-oxides as main product respectively. Rozen reported that
the rapid oxidation of C and D by HOF▪CH CN complex provided mono-N-oxide and mixture of
3
mono-N-oxides and 1,4-N-oxides as product respectively, as shown in Fig.3. It shows that the oxidation of
N4 atom is sterically hindered by the presence of substituent in position 5, but the hindrance in position 2
or 3 does not cause any problem.
2
/ 18

Fig. 3 The oxidative reactions of quinoxaline derivatives
The electronic effect of substituent in position 2 or 3 can lead to the occurrence of the oxidation in
[8]
position 1 and 4 under different oxidation conditions , the reason of which is unknown. Sometimes the
[9]
hydrogen bond interaction also makes one mono-N-oxide main product , as shown in Fig. 4.
3
/ 18

Fig. 4 Selective oxidation of quinoxaline derivatives
In this work, the oxidation of 2-methylamino-3-methyl quinoxaline gives a mixture of a
large amount of monoxide and small amount of dioxide. In order to identify the structure of
1
the monoxide, HNMR study, quantum calculation and crystal structure are afforded in this
paper. At last, an explanation on why the monoxide is main product is given.
2
. Experiments
2
.1. Synthesis
The synthetic route of monoxide and dioxide of amino quinoxaline is shown in Fig. 5. All
solvents had been distilled before we used them, and other reagents were obtained from
commercial suppliers in analytically pure forms. Melting points were measured with WRS-1B
1
13
micromelting apparatus and remain uncorrected. H NMR and C NMR spectra were
recorded on BRUKER AV (400 MHz and 100 MHz, respectively) spectrometer with TMS as
an internal standard. The chemical shift values are on δ scale and the coupling constants (J)
are in Hz. Electrospray ionization (ESI) mass spectra are measured on an Agilent 1100
IC/MSD TrapXCT and are reported as m/z.
4
/ 18

Fig. 5 The synthetic route of monoxide and dioxide of compound 3. a) H O, RT; b) POCl , 90 ˚C; c)
2
3
CH NH , ethanol, RT; d) MCPBA, CH Cl , RT.
3
2
2
2
2
.1.1 Synthesis of 3-methyl quinoxalin-2(1H)-one (1) and 2-chloro-3-methyl quinoxaline (2)
[
10,11]
Compound 1 and 2 were synthesized according to the references
and their
characterization data are shown as following:
1
Compound 1: H NMR (DMSO-d6) δ : 12.28 (s, 1H, NH), 7.67(d, J = 8.0 Hz, 1H,
Ar-H), 7.45 (t, J = 7.2 Hz , 1H, Ar-H), 7.27 (1H, J = 8.2 Hz, Ar-H), 7.25 (t, J = 8.4 Hz, 1H,
13
Ar-H ), 2.39 (s, 3H, CH ); C NMR (DMSO-d6): 159.6, 155.4, 132.4, 132.1, 129.7, 128.3,
3
1
23.5, 115.7, 21.0.
1
Compound 2: H NMR (CDCl ) δ: 7.98 (d, J = 8.4 Hz, 1H, Ar-H), 7.95 (d, J = 7.6 Hz ,
3
1
H, Ar-H), 7.72 (t, J = 5.2 Hz, 1H, Ar-H ), 7.70 (t, J = 4.0 Hz, 1H, Ar-H), 2.82 (s, 3H, CH3);
1
3
C NMR (CDCl ) δ: 152.8, 147.8, 140.9, 140.8, 130.1, 130.0, 128.4, 128.1, 23.3.
3
2
.1.2. Synthesis of 2-methylamino-3-methyl quinoxaline (3)
5
/ 18

Compound 2 (1.0g, 5.6mmol) was dissolved in 30mL ethanol and then 15mL 40%
methylamine aqueous solution was added. The mixture was stirred in room temperature and
the reaction was monitored by TLC. The reaction was stopped after 36h. The mixture was
extracted by CH Cl , and the organic phase was washed by water twice and then dried by
2
2
anhydrous Na SO . The solvent was removed and the residue was chromatographed on a
2
4
silica gel column by gradient elution to give product 3, with petroleum ether /ethanol (v/v
from 10:1 to 8:1 to 5:1 to 3:1) as elution.
1
Yield 83.4%, white solid, m.p. 93-94˚C; H NMR (CDCl ) δ: 7.81 (d, J = 8.0 Hz, 1H,
3
Ar-H), 7.72 (d, J = 8.4 Hz , 1H, Ar-H), 7.53 (t, J = 7.6 Hz, 1H, Ar-H ), 7.36 (t, J = 7.6 Hz, 1H,
1
3
Ar-H), 4.82 (br, 1H, NH), 3.16 (d, J = 4.0 Hz, 3H, CH NH), 2.55 (s, 3H, CH ); C NMR
3
3
+
(
CDCl ) δ: 151.5, 145.0, 141.5, 136.5, 128.8, 127.9, 125.9, 124.1, 28.3, 20.9; HRMS (ESI ):
3
+
calcd for C H N [M+H] = 174.1026; found: 174.1031.
1
0
12
3
2
.1.3.
Synthesis
of
2-methylamino-3-methyl
quinoxaline
4-oxide
(4)
and
2
-methylamino-3-methyl quinoxaline 1,4-dioxide (5)
Compound 3 (0.810 g, 4.7 mmol) was dissolved in 30 mL CH Cl , and then m-CPBA
2
2
(3.032 g, 18.7 mmol) was added. The mixture was stirred under room temperature till
compound 3 was consumed (judged by TLC, about 2h). The mixture was washed by NaHSO3,
NaOH aqueous solution and saturated NaCl aqueous solution. The organic phase was dried by
anhydrous Na SO . After the removal of solvent, the residue was chromatographed on a silica
2
4
gel column. Compound 4 was obtained with petroleum ether /ethyl acetate (v/v, 1:1) as
elution and compound 5 was obtained with ethyl acetate /ethanol (v/v, 4:1) as elution.
6
/ 18

1
Compound 4: Yield 79.7%, white solid, m.p. 200-201˚C; H NMR (CDCl ) δ: 8.42 (d, J
3
=
=
8.4 Hz, 1H, Ar-H), 7.74 (d, J = 8.0 Hz , 1H, Ar-H), 7.59 (t, J = 7.6 Hz, 1H, Ar-H ), 7.38 (t, J
7.6 Hz, 1H, Ar-H), 4.76 (br, 1H, NH), 3.17 (d, J = 4.8 Hz, 3H, CH NH), 2.58 (s, 3H, CH );
3
3
1
3
C NMR (DMSO-d6) δ: 153.8, 142.5, 131.7, 131.5, 130.7, 126.7, 123.8, 118.8, 28.8, 11.8;
+
+
HRMS (ESI ): calcd for C H N O [M+H] = 190.0975; found: 190.0976.
10
12
3
1
Compound 5: Yield 2.1%, yellow-green solid, m.p. 161-162˚C; H NMR (CDCl ) δ: 8.52
3
(d, J = 8.4 Hz, 1H, Ar-H), 8.44 (d, J = 8.4 Hz , 1H, Ar-H), 7.77 (t, J = 7.6 Hz, 1H, Ar-H ),
13
7
.59 (t, J = 8.0 Hz, 1H, Ar-H), 3.27 (d, J = 5.6 Hz, 3H, CH NH), 2.85 (s, 3H, CH ); C NMR
3 3
(DMSO-d6) δ: 147.0, 134.2, 133.1, 131.8, 131.7, 127.0, 119.8, 117.9, 32.5, 14.7; HRMS
+
+
(
ESI ): calcd for C H N O [M+H] = 206.0924; found: 206.0916.
1
0
12
3
2
2
.2 Computational method
All geometry optimizations and calculations are performed by means of B3LYP with
[
12]
Gaussian 03 program and 6-311G (D) basis set for all atoms
.
3
. Results and discussion
3
.1 Identification of the structure of compound 4
3
.1.1 NMR analysis of compound 4
1
In H NMR of compound 2, the peaks of H5 and H8 are very close (7.98 and 7.96 ppm,
both are double peak), but the peaks of H5 and H8 in compound 3 separate clearly (7.81 and
7
.72 ppm). We assign the peak of 7.81 ppm to H5 and that of 7.72 ppm to H8 respectively,
1
according to the resonance of compound 3, which is shown in Fig. 6 (left). In H NMR of
7
/ 18

compound 4, two double peaks were respectively found in 8.42 ppm and 7.74 ppm, which
implies that the peak of H5 shifted to downfield and the peak of H8 remained unchanged.
Gates reported that the formation of N-O coordinate bond would make the chemical shifts of
[6]
H atoms in peri-position shift downfield , so we propose that the O atom of compound 4
bond with N4 and not with N1, as shown in Fig. 6 (right).
Fig. 6 Resonance of compound 3 (left) and the effect of N-O coordinate bond of compound 4
on chemical shift of H atom in peri-position (right)
3
.1.2 Calculation of the structure of compound 3 and its oxides
In this work, the treatment of compound 3 gave a monoxide as main product (proved by
1
HRMS). Although the H NMR mentioned above implies that the structure of the monoxide is
4
-oxide (as shown in Fig. 5), it is necessary to provide other proofs to identify the structure of
the monoxide. So compound 3 and its monoxides and dioxide are all calculated and the result
is shown in Fig. 7.
8
/ 18

Compound 3 (charge of N1: -0.38; N4:-0.32)
4 (4-oxide, 0.0 kJ/mol, as reference)
1-oxide, relative energy: 34.3 kJ/mol
5 (1,4-dioxide of compound 3)
Fig. 7 The optimized structures of compound 3 and its oxides (with numbers depicting carbon
atoms and their sequence in this paper, the same for the whole paper)
Fig. 7 shows that 4-oxide of compound 3 (0.0 kJ/mol, calculated as reference) is more
stable than 1-oxide of compound 3 (34.3kJ/mol, relative energy), which is consistent with the
1
conclusion of H NMR analysis and indicates that the monoxide of compound 3 obtained in
this work possesses 4-oxide structure.
3
.1.3 Crystal structure of compound 4
In this work, the crystal structure of compound 4 is obtained and shown in Fig. 8, and its
9
/ 18

bond length data are listed in Table 1.
Fig. 8 The crystal structure of compound 4 (CCDC: 1975394)
Table 1 Comparison of bond length values (in 0.1 nm) of crystal with those calculated
Bond
C14-C11
N6-O
C13-C9
C9-C8
C8-C4
C4-C14
C4-N6
Crystal
1.377
1.379
1.306
1.269
1.367
1.377
1.415
1.416
1.394
1.413
1.405
1.402
1.414
1.413
Calculated*
Bond
C8-N3
N3-C5
N6-C1
C1-C5
C1-C1AA
C5-N2
N2-C0AA
Crystal
1.366
1.361
1.333
1.318
1.341
1.350
1.439
1.434
1.491
1.494
1.368
1.374
1.457
1.455
Calculated*
*
The calculated values have been shown in compound 4 in Fig. 7
It is verified in Fig. 8 that the monoxide of compound 3 obtained in this work is 4-oxide,
1
which implies that both the H NMR analysis and quantum calculation result are correct.
Comparing the bond length values of crystal with those calculated (which have been shown in
compound 4 in Fig. 7), it can be found that most of them are quite approximative, indicating
that the calculation result is precise. The largest difference comes from the bond length of
N6-O, 1.306 Å for crystal and 1.269 Å for calculation, which is not surprising.
1
0 / 18

Fig. 9 shows the crystal packing structure of compound 3. Compound 3 is a planar
molecule, so the molecules of compound 3 pack together through a π-π interaction. The π-π
interaction may be weak because the distance between two planes of molecules of compound
3 is about 3.40 Å. There is also a weak ionic interaction between two molecules of compound
3 because the distance between N cation of one molecule and O anion of another molecule is
3.446 Å. Fig. 9 also shows that there is a strong hydrogen bond between molecules of
compound 3. The distance between O anion of one molecule and H atoms (of N-H) of another
molecule is only 2.055 Å.
In gas phase, molecule is isolated, so N cation can only interact with O anion, which
makes the intramolecular N-O interaction in gas phase stronger than that in crystal. That is the
reason why the calculated bond length value of N-O is only 1.269 Å.
Fig. 9 The crystal packing structure of compound 3.
11 / 18

3
.2 Why 4-oxide is main product?
In this work, the oxidation of compound 3 afforded a monoxide as main product and only
a little dioxide (compound 5) as byproduct though excessive MCPBA was used. Although it
has been understood that the monoxide possesses 4-oxdie structure, another question should
be discussed in this section: why 4-oxide is main product?
3
.2.1 Steric effect
At first, steric effect is considered. In molecular structure of 4-oxide, all atoms are
coplanar except of H atoms. While in 1-oxide, N11-C12 bond deviates the molecule plane
about 49° due to the repulsion interaction between 2p orbital of O atom and C-H bond orbital
of CH group, which is shown in Scheme 1. Does this repulsion play a key role? In order to
3
answer this question, two new molecules E and F are calculated and the result is shown in Fig.
1
0.
Scheme 1 The repulsion interaction between O atom with CH in 1-oxide of quinoxaline
3
1
2 / 18

E (0.0 kJ/mol, as reference)
F (5.1kJ/mol, relative energy)
Fig. 10 The optimized molecule structures of E and F.
In E and F molecules, all atoms except H atoms are coplanar, and both of them have no
steric hindrance. The difference between energies of E and F is only 5.1 kJ/mol, which is much
less than that between 4-oxide and 1-oxide of compound 3 (34.3 kJ/mol), which indicates 1)
steric hindrance has a great effect on molecular stability, which is the reason why monoxide is
main product during the oxidation of compound 3; 2) steric effect is not the only factor
affecting stabilities of oxide of quinoxaline. That is to say, electronic effect should be
considered.
In order to validate that steric hindrance plays a great role in the synthesis of dioxide of
quinoxaline derivatives, we synthesized compound 7 via intermediate 6 (details in supporting
[
13, 14]
file), as shown in Fig. 11. Both 6 and 7 are compounds that have been reported
. There is
no steric hindrance in compound 7, so the treatment of compound 6 with excessive MCPBA
gives dioxide as main product (yield > 70%).
1
3 / 18

Fig. 11 Synthetic route of compound 7. a) 2,3-Butanedione, H O, RT; b) MCPBA, CH Cl ,
2
2
2
RT
3
.2.2 Electronic effect
In molecule structure of compound 3, the charge of N1 is -0.38 and that of N4 is -0.32,
but the electron population number of 2p orbital of N1 atom is 1.49 and that of N4 is 1.53.
y
According to this calculation result, it is difficult to draw a conclusion of the question which
N atom prefers to give its 2p orbital electron to form oxide. So the two conjugative acid of
y
compound 3 (G and K) are calculated and the result is shown in Fig. 12.
H
H 12
H
H8
1
.461
1
.374
7
1.350
1
.417
9
8
N1
N
H7
.417
H6
H 1.005
2
1
1
.424
.405
1.326
.328
1
.444
1
1
1
.491
6
10
.375
3
H
N4
5
13
H
H
1
1
.376
H4
H5
1
.016
G (1-conjugative acid, 0.0 kJ/mol, as reference)
K (4-conjugative acid, relative energy: 12.0 kJ/mol)
Fig. 12 Optimized structures of compound G and K
In molecule structures of G (1-conjugative acid of compound 3) and K (4-conjugative
1
4 / 18

acid of compound 3), all atoms are coplanar except of H atoms, so both of them have no steric
hindrance. Calculated result shows that G is more stable than K, which indicates that it is
+
easier for N1 atom to afford its 2p electron to bond with other atoms (with H to form
y
conjugative acid and with O atom to form oxide). That is because the N1 atom (-0.38) has a
larger negative charge compared with N4 atom (-0.32). But now the monoxide we obtained in
this work is 4-oxide but not 1-oxide, which leads to the conclusion: 4-oxide is more stable
than 1-oxide.
3
.2.3 The reason why 4-oxide is more stable than 1-oxide
Not only steric effect makes 4-oxide more stable than 1-oxide, electronic effect is also
responsible to this fact. 1-Oxide and 4-oxide have different conjugative system, which is
shown in scheme 2.
Scheme 2 Conjugative resonances of 4-oxide (up) and 1-oxide (down) of compound 3
In conjugative system of 4-oxide of compound 3, C2 atom carries positive charge. While
in that of 1-oxide of compound 3, C2 atom carries negative charge. Since C2 atom is bonded
1
5 / 18

to the amino group, which is a strong electron donor group. Positive charge in C2 atom is
stable and negative charge in C2 atom is unstable, so 4-oxide of compound 3 is more stable
than 1-oxide of compound 3.
4
. Conclusions
In this paper, the oxidation of compound 3 gives monoxide as main product, because
1
there is steric hindrance in dioxide. H NMR analysis, quantum calculation and crystal
structure all show that the monoxide obtained in this work possesses 4-oxide structure, and
subsequent analysis of the steric effect and conjugative effect both support this conclusion.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This study is supported by the Natural Science Foundation of Fujian Province of China
(2017J01578).
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Highlights
. The work includes synthesis, quantum calculation and crystal
structure.
1
2
3
4
1
13
. All products unknown are characterized by H NMR, C
NMR and HRMS.
1
. The structure of monoxide is identified by H NMR analysis,
calculation and crystal structure.
. A detailed explanation that 4-oxide is main product is given.

Declaration of interest statement
We declared that we have no conflicts of interest to this work.