Regioselectivity in 2-X-pyrazine aminations by O-mesitylenesulfonylhydroxylamine

Article abstract of DOI:10.1016/j.tetlet.2009.09.103

The regioselectivity of 2-X-pyrazine aminations by O-mesitylenesulfonylhydroxylamine was studied experimentally and the results are discussed from the viewpoint of electronic and steric factors. DFT calculations are consistent with the reaction proceeding according to an S_N2 mechanism.

Full text of DOI:10.1016/j.tetlet.2009.09.103

Tetrahedron Letters 50 (2009) 6779–6782
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselectivity in 2-X-pyrazine aminations
by O-mesitylenesulfonylhydroxylamine
Gennady I. Borodkin a,b, , Aleksey Yu. Vorob’ev a,b, Makhmut M. Shakirov a, Vyacheslav G. Shubin a
*
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Acad. Lavrentiev Ave. 9, Novosibirsk 630090, Russia
b Novosibirsk State University, Pirogov st. 2, Novosibirsk 630090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2009
Revised 7 September 2009
Accepted 18 September 2009
Available online 24 September 2009
The regioselectivity of 2-X-pyrazine aminations by O-mesitylenesulfonylhydroxylamine was studied
experimentally and the results are discussed from the viewpoint of electronic and steric factors. DFT cal-
culations are consistent with the reaction proceeding according to an SN2 mechanism.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Selectivity
N-Amine salts
Azines
Mechanism
Linear free energy relationship
DFT calculations
N-Amine salts of N-heteroaromatic compounds are used widely
as reagents in aminations of aromatic compounds,1 and as interme-
diates in syntheses of N-imines and various heterocyclic com-
pounds.2–12 Nitrogen-rich salts of N-amines manifest themselves
as high energy materials.13–15 Azaarenes, in which two or several
nitrogens are in different environments, exhibit marked alteration
in reactivity patterns.3,5 The factors determining the regioselectivity
of amination of such compounds are not clear as yet. The electronic
influence of substituents in 3-Br, 4-Me, and 5-NO2-1,10-phen-
anthrolines on reactions with O-mesitylenesulfonylhydroxylamine
was studied earlier.16 It was found that the ratio of isomeric
amino-cations formed was determined by their relative stability.
In continuation of our studies on the regioselectivity of azine ami-
nation, we chose to examine substituted pyrazines as model com-
pounds. This choice was determined by their wide use in the
synthesis of N-amine salts.5 Besides, unlike 1,10-phenanthroline, in
a pyrazine molecule both nitrogen atoms are situated in the same ring
and the proximity of a substituent to the reaction center can result in
certain differencesintheaminationprocess. Whenasubstituentislo-
cated at a point remote from the reaction center, only electronic ef-
fects need usually be considered. When the structural modification
is close to this center, our understanding is less advanced.
Reaction of 2-X-pyrazines 1a–i with O-mesitylenesulfonylhydr-
oxylamine in CH2Cl2 leads to salts 2 and 3. The nitrile group pre-
vents amination of 1j, whereas the tert-butyl substituent in 1f
directs the amination to position 4, exclusively.
Interestingly, the amination of 2-(N-acetylamino)pyrazine 1i
results in the formation of 2-methyl[1,2,4]triazolo[1,5-a]pyrazine
N
N
X
N
MesSO3NH2
-
MesSO3
-
+
MesSO3
CH2Cl2
N
X
N
X
N
NH2
NH2
1 a-j
2a-e,g-i
3a-i
X = H (a), Me (b), Et (c), Pr (d), i-Pr (e), t-Bu (f), CH(OH)Me (g), NH2 (h), NHAc (i), CN (j)
* Corresponding author. Tel.: +7 383 330 7651; fax: +7 383 330 9752.
E-mail address: gibor@nioch.nsc.ru (G.I. Borodkin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.103

6780
G. I. Borodkin et al. / Tetrahedron Letters 50 (2009) 6779–6782
Table 1
1H chemical shifts (d, ppm) and spin–spin coupling constants (Hz) of cations 2 and 3a
b
X
Cation
X
H-2
H-3
H-5
H-6
NH2
H
2a
—
8.74 (1H, ddd, 4.0, 1.6,
9.14 (1H, dd, 4.0,
9.14 (1H, dd, 4.0, 1.0)
8.74 (1H, ddd, 4.0, 1.6,
9.60
1.0)
—
1.0)
1.0)
(2H)
9.08
(2H)
9.51
(2H)
9.6 (2H)
Me
Et
2b
3b
2c
3c
2d
3d
2e
3e
3f
2.67 (3H, ddd, 0.8, 0.8, 0.4)
2.60 (3H, ddd, 0.7, 0.7, 0.7)
9.13 (1H, qd, 0.8,
0.7)
—
8.97 (1H, dq, 4.0, 0.8)
8.80 (1H, ddq, 4.0, 0.7,
0.4)
8.62 (1H, ddq, 3.9, 1.5,
0.7)
8.84 (1H, ddt, 4.0, 0.8,
0.4)
8.66 (1H, ddt, 3.9, 1.6,
0.6)
8.85 (1H, dd, 4.0, 0.8)
8.71 (1H, dqd, 1.5, 0.7,
0.7)
—
9.01 (1H, dqd, 3.9, 0.7,
0.7)
8.98 (1H, dt, 4.0, 0.7)
1.30 (3H, t, 7.4) 3.05 (2H, qddd,
7.4, 0.8, 0.7, 0.4)
1.24 (3H, t, 7.6) 2.87 (2H, qdd,
7.6, 0.6, 0.5)
0.95 (3H, t, 7.4) 1.71 (2H, tq,
7.8, 7.4) 3.01 (2H, t, 7.8)
0.88 (3H, t, 7.4) 1.66 (2H, tq,
7.6, 7.4) 2.80 (2H, t, 7.6)
1.32 (6H, d, 6.8) 3.64 (1H, sept,
6.8)
9.08 (1H, td, 0.8,
0.8)
—
8.78 (1H, ddt, 1.6, 0.9,
0.5)
—
9.03 (1H, dd, 3.9, 0.9)
8.98 (1H, d, 4.0)
9.6 (2H)
9.6 (2H)
9.1 (2H)
9.5 (2H)
9.5 (2H)
Pr
9.08 (1H, d, 0.8)
8.80 (1H, dd, 1.6, 0.9)
—
—
9.04 (1H, dd, 3.9, 0.9)
8.99 (1H, d, 4.0)c
8.68 (1H, dd, 3.9, 1.6)
8.81 (1H, d, 4.0)c
i-Pr
9.19 (1H)c
—
1.23 (6H, d, 6.9) 3.16 (1H, sept, 8.83 (1H, dd, 1.5, 0.9)
6.9)
9.05 (1H, dd, 3.9, 0.9)
8.67 (1H, dd, 3.9, 1.5)
t-Bu
CH(OH)Me 2g
1.35 (9H, s)
1.55 (3H, d, 6.6) 5.34 (1H, qdd,
6.6, 0.6, 0.6) 5.2 (1H, br s)
8.82 (1H, dd, 1.5, 0.9)
—
—
9.10 (1H, dd, 3.8, 0.9)
9.05 (1H, dd, 4.0, 0.6)
8.63 (1H, dd, 3.8, 1.5)
8.81 (1H, dd, 4.0, 0.8)
9.5 (2H)
9.1 (2H)
9.22 (1H, dd, 0.8,
0.6)
—
3g
1.44 (3H, d, 6.6) 4.91 (1H, qdd, 8.80 (1H, ddd, 1.7, 0.9,
9.04 (1H, dd, 3.9, 0.9)
7.90 (1H, d, 4.4)
8.66 (1H, ddd, 3.9, 1.7,
0.8)
8.07 (1H, dd, 4.4, 1.0)
9.6 (2H)
6.6, 0.8, 0.8) 5.2 (1H, br s)
8.84 (2H, br s)
0.8)
—
NH2
2h
8.61 (1H, d, 1.0)
7.14
(2H)
3h
3i
7.68 (2H, br s)
2.20 (3H, s) 11.6 (1H, br s)
7.84 (1H, dd, 1.5, 0.9)
9.42 (1H, dd, 1.5, 0.9)
—
—
7.80 (1H, dd, 3.8, 1.5)
8.83 (1H, dd, 3.9, 0.9)
8.37 (1H, dd, 3.8, 0.9)
8.43 (1H, dd, 3.9, 1.5)
9.0 (2H)
9.6 (2H)
NHAc
a
b
c
Spectra in DMSO-d6. Chemical shifts are referenced to TMS with DMSO as a secondary internal standard (d 2.50 ppm).
Broad singlet.
Some constants are not determined because of low signal intensity.
4.17 The corresponding 1-amino-2-(N-acetylamino)pyrazinium 2i
undergoes rapid ring closure, such that cation 2i cannot be ob-
served.
It has been proven that in the case of X = alkyl, only steric effects
are essential (Table 2, Fig. 1)
:
lgð2 : 3Þ ¼ ðꢀ0:19 ꢁ 0:07Þ þ ð0:84 ꢁ 0:15ÞEso
r ¼ 0:958; s ¼ 0:13; n ¼ 5
N
N
NH2
N
ð1Þ
ð2Þ
O
-
MesSO3
lgð2 : 3Þ ¼ ðꢀ0:18 ꢁ 0:04Þ ꢀ ð0:41 ꢁ 0:03ÞF
r ¼ 0:990; s ¼ 0:06; n ¼ 5
-H3O+MesSO3
-
N
N
N
N
N
H
NH2
N
NH2
In the case of other substituents, the electronic effect is signifi-
cant: a correlation of lg (2:3) with Eq. (3) using the rI,
2i
4
5
r
oR, and Eos
For the cations that were observed, the structures were estab-
lished by means of 1H NMR spectroscopy (Table 1). In addition,
the structures of cations 2a,h and 3i were determined by X-ray dif-
fraction.18 Assignment of the proton signals was accomplished
using various 2D-NMR techniques. Application of NOESY tech-
niques was based on detection of the Overhauser effect between
the protons of the NH2 group and H-2(6) located in proximity to
each other. The nJ(H,H) values of the cations were determined by
analysis of the spin systems (i.e., simulation and iteration) in the
1H NMR spectra. The resonance due to H-2 in cation 3h occurs at
a relatively high frequency. This is readily explained in terms of a
contribution from the resonance structure 5.
constants gives the following result (Table 2):
lgð2 : 3Þ ¼ ðꢀ0:24 ꢁ 0:08Þ þ ð0:87 ꢁ 0:98ÞrI ꢀ ð1:03 ꢁ 0:60ÞrRo
þ ð0:94 ꢁ 0:11ÞEos r ¼ 0:977; s ¼ 0:12; n ¼ 8
ð3Þ
In order to gain an insight into the reactivity and regioselectiv-
ity of the amination of X-pyrazines 1 (X = H, Me, Et, Pr, i-Pr,
CH(OH)CH3, NH2) in terms of their prediction, the energy barriers
were calculated using the DFT/PBE/3z method23–25 (cf. Ref. 18).
For pyrazines 1b–e,g,h, the asymmetry of the transition state
structures was taken into account based on their dependence on
the nature of the X-substituent on the ring. Table 2 gives the lowest
barriers from these variants for each substituent X. All the
transition states have a single negative normal mode and the
oscillatory vector corresponds to the movement of the NH2 group
from the oxygen atom of the OSO2Mes group to the nitrogen atom
of the pyrazine (Fig. 2). The intrinsic reaction coordinates (IRCs) go
from the transition states directly to the products or to the
reactants.
The isomeric ratio (2:3) was determined by 1H NMR spectros-
copy (Table 2). The ratio is kinetically controlled and highly
responsive to substituent effects. The kinetic control was con-
firmed by the invariance of the 1H NMR spectra of ions 2h and 3i
after aging solutions of the respective salts in DMSO-d6 at 100 °C
for four hours. Consequently, intramolecular and/or intermolecular
þ
transfer of the NH2 cation from one nitrogen atom to another in
the pyrazinium ring does not occur.
Taking into account the proximity of the reaction center to the
X-substituent in 2-X-pyrazines, it can be assumed that the ratio of
isomeric cations is determined not only by electronic effects, but
also by steric effects. The difference in the inductive influence of
the alkyl substituents at positions 2 and 3 is probably insignificant.
As carefully checked, the correlations are statistically reliable. Two-parametric
correlations between lg(2:3) and the EoS ðFÞ-,
rI-constant result in no statistically
significant changes.

G. I. Borodkin et al. / Tetrahedron Letters 50 (2009) 6779–6782
6781
Table 2
Ratio of isomeric cations 2 and 3,
r
I, Es, Eo and roR-constants of substituents and differences in calculated energy barriers
s
Eso
F22
E–calcd (kJ/mol)
D
E–calcd (kJ/mol)
0.00
20,21
20
b
c
X
lg (2:3)
rI19
rRo
Es
H
Me
Et
Pr
0.0
0
0.00
ꢀ0.10
ꢀ0.10
ꢀ0.11
ꢀ0.12
ꢀ0.08
ꢀ0.47
ꢀ0.41
1.24
0.00
0.25
0.00
ꢀ0.28
0.00
0.73
0.52
2.12
0.64
—
62.8
ꢀ0.173 0.003a
ꢀ0.498 0.017a
ꢀ0.478 0.012a
ꢀ1.020 0.055a
ꢀ0.479 0.003a
0.406 0.015a
ꢀ0.01
ꢀ0.01
ꢀ0.01
0.01
0.04
0.17
0.28
57.3 (57.7)
59.3 (58.5)
63.3 (58.4)
72.0 (58.6)
73.3 (64.2)
ꢀ0.38
ꢀ0.07
ꢀ0.36
ꢀ0.47
0.09
ꢀ0.27
ꢀ0.56
ꢀ0.87
ꢀ0.44
0.00
0.84
1.17
13.43
9.08
i-Pr
CH(OH)Me
NH2
NHAc
0.00d
ꢀ0.75d
36.3 (54.1)
ꢀ17.87
ꢀ0.473 0.019a
ꢀ0.95
—
e
e
a
This value is given as the standard deviation of 5–8 measurements in the NMR spectra.
The Eos constant was corrected for the hyperconjugation effect of the
a-hydrogen and a-carbon atoms, which is related to the Taft Es constant by the following equation:
b
Eos ¼ Es ꢀ 0:33ð3 ꢀ nHÞ ꢀ 0:13nC.22
c
Activation barrier for the amination of the 3-X isomer is given in parentheses.
The values are calculated in accordance with the isosteric principle.22
The transition state was not found.
d
e
lgð2 : 3Þ ¼ ðꢀ0:28 ꢁ 0:08Þ ꢀ ð0:042 ꢁ 0:009Þ
r ¼ 0:91; s ¼ 0:21; n ¼ 7
D
E–calcd
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
H
ð4Þ
Me
The calculated activation barriers for amination in the case of
2-CN-pyrazine (E–calcd ¼ 77:0 and 79:5 kJ=mol for positions 1 and
4, respectively) are higher than those for the other pyrazines (Table
2). This is in agreement with the data mentioned above regarding
the inertness of compound 1j.
Thus, the results obtained with the use of the linear free energy
relationship testify that the regioselectivity of the amination of
2-X-pyrazines is determined by both the electronic and steric
effects of substituents X. To the best of our knowledge, the linear
free energy relationship has never been used with respect to the
regioselectivity of azine amination. DFT calculations corroborate
the experimental results and are consistent with the reaction pro-
ceeding according to an SN2 mechanism. Data on the difference in
activation barriers for the formation of cations 2 and 3 obtained
using the DFT method are in accordance with the experimental
data on the regioselectivity of the amination reaction.
Pr
Et
i-Pr
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
F
Figure 1. Plot of lg(2:3) versus F.
Acknowledgments
This study was performed with financial support by the Russian
Foundation for Basic Research (Project No. 09-03-00116-a) and the
Russian Academy of Sciences (Program No. 5.1.4). We thank Dr. Z.
Todres for critical reading of this work and helpful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.103.
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