SNH reactions of pyrazine N-oxides and 1,2, 4-triazine 4-oxides with CH-active compounds

Article abstract of DOI:10.1023/A:1025601311393

Nucleophilic substitution of hydrogen in pyrazine N-oxides under the action of CH-active compounds requires activation with acylating agents. This activation facilitates aromatization of intermediate σ^H adducts via elimination of the acid resid

Full text of DOI:10.1023/A:1025601311393

1
588
Russian Chemical Bulletin, International Edition, Vol. 52, No. 7, pp. 1588—1594, July, 2003
SNH reactions of pyrazine Nꢀoxides and 1,2,4ꢀtriazine 4ꢀoxides
with CHꢀactive compounds
D. N. Kozhevnikov, I. S. Kovalev, A. M. Prokhorov, V. L. Rusinov, and O. N. Chupakhinb
a
a
a
aꢀ
aUral State Technical University,
1
9 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 0458. Eꢀmail: dnk@htf.ustu.ru
b
I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
2
0 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 1189. Eꢀmail: chupakhin@ios.uran.ru
Nucleophilic substitution of hydrogen in pyrazine Nꢀoxides under the action of CHꢀactive
compounds requires activation with acylating agents. This activation facilitates aromatization
H
of intermediate σ adducts via elimination of the acid residue to form substituted pyrazines.
More electrophilic 1,2,4ꢀtriazine 4ꢀoxides react with carbanions derived from CHꢀactive comꢀ
pounds without additional activation according to a scheme, which has previously been unꢀ
known for azine Nꢀoxides. This scheme involves aromatization of σH adducts through eliminaꢀ
tion of water by the E1cb mechanism. The reaction products occur in DMSOꢀd solutions
6
predominantly as 6ꢀmethyleneꢀ1,6ꢀdihydropyrazines and 5ꢀmethyleneꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriꢀ
azines.
Key words: nucleophilic substitution of hydrogen, 1,2,4ꢀtriazine 4ꢀoxide, pyrazine 1ꢀoxide,
carbanion, CHꢀactive compounds.
The nucleophilic substitution of hydrogen (SNH) in
Scheme 1
azine Nꢀoxides involves two main steps, viz., the addition
of a nucleophile at the unsubstituted carbon atom of the
heterocyclic system and aromatization of the resulting
H
1,2
σ
adducts, the latter reaction being generally the key
–
step of the process. Since elimination of the H ion, as
such, is highly improbable, further transformations of σ
H
adducts involve their aromatization through oxidation or
autoaromatization accompanied by ipsoꢀ or teleꢀeliminaꢀ
tion of the nucleofuge.
Oxidative aromatization of σH adducts (Scheme 1,
path a) takes place, for example, in the case of direct
amination of pyridazine 1ꢀoxides and 1,2,4ꢀtriazine
3
,4
4
ꢀoxides,
reactions of 1,2,4ꢀtriazine 4ꢀoxides with
5
6
7,8
phenols and indoles, cyanation of quinoline 1ꢀoxides,
and hydrolysis of 5,8ꢀdimethylꢀ5,7(6H,8H )ꢀdioxoꢀ
9
pyrimido[4,5ꢀe][1,2,4]ꢀtriazine 4ꢀoxide.
H
Autoaromatization of σ adducts does not require the
presence of an external oxidizing agent, because the proꢀ
ton abstraction from the geminal center of σH adducts
proceeds with elimination of an auxiliary group. Three
main types of autoaromatization can be distinguished deꢀ
pending on the mode of introduction of an auxiliary group
H
into the σ adduct.
L, X are good leaving groups, E is R (Alk, Ar), RCO
The 1,2ꢀelimination of HX can proceed in reactions
performed with the use of nucleophiles bearing the
nucleofuge group X. In these reactions, the hydrogen atom
is eliminated from the substrate and the X group is reꢀ
moved from the nucleophile fragment (Scheme 1, path b).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1504—1510, July, 2003.
066ꢀ5285/03/5207ꢀ1588 $25.00 © 2003 Plenum Publishing Corporation
1

Nucleophilic substitution in azine Nꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1589
Such reactions are called10 vicarious nucleophilic substiꢀ
tution. The reactions of quinoline 1ꢀoxides or 3ꢀmethoxyꢀ
conditions, all reactions proceed according to the general
scheme of autoaromatization of σ adducts.
H
1
,2,4ꢀtriazine 1ꢀoxide with anions of halomethyl aryl sulꢀ
1
1,12
fones
can serve as examples of such transformations
Results and Discussion
in the series of azine Nꢀoxides.
In teleꢀsubstitution reactions, aromatization of σH adꢀ
ducts proceeds through elimination of the leaving group
from the atom of the azine core separated from the site of
nucleophilic attack by one or several bonds (Scheme 1,
path c). The synthesis of 5ꢀaminoꢀ1,2,4ꢀtriazine 4ꢀoxides
from 3ꢀpyrrolidinoꢀ1,2,4ꢀtriazine 4ꢀoxides1 provides an
example.
It was found that 2ꢀaminoꢀ3ꢀethoxycarbonylpyrazine
1ꢀoxides 1a,b did not react with CHꢀactive compounds or
carbanions, which were generated from these compounds
in the presence of bases, without additional activation. As
expected, Oꢀacyl pyrazinium salts used in situ appeared to
be more reactive. Thus, pyrazine Nꢀoxides 1a,b were inꢀ
3
H
volved in the SN reactions with malononitrile (2a),
Finally, the presence of the Nꢀoxide group makes it
possible to carry out aromatization of σ adducts via elimiꢀ
cyanoacetic ester (2b), indaneꢀ1,3ꢀdione (2c), and barbiꢀ
turic acid (2d) in the presence of benzoyl chloride or
acetic anhydride to give the corresponding 2ꢀacylaminoꢀ
3ꢀethoxycarbonylꢀ6ꢀmethyleneꢀ5ꢀphenylꢀ1,6ꢀdihydroꢀ
pyrazines 3a—d (Scheme 2). The formation of Oꢀacyl
salts and acylation of the amino group activate pyrazine
Nꢀoxides 1a,b with respect to the nucleophilic attack.
H
nation of hydrogen together with an oxygenꢀcontaining
fragment (Scheme 1, path d). As an example, we refer to
the reactions of quinoline, pyrazine, and 1,2,4ꢀtriazine
Nꢀoxides with water or alcohols in the presence of acetic
1
4—16
anhydride or benzoyl chloride.
In the presence of
H
acylating agents, the reactions of pyridine, quinoline, and
Autoaromatization of intermediate σ adducts acylated
1
7
isoquinoline Nꢀoxides with diethyl phosphite, potasꢀ
sium cyanide,18 cyanoacetic ester, malonic ester, nitroꢀ
acetic ester, dimedone, oxazoline, thiazoline, rhodanine,
at the oxygen atom of the Nꢀoxide group is facilitated due
to elimination of the hydrogen atom, that is subjected to
substitution, as the proton together with the anion of
acetic or benzoic acid.
The presence of the additional nitrogen atom in
1,2,4ꢀtriazine 4ꢀoxide promotes the nucleophilic substiꢀ
tution of hydrogen. In attempting to carry out the reacꢀ
tions with CHꢀactive compounds without additional actiꢀ
vation of the substrate, we discovered a new pathway of
1
9,20
Meldrum's acid, and barbituric acid
as well as cyanꢀ
ation of pyrazine Nꢀoxides2
1,22
proceed according to this
scheme.
In the present study, we considered the SNH reactions
of derivatives of pyrazine 1ꢀoxide and 1,2,4ꢀtriazine
ꢀoxide with CHꢀactive compounds. In spite of different
4
Scheme 2
1
1
: R = Ph (a), Me (b)
1
2
1
2
1
2
R = Ph, R = Me (3a,c); R = Me, R = Ph (3b); R = R = Ph (3d)
X = Y = CN (2a, 3a); X = CN, Y = CO Et (2b, 3b);
2
CHXY =
(2c, 3c),
(2d, 3d)

1
590
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Kozhevnikov et al.
nucleophilic substitution of hydrogen, which has been
unknown for azine Nꢀoxides. Earlier,2 we have reported
the reactions of 3,6ꢀdiarylꢀ1,2,4ꢀtriazine 4ꢀoxides with
carbanions generated from certain CHꢀactive compounds.
In continuation of these studies, we found that 1,2,4ꢀtriꢀ
azine 4ꢀoxides 4a—e react with malononitrile (2a), aceꢀ
tophenone (2e), 4ꢀmethylacetophenone (2f), 2ꢀacetylꢀ
thiophene (2g), phenylacetonitrile (2h), 4ꢀchlorophenylꢀ
acetonitrile (2i), and 2ꢀthienylacetonitrile (2j) in a basic
medium to give products of nucleophilic substitution of
hydrogen, viz., the corresponding 5ꢀsubstituted 1,2,4ꢀtriꢀ
azines 5a—k. The reactions were accompanied by the loss
of the Nꢀoxide function (Scheme 3). The process is indeꢀ
pendent of the nature of substituents at positions 3 and 6
of the triazine ring but depends on the nature of the
CHꢀactive compound. The reaction of 1,2,4ꢀtriazine
The following mechanism may be proposed for the
3
SNH reactions of 1,2,4ꢀtriazine 4ꢀoxides 4 with carbanions.
1
H
According to the commonly accepted concepts, S reꢀ
N
actions begin with the rapid reversible addition of a nuꢀ
cleophile at the unsubstituted carbon atom followed by
H
slow aromatization of the resulting σ adducts. Hence, it
is reasonable to assume that the addition of a carbanion at
H
position 5 of heterocycles 4 gives rise to anionic σ adꢀ
ducts E. Due to the strong electronꢀwithdrawing properꢀ
ties of the 1,2,4ꢀtriazine ring, the proton attached to the
sp ꢀhybridized carbon atom at position 5 is sufficiently
3
labile even compared to the methine proton of a fragment
of the CHꢀactive compound. The migration of one of
these protons to the oxygen atom gives rise to anions F
and G, respectively (Scheme 4). The pathway of further
transformations depends on the equilibrium between anꢀ
ions E, F, and G. Thus, anion E can undergo only oxidaꢀ
4
ꢀoxide 4a with 1,3ꢀdimethylbarbituric acid in the presꢀ
H
+
ence of a base afforded only stable σ adduct 6, whereas
autoaromatization products were not detected in this reꢀ
action.
tive aromatization (–2e, –H ). By contrast, anion F can
be subjected to autoaromatization with elimination of the
–
HO ion to form directly products of nucleophilic substiꢀ
Therefore, the highly electrophilic character of the
,2,4ꢀtriazine ring makes it possible to perform the reacꢀ
tution of hydrogen. In this case, the transformation of the
anionic σ adduct is accompanied by dehydration by the
H
1
tion without activation of the substrate, and the generaꢀ
tion of the Nꢀacyloxyꢀ or Nꢀalkoxyꢀ1,2,4ꢀtriazinium catꢀ
ions is not needed.
E1cb mechanism. Most likely, the reaction under considꢀ
eration proceeds according to this scheme. Anion G can
be generated in reactions performed with the use of
Scheme 3
2
4
: X = Y = CN (a); X = Bz, Y = H (e), X = pꢀTolCO, Y = H (f); X = 2ꢀthenoyl, Y = H (g); X = Ph, Y = CN (h);
X = pꢀClC H , Y = CN (i); X = thienylꢀ2, Y = CN (j)
6
4
1
2
1
2
1
2
: R = R = Ph (a); R = Ph, R = pꢀClC H (b); R = pꢀClC H , R = Ph (c);
6
4
6 4
1
2
1
2
R = Ph, R = furylꢀ2 (d); R = pꢀClC H , R = furylꢀ2 (e)
6
4
5
a
b
c
d
e
f
R1
Ph
Ph
Ph
R2
Ph
Ph
Ph
2ꢀfuryl
Ph
X
Bz
pꢀTolCO
2ꢀthenoyl
2ꢀthenoyl
CN
Y
H
H
H
H
5
g
h
i
j
k
l
R1
Ph
Ph
R2
Ph
X
Y
Ph
Ph
Ph
CN
CN
CN
CN
CN
CN
pꢀClC H4
6
pꢀClC H4
Ph
Ph
Ph
6
pꢀClC H
Ph
pꢀClC H4
pꢀClC H4
2ꢀthienyl
6
4
6
Ph
Ph
CN
CN
pꢀClC H4
6
6
pꢀClC H
CN
Ph
2ꢀfuryl
6
4
1
2
1
2
7
: R = R = Ph (a); R = Ph, R = pꢀClC H (b)
6
4

Nucleophilic substitution in azine Nꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1591
CHꢀactive compounds possessing strong acidic properꢀ
ties and aromatization of this anion is also hindered. That
is the reason why the reaction of 1,2,4ꢀtriazine 4ꢀoxide
with dimethylbarbituric acid ceased at the step of formaꢀ
1H NMR spectroscopy, and mass spectrometry. The strucꢀ
tures of 1,2,4ꢀtriazines 5a,e,f,h were confirmed by the
independent synthesis involving the replacement of the
cyano group in 5ꢀcyanoꢀ1,2,4ꢀtriazines 7a,b by the
malononitrile, phenylacetonitrile, or acetophenone resiꢀ
H
tion of the σ adduct.
2
4
due according to a method described earlier.
Two prototropically isomeric forms A and B (see
Scheme 2) and C and D (see Scheme 3) can be proposed
for products 3a—d and 5a—l, respectively. Substantial
Scheme 4
1
differences in the H NMR spectra of these two isomers
(
highꢀfield signal for the methine proton of form A (C)
and a lowꢀfieldꢀsignal for the proton of the NH group of
form B (D)) allowed us to use this method for determinꢀ
ing the isomer ratio in solutions. It was found that the
equilibrium between two possible isomeric forms of
pyrazines 3a—d in DMSOꢀd6 solutions is completely
shifted to 1,6ꢀdihydropyrazines B (see Scheme 2).
In DMSOꢀd solutions, 1,2,4ꢀtriazines 5a—d containꢀ
6
ing the ArCO group at position 5 of the heterocycle occur
as 5ꢀphenacylꢀ1,2,4ꢀtriazines H and 5ꢀaroylmethyleneꢀ
4
,5ꢀdihydroꢀ1,2,4ꢀtriazines I (Scheme 5). The isomer raꢀ
tio depends on the nature of substituents in 1,2,4ꢀtriꢀ
azine, form I being most favorable. The latter form is,
apparently, additionally stabilized by an intramolecular
hydrogen bond.
Scheme 5
The aboveꢀconsidered mechanism of autoaromatizaꢀ
tion of σH adducts is supported by the formation of
2
5
5
ꢀcyanoꢀ1,2,4ꢀtriazines and 5ꢀcyanamidoꢀ1,2,4ꢀtriꢀ
2
6
H
azines in the SN reactions of 1,2,4ꢀtriazine 4ꢀoxides 4
with cyanide anions as well as with cyanamide under baꢀ
sic conditions. In these processes, the fragment introꢀ
duced by the nucleophile possesses strong electronꢀwithꢀ
drawing properties, which enhances the mobility of the
H
proton in the σ adduct of type E (see Scheme 4) and,
The introduction of the arylacetonitrile fragment into
the 1,2,4ꢀtriazine molecule results in the fact that comꢀ
consequently, facilitates aromatization of the latter acꢀ
cording to the proposed mechanism.
pounds 5e—k in DMSOꢀd occur exclusively as 5ꢀcyanoꢀ
6
H
The SN reactions of azine Nꢀoxides can proceed by
methyleneꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazines D. This phenomꢀ
1
3
the aboveꢀconsidered mechanism only if the proton in
enon has also been observed earlier for 5ꢀcyanomethylꢀ
1,2,4ꢀtriazines. However, a double set of signals for the
protons of the aryl substituents suggests the possible existꢀ
ence of 1,2,4ꢀtriazines 5g—k as two E and Z isomers D and
D´ with respect to the exocyclic C=C bond (Scheme 6).
By contrast, the product of the reaction of 1,2,4ꢀtriꢀ
azine 4ꢀoxide 1d with 2ꢀcyanomethylthiophene 2j, viz.,
5ꢀ(αꢀcyanoꢀαꢀthienylꢀ2ꢀmethylene)ꢀ3,6ꢀdiphenylꢀ4,5ꢀ
H
the σ adduct is characterized by sufficiently high mobilꢀ
ity, which is substantially influenced by the electronꢀwithꢀ
drawing properties of the heterocycle. As was demonꢀ
strated above, pyrazine Nꢀoxides do not react with carbꢀ
anions without additional activation. In the series of
H
monoꢀ and diazines, the σ adduct is insufficiently stabiꢀ
lized as an anion of type F due to which quinoline Nꢀoxides
and phthalazine 2ꢀoxides react with carbanions only acꢀ
cording to the scheme of oxidative (see Scheme 1,
dihydroꢀ1,2,4ꢀtriazine (5l), occurs in a DMSOꢀd soluꢀ
6
tion as one isomer (D). It can be assumed that the addiꢀ
tional Coulomb interaction between the S atom and the
H atom of the triazine ring stabilizes Z isomer 5l (D). The
further assignment of the signals in the NMR spectra to a
particular isomer was made by comparing them with the
spectrum of compound 5l (D).
path a)7
,8,27,28
or vicarious (path b) nucleophilic substiꢀ
11
tution of hydrogen with retention of the Nꢀoxide funcꢀ
tion.
The structures of compounds 3a—d, 5, and 6 were
established based on the results of elemental analysis,

1592
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Kozhevnikov et al.
Scheme 6
This enabled us to distinguish the signals of aromatic
2 mmol) and malononitrile (72 mg, 2 mmol) were dissolved in
Ac O (5 mL). Then Et N (0.8 mL, 6 mmol) was added. The
substituents in the 1,2,4ꢀtriazine ring corresponding to
2
3
1
reaction mixture was kept at ∼ 20 °C for 24 h and concentrated in
vacuo. The residue was recrystallized from benzene. The yield
isomer D. This is particularly valid for the substituent R
at position 6 of the 1,2,4ꢀtriazine ring and the aromatic
moiety of the nucleophilic fragment for which the proton
signals should change most substantially on going from
one isomer to another because these substituents in form D
are in close proximity. Due to the mutual anisotropic
influence of two benzene rings, the signals for the protons
1
was 260 mg (37%), m.p. 205 °C. H NMR, δ: 1.25 (t, 3 H,
CH CH ); 2.41 (s, 3 H, COCH ); 4.22 (q, 2 H, CH CH );
2
3
3
2
3
7
.34—7.41 (m, 5 H, Ph); 10.52 (s, 1 H, NHAc). MS,
+
m/z (Irel (%)): 349 [M] (100). Found (%): C, 61.74; H, 4.40.
C H N O (349.4). Calculated (%): C, 61.89; H, 4.33.
18
15
5
3
2ꢀBenzoylaminoꢀ6ꢀcyano(ethoxycarbonyl)methyleneꢀ3ꢀ
ethoxycarbonylꢀ5ꢀmethylꢀ1,6ꢀdihydropyrazine (3b). Pyrazine
ꢀoxide 1b (395 mg, 2 mmol) and ethyl cyanoacetate 2b
0.21 mL, 2 mmol) were dissolved in DMF (5 mL). Then benꢀ
1
of these fragments in the H NMR spectra are shifted
1
(
upfield. The characteristic signals revealed for forms D
and D´ allowed us to determine the isomer ratio by comꢀ
paring the integral intensities of the corresponding proꢀ
tons. Analysis of the spectra demonstrated that the comꢀ
position of the mixture depends on the nature of substituꢀ
ents, primarily, of the aromatic substituent in the nucleoꢀ
philic fragment. For example, the introduction of the
chlorine atom at the para position of the latter substituent
increases steric hindrances to the formation of isomer D´
thus decreasing its proportion in the mixture of two forms.
Therefore, the nucleophilic substitution of hydrogen
in azine Nꢀoxides with anionic nucleophiles can proceed
with autoaromatization of intermediate σH adducts via
formal elimination of water by the E1cb mechanism. In
these processes, the electronꢀwithdrawing properties of
the heterocycle play a decisive role.
zoyl chloride (1.2 mL, 10 mmol) was added and the reaction
mixture was heated at 100 °C for 1 h. The precipitate that
formed was filtered off and recrystallized from DMF. The yield
1
was 317 mg (40%), m.p. 237 °C. H NMR, δ: 1.34 and 1.40
(
both t, 3 H each); 2.73 (s, 3 H, 5ꢀMe); 4.30 (q, 2 H); 4.40
(q, 2 H); 7.60—7.99 (m, 5 H, Ph); 12.50 (s, 1 H, NHBz); 15.85
+
(s, 1 H, 1ꢀNH). MS, m/z (Irel (%)): 396 [M] (100). Found (%):
C, 60.55; H, 5.24; N, 14.21. C20H20N4O5 (396.4). Calcuꢀ
lated (%): C, 60.60; H, 5.09; N, 14.13.
2
ꢀAcetylaminoꢀ6ꢀ(1,3ꢀdioxoindanꢀ2ꢀylidene)ꢀ3ꢀethoxyꢀ
carbonylꢀ5ꢀphenylꢀ1,6ꢀdihydropyrazine (3c). Pyrazine 1ꢀoxide 1a
780 mg, 3 mmol) and 1,3ꢀindanedione 3 (438 mg, 3 mmol)
were dissolved in CF COOH (3 mL) and then Ac O (1 mL) was
(
3
2
added. The reaction mixture was kept for 24 h. The precipitate
that formed was filtered off and recrystallized from toluene. The
1
yield was 760 mg (59%), m.p. >250 °C. H NMR (CDCl ), δ:
.
3
1
.44 (t, 3 H, CH CH ); 2.39 (s, 3 H, CH CO); 4.42 (q, 2 H,
2 3 3
Experimental
CH CH ); 7.37—7.66 (m, 9 H, H arom.); 11.62 (s, 1 H, NHAc);
2 3
1
6.25 (br.s, 1 H, H(1)). MS, m/z (Irel (%)): 429 [M]+ (100).
Found (%): C, 67.30; H, 4.28; N, 9.73. C H N O (429.4).
1
The H NMR spectra were recorded on a Bruker WMꢀ250
2
4
19
3
5
spectrometer (250.1 MHz) using DMSOꢀd as the solvent (unꢀ
Calculated (%): C, 67.13; H, 4.46; N, 9.78.
6
less otherwise indicated) with Me Si as the internal standard.
2ꢀBenzoylaminoꢀ3ꢀethoxycarbonylꢀ5ꢀphenylꢀ6ꢀ(2,4,6ꢀtriꢀ
oxopyrimidinꢀ5ꢀylidene)ꢀ1,6ꢀdihydropyrazine (3d). Pyrazine
1ꢀoxide 1a (500 mg, 1.93 mmol) and benzoyl chloride (1 mL)
were added to a suspension of sodium barbiturate (900 mg,
6 mmol) in DMF (10 mL). The reaction mixture was heated for
4
The signals belonging to forms C, D, and D´ are labeled by the
corresponding indices (see Scheme 6). The mass spectra were
obtained on a Varian MATꢀ311A instrument (electron beam
ionization); the energy of ionizing electrons was 70 eV; direct
inlet of samples. The course of the reactions and purities of the
products were monitored by TLC on Silufol UVꢀ254 plates usꢀ
ing ethyl acetate as the eluent; visualization was carried out with
UV light.
1 h, diluted with water, and neutralized with a 25% NH soluꢀ
3
tion to pH 7. The precipitate that formed was filtered off, washed
with water, and recrystallized from aqueous AcOH. The yield
1
was 330 mg (36%), m.p. 250 °C. H NMR, δ: 1.36 (t, 3 H,
.
The commercial CHꢀactive compounds were used as nuꢀ
cleophiles. Heterocyclic substrates, viz., pyrazine 1ꢀoxides 1,
CH CH ); 4.39 (q, 2 H, CH CH ); 7.32—8.05 (m, 10 H,
2
3
2
3
2
8
H arom.); 10.99—11.80 (br.s, 3 H, 3 NH). MS, m/z (I (%)):
rel
9
24
+
1
,2,4ꢀtriazine 4ꢀoxides 4,2 and 5ꢀcyanoꢀ1,2,4ꢀtriazines 7, were
synthesized according to known procedures.
ꢀAcetylaminoꢀ6ꢀdicyanomethyleneꢀ3ꢀethoxycarbonylꢀ5ꢀ
phenylꢀ1,6ꢀdihydropyrazine (3a). Pyrazine 1ꢀoxide 1a (520 mg,
473 [M] (43). Found (%): C, 60.81; H, 4.16. C H N O
2
4
19
5
6
(473.5). Calculated (%): C, 60.89; H, 4.05.
Reactions of 1,2,4ꢀtriazine 4ꢀoxides 4 with CHꢀactive comꢀ
pounds 2a,e—j (general procedure). The corresponding precurꢀ
2

Nucleophilic substitution in azine Nꢀoxides
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1593
sor of the carbanion (1.1 mmol) and then 1,2,4ꢀtriazine 4ꢀoxide 4
3ꢀ(4ꢀChlorophenyl)ꢀ5ꢀdicyanomethyleneꢀ6ꢀphenylꢀ4,5ꢀdiꢀ
(
1 mmol) were added to a suspension of triturated KOH (500 mg)
in DMF (3 mL). The reaction mixture was stirred at ∼ 20 °C for
—5 h, diluted with water, and acidified with dilute HCl to
hydroꢀ1,2,4ꢀtriazine (5f). The yield was 210 mg (63%), m.p.
>270 °C. H NMR, δ: 7.40—7.60 (m, 5 H); 7.65 (m, 2 H); 8.20
1
1
(m, 2 H); 14.8 (br.s, 1 H, NH). Found (%): C, 65.21; H, 3.15;
N, 21.00. C18H10ClN5 (331.7). Calculated (%): C, 65.17;
pH 3. The precipitate that formed was filtered off and recrystalꢀ
lized from EtOH or AcOH.
+
H, 3.04; N, 21.11. MS, m/z (I (%)): 333 [M] (28) and
331 [M] (81).
rel
+
Synthesis of 1,2,4ꢀtriazines 5a,e,f,h by the reactions of
5
ꢀcyanoꢀ1,2,4ꢀtriazines 7a,b with CHꢀactive compounds 2a,e,h.
5ꢀCyano(phenyl)methyleneꢀ3,6ꢀdiphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀ
triazine (5g). The yield was 300 mg (86%), m.p. 256 °C. H NMR,
1
Compound 2a,e,h (1.05 mmol) was added with stirring to a 60%
NaH suspension in mineral oil (45 mg, 1.1 mmol of NaH) in
THF (4 mL). After 15 min, the corresponding 5ꢀcyanoꢀ1,2,4ꢀ
triazine 7a,b (1.0 mmol) was added. The reaction mixture was
stirred at ∼ 20 °C for 2 h. The solvent was evaporated in vacuo.
The residue was dissolved in water and acidified with dilute HCl
to рH 3. The precipitate that formed was filtered off and recrysꢀ
tallized from EtOH.
D´
D´
δ: 6.90 (br.s, 2.25 H, Ph); 6.90—7.10 (m, 1.35 H, 6ꢀPh);
D,D´
D
D
7.20—7.70 (m, 8.1 H, arom.
1.1 H); 8.2 (m, 0.9 H); 13.4 (br.s, 1 H, NH). Found (%):
C, 79.41; H, 4.66; N, 15.91. C H N (348.4). Calculated (%):
); 7.88 (m, 1.1 H); 8.02 (m,
D´
2
3
16
4
C, 79.29; H, 4.63; N, 16.08. MS, m/z (Irel (%)): 348 [M]+ (21).
3ꢀ(4ꢀChlorophenyl)ꢀ5ꢀcyano(phenyl)methyleneꢀ6ꢀphenylꢀ
4,5ꢀdihydroꢀ1,2,4ꢀtriazine (5h). The yield was 350 mg (91%),
1
D´
D´
5
ꢀPhenacylꢀ3,6ꢀdiphenylꢀ1,2,4ꢀtriazine (5a). The yield was
m.p. >270 °C. H NMR, δ: 6.95 (br.s, 2.25 H, Ph); 7.05 and
2
3
D´
D
D
1
60 mg (45%), m.p. 194—196 °C (192—194 °C, cf. lit. data ).
7.23 (both m, 1.35 H each, 6ꢀPh); 7.30 (m, 0.55 H); 7.41
(m, 1.1 H); 7.49 (m, 1.65 H); 7.62—7.76 (m, 3.1 H); 7.82
(m, 1.1 H); 8.01 (m, 1.1 H); 8.18 (m, 0.9 H); 13.3 (br.s, 1 H,
NH). Found (%): C, 72.21; H, 3.90; N, 14.78. C H ClN
1
C
D
D
D
H NMR, δ: 4.74 (s, 0.4 H, CH ); 6.32 (s, 0.8 H, CH);
2
.40—7.95 (m, 13 H); 8.31D (m, 1.6 H); 8.46 (m, 0.4 H); 15.7
br.s, 0.8 H, NH). Found (%): C, 78.49; H, 4.75; N, 12.20.
C H N O (351.4). Calculated (%): C, 78.61; H, 4.88; N, 11.96.
C
D
D
D´
7
(
2
3
15
4
(382.8). Calculated (%): C, 72.16; H, 3.95; N, 14.63. MS,
2
3
17
3
+
+
3
,6ꢀDiphenylꢀ5ꢀ(pꢀtoluoyl)methylꢀ1,2,4ꢀtriazine (5b). The
m/z (Irel (%)): 384 [M] (6) and 382 [M] (17).
1
D
yield was 145 mg (40%), m.p. 183—185 °C. H NMR, δ: 2.40
6ꢀ(4ꢀChlorophenyl)ꢀ5ꢀcyano(phenyl)methyleneꢀ3ꢀphenylꢀ
4,5ꢀdihydroꢀ1,2,4ꢀtriazine (5i). The yield was 325 mg (85%),
s, 2.55 H, Me); 2.42 (s, 0.45 H, Me); 6.32C (s, 0.85 H, CH);
C
(
C
1
D´
D´
4
8
.70 (s, 0.30 H, CH ); 7.25 (m, 2 H); 7.40—7.85 (m, 10 H);
.32 (m, 1.7 H); 8.46 (m, 0.3 H); 15.6 (br.s, 0.85 H, NH).
m.p. >270 °C. H NMR, δ: 6.98 (br.s, 2.25 H, Ph); 7.03 and
2
D
C
D
D´
D
7.22 (both m, 0.9 H and 0.9 H, 4ꢀClC H ); 7.30 (m, 0.55 H);
7.42 (m, 1.1 H); 7.52—7.68 (m, 5.2 H); 7.85 (m, 1.1 H);
8.04 (m, 1.1 H); 8.18 (m, 0.9 H); 13.3 (br.s, 1 H, NH).
Found (%): C, 72.05; H, 4.08; N, 14.58. C H ClN (382.8).
6 4
D
D
Found (%): C, 79.01; H, 5.33; N, 11.72. C H N O (365.4).
Calculated (%): C, 78.88; H, 5.24; N, 11.50.
,6ꢀDiphenylꢀ5ꢀ(2ꢀthenoyl)methylꢀ1,2,4ꢀtriazine (5c). The
2
4
19
3
D
D´
3
2
3
15
4
1
C
yield was 240 mg (67%), m.p. 180—183 °C. H NMR, δ: 4.68
Calculated (%): C, 72.16; H, 3.95; N, 14.63. MS, m/z (I (%)):
rel
D
D
+
+
(
s, 0.7 H, CH ); 6.16 (s, 0.65 H, CH); 7.14 (dd, 0.65 H,
384 [M] (8) and 382 [M] (24).
2
C
J = 4.8 and 4.0 Hz); 7.20 (dd, 0.35 H, J = 4.8 and 4.1 Hz);
5ꢀ(4ꢀChlorophenyl)cyanomethyleneꢀ3,6ꢀdiphenylꢀ4,5ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazine (5j). The yield was 310 mg (81%), m.p.
D
D
7
.56 (dd, 0.65 H, J = 4.8 and 0.9 Hz); 7.78 (dd, 0.65 H,
C
1
D´
D´
J = 4.0 and 0.9 Hz); 7.94 (dd, 0.35 H, J = 4.8 and 1.1 Hz);
>270 °C. H NMR, δ: 6.90 (br.s, 1.4 H, ClC H ); 7.00—7.30
6 4
.96 (dd, 0.35 H, J = 4.1 and 1.1 Hz); 8.23D (m, 1.3 H); 8.45
C
C
(m, 1.75 H, 6ꢀPh); 7.39 (m, 1.3 H); 7.40—7.75 (m, 6.25 H);
D
7
D
D
D´
D´
(
m, 0.7 H); 15.6 (br.s, 0.65 H, NH). Found (%): C, 70.41;
7.90 (m, 1.3 H); 8.04 (m, 1.3 H); 8.19 (m, 0.7 H); 13.6
(br.s, 1 H, NH). Found (%): C, 71.82; H, 3.74; N, 14.71.
C23H15ClN4 (382.8). Calculated (%): C, 72.16; H, 3.95;
N, 14.63.
H, 4.30; N, 11.93. C21H15N OS (357.4). Calculated (%):
C, 70.57; H, 4.23; N, 11.76.
3
6
ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(2ꢀfuryl)ꢀ5ꢀ(2ꢀthenoyl)methylꢀ1,2,4ꢀ
triazine (5d). The yield was 225 mg (59%), m.p. 203—205 °C.
6ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(4ꢀchlorophenyl)cyanomethyleneꢀ3ꢀ
phenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazine (5k). The yield was 370 mg
1
C
D
C
H NMR, δ: 4.66 (s, 0.4 H, CH ); 6.15 (s, 0.8 H, CH); 6.71
2
1
D´
D´
(
1
dd, 0.2 H, J = 3.0 and 1.1 Hz); 6.79 (dd, 1 H, J = 3.0 and
(89%), m.p. >270 °C. H NMR, δ: 6.80 and 7.10 (both m,
.0 Hz); 7.13D (dd, 1 H, J = 4.9 and 4.0 Hz); 7.20 (dd, 0.2 H,
C
0.7 H each, ClC H ); 7.12 and 7.21 (both m, 0.7 H each,
D´
D´
6 4
C
D
C
ClC H ); 7.88 (m, 2 H); 8.01 (m, 1.3 H); 8.15D´ (m, 0.7 H);
D
D
J = 4.9 and 4.0 Hz); 7.31 (m, 0.4 H); 7.38 (m, 1.6 H); 7.42
6 4
(
(
d, 0.2 H, J = 3.0 Hz); 7.48 (d, 1 H, J = 3.0 Hz); 7.50—7.62
13.5 (br.s, 1 H, NH). Found (%): C, 66.07; H, 3.17; N, 13.49.
C23H14Cl N (417.3). Calculated (%): C, 66.20; H, 3.38;
N, 13.43.
D
C
m, 2.8 H); 7.76 (dd, 1 H, J = 4.0 and 1.0 Hz); 7.91 (d, 0.2 H,
2
4
C
C
J = 1.1 Hz); 7.93 (dd, 0.2 H, J = 4.9 and 1.0 Hz); 7.95 (dd,
D
0
.2 H, J = 4.0 and 1.0 Hz); 8.39 (d, 1 H, J = 1.0 Hz); 15.3
br.s, 0.8 H, NH). Found (%): C, 59.61; H, 3.34; N, 11.17.
C H ClN O S (381.8). Calculated (%): C, 59.77; H, 3.17;
5ꢀCyano(2ꢀthienyl)methyleneꢀ3ꢀfurylꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ
(
1,2,4ꢀtriazine (5l). The yield was 210 mg (61%), m.p. >270 °C.
1
H NMR, δ: 6.87 (dd, 1 H, J = 3.2 and 1.3 Hz); 7.08 (dd, 1 H,
19
12
3
2
N, 11.00.
ꢀDicyanomethyleneꢀ3,6ꢀdiphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazine
J = 4.8 and 4.1 Hz); 7.21 (dd, 1 H, J = 4.8 and 1.0 Hz); 7.48
(m, 3 H); 7.55 (dd, 1 H, J = 4.1 and 1.0 Hz); 7.60 (d, 1 H,
J = 3.2 Hz); 7.63 (m, 2 H); 8.13 (d, 1 H, J = 1.3 Hz); 13.6 (br.s,
1 H, NH). Found (%): C, 66.12; H, 3.56; N, 16.35. C H N OS
5
(
5e). The yield was 160 mg (54%), m.p. 264—267 °C (decomp.).
1
D´
D´
D´
H BNR, δ: 6.88—6.92 (m, 2.0 H, Ph); 7.00 and 7.24
19
12
4
D´
(
(
both m, 1.2 H and 0.8 H, 6ꢀPh); 7.32—7.62 (m, 6.8 H); 7.68
(344.4). Calculated (%): C, 66.26; H, 3.51; N, 16.27.
D
D´
m, 1.2 H); 8.04 (m, 1.2 H); 8.20 (m, 0.8 H); 13.3 (br.s, 1 H);
.45 (m, 3 H); 7.62 (m, 2 H); 7.72 (m, 3 H); 8.19 (m, 2 H); 14.9
br.s, 1 H, NH). Found (%): C, 72.81; H, 3.58; N, 23.71.
C H N (297.3). Calculated (%): C, 72.72; H, 3.73; N, 23.55.
4ꢀHydroxyꢀ5ꢀ(6ꢀhydroxyꢀ1,3ꢀdimethylꢀ2,4ꢀdioxo(1H,3H )ꢀ
pyrimidinꢀ5ꢀyl)ꢀ3,6ꢀdiphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazine (6). The
7
(
1
yield was 760 mg (59%), m.p. >270 °C. H NMR, δ: 3.07 (s,
.
6 H, 2NMe); 6.34 (s, 1 H, H(5)); 7.32—8.06 (m, 10 H, 2Ph);
11.62 (br.s, 1 H, OH); 12.78 (br.s, 1 H, OH). Found (%):
18
11
5
MS, m/z (Irel (%)): 297 [M]+ (87).

1594
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Kozhevnikov et al.
C, 62.10; H, 4.85; N, 17.21. C21H19N O (405.4). Calcuꢀ
lated (%): C, 62.22; H, 4.72; N, 17.27.
14. M. J. Dimsdale, J. Heterocycl. Chem., 1979, 16, 1209.
15. M. Hayashida, H. Honda, and M. Hamana, Heterocycles,
990, 31, 1325.
5
4
1
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ32627)
and the US Civilian Research and Development Foundaꢀ
tion (CRDF, Grant RECꢀ005).
16. H. Neunhoeffer and V. Böhnisch, Liebigs Ann. Chem.,
1976, 153.
17. M. Hamana, Croat. Chem. Acta, 1986, 59, 89.
1
1
8. W. K. Fife, J. Org. Chem., 1983, 48, 1375.
9. M. M. Yousif, S. Saeki, and M. Hamana, J. Heterocycl.
Chem., 1980, 17, 1029.
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1
1
1
Received February 5, 2003