A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives

Article abstract of DOI:10.1007/s11172-005-0311-7

A new in principle method for the synthesis of 6-aryl(hetaryl)-3,5-diamino- 1,2,4-triazines by decomposition of pre-synthesized tetrazolo[1,5-b][1,2,4] triazines was developed. The advantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.

Full text of DOI:10.1007/s11172-005-0311-7

726
Russian Chemical Bulletin, International Edition, Vol. 54, No. 3, pp. 726—732, March, 2005
A new approach to the synthesis of lamotrigine and other
3,5ꢀdiaminoꢀ1,2,4ꢀtriazine derivatives
b
E. N. Ulomskii,a T. S. Shestakova,a S. L. Deev,b V. L. Rusinov,a and O. N. Chupakhin
ꢀ
аUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 0458. Eꢀmail: rusinov@htf.ustu.ru
bI. Ya. Postovskii Institute of Organic Synthesis,
Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Еꢀmail: chupakhin@ios.uran.ru
A new in principle method for the synthesis of 6ꢀaryl(hetaryl)ꢀ3,5ꢀdiaminoꢀ1,2,4ꢀtriazines
by decomposition of preꢀsynthesized tetrazolo[1,5ꢀb][1,2,4]triazines was developed. The adꢀ
vantages of this method over traditional methods were demonstrated using the synthesis of a
modern antiepileptic preparation lamotrigine, as an example.
Key words: destruction, 3,5ꢀdiaminoꢀ1,2,4ꢀtriazines, condensation.
The remarkable diversity of the purposes of modern
convincing from our stanpoint, of synthesis of physiologiꢀ
organic synthesis requires new nontrivial approaches and
methods for the preparation of heterocyclic compounds,
because traditional cyclization routes do not always proꢀ
vide the best results. Therefore, synthetic chemists have
to consider once again known transformations that have
previously been regarded only as peculiar properties or
side processes. Examples of such reactions include diꢀ
verse degradations of fused azoloazines with a bridging
nitrogen atom. Our observations and published data show
that degradation processes are rather frequently encounꢀ
tered in these compounds and represent an integral part
of their reactivities.1—8 It should be noted that the deꢀ
struction route can be controlled to give products of cleavꢀ
age of both the azole ring and the azine fragment. This
strategy resulted in the synthesis of diverse pyrimiꢀ
dine1,2,3—6 and 1,2,4ꢀtriazine1,2,7,8 derivatives. All these
data indicate that cleavage of fused nitrogen heterocycles
of this type can appear as a general and efficient synꢀ
thetic tool.
Nevertheless, no publications in which the destrucꢀ
tion of a nitrogenꢀcontaining heterocycle has been used
deliberately to prepare compounds with useful properties
are available. This is not surprising, as this type of reacꢀ
tion has not yet been properly appreciated by organic
chemists and the attitude towards this method is rather
negative. Indeed, the destruction takes place in some synꢀ
theses of practically valuable compounds: drugs, natural
products, anomalous nucleosides9—11 and, therefore, ring
opening is treated as an undesirable side process.
cally active substances, derivatives of 3,5ꢀdiaminoꢀ6ꢀarylꢀ
1,2,4ꢀtriazines,12,13 having a marked antimalarial action
and the antiepileptic drug lamotrigine, 3,5ꢀdiaminoꢀ6ꢀ
(2,3ꢀdichlorophenyl)ꢀ1,2,4ꢀtriazine, widely used in cliniꢀ
cal practice.14
Two key methods for the synthesis of 3,5ꢀdiaminoꢀ6ꢀ
arylꢀ1,2,4ꢀtriazines have been reported; these can be exꢀ
emplified in the preparation of lamotrigine (1а). One
method is underlain by condensation of arylacetyl cyaꢀ
nide 2 with aminoguanidine15 (Scheme 1). It is noteworꢀ
thy that this method, simple as it may seem, has substanꢀ
tial drawbacks. The condensation of compound 2 with
aminoguanidine proceeds in a yield not higher than 16%.
The synthesis of aroyl cyanide 2 from chloride 3 presents
a serious problem itself. The yield of compound 2 can
markedly drop due to the side selfꢀcondensation, resultꢀ
ing in the formation of αꢀaroyloxy(αꢀarylmalono)dinitrile
Ar—C(CN)2—OCO—Ar.16 The overall yield of lamoꢀ
trigine (1а) according to Scheme 1 does not exceed 13%.
The other method used to prepare compound 1а is
based on the replacement of oxoꢀ and thioxo fragments
in compound 4, which is in turn obtained by condenꢀ
sation of thiosemicarbazide with 2,3ꢀdichlorophenylꢀ
glyoxal 5 17(Scheme 2). The overall yield of compound 1а
according to Scheme 2 does not exceed 18%.
The presented data indicate that the methods used to
prepare lamotrigine can hardly be called perfect.
In this communication, we propose a new method for
the synthesis of 6ꢀarylꢀ and 6ꢀhetarylꢀ3,5ꢀdiaminoꢀ1,2,4ꢀ
triazines based on the strategy of preliminary synthesis of
fused heterocycles and subsequent destruction of one
This communication demonstrates the expediency of
using degradation in the synthesis by presenting examples,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 713—719, March, 2005.
1066ꢀ5285/05/5403ꢀ0726 © 2005 Springer Science+Business Media, Inc.

New method of synthesis of Lamotrigine
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
727
Scheme 1
Scheme 2
cyclic fragment. This method can probably be called "reꢀ
constructive," because the structure created initially subꢀ
sequently undergoes a partial destruction.
tive component, we used αꢀformylꢀαꢀarylacetonitriles
8a—h and hetarylacetonitriles 8i,j (Scheme 3). The use of
formyl derivatives 8a—h is due to the fact that arylacetoꢀ
nitriles themselves do not enter into azo coupling due to
the low CHꢀacidity.18 In order to increase the CHꢀactivꢀ
ity of arylacetonitriles, we developed a simple approach
based on introducing an easily leaving electronꢀwithdrawꢀ
ing substituent, a formyl group, which is eliminated on
the formation of hydrazone 9a—h.
Results and Discussion
We found that cleavage of fused 6ꢀarylꢀ and 6ꢀhetarylꢀ
7ꢀaminotetrazolo[1,5ꢀb][1,2,4]triazines (6a—j) is an effiꢀ
cient and readily accessible method for the synthesis of a
number of 6ꢀsubstituted 3,5ꢀdiaminoꢀ1,2,4ꢀtriazine deꢀ
rivatives 1a—j.
Compounds 6a—j were prepared using coupling with
tetrazolyldiazonium salt (7) (Scheme 3). As the CHꢀacꢀ
Formylacetonitriles 8b—h were obtained directly
from readily available benzyl cyanides. Compound 8a
Scheme 3
6,8—11: R = 2,3ꢀCl2C6H3 (a); 2,4ꢀCl2C6H3 (b), 2ꢀFC6H4 (c),
(d), 3,4ꢀF2C6H3 (e), 2,3,4,5ꢀF4C6H (f), Ph (g), 3,5ꢀ(CF3)2C6H3 (h),
(i),
(j)
8a—h: X = CHO; 8i,j: X = H

728
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Ulomskii et al.
Table 1. Melting points, yields, molecular masses (according to
mass spectrometry data) and IRꢀspectral data of compounds
1a—j and 6a—j
was synthesized from 2,3ꢀdichlorotoluene via bromoꢀ
methyl 2,3ꢀdichlorobenzene, which was then treated with
sodium cyanide and formylated. This gave formyl derivaꢀ
tive 8a in a 69% overall yield based on 2,3ꢀdichloroꢀ
toluene.
In the case of compounds 8i,j, the presence of elecꢀ
tronꢀwithdrawing pyridine and benzimidazole heterocycle
substituents, respectively, markedly facilitates the reacꢀ
tion with compound 7 and does not require additional
activation by a formyl group.
Tetrazolyldiazonium salt 7 was obtained from
5ꢀaminotetrazole, which is a commercial chemical or is
prepared from aminoguanidine nitrate.19
Salt 7 reacts with CHꢀactive components 8a—j in the
presence of sodium carbonate or acetate. The reaction
affords hydrazones 9a—j, which are converted into
tetrazolo[1,5ꢀb][1,2,4]triazines 6a—j on refluxing in aceꢀ
tic acid or DMF.
The mass spectra of compounds 6a—j exhibit a moꢀ
lecular ion peak (Table 1). The 1H NMR spectra contain
resonance signals for the aryl protons at 7.00—8.50 ppm.
The amino group protons are responsible most often for a
twoꢀproton broadened singlet at 7.40—8.80 ppm. Comꢀ
pounds 6i,j in which the amino group is manifested as two
oneꢀproton broadened singlets are exceptions (Table 2).
The IR spectra of compounds 6a—j exhibit signals at
3150—3350 cm–1 due to the stretching vibrations of the
amino group (see Table 1). The lack of stretching signals
for the azido group at 2120—2160 cm–1 confirms that the
tetrazole ring in compounds 6a—j is annelated to the
triazine ring.
XꢀRay diffraction analysis of compounds 6g (R = Ph)
revealed the mode of annelation of the tetrazole and triꢀ
azine rings in 6а—j, which was classified as [1,5ꢀb]ꢀanꢀ
nelation (Fig. 1, Table 3). The geometric parameters of
the molecule are close to the usual values for tetrazoꢀ
lo[1,5ꢀb][1,2,4]triazines.20 The azole and azine rings are
coplanar; their mean plane forms a dihedral angle of 49.4o
with the phenyl group. In the crystal, the molecules form
centrosymmetric dimers with intermolecular hydrogen
bonds (see Fig. 1, Table 4). The dimers, in turn, are
linked by weaker hydrogen bonds.
Comꢀ
pound
M.p.
/°C
Yield
(%)a
[M]+,
m/z (I (%))
IR spectrum,
ν/cm–1
1a
1b
1c
1d
1e
1f
218b
76 (А)
256 (67)
256 (70)
205 (64)
193 (73)
223 (59)
259 (78)
187 (72)
323 (65)
188 (87)
227 (80)
282 (41)
282 (34)
231 (47)
219 (41)
249 (37)
285 (44)
213 (34)
349 (33)
214 (27)
253 (32)
3140, 3180,
3420 (NH)
3160, 3190,
3350 (NH)
3180, 3200,
3380 (NH)
3150, 3220,
3380 (NH)
3200, 3330,
3460 (NH)
3170, 3210,
3410 (NH)
3180, 3200,
3400 (NH)
3190,3200,
3400 (NH)
3120, 3230,
3380 (NH)
3180, 3200,
3400 (NH)
3170,
3290 (NH)
3140,
3290 (NH)
3130,
3280 (NH)
3120,
3300 (NH)
3200,
3350 (NH)
3150,
3270 (NH)
3180,
3310 (NH)
3190,
3340 (NH)
3160,
221—222b 70 (A)
65 (B)
230b
78 (A)
254b
63 (A)
60 (B)
219—220b 72 (A)
198b
201c
89 (A)
1g
1h
1i
79 (А)
75 (B)
198—200b 72 (А)
225—227c 78 (А)
1j
256d
240d
78 (A)
68
6a
6b
6c
6d
6e
6f
210—212d
226d
70
70
218d
72
190d
68
218—220d
228e
87
6g
6h
6i
74
218d
85
252d
72
3250 (NH)
3150,
6j
272d
80
3300 (NH)
It should be noted that cyclization of hydrazones 9а—j
can yield only compounds 10a—j in which the azole and
azine rings are annelated according to the [5,1ꢀc] pattern.
The only possible route from compounds 9а—j to tetrazoꢀ
lo[1,5ꢀb]triazines 6a—j is that via azides 11a—j. Thus, the
synthesis of hetarylamines 6a—j is a sequence of transforꢀ
mations that involves opening of the tetrazole ring in
azoloazines 10a—j.
The most important problem solved in this study is the
destruction of the azole ring in tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀ
triazines 6a—j. It is known that the transformation of the
tetrazole ring in 8ꢀmethoxytetrazolo[1,5ꢀc]pyrimidine into
an amino group is accomplished using triphenylphosphine.
a The method of synthesis is indicated in parentheses.
b Recrystallized from isopropyl alcohol
с Recrystallized from ethanol.
d Recrystallized from DMF.
е Recrystallized from acetic acid.
6ꢀAminoꢀ5ꢀmethoxypyrimidine was formed in this reꢀ
action21
.
We found that treatment of tetrazolotriazines 6b,d,g
with triphenylphosphine in acetic acid affords diaminoꢀ
1,2,4ꢀtriazines 1b,d,g. In order to upgrade the standard
procedure for degradation of the tetrazole ring in fused

New method of synthesis of Lamotrigine
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
729
Table 2. 1H NMR data for compounds 1a—j and 6a—j
in a weakly acidic medium in the presence of a freshly
prepared copper powder gives 3,5ꢀdiaminoꢀ1,2,4ꢀtriꢀ
azines 1a—j. Apparently, the destruction of the tetrazole
ring in compounds 6a—j proceeds via azides 11a—j
(Scheme 4). The yields of 3,5ꢀdiaminoꢀ1,2,4ꢀtriazines
1a—j vary from 65 to 90%. The overall yield of compound
1a was 36% based on dichlorotoluene, which is at least
twice as high as the yields in the known syntheses of
Lamotrigine (13% from 2,3ꢀdichlorobenzoic acid15 and
18% from 2,3ꢀdichlorophenylglyoxal17).
Comꢀ
pound
δ
Ar
NH2 (br.s)
1a
1b
7.33—7.45 (m, 2 Н, C6H3Сl2);
7.67—7.69 (m, 1 Н, С6H3Сl2)
7.35—7.45 (m, 2 H, C6H3Cl2);
7.53—7.55 (m, 1 H,
6.39, 6.66
(2 H each, NH2)
6.18, 6.43
(2 H each, NH2)
2,4ꢀCl2C6H3)
1c
1d
1e
1f
7.16—7.29, 7.39—7.47
6.18, 6.47
(2 H, NH2)
6.27, 6.75
(2 H each, NH2)
6.23, 6.74
(2 H each, NH2)
6.33, 6.72
(2 H each, NH2)
6.22, 6.55
(2 H each, NH2)
6.44, 6.90
(2 Н, NH2)
(both m, 2 H each, C6H4F)
7.07—7.11 (m, 1 H, C4H3S);
7.38—7.42 (m, 2 Н, С4Н3S)
7.33—7.51 (m, 3 Н, C6H3F2)
Scheme 4
7.23—7.28 (m, 1 Н, С6HF4)
7.41—7.57 (m, 5 Н, Ph)
1g
1h
1i
7.88 (s, 1 H, C6H3(CF3)2);
8.11 (s, 2 H, C6H3(CF3)2)
7.24—7.39 (m, 2 Н,
С5H4N+NH); 7.84—7.85
(m, 1 H, C5H4N)
6.54 (2 Н, NH2);
9.20 (1 Н, NH)
8.40—8.53 (m, 2 Н, C5H4N)
7.10—7.19 (m, 2 H, C6H4);
7.47—7.62 (m, 3 H,
1j
6.60 (2 Н, NH2);
8.94 (1 Н, NH);
12.50 (1 Н, NH)
8.75 (2 Н, NH2)
C6H4+NH)
6a
7.57—7.70 (m, 2 Н, С6H3Cl2);
7.84—7.96 (m, 1 Н, С6H3Cl2)
7.55—7.70 (m, 3 Н, С6H3Cl2)
7.31—7.43 (m, 2 H, C6H4F);
7.50 (br.s, 2 Н, NH2);
6b
6c
8.72 (2 Н, NH2)
8.68 (2 Н, NH2)
1, 6, 11: R = 2,3ꢀCl2C6H3 (a), 2,4ꢀCl2C6H3 (b), 2ꢀFC6H4 (c),
(d), 3,4ꢀF2C6H3 (e), 2,3,4,5ꢀF4C6H (f), Ph (g),
7.60—7.70 (m, 2 Н, C6H4F)
7.25—7.28 (m, 1 Н, С4Н3S);
7.88—7.90 (m, 2 Н, С4Н3S)
7.51—7.66 (m, 2 Н, С6Н3F2);
7.70—7.74 (m, 1 H, С6Н3F2)
7.59—7.66 (m, 1 H, С6НF4)
6d
6e
6f
8.20 (2 Н, NH2)
8.70 (2 H, NH2)
3,5ꢀ(CF3)2C6H3 (h),
(i),
(j)
7.70, 8.80
(1 H each, NH2)
7.43 (2 Н, NH2)
The additional twoꢀproton broadened singlet in the
1H NMR spectrum of compounds 1a—j (see Table 2)
attests to the presence of a second amino group resulting
from destruction of the tetrazole ring. The same fact
is demonstrated by the IR and mass spectra of comꢀ
pounds 1a—j. The IR spectra were found to exhibit addiꢀ
tional signals at 3140—3460 cm–1 absent in the spectra of
starting tetrazolotriazines 6a—j. The mass spectra contain
molecular ion peaks for diaminoꢀ1,2,4ꢀtriazines (see
Table 1). In addition, all physicochemical characteristics
of compound 1a we prepared are identical to those for a
substance of Glaxo Wellcome lamotrigine.
6g
6h
6i
7.58—7.60 (m, 3 Н, Ph);
7.65—7.74 (m, 2 Н, Ph)
8.13 (s, 1 H, C6H3(CF2)2);
8.29 (s, 2 H, C6H3(CF2)2)
7.66—7.71, 8.09—8.16
8.48—8.51, 8.77—8.79
(all m, 1 H each, С5Н5N);
(m, 1 Н, С5Н5N)
8.00 (2 Н, NH2)
9.10 (1 Н, NH2);
10.06 (1 Н, NH2)
6j
7.29—7.38, 7.70—7.81
(both m, 2 H each, С6Н4);
10.06 (br.s, 1 Н, NH)
9.29, 10.00
(1 H each, NH2)
Thus, using the synthesis of the antiepileptic drug
Lamotrigine 1a and other 3,5ꢀdiaminoꢀ1,2,4ꢀtriazine
1b—j derivatives as examples, we demonstrated that degꢀ
radation of fused heterocyclic structures can provide an
efficient and facile method for the synthesis of heteroꢀ
cycles.
heterocycles, we developed a new method for the deꢀ
struction of tetrazolo[1,5ꢀb]ꢀ1,2,4ꢀtriazines in the presꢀ
ence of copper. This method is simpler and less expensive
and, in addition, it increases the yields of amino comꢀ
pounds (see Table 1). Thus refluxing of compounds 6a—j

730
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
Ulomskii et al.
C(4´)
C(5´)
C(6´)
C(3´)
N(5)
C(2´)
N(3)
N(4)
C(1´)
C(6)
C(7)
N(2)
N(1)
C(8a)
N(8)
N(9)
N(1C)
N(1B)
N(8A)
N(9A)
N(1A)
C(7A)
C(6A)
C(8aA)
N(4A)
N(2A)
N(3A)
C(2A´)
C(1A´)
N(5A)
C(3A´)
C(6A´)
C(5A´)
C(4A´)
Fig. 1. Structure of molecule 6g.
chamber was 100—300 °C. The melting points were determined
on a Boetius hot stage. TLC was performed on Silufol UVꢀ254
plates in ethyl acetate (100%), the plates being visualized by UV
irradiation and iodine vapor.
Commercial arylacetonitriles and 2,3ꢀdichlorotoluene
(Lancaster) and aminotetrazole (Aldrich) were used.
Aryl(formyl)acetonitriles 8a—h were synthesized by a reported
procedure.22
Experimental
The IR sperctra of the products were recorded in КВr
on a Specord 75 IR spectrometer. 1H NMR spectra (in
DMSOꢀd6 + CCl4) were measured on a Bruker WMꢀ250 instruꢀ
ment using Me4Si as the internal standard. The mass spectra of
the compounds were run on a VarianꢀMATꢀ311A instrument
with direct sample injection into the ion source, the ionizing
electron energy was 70 eV, and the temperature in the ionization
2ꢀCyanomethylpyridine 8i and 2ꢀcyanomethylbenzimidazole
8j were prepared by previously described procedure.23,24
Table 3. Selected bond lengths (d) and bond angles (ω) in compounds 6g
Bond
d/Å
Bond
d/Å
Bond
d/Å
Bond
d/Å
N(1)—N(2) 1.3631(19)
N(1)—C(8a) 1.3315(16)
N(2)—N(3) 1.2963(18)
N(3)—N(4) 1.3563(15)
N(4)—N(5) 1.3540(14)
N(4)—C(8a) 1.3531(16)
N(5)—C(6) 1.3015(16)
N(8)—C(8a) 1.3379(16)
C(6)—C(7)
1.4765(16)
1.4867(16)
1.3903(17)
1.3912(18)
C´(2)—C´(3)
C´(3)—C´(4)
C´(4)—C´(5)
C´(5)—C´(6)
1.3904(18)
1.380(2)
1.381(2)
1.389(2)
C(6)—C´(1)
C´(1)—C´(2)
C´(1)—C´(6)
N(8)—C(7)
N(7)—C(2)
1.3356(14)
1.3212(16)
Angle
ω/deg
Angle
ω/deg
Angle
ω/deg
N(1)—N(2)—N(3)
N(2)—N(1)—C(8a)
N(2)—N(3)—N(4)
N(5)—N(4)—N(3)
C(8a)—N(4)—N(3)
C(8a)—N(4)—N(5)
C(6)—N(5)—N(4)
N(1)—C(8a)—N(8)
C(7)—N(8)—C(8a)
112.90(11)
105.33(11)
10.30(11)
123.63(11)
110.14(11)
125.92(11)
113.11(10)
130.50(12)
114.98(10)
N(1)—C(8a)—N(4)
N(8)—C(8a)—N(4)
N(9)—C(7)—N(8)
N(9)—C(7)—C(6)
N(8)—C(7)—C(6)
N(5)—C(6)—C(7)
N(5)—C(6)—C´(1)
C(7)—C(6)—C´(1)
107.32(12)
122.14(11)
119.48(10)
119.57(10)
120.95(11)
122.31(10)
114.98(10)
122.69(10)
C´(2)—C´(1)—C´(9)
C´(2)—C´(1)—C(6)
C´(6)—C´(1)—C(6)
C´(1)—C´(2)—C´(3)
C´(4)—C´(3)—C´(2)
C´(3)—C´(4)—C´(5)
C´(4)—C´(5)—C´(6)
C´(5)—C´(6)—C´(1)
119.83(11)
118.90(11)
121.06(11)
120.00(13)
120.04(14)
120.02(13)
120.58(14)
119.50(13)
Table 4. Hydrogen bonds H...A < r(A) + 2.000 Å and D–H...A angles (deg)
D—H
d(D—H)
d(H...A)
∠D—H...A
d(D...A)
A
N(9)—Ha(9)
N(9)—Hb(9)
0.934
0.888
2.111
2.290
176.16
155.60
3.043
3.120
N(8) (–x, –y, –z + 1)
N(1) (x, –y + 1/2, z + 1/2)

New method of synthesis of Lamotrigine
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 3, March, 2005
731
Table 5. Elemental analysis data for compounds 1a—j and 6a—j
using the SHELXSꢀ9725 and SHELXLꢀ9726 software in the
anisotropic (or isotropic for H atoms) approximation down
to R = 0.0473 (wR2 = 0.1426) for 1949 reflections with
Comꢀ
pound
Found
Calculated
Molecular
formula
(%)
F
2 > 4σ(F 2o), the fitting factor GOOF being 1.001.
2,3ꢀDichlorophenylacetonitrile. A suspension of 2,3ꢀdiꢀ
С
Н
N
chlorotoluene (10 g, 0.062 mol) and bromosuccinimide (10.6 g,
0.059 mol) in 30 mL of CCl4 was refluxed for 2 h and the
precipitate was filtered off. A solution of NaCN (4 g, 0.082 mol)
in 20 mL of water and 18ꢀcrownꢀ6 (0.2 g) were added to the
resulting solution. The reaction mixture was stirred for 48 h, the
organic layer was separated, and CCl4 was evaporated to give
2,3ꢀdichlorophenylacetonitrile as a dark oil, which was used
without further purification.
6ꢀArylꢀ and 6ꢀhetarylꢀ7ꢀaminotetrazolo[1,5ꢀb][1,2,4]triꢀ
azines 6a—j. Concentrated HCl (5 mL) was added to a solution
of aminotetrazole (2 g, 0.02 mmol) in 100 mL of water. After
cooling the reaction mixture to –2 °C, NaNO2 (1.4 g, 0.02 mol)
in 20 mL of water was added dropwise with intense stirring and
the mixture was kept for 30 min at –2 °C. A mixture of
aryl(formyl)acetonitrile (8a—h) or hetarylacetonitrile (8i,j)
(0.02 mol) and sodium acetate (4.9 g) in 5 mL of water and
15 mL of ethanol were added to the resulting diazonium salt and
the mixture was stirred for 2 h at room temperature and filtered.
The precipitate was dissolved in 7 mL of acetic acid or 10 mL of
DMF and the solution was refluxed and cooled. The precipitate
was filtered off, crystallized, and dried.
1a
1b
1c
1d
1e
1f
42.32
42.21
42.05
42.21
48.76
48.43
43.44
43.51
45.23
44.82
42.00
41.71
57.71
57.74
40.69
40.88
51.14
51.06
52.45
52.86
38.45
38.32
38.38
38.32
46.90
46.76
38.18
38.35
43.34
43.38
38.06
37.91
51.01
50.70
37.95
37.84
44.76
44.86
47.58
47.43
2.63
2.76
2.80
2.76
4.51
4.52
3.65
3.65
3.75
3.76
2.13
1.94
4.83
4.85
2.07
2.18
4.28
4.28
3.83
3.99
2.05
1.79
2.12
1.79
2.43
2.62
2.16
2.30
2.03
2.02
1.14
1.06
3.41
3.31
1.44
1.44
2.87
2.82
2.72
2.79
27.24
27.35
27.50
27.35
31.51
31.38
35.97
36.24
29.14
29.04
26.98
27.02
37.29
37.41
21.65
21.67
44.97
44.66
43.23
43.15
34.55
34.76
34.81
34.76
42.73
42.41
45.20
44.72
39.37
39.35
34.56
34.38
45.75
45.99
28.09
28.08
52.23
52.31
49.71
49.78
C9H7N5Cl2
C9H7N5Cl2
C9H8N5F•H2O
C7H7N5S
C9H7N5F2•H2O
C9H5N5F4
C9H9N5
1g
1h
1i
C11H7N5F6
C8H8N6
1j
C10H9N7
6ꢀArylꢀ and 6ꢀhetarylꢀ3,5ꢀdiaminoꢀ1,2,4ꢀtriazines 4a—j.
6a
6b
6c
6d
6e
6f
C9H5N7Cl2
C9H5N7Cl2
C9H6N7F
C7H5N7S
A.
A
mixture 6ꢀarylꢀ and 6ꢀhetarylꢀ7ꢀaminotetrazoꢀ
lo[1,5ꢀb][1,2,4]triazine 6a—j (0.02 mol), a copper powder
(2.52 g, 0.04 mol) freshly prepared by a known method,27 and
5 mL of acetic acid was refluxed for 2 h. Aqueous ammonia
(25%, 80 mL) was added and the product was filtered off, crysꢀ
tallized, and dried.
B. A mixture of 6ꢀarylꢀ and 6ꢀhetarylꢀ7ꢀaminotetrazoꢀ
lo[1,5ꢀb][1,2,4]triazine 6b,d,g (0.02 mol) and triphenylphosphine
(5.30 g, 0.02 mol) and 10 mL of acetic acid was refluxed for 2 h.
Aqueous ammonia (25%, 80 mL) was added to the reaction
mixture and the product was filtered off, washed with diethyl
ether, crystallized, and dried.
C9H5N7F2
C9H3N7F4
C9H7N7
6g
6h
6i
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ96093)
and the Ministry of Science and Education (Project
NShꢀ1766.2003, RECꢀ005ꢀXA), and Federal Agency on
Education (grant A04ꢀ2.11ꢀ499).
C11H5N7F6
C8H6N8
6j
C10H7N9
References
All other domestically produced solvents and reagents were
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The product yields and the solvents used for crystallization
are indicated in Table 1, and the results of elemental analysis are
in Table 5.
XꢀRay diffraction study of 6g was carried out on a CADꢀ4
EnrafꢀNonius automated diffractometer (λꢀMoꢀKα, graphite
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Received January 28, 2005;
in revised form March 4, 2005