Chloromethyl-, dichloromethyl-, and trichloromethyl-1,2,4-triazines and their 4-oxides: Method for the synthesis and tele-substitution reactions with C-nucleophiles

Article abstract of DOI:10.1023/B:RUCB.0000042289.07168.8f

A simple procedure was developed for the synthesis of 1,2,4-triazines and their 4-oxides containing the ClCH₂, Cl₂CH, or CCl ₃ group at position 3 by cyclization of 2-aryl-2-hydrazono-1- oximinoethanes with the corresponding chloroacetonitriles. The reaction pathway depends on the number of halogen atoms in the acetonitrile used. The reactions with trichloroacetonitrile, monochloroacetonitrile, and dichloroacetonitrile afford 3-trichloromethyl-1,2,4-triazines, 3-chloromethyl-1,2,4-triazine 4-oxides, and a mixture of the corresponding dichloromethyltriazines and their 4-oxides, respectively. The reactions of 3-trichloromethyl-1,2,4-triazines with indoles and phenols are accompanied by tele-substitution with elimination of halogen from the trichloromethyl group to give 5-indolyl- (or 5-hydroxyphenyl)-3-dichloromethyl-1,2,4-triazines.

Full text of DOI:10.1023/B:RUCB.0000042289.07168.8f

Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1295—1300, June, 2004
1295
Chloromethylꢀ, dichloromethylꢀ, and trichloromethylꢀ1,2,4ꢀtriazines and
their 4ꢀoxides: method for the synthesis and
teleꢀsubstitution reactions with Cꢀnucleophiles
D. N. Kozhevnikov,ꢀ N. N. Kataeva, V. L. Rusinov, and O. N. Chupakhin
Urals State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 0458. Eꢀmail: dnk@htf.ustu.ru
A simple procedure was developed for the synthesis of 1,2,4ꢀtriazines and their 4ꢀoxides
containing the ClCH2, Cl2CH, or CCl3 group at position 3 by cyclization of 2ꢀarylꢀ2ꢀhydrazonoꢀ
1ꢀoximinoethanes with the corresponding chloroacetonitriles. The reaction pathway depends
on the number of halogen atoms in the acetonitrile used. The reactions with trichloroacetonitrile,
monochloroacetonitrile, and dichloroacetonitrile afford 3ꢀtrichloromethylꢀ1,2,4ꢀtriazines,
3ꢀchloromethylꢀ1,2,4ꢀtriazine 4ꢀoxides, and a mixture of the corresponding dichloroꢀ
methyltriazines and their 4ꢀoxides, respectively. The reactions of 3ꢀtrichloromethylꢀ1,2,4ꢀ
triazines with indoles and phenols are accompanied by teleꢀsubstitution with elimination of
halogen from the trichloromethyl group to give 5ꢀindolylꢀ (or 5ꢀhydroxyphenyl)ꢀ3ꢀdiꢀ
chloromethylꢀ1,2,4ꢀtriazines.
Key words: teleꢀsubstitution of chlorine, 3ꢀtrichloromethylꢀ1,2,4ꢀtriazines, 3ꢀchloromethylꢀ
1,2,4ꢀtriazine 4ꢀoxides, indoles, phenols.
Aromatic nucleophilic substitution reactions proceedꢀ
ing according to the addition—elimination pattern inꢀ
volve two major steps, viz., the formation of adducts
and their aromatization.1—3 An important characteristic
feature of these reactions with aromatic and heteroaroꢀ
matic substrates, including those containing nucleofuge
groups (X = Hal, CHal3, OR, OS, CN, or NO2), is that
σHꢀadducts bearing the hydrogen atom at the sp3ꢀhybridꢀ
ized carbon atom are formed more rapidly than σXꢀadꢀ
ducts.3 Since elimination of the hydride anion, as such, is
thermodynamically unfavorable (unlike ipsoꢀsubstitution
resulting in elimination of groups readily leaving as anꢀ
ions), nucleophilic substitution of hydrogen involves other
types of aromatization, viz., oxidative aromatization or
autoaromatization of σHꢀadducts.2 Autoaromatization is
achieved due to elimination of hydrogen together with
the auxiliary group L. The latter can be involved in
σHꢀadducts as either a fragment of a nucleophile (vicariꢀ
ous nucleophilic substitution of hydrogen) or a fragment
of the substrate (cineꢀ and teleꢀsubstitutions) and can also
be formed upon the addition of a nucleophile (deoxyꢀ
genative nucleophilic substitution of hydrogen in the seꢀ
ries of azine Nꢀoxides).2 The teleꢀsubstitution reactions
can proceed through elimination of the leaving group L
from both the aromatic (heteroaromatic)4 ring and the
carbon atom in the α position of the side aliphatic chain.
Up to now, the latter process has been observed only in
reactions of diꢀ and trichloromethyl derivatives of elecꢀ
trophilic arenes and hetarenes with nucleophiles under
basic conditions, for example, in the reactions of diꢀ
chloromethylpyridazine,5 trichloromethylpyrimidine,6 or
chloromethyl(phenyl)pyridazine7 with alkoxide anions as
well as in the reaction of trichloromethylnitrobenzene
with methyl thioglycolate in the presence of triethylꢀ
amine.8
In the present study, we report the data on teleꢀsubstiꢀ
tution of the chlorine atom from the side chain in the
reactions with mild neutral aromatic and heteroaromaꢀ
tic Cꢀnucleophiles. We carried out this reaction with
3ꢀtrichloromethylꢀ1,2,4ꢀtriazines 1 as substrates. It seems
reasonable to use 1,2,4ꢀtriazines taking into account high
reactivity of these heterocycles in nucleophilic substituꢀ
tion of hydrogen with different pathways of aromatization
of intermediate σHꢀadducts.9 We rejected the synthesis of
the starting chloromethylꢀ1,2,4ꢀtriazines by direct chloꢀ
rination of the corresponding methyl derivatives10 and
developed a much more facile method. This method inꢀ
volves cyclization of αꢀoximinoacetophenone hydrazones
2 by the reactions with chloromethylacetonitriles 3a—c in
methanol in the presence of sodium methoxide followed
by acidification with trifluoroacetic acid (Scheme 1). As a
result, we prepared the corresponding 3ꢀchloromethylꢀ
1,2,4ꢀtriazines 1a—c and/or 3ꢀchloromethylꢀ1,2,4ꢀtriꢀ
azine 4ꢀoxides 4a—c. The reaction pathway is determined
by the number of chlorine atoms in the acetonitrile molꢀ
ecule. For example, the reaction with trichloroacetonitrile
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1243—1247, June, 2004.
1066ꢀ5285/04/5306ꢀ1295 © 2004 Plenum Publishing Corporation

1296
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Kozhevnikov et al.
Scheme 1
Reagents and conditions: i. 1) MeONa/MeOH; 2) CF3COOH; ii. R = CH2Cl or CHCl2; iii. R = CCl3 or CHCl2.
Ar = Ph (a), 4ꢀClꢀC6H4 (b), 4ꢀMeꢀC6H4 (c); R = CCl3 (1, 3a), CH2Cl (3b, 4), CHCl2 (3c, 5, 6); B is a base
afforded exclusively 3ꢀtrichloromethylꢀ1,2,4ꢀtriazines 1a.
On the contrary, the reaction with monochloroacetonitrile
produced only 3ꢀchloromethylꢀ1,2,4ꢀtriazine 4ꢀoxides 4b.
Dichloroacetonitrile, as expected, occupies an intermeꢀ
diate place and gave a mixture of 3ꢀdichloromethylꢀ1,2,4ꢀ
triazines 5 and their 4ꢀoxides 6 in a nearly 1 : 1 ratio.
Apparently, the reaction proceeds through intermediꢀ
ate A. Further cyclization of the latter can follow two
pathways: the attack of the oximine nitrogen atom on the
amidine carbon atom followed by elimination of ammoꢀ
nia from intermediate B to form 1,2,4ꢀtriazine 4ꢀoxides 4
and 6 or, alternatively, the attack of the amino group on
the carbon atom of the oximine fragment with eliminaꢀ
tion of the hydroxylamine molecule from intermediate C
to give 1,2,4ꢀtriazines 1 and 5. The reaction pathway
depends on the electronꢀwithdrawing properties of the
substituent R in the starting nitrile. The stronger elecꢀ
tronꢀwithdrawing trichloromethyl group directs the reacꢀ
tion toward 1,2,4ꢀtriazines 1, whereas the monochloroꢀ
methyl groups directs the reaction toward 1,2,4ꢀtriazine
4ꢀoxides 4, and the dichloromethyl group occupies an
intermediate place.
The electrophilicity of the heterocycle in 3ꢀtrichloroꢀ
methylꢀ1,2,4ꢀtriazines 1a—c is additionally enhanced due
to the presence of the electronꢀwithdrawing trichloroꢀ
methyl group. However, it is insufficient for the reaction
with aromatic Cꢀnucleophiles to proceed. It is necessary
to activate the heterocyclic substrate by protonation givꢀ
ing rise to the more electrophilic azinium cation, which
can be involved in the reaction.11 As a result, 3ꢀtriꢀ
chloromethylꢀ1,2,4ꢀtriazines 1a—c react with indole or
1ꢀmethylindole in the presence of HCl or trifluoroacetic
acid to give products of teleꢀsubstitution, viz., 3ꢀdiꢀ
chloromethylꢀ5ꢀ(indolꢀ3ꢀyl)ꢀ1,2,4ꢀtriazines 7a—d, in
60—70% yields (Scheme 2, Table 1), accompanied by
elimination of one of the chlorine atoms in the side triꢀ
chloromethyl group. Aromatic Cꢀnucleophiles (phenols)
react with trichloromethylꢀ1,2,4ꢀtriazines analogously to
indoles. Refluxing of compounds 1a—c with 2,6ꢀdimethylꢀ
phenol, resorcinol, or 4ꢀhexylresorcinol in acetic acid in
the presence of trifluoroacetic acid afforded the correꢀ
sponding 3ꢀdichloromethylꢀ5ꢀhydroxyphenylꢀ1,2,4ꢀtriꢀ
azines 7e—l.
The structures of the compounds synthesized were
confirmed by NMR spectroscopy and mass spectrometry.
In addition to the signals for the protons of the indole
fragment, which is evidence that the reaction proceeds at
position 3 of indole, and the signals for the protons of the
1
aromatic substituent, the H NMR spectra of dichloroꢀ
methylꢀ1,2,4ꢀtriazines 7a—l show a oneꢀproton singlet
for the methine proton of the dichloromethyl group at
δ 7.43—7.50. The presence of two chlorine atoms is eviꢀ
denced by the presence of a triplet of the molecular ion
peak in the mass spectra of the products. Besides, the
signals for the protons of the indole fragment in the series
of 5ꢀindolylꢀ1,2,4ꢀtriazines 7a—d are characteristic.12 In
this respect, the signal for the proton at position 4´ of the
indole fragment is particularly prominent. This signal is
substantially shifted downfield compared to the signals of
the other protons (δ 8.40—8.60) due to the anisotropic
effect of the benzene ring of the substituent at position 6
of the triazine ring.
It is known9 that under acidic conditions, 1,2,4ꢀtriꢀ
azines and their Nꢀoxides rather readily add various nuꢀ
cleophiles, including indoles, to form σHꢀadducts at posiꢀ
tion 5 of the heterocycle if the latter is devoid of substituꢀ

Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1297
teleꢀSubstitution in chloromethyltriazines
Scheme 2
7
Yield (%)
7
Yield (%)
A
B
C
D
Nu =
(7a—c),
(7g—i),
(7d),
(7e,f),
a
b
c
d
e
f
70
75
65
61
87
80
55
65
55
—
—
—
g
h
i
j
k
l
85
60
70
78
65
70
—
51
58
—
—
—
(7j—l)
A — THF, CF3COOH (0.1—0.2 mL);
1) CF3COOH—CHCl3,
Ar = Ph (1a, 7a,d,e,g,j), 4ꢀClC6H4 (1b, 7b,h,k), 4ꢀMeC6H4 (1c, 7c,f,i,l)
B
—
2) AcOH, 117 °C; C — AcOH +
+ CF3COOH (0.1—0.2 mL), 117 °C;
D — 1) CF3COOH, 2) AcOH, 117 °C.
ents. The formation of such intermediates is reliably deꢀ
tected by NMR spectroscopy or their isolation from reacꢀ
tion mixtures. Apparently, the reaction under considerꢀ
ation also starts with the addition of a nucleophile (inꢀ
dole) at position 5 of 1,2,4ꢀtriazine 1 (see Scheme 2).
Further aromatization of σHꢀadducts 8 occurs through
elimination of hydrogen together with one of the chlorine
atoms of the trichloromethyl group. Subsequent protoꢀ
tropic isomerization of intermediate D affords aromatic
products 7a—l. We succeeded in finding conditions under
which the reaction is terminated in the step of addition of
the nucleophile. The presence of an acid at a high conꢀ
centration does not hinder and even facilitates the addiꢀ
tion of the nucleophile to the triazine ring resulting, howꢀ
ever, in protonation of intermediates 8 to form the catꢀ
ionic form of the σꢀadduct (Е). Evidently, elimination of
HCl from the positively charged molecule Е seems to be
highly improbable. Actually, the use of an excess of
trifluoroacetic acid in the reactions of trichloromethylꢀ
triazines 1a—c with indole or resorcinol allowed us to
isolate σHꢀadducts 8a—c. The latter appeared to be insufꢀ
ficiently stable to be purified. Hence, their structures were
studied only by 1H NMR spectroscopy. The spectra show
characteristic signals12 as oneꢀproton singlets at δ 6.2—6.3
corresponding to the protons bound to the sp3ꢀhybridized
carbon atom at position 5 of the triazine ring. σHꢀAdducts
8a—c undergo aromatization through elimination of
HCl already upon heating over a short period in acetic
acid to give the corresponding dichloromethylindolyltriꢀ
azines 7a—c.
It should be noted that monochloromethyltriazine
4ꢀoxides 4 are not involved in teleꢀsubstitution reactions
under the aboveꢀdiscussed conditions.
To summarize, nucleophilic aromatic substitution of
hydrogen (SNH), where aromatization of intermediate
σHꢀadducts occurs through elimination of the hydrogen
atom together with an auxiliary group, viz., the halogen
atom in the α position of the side chain, can take place in
the reactions of neutral nucleophiles with a substrate that
is activated by protonation.
Experimental
The NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer (250 MHz) in DMSOꢀd6 with Me4Si as the internal
standard. The electronꢀionization mass spectra were obtained

1298
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Kozhevnikov et al.
on a Varian MATꢀ311A instrument. The starting oximinoacetoꢀ
phenone hydrazones were prepared according to a known proꢀ
cedure.13
to pH 3. The precipitate that formed was filtered off and recrysꢀ
tallized from ethanol to prepare a mixture consisting of triazine
and triazine 4ꢀoxide. The products were separated by column
chromatography on silica gel using a 5 : 1 CHCl3—hexane mixꢀ
ture as the eluent.
3ꢀDichloromethylꢀ6ꢀphenylꢀ1,2,4ꢀtriazine (5a). The yield was
461 mg (1.92 mmol, 38%), m.p. 96—98 °C. 1H NMR, δ: 7.53 (s,
1 H, CHCl2); 7.59 (m, 3 H, Ph); 8.26 (m, 2 H, Ph); 9.54 (s, 1 H,
H(5)). MS, m/z (Irel (%)): 239 (9) and 241 (6) [M]+. Found (%):
C, 50.24; H, 2.83; N, 17.44. C10H7Cl2N3. Calculated (%):
C, 50.03; H, 2.94; N, 17.50.
3ꢀDichloromethylꢀ6ꢀphenylꢀ1,2,4ꢀtriazine 4ꢀoxide (6a). The
yield was 328 mg (1.28 mmol, 26%), m.p. 149—151 °C.
1H NMR, δ: 7.58 (m, 4 H, Ph + CHCl2); 8.22 (m, 2 H, Ph);
9.37 (s, 1 H, H(5)). MS, m/z (Irel (%)): 255 (20) and 257 (13)
[M]+. Found (%): C, 47.68; H, 2.62; N, 16.04. C10H7Cl2N3O.
Calculated (%): C, 46.90; H, 2.76; N, 16.31.
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀdichloromethylꢀ1,2,4ꢀtriazine (5b).
The yield was 494 mg (1.8 mmol, 36%), m.p. 132—133 °C.
1H NMR, δ: 7.53 (s, 1 H, CHCl2); 7.61 and 8.29 (both m,
2 H each, C6H4Cl); 9.58 (s, 1 H, H(5)). MS, m/z (Irel (%)): 273
(9), 275 (8) and 277 (2) [M]+. Found (%): C, 43.84; H, 2.25;
N, 15.16. C10H6Cl3N3. Calculated (%): C, 43.75; H, 2.20;
N, 15.31.
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀdichloromethylꢀ1,2,4ꢀtriazine 4ꢀoxide
(6b). The yield was 290 mg (1 mmol, 20%), m.p. 206—209 °C.
1H NMR, δ: 7.60 (m, 3 H, C6H4Cl + CHCl2); 8.23 (m, 2 H,
C6H4Cl); 9.43 (s, 1 H, H(5)). MS, m/z (Irel (%)): 289 (25), 291
(24) and 293 (8) [M]+. Found (%): C, 41.50; H, 1.81; N, 14.12.
C10H6Cl3N3O. Calculated (%): C, 41.34; H, 2.08; N, 14.46.
3ꢀDichloromethylꢀ5ꢀ(indolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ1,2,4ꢀtriazine
(7a). Trichloromethylꢀ1,2,4ꢀtriazine 1a (550 mg, 2 mmol) and
indole (235 mg, 2 mmol) were dissolved in THF (2 mL). Then
one—two drops of hydrochloric or trifluoroacetic acid were
added and the reaction mixture was kept at ~20 °C for 16 h. The
precipitate that formed was filtered off and recrystallized from
acetic acid. The yield was 470 mg (70%), m.p. 283 °C. 1H NMR,
δ: 6.80 (d, 1 H, H(2´), J = 3.3 Hz); 7.19 and 7.22 (both dd, 1 H,
H(5´), H(6´), J = 3.5 Hz, J = 3.5 Hz); 7.40 (m, 1 H, H(7´));
7.42 (s, 1 H, CHCl2); 7.55—7.70 (m, 5 H, Ph); 8.67 (m, 1 H,
H(4´)); 11.77 (br.d, 1 H, NH, J = 3.3 Hz). MS, m/z (Irel (%)):
358 (8), 356 (46), 354 (70) [M]+. Found (%): C, 60.64; H, 3.21;
N, 15.50. C18H12Cl2N4. Calculated (%): C, 60.86; H, 3.41;
N, 15.77.
6ꢀPhenylꢀ3ꢀtrichloromethylꢀ1,2,4ꢀtriazine (1a). Trichloroꢀ
acetonitrile (2.5 mL, 25 mmol) was added with stirring and
cooling with cold water to a solution of MeONa, which was
prepared from sodium (10 mg) and methanol (10 mL). After
10—20 min, αꢀoximinoacetophenone hydrazone (2a, 3.25 g,
20 mmol) was added. After 20—30 min, the reaction mixture
was acidified with trifluoroacetic acid to pH 4 and kept at ~20 °C
for 16 h. Crystals of product 1a were filtered off and recrystalꢀ
lized from ethanol. The yield was 4.3 g (78%), m.p. 145—146 °C.
1H NMR, δ: 7.62 and 8.18 (both m, 3 H, 2 H); 9.65 (s, 1 H,
H(5)). MS, m/z (Irel (%)): 279 (1), 277 (9), 275 (28), 273 (30)
[M]+. Found (%): C, 43.52; H, 2.08; N, 15.07. C10H6Cl3N3.
Calculated (%): C, 43.75; H, 2.20; N, 15.31.
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀtrichloromethylꢀ1,2,4ꢀtriazine (1b) was
prepared analogously to 1a starting from trichloroacetonitrile
(2.5 mL, 25 mmol) and 4ꢀchloroꢀαꢀoximinoacetophenone hydrꢀ
azone (2b, 3.95 g, 20 mmol). The yield was 4.6 g (75%), m.p.
1
138—140 °C. H NMR, δ: 7.60 and 8.17 (both m, 2 H); 9.64
(s, 1 H, H(5)). Found (%): C, 38.65; H, 1.49; N, 13.34.
C10H5Cl4N3. Calculated (%): C, 38.87; H, 1.63; N, 13.60.
6ꢀ(4ꢀMethylphenyl)ꢀ3ꢀtrichloromethylꢀ1,2,4ꢀtriazine (1c)
was prepared analogously to 1a starting from trichloroacetonitrile
(2.5 mL, 25 mmol) and 4ꢀmethylꢀαꢀoximinoacetophenone hydrꢀ
azone (2c, 3.54 g, 20 mmol). The yield was 4.0 g (70%), m.p.
180—181 °C. 1H NMR, δ: 2.46 (s, 3 H); 7.41 and 8.19 (both m,
2 H); 9.57 (s, 1 H, H(5)). MS, m/z (Irel (%)): 291 (2), 289 (5),
287 (6) [M]+. Found (%): C, 45.65; H, 2.72; N, 14.34.
C11H8Cl3N3. Calculated (%): C, 45.79; H, 2.79; N, 14.56.
3ꢀChloromethylꢀ6ꢀphenylꢀ1,2,4ꢀtriazine 4ꢀoxide (4a) was
prepared analogously to 1a starting from chloroacetonitrile
(1.6 mL, 25 mmol) and αꢀoximinoacetophenone hydrazone (2a,
3.25 g, 20 mmol). The yield was 2.9 g (66%), m.p. 188—189 °C.
1H NMR, δ: 5.01 (s, 2 H, CH2Cl); 7.58 and 8.20 (both m, 3 H,
2 H); 9.36 (s, 1 H, H(5)). Found (%): C, 54.34; H, 3.63; N, 19.28.
C10H8ClN3O. Calculated (%): C, 54.19; H, 3.64; N, 18.96.
3ꢀChloromethylꢀ6ꢀ(4ꢀchlorophenyl)ꢀ1,2,4ꢀtriazine 4ꢀoxide
(4b) was prepared analogously to 1a starting from chloroꢀ
acetonitrile (1.6 mL, 25 mmol) and 4ꢀchloroꢀαꢀoximinoacetoꢀ
phenone hydrazone (2b, 3.95 g, 20 mmol). The yield was 4.1 g
1
(80%), m.p. 162—163 °C. H NMR, δ: 5.04 (s, 2 H, CH2Cl);
7.61 and 8.24 (both m, 2 H); 9.36 (s, 1 H, H(5)). Found (%):
C, 46.91; H, 2.86; N, 16.71. C10H7Cl2N3O. Calculated (%):
C, 46.90; H, 2.76; N, 16.41.
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀdichloromethylꢀ5ꢀ(indolꢀ3ꢀyl)ꢀ1,2,4ꢀ
triazine (7b) was prepared analogously to 7a starting from 1b
(620 mg, 2 mmol) and indole (235 mg, 2 mmol). The yield was
3ꢀChloromethylꢀ6ꢀ(4ꢀmethylphenyl)ꢀ1,2,4ꢀtriazine 4ꢀoxide
(4c) was prepared analogously to 1a starting from chloroꢀ
acetonitrile (1.6 mL, 25 mmol) and 4ꢀmethylꢀαꢀoximinoacetoꢀ
phenone hydrazone (2c, 3.54 g, 20 mmol). The yield was 3.4 g
1
585 mg (75%), m.p. 256—258 °C. H NMR, δ: 6.95 (d, 1 H,
H(2´), J = 3.3 Hz); 7.19 and 7.23 (both dd, 1 H, H(5´), H(6´),
J = 3.5 Hz, J = 3.5 Hz); 7.42 (s, 1 H, CHCl2); 7.44 (m, 1 H,
H(7´)); 7.55 and 7.70 (both m, 2 H); 8.63 (m, 1 H, H(4´)); 11.79
(br.d, 1 H, NH, J = 3.3 Hz). MS, m/z (Irel (%)): 392 (6), 390
(19), 388 (20) [M]+. Found (%): C, 55.23; H, 2.69; N, 14.09.
C18H11Cl3N4. Calculated (%): C, 55.48; H, 2.85; N, 14.38.
3ꢀDichloromethylꢀ5ꢀ(indolꢀ3ꢀyl)ꢀ6ꢀ(4ꢀmethylphenyl)ꢀ1,2,4ꢀ
triazine (7c) was prepared analogously to 7a starting from 1c
(580 mg, 2 mmol) and indole (235 mg, 2 mmol). The yield was
1
(72%), m.p. 130—131 °C. H NMR, δ: 2.43 (s, 3 H); 5.00 (s,
2 H, CH2Cl); 7.38 and 8.12 (both m, 2 H); 9.29 (s, 1 H, H(5)).
Found (%): C, 56.25; H, 4.26; N, 18.09. C11H10ClN3O. Calcuꢀ
lated (%): C, 56.06; H, 4.28; N, 17.83.
Synthesis of 6ꢀarylꢀ3ꢀdichloromethylꢀ1,2,4ꢀtriazines and their
4ꢀoxides 5 and 6 (general procedure). Dichloroacetonitrile
(0.52 mL, 6.5 mmol) was added to a solution of MeONa, which
was prepared from sodium (0.1 g) and methanol (10 mL). After
10 min, the corresponding isonitrosoacetophenone hydrazone
(5 mmol) was added. The reaction mixture was kept at room
temperature for 20 min and acidified with trifluoroacetic acid
1
480 mg (65%), m.p. 287—289 °C. H NMR, δ: 2.45 (s, 3 H);
6.88 (d, 1 H, H(2´), J = 3.6 Hz); 7.26 and 7.29 (both dd, 1 H,
H(5´), H(6´), J = 2.4 Hz, J = 2.4 Hz); 7.44 (m, 2 H); 7.50 (m,
1 H, H(7´)); 7.57 (m, 2 H); 7.71 (s, 1 H, CHCl2); 8.78 (m, 1 H,

Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1299
teleꢀSubstitution in chloromethyltriazines
H(4´)); 11.89 (br.d, 1 H, NH, J = 3.6 Hz). Found (%): C, 61.64;
H, 3.69; N, 14.98. C19H14Cl2N4. Calculated (%): C, 61.80;
H, 3.82; N, 15.17.
C6H13); 1.47 and 2.49 (both m, 2 H each, C6H13); 6.22 (s, 1 H,
H(3´)); 7.22 (s, 1 H, H(6´)); 7.39 (m, 2 H, ClC6H4); 7.45 (s,
1 H, CHCl2); 7.59 (m, 2 H, ClC6H4); 9.65 and 9.67 (both s,
1 H each, OH). Found (%): C, 56.40; H, 4.72; N, 9.00.
C22H22Cl3N3O2. Calculated (%): C, 56.61; H, 4.75; N, 9.00.
3ꢀDichloromethylꢀ5ꢀ(5ꢀhexylꢀ2,4ꢀdihydroxyphenyl)ꢀ6ꢀ
(4ꢀmethylphenyl)ꢀ1,2,4ꢀtriazine (7l). The yield was 70%, m.p.
3ꢀDichloromethylꢀ5ꢀ(1ꢀmethylindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ1,2,4ꢀtriꢀ
azine (7d) was prepared analogously to 7a starting from 1a
(550 mg, 2 mmol) and 1ꢀmethylindole (0.26 mL, 2 mmol). The
yield was 445 mg (61%), m.p. 239—241 °C. 1H NMR, δ: 3.49 (s,
3 H, NMe); 6.78 (s, 1 H, H(2´)); 7.20—7.33 (m, 2 H, H(5´),
H(6´)); 7.43 (s, 1 H, CHCl2); 7.45 (m, 1 H, H(7´)); 7.50—7.70
(m, 5 H, Ph); 8.62 (m, 1 H, H(4´)). MS, m/z (Irel (%)): 372 (5),
370 (30), 368 (46) [M]+. Found (%): C, 61.66; H, 3.74; N, 14.87.
C19H14Cl2N4. Calculated (%): C, 61.80; H, 3.82; N, 15.17.
Synthesis of 3ꢀdichloromethylꢀ5ꢀhydroxyphenylꢀ1,2,4ꢀtriꢀ
azines 7e—l (general procedure). Trichloromethylꢀ1,2,4ꢀtriazꢀ
ine (2 mmol) and phenol (2 mmol) were dissolved in acetic acid
(5 mL) and then trifluoroacetic acid (1 mL) was added. The
reaction mixture was refluxed for 2 h and kept at ~20 °C for 16 h.
The precipitate that formed was filtered off and recrystallized
from acetic acid.
1
203—205 °C. H NMR, δ: 0.89 and 1.27 (both m, 3 H each,
C6H13); 1.40 (m, 2 H, C6H13); 2.37 (m, 5 H, C6H13, Me); 6.23
(s, 1 H, H(3´)); 7.07 (s, 1 H, H(6´)); 7.17 (m, 2 H, MeC6H4);
7.44 (s, 1 H, CHCl2); 7.47 (m, 2 H, MeC6H4); 9.69 and 9.85
(both s, 1 H each, OH). Found (%): C, 61.68; H, 5.60; N, 9.37.
C23H25Cl2N3O2. Calculated (%): C, 61.89; H, 5.65; N, 9.41.
Synthesis of 5ꢀsubstituted 3ꢀtrichloromethylꢀ4,5ꢀdihydroꢀ
1,2,4ꢀtriazines 8 (general procedure). The corresponding triꢀ
chloromethyltriazine 1 (1 mmol) and indole or resorcinol
(1 mmol) were dissolved in trifluoroacetic acid (3 mL) and kept
at ~20 °C for 16 h. The solvent was removed under reduced
pressure. The residue was treated with a 5% Na2CO3 solution.
The precipitate that formed was filtered off. Adducts 8 are unꢀ
stable, cannot be purified, and were characterized only by
1H NMR spectroscopy.
3ꢀDichloromethylꢀ5ꢀ(4ꢀhydroxyꢀ3,5ꢀdimethylphenyl)ꢀ6ꢀpheꢀ
nylꢀ1,2,4ꢀtriazine (7e). The yield was 87%, m.p. 176—179 °C.
1H NMR, δ: 2.05 (s, 6 H, 2 Me); 7.16 (s, 2 H); 7.51 (m, 5 H);
7.75 (s, 1 H); 9.10 (s, 1 H, OH). Found (%): C, 59.79; H, 4.10;
N, 11.52. C18H15Cl2N3O. Calculated (%): C, 60.01; H, 4.20;
N, 11.66.
5ꢀ(Indolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ3ꢀtrichloromethylꢀ4,5ꢀdihydroꢀ
1,2,4ꢀtriazine (8a). The yield was 341 mg (0.87 mmol, 87%).
1H NMR, δ: 6.26 (s, 1 H, H(5)); 7.06 (m, 3 H); 7.32 (m, 4 H);
7.76 (m, 3 H); 10.86 (s, 1 H); 11.52 (br.s, 1 H).
3ꢀDichloromethylꢀ5ꢀ(4ꢀhydroxyꢀ3,5ꢀdimethylphenyl)ꢀ6ꢀ
(4ꢀmethylphenyl)ꢀ1,2,4ꢀtriazine (7f). The yield was 80%, m.p.
6ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(indolꢀ3ꢀyl)ꢀ3ꢀtrichloromethylꢀ4,5ꢀ
dihydroꢀ1,2,4ꢀtriazine (8b). The yield was 320 mg (0.75 mmol,
1
201—203 °C. H NMR, δ: 2.09 (s, 6 H, 2 Me); 2.40 (s, 3 H,
1
Me); 7.17 (s, 2 H); 7.24 (m, 2 H); 7.46 (m, 3 H); 8.92 (s, 1 H,
OH). Found (%): C, 60.84; H, 4.54; N, 11.06. C19H17Cl2N3O.
Calculated (%): C, 60.97; H, 4.58; N, 11.23.
85%). H NMR, δ: 6.36 (s, 1 H, H(5)); 7.01 (m, 1 H); 7.08,
7.25, 7.42, and 7.71 (all m, 1 H each); 7.80 (m, 2 H); 11.09
(s, 1 H); 11.16 (br.s, 1 H).
3ꢀDichloromethylꢀ5ꢀ(2,4ꢀdihydroxyphenyl)ꢀ6ꢀphenylꢀ1,2,4ꢀ
triazine (7g). The yield was 85%, m.p. 218—221 °C. 1H NMR, δ:
6.18 and 6.36 (both m, 1 H each); 7.40 (m, 4 H); 7.50 (s, 1 H,
CHCl2); 7.58 (m, 2 H, Ph); 9.81 (s, 1 H, OH). Found (%):
C, 54.96; H, 3.18; N, 11.93. C16H11Cl2N3O2. Calculated (%):
C, 55.19; H, 3.18; N, 12.07.
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀdichloromethylꢀ5ꢀ(2,4ꢀdihydroxypheꢀ
nyl)ꢀ1,2,4ꢀtriazine (7h). The yield was 60%, m.p. 215—218 °C.
1H NMR, δ: 6.15 (m, 1 H); 6.38 (m, 2 H); 7.38 (m, 3 H); 7.51
(s, 1 H, CHCl2); 7.59 and 9.72 (both m, 2 H each). Found (%):
C, 50.13; H, 2.60; N, 10.95. C16H10Cl3N3O2. Calculated (%):
C, 50.22; H, 2.63; N, 10.98.
3ꢀDichloromethylꢀ5ꢀ(2,4ꢀdihydroxyphenyl)ꢀ6ꢀ(4ꢀmethylꢀ
phenyl)ꢀ1,2,4ꢀtriazine (7i). The yield was 70%, m.p. 138—139 °C.
1H NMR, δ: 2.35 (s, 3 H, Me); 6.15 and 6.35 (both m, 1 H each);
7.16 (m, 2 H); 7.34 (m, 1 H); 7.47 (m, 3 H); 9.75 (m, 2 H).
Found (%): C, 56.06; H, 3.69; N, 11.32. C17H13Cl2N3O2. Calꢀ
culated (%): C, 56.37; H, 3.62; N, 11.60.
3ꢀDichloromethylꢀ5ꢀ(5ꢀhexylꢀ2,4ꢀdihydroxyphenyl)ꢀ6ꢀpheꢀ
nylꢀ1,2,4ꢀtriazine (7j). The yield was 78%, m.p. 197—198 °C.
1H NMR, δ: 0.86 (m, 3 H, C6H13); 1.26 (m, 6 H, C6H13); 1.43
and 2.41 (both m, 2 H each, C6H13); 6.22 (s, 1 H, H(3´)); 7.18
(s, 1 H, H(6´)); 7.37 (m, 3 H, Ph); 7.55 (m, 1 H, Ph); 7.74 (s,
1 H, CHCl2); 9.74 and 9.85 (both s, 1 H each, OH). Found (%):
C, 60.94; H, 5.29; N, 9.59. C22H23Cl2N3O2. Calculated (%):
C, 61.12; H, 5.36; N, 9.72.
5ꢀ(Indolꢀ3ꢀyl)ꢀ6ꢀ(4ꢀmethylphenyl)ꢀ3ꢀtrichloromethylꢀ4,5ꢀ
dihydroꢀ1,2,4ꢀtriazine (8c). The yield was 324 mg (0.8 mmol,
90%). H NMR, δ: 2.27 (s, 3 H, Me); 6.34 (s, 1 H, H(5)); 7.02
and 7.09 (both m, 1 H each); 7.17 (m, 3 H); 7.35 (m, 1 H); 7.73
(m, 3 H); 11.05 (s, 1 H); 11.85 (br.s, 1 H).
6ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(2,4ꢀdihydroxyphenyl)ꢀ3ꢀtrichloroꢀ
methylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazine (8h). The yield was 294 mg
(0.7 mmol, 71%). 1H NMR, δ: 6.13 and 6.15 (both m, 1 H each);
6.35 (s, 1 H, H(5)); 6.80 (m, 1 H); 7.53 and 7.80 (both m,
2 H each); 9.90 (s, 2 H); 11.56 (br.s, 1 H).
5ꢀ(2,4ꢀDihydroxyphenyl)ꢀ6ꢀ(4ꢀmethylphenyl)ꢀ3ꢀtrichloroꢀ
methylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazine (8i). The yield was 284 mg
(0.71 mmol, 71%). 1H NMR, δ: 2.28 (s, 3 H, Me); 6.12 and 6.14
(both m, 1 H each); 6.34 (s, 1 H, H(5)); 6.80 (m, 1 H); 7.18 and
7.64 (both m, 2 H each); 9.84 (s, 2 H); 11.29 (br.s, 1 H).
1
This study was in part financially supported by the
Russian Foundation for Basic Research (Project No. 02ꢀ
03ꢀ32627), the US Civilian Research and Development
Foundation (CRDF), and the Ministry of Education of
the Russian Federation (Grant Y1ꢀ05ꢀ03).
References
6ꢀ(4ꢀChlorophenyl)ꢀ3ꢀdichloromethylꢀ5ꢀ(5ꢀhexylꢀ2,4ꢀdiꢀ
hydroxyphenyl)ꢀ1,2,4ꢀtriazine (7k). The yield was 65%, m.p.
210—212 °C. H NMR, δ: 0.90 (m, 3 H, C6H13); 1.30 (m, 6 H,
1. F. Terrier, Nucleophilic Aromatic Displacement: the Influence
of the Nitro Group, VCH Publishers, Inc., New York,
1991, 460.
1

1300
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Kozhevnikov et al.
2. O. N. Chupakhin, V. N. Charushin, and H. C. van der Plas,
Nucleophilic Aromatic Substitution of Hydrogen, Academic
Press, San Diego, 1994, 246.
3. M. Makosha, Izv. Akad. Nauk, Ser. Khim., 1996, 531 [Russ.
Chem. Bull., 1996, 45, 491 (Engl. Transl.)].
4. H. C. van der Plas, M. Wozniak, and A. van Veldhuizen,
Rec. Trav. Chim., 1978, 97, 130.
5. E. J. J. Grabowski, E. W. Tristram, R. Tull, and P. I. Pollak,
Tetrahedron Lett., 1968, 5931.
9. D. N. Kozhevnikov, V. L. Rusinov, and O. N. Chupakhin,
Adv. Heterocycl. Chem., 2002, 82, 261.
10. S. Konno, M. Yokoyama, and H. Yamanaka, Heterocycles,
1982, 19, 1865.
11. V. L. Rusinov, D. N. Kozhevnikov, E. N. Ulomskii, O. N.
Chupakhin, G. G. Aleksandrov, and H. Neunhoeffer,
Zh. Org. Khim., 1998, 34, 429 [Russ. J. Org. Chem., 1998, 34,
400 (Engl. Transl.)].
12. V. L. Rusinov, D. N. Kozhevnikov, I. S. Kovalev, O. N.
Chupakhin, and G. G. Aleksandrov, Zh. Org. Khim., 2000,
36, 1081 [Russ. J. Org. Chem., 2000, 36 (Engl. Transl.)].
13. B. B. Dey, J. Chem. Soc. London, 1914, 105, 1039.
6. R. S. Dainter, T. Jackson, A. H. H. Omar, H. Suschitzky,
B. J. Wakefield, N. Hughes, and A. J. Nelson, J. Chem. Soc.,
Perkin Trans. 1, 1989, 283.
7. G. Heinisch and T. Huber, Liebigs Ann. Chem., 1992, 19.
8. T. Giannopoulos, J. R. Ferguson, B. E. Wakefield, and
G. Varvounis, Tetrahedron, 2000, 56, 447.
Received December 29, 2003;
in revised form March 22, 2004