New possibilities of 1,2,4-triazines functionalization: First examples of synthesis and structure of boron-containing 1,2,4-triazines

Article abstract of DOI:10.1016/j.tetlet.2004.02.121

By oxidation of 3-thioderivatives of 1,2,4-triazine 1a,b 3-alkylsulfonic derivatives 2a,b were obtained. Interaction of the sulfonic derivative 2a with indole leads to 3-oxo-5-indolyl-5-phenyl-as-triazine 4. The sulfone 2a reacts with 1-ethyl-2,6-dimethylquinolinium iodide to give 3-(1-ethyl-6-methyl-1,2- dihydroquinoline-2-methylene)-5-phenyl-1,2,4-triazine 5. The 3-morpholino- 3 and 3-thioderivatives 6, 7a,b of as-triazine were obtained by interaction of the sulfone 2 with morpholine and organic boron-containing thiols. The crystal structure of boron-containing derivative of as-triazine 7b was investigated by X-ray analysis.

Full text of DOI:10.1016/j.tetlet.2004.02.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3249–3252
New possibilities of 1,2,4-triazines functionalization: first examples
of synthesis and structure of boron-containing 1,2,4-triazines
Yuri Azev,a,b, Enno Lork,a Thomas Duelcksa and Detlef Gabela,*
aDepartment of Chemistry, University of Bremen, D-28334 Bremen, Germany
bUral Scientific Research Institute of Technology of Medicinal Preparations, 620219 Ekaterinburg, Russian Federation
Received 13 January 2004; revised 23 February 2004; accepted 25 February 2004
Abstract—By oxidation of 3-thioderivatives of 1,2,4-triazine 1a,b 3-alkylsulfonic derivatives 2a,b were obtained. Interaction of the
sulfonic derivative 2a with indole leads to 3-oxo-5-indolyl-5-phenyl-as-triazine 4. The sulfone 2a reacts with 1-ethyl-2,6-dimethyl-
quinolinium iodide to give 3-(1-ethyl-6-methyl-1,2-dihydroquinoline-2-methylene)-5-phenyl-1,2,4-triazine 5. The 3-morpholino- 3
and 3-thioderivatives 6, 7a,b of as-triazine were obtained by interaction of the sulfone 2 with morpholine and organic boron-
containing thiols. The crystal structure of boron-containing derivative of as-triazine 7b was investigated by X-ray analysis.
Ó 2004 Elsevier Ltd. All rights reserved.
The 1,2,4-triazine derivatives glyacitidine and tetracit-
idine in their nucleotide forms suppress the synthesis of
pyrimidine bases and possess antitumour activity1;2. The
as-triazine cycle is part of the pyrimidotriazine nucleus
in natural antibiotics, such as fervenuline, xantotricine,
reumicine and 2-methylfervenuline (MSD-92)3.
By oxidation of the 3-alkylthioderivatives of 1,2,4-tri-
azine 1a,b (Scheme 1) with gaseous chlorine in a water
suspension at 5–10 °C the corresponding 3-alkylsulfonyl
derivatives 2a,b were obtained.à
à
All new compounds gave satisfactory mass spectra. Spectra with
boron fragments gave the expected isotope distribution pattern.
These ions are indicated with à; the indicated masses correspond to
the maximum intensity peak of a fragment showing the expected
isotope distribution pattern for 10 boron atoms with natural
abundance of 10B and 11B. Structure was established by 1H NMR.
Indicated are: No of compound, yield %, mp °C (solvent for
crystallization). Molecular ion mass, m=z (relative intensity, %). 1H
NMR in DMSO-d6, 200 MHz: 2a, 65–70, 139–140 (ethanol). 249 (8),
[M]þÁ. 1.33 (t, 3H, J ¼ 7:3 Hz, CH3), 3.80 (kv, 2H, J ¼ 7:3 Hz, CH2),
7.55–7.85 (m, 3H, 3 Â CHarom), 8.35–8.55 (m, 2H, 2 Â CHarom). 2b,
60–65, 171–172 (ethanol). 315 (17), [M]þÁ. 3.60 (s, 3H, CH3), 7.86 (d,
2H, J ¼ 8:8 Hz, 2Harom), 8.36 (d, 2 Â CH, J ¼ 8:8 Hz, 2Harom), 10.35
(s, 1H, CHtriazin). 5, 60–65, 142–143 (ethanol). 340 (80) [M]þÁ. 1.37 (t,
3H, J ¼ 6:8 Hz, CH3); 2.32 (s, 3H, CH3), 4.17 (kv, 2H, J ¼ 6:8 Hz,
CH2), 5.75 (s, 1H, H), 7.20–9.10 (m, 10H, CHarom), 9.38 (s, 1H,
CHtriazin). 6, 75–80, 168–170 (ethanol). 279 (46) [M]þÁ. 2.39 (s, 3H,
CH3), 7.34 (d, 2H, J ¼ 7:8 Hz, 2 Â CHarom), 814 (d, 2H, J ¼ 7:8 Hz,
2 Â CHarom), 9.82 (s, 1H, CHtriazine). 7a, 40–45, 199–200, 329z (75),
[M]þÁ. )0.50–2.50 (br b 11H, B12H11), 2.66 (s, 6H, 2CH3lutidine), 7.50–
7.90 (m, 5H, CHarom), 8.34 (t, 1H, J ¼ 7:6 Hz, 4-CHlutidine), 8.49 (d,
2H, J ¼ 7:6 Hz, C3H, C5Hlutidine), 9.62 (s, 1H, CHtriazin). 7b, 30–35,
227–229, 408z (25) [M]þÁ. )0.50–2.50 (br b, 11H, B12H11), 2,68 (s, 6H,
2 Â CH3lutidine), 7.72 (d, 2H, J ¼ 7:8 Hz, C3H, C5Hlutidine), 7.83 (d, 2H,
J ¼ 8:8 Hz, 2CH), 8.36 (t, 1H, J ¼ 7:8 Hz, CHlutidine), 8.43 (d, 2H,
J ¼ 8:8 Hz, 2CHarom), 9.60 (s, 1H, CHtriazine). 8, 75–80, 96–97. 344z
The transport and accumulation of boron-containing
compounds into tumour tissue, which is necessary for
further improvement of BNCT (boron neutron cancer
therapy), is a continuing challenge.4 It seems advanta-
geous to use 1,2,4-triazines as heterocyclic carriers of
boron-containing fragments.
In the present work we investigated the possibilities of
synthesis of various derivatives starting from 2-thio-
substituted as-triazines. It was intended to change the
nucleofugacity of the 2-thiogroup by its oxidation to
alkylsulfone, and also to activate the triazine cycle by its
protonation. Activation of the nucleophilic agent was
realized by generation of the corresponding anion by
means of treatment of the reaction mixture with an
organic base.
Keywords: Triazine; Boranes; Boron neutron capture therapy; Mass
spectrometry.
* Corresponding author. Tel.: +49-421-218-2200; fax: +49-421-218-
2871; e-mail addresses: azural@dialup.utk.ru; gabel@chemie.uni-
bremen.de
(100), [M]þÁ
. )0.50–2.50 (br b, 11H, B12H11), 2.68 (s, 6H,
2 Â CH3lutidine), 3.08 (s, 3H, 3 Â SH3), 7.55–7.85 (m, 5H, CHarom),
Fax: +7-3432-516281.
8.20–8.50 (m, 3H, CHlutidine), 10.27 (s, 1H, CHtriazin).
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.121

3250
Y. Azev et al. / Tetrahedron Letters 45 (2004) 3249–3252
N
N
N
N
N
N
N
N
+
N
N
SR1
R2
S
N
H
+
O
-
2
3
1a,b
8
+
N
H
N
N
N
N
N
N
N
S
N
N
H
+
S
R
SO2R1
R2
-
2
2a,b
6
7a,b
N
NH
N
H
O
N
N
N
1, 2 a R1=C2H5, R2=Ph
N
Et
b
R1=CH3, R2=pBrPh
N
H
7
a R2=Ph
b
R2=pBrPh
5
4
Scheme 1.
Upon short heating of compounds 2a with morpholine
in ethanol the alkylsulfonic group was smoothly
substituted and the described5 morpholyl derivative 3a
was formed.
C13
C14
C12
C15
C16
N5
We discovered a unusual transformation of the sulfone
2a when it was heated with indole in ethanol in presence
of trifluoroacetic acid. In result of this reaction 3-oxo-5-
indolyl-5-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine 4 was
obtained. In this case, probably at first a hydrolysis of
the sulfonic group occurred, resulting in the formation
C17
C18
N3
N2
C1
B1
of
indole was added and compound 4 was formed as
described in Ref. 6 (Scheme 2).
3-oxo-5-phenyl-2,3-dihydro-1,2,4-triazine;
then
C2
C11
O1
S1
C3
N1
The sulfone 2a reacts with 1-ethyl-2,6-dimethylquino-
linium iodide in presence of triethylamine in DMSO at
room temperature to form 3-(1-ethyl-6-methyl-1,2-
dihydroquinoline-2-methylene)-5-phenyl-1,2,4-triazine
5. The sulfonic group in 2a was substituted by reaction
with thiocresol in presence of lutidine at room temper-
ature. As result of this reaction 3-p-methylphenylthio-4-
phenyl-1,2,4-triazine 6 was obtained with high yield.
S2
C5
C7
C4
C9
C10
C6
C8
Interaction of the sulfones 2 in CH3CN with the boron-
containing thiol Na2B12H11SH as nucleophile7 at room
temperature in presence of lutidine gave the first boron-
containing derivatives of 1,2,4-triazine 7a,b, analogous
to the reaction with morpholine. Sulfone 2 (0.078 g,
0.3 mmol) was stirred with 0.095 g (0.43 mmol)
Na2B12H11SH in 2 mL of acetonitrile in the presence of
0.05 mL lutidine for 3 h at room temperature. The
reaction mixture was filtered and the filtrate was evap-
orated in vacuo. The residue was treated with 2 mL of
Br1
Figure 1. Molecular structure of compound 7b. Selected bond lengths
ꢀ
(A): S(1)–C(1) 1.703(5), S(1)–B(1) 1.900(6), N(1)–C(3) 1.315(6), N(1)–
C(1) 1.355(6), C(1)–N(2) 1.328(6), N(2)–N(3) 1.337(6), N(3)–C(2)
1.303(6), C(2)–C(3) 1.430(7), C(3)–C(4) 1.471(7), C(4)–C(5) 1.392(7),
C(4)–C(9) 1.404(7), C(5)–C(6) 1.393(7), C(6)–C(7) 1.380(7), C(7)–C(8)
1.372(7), C(7)–Br(1) 1.884(5), C(8)–C(9) 1.388(7), N(5)–C(17) 1.343(7),
N(5)–C(12) 1.347(7), C(12)–C(14) 1.372(7). Selected bond angles (°):
C(1)–S(1)–B(1) 108.0(3), B(5)–B(1)–S(1) 113.3(4), B(9)–B(1)–S(1)
125.1(4), B(11)–B(1)–S(1) 116.3(4), B(2)–B(1)–S(1) 128.9(4), B(3)–
B(1)–S(1) 121.0(4), C(3)–N(1)–C(1) 117.9(4), N(2)–C(1)–N(1) 119.3(5),
N(2)–C(1)–S(1) 123.3(4), N(1)–C(1)–S(1) 117.3(4), C(1)–N(2)–N(3)
125.4(5), C(2)–N(3)–N(2) 115.7(5), N(3)–C(2)–C(3) 121.0(5), N(1)–
C(3)–C(2) 120.4(5), N(1)–C(3)–C(4) 117.4(5), C(2)–C(3)–C(4) 122.1(5),
C(5)–C(4)–C(9) 119.4(5), C(5)–C(4)–C(3) 122.0(5), C(9)–C(4)–C(3)
118.6(5), C(4)–C(5)–C(6) 120.2(5), C(7)–C(6)–C(5) 119.3(5), C(8)–
C(7)–C(6) 121.4(5), C(8)–C(7)–Br(1) 118.2(4), C(6)–C(7)–Br(1)
120.4(4), C(7)–C(8)–C(9) 119.9(5), C(8)–C(9)–C(4) 119.8(5).
N
NH
2a
N
O
4
Scheme 2.

Y. Azev et al. / Tetrahedron Letters 45 (2004) 3249–3252
3251
.
.
+
-B12H11
N
N
-CH3S
-N2
N
N
+
N
N
C9H6N3
R2
S+
SCH3
-
2
M-B12H11
C10H9N3S
.
+
C10H9NS
Scheme 3.
1
N
C
2' C3
C
C
'
4' C6
CH
'
SCH
3
C
2
N 2
3
C5'
C
3
5
1
'
6
C6
6'
3'
5
1'
2'
133.6
133.7
173.0
128.7
130.2
5'
4'
143.7
155.0
15.2
25.2
N
S
4
C2'
C6'
C1'
N
C3'
C5'
C3
166.1
C5
N
C6
150.0
C4
SO2CH2
46.7
CH3
'
129.4
132.7
130.5
7.5
N
S
157.6
134.8
O
O
C2'
C6'
'
+
N
N
H
S
C
C1
C4
'
3'
5'
N
N
C5
C3
C6
146.7
C
132.8 130.4
131.0
176.0
159.9
135.8
-
2
B
H
12 11
C2'
N
N
C6'
C1'
C3'
C5'
C3
C5
C6
SCH3
23.5
C4
'
+
S
CH3
132.7
164.7
129.3
153.9 147.7
134.7
130.5
-
2
B
H
12 11
.
.
.
.
20
160
180
140
120
40
Figure 2. Chemical shifts of C-atoms in the 13C NMR spectra of the 3-thioderivatives of as-triazine.
water and 7 was obtained as solid. It was filtered,
redissolved in dimethylsulfoxide and precipitated with
ethanol.
cycle (Fig. 1). Both protonation of the triazine cycle of
compound 7 and formation of a stable salt show that the
basicity of the triazine cycle is raised considerably as a
result of the electron-donating influence of the boron-
containing substituent.–
The negative fast atom bombardment (FAB) mass
spectrum of compound 7a,b shows an ion, which cor-
responds to the boron-containing molecular anion of
this compound. In the positive-ion FAB spectrum an
ion at m=z 108 corresponding to the protonated lutidine
(C7H10Nþ) is observed.
–
Crystal
data
for
7b:
At
173(2) K,
a
crystal
of
C18H33N4B12BrOS2 Â (CH3)2SO (0.60 Â 0.30 Â 0.10 mm) is mono-
clinic, a ¼ 1424:7ð1Þ, b ¼ 1175:3ð1Þ, c ¼ 1783:7ð2Þ pm, a ¼ 90,
b ¼ 100:65ð1Þ, c ¼ 90°, V ¼ 2:9353ð5Þ nm3, space group P21=c,
Z ¼ 4, Dc ¼ 1:347 Mg/m3, l ¼ 1:565 mmꢀ1, wavelength 71.073 pm,
F ð000Þ ¼ 1216, diffractometer Siemens P4, theta range for data
collection 2.50°–25.00°, index ranges ꢀ16 6 h 6 1, ꢀ13 6 k 6 1,
ꢀ21 6 l 6 20, reflections collected 6521, independent reflections
5128 [Rint ¼ 0:0336], completeness to h ¼ 25:00° 99.4%, refinement
method full-matrix least-squares on F 2, data/restraints/parameters
5128/0/368, Goodness-of-fit on F 2 1.013, final R indices [I > 2rðIÞ]
The 1H NMR-spectrum of compound 7 contains proton
signals of the as-triazine moiety and those of one mol-
ecule of lutidine.
The X-ray investigation of crystals of 7b§ showed that
this compound is a salt of the singly-charged anion of
the boron-containing sulfide of as-triazine with the cat-
ion of the protonated lutidine. It is important to note
that one negative charge of the boron moiety is com-
pensated by protonation of the N-2-atom of the triazine
R1 ¼ 0:0620, wR2 ¼ 0:1122,
R
indices (all data) R1 ¼ 0:1359,
ꢀ3
ꢀ
wR2 ¼ 0:1411, largest diff. peak and hole 0.389 and )0.446 eA
.
The structure was solved by direct methods, subsequent least-squares
refinement located the positions of the remaining atoms in the
electron density maps. All nonhydrogen atoms were refined with
individual anisotropic deflection parameters. H-atoms were calcu-
lated with common isotropic temperature factors. All calculations
§
Crystals of compound 7b for X-ray analysis were obtained by
crystallization from DMSO and are the solvate with one molecule of
DMSO.
were performed with the SHELX program package.8 The figure was
9
done with the program DIAMOND
.

3252
Y. Azev et al. / Tetrahedron Letters 45 (2004) 3249–3252
Treatment of the boron-containing derivative 7a
(0.044 g, 0.1 mmol) with methyl iodide (0.03 g, 0.2 mmol)
in 0.3 mL dimethylformamide at room temperature for
24 h gave the S-methylderivative 8, which was isolated
by dilution with water and washing of the oil with eth-
anol and water.
References and notes
1. Handschumacher, R. E.; Calabresi, P.; Welch, A. D.; Bono,
V.; Faloon, H.; Frei, E., III. Cancer Chemother. Rep. 1962,
21, 1; Chem. Abstr. 1962, 57, 14367c.
2. Chernetskii, V. P.; Alexeeva, I. V. Mol. Osn. Zhiznennykh
Protsessov, Dokl. Sess. Otd. Bio., Chim., Biofiz., Fiziol.,
Akad. Nauk Ukr. SSR, Probl. Mol. Biol., Kiev 1966, 1965,
75; Chem. Abstr. 1967, 67, 40256c.
3. Brown, D. J.; Lynn, R. K. In Chemistry and Biology of
Pteridines; Pfleiderer, W., Ed.; Walter de Gruyter: New
York, 1975; pp 575–601; Registr lekarstvennych sredstv
Rossii. Infarmchim. Moskva 1993, 738 (in Russian).
4. Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F. G.;
Barth, R. F.; Codogni, I. M.; Wilson, J. G. Chem. Rev.
1998, 98, 1515–1562.
In the electron impact (EI) mass spectra of compound 8
the following ions were registered: m=z 203
(C10H9N3S[M)B12H11], meas. 203.05225 amu, theor.
203.05171 amu, D ¼ 2:6 ppm) and ions resulting from
the cleavage of N2 and SCHÁ3 from this ion: m=z 175
(C10H9NS, meas. 175.04535 amu, theor. 175.04558 amu,
D ¼ 1:3 ppm) and m=z 156 (C9H6N3, meas.
15,605,635 amu, theor. 156.05617, D ¼ 1:2 ppm)
(Scheme 3).
5. Lalezari, I.; Shafiee, A. J. Heterocycl. Chem. 1971, 8(4),
689–691.
6. Neunhoeffer, H.; Azev, Yu. A.; Alexeev, S. G. Mendeleev
Commun. 1996, 3, 115–116.
€
7. Gabel, D.; Moller, D.; Harfst, S.; Rosler, J.; Ketz, H. Inorg.
Chem. 1993, 32, 2276–2278.
8. Sheldrick, G. M. SHELX program package; University of
Figure 2 shows a diagram of chemical shifts (CS) of the
13C-atoms in 3-thiosubstituted 1,2,4-triazines. It is seen
that a variation of the substituent at the S-atom has a
noticeable influence on CS of the C-3- and C-6-atoms
(mutual para-position), while the change of CS of C-5 is
insignificant; it must be marked that the alkylsulfonic
group essentially decreases CS of the C-3-atom, while on
the contrary the electron-donating boron-containing
substituent essentially increases it.
€
Gottingen: Germany, 1993.
9. DIAMOND – Visual Crystal Structure Information System,
Crystal impact, Postfach 1251, D-53002 Bonn, Germany.