1246
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Zhumabaeva et al.
ButOK, which was confirmed by 1H NMR, MS, and TLC
data (see Table 3). In a reaction of 3ꢀfluoroꢀ4ꢀisopropoxyꢀ
nitrobenzene (1c) with guanidine under analogous condiꢀ
tions at room temperature, the starting compound was
recovered. The reaction at 60—62 °C for 6 h gave an oily
mixture inseparable by column chromatography. Triazines
6c and 7c (R = OPri) obtained in the ratio 2 : 1 were
identified from the 1H NMR spectra (see Table 2).
triazine as the major product, depending on the substituꢀ
ent R and the reaction conditions.
Experimental
1
H NMR spectra were recorded on Bruker WPꢀ250
(250.13 MHz) and Bruker DRXꢀ400 spectrometers
(400.13 MHz) with Me4Si as the internal standard. Mass spectra
were recorded on a Varian MATꢀ311A spectrometer (acceleratꢀ
ing voltage 3 kV, ionizing electron energy 70 eV, direct inlet
probe). The course of the reaction was monitored and the purity
of the compounds obtained was checked by TLC on Silufol
UVꢀ254 plates in CHCl3—ethanol (4 : 1) and CH2Cl2—ethanol
(8 : 1). The characteristics of the compounds obtained are sumꢀ
marized in Tables 1—3.
A reaction of 3ꢀfluoroꢀ4ꢀmorpholinoꢀ1ꢀnitrobenzene
(1e) with guanidine (60—62 °C, 6 h) yielded a 1 : 1 mixꢀ
ture of triazines 6e and 7e; after a 12ꢀh reaction under
the same conditions, 3ꢀaminoꢀ5ꢀfluoroꢀ6ꢀmorpholinoꢀ
1,2,4ꢀbenzotriazine (6e) was isolated in 51% yield by preꢀ
cipitation with water from a 2 : 1 mixture of the isomers.
Triazines 6f and 7f obtained in the ratio 3 : 1 from
3ꢀfluoroꢀ1ꢀnitroꢀ4ꢀpyrrolidinobenzene (1f) were identiꢀ
3,4ꢀDifluoroꢀ1ꢀnitrobenzene (1a). oꢀDifluorobenzene (172 g,
1.5 mol) was added dropwise to a stirred, iceꢀcooled nitrating
mixture (prepared from HNO3 (d = 1.36, 195 mL) and H2SO4
(d = 1.84, 225 mL)) so that the reaction temperature was no
higher than 60—70 °C. The reaction mixture was stirred at
60—70 °C for 6 h, cooled to 25 °C, and poured onto finely
crushed ice and water (350 mL). The organic layer was sepaꢀ
rated, the product from the mother liquor was extracted with
CHCl3 (2×50 mL), and the extract was washed with water
(100 mL), 10% Na2CO3, and again with water to pH 7. The
extracts in chloroform were combined with the organic layer,
dried over CaCl2, and concentrated in a rotary evaporator to an
oily yellow residue. The yield of compound 1a was 217 g (91%),
1
fied from the H NMR spectrum of the mixture (see
Table 2).
The structures of triazines 6c—f and 7b—f were deterꢀ
1
mined from elemental analysis, H NMR, and MS data.
Signals for the F atoms in the products were assigned
n
1
from the coupling constants JF,H. The H NMR spectra
of compounds 6c—f show a signal for the H(7) proton at δ
6.61—7.31 as a characteristic doublet of doublets and a
signal for the H(8) proton at δ 7.52—8.20 with the vicinal
3
4
constant JH(7),H(8) and the constants JH(7),F(5) and
5JH(8),F(5) at the F atom. In contrast, in the spectra of
triazines 7b—f, a signal for the H(5) proton appears as a
doublet at δ 6.30—7.05, while a signal for the H(8) proton
appears as a doublet at δ 7.42—7.85, both having only the
coupling constants 4JH(5),F(7) and 3JH(8),F(7) at the F atom
(see Tables 2 and 3).
20
nD = 1.5088.
Synthesis of substituted 3ꢀfluoroꢀ1ꢀnitrobenzenes 1b—d (genꢀ
eral procedure). Finely divided NaOH (48 mmol) was dissolved
with heating in stirred DMSO (100 mL). An appropriate alcohol
(13 mmol) in DMSO (10 mL) and then 3,4ꢀdifluoroꢀ1ꢀnitrobenꢀ
zene (1a) (13 mmol) were added with cooling and stirring. The
reaction mixture was stirred at 25 °C for 1 h, poured into ice
water (70 mL), and acidified with 10% HCl to pH 3—4. The
precipitate that formed was filtered off and recrystallized from
ethanol.
Synthesis of substituted 3ꢀfluoroꢀ1ꢀnitrobenzenes 1e,f (genꢀ
eral procedure). An appropriate amine (2.1 mmol) in DMSO
(2 mL) was added in portions to a stirred solution of 3,4ꢀdifluoroꢀ
1ꢀnitrobenzene (1a) (2 mmol) in DMSO (2 mL). The reaction
mixture was heated on a water bath with stirring for 2 h and then
cooled. Ice water (70 mL) was added and the precipitate was
filtered off and recrystallized from ethanol.
3ꢀAminoꢀ6ꢀtertꢀbutoxyꢀ5ꢀfluoroꢀ1,2,4ꢀbenzotriazine (6d).
A. Potassium tertꢀbutoxide (1.88 g, 17 mmol) was dissolved in
dry THF (15 mL) by stirring at 25 °C for 30 min. Guanidine
hydrochloride (0.38 g, 4 mmol) was added. After 10 min, a
solution of compound 1a (0.3 g, 2 mmol) in dry THF (10 mL)
was added to the resulting suspension. The reaction mixture was
stirred at 60—62 °C for 6 h, cooled, and poured into ice water
(100 mL). The yellow precipitate that formed was filtered off,
dried, and recrystallized from ethanol. The yield of triazine 6d
was 0.23 g (51%).
B. Potassium tertꢀbutoxide (1.34 g, 12 mmol) was dissolved
in dry THF (15 mL) by stirring at 25 °C for 30 min. Guanidine
hydrochloride (0.27 g, 2.8 mmol) was added. After 10 min, a
solution of 4ꢀtertꢀbutoxyꢀ3ꢀfluoroꢀ1ꢀnitrobenzene (1d) (0.3 g,
1.4 mmol) in THF (10 mL) was added to the resulting suspenꢀ
The assumption of the formation of the 1,2,4ꢀtriazine
ring through the corresponding Nꢀoxides is based on
MS data. The mass spectra of a mixture of morpholinoꢀ
1,2,4ꢀbenzotriazines 6e and 7e contain the molecular ion
peaks [M]+ of Nꢀoxides 4e and 5e with m/z 265 (Irel = 7%).
For a mixture of pyrrolidinoꢀ1,2,4ꢀbenzotriazines 6f
and 7f, the molecular ion peaks [M]+ of Nꢀoxides 4f and 5f
appear with m/z 249 (Irel = 6%). We failed to isolate the
1,2,4ꢀtriazine Nꢀoxides since the Nꢀoxide bond underꢀ
goes easy in situ reduction by an excess of ButOK.
Reactions with nitroarenes containing fragments of
primary amines (methylamine, ethylamine, cyclohexylꢀ
amine, and monoethanolamine) did not give the correꢀ
sponding 3ꢀaminoꢀ1,2,4ꢀbenzotriazines. Apparently, this
is due to the insufficient electrophilicities of fluoroꢀconꢀ
taining nitrobenzenes, which hinders the nucleophilic subꢀ
stitution of the guanidino group for hydrogen.
Thus, we carried out for the first time a tandem of
SNHꢀreactions and cyclocondensation with the participaꢀ
tion of nitro group for fluoroꢀcontaining nitroarenes as a
route to novel 5ꢀ and 7ꢀfluoroꢀcontaining 3ꢀaminobenzoꢀ
1,2,4ꢀtriazines. Competitive SNHꢀprocesses in 4ꢀRꢀ3ꢀ
fluoroꢀ1ꢀnitrobenzenes afford 5ꢀfluoroꢀ or 7ꢀfluoroꢀ1,2,4ꢀ