Reaction of N-Alkyl-6(4)-bromo-2,1,3-benzoxadiazol-4(6)-amines with terminal alkynes

Article abstract of DOI:10.1134/S1070428012010228

N-Alkyl-6(4)-bromo-2,1,3-benzoxadiazol-4(6)-amines reacted with terminal alkynes to give aminosubstituted 2,1,3-benzoxadiazoles containing acetylenic fragments directly attached to the carbocycle. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012010228

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 1, pp. 137–140. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © L.M. Gornostaev, A.S. Kuznetsova, N.V. Geets, E.A. Bocharova, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 1, pp. 142–144.
Reaction of N-Alkyl-6(4)-bromo-2,1,3-benzoxadiazol-4(6)-amines
with Terminal Alkynes
L. M. Gornostaev, A. S. Kuznetsova, N. V. Geets, and E. A. Bocharova
Astaf’ev Krasnoyarsk State Pedagogical University, ul. A. Lebedevoi 89, Krasnoyarsk, 660049 Russia
e-mail: gornostaev@kspu.ru
Received April 5, 2011
Abstract—N-Alkyl-6(4)-bromo-2,1,3-benzoxadiazol-4(6)-amines reacted with terminal alkynes to give amino-
substituted 2,1,3-benzoxadiazoles containing acetylenic fragments directly attached to the carbocycle.
DOI: 10.1134/S1070428012010228
2,1,3-Benzoxadiazoles (benzofurazans) containing
a dialkylamino group in the carbocycle exhibit lumi-
nescent properties and are suitable for use as fluores-
cent labels in biochemical studies [1]. Derivatives of
benzofurazans having an acetylenic fragment with the
triple bond considerably distant from the carbocycle
can also be used as fluorescent labels [2]; acetylenic
benzofurazan derivatives in which the triple-bonded
carbon atom is directly attached to the carbocycle were
not reported previously.
The goal of the present work was to study cross-
coupling of bromobenzofurazans I, III, and V with
terminal alkynes according to Sonogashira [3].
2,1,3-Benzoxadiazoles III and V having a bromine
atom in position 4 or 6, as well as 4,6-dibromo deriv-
atives I, reacted with phenylacetylene and 2-methyl-
but-3-yn-2-ol in boiling benzene in the presence of
triphenylphosphine, palladium(II) chloride, copper(I)
iodide, and triethylamine under argon to give the
corresponding alkynylbenzofurazans II, IV, and VI,
Scheme 1.
O
N
N
R3
R3
IIa, IIb
R1
R4
N
N
N
N
PdCl2(PPh3)2, CuI
+
HC CR3
O
O
R2
R3
I, IIIa, IIIb, Va, Vb
IVa–IVc
O
N
N
R4
R3
VIa–VIc
I, R1 = R2 = Br; II, R3 = Ph (a), HOCMe2 (b); III, R2 = Br, R1 = morpholino (a), Me2N (b); V, R1 = Br, R2 = morpholino (a),
Me2N (b); IV, VI, R3 = Ph, R4 = morpholino (a), Me2N (b); R3 = HOCMe2, R4 = morpholino (c).
137

GORNOSTAEV et al.
138
Scheme 2.
N
O
O
N
N
N
KOH, toluene
Me
HO
N
N
HC
O
O
Me
IVc
VII
which were isolated by conventional methods
(Scheme 1). The reactions involved replacement of
either both bromine atoms (I → II) or one bromine
atom in position 6 (III → IV) or 4 (V → VI). Using
compound IVc as an example we showed that such
compounds may be converted into terminal ethynyl-
benzofurazans (Scheme 2).
4,6-Bis(phenylethynyl)-2,1,3-benzoxadiazole
(IIa). A solution of 0.70 g (2.5 mmol) of dibromo-
benzofurazan I, 0.82 ml (7.5 mmol) of phenylace-
tylene, and 2 ml of triethylamine in 10 ml of benzene
was heated for 20 min under reflux in an argon
atmosphere. A catalytic mixture consisting of 0.02 g
(2 mol %) of PdCl2(PPh3)2 and 0.009 g (2 mol %) of
CuI was added, and the mixture was heated for 1 h
under reflux in a stream of argon. The precipitate of
triethylamine hydrobromide was filtered off and
washed on a filter with 5–10 ml of boiling benzene.
The filtrate was concentrated to a volume of 2 ml, the
residue was ground with 7–10 ml of heptane, and the
greenish precipitate was filtered off and recrystallized
from heptane. Yield 0.67 g (84%), mp 121–123°C.
Electronic absorption spectrum, λmax, nm (logε): 256
The structure of the newly synthesized compounds
was confirmed by their 1H NMR and mass spectra and
elemental analyses. The positions of the long-wave
absorption maxima in the electronic absorption spectra
of initial compounds I, III, and V and final products
II, IV, and VI differ insignificantly. Compounds IV
and VI showed luminescence, and the position of their
emission maxima differed insignificantly from those
typical of the corresponding initial compounds.
1
(4.39), 299 (4.37), 356 (4.24). H NMR spectrum
(DMSO-d6), δ, ppm: 7.49–7.53 m (6H, Harom), 7.66–
7.69 m (4H, Harom), 7.97 d (1H, 5-H, J = 1 Hz), 8.38 d
(1H, 7-H, J = 1 Hz). Mass spectrum, m/z (Irel, %):
320 (100) [M]+, 288 (18.32), 264 (39.24), 160 (16.52),
105 (51.15), 77 (60.46). Found, %: C 81.79; H 3.75;
N 8.58. C22H12N2O. Calculated, %: C 82.50; H 3.75;
N 8.75.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DRX-500 spectrometer (500 MHz) using tetramethyl-
silane as internal reference. The progress of reactions
and the purity of products were monitored by thin-
layer chromatography on Silufol UV-254 plates. The
melting points were determined on a Boetius melting
point apparatus. The luminescence spectra were meas-
ured on a Cary Eclipse scanning spectrofluorimeter
from solutions in acetonitrile (cell path length 1 cm,
concentration 2×10–4 M). The mass spectra were
obtained on a Finnigan MAT 8200 mass spectrometer.
The electronic absorption spectra were recorded on
an Evolution 300 spectrophotometer from solutions in
THF (cell path length 1 cm, concentration 1×10–4 M).
Compounds IIb, IVa–IVc, and VIa–VIc were syn-
thesized in a similar way.
4,4′-(2,1,3-Benzoxadiazol-4,6-diyl)bis(2-methyl-
but-3-yn-2-ol) (IIb) was synthesized from 0.70 g
(2.5 mmol) of compound I and 0.73 ml (7.5 mmol) of
2-methylbut-3-yn-2-ol using 10 ml of benzene, 2 ml of
triethylamine, 0.02 g (2 mol %) of PdCl2(PPh3)2, and
0.009 g (2 mol %) of CuI. Yield 0.50 g (70%), color-
less powder, mp 108–111°C. Electronic absorption
spectrum, λmax, nm (logε): 246 (4.34), 279 (3.65), 332
4,6-Dibromo-2,1,3-benzoxadiazole (I) was syn-
thesized according to the procedure reported in [4],
and amino derivatives III and V were prepared as
described in [5].
1
(3.89). H NMR spectrum (DMSO-d6), δ, ppm: 1.49 s
(6H, CH3), 1.51 s (6H, CH3), 5.65 s (1H, OH), 5.71 s
(1H, OH), 7.53 d (1H, 5-H, J = 2 Hz), 8.10 d (1H, 7-H,
J = 2 Hz). Mass spectrum, m/z (Irel, %): 284 (8.21)
[M]+, 269 (13.51), 251 (14.31), 127 (10.51), 43 (100).
Found, %: C 66.96; H 5.58; N 9.65. C16H16N2O3. Cal-
culated, %: C 67.60; H 5.60; N 9.80.
4-Bromo-6-morpholino-2,1,3-benzoxadiazole
(Va) [5]. Electronic absorption spectrum, λmax, nm
(logε): 253 (4.09), 294 (3.79), 386 (3.58). Lumines-
cence spectrum: λmax 546 nm.
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REACTION OF N-ALKYL-6(4)-BROMO-2,1,3-BENZOXADIAZOL-4(6)-AMINES
139
0.0072 g (2 mol %) of CuI. Yield 0.48 g (83%), orange
powder, mp 144–145°C. Electronic absorption spec-
trum, λmax, nm (logε): 243 (4.22), 290 (4.15), 329 (4.08),
390 (3.69). Luminescence spectrum: λmax 545 nm.
1H NMR spectrum (DMSO-d6), δ, ppm: 3.39 t (4H,
CH2N, J = 5 Hz), 3.76 t (4H, CH2O, J = 5 Hz), 6.92 d
(1H, 5-H, J = 2 Hz), 7.49–7.52 m (3H, Harom), 7.63–
7.66 m (2H, Harom), 7.99 d (1H, 7-H, J = 2 Hz). Mass
spectrum, m/z (Irel, %): 305 (100) [M]+, 290 (15.52),
247 (12.91), 105 (10.81). Found, %: C 70.15; H 4.81;
N 13.47. C16H15N3O2. Calculated, %: C 70.82; H 4.92;
N 13.63.
4-Morpholino-6-(phenylethynyl)-2,1,3-benzoxa-
diazole (IVa) was synthesized from 0.54 g (1.9 mmol)
of compound IIIa and 0.31 ml (2.85 mmol) of phenyl-
acetylene using 10 ml of benzene, 0.5 ml of triethyl-
amine, 0.016 g (2 mol %) of PdCl2(PPh3)2, and
0.0072 g (2 mol %) of CuI. Yield 0.31 g (53%), yellow
powder, mp 117–119°C. Electronic absorption spec-
trum, λmax, nm (logε): 248 (4.31), 299 (4.25), 331
1
(3.91), 413 (3.60). H NMR spectrum (DMSO-d6), δ,
ppm: 3.60 t (4H, CH2N, J = 5 Hz), 3.83 t (4H, CH2O,
J = 5 Hz), 6.60 s (1H, 5-H), 7.47–7.49 m (3H, Harom),
7.62–7.65 m (2H, Harom), 7.64 m (1H, 7-H). Mass
spectrum, m/z (Irel, %): 305 (100) [M]+, 247 (29.33),
217 (28.53), 190 (21.42). Found, %: C 70.75; H 4.84;
N 13.63. C16H15N3O2. Calculated, %: C 70.82; H 4.92;
N 13.63.
N,N-Dimethyl-7-(phenylethynyl)-2,1,3-benzoxa-
diazol-5-amine (VIb) was synthesized from 0.50 g
(2 mmol) of compound Vb and 0.32 ml (3 mmol) of
phenylacetylene using 10 ml of benzene, 0.50 ml of
triethylamine, 0.017 g (2 mol %) of PdCl2(PPh3)2, and
0.0076 g (2 mol %) of CuI. Yield 0.30 g (57%), yellow
powder, mp 98–100°C. Electronic absorption spec-
trum, λmax, nm (logε): 246 (4.19), 305 (4.10), 429
N,N-Dimethyl-6-(phenylethynyl)-2,1,3-benzoxa-
diazol-4-amine (IVb) was synthesized from 0.24 g
(1 mmol) of compound IIIb and 0.16 ml (1.5 mmol) of
phenylacetylene using 10 ml of benzene, 0.3 ml of
triethylamine, 0.009 g (2 mol %) of PdCl2(PPh3)2, and
0.004 g (2 mol %) of CuI. Yield 0.16 g (61%), orange
powder, mp 89–91°C. Electronic absorption spectrum,
λmax, nm (logε): 250 (4.35), 302 (4.29), 437 (3.69).
1H NMR spectrum (CDCl3), δ, ppm: 3.38 s (6H, CH3),
6.16 s (1H, 5-H), 7.29 s (1H, 7-H), 7.41 m (3H, Harom),
7.59 m (2H, Harom). Mass spectrum, m/z (Irel, %): 263
(100) [M]+, 220 (24.02), 190 (12.61), 126 (12.71),
77 (13.71). Found, %: C 72.32; H 4.85; N 15.79.
C16H13N3O. Calculated, %: C 73.00; H 4.94; N 15.97.
1
(3.64). H NMR spectrum (DMSO-d6), δ, ppm: 2.50 s
(6H, CH3), 6.50 d (1H, 5-H, J = 2 Hz), 7.48–7.50 m
(3H, Harom), 7.63–7.65 m (2H, Harom), 7.80 d (1H, 7-H,
J = 2 Hz). Mass spectrum, m/z (Irel, %): 263 (67.57)
[M]+, 190 (24.42), 164 (17.92), 126 (31.83), 105
(39.54), 77 (56.26), 63 (29.53), 51 (31.83), 42 (100),
39 (38.64). Found, %: C 72.77; H 5.07; N 15.93.
C16H13N3O. Calculated, %: C 73.00; H 4.94; N 15.97.
2-Methyl-4-(6-morpholino-2,1,3-benzoxadiazol-
4-yl)but-3-yn-2-ol (VIc) was synthesized from 0.54 g
(1.9 mmol) of compound Va and 0.28 ml (2.85 mmol)
of 2-methylbut-3-yn-2-ol using 10 ml of benzene,
0.5 ml of triethylamine, 0.016 g (2 mol %) of
PdCl2(PPh3)2, and 0.0072 g (2 mol %) of CuI. Yield
0.33 g (62%), yellow powder, mp 136–138°C. Elec-
tronic absorption spectrum, λmax, nm (logε): 256 (4.01),
311 (3.88), 389 (3.55). Luminescence spectrum:
2-Methyl-4-(7-morpholino-2,1,3-benzoxadiazol-
5-yl)but-3-yn-2-ol (IVc) was synthesized from 0.28 g
(1 mmol) of compound IIIa and 0.14 ml (1.5 mmol) of
2-methylbut-3-yn-2-ol using 10 ml of benzene, 0.3 ml
of triethylamine, 0.009 g (2 mol %) of PdCl2(PPh3)2,
and 0.004 g (2 mol %) of CuI. Yield 0.20 g (70%),
yellow powder, mp 123–125°C. Electronic absorption
spectrum, λmax, nm (logε): 250 (4.24), 312 (3.44), 408
1
λmax 541 nm. H NMR spectrum (DMSO-d6), δ, ppm:
1
(3.54). H NMR spectrum (DMSO-d6), δ, ppm: 1.50 s
1.51 s (6H, CH3), 3.33 t (4H, CH2N, J = 5 Hz), 3.72 t
(4H, CH2O, J = 5 Hz), 5.66 s (1H, OH), 6.83 s (1H,
5-H), 7.73 s (1H, 7-H). Mass spectrum, m/z (Irel, %):
287 (100) [M]+, 272 (25.23), 214 (15.62), 43 (75.68).
Found, %: C 62.70; H 5.90; N 14.60. C15H17N3O3. Cal-
culated, %: C 62.70; H 5.90; N 14.60.
(6H, CH3), 3.55 t (4H, CH2N, J = 5 Hz), 3.81 t (4H,
CH2O, J = 5 Hz), 5.59 s (1H, OH), 6.40 s (1H, 5-H),
7.43 s (1H, 7-H). Mass spectrum, m/z (Irel, %): 287
(84.98) [M]+, 214 (100), 184 (36.14), 43 (74.67).
Found, %: C 62.63; H 5.74; N 14.51. C15H17N3O3.
Calculated, %: C 62.70; H 5.90; N 14.60.
6-Ethynyl-4-morpholino-2,1,3-benzoxadiazole
(VII). Powdered potassium hydroxide, 0.56 g
(10 mmol), was added to 0.41 g (1.4 mmol) of com-
pound IVc in 30 ml of toluene. The mixture was
stirred for 10 min on heating under reflux, the precip-
itate was filtered off and washed on a filter with 15–
6-Morpholino-4-(phenylethynyl)-2,1,3-benzoxa-
diazole (VIa) was synthesized from 0.54 g (1.9 mmol)
of compound Va and 0.31 ml (2.85 mmol) of phenyl-
acetylene using 10 ml of benzene, 0.5 ml of triethyl-
amine, 0.016 g (2 mol %) of PdCl2(PPh3)2, and
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GORNOSTAEV et al.
140
20 ml of boiling toluene, and the filtrate was washed
with water, dried over calcium chloride, and concen-
trated to a volume of 2 ml. The residue was ground
with 7–10 ml of diethyl ether, and the yellow precip-
itate was filtered off and recrystallized from heptane–
diethyl ether, 4:1. Yield 0.25 g (80%), mp 98–100°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 3.57 t (4H,
CH2N, J = 5 Hz), 3.81 t (4H, CH2O, J = 5 Hz), 4.55 s
(1H, ≡CH), 6.49 d (1H, 5-H, J = 2 Hz), 7.70 d (1H,
7-H, J = 2 Hz). Mass spectrum, m/z (Irel, %): 229
(80.88) [M]+, 171 (76.18), 141 (100), 114 (37.04), 87
(35.04), 64 (14.61), 63 (25.52), 62 (19.82), 52 (15.72),
42 (26.53). Found, %: C 61.57; H 4.76; N 18.05.
C12H11N3O. Calculated, %: C 62.88; H 4.80; N 18.34.
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