Semmler-Wolff aromatization of 4-hydroxyimino-4,5,6,7-tetrahydro-[2,1,3] benzoxadiazole and 4-hydroxyimino-4,5,6,7-tetrahydro[2,1,3]benzoxadiazole 1-oxide and some properties of the obtained amines

Article abstract of DOI:10.1007/s10593-010-0596-9

The Semmler-Wolff aromatization of 4-hydroxyimino-4,5,6,7-tetrahydro[2,1,3] benzoxadiazole and its 1-oxide derivative in sulfuric acid and in acetic anhydride gave 4-amino[2,1,3]benzoxadiazole and 4-acetamido[2,1,3]benzoxadiazole 1-oxide. Some reactions o

Full text of DOI:10.1007/s10593-010-0596-9

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
SEMMLER-WOLFF AROMATIZATION OF
4-HYDROXYIMINO-4,5,6,7-TETRAHYDRO-
[2,1,3]BENZOXADIAZOLE AND 4-HYDROXYIMINO-
4,5,6,7-TETRAHYDRO[2,1,3]BENZOXADIAZOLE
1-OXIDE AND SOME PROPERTIES OF THE
OBTAINED AMINES
V. A. Samsonov1**, G. E. Sal'nikov1, and L. B. Volodarskii1*
The Semmler-Wolff aromatization of 4-hydroxyimino-4,5,6,7-tetrahydro[2,1,3]benzoxadiazole and its
1-oxide derivative in sulfuric acid and in acetic anhydride gave 4-amino[2,1,3]benzoxadiazole and
4-acetamido[2,1,3]benzoxadiazole 1-oxide. Some reactions of the resultant amines were studied.
Keywords: 4-amino[2,1,3]benzoxadiazole, 4-acetamido[2,1,3]benzoxadiazole 1-oxide, oximes, Semmler-
Wolff reaction, 1H NMR spectroscopy, 13C NMR spectroscopy, 15N NMR spectroscopy.
The rearrangement of oxides of ,-unsaturated cyclic ketones and ketone oximes within condensed
systems to give aromatic amines by the action of acid reagents has long been known and has been studied in
detail by a whole series of workers [1-3]. However, there is still no completely clear understanding of all the
transformation steps leading from oximes to amines and the effect of the reagents and reaction conditions. The
Semmler-Wolff reaction and Beckmann rearrangement are carried out under the same conditions. The
conditions for these reactions are usually optimized experimentally.
We have already shown that 4-hydroxyimino-4,5,6,7-tetrahydro[2,1,3]benzodiazole (1) and 4-hydroxy-
imino-4,5,6,7-tetrahydro[2,1,3]benzodiazole 1-oxide (2), may be obtained in good yield [4]. In the present work,
we examined the feasibility of converting these compounds into amino derivatives of [2,1,3]benzoxadiazole and
[2,1,3]benzoxadiazole 1-oxide using the Semmler-Wolff aromatization.
Oxime 1 is an 8:1 mixture of derivatives with syn and anti configuration of the oxime group [4]. The
starting oxime must be in the anti configuration for the aromatization [1]. We have found that isomerization
_______
* Deceased.
** To whom correspondence should be addressed, e-mail: Samson@nioch.nsc.ru.
1N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of
Sciences, Novosibirsk 630090.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1073-1085, July, 2010. Original
article submitted March 9, 2010.
868
0009-3122/10/4607-0868©2010 Springer Science+Business Media, Inc.

occurs upon dissolving the syn isomer in sulfuric acid and a mixture of both isomers is formed in the resultant
solution. Thus, we would expect that the oxime configuration will not have great significance in the
aromatization in acids. The authors of work [3] came to the same conclusion.
Three major products were isolated following heating oxime 1 in sulfuric acid at 123-125°C.
4-Amino[2,1,3]benzoxadiazole (3) was isolated in 34% yield. Better results were obtained using PPA. The
product obtained was similar to 4-amino[2,1,3]benzoxadiazole described by Uchiyama et al. [5].
The second product isolated in 13% yield was 4-amino-5-hydroxy-2,1,3-benzoxadiazole (4). The
structure of this compound was established using analytical and spectral data and also by its conversion into
4-amino-5-methoxy[2,1,3]benzoxadiazole (5) by treatment with diazomethane and comparison of these data
with literature results [6]. 7-Ethyloxazolo[4,5-e][2,1,3]benzoxadiazole (6) was obtained smoothly in the reaction
of benzoxadiazole 4 with triethyl orthopropionate, which supports the assignment of the structure of 4.
A previously unreported product, 7a, was obtained in 8% yield in addition to the above products. The IR
spectrum of compound 7a shows NH2 group stretching bands at 3230, 3350, and 3480 cm-1, and a C=N
1
stretching band at 1630 cm-1. The H NMR spectrum in CDCl3 shows a multiplet for four protons at
2.77-3.16 ppm, a broad singlet for the NH2 group protons at 4.73 ppm, doublet for one proton at 6.42 ppm,
triplet for one proton at 7.67 ppm, and doublet for one proton at 8.25 ppm. The 13C NMR spectrum shows
signals for CH2 group carbon atoms at 16.90 and 23.30 ppm, for CH group carbon atoms at 104.04, 134.35, and
136.17 ppm, and signals at 107.48, 123.02, 137.34, 144.87, 148.29, 149.19, and 152.71 ppm for carbon atoms
not bound to hydrogen. The mass spectrum of compound 7a shows a molecular ion peak at m/z 255. Treating 7a
with acetic anhydride gives acetyl derivative 7b. In the presence of palladium on carbon black as a catalyst,
compounds 7a,b readily add a molecule of hydrogen to give compounds 8a,b. These data and the results
1
1
obtained from two-dimensional H-13C, 13C-13C, and H-15N NMR correlations for direct and long-range
coupling constants (see Experimental) permitted us to assign the structure of 7'-amino-6,7-dihydro-
4,4'-di[2,1,3]benzoxadiazole to product 7a.
2'
O
2
O
OH
3N
1' N
N3'
N1
N
NH2
NH2
HO
+
7'a
3a
4
3'a
4'
N
N
N
N
N
7
O
O
O
RHN
+
7'
N
5
6
6'
5'
1
3
4
7a,b
MeCH2C(OEt)3
CH2N2
H2
Pd/C
O
O
NH2
N
N
N
N
N
MeO
O
N
O
N
N
N
RNH
O
8a,b
5
6
7,8 a R= H, b R = Ac
The formation of compounds 3 and 4 can be explained on the basis of the reported schemes for the
Semmler-Wolff reaction. The oxime initially undergoes isomerization leading to an azirine, which, upon
protonation gives carbocation A. Then, this intermediate is stabilized by the loss of a proton to give amine 3 or
adds water to give amino alcohol B, which is oxidized to give aminophenol 4. We should note that the formation
of aminophenols has not been noted previously in studies of the Semmler-Wolff reaction.
869

TABLE 1. Characteristics of Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield, %
C
H
N
C6H5N3O2
47.78
47.68
3.25
3.34
27.90
27.81
147-149
13
4
С9H7N3O2
С12H9N5O2
C14H11N5O3
C12H11N5O2
C14H13N5O3
C12H7N5O2
C12H9N3O
C13H11N3O
C13H11N3O
C13H11N3O
C13H11N3O2
C13H11N3O2
C8H7N3O3
C12H13N3O3
C11H13N3O3
C8H7N3O3
C8H7N3O2
57.20
57.14
56.48
56.47
56.47
56.56
56.12
56.02
56.26
56.18
57.12
56.91
68.12
68.23
69.11
69.32
69.36
69.32
69.38
69.32
64.70
64.72
64.65
64.72
50.00
49.74
58.11
58.29
56.22
56.16
49.83
49.74
3.55
3.70
3.48
3.55
3.40
3.73
4.28
4.31
4.32
4.38
2.78
2.79
4.15
4.30
4.88
4.92
4.90
4.92
4.93
4.92
4.60
4.60
4.48
4.60
3.80
3.65
5.24
5.30
5.50
5.57
3.60
3.65
22.08
22.22
27.60
27.44
23.50
23.56
27.08
27.23
23.31
23.40
27.71
27.66
19.72
19.90
18.59
18.66
18.52
18.66
18.45
18.66
17.34
17.42
17.48
17.42
21.68
21.76
17.12
17.00
17.79
17.86
21.69
21.76
145-147
212-214
230-232
173-175
157-159
207-208
78-80
71
6
8*2
83
7a
7b
8a
80
83
8b
11
6.7
68
12a
12b
12c
12d
12e
12f
14
82-84
45.6
51
93-95
75-77
49
93-94
64
102-103
131-133
240-242
165-168 (dec.)
185-187 (dec.)
98-100
72
8.8
61
16
65.7
2.0*3
8.8
17
18
54.32
54.23
3.65
3.98
23.68
23.72
19
_______
* Recrystallization solvents: compounds 7a,b, 8a,b, 11, 16-18 – ethanol,
compounds 12a,c-f – hexane, compound 12b – pentane, compound 4 –
ethyl acetate, compounds – 6, 14, 19 1:3 ethyl acetate–hexane.
*2 The yield of compound 7a obtained from amine 3 and ketone 9 was 29.6%.
*3 The yield of compound 18 upon the acylation of compound 4 using
acetic anhydride was 74%.
NH
H+
H+
N
N
N
+
N
N
1
O
–H2O
O
A
+
H
–
H+
+ H2O
–
NH
NH
NH2
HO
HO
N
N
N
N
N
[O]
O
O
O
4
3
N
B
870

TABLE 2. Spectral Characteristics of Products
Com-
pound
UV spectrum,
max (log )
IR spectrum,
1H NMR spectrum, δ, ppm (J, Hz)*
5.28 (2Н, br. s, NH2);
ν, cm-1
λ
4
1636 (C=N),
426 (4.14)
3263, 3325, 3370,
3415 (NH2, ОН)
7.10, 7.28 (each 1Н, both d, J = 10.0, Н arom);
9.56 (1Н, br. s, ОН)
6
1548 (C=N),
1573, 1639
235 (4.09), 1.46 (3H, t, J = 7.8, СН3); 3.03 (2Н, q, J = 7.5, СН2);
329 (3.54) 7.67, 7.72 (each 1Н, both d, J = 9.6, Н arom)
278 (3.96), 2.77-2.89 (2H, m, СН2); 3.05-3.16 (2H, m, СН2);
7a*2
1634 (C=N),
3227, 3354,
3480 (NH2)
445 (3.60)
4.73 (2Н, br. s, NH2);
6.42, 8.25 (each 1Н, both d, J = 7.2, Н arom);
7.67 (1Н, t, J = 4.8, СН)
7b
8a
1703 (С=О),
3312 (NH)
266 (4.11), 2.18 (3Н, s, СН3); 2.63-2.87 (2H, m, СН2);
390 (3.85)
2.98-3.13 (2H, m, СН2); 7.48 (1Н, t, J = 3.5, СН);
7.92-8.05 (2Н, m, 2СН arom); 10.61 (1Н, s, NH)
1641 (C=N),
3230, 3342,
3430 (NH2)
415 (3.48)
1.67-2.21 (4H, m, 2СН2); 2.75-3.10 (2H, m, СН2);
4.46-4.55 (1H, m, СН);
6.26, 7.14 (each 1Н, both d, J = 7.5, Н arom);
6.49 (2Н, br. s, NH2)
8b
11
1691 (С=О),
3321 (NH)
235 (4.11), 2.20 (3Н, s, СН3); 1.78-2.31 (4H, m, 2СН2);
359 (3.77)
2.80-3.40 (2H, m, СН2); 4.67-4.75 (1H, m, СН);
7.43, 8.06 (each 1Н, both d, J = 7.7, Н arom);
10.69 (1Н, s, NH)
1622 (C=N),
3303 (NH)
418 (3.41)
7.05 (2H, d, J = 6.9, Н arom);
7.48-7.56 (2Н, m, Н arom);
7.61 (2H, d, J = 9.0, Н arom); 9.87 (1Н, s, NH)
12a
12b
1595 (C=N),
3307 (NH)
268 (4.04), 6.80 (1H, br. s, NH); 6.83 (1H, d, J = 7.4, Н arom);
423 (3.79)
7.08-7.43 (7Н, m, Н arom)
1616 (C=N),
3391 (NH)
412 (3.65)
4.53 (2Н, d, J = 5.6, СН2); 5.44 (1Н, br. s, NH);
6.11, 7.21 (each 1Н, both d, J = 7.2, Н arom);
7.05 (1Н, d, J = 9.1, Н arom); 7.24-7.45 (5Н, m, Н arom)
12c
1610 (C=N),
3403 (NH)
428 (4.34), 2.35 (3Н, s, СН3); 6.71 (1Н, d, J = 7.1, Н arom);
268 (4.62), 6.75 (1Н, br. s, NH); 7.11 (1Н, d, J = 8.7, Н arom);
233 (4.78)
7.18 (4Н, s, Н arom); 7.19-7.24 (1Н, m, Н arom)
12d
12e
1584 (C=N),
3403 (NH)
422 (4.61)
2.30 (3Н, s, СН3); 6.35 (1Н, d, J = 7.2, Н arom);
6.51 (1Н, br. s, NH); 7.08-7.42 (6Н, m, Н arom)
1594 (C=N),
3357 (NH)
265 (3.80), 3.84 (3Н, s, ОСН3); 6.56 (1Н, d, J = 7.4, Н arom);
430 (3.86)
6.72 (1Н, br. s, NH); 6.96, 7.26 (each 2Н, d, J = 8.8, Н arom);
7.08-7.22 (2Н, m, Н arom)
12f
13
1623 (C=N),
3409 (NH)
263 (4.73), 3.91 (3Н, s, ОСН3); 6.95-7.30 (7Н, m, NH, Н arom);
425 (4.96)
7.51 (1Н, dd, J1 = 7.6, J2 = 1.8, Н arom)
1621 (С=N),
1685 (С=О),
3348 (NH)
382 (3.32)
2.19 (3Н, s, СН3); 7.16 (1Н, d, J = 8.5, Н arom);
7.25-7.33 (1Н, m, Н arom);
8.1 (1Н, d, J = 7.1, H arom); 10.56 (1H, s, NН)
14
16
1625, 1647
(С=N)
280 (3.88)
2.51 (3H, s, CH3); 3.00-3.09 (2H, m, СН2);
3.11-3.19 (2H, m, СН2)
1678 (С=О),
262 (4.64), 2.19 (3Н, s, СН3); 2.56 (3Н, s, СН3);
2.59 (3Н, s, СН3); 7.73-7.83 (1Н, m, Н arom);
8.12 (1Н, d, J = 8.4, Н arom);
3112 (NH)
390 (4.54)
8.89 (1Н, d, J = 7.9, Н arom); 13.79 (1Н, s, NH)
17
18
19
1693 (С=О),
3062 (NH)
251 (4.92), 1.68 (6Н, s, 2СН3); 2.18 (3Н, s, СН3);
520 (4.46)
6.77-6.84 (2Н, m, Н arom);
7.80-7.85 (1Н, m, Н arom); 10.40 (1Н, s, NH)
1643 (С=О),
3320 (NH)
355 (3.14)
2.09 (3Н, s, СН3); 5.68 (1H, br. s, ОН);
7.54, 7.81 (each 1Н, both d, J = 9.3, Н arom);
9.76 (1Н, br. s, NH)
1656 (С=N)
263 (3.83)
2.49 (3Н, s, СН3); 3.09-3.17 (2H, m, СН2);
3.24-3.32 (2H, m, СН2)
_______
1
*The H NMR spectra were taken in DMSO-d6 (4, 7b, 8b, 11, 13, 14, 16,
and 18) and in CDCl3 (6, 7a, 8a, 12a-f, 17, and 19).
1
*2 For the complete assignment of the signals in the H NMR spectrum of
amine 7a, see Experimental.
871

The formation of product 7a does not follow from the generally accepted mechanisms of the Semmler-Wolff
reaction. Amine 7a may be formed in the reaction of amine 3 with ketone 9, which, in turn, can be formed from
oxime 1 under acid conditions. Indeed, the reaction of amine 3 with previously synthesized 4-oxo-4,5,6,7-
tetrahydro-[2,1,3]benzoxadiazole (9) [4] under the conditions of the aromatization reaction gave product 7a in about
30% yield.
O
N
3
7a
+
O
N
9
The alkylation of amine 3 by ketone 9 apparently occurs in this case. We might have assumed that
amine 7a would also form during work-up of the reaction mixture. However, 4-hydroxy[2,1,3]benzoxadiazole
(10), whose structure was established using spectral and analytical data and by comparison with the published
data for this compound [7], was obtained upon heating amine 3 with aqueous sulfuric acid. Di[2,1,3]benz-
oxadiazol-4-yl)amine (11) was also isolated from the reaction mixture. The structure of this product is in accord
with its spectral and analytical data.
The formation of compounds 10 and 11 is attributed to the ease of the replacement of the amino group in
amine 3. Indeed, the action of anilines or benzylamine on amine 3 gives 4-arylamino[2,1,3]benzoxadiazoles 12a
and 12c-f and 4-benzylamino[2,1,3]benzoxadiazole (12b).
H
R
OH
O
O
N
N
N
H
N
N
N
N
N
N
N
+
3
O
O
12a–f
10
11
12a R = Ph, b R = CH2Ph, c R = p-MeС6Н4, d R = o-MeС6Н4, e R = p-MeOС6Н4,
f R = o-MeOС6Н4
We used the Semmler-Wolff aromatization in an attempt to obtain 4-amino[2,1,3]benzoxadiazole
1-oxide from oxime 2. Under the conditions for the preparation of amine 3, oxime 2 decomposes. However,
changing the reaction conditions and using acetic anhydride in the previously presence of sulfuric acid gave
4-acetylamido[2,1,3]benzoxadiazole 1-oxide (13), described previously [8], in about 30% yield. The reaction
mixture also yielded 7-methyl-4,5-dihydrooxazolo[4,5-e][2,1,3]benzoxadiazole 3-oxide (14) and 4-acetamido-
[2,1,3]benzoxa-diazole (15). The structures of these products are in accord with their spectral and analytical data
(see Experimental, Tables 1-4).
Me
NHCOMe
N
NOH
NHCOMe
N
N
O
N
N
Ac2O
N
N
O
+
O
+
–
+
O
O
+
H2SO4
N
+
N
_
_
O
O
O
13
15
2
14
872

TABLE 3. 13C NMR Spectra of Compounds Synthesized
Com-
pound
13С NMR spectra, δ, ppm*
С=N
C–H
Other signals
3
144.69, 149.85
103.51, 106.23,
134.92
133.41
4
5
6
137.99, 145.25
140.26, 144.56
101.94, 129.56
103.83, 124.16
113.09, 118.88
117.93, 146.96 (С-5)
57.27 (ОСН3), 120.63, 146.93 (С-5)
10.80 (CH3), 22.04 (CH2), 126.95
142.97, 148.97,
151.06, 169.25
7a*2
7b
144.87, 148.29,
149.19, 152.71
104.04, 134.35,
136.17
16.90 (СН2), 23.30, 107.48, 123.02,
137.34
144.79, 147.45,
148.55, 152.34
116.29, 132.20, 140.46
35.32, 104.10, 133.32
131.97, 117.56, 35.44
16.57, 23.52 (CH2), 23.83 (CH3),
116.36, 122.18, 126.41, 169.87 (C=O)
8a
145.04, 148.46,
152.49, 154.54
19.48, 20.58, 29.29 (СН2),
113.53, 136.24
8b
145.25, 148.06,
152.46, 153.91
19.42, 20.52, 23.80 (CH3),
29.10 (CH2), 123.41, 125.80,
169.81 (C=O)
10
145.18, 146.22
145.25, 150.04
145.25, 149.91
105.35, 109.41, 134.39
108.03, 115.41, 130.93
150.58
11
130.40
12а
104.29, 104.46, 121.05,
123.90, 129.48, 133.49
132.56, 139.44
12b
12c
144.47, 149.54
146.06, 149.90
101.32, 101.89, 127.01,
127.35, 128.45, 133.60
47.26 (CH2), 135.63, 136.91
103.62, 103.82, 121.60,
129.98, 133.85
20.73 (CH3), 133.11, 133.59, 136.65
17.35 (CH3), 132.04, 137.08
12d*3 144.76, 149.69
103.46, 103.65, 123.58,
125.20, 126.62, 130.97,
133.31
102.68, 103.05, 114.40,
124.15, 133.42
12e
12f
144.72, 149.66
145.39, 149.69
55.10 (OCH3),
131.70, 133.85, 156.46 (C–OCH3)
104.23, 104.32, 110.58,
118.44, 120.28, 122.87,
133.28
55.29 (OCH3),
128.88, 131.76, 149.46 (C–OCH3),
13
14
15
16
114.62, 148.28
106.26, 118.43, 131.10
23.87 (OCH3),
127.79, 169.96 (C=O)
111.11, 149.11,
155.46, 163.13
13.63 (CH3), 16.92,
18.35 (CH2), 123.94
144.53, 149.12
109.35, 116.59, 133.07
112.50, 118.30, 131.34
23.97 (СН3), 126.57 (С-4),
169.95 (С=О)
13.91, 14.23, 25.80 (CH3);
125.51, 133.94, 136.60, 141.39,
142.69, 168.32 (C=O)
17
108.43, 115.02, 132.03
114.82, 130.96
23.58, 24.50 (CH3),
96.51 (C2), 129.97, 130.64, 135.96,
168.67 (C=O)
18
19
146.81, 148.50
22.68 (CH3), 104.58, 153.50 (C–O),
169.37 (C=O),
150.50, 152.90,
162.90
13.59 (CH3), 17.64,
19.15 (CH2), 124.69, 145.32
_______
*The 13C NMR spectra were taken in DMSO-d6 (4, 7b, 8b, 9, 10, 13, 14,
16, and 18) and in CDCl3 (3, 5, 6, 7a, 8a, 11a-f, 15, 17, and 19).
*2 The complete assignment of the signals in the 13C NMR spectrum of
compound 7a is given in the Experimental.
*3 Overlap of signals in the 13C NMR spectrum.
873

Oxide 13 undergoes the usual reactions of [2,1,3]benzoxadiazole 1-oxides [9]. This oxide reacts with
2-butanone in the presence of ammonia to give quinoxaline di-N-oxide 16 and with 2-nitropropane to give
2H-benzimidazole 1,3-dioxide 17. The structures of these products are in accord with their analytical and
spectral data.
O
O
–
Me
–
NO2
O
N
NH
Me
NH
O
+
+
Me
Me
Me
N
MeCH2COMe
NH3
Me
NEt3
Me
Me
13
N
N
O
+
–
+
–
O
16
17
Under the conditions for the aromatization of oxide 2, oxime 1 also gives a mixture of products.
Me
NHCOMe
N
HO
N
N
O
Ac2O
N
N
1
15
+
+
O
O
H2SO4
18
19
The reaction mixture yielded 4-acetamido[2,1,3]benzoxadiazole (15), 4-acetamido-5-hydroxy[2,1,3]-
benzoxadiazole (18), and 7-methyl-4,5-dihydrooxazolo[4,5-e][2,1,3]benzoxadiazole (19). The structures of
these products are in accord with their analytical and spectral data.
Thus, we have shown that the Semmler-Wolff aromatization can be used to effect the facile conversion
of oximes of tetrahydro[2,1,3]benzoxadiazole 1 and tetrahydro[2,1,3]benzoxadiazole 1-oxide 2 to amine
derivatives of [2,1,3]benzoxadiazole and [2,1,3]benzoxadiazole 1-oxide.
TABLE 4. Mass Spectra of Compounds Synthesized
Compounds
m/z (Irel, %)
4
5
151 [М]+ (100), 134 (38), 107 (16), 80 (69)
165 [М]+ (82), 150 (100), 120 (18), 96 (14), 92 (26), 80 (45).
Found: m/z 165.0532. C7H7N3O2. Calculated: M = 165.0533
6
189 [М]+ (54), 104 (68), 76 (28)
7a
255 [М]+ (100), 225 (29), 215 (79), 208 (25), 199 (36), 185 (53), 169 (55)
297 [М]+ (16), 255 (100), 225 (16), 215 (38), 199 (15), 185 (17), 169 (17)
257 [М]+ (100), 240 (16), 189 (33), 173 (19), 169 (17), 143 (15), 169 (55)
299 [М]+ (10), 257 (100), 189 (10)
7b
8a
8b
11
253 [М]+ (100), 223 (73), 206 (21), 193 (44)
12a
12b
12c
12d
12e
12f
13
211 [М]+ (100), 194 (29), 181 (85), 154 (18)
225 [М]+ (37)
225 [М]+ (100), 210 (22), 208 (27), 195 (44), 193 (20), 180 (87)
225 [М]+ (91), 210 (32), 208 (14), 195 (47), 193 (24), 180 (100)
241 [М]+ (100), 226 (16), 211 (40), 196 (52), 180 (28). 168 (17)
241 [М]+ (100), 226 (14), 210 (18), 196 (37), 193 (22), 180 (34)
193 [М]+ (37), 151 (100), 133 (19), 91 (40)
14
193[М]+ (60)
16
247 [М]+ (100), 231 (16), 205 (30), 188 (51), 171 (90)
235 [М]+ (100), 193 (44), 176 (18), 162 (12), 146 (11), 135 (49), 117 (14)
193 [М]+ (25), 151 (100), 134 (15)
17
18
19
177 [М]+ (36), 137 (100)
874

EXPERIMENTAL
The IR spectra were taken on a Bruker Vector spectrometer for KBr pellets (c = 0.25%). The strongest
1
absorption bands in the spectra are given. The H and 13C NMR spectra were taken on a Bruker AM 400
spectrometer at 400 and 100 MHz, respectively, and on a Bruker Avance DRX-500 spectrometer at 500 and
125 MHz, respectively, in CDCl3 and DMSO-d6 for 10% solutions at 25°C. The chemical shifts were measured
relative to the residual solvent signals: CHCl3 (7.24 and 76.90 ppm, respectively), and  2.50 and 39.50 ppm,
respectively, for DMSO-d6. The multiplicity of the signals in the 13C NMR spectra was determined in JMOD
and using the 13C-H correlations.
1
The H, 13C, and 15N NMR spectra for compound 7a were recorded on a Bruker Avance-III 600
spectrometer at 600, 150, and 61 MHz, respectively in DMSO-d6. The chemical shifts of the hydrogen and
1
carbon atoms in the H and 13C NMR spectra were determined relative to the residual signals of the DMSO-d6
solvent ( 2.50 and 39.50 ppm, respectively) and the chemical shifts of the nitrogen atoms in the 15N NMR
spectra were determined relative to ammonia as an external standard. The establishment of the structure of
1
compound 7a and the assignment of the signals in the H and 13C NMR spectra were carried out using
1
two-dimensional H-13C inverse correlations for the direct (HSQC [10-12]) and long-range coupling constants
13
1
1
(HMBC [13]) and C-13C correlations with detection relative to H (1,1-ADEQUATE [14]). The JCH coupling
constants were determined from the 13C NMR spectrum without proton decoupling. The assignment of the
signals in the N NMR spectrum was carried out relative to the two-dimensional H-15N inverse correlation for
long-range coupling constants (HMBC). The chemical shifts of the signals in the 15N NMR spectrum and the
1JNH coupling constants were obtained from the two-dimensional HMBC spectrum. (The spectral data for the
two-dimensional NMR spectra for compound 7a may be obtained from the authors upon request).
The mass spectra were taken on a Thermo-Scientific DFS mass spectrometer with direct sample inlet.
The ionizing electron energy was 70 eV and the ion source temperature was 180°C. The reaction course and
purity of the compounds were monitored by thin-layer chromatography on Sorbfil UV-254 plates. The
chromatograms were developed by UV light and iodine vapor. Products 1, 2, and 9 were prepared according to
our reported procedures [4]. The melting points were determined on a Koefler microheating block. The
elemental analysis was carried out in the Microanalysis Laboratory at the Novosibirsk Institute of Organic
Chemistry, Siberian Branch of the Russian Academy of Sciences.
15
1
We used a sample of PPA prepared by the evaporation of orthophosphoric acid in vacuum at 15 mm Hg
at 150°C and also by dissolving P2O5 in heated orthophosphoric acid until the total P2O5 content in the mixture
was 80%. In the syntheses, we used chemically-pure grade sulfuric acid State Standard 4204-66.
The identification of previously described compounds was carried out by comparison of their IR spectra
and melting points.
Isomerization of Oximes. syn-Isomer of compound 1 (0.5 g, 3 mmol) was added to concentrated
sulfuric acid (5 ml) and the mixture was stirred for 2 h at 60°C. The reaction mixture was poured into 20 g
crushed ice and extracted with three 20-ml portions of ethyl acetate. The combined extract was washed with
two 20-ml portions of saturated aqueous NaCl and dried over MgSO4. The solvent was evaporated and the
residue was subjected to chromatography on silica gel using 1:1 ethyl acetate–hexane as the eluent to give 0.28 g
starting oxime and 0.15 g anti-isomer.
4-Amino[2,1,3]benzoxadiazole (3). A. A solution of oxime 1 (70.0 g, 460 mmol) in concentrated
sulfuric acid (150 ml) was added dropwise with stirring to 80 ml concentrated sulfuric acid heated to 125°C over
about 90 min maintaining the temperature at 123-128°C. The reaction mixture was maintained for 30 min at
125°C, cooled, and poured over 500 g crushed ice. The mixture was brought to pH 10 by adding 25%
ammonium hydroxide. The precipitate was filtered off, washed with water, dried, and placed in a steam
distillation apparatus, and distilled. Pure 4-amino[2,1,3]benzoxadiazole was steam distilled. The yield of amine
3 was 21.0 g (34%); mp 110-111°C (benzene) (mp 110-111°C [7]). The residue after the steam distillation
875

was subjected to chromatography on silica gel using 5:1 CCl4–CHCl3 as the eluent to give 9.3 g compound 7a.
1H NMR spectrum, , ppm (J, Hz): 8.01 ((1H, d, J6,5 = 7.8, H-5'); 7.40 (1H, m, H-5); 6.82 (2H, s, NH2); 6.35
(1H, d, J5,6 = 7.8, H-6'); 3.06 (2H, m, H-7); 2.76 (2H, m, H-6). 13C NMR spectrum, , ppm (J, Hz): 152.59
(C-7a), 149.10 (C-3a), 148.23 (C-3'a), 144.82 (C-7'a), 137.33 (C-7'), 136.03 (1JCH = 162.0, C-5), 134.24
(1JCH = 159.0, C-5'), 122.98 (C-4), 107.53 (C-4'), 104.04 (1JCH = 162.0, C-6'), 23.26 (1JCH = 131.0, C-6), 16.85
(1JCH = 134.0, C-7). 15N NMR spectrum, , ppm (J, Hz): 410.6 (N-1'), 409.3 (N-3'), 395.7 (N-3), 393.8 (N-1).
70.1 (1JNH = 88.8, NH2).
The aqueous solution obtained after filtration of the precipitate was brought to pH 3 and extracted with
three 100-ml portions of ethyl acetate. The extract was washed with three 50-ml portions of saturated aqueous
NaCl and dried over magnesium sulfate, filtered, and evaporated. The residue was triturated with hexane to give
9.0 g amine 4.
B. Oxime 1 (1.0 g, 6.5 mmol) was added in small portions with stirring to 5 ml PPA heated to 120°C at a
rate such that the temperature of the reaction mixture remains in the range 120-130°C. After addition of the
entire amount of oxime 1, the reaction mixture was maintained at 125°C for 1 h, cooled, and poured onto 50 g
ice. After decomposition, the reaction mixture was neutralized by adding 25% ammonium hydroxide and then
extracted with four 20-ml portions of ethyl acetate. The combined extract was washed with saturated aqueous
NaCl and dried over magnesium sulfate. The solvent was distilled off and the residue was steam distilled to give
0.41 g (50%) amine 3, mp 110-111°C. The residue after steam distillation was subjected to chromatography on
silica gel using 5:1 CCl4–CHCl3 as the eluent to give 0.1 g (5.9%) compound 7a.
4-Amino-5-methoxy[2,1,3]benzoxadiazole (5). A solution of diazomethane obtained from nitroso-
methylurea (1.0 g) in ether was added with stirring to amine 4 (0.5 g, 3.3 mmol) in 100 ml ethyl ether. The
mixture was stirred for 4 h and the solvent was distilled off. The residue was subjected to chromatography on
silica gel with 1:1 ethyl acetate–hexane as the eluent to give 0.34 g (62.3%) amine 5; mp 85-88°C (ethanol)
(mp 88°C [6]).
7-Ethyloxazolo[4,5-e][2,1,3]benzoxadiazole (6). Triethyl orthopropionate (8.0 g, 45 mmol) was added
to amine 4 (1.0 g, 6.6 mmol). The mixture was boiled for 1h. The solvent was evaporated off. The residue was
treated with 10 ml 5% aqueous NaOH and extracted with three 20-ml chloroform portions. The extract obtained
was washed with three 20-ml water portions and dried over magnesium sulfate. The solvent was distilled off and
the residue was subjected to chromatography on alumina using 1:3 ethyl acetate–hexane as the eluent to give
0.84 g benzoxadiazole 6.
7'-Amino-6,7-dihydro-4,4'-di[2,1,3]benzoxadiazole (7a). Ketone 9 (1.1 g, 7.9 mmol) was added to a
solution of amine 3 (1.0 g, 7.4 mmol) in concentrated sulfuric acid (10 ml) and the mixture was heated for 2 h
at 125-128°C. The reaction mixture was cooled and poured over 100 g crushed ice. The mixture was brought to
pH 8 by adding ammonium hydroxide and the product was extracted with three 50-ml portions of ethyl acetate.
The combined extract was washed with saturated aqueous NaCl and dried over magnesium chloride. The solvent
was evaporated off and the residue was subjected to chromatography on silica gel using CCl4 as the eluent to
give 0.39 g (39%) starting amine 3 and 0.34 g (29.6% relative to reacted amine) amine 7a.
7'-Acetamido-6,7-dihydro-4,4'-di[2,1,3]benzoxadiazole (7b). Amine 7a (3.8 g, 15 mmol) was added to
acetic anhydride (20 ml) and stirred for 1 h at room temperature. The acetamide precipitate formed was filtered
off and dried to give 3.90 g compound 7b.
7'-Amino-4,5,6,7-tetrahydro-4,4'-di[2,1,3]benzoxadiazole (8a). Palladium (4%) on activated charcoal
(0.3 g) was added to a solution of amine 7a (1.0 g, 3.9 mmol) and the mixture was hydrogenated in a
hydrogenation apparatus at atmospheric pressure and room temperature. The catalyst was filtered off and the
solvent was evaporated off. The residue was suspended in hexane and filtered to give 0.8 g amine 8a.
7'-Acetamido-4,5,6,7-tetrahydro-4,4'-di[2,1,3]benzoxadiazole (8b) was obtained from amine 7b
analogously to the preparation of acetamide 8a.
876

4-Hydroxy[2,1,3]benzoxadiazole (10). Amine 3 (20 g, 148 mmol) was added to 200 ml 10% aqueous
sulfuric acid and the mixture was heated on a water bath for 4 h. Then, the mixture was cooled and extracted
with four 100-ml portions of ethyl acetate. The combined extract was extracted with four 60-ml portions of
20% aqueous potassium carbonate. The aqueous extract was carefully brought to pH 3 by adding 30% aqueous
sulfuric acid and extracted with four 100-ml portions of ethyl acetate. The combined extract was washed once
with saturated aqueous NaCl (200 ml) and dried over magnesium sulfate. The solvent was distilled off and the
residue was subjected to chromatography on silica gel using 1:2 ether–hexane as the eluent to give about
12.0 g (60%) benzoxadiazole 10; mp 148-150°C (mp 148-150°C [7]). The ethyl acetate extract obtained after
extraction with 20% aqueous potassium carbonate was dried over magnesium sulfate, filtered, and evaporated.
The residue was subjected to chromatography on silica gel using 1:3 ethyl acetate–hexane to give 2.5 g (6.7%)
di[2,1,3]benzoxadiazol-4-yl)amine (11).
4-Phenylamino[2,1,3]benzoxadiazole (12a). Amine 3 (1.0 g, 7.4 mmol) and p-toluenesulfonic acid
(0.05 g) were added to 10 ml aniline and the mixture was heated at reflux for 30 min. Excess aniline was
distilled off in vacuum and the residue was subjected to chromatography on alumina with pentane as the eluent
to give 1.06 g compound 12a.
4-(4-Methylphenylamino)[1,2,3]benzoxadiazole (12c), 4-(2-Methylphenylamino)-2,1,3-benzoxadiazole
(12d), 4-(4-Methoxyphenylamino)[2,1,3]benzoxadiazole (12e), and 4-(2-Methoxyphenylamino)[2,1,3]benz-
oxadiazole (12f) were obtained analogously to the preparation of compound 12a.
4-Benzylamino[2,1,3]benzoxadiazole (12b). Amine 3 (0.5 g, 3.7 mmol) and p-toluenesulfonic acid
(0.05 g) were added to benzylamine (5 ml) and the mixture was maintained for 6 h at 120°C. After cooling,
20 ml 1% hydrochloric acid was added and the product was extracted with three 20-ml portions of ethyl acetate.
The combined extract was washed with two 10-ml portions of saturated aqueous NaCl, and dried over
magnesium sulfate. The drying agent was filtered off and the solvent was evaporated off in vacuum. The residue
was subjected to chromatography on silica gel with toluene as the eluent to give 0.38 g amine 12b.
4-Acetamido[2,1,3]benzoxadiazole 1-Oxide (13), 7-Methyl-4,5-dihydrooxazolo[4,5-e][2,1,3]benz-
oxadiazole 3-oxide (14), and 4-acetamido-2,1,3-benzoxadiazole (15). Acetic anhydride (60 ml) was added to
oxime 2 (12.0 g, 71 mmol). The reaction mixture was heated to 70°C and stirred until oxime 2 was completely
dissolved. Then, concentrated sulfuric acid (1.5 ml) was added and the mixture was carefully heated to 100°C
until the onset of an exothermal reaction. Heating was discontinued. The reaction mixture evolved heat
spontaneously and reached reflux. After completion of the reaction, the mixture was cooled, poured into
ice water (300 ml) and left stand for 4 h. The mixture was cautiously neutralized by adding dry sodium
carbonate and extracted with four 75-ml portions of ethyl acetate. The combined extract was washed with
saturated aqueous NaCl and dried over magnesium sulfate. The solvent was distilled off and the residue was
subjected to chromatography on silica gel using 1:2 ethyl acetate–hexane as the eluent with the consecutive
isolation of 3.95 g (28.8%) compound 13; mp 168-170°C (3:1 ethyl acetate–hexane) (mp 162-163°C [8]), 1.2 g
(8.8%) 14, and 0.72 g (5.7%) compound 15; mp 163-165°C (3:1 ethyl acetate–hexane) (mp 162-163°C [7]).
4-Acetamido-2,1,3-benzoxadiazole (15), 4-Acetamido-5-hydroxy[2,1,3]benzoxadiazole (18), and
7-Methyl-4,5-dihydrooxazolo[4,5-e][2,1,3]benzoxadiazole (19) were obtained analogously to compounds 13-15
from oxime 1 (10 g, 65 mmol). Chromatography on silica gel with 3:1 hexane–ethyl acetate led to the consecutive
isolation of 4.40 g (38%) compound 15, 0.25 g (2.0%) compound 18, and 1.02 g (8.8%) compound 19.
Benzoxadiazole 18 was also obtained from 4 analogously to the preparation of 7b.
5-Acetamido-2,3-dimethylquinoxaline 1,4-Dioxide (16). A weak stream of ammonia was passed
during 4 h through a solution of amine 13 (1.0 g, 5.2 mmol) in a mixture of 2-butanone (15 ml) and methanol
(15 ml) at 50°C. The reaction mixture was left for 8 h at room temperature. The precipitate was filtered off to
give 0. 78 g dioxide 16.
4-Acetamido-2,3-dimethyl-2H-benzimidazole 1,3-Dioxide (17). 2-Nitropropane (0.6 g, 6.7 mmol) and
triethylamine (0.6 g, 6 mmol) were added to a solution of amine 13 (0.4 g, 2.07 mmol) in chloroform (10 ml).
877

The reaction mixture was left stand at room temperature for 240 h. The solvent was distilled off and the residue was
subjected to chromatography on alumina with ether as the eluent to give 0.32 g dark-red crystalline dioxide 17.
REFERENCES
1.
R. T. Conley and S. Ghosh, in: B. S. Thyagarajan (editor), Mechanisms of Molecular Migration, vol. 4,
Wiley-Interscience, New York (1971), p. 251.
2.
3.
4.
M. I. El-Sheikh and J. M. Cook, J. Org. Chem., 45, 2585 (1980).
Y. Tamura, Y. Yoshimoto, K. Sakai, and Y. Kita, Synthesis, 483 (1980).
V. A. Samsonov and L. B. Volodarskii, Khim. Geterotsikl. Soedin., 1408 (1991). [Chem. Heterocycl.
Comp., 27, 1135 (1991)].
5.
S. Uchiyama, T. Santa, N. Okiyama, K. Azuma, and K. Imai, J. Chem. Soc., Perkin Trans. 2, 1199
(2000).
6,
7.
N. Okiyama, S. Uchiyama, M. Onoda, K. Imai, and T. Santa, Heterocycles, 58, 165 (2002).
V. A. Samsonov and L. B. Volodarskii, Khim. Geterotsikl. Soedin., 1135 (2000). [Chem. Heterocycl.
Comp., 36, 996 (2000)].
8.
9.
A. J. Boulton, P. B. Ghosh, and A. R. Katritzky, J. Chem. Soc. (B), 1004 (1966).
L. I. Khmel'nitskii, S. S. Novikov, and T. I. Godovikova, Chemistry of Furoxanes. Reactions and
Applications [in Russian], Nauka, Moscow (1983).
10.
11.
12.
A. G. Palmer III, J. Cavanagh, P. E. Wright, and M. Rance, J. Magn. Reson., 93, 151 (1991).
L. E. Kay, P. Keifer, and T. Saarinen, J. Am. Chem. Soc., 114, 10663 (1992).
J. Schleucher, M. Schwendinger, M. Sattler, P. Schmidt, O. Schedletzky, S. J. Glaser, O. W. Sorensen,
and C. Griesinger, J. Biomol. NMR, 4, 301 (1994).
13.
14.
A. Bax and M. F. Summers, J. Am. Chem. Soc., 108, 2093 (1986).
B. Reif, M. Köck, R. Kerssenbaum, H. Kang, W. Fenical, and C. Griesinger, J. Magn. Reson., Ser. A,
118, 282 (1996).
878