Nucleophilic substitution in benzo-1,2,3,4-tetrazine 1,3-dioxides

Article abstract of DOI:10.1023/A:1021396317258

Nucleophilic substitution in nitro- and bromobenzo-1,2,3,4-tetrazine 1,3-dioxides (BTDOs) was studied. In most cases, the bromo and nitro groups are replaced by methylamino, dimethylamino, azido, and methoxy groups without opening of the tetrazine ring. I

Full text of DOI:10.1023/A:1021396317258

Russian Chemical Bulletin, International Edition, Vol. 51, No. 10, pp. 1849—1856, October, 2002
1849
Nucleophilic substitution in benzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxides
ꢀ
O. Yu. Smirnov, A. M. Churakov, A. Yu. Tyurin, Yu. A. Strelenko, S. L. Ioffe, and V. A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: churakov@ioc.ac.ru
Nucleophilic substitution in nitroꢀ and bromobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxides
(BTDOs) was studied. In most cases, the bromo and nitro groups are replaced by methylamino,
dimethylamino, azido, and methoxy groups without opening of the tetrazine ring. It was
illustrated with the reactions of dibromoꢀBTDOs with sodium methoxide that the reactivity of
positions 5 to 8 in their benzene ring as regards nucleophilic substitution changes in the
1
following order: 6 > 8 > 7 > 5. The structures of the BTDOs obtained were confirmed by H,
13C, and 14N NMR data.
Key words: benzoꢀ1,2,3,4ꢀtetrazines, Nꢀoxides, nucleophilic substitution.
This work was done within the scope of the systematic
investigation of benzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxides
(BTDOs).1,2 Here we studied nucleophilic substitution in
halogen and nitro derivatives of this new heterocyꢀ
clic system. The primary question to be answered was:
whether can such reactions occur without opening of the
1,2,3,4ꢀtetrazine 1,3ꢀdioxide (TDO) ring. In addition, it
was interesting to compare substitution rates for halogen
atoms and nitro groups in different positions of the BTDO
benzene ring.
Accessible 6ꢀ, 7ꢀ, and 8ꢀbromoꢀBTDOs 1a—c and
7ꢀ and 5ꢀnitroꢀBTDOs 2a,b were chosen as objects of
investigation. Methanolic KOH (Table 1, reaction 1),
sodium azide in DMF (reaction 2), dimethylamine in
DMF (reaction 3), and methylamine in DMSO (reacꢀ
tion 4) were used as nucleophilic reagents. Reactions were
Table 1. Synthesis of BTDOs 3a—c, 4a—c, 5a—c, and 6a—c from BTDOs 1a—c and 2a (20 °C)
b
Reacꢀ Starting
X
Ca
/mol L–1
Solvent
Reagent
τ
Product
Y
Yield
(%)
tion
BTDO
/h
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
1a
1b
1c
2a
1a
1b
1c
2a
1a
1b
1c
2a
1a
1b
1c
2a
7ꢀBr
6ꢀBr
8ꢀBr
7ꢀNO2
7ꢀBr
6ꢀBr
8ꢀBr
7ꢀNO2
7ꢀBr
6ꢀBr
8ꢀBr
7ꢀNO2
7ꢀBr
6ꢀBr
8ꢀBr
0.018
0.018
0.018
0.04
0.15
0.15
0.15
0.15
0.25
0.5
MeOH
MeOH
MeOH
MeOH/KOH
MeOH/KOH
MeOH/KOH
MeOH/KOH
NaN3
1c
3
0.5c
1
48
0.3
0.7
1
24
0.15
6
8
9
0.1
1.5
2d
3a
3b
3c
3a
4a
4b
4c
4a
5a
5b
5c
5a
6a
6b
6c
6a
7ꢀMeO
6ꢀMeO
8ꢀMeO
7ꢀMeO
7ꢀN3
6ꢀN3
8ꢀN3
7ꢀN3
7ꢀMe2N
6ꢀMe2N
8ꢀMe2N
7ꢀMe2N
7ꢀMeNH
6ꢀMeNH
8ꢀMeNH
7ꢀMeNH
45
83
27
76
53
88
90
75
45
94
75
76
89
92
89
0
MeOH
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF
DMF/H2O
DMF/H2O
DMF/H2O
DMSO
NaN3
NaN3
NaN3
Me2NH
Me2NH
Me2NH
Me2NH
MeNH2
MeNH2
MeNH2
MeNH2
0.5
0.17
0.25
0.25
0.25
0.25
DMSO
DMSO
DMSO
7ꢀNO2
a Concentration of the starting BTDO.
b Reaction time.
c At 65 °C.
d The time required for complete consumption of the starting BTDO 2a.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1701—1707, October, 2002.
1066ꢀ5285/02/5110ꢀ1849 $27.00 © 2002 Plenum Publishing Corporation

1850
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Smirnov et al.
conducted until the starting BTDOs were completely conꢀ
sumed (TLC). Reaction times and other conditions are
specified in Table 1.
It was found that bromoꢀBTDOs 1a—c react with the
above nucleophiles to give products 3a—c, 4a—c, 5a—c,
and 6a—c in 27—94% yields (Scheme 1).
Scheme 1
11 were detected in the reaction mixture. A ratio between
monosubstituted products 9 and 10, determined from inteꢀ
grated signal intensities in the 1H NMR spectra (Scheme 2,
Table 2), was taken to be a ratio between the substitution
rates at different ring positions.
The nitro group in BTDO is not always replaced
smoothly. The reactions of 7ꢀnitroꢀBTDO 2a with such
nucleophiles as MeO–, N3–, and
HNMe2 afford the same products
3a, 4a, and 5a as in the reactions
As regards the ease of nucleophilic substitution, the
positions in the benzene ring are arranged as follows:
6 > 8 > 7 > 5 (Table 2). This order correlates with the
activity order for monosubstituted BTDOs and is the opꢀ
posite of the order found for electrophilic substitution in
BTDOs.2
with bromoꢀBTDOs, yet proceedꢀ
ing somewhat more rapidly (see
Table 1, reactions 1—3). Howꢀ
ever, an analogous reaction with
MeNH2 yields a mixture containꢀ
ing no expected product 6a. Neiꢀ
With excess KOH or for a longer reaction time,
BTDO 8 gave dimethoxy derivatives 11. Compounds 11a
and 11b are stable; they were isolated in good yields.
The structures of BTDOs 3—6 and 9—11 were deterꢀ
mined from IR and 1H, 13C, and 14N NMR data (Tables 3
and 4) and mass spectra. The spectra of BTDO were
analyzed in detail previously.2 Experimental chemiꢀ
cal shifts in the 13C NMR spectra of BTDO coinꢀ
cide well with those calculated according to an addiꢀ
tive scheme. The chemical shifts for monosubstituted
BTDOs were calculated from the δ values for unsubstiꢀ
tuted BTDO, while analogous calculation for disubstiꢀ
tuted BTDOs 9—11 was based on the chemical shifts
of the corresponding methoxyꢀBTDOs (for details,
see Ref. 2).
ther do the expected products
form in the reactions of 5ꢀnitroꢀBTDO 2b with any of the
above nucleophiles. Apparently, the TDO ring undergoes
opening in this reaction.
As can be seen in Table 1, the reactions of monoꢀ
bromoꢀBTDOs with the nucleophiles studied proceed at
rates decreasing in the order: 6ꢀBr > 8ꢀBr > 7ꢀBr (the
rates were estimated from the time required for complete
consumption of the starting BTDO).
Probably, nucleophilic substitution follows the addiꢀ
tion—elimination (AE) mechanism. In this case, the variaꢀ
tion in substitution rates with ring positions is due to
different thermodynamic stabilities of intermediate anꢀ
ionic σꢀcomplexes 7.
Better delocalization of the negative charge over the
TDO ring in complexes 7a,b makes them more stable
than complexes 7c,d. For this reason, positions 6 and 8
are preferable for substitution, though the 5ꢀ and 7ꢀBr
atoms can also be replaced rather easily. Thus, nucleoꢀ
philic substitution in BTDO is possible for any position of
the benzene ring.
Table 2. Synthesis of BTDOs 9 and 10
from BTDO 8
Starting
BTDO
Ratio
of products (%)
Relative substitution rates for 6,8ꢀdibromoꢀ, 6,7ꢀdiꢀ
bromoꢀ, and 5,7ꢀdibromoꢀBTDOs 8a—c were determined
in their reactions with methanolic KOH. These reactions
were stopped when trace amounts of dimethoxyꢀBTDO
8а
8b
8c
9a : 10a (62 : 38)
9b : 10b (98 : 2)
9c : 10c (90 : 10)

Nucleophilic substitution in benzotetrazine dioxides Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1851
Scheme 2
i. MeOH/KOH.
Scheme 3
Scheme 4
8ꢀBromoꢀBTDO 1c was synthesized according to the
known method3 by treating azoxyaniline 14 with a soluꢀ
tion of nitric anhydride in MeCN (Scheme 4).
Compound 14 was synthesized according to the
method described earlier.4 2,6ꢀDibromoaniline was oxiꢀ
dized into nitroso compound 12, which was treated with
N,Nꢀdibromoꢀtertꢀbutylamine to give compound 13. The
i. 210 °C, 300 atm.

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Smirnov et al.
1
Table 3. H and 14N NMR spectra of BTDOs 3a—c, 4a—c, 5a—c, 6a—c, 9a—c, 10a—c, and 11a,b
Comꢀ
pound
Solventa
1H NMR, δ (J/Hz)a
14N NMR, δ (∆ν1/2/Hz)
4
3a
3b
3c
4a
4b
4c
5a
5b
5c
Acetoneꢀd6
Acetoneꢀd6
DMSOꢀd6
Acetoneꢀd6
Acetoneꢀd6
Acetoneꢀd6
Acetoneꢀd6
DMSOꢀd6
DMSOꢀd6
4.10 (s, 3 H, Ме); 7.66 (d, 1 Н, H(8), J = 2.7);
–45 (40), –51 (55) (N(1), N(3))
–43 (65), –45 (55) (N(1), N(3))
–41 (110), –49 (130) (N(1), N(3)
3
7.78 (dd, 1 Н, H(6), J = 9.3); 7.87 (d, 1 Н, H(5))
4.12 (s, 3 H, Ме); 7.26 (d, 1 Н, H(5), J = 2.4);
7.44 (dd, 1 Н, H(7)); 8.25 (d, 1 Н, H(8), J = 9.5)
4.01 (s, 3 H, Ме); 7.36 (d, 1 Н, H(7), J = 10.1);
7.40 (d, 1 Н, H(5), J = 10.1); 8.00 (t, 1 Н, H(6))
4
7.86 (dd, 1 Н, H(6)); 7.93 (d, 1 Н, H(8), J = 2.6);
–43 (55), –50 (95) (N(1), N(3));
–143 (110) (N3)b
–42 (45), –46 (45) (N(1), N(3));
–144 (60) (N3)b
–39 (60), –46 (75) (N(1), N(3));
–142 (120) (N3)b
–49 (45), –55 (60) (N(1), N(3))
3
7.95 (d, 1 Н, H(5), J = 8.9)
7.53 (d, 1 Н, H(5), J = 2.3); 7.55 (dd, 1 Н, H(7));
8.34 (d, 1 Н, H(8), J = 8.9)
7.63, 7.69 (both dd, 1 H each, H(5), H(7), J = 8.1,
3
4J = 1.1); 8.04 (t, 1 Н, H(6))
4
3.26 (s, 6 H, 2 Ме); 7.12 (d, 1 Н, H(8), J = 2.7);
7.72 (d, 1 Н, H(5), J = 9.4); 7.81 (dd, 1 Н, H(6))
3.21 (s, 6 H, 2 Ме); 6.69 (d, 1 Н, H(5), J = 2.6);
7.41 (dd, 1 Н, H(7)); 8.02 (d, 1 Н, H(8), J = 9.4)
2.97 (s, 6 H, 2 Ме); 7.07, 7.11 (both d, 1 H each, H(5),
3
–45 (220) (N(1), N(3))
–43 (220) (N(1), N(3))
3
H(7), J = 10); 7.80 (t, 1 Н, H(6))
6a
6b
DMSOꢀd6
DMSOꢀd6
2.88 (s, 3 Н, Ме); 6.85 (s, 1 Н, Н(8)); 7.53, 7.65 (both d,
–51 (95), –56 (130) (N(1), N(3))c
–44 (50), –49 (80) (N(1), N(3))c
3
1 H each, H(5), H(6), J = 9.4); 7.50 (br.s, 1 H, NH)c
3
4
2.90 (d, 3 H, Ме, J = 4.4); 6.50 (d, 1 Н, H(5), J = 2.3);
3
7.14 (dd, 1 Н, H(7)); 7.92 (d, 1 Н, H(8), J = 9.5);
7.96 (br.s, 1 H, NH)c
3
3
6c
9a
Acetoneꢀd6
DMSOꢀd6
3.11 (d, 3 H, Ме, J =7.7); 6.85 (d, 2 Н, H(5), H(7), J =
–37 (50), –47 (50) (N(1), N(3))
–44 (70), –46.5 (90) (N(1), N(3))c
3
12.3); 7.84 (t, 1 Н, H(6), J = 12.3); 8.85 (br.s, 1 H, NH)
4
4.01 (s, 3 Н, Ме); 7.35 (d, 1 Н, H(5), J = 2.5);
7.75 (d, 1 Н, H(7))
9b
9c
DMSOꢀd6
DMSOꢀd6
4.12 (s, 3 Н, Ме); 7.48 (s, 1 Н, H(5)); 8.52 (s, 1 Н, H(8))
4.01 (s, 3 Н, Ме); 7.66 (d, 1 Н, H(8), J = 2.6);
–46 (350) (N(1), N(3))
–44 (100), –52 (180) (N(1), N(3))c
4
8.22 (d, 1 Н, H(6))
4.05 (s, 3 Н Ме); 7.53 (d, 1 Н, H(7), J = 1.8);
4
10a
DMSOꢀd6
–41 (70), –46 (90) (N(1), N(3))c
7.73 (d, 1 Н, H(5))
4.11 (s, 3 Н Ме); 7.70 (s, 1 Н, H(8)); 8.38 (s, 1 Н, H(5))
4.07 (s, 3 Н, Ме); 7.81 (d, 1 Н, H(8), J = 1.7);
10b
10c
DMSOꢀd6
DMSOꢀd6
–48 (200) (N(1), N(3))c
–44 (90), –51 (130) (N(1), N(3))c
4
8.03 (d, 1 Н, H(6))
3.97 (s, 3 Н, MeOC(8)); 3.99 (s, 3 Н, MeOC(6));
6.84 (d, 1 Н, H(5)); 6.86 (d, 1 Н, H(7))
11a
11b
DMSOꢀd6
Acetoneꢀd6
–43 (70), –45 (70) (N(1), N(3))c
4.12, 4.16 (both s, 3 H each, Ме); 7.25, 7.60 (both s, 1 H each, –48 (60) (N(1), N(3))
H(5), H(8))
a The spectra were recorded at 298 K, unless otherwise specified.
b Chemical shift for the central nitrogen atom of the azido group (cf. Ref. 5).
c The NMR spectrum was recorded at 343 K.
the NMR spectra were described previously.2 The course of the
reaction of the latter with ammonia in an autoclave yielded
reaction was monitored by TLC (Silufol UVꢀ254). Compounds
1a,b and 8a—c were synthesized by closing the tetrazine ring;3
compounds 2a,b were prepared by nitration of BTDO.2 Reacꢀ
tion products were purified using preparative TLC on Silpearl
silica gel. Melting points were determined on a Kofler hot stage.
All BTDOs, except for amino derivatives, are bright yellow;
6ꢀaminoꢀBTDOs are red, while 7ꢀaminoꢀBTDOs are violet.*
Synthesis of methoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxides
3a—c from BTDOs 1a—c and 2a (general procedure). A solution
of KOH (112 mg, 2 mmol) in 5 mL of MeOH was added to a
aniline 14.
Experimental
IR spectra were recorded on a URꢀ20 instrument. Mass
spectra were obtained with a Varian MATꢀ311A instrument (EI,
70 eV). 1H, 13C, 14N, and 15N NMR spectra were recorded
on a Bruker AMꢀ300 spectrometer (300.13, 75.5, 21.5, and
30.42 MHz, respectively); the chemical shifts were measured
with reference to Me4Si (1H and 13C) and MeNO2
15N, external standard). The procedures used while recording
(
14N and
* UV spectra of BTDO were described in Ref. 6.

Nucleophilic substitution in benzotetrazine dioxides Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Table 4. 13C NMR spectra of BTDOs 3a—c, 4a—c, 5a—c, 6a—c, 9a—c, 10a,c, and 11a
1853
Comꢀ
pounda
δ
(δcalc), J/Hz
exp
С(4а)
С(5)
С(6)
С(7)
С(8)
С(8а) br.s
Ме
3ab
3b
3c
140.9 (136.8)
146.7 (144.4)
126.8 (126.3)
102.8 (109.8)
114.9 (116.3)
131.4 (124.8)
166.8 (169.9)
138.6 (139.5)
162.9 (163.8)
123.7 (117.4)
112.2 (117.4)
98.5 (105.5)
121.0 (120.0)
152.5 (150.4)
3JC(8),H(6) = 9.4
107.9 (110.8)
129.8 (130.1)
123.2 (120.1)
120.4 (113.6)
57.4
57.3
57.2
145.5 (144.4)
3JC(4a),H(6) = 9.9
142.4 (140.4)
4ab
127.2 (126.9)
131.8 (130.1)
3JC(6),H(5) = 6.1 3JC(7),H(5) = 11.0
144.9 (144.3)
129.5 (130.7)
—
3JC(4a),H(6) = 9.7
3JC(4a),H(8) = 5.0
145.1 (145.0)
4b
4c
111.6 (115.1)
150.2 (150.4)
124.3 (122.7)
121.2 (120.6)
125.3 (123.7)
121.6 (119.9)
128.2 (128.5)
—
—
3JC(4a),H(8) = 5.3 3JC(5),H(7) = 4.6 3JC(6),H(8) = 10.8 3JC(7),H(5) = 5.8
145.4 (146.5)
3JC(4a),H(6) = 10.5
136.2 (131.3)
120.0c (120.9)
137.7 (140.9)
122.4c (123.2)
133.8 (131.9)
3JC(8),H(6) = 9.6
92.7 (103.5)
3JC(8),H(6) = 4.0
120.3c (119.4)
145.6 (141.5)
89.9 (102.7)
5ad
124.7 (124.7)
126.3 (122.6)
151.3 (154.4)
39.5
3JC(6),H(8) = 6.1
e
e
e
5b
5c
6ad
—
97.55 (108.4)
115.3c (112.2)
128.9c (125.0)
—
120.0c (116.0)
110.9c (112.2)
152.1 (153.2)
—
40.2
43.3
29.2
137.4 (143.8)
137.4 (133.7)
137.6 (138.9)
124.7c (122.2)
112.2 (116.0)
128.8 (128.8)
6bd,f
6c
147.1 (144.1)
144.7 (144.1)
95.0 br.s (108.0)
106.7c (112.6)
157.1 (159.8)
139.2 (139.2)
123.5 br.s (115.6) 120.2 br.s (119.7)
119.8 (116.4)
116.9 (111.8)
29.4
29.9
109.1c (115.6)
143.5 (140.3)
3JC(8),H(6) = 9.2
113.8 (114.8)
3JC(4a),H(6) = 10.2
148.5 (148.7)
9a
103.4 (101.5)
164.9 (168.8)
3JC(6)OMe = 9.0
2JC(6),H(7) = 3.8
162.7 (169.9)
3JC(6),H(8) = 8.9
132.6 (134.5)
128.1 (126.8)
122.4 (126.3)
57.3
9b
9c
145.6 (145.5)
3JC(4a),H(8) = 5.8
137.9 (144.0)
3JC(4a),H(6) = 8.3
3JC(4a),H(8) = 5.0
146.2 (147.5)
103.2 (104.8)
118.5 (120.6)
117.9 (117.5)
3JC(7),H(5)= 8.9
161.0 (164.9)
123.07 (124.1)
98.1 (97.3)
123.12 (125.0)
3JC(8a),H(5) = 7.3
130.2 (131.8)
58.4
57.2
10a
10c
11a
117.2 (118.0)
3JC(5),H(7) = 5.2
132.6 (132.4)
120.4 (126.9)
166.8 (169.6)
115.2 (115.3)
125.0 (125.6)
95.5 (97.8)
152.9 (151.3)
120.1 (122.4)
3JC(8a),H(7) = 8.5
3JC(8a),H(5) = 6.3
129.2 (129.9)
58.0
57.7
135.2 (128.1)
3JC(4a),H(6) = 7.5 2JC(5),H(8) = 4.3
3JC(4a),H(8) = 5.0 2JC(5),H(6) = 5.2
152.3 (157.0)
111.8 (113.1)
3JC(8),H(6) = 5.4
148.1 (146.7)
102.4 (100.5)
154.0 (153.7)
116.5 (112.5)
56.9g
57.3h
a The spectra were recorded in DMSOꢀd6 at 298 K, unless otherwise specified.
b In acetoneꢀd6.
c Assignments of the signals may be interchanged.
d The spectrum was recorded at 343 K.
e No signals appeared because of poor solubility of the compound.
f At 298 K, all signals are broadened, except those for the C(6) atom and the HNMe group; two signals for the latter appear at δ 29.3
and 29.4 in an intensity ratio of 1 : 8.
g MeOC(6).
h MeOC(8).
stirred solution of a BTDO (1a—c) (243 mg, 1 mmol) in 50 mL of
MeOH or BTDO 2a (209 mg, 1 mmol) in 20 mL of MeOH (the
reaction conditions are specified in Table 1). After the reaction
was completed (TLC), the reaction mixture was neutralized with
aqueous HCl. After 90% of the solvent was removed in vacuo, the
product was filtered off, washed with water, and dried in vacuo.
7ꢀMethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (3a). A. Synꢀ
thesis from 7ꢀbromoꢀBTDO 1a. The yield of compound 3a was
87 mg (45%), m.p. 163—165 °C (from CH2Cl2). Found (%):
C, 43.25; H, 3.14; N, 28.75. C7H6N4O3. Calculated (%):
C, 43.31; H, 3.11; N, 28.86. IR (KBr), ν/cm–1: 1404, 1486
(N(O)NN(O)N). MS, m/z: 194 [M]+.
B. Synthesis from 7ꢀnitroꢀBTDO 2a. The yield of compound
3a was 145 mg (75%). The product is identical with that obꢀ
tained from BTDO 1a.*
* Hereafter, the products were identified from melting points,
1H NMR spectra, and TLC data.

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Smirnov et al.
6ꢀMethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (3b) was obꢀ
tained from BTDO 1b. The yield of compound 3b was 161 mg
(83%), m.p. 210—211 °C (from CH2Cl2). Found (%): C, 43.20;
H, 3.08; N, 28.61. C7H6N4O3. Calculated (%): C, 43.31; H, 3.11;
N, 28.86. IR (KBr), ν/cm–1: 1424, 1496 (N(O)NN(O)N). MS,
m/z: 194 [M]+.
8ꢀMethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (3c) was obꢀ
tained from BTDO 1c. The yield of compound 3c was 53 mg
(27%), m.p. 193—195 °C (from CH2Cl2). Found (%): C, 43.23;
H, 3.15; N, 28.58. C7H6N4O3. Calculated (%): C, 43.31; H, 3.11;
N, 28.86. IR (KBr), ν/cm–1: 1405, 1510 (N(O)NN(O)N). MS,
m/z: 194 [M]+.
Synthesis of azidobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxides 4a—c
from BTDOs 1a—c and 2a (general procedure). A solution of
NaN3 (130 mg, 2 mmol) in 3 mL of DMF and 0.25 mL of water
was added to a stirred solution of BTDO 1 or 2 (1 mmol) in 4 mL
of DMF (the reaction conditions are specified in Table 1). After
the reaction was completed, the reaction mixture was poured
into water, and the product was filtered off, washed with water,
and dried in vacuo.
7ꢀAzidobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (4a). A. Syntheꢀ
sis from 7ꢀbromoꢀBTDO 1a. The yield of compound 4a was
108 mg (53%), m.p. 140—146 °C (decomp.) (from CH2Cl2).
Found (%): C, 35.01; H, 1.44; N, 47.64. C6H3N7O2. Calcuꢀ
lated (%): C, 35.13; H, 1.47; N, 47.80. IR (KBr), ν/cm–1: 1400,
1485 (N(O)NN(O)N); 2132 (N3). MS, m/z: 205 [M]+.
B. Synthesis from 7ꢀnitroꢀBTDO 2a. The yield of compound
4a was 154 mg (75%). The product is identical with that obꢀ
tained from BTDO 1a.
Calculated (%): C, 46.38; H, 4.38; N, 33.80. IR (KBr), ν/cm–1
1404, 1468 (N(O)NN(O)N). MS, m/z: 207 [M]+.
:
8ꢀDimethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (5c)
was obtained from BTDO 1c. The yield of compound 5c was
155 mg (75%), violet crystals, m.p. 212—214 °C (decomp.) (from
MeCN). Found (%): C, 46.45; H, 4.40; N, 33.82. C8H9N5O2.
Calculated (%): C, 46.38; H, 4.38; N, 33.80. IR (KBr), ν/cm–1
:
1412, 1512 (N(O)NN(O)N). MS, m/z: 207 [M]+.
Synthesis of compound 5a from 7ꢀbromoꢀBTDO 1a. A satuꢀ
rated solution of Me2NH (2 mL) in DMF was added to a stirred
solution of BTDO 1a (243 mg, 1 mmol) in 2 mL of DMF (the
reaction conditions are specified in Table 1). The reaction mixꢀ
ture was treated as described above. The yield of compound 5a
was 93 mg (45%). The product is identical with that obtained
from BTDO 2a.
Synthesis of methylaminoꢀBTDOs 6a—c from compounds
1a—c (general procedure). A solution of BTDO 1 (243 mg,
1 mmol) was added to a stirred saturated solution of MeNH2
(0.322 mg, 10.4 mmol) in 4 mL of DMSO (the reaction condiꢀ
tions are specified in Table 1). After the reaction was completed,
the reaction mixture was poured into water, and the product was
filtered off, washed with water, EtOH (4 mL), and Et2O (4 mL),
and dried in vacuo.
7ꢀMethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (6a). The
yield of compound 6a was 172 mg (89%), violet crystals (from
MeCN), decomp. 240 °C (without melting). Found (%):
C, 43.70; H, 3.70; N, 35.98. C7H7N5O2. Calculated (%):
C, 43.53; H, 3.65; N, 36.26. IR (KBr), ν/cm–1: 1450
(N(O)NN(O)N). MS, m/z: 193 [M]+.
6ꢀAzidobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (4b) was obtained
from BTDO 1b. The yield of compound 4b was 180 mg (88%),
m.p. 156—158 °C (decomp.) (from CH2Cl2). Found (%):
C, 34.93; H, 1.51; N, 47.59. C6H3N7O2. Calculated (%):
C, 35.13; H, 1.47; N, 47.80. IR (KBr), ν/cm–1: 1428, 1500
(N(O)NN(O)N); 2122 (N3). MS, m/z: 205 [M]+.
6ꢀMethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (6b). The
yield of compound 6b was 178 mg (92%), red crystals (from
MeCN), decomp. 240 °C (without melting). Found (%):
C, 43.69; H, 3.68; N, 36.02. C7H7N5O2. Calculated (%):
C, 43.53; H, 3.65; N, 36.26. IR (KBr), ν/cm–1: 1432, 1490
(N(O)NN(O)N). MS, m/z: 193 [M]+.
8ꢀAzidobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (4c) was obtained
from BTDO 1c. The yield of compound 4c was 185 mg (90%),
decomp. 110—120 °C (without melting). Found (%): C, 35.10;
H, 1.44; N, 47.88. C6H3N7O2. Calculated (%): C, 35.13; H, 1.47;
N, 47.80. IR (KBr), ν/cm–1: 1403, 1520 (N(O)NN(O)N);
2129 (N3). MS, m/z: 205 [M]+.
8ꢀMethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (6c). The
yield of compound 6c was 173 mg (89%), violet crystals, m.p.
240—246 °C (decomp.) (from MeCN). Found (%): C, 43.59;
H, 3.59; N, 35.92. C7H7N5O2. Calculated (%): C, 43.53; H, 3.65;
N, 36.26. IR (KBr), ν/cm–1: 1435, 1507 (N(O)NN(O)N). MS,
m/z: 193 [M]+.
Synthesis of dimethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxꢀ
ides 5a—c from BTDOs 1b,c and 2a (general procedure). A 30%
aqueous solution of Me2NH (0.6 mL, 4 mmol) was added to a
stirred solution of BTDO (1 mmol) in DMF (the reaction conꢀ
ditions are specified in Table 1). After the reaction was comꢀ
pleted, the reaction mixture was poured into water, and the
precipitate that formed was filtered off, washed with water, EtOH
(4 mL), and Et2O (4 mL), and dried in vacuo.
Synthesis of 7ꢀdimethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdiꢀ
oxide (5a) from 7ꢀnitroꢀBTDO 2a. The yield of compound 5a
was 157 mg (76%), violet crystals, m.p. 247—253 °C (decomp.)
(from MeCN). Found (%): C, 46.49; H, 4.35; N, 33.51.
C8H9N5O2. Calculated (%): C, 46.38; H, 4.38; N, 33.80.
IR (KBr), ν/cm–1: 1408, 1474 (N(O)NN(O)N). MS, m/z:
207 [M]+.
Synthesis of bromomethoxyꢀBTDOs 9a—c and 10a—c from
compounds 8a—c (general procedure). A solution of KOH (70 mg,
1.24 mmol) in 5 mL of MeOH was added at 20 °C to a stirred
solution of BTDO 8 (200 mg, 0.62 mmol) in a minimum amount
of MeOH. The reaction was stopped when trace amounts of
disubstituted products were detected (TLC, benzene—Et2O,
5 : 1). The reaction mixture was neutralized with aqueous HCl,
and the solvent was removed in vacuo. The ratio between isoꢀ
mers 9 and 10 was determined from integrated signals in the
1H NMR spectra (see Table 2). The products were separated by
preparative TLC (benzene—Et2O, 5 : 1).
8ꢀBromoꢀ6ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide
(9a) and 6ꢀbromoꢀ8ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdiꢀ
oxide (10a). The reaction of a solution of BTDO 8a (200 mg)
in 65 mL of MeOH was carried out for 2.3 h. The unreacted
8a (60 mg, 70% conversion) was recovered; the yields of
compounds 9a and 10a were 59 mg (50%, from the conꢀ
sumed 8a) and 37 mg (31%, from the consumed 8a), respecꢀ
tively.
6ꢀDimethylaminobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (5b)
was obtained from BTDO 1b. The yield of compound 5b was
195 mg (94%), red crystals, m.p. 274—276 °C (decomp.) (from
MeCN). Found (%): C, 46.51; H, 4.35; N, 33.62. C8H9N5O2.

Nucleophilic substitution in benzotetrazine dioxides Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1855
Compound 9a, m.p. 209—210 °C (from CH2Cl2). Found (%):
C, 30.57; H, 1.83; Br, 29.40; N, 20.30. C7H5BrN4O3. Calcuꢀ
lated (%): C, 30.79; H, 1.85; Br, 29.26; N, 20.52. IR (KBr),
ν/cm–1: 1410, 1490 (N(O)NN(O)N). MS, m/z (integral intenꢀ
sity ratio): 272, 274 [M]+ (1 : 1).
Compound 10a, m.p. 213—215 °C (decomp.) (from CH2Cl2).
Found (%): C, 30.65; H, 1.84; Br, 29.15; N, 20.23. C7H5BrN4O3.
Calculated (%): C, 30.79; H, 1.85; Br, 29.26; N, 20.52. IR (KBr),
ν/cm–1: 1400, 1505 (N(O)NN(O)N). MS, m/z (integral intenꢀ
sity ratio): 272, 274 [M]+ (1 : 1).
7ꢀBromoꢀ6ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (9b)
and 6ꢀbromoꢀ7ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide
(10b). The reaction of a solution of BTDO 8b (200 mg) in
200 mL of MeOH was carried out for 2.3 h. The unreacted 8b
(75 mg, 62% conversion) was recovered; the yields of comꢀ
pounds 9b and 10b were 96 mg (91%, from the consumed 8b)
and 2 mg (2%, from the consumed 8b), respectively.
Compound 9b, m.p. 214—216 °C (from CH2Cl2). Found (%):
C, 30.57; H, 1.86; Br, 29.36; N, 20.34. C7H5BrN4O3. Calcuꢀ
lated (%): C, 30.79; H, 1.85; Br, 29.26; N, 20.52. IR (KBr),
ν/cm–1: 1420, 1505 (N(O)NN(O)N). MS, m/z (integral intenꢀ
sity ratio): 272, 274 [M]+ (1 : 1).
Compound 10b, m.p. 240—243 °C (decomp.) (from CH2Cl2).
MS, m/z (integral intensity ratio): 272, 274 [M]+ (1 : 1).
5ꢀBromoꢀ7ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (9c)
and 7ꢀbromoꢀ5ꢀmethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide
(10c). The reaction of a solution of BTDO 8c (200 mg) in 75 mL
of MeOH was carried out for 2.3 h. The unreacted 8c (110 mg,
45% conversion) was recovered; the yields of compounds 9c and
10c were 56 mg (73%, from the consumed 8c) and 7 mg (9%,
from the consumed 8c), respectively.
Compound 9c, m.p. 203—204 °C (from CH2Cl2). Found (%):
C, 30.75; H, 1.88; Br, 29.1; N, 20.4. C7H5BrN4O3. Calcuꢀ
lated (%): C, 30.79; H, 1.85; Br, 29.26; N, 20.52. IR (KBr),
ν/cm–1: 1440, 1512 (N(O)NN(O)N). MS, m/z (integral intenꢀ
sity ratio): 272, 274 [M]+ (1 : 1).
added at 20 °C to a solution of 2,6ꢀdibromoaniline (2.51 g,
10 mmol) in 40 mL of CH2Cl2. After 4 h, the precipitate of
mꢀchlorobenzoic acid that formed was filtered off. The resulting
solution was washed with aqueous Na2CO3 to remove the reꢀ
sidual amount of the acid, dried over MgSO4, and concentrated
to give nitroso compound 12 (2.52 g, 95%). After recrystallizaꢀ
tion from CHCl3, m.p. 134—135 °C (Ref. 7: m.p. 135—136 °C).
MS, m/z (integral intensity ratio): 263, 265, 267 [M]+ (1 : 2 : 1).
2,6ꢀDibromo(tertꢀbutylꢀNNOꢀazoxy)benzene (13). A solution
of N,Nꢀdibromoꢀtertꢀbutylamine (12 g, 0.052 mol) in 50 mL of
CH2Cl2 was added at 20 °C to a stirred suspension of nitroso
compound 12 (13.25 g, 0.05 mol) in 300 mL of CH2Cl2. The
reaction mixture was stirred until the nitroso compound was
dissolved completely and then kept for 12 h. The solvent was
evaporated in vacuo, and the residue was washed with aqueous
sodium sulfite to remove an excess of N,Nꢀdibromoꢀtertꢀbutylꢀ
amine. Recrystallization from hexane gave product 13 (14.1 g,
84%), m.p. 107—107.5 °C. Found (%): C, 35.80; H, 3.55;
Br, 47.48; N, 8.19. C10H12Br2N2O. Calculated (%): C, 35.74;
H, 3.60; Br, 47.56; N, 8.34. 1H NMR (CDCl3), δ: 1.51
(s, 9 H, 3 CH3); 7.05 (t, 1 H, H(4), J = 8.0 Hz); 7.47
(d, 2 H, H(3), H(5)). 13C NMR (CDCl3), δ: 25.4 (Me);
60.4 (CMe3); 116.0 (C(2)); 130.4 (C(4)); 132.4 (C(3));
147.6 (C(1)). MS, m/z (integral intensity ratio): 334, 336,
338 [M]+ (1 : 2 : 1).
3ꢀBromoꢀ2ꢀ(tertꢀbutylꢀNNOꢀazoxy)aniline (14). A solution
of compound 13 (1.68 g, 5 mmol) in 50 mL of toluene was
placed in a 150ꢀmL steel autoclave precooled with liquid nitroꢀ
gen. Liquid NH3 (75 mL) was added, and the reaction mixture
was heated at 210 °C and a pressure of 300 atm for 24 h. The
solvent was removed in vacuo, and the residue was separated by
column chromatography on silica gel (eluent was hexane—ethyl
acetate, 19 : 1). The unreacted 13 (0.7 g, 58% conversion) was
recovered. Aniline 14 was obtained as an oil; the yield was 0.67 g
(85%, from the consumed 13). Found (%): C, 44.29; H, 5.13;
Br, 29.47; N, 15.24. C10H14BrN3O. Calculated (%): C, 44.13;
H, 5.19; Br, 29.36; N, 15.44. IR (film between NaCl plates),
ν/cm–1: 1480 (N(O)=N); 3340, 3460 (NH2). 1H NMR (CDCl3),
δ: 1.45 (s, 9 H, 3 CH3); 4.60 (br.s, 2 H, NH2); 6.65 (dd, 1 H,
H(6), J = 7.8 Hz, J = 1.1 Hz); 6.81 (dd, 1 H, H(4), J = 7.8 Hz,
J = 1.1 Hz); 6.84 (d, 1 H, H(5), J = 7.8 Hz). 13C NMR (CDCl3),
δ: 25.5 (Me); 59.9 (CMe3); 115.2 (C(3)); 116.3 (C(6)); 121.2
(C(4)); 130.2 (C(5)); 136.3 (br.s, C(2)); 141.7 (C(1)). MS, m/z
(integral intensity ratio): 271, 273 [M]+ (1 : 1).
Compound 10c, m.p. 184—185 °C (from CH2Cl2). IR (KBr),
ν/cm–1: 1404, 1485 (N(O)NN(O)N). MS, m/z (integral intenꢀ
sity ratio): 272, 274 [M]+ (1 : 1).
6,8ꢀDimethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (11a). A
solution of KOH (224 mg, 4 mmol) in 5 mL of MeOH was
added to a stirred solution of BTDO 8a (322 mg, 1 mmol) in
50 mL of MeOH. After 6 h, the reaction mixture was neutralized
with aqueous HCl. The solvent was evaporated, and chromatogꢀ
raphy (benzene—Et2O, 5 : 1) gave compound 11a (164 mg,
74%), m.p. 209—210 °C (from CH2Cl2). Found (%): C, 42.79;
H, 3.68; N, 24.69. C8H8N4O4. Calculated (%): C, 42.86; H, 3.60;
N, 24.99. IR (KBr), ν/cm–1: 1424, 1484 (N(O)NN(O)N). MS,
m/z: 224 [M]+.
6,7ꢀDimethoxybenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (11b).
Compound 8b (322 mg, 1 mmol) was added to a stirred solution
of KOH (224 mg, 4 mmol) in 50 mL of MeOH. After 16 h, the
reaction mixture was neutralized with aqueous HC1. The solꢀ
vent was evaporated, and chromatography (benzene—Et2O, 5 : 1)
gave compound 11b (120 mg, 54%), m.p. 255—256 °C (from
CH2Cl2). Found (%): C, 42.76; H, 3.65; N, 24.8. C8H8N4O4.
8ꢀBromobenzoꢀ1,2,3,4ꢀtetrazine 1,3ꢀdioxide (1c). A soluꢀ
tion of aniline 14 (544 mg, 2 mmol) in 4 mL of dry MeCN was
added dropwise over 10 min to a stirred suspension of N2O5
(870 mg, 8 mmol) in 8 mL of dry MeCN while maintaining the
temperature at a level of –20 °C. Stirring was continued at this
temperature for an additional 5 min. The precipitate that formed
was filtered off, washed with 5 mL of cold MeOH, and dried in
vacuo to give BTDO 1c (209 mg, 43%), m.p. 208—209 °C
(CH2Cl2). Found (%): C, 29.58; H, 1.23; Br, 33.02, N, 22.81.
C6H3BrN4O2. Calculated (%): C, 29.65; H, 1.24; Br, 32.88;
N, 23.05. IR (KBr), ν/cm–1: 1404, 1515 (N(O)NN(O)N).
1H NMR (acetoneꢀd6), δ: 7.90, 8.13 (both dd, 1 H each, H(5),
H(7), 3J = 8.3 Hz, 4J = 1.4 Hz); 7.97 (t, H(6)). 13C NMR
(DMSOꢀd6), δ: 112.3; 124.2 (CH); 127.2 (br.s); 137.4 (CH);
Calculated (%): C, 42.86; H, 3.60; N, 24.99. IR (KBr), ν/cm–1
:
1428, 1516 (N(O)NN(O)N). 13C NMR (DMSOꢀd6), δ: 57.1,
57.5 (both Me); 97.1, 102.3 (both CH). MS, m/z: 224 [M]+.
2,6ꢀDibromonitrosobenzene (12). A solution of 55% mꢀchloꢀ
roperbenzoic acid (3.76 g, 12 mmol) in 30 mL of CH2Cl2 was
137.6 (CH); 146.0. 14N NMR (acetoneꢀd6), δ: –42 (∆ν
=
1/2
25 Hz), –49 (∆ν1/2 = 120 Hz) (N(1) and N(3)). MS, m/z (inteꢀ
gral intensity ratio): 242, 244 [M]+ (1 : 1).

1856
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Smirnov et al.
4. A. M. Churakov, O. Yu. Smirnov, S. L. Ioffe, Yu. A.
Strelenko, and V. A. Tartakovsky, Izv. Akad. Nauk, Ser.
Khim., 1994, 1620 [Russ. Chem. Bull., 1994, 43, 1532 (Engl.
Transl.)].
This work was financially supported in part by the
Federal Target Program "Integratsiya nauki i vysshego
obrazovaniya" (Project No. IO 667).
5. F. R. Benson, The High Nitrogen Compounds, Wiley, New
York, 1984, p. 328.
References
6. K. I. Rezchikova, A. M. Churakov, K. Ya. Burshtein, V. A.
Shlyapochnikov, and V. A. Tartakovsky, Mendeleev Commun.,
1997, 174.
7. R. R. Holmes and R. P. Bayer, J. Am. Chem. Soc., 1960,
82, 3454.
1. O. Yu. Smirnov, Ph.D. (Chem.) Thesis, N. D. Zelinsky Instiꢀ
tute of Organic Chemistry of the Russian Academy of Sciꢀ
ences, Moscow, 1995, 120 pp.
2. O. Yu. Smirnov, A. M. Churakov, Yu. A. Strelenko, S. L.
Ioffe, and V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim.,
2002, 1694 [Russ. Chem. Bull., Int. Ed., 2002, 1841] and the
references cited therein.
3. A. M. Churakov, O. Yu. Smirnov, S. L. Ioffe, Yu. A. Strelenko,
and V. A. Tartakovsky, Eur. J. Org. Chem., 2002, 2342.
Received February 4, 2002;
in revised form May 17, 2002