An unusual cascade of S N reactions of benzotetrazine 1,3-dioxide derivatives

Article abstract of DOI:10.1007/s11172-010-0017-3

An unusual cascade of S _NAr reactions was discovered in the series of benzo-1,2,3,4-tetrazine 1,3-dioxides containing two adjacent nucleofuges X and Y in the benzene ring. First, the 1,2,3-triazole anion displaces the anion X^s- from

Full text of DOI:10.1007/s11172-010-0017-3

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 361—365, February, 2009
361
An unusual cascade of SN reactions
of benzotetrazine 1,3ꢀdioxide derivatives*
A. Yu. Tyurin, O. Yu. Smirnov, A. M. Churakov, Yu. A. Strelenko, and V. A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: churakov@ioc.ac.ru
An unusual cascade of SNAr reactions was discovered in the series of benzoꢀ1,2,3,4ꢀ
tetrazine 1,3ꢀdioxides containing two adjacent nucleofuges X and Y in the benzene ring. First,
the 1,2,3ꢀtriazole anion displaces the anion X– from the more reactive site. Then the nucleoꢀ
phile X– displaces the adjacent group Y. For instance, 1,2,3ꢀtriazole reacts with 6ꢀazidoꢀ
5ꢀnitrobenzotetrazine 1,3ꢀdioxide to give 5ꢀazidoꢀ6ꢀ(1,2,3ꢀtriazolꢀ2ꢀyl)benzotetrazine
1,3ꢀdioxide, with 8ꢀazidoꢀ7ꢀnitrobenzotetrazine 1,3ꢀdioxide to give 7ꢀazidoꢀ8ꢀ(1,2,3ꢀtriazolꢀ
2ꢀyl)benzotetrazine 1,3ꢀdioxide and 7ꢀazidoꢀ8ꢀ(1,2,3ꢀtriazolꢀ1ꢀyl)benzotetrazine 1,3ꢀdioxide,
and with 7ꢀbromoꢀ6ꢀ(phenylthio)benzotetrazine 1,3ꢀdioxide to give 7ꢀphenylthioꢀ6ꢀ(1,2,3ꢀ
triazolꢀ2ꢀyl)benzotetrazine 1,3ꢀdioxide.
Key words: 1,2,3,4ꢀbenzotetrazine 1,3ꢀdioxides, 1,2,3ꢀtriazoles, SNAr reactions; 1H, 13C,
and 14N NMR spectroscopy.
Earlier, we have reported on the synthesis of a number
of benzotetrazine 1,3ꢀdioxides (BTDO) annulated with
tetraazapentalene fragments.1—3 They were obtained by
the thermolysis of BTDO with azido groups and 1,2,3ꢀtriꢀ
azole fragments that are ortho to each other, the latter
being in position 6 or 8. Our next goal was to synthesize
azidoꢀBTDO 1, 2, and 3 containing a triazole fragment in
position 5 or 7 using nucleophilic substitution reactions
as described previously.1—3
BTDO
Earlier,4 with reactions of monoꢀ and dibromoꢀBTDO
with the methoxide ion as examples, we have demonꢀ
strated that the nucleophilic substitution rates differ for
different positions in the BTDO ring, decreasing in the
order: 6 > 8 > 7 > 5. In most cases, this order is also true
for reactions with other nucleophiles.5 The substitution
rate difference can be explained by the different thermoꢀ
dynamic stabilities of intermediate anionic σꢀcomplexes.
According to quantumꢀchemical calculations (B3LYP/
6ꢀ31+G(d,p)) of the total energies of model isomeric
anions A and B, isomer A is thermodynamically more
stable than isomer B by 6.5 kcal mol–1
.
In the preceding work,1 we have described the
sequence of transformations 4 → 6 (Scheme 1). First, in a
reaction of 6ꢀbromoꢀ5ꢀnitroꢀBTDO 4 with 1,2,3ꢀtriazole
in DMF in the presence of Na2CO3, the Br atom is
replaced by the triazole fragment. Then the nitro group
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 357—361, February, 2009.
1066ꢀ5285/09/5802ꢀ0361 © 2009 Springer Science+Business Media, Inc.

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Tyurin et al.
Scheme 1
in BTDO 5 is replaced by the azido group via treatment
with NaN3 in DMF.
In an attempted synthesis of BTDO 1, we changed
the sequence of reactions. First, we obtained 6ꢀazidoꢀ
7ꢀnitroꢀBTDO 7 from BTDO 4 and NaN3 according
to a known procedure.6 Then BTDO 7 was treated with
1,2,3ꢀtriazole in DMF in the presence of Na2CO3 in the
hope of directing the attack of the triazole at position 5.
However, the substituents in product 6 (74% yield) were
arranged inversely relative to the expected BTDO 1. The
structure of this product is identical with that obtained
earlier1 and hence is undoubted.
The formation of BTDO 6 can be explained as folꢀ
lows. In the first step, the triazole anion attacks BTDO 7
at the most reactive site 6 (Scheme 2), giving anionic
complex C. Then the azide anion is eliminated to form
BTDO 5. However, the process goes on: the azide anion
as a nucleophile attacks position 5 of BTDO 5 to give
anionic intermediate D and finally, through elimination
of the nitrite anion, BTDO 6.
Thus, Scheme 1 is unsuitable for the synthesis of
BTDO 1. Nevertheless, the cascade of SN reactions shown
in Scheme 2 is of interest in itself. We found no references
to similar cascades in the literature and wanted to know
how far this process is of general character.
7,8ꢀDisubstituted BTDO was used as an object of
investigation (Scheme 3). Earlier,3 we have demonstrated
that 8ꢀbromoꢀ7ꢀnitroꢀBTDO 8 reacts with triazole in
acetone in the presence of Na2CO3 to give BTDO 9
and 10 via replacement of the Br atom in position 8
(Scheme 3). A subsequent reaction of BTDO 9 with NaN3
in DMF results in replacement of the nitro group, yielding
BTDO 11 (see Ref. 3). The inverted reaction sequence
Reagents and conditions: i, 1,2,3ꢀtriazole, Na CO , DMF, 20 °C,
2—3 h.
2
3
Scheme 2

Cascade of SN reactions
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
363
(first, BTDO 8 reacted with NaN37 and then the resulting
BTDO 13 reacted with the triazole anion) gave BTDO 11
and 12 in 18 and 23% yields, respectively; BTDO 2 was
not obtained at all.
Scheme 4
Scheme 3
Reagents and conditions: i, 1,2,3ꢀtriazole, KOH, DMF, 20 °C,
15 min (see Ref. 2); ii, PhSH/K CO ; iii, 1,2,3ꢀtriazole, KOH,
2
3
DMSO, 20 °C, 12 h.
benzenethiol in DMSO—K2CO3 and then the resulting
BTDO 17 reacted with triazole in DMSO in the presence
of KOH. It turned out that the triazole anion displaces
from position 6 even such a poor leaving group as the
benzenethiolate anion, although at an appreciably lower
rate. The anion PhS– in turn displaces the Br– anion from
position 7 to give BTDO 16. The low yield of this product
(52%) is due to the losses during its isolation. In any case,
no other products of this reaction were detected by TLC
in noticeable amounts.
Reagents and conditions: i, 1,2,3ꢀtriazole, Na CO .
2
3
Another object of investigation was 6,7ꢀdisubstituted
BTDO (Scheme 4). A reaction of dibromoꢀBTDO 14
with 1,2,3ꢀtriazole in DMF in the presence of KOH results
in replacement of the Br(6) atom (see Ref. 2). When
BTDO 15 was treated with benzenethiol in DMF in the
presence of K2CO3, the Br(7) atom is replaced to give
BTDO 16.
For unambiguous determination of the structure of
BTDO 16, this insoluble compound was oxidized into
wellꢀsoluble sulfoxide 18 (Scheme 5) identified from its
1H and 13C NMR spectra with the nuclear Overhauser
effect (NOE) and selective polarization transfer (SPT)
from protons. Moreover, BTDO 18 was transformed into
azido derivative 19 by a reaction with NaN3; compound
19 was identical with an authentic sample.2 Note that the
latter reaction follows a normal SNAr reaction pathway:
In further experiments, the reaction sequence was
changed. First, BTDO 14 was used in a reaction with

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Tyurin et al.
Scheme 5
divided Na2CO3 (100 mg, 0.94 mmol) were added at 20 °C to
a stirred solution of BTDO 13 (200 mg, 0.8 mmol) in DMF
(2 mL). The reaction mixture was stirred for 1 h and poured into
water. The precipitate was filtered off, washed with water, and
dried in vacuo. After the extraction with AcOEt, the residue was
identified as a nearly pure 7ꢀazidoꢀ8ꢀ(triazolꢀ1ꢀyl)benzotetrazine
1,3ꢀdioxide (12). The extract was concentrated and the residue
was separated by column chromatography (silica gel, CHCl3—
AcOEt, 2 : 3) into 7ꢀazidoꢀ8ꢀ(triazolꢀ2ꢀyl)ꢀbenzotetrazine
1,3ꢀdioxide (11) (40 mg, 18%) and BTDO 12. The total yield
of BTDO 12 was 50 mg (23%). Compounds 11 and 12 were
identical with the corresponding authentic samples.3
7ꢀBromoꢀ6ꢀ(phenylthio)benzotetrazine 1,3ꢀdioxide (17).
Benzenethiol (160 mg, 2.31 mmol) and finely divided K2CO3
(70 mg, 0.51 mmol) were added at 20 °C to a stirred solution of
6,7ꢀdibromobenzotetrazine 1,3ꢀdioxide 14 (161 mg, 0.5 mmol)
in DMSO (6 mL). After 15 min, the reaction mixture was
diluted with water. The precipitate that formed was filtered off,
washed with MeOH and Et2O, and dried. The yield of BTDO 17
was 172 mg (98%), m.p. 177—178 °C. Found (%): C, 41.36;
H, 1.99; Br, 22.59; N, 15.73, S, 9.02. C12H7BrN4O2S. Calcuꢀ
lated (%): C, 41.04; H, 2.01; Br, 22.75; N, 15.95; S, 9.13.
IR (KBr, ν/cm–1): 1275 m, 1368 s, 1435 s, 1515 s, 1578 m.
1H NMR (DMSOꢀd6), δ: 6.68 (s, 1 H, H(5)); 7.67 (m, 5 H, Ph);
8.54 (s, 1 H, H(8)). 13C NMR (DMSOꢀd6), δ: 117.8 (C(8)),122.3
(C(5)), 125.8 (C(8a)), 125.8 (ipsoꢀC, Ph), 127.6 (C(7)), 130.8
(mꢀC, Ph), 131.1 (pꢀC, Ph), 135.2 (oꢀC, Ph), 142.4 (C(4a)),
the azide ion attacks position 7, thus displacing the
phenylsulfoxy group.
The mechanism of transformations 13 → 11 and 17 → 16
is similar to that shown in Scheme 2: the initial attack of
the 1,2,3ꢀtriazole anion on BTDO displaces the correꢀ
154.3 (C(6)). 14N NMR (DMSOꢀd6), δ: –45 (Δν = 200 Hz)
1/2
(N(1), N(3)). MS, m/z: 350, 352 (1 : 1) [M]+.
–
sponding anion (N3 or PhS–) from the more reactive
7ꢀPhenylthioꢀ6ꢀ(triazolꢀ2ꢀyl)benzotetrazine 1,3ꢀdioxide (16).
Benzenethiol (15 mg, 0.14 mmol) and finely divided K2CO3
(15 mg, 0.11 mmol) were added at 20 °C to a stirred solution of
7ꢀbromoꢀ6ꢀ(triazolꢀ2ꢀyl)benzotetrazine 1,3ꢀdioxide (15) (31 mg,
0.1 mmol) in DMF (6 mL). After 20 h, the reaction mixture was
diluted with water. The precipitate that formed was filtered off,
washed with water, MeOH, and Et2O, and dried. The yield of
BTDO 16 was 25 mg (75%), m.p. 294 °C (from DMSO). Found
(%): C, 49.59; H, 2.66; N, 28.71; S, 9.33. C14H9N7O2S. Calꢀ
culated (%): C, 49.55; H, 2.67; N, 28.89; S, 9.45. IR (KBr,
ν/cm–1): 1365 s, 1420 s, 1459 s, 1480 m, 1510 m, 1650 m.
1H NMR (DMSOꢀd6), δ: 7.50 (s, 1 H, H(5)); 7.60 (m, 5 H, Ph);
8.80 (s, 1 H, H(8)); 8.87 (s, 2 H, triazole). 14N NMR (DMSOꢀd6),
δ: –46 (Δν1/2 = 300 Hz) (N(1), N(3)). MS, m/z: 339 [M]+.
Reaction of 7ꢀbromoꢀ6ꢀ(phenylthio)benzotetrazine 1,3ꢀdiꢀ
oxide (17) with 1,2,3ꢀtriazole. 1,2,3ꢀTriazole (98 mg, 1.42 mmol)
and finely divided KOH (80 mg, 1.42 mmol) were added at
20 °C to a stirred solution of BTDO 17 (500 mg, 1.24 mmol) in
DMSO (10 mL). The reaction mixture was stirred for 12 h. The
precipitate was filtered off, washed with MeOH and Et2O, and
dried to give nearly pure 7ꢀphenylthioꢀ6ꢀ(triazolꢀ2ꢀyl)benzoꢀ
tetrazine 1,3ꢀdioxide (16) (250 mg, 52%), which was identical
with the product obtained in the preceding entry.
position and then this anion as a nucleophile displaces the
adjacent group.
Experimental
1H, 13C, and 14N NMR spectra were recorded on a Bruker
AMꢀ300 spectrometer (300.13, 75.5, and 21.5 MHz, respecꢀ
tively). Chemical shifts were referenced to Me4Si (1H and 13C)
or MeNO2 (14N, an external standard, highꢀfield chemical shifts
are negative). IR spectra were recorded on a URꢀ20 instrument.
Mass spectra were measured on a Varian MATꢀ311A instrument
(EI, 70 eV). The course of the reactions was monitored by TLC
on Silufol UVꢀ254 plates. The compounds obtained in the present
work were identified by comparing their IR and 1H NMR specꢀ
tra and melting points with those of the corresponding authentic
samples.
Caution! The compounds obtained are sensitive to impact and
friction and must be handled as with explosives.
Reaction of 6ꢀazidoꢀ5ꢀnitrobenzotetrazine 1,3ꢀdioxide (7) with
1,2,3ꢀtriazole. 1,2,3ꢀTriazole (33 mg, 0.48 mmol) and finely
divided Na2CO3 (51 mg, 0.48 mmol) were added at 20 °C to a
stirred solution of BTDO 7 (100 mg, 0.4 mmol) in DMF (2 mL).
The reaction mixture was stirred for 2 h and poured into water.
The precipitate was filtered off, washed with water, and purified
by column chromatography on silica gel with benzene as
an eluent. The yield of 5ꢀazidoꢀ6ꢀ(triazolꢀ2ꢀyl)ꢀbenzotetrazine
1,3ꢀdioxide (6) was 80 mg (74%). The product was identical
with an authentic sample.1
7ꢀPhenylsulfoxyꢀ6ꢀ(triazolꢀ2ꢀyl)benzotetrazine 1,3ꢀdioxide
(18). 4ꢀEthoxycarbonylperoxybenzoic acid (0.3 mmol) was
added to a stirred suspension of BTDO 16 (100 mg, 0.3 mmol)
in CH2Cl2 (15 mL). The reaction mixture was stirred at 20 °C
for 1.5 h. The precipitate of 4ꢀethoxycarbonylbenzoic acid was
filtered off and washed with CH2Cl2. The filtrate was concenꢀ
trated in vacuo and the residue was washed with Et2O and dried
to give nearly pure BTDO 18 (58 mg, 54%). The ethereal rinse
solution was concentrated and purified by column chromatoꢀ
Reaction of 8ꢀazidoꢀ7ꢀnitrobenzotetrazine 1,3ꢀdioxide (13)
with 1,2,3ꢀtriazole. 1,2,3ꢀTriazole (67 mg, 0.97 mmol) and finely

Cascade of SN reactions
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
365
graphy (silica gel, CHCl3), which gave an additional crop
(31 mg) of BTDO 18. The total yield of BTDO 18 was 84%,
m.p. 254—256 °C. Found (%): C, 47.48; H, 2.57; N, 27.33;
S, 8.90. C14H9N7O3S. Calculated (%): C, 47.32; H, 2.55;
N, 27.59; S, 9.02. IR (KBr, ν/cm–1): 1160 s, 1217 m, 1275 m,
1370 s, 1405 m, 1433 s, 1455 m, 1490 m, 1515 s, 1585 m, 1618 w.
1H NMR (acetoneꢀd6), δ: 7.42 (m, 3 H, Ph); 7.70 (m, 2 H, Ph);
8.26 (s, 2 H, triazole); 8.44 (s, 1 H, H(5)); 9.30 (s, 1 H, H(8)).
13C NMR (DMSOꢀd6), δ: 114.2 (C(5)); 118.5 (C(8)); 126.9
(oꢀC, Ph); 127.3 (br.s, C(8a), 2J = 3.2 Hz); 129.4 (mꢀC, Ph);
131.8 (pꢀC, Ph); 139.0 (triazole); 141.2 (C(6), 3J = 8.4 Hz);
141.8 (C(7), 2J = 4.2 Hz); 144.8 (ipsoꢀC, Ph); 145.5 (C(4a),
3J = 5.9 Hz). For signal assignments, the SPT and NOE techꢀ
niques were used. 14N NMR (acetoneꢀd6), δ: –42 (Δν1/2 = 60 Hz),
–45 (Δν1/2 = 80 Hz) (N(1), N(3)). MS, m/z: 355 [M]+.
7ꢀAzidoꢀ6ꢀ(triazolꢀ2ꢀyl)benzotetrazine 1,3ꢀdioxide (19).
Finely divided NaN3 (10 mg, 0.15 mmol) was added at 20 °C to
a stirred solution of BTDO 18 (36 mg, 0.1 mmol) in DMF
(5 mL). After 40 min, the reaction mixture was diluted with
water and the product was extracted with AcOEt. The extract
was concentrated in vacuo. The residue was washed with water
and purified by column chromatography (silica gel, CHCl3) to
give BTDO 19 (14 mg, 51%). The product was identical with an
authentic sample.2
References
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Tartakovsky, Izv. Akad. Nauk, Ser. Khim., 2008, 186 [Russ.
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00409).
Received July 16, 2008