A one-pot, three-component synthesis of 3-(1 H -pyrazol-1-yl)-4 H,7 H -[1,2,4,5]tetraazino[6,1- b ][1,3]benzoxazin-7-ones under solvent-free conditions

Article abstract of DOI:10.1055/s-0034-1378928

A one-pot, three-component synthesis of 3-(1H-pyrazol-1-yl)-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones is described which involves heating a mixture of 1,2-dihydro-3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine, aldehydes, and dimedon

Full text of DOI:10.1055/s-0034-1378928

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 177–182
letter
177
M. Adib et al.
Letter
Synlett
A One-Pot, Three-Component Synthesis of 3-(1H-Pyrazol-1-yl)-
4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones under
Solvent-Free Conditions
???
Mehdi Adib*a
N
R
O
O
Mehdi Soheilizada
Long-Guan Zhub
Jing Wub
H
N
N
O
O
N
N
PTSA (cat.)
N
N
N
RCHO
+
+
solvent-free
120 °C
N
N
N
HN NH
N
a School of Chemistry, College of Science, University of Tehran,
P. O. Box 14155-6455 Tehran, Iran
+
9
8
2
(
1
6
)
6
4
9
5
2
9
1
madib@khayam.ut.ac.ir
b Chemistry Department, Zhejiang University, Hangzhou
310027, P. R. of China
Received: 17.08.2014
Accepted after revision: 13.10.2014
Published online: 14.11.2014
tetrazine derivatives are coupled to electron-rich thiophene
groups.4 They have also been frequently used as building
blocks in organic transformations or bridging ligands in
metal complexes.5 1,2,4,5-Tetrazines6 are the most import-
ant class of tetrazines that, due to the four electronegative
nitrogen atoms in the tetrazine ring, have great synthetic
utility and are capable of participating in inverse electron-
demand Diels–Alder cycloadditions,7 providing access to a
wide range of other heterocycles such as dihydropyridazine
and pyridazine systems.8 1,2,4,5-Tetrazines, containing het-
erocyclic azole fragments at 3- and 6 positions, are capable
of substituting these fragments with nucleophiles such as
amines and alcohols.9 Among these, 1,2-dihydro-3,6-dipyr-
azolyl-1,2,4,5-tetrazines are heterocycles of particular im-
portance because they are including two pyrazole groups at
C-3 and C-6 that can be used as good leaving groups for nu-
cleophilic substitution reactions. In addition, they possess
two active NH groups in the tetrazine ring that can act as a
good N-nucleophilic heterocycle.
Three-component reaction between aldehydes, 4-
phenylurazole, and dimedone has been shown to give
bridgehead-fused 5:5:6 systems with two ring-junction ni-
trogen atoms, 1H,6H-[1,2,4]triazolo[1,2-a]indazole-1,3,8-
triones (1, Figure 1).10 Fused 6:5:6 systems, 1H-indazo-
lo[1,2-b]phthalazine-1,6,11-triones (2, Figure 1), were ob-
tained by use of phthalhydrazide as the hydrazide compo-
nent in a similar reaction.11
DOI: 10.1055/s-0034-1378928; Art ID: st-2014-d0691-l
Abstract A one-pot, three-component synthesis of 3-(1H-pyrazol-1-
yl)-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones is de-
scribed which involves heating a mixture of 1,2-dihydro-3,6-bis(3,5-di-
methyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine, aldehydes, and dimedone in
the presence of a catalytic amount of p-toluenesulfonic acid under sol-
vent-free conditions. The bridgehead-fused 6:6:6 systems with one
ring-junction nitrogen atom were obtained in excellent yields.
Key words [1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones, 1,2-di-
hydro-3,6-bis(1H-pyrazol-1-yl)-1,2,4,5-tetrazine, solvent-free reaction,
multicomponent reactions, cyclizations, heterocycles
Multicomponent reactions (MCR) have been proved to
be a powerful tool in organic and medicinal chemistry and
are widely used for the synthesis of chemically and biologi-
cally important compounds. They enable multistep synthe-
ses to be conducted in a one-pot operation to obtain a vari-
ety of valuable products from readily available starting ma-
terials. These reactions hold the possibility for convenient,
safe, short, selective, high-yielding, and environmentally
benign procedures and to reduce generation of chemical
waste.1
A major challenge for synthetic chemists is to develop
environment-friendly synthetic procedures. One of the
most promising approaches is the solvent-free organic syn-
thesis. These reactions may provide greater selectivity, pro-
ceed with enhanced reaction rates, give cleaner products,
and involve simple manipulation.2
O
R
R
O
O
O
N
N
N
N
N
Tetrazines, an important class of high-nitrogen organic
compounds, have received much synthetic attention be-
cause of their inherent biological potential.3 These hetero-
cyclic compounds can readily be implemented in various
functional molecular systems, such as polymers in which
O
O
1
2
Figure 1 Fused bridgehead polycyclic systems synthesized from alde-
hydes, dimedone, and cyclic hydrazides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

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To the best of our knowledge, there has been no report
concerning the use of 1,2-dihydro-3,6-dipyrazolyl-1,2,4,5-
tetrazine as a starting material for the preparation of com-
plex heterocyclic compounds. Hence, in this study we pro-
posed using this heterocycle in MCR. 1,2-Dihydro-3,6-
bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine
(DHBPTz; 5) was first introduced by Scott in 1957.12 As
shown in Scheme 1, this heterocycle is readily prepared via
condensation reaction of a triaminoguanidinum salt (3) and
acetylacetone (4) in water.13
8 and 3,5-dimethyl-1H-pyrazole (9) could be detected by
NMR spectroscopy.15 The scope of the procedure was as-
sessed with a range of representative aldehydes. The pres-
ent procedure is quite general as a wide range of aromatic,
aliphatic, and heterocyclic aldehydes 6 reacted readily with
DHBPTz (5) and dimedone (7) to produce the corresponding
4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones
8
in excellent yields under the reaction conditions indicated
in Scheme 2 and Table 1.
The structures of the isolated products were deduced on
1
the base of IR, H NMR and 13C NMR spectroscopy, mass
NNH2⋅HX
spectrometry, and elemental analysis. The IR spectrum of
8e showed the stretching bands for N–H, C=O, and C=N
bonds at 3220, 3124, 1695, and 1648 cm–1. The mass spec-
trum of 8e displayed the molecular ion [M+] peaks at m/z =
440 [M+, 37Cl] and 438 [M+, 35Cl], which was consistent with
the 1:1:1 adduct of DHBPTz, 4-chlorobenzaldehyde, and di-
medone, with the loss of H2O and a 3,5-dimethyl-1H-pyra-
H2NHN
NHNH2
O
3
N
N
H2O
N
N
+
70 °C
1–2 h
O
N
N
HN NH
5
X = Cl, NO3
4
1
zole molecule (9). The H NMR spectrum of 8e exhibited
Scheme 1 Synthesis of 1,2-dihydro-3,6-bis(3,5-dimethyl-1H-pyrazol-
four single lines readily recognized as arising from the two
methyl groups of the cyclohexenone ring (at δ = 0.99 and
1.00 ppm) and the two methyl groups of the pyrazole ring
(δ = 2.28 and 2.35 ppm), as well as two AB quartet systems
(CHAHB and CHCCHD) for the diastereotopic H atoms of the
two methylene moieties in the cyclohexenone ring (at δA =
1.79 ppm, δB = 1.80 ppm, 2J = 17.3 Hz; and at δC = 2.18 ppm,
δD = 2.23 ppm, 2J = 16.4 Hz). Two single sharp lines were ob-
served at δ = 6.05 and 6.36 ppm due to the CH moieties of
pyrazole and oxazine rings, respectively. Finally, two appar-
ent doublets were seen at δ = 7.31 and 7.45 ppm for the four
protons of the 4-chlorophenyl substituent, along with a
fairly sharp singlet at δ = 8.51 ppm for the NH group of
1-yl)-1,2,4,5-tetrazine (DHBPTz)
As part of our continuing efforts on the development of
new routes for the preparation of biologically active hetero-
cyclic compounds and pursuing our studies on MCR,14 we
describe herein a novel, one-pot approach to the synthesis
of 4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones.
Thus, a mixture of DHBPTz (5), an aldehyde 6, and 5,5-di-
methyl-1,3-cyclohexanedione (dimedone, 7), in the pres-
ence of a catalytic amount of p-toluenesulfonic acid (PTSA)
was heated at 120 °C under solvent-free conditions. TLC
monitoring of the reaction mixture indicated formation of a
new product, which was isolated and purified. Identifica-
tion of its structure by NMR spectroscopy and mass spec-
trometry revealed it to be the fused tricyclic 6:6:6 system,
4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzox- azin-7-one 8,
not the expected product 10 as has been previously report-
ed with similar cyclic hydrazides.10,11 No product other than
1
tetrazine ring. The H-decoupled 13C NMR spectrum of 8e
showed characteristic signals at δ = 11.9, 13.6, 28.2, and
28.6 ppm due to the four methyl substituents, a deshielded
signal at δ = 191.6 ppm arising from the carbonyl group, as
well as 13 other distinct resonances (2 CH2, 4 CH, and 9 C)
in agreement with the proposed structure.15
N
N
R
O
O
N
N
R
H
N
N
O
O
N
N
PTSA (cat.)
O
N
N
N
N
N
N
N
N
+
RCHO
+
+
solvent-free
120 °C
N
N
H
N
N
HN NH
N
R = alkyl, aryl
N
5
6
7
8
9
10 (not observed)
Scheme 2 Three-component reaction between DHBPTz, aldehydes, and dimedone – synthesis of 4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-
ones 8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

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Table 1 Synthesis of 4H,7H-[1,2,4,5]Tetraazino[6,1-b][1,3]benzoxazin-7-ones 8a–k
Entry
Product
Aldehyde
Structure of 8
Time (min)
Yield of 8 (%)a
CHO
N
N
O
H
N
1
8a
10
92
N
N
N
O
CHO
N
N
O
2
3
4
8b
8c
8d
8
94
94
95
H
N
N
N
N
O
OMe
CHO
N
N
O
8
H
N
MeO
N
N
N
O
OMe
OMe
O
MeO
MeO
CHO
N
N
10
H
N
N
N
N
O
Cl
CHO
N
N
O
5
8e
10
92
H
N
Cl
Cl
N
N
N
O
Cl
O
CHO
N
N
H
N
6
8f
12
90
N
N
N
O
NO2
CHO
N
N
O
7
8g
12
90
H
N
O2N
N
N
N
O
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

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Table 1 (continued)
Entry
Product
Aldehyde
Structure of 8
Time (min)
Yield of 8 (%)a
CHO
8
8h
10
91
N
N
O
H
N
N
N
N
O
O
S
N
N
O
O
H
N
9
8i
12
90
CHO
S
N
N
N
N
N
N
N
H
N
10
11
8j
15
15
85
87
MeCHO
N
N
O
Pr
N
N
O
H
N
8k
MeCH2CH2CHO
N
N
O
a Isolated yields.
A plausible mechanism for the formation of the 4H,7H-
[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones 8 is pro-
vided in Scheme 3. It is reasonable to assume that the ene-
dione 11, formed by Knoevenagel condensation of the alde-
hyde 6 and dimedone (7), may undergo Michael addition of
DHBPTz (5) to give the adduct 12. This adduct may cyclize
via nucleophilic attack of the enol onto the active imine
bond of the tetrazine moiety to give intermediate 13. This
intermediate may undergo elimination of 3,5-dimethyl-1H-
pyrazole (9) to afford the corresponding 4H,7H-
[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-one 8.
In summary, we have developed a novel and efficient
approach for the preparation of 4H,7H-[1,2,4,5]tetraazi-
no[6,1-b][1,3]benzoxazin-7-ones via a cyclocondensation
reaction of 1,2-dihydro-3,6-bis(3,5-dimethyl-1H-pyrazol-
1-yl)-1,2,4,5-tetrazine, aldehydes, and 5,5-dimethyl-1,3-cy-
clohexanedione under solvent-free conditions. The simplic-
ity of the starting materials, short reaction times, one-pot
procedure, as well as solvent-free conditions and excellent
yields of the products are the main advantages of the re-
ported reaction.
Pz
HN
N
N
R
O
O
R
O
O
O
O
R
R
O
HN
H
N
••
H
N
H
N
Pz
Pz
+
Pz
H+
N
N
N
N
Pz
+
RCHO
N
••
OH
N
N
N
– H2O
5
Pz
12
N
H
O
N
O
N
N
H
11
7
6
N
13
8
9
N
Pz =
N
Scheme 3 Suggested reaction mechanism for the formation of 4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones 8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

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Acknowledgment
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N. Russ. J. Org. Chem. 1999, 35, 1363. (b) Rusinov, G. L.; Latosh,
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E.; Hiskey, M. A. J. Heterocycl. Chem. 1998, 35, 1329.
This research was supported by the Research Council of the University
of Tehran.
(10) (a) Chari, M. A.; Karthikeyan, G.; Pandurangan, A.; Naidu, T. S.;
Sathyaseelan, B.; Zaidi, S. M. J.; Vinu, A. Tetrahedron Lett. 2010,
51, 2629. (b) Hasaninejad, A.; Zare, A.; Shekouhy, M. Tetrahedron
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378928.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(15) Typical Procedure for the Preparation of Compounds 8a–k
A mixture of DHBPTz (0.272 g, 1.0 mmol), benzaldehyde (0.127
g, 1.2 mmol), dimedone (0.140 g, 1.0 mmol) and PTSA (0.052 g,
0.3 mmol) was heated at 120 °C for the time indicated in Table
1. After completion of the reaction as indicated by TLC monitor-
ing, the reaction mixture was cooled to r.t., and the residue was
purified by column chromatography using n-hexane–EtOAc
(5:1) as eluent. The solvent was removed and the pure product
8a was obtained.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-9,9-dimethyl-6-phenyl-
6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]-
benzoxazin-7-one (8a)
Yield 0.372 g (92%); yellow powder; mp 167 °C. IR (KBr): 3255
and 3144 (NH), 1709 (C=O), 1642 (C=N), 1601, 1491, 1370,
1318, 1270, 1219, 1113, 1028, 971, 911, 773, 744 cm–1. 1H NMR
(500.1 MHz, CDCl3): δ = 1.04 and 1.05 (2 × s, 6 H, 2 × CH3), 1.83
(s, 2 H, CH2), 2.21 (d, 2J = 16.5 Hz, 1 H, CHCCHD), 2.28 (d, 2J = 16.5
Hz, 1 H, CHCCHD), 2.31 and 2.40 (2 × s, 6 H, 2 × CH3), 6.08 (s, 1 H,
pyrazole CH), 6.42 (s, 1 H, NCH), 7.31 (t, J = 7.5 Hz, 1 H, CH), 7.39
(t, J = 7.5 Hz, 2 H, 2 × CH), 7.53 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.95 (s,
1 H, NH). 13C NMR (125.8 MHz, CDCl3): δ = 11.9 and 13.7 (2 ×
pyrazole CH3), 28.4 and 28.6 [C(CH3)2], 34.6 (CH2C=C), 34.7
[C(CH3)2], 50.8 (CH2C=O), 64.0 (NCH), 109.7 (pyrazole CH), 114.0
(C), 127.1, 128.2 and 128.7 (3 × CH), 135.8, 139.2, 143.0, 150.2,
152.5 and 157.8 (6 × C), 191.5 (C=O). MS: m/z (%) = 404 (58)
[M+], 368 (6), 339 (6), 327 (100), 243 (25), 227 (36), 202 (10),
179 (23), 163 (22), 149 (36), 122 (20), 95 (32), 77 (32). Anal.
Calcd (%)for C22H24N6O2 (404.47): C, 65.33; H, 5.98; N, 20.78.
Found: C, 65.30; H, 6.05; N, 20.72.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

182
M. Adib et al.
Letter
Synlett
6-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)-9,9-
dimethyl-6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino-
[6,1-b][1,3]benzoxazin-7-one (8e)
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-9,9-dimethyl-6-propyl-
6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino[6,1-
b][1,3]benzoxazin-7-one (8k)
Yield 0.404 g (92%); yellow powder; mp 207 °C. IR (KBr): 3220
and 3124 (NH), 1695 (C=O), 1648 (C=N), 1593, 1492, 1458,
1370, 1321, 1272, 1220, 1115, 1087, 1018, 970, 909, 831, 791,
743, 680 cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 0.99 and 1.00 (2
× s, 6 H, 2 × CH3), 1.79 (d, 2J = 17.3 Hz, 1 H, CHACHB), 1.80 (d, 2J =
17.3 Hz, 1 H, CHACHB), 2.18 (d, 2J = 16.4 Hz, 1 H, CHCCHD), 2.23
(d, 2J = 16.4 Hz, 1 H, CHCCHD), 2.28 and 2.35 (2 × s, 6 H, 2 × CH3),
6.05 (s, 1 H, pyrazole CH), 6.36 (s, 1 H, NCH), 7.31 (d, J = 8.8 Hz, 2
Yield 0.322 g (87%); yellow powder; mp 189 °C. IR (KBr): 3237
(NH), 1713 (C=O), 1670 (C=N), 1628, 1593, 1493, 1439, 1382,
1323, 1279, 1223, 1134, 1110, 1085, 1028, 970, 934, 904, 850,
814, 773, 716, 670 cm–1. 1H NMR (400.1 MHz, CDCl3): δ = 0.96 (t,
J = 7.3 Hz, 3 H, CH2CH3), 0.98 and 1.01 (2 × s, 6 H, 2 × CH3), 1.40–
1.51 (m, 2 H, CH2), 1.62 (d, J = 17.4 Hz, 1 H, CHACHB), 1.63–1.71
(m, 1 H, CH), 1.72 (d, J = 17.4 Hz, 1 H, CHACHB), 1.81–1.88 (m, 1
H, CH), 2.18 (d, J = 16.3 Hz, 1 H, CHCCHD), 2.24 (d, J = 16.3 Hz, 1
H, CHCCHD), 2.27 and 2.36 (2 × s, 6 H, 2 × CH3), 5.37 (br d, J = 6.3
Hz, 1 H, NCHCH2), 6.04 (s, 1 H, pyrazole CH), 7.55 (s, 1 H, NH).
13C NMR (100.6 MHz, CDCl3): δ = 11.8, 13.6 and 13.8 (2 × pyra-
zole CH3 and CH2CH3), 18.3 (CH2CH3), 28.1 and 28.7 [C(CH3)2],
34.4 (CH2C=C), 34.5 [C(CH3)2], 36.2 (CHCH2), 50.8 (CH2C=O), 62.3
(NCH), 109.6 (pyrazole CH), 113.9, 135.8, 142.9, 150.5, 152.4
and 158.6 (6 × C), 191.7 (C=O). MS: m/z (%) = 370 (5) [M+], 327
(100), 273 (3), 243 (22), 163 (20), 95 (12), 67 (8), 55 (7). Anal.
Calcd (%) for C19H26N6O2 (370.45): C, 61.60; H, 7.07; N, 22.69.
Found: C, 61.51; H, 6.93; N, 22.57.
H, 2 × CH), 7.45 (d, J = 8.8 Hz, 2 H, 2 × CH), 8.51 (s, 1 H, NH). 13
C
NMR (100.6 MHz, CDCl3): δ = 11.9 and 13.6 (2 × pyrazole CH3),
28.2 and 28.6 [C(CH3)2], 34.6 (CH2C=C), 34.7 [C(CH3)2], 50.7
(CH2C=O), 63.3 (NCH), 109.7 (pyrazole CH), 113.5 (C), 128.5 and
128.8 (4 × CH), 133.9, 135.6, 137.9, 143.1, 150.5, 152.6 and
157.8 (7 × C), 191.6 (C=O). MS: m/z (%) = 440 (20) [M+, 37Cl], 438
(65) [M+, 35Cl], 353 (2), 342 (4), 327 (100), 271 (5), 243 (42), 179
(30), 163 (45), 95 (28), 67 (18), 55 (17). Anal. Calcd (%) for
C22H23ClN6O2 (438.92): C, 60.20; H, 5.28; N, 19.15. Found: C,
60.18; H, 5.32; N, 19.11.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 177–182

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