Heterocyclic synthesis using nitrilimines. Part 13: Synthesis of new1,2,3,4-tetrahydro-s-tetrazine derivatives

Article abstract of DOI:10.1016/j.tet.2009.08.036

The reaction of C-aroyl-N-arylnitrilimines with 1,1-dimethylhydrazine or 1-methyl-1-phenylhydrazine led to the formation of the acyclic electrophilic addition products, which underwent thermal oxidative cyclization at CH₃ to 1,2,3,4-tetrahydro-

Full text of DOI:10.1016/j.tet.2009.08.036

Tetrahedron 65 (2009) 8722–8726
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heterocyclic synthesis using nitrilimines. Part 13: Synthesis
of new 1,2,3,4-tetrahydro-s-tetrazine derivatives
*
Hany M.M. Dalloul
Department of Chemistry, Faculty of Applied Science, Al-Aqsa University of Gaza, PO Box 4051, Gaza 76888, Palestine, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2009
Received in revised form 30 July 2009
Accepted 13 August 2009
Available online 19 August 2009
The reaction of C-aroyl-N-arylnitrilimines with 1,1-dimethylhydrazine or 1-methyl-1-phenylhydrazine
led to the formation of the acyclic electrophilic addition products, which underwent thermal oxidative
cyclization at CH3 to 1,2,3,4-tetrahydro-s-tetrazines. Both analytical and spectroscopic data of all the
synthesized compounds are in full agreement with the proposed structures.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
s-Tetrazines
Formazanes
Nitrilimines
Electrophilic addition
Cyclization
1. Introduction
suitably located electrophilic centers.26–28 In continuation of our
research line dealing with the construction of the heterocyclic
Tetrazines have been known for long time1–4 and have been
utilized for a diverse range of practical and synthetic applica-
tions.2,5 Tetrazines exhibit dye,6 insecticide,7 optical,8,9 electro-
chemical,10 and biomedical11,12 properties. Some 1,2,4,5-tetrazine
derivatives have been reportedly used as anti-tumor13 and anti-
inflammatory14 agents. Azolotetrazinones have been the focus of
medicinal chemists in the past decades because of the out-
standing antineoplastic activity exhibited by them. Likewise,
imidazotetrazines15–17 (mitozolomide and temozolomide) have
attracted remarkable attention owing to their efficiency against
malignant melanoma, mycosis, fungoides, and brain tumors. Re-
cently, it has been reported the synthesis of polymers based upon
tetrazine or substituted tetrazine moieties.18–20 Furthermore, tet-
razine chemistries have been useful in the molecular recognition
of environmental contaminants,21 as anion binders22 and in metal
complexation, where 1,4- and 3,6-disubstituted 1,2,4,5-tetrazines
have been studied for their complexing behavior toward transi-
tion metals.20,23–25 Several methods have been reported in liter-
ature for the synthesis of tetrazine derivatives, some of which
employed the cyclocondensation of nitrilimines, generated in situ
from the corresponding hydrazonoyl halides by the action of
systems by means of the nitrilimines cyclocondensation metho-
dology, we investigated the synthesis of some new 1,2,4,5-tetra-
zine derivatives 5a–l.
2. Results and discussion
The precursors of nitrilimines hydrazonoyl halides 1 employed
in this study were prepared by a modified literature procedure.
Recently, we found that nitrilimines 2 react with 1,1-dimethyl- and
1-methyl-1-phenylhydrazine at room temperature for 6–12 h
yielding unexpected amidrazones 626,29,30 (Scheme 1). The same
reaction was found time dependent, when stirred for 20–30 min at
room temperature gave acyclic electrophilic addition products 4a–l
as indicated by TLC (Scheme 1). Cyclization to the corresponding
1,2,4,5-tetrazines 5a–l did not occur. This behavior is similar to that
reported by Ferwanah et al.,29 where the treatment of different
nitrilimines with 1-formyl-, 1-acetyl-, and 1-ethoxycarbonyl-1-
methylhydrazines afforded the corresponding acyclic adducts,
which underwent thermal cyclization to tetrazine rings in presence
of charcoal. The acyclic adducts 4a–l were cyclized intramolecularly
to the corresponding 1,2,3,4-tetrahydro-1,2,4,5-tetrazines 5a–l by
heating them with activated charcoal or lithium hydride in
refluxing benzene or toluene for 2–4 h (Scheme 1). It is worth
noting that the most frequently used method for the preparation of
tetrahydro-1,2,4,5-tetrazines is the cyclization of alkylformazanes
by heating or base treatment.31
a
suitable base, with nucleophilic substrates incorporating
* Tel.: þ972 0599 345943; fax: þ972 08 2845488.
E-mail address: hanydallool@yahoo.com
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.036

H.M.M. Dalloul / Tetrahedron 65 (2009) 8722–8726
8723
O
Structure elucidation of the obtained tetrahydro-1,2,4,5-tetra-
zines 5a–l was achieved by analytical and spectral data, which
summarized in Experimental section. Their mass spectra displayed
the correct molecular ion peaks (Mþ) in accordance with the sug-
gested structures and showed the loss of hydrogen molecule. The IR
spectra exhibited only one absorption band in the 3260–3220 cmꢁ1
region for NH of the tetrazine ring. The 1H NMR spectra of com-
pounds 5a–l showed all the signals of the proposed structures,
indicating the disappearance of Ar–NH proton and the N–CH3 sig-
Ar
N
N
H
R
THF/
6-12h
rt
NH2
Ar
6
O
R
N
N
-
+
Ar
NH
H
O
N
Et3N
-HX
N
Ar
O
R
N
rt
THF/
X
CH3
R
2
+
20-30 min
1
N
N
CH3
Y
H
Y
H2N
N
nal (
d
¼3.2–3.0 ppm) of acyclic adducts 4a–l is replaced by a highly
4a-l
deshielded CH2 signal (
d
¼5.2–5.0 ppm) in compounds 5a–l. This is
3
or LiH
Pd/C
Δ/2-4h
similar to reported values of CH2 flanked by two nitrogens in six-
membered heterocycles.26,29,30 Finally, also the 13C NMR data il-
lustrated that compounds 5a–l have the assigned cyclic structure,
where the N-methyl carbon signal of 4a–l at about 42–38 ppm
disappeared; meanwhile new methylene signal appeared at about
61–56 ppm,26,29,30 whereas the signal of the C]N carbon was
recorded at 143 ppm. The 1H and 13C NMR data for compounds 5a–l
were presented in Experimental section.
X = Cl or Br
Ar = 4-ClC6H4-
Ar
O
N
N
N
N
a, Me/Me; b, Me/Ph; c, Ph/Me; d, Ph/Ph; e, PhNH/Me;
f, PhNH/Ph; g, 2-Furyl/Me; h, 2-Furyl/Ph; i, 2-Thienyl/Me;
j, 2-Thienyl/Ph; k, 2-Naphthyl/Me; l, 2-Naphthyl/Ph
R/Y:
R
H
Y
5a-l
Scheme 1. Synthetic pathway for the preparation of compounds 4a–l and 5a–l.
3. Experimental
3.1. General
A plausible reaction mechanism for this cyclization started by
the oxidation of the acyclic adducts 4a–l to formazanes 7, which
cyclized as reported by Neugebauer and McConnachie31 to the
corresponding tetrahydro-s-tetrazines 5a–l. The formazane
7
All melting points were determined on an A. Kru¨ss Melting Point
Meter and are uncorrected. The IR spectra were measured as po-
tassium bromide pellets using a Satellite 3000 Mid infrared spec-
trophotometer. The 1H NMR and 13C NMR spectra were recorded on
cyclized to the delocalized zwitterionic tetrazoles 8, which changed
through fast proton transfer to the isomeric ylid 9. This ylid cyclized
to the tetrazines 5a–l in Stevens-type rearrangement (Scheme 2).
Ar
H
Ar
NH
Ar
Ar
O
R
N
N
NH
CH3
O
R
N
N
O
R
N
N
N
N
O
R
N
-
N
[O]
CH3
Δ
CH3
Y
N
N
N+
Y
N
CH3
H
Y
Y
4a-l
7
8
Fast proton
trasfer
Ar
Ar
Ar
O
O
N N
N N
O
N
N
Stevens-type
CH2
Y
N N+
Y
CH2
rearrangement
R
R
N N
-
R
N
N+
CH2
H
H
H
Y
9
5a-l
Scheme 2. The suggested reaction mechanism for compounds 5a–l.
2.1. Spectral data analysis
a Bruker AM 300 MHz spectrometer at room temperature in CDCl3
solution using tetramethylsilane (TMS) as internal reference.
The characteristic data of acyclic compounds 4a–l are given in
detail in Experimental section. All compounds gave satisfactory
combustion analysis for the proposed structures, which were
confirmed on the basis of their spectroscopic data. The mass spectra
Chemical shifts were recorded as d values in parts per million (ppm)
downfield from internal TMS. Electron impact (EI) mass spectra
were run on Shimadzu GCMS-QP1000 EX spectrometer at 70 eV.
Elemental analyses were performed at Cairo University, Egypt. The
hydrazonoyl halides 1a–l32,33 were prepared according to literature
procedures. 1,1-Dimethylhydrazine and 1-methyl-1-phenylhydra-
zine were purchased from Across Organics Company, Belgium, and
used without further purification.
ꢀ
showed the correct molecular ion peaks (Mþ ) in accordance with
the suggested structures. The IR spectra of title compounds 4a–l
revealed two absorption bands at the 3380–3200 cmꢁ1 region and
the carbonyl absorption band at the 1690–1640 cmꢁ1 region. Their
1H NMR spectra showed two signals for Ar–NH and NH proton
appeared as singlet at 10.5–10.3 ppm and 6.5–6.2 ppm, re-
spectively. The N-methyl protons in all compounds appeared as
singlet at 3.2–3.0 ppm. The 13C NMR spectra also illustrated that
compounds 4a–l have the assigned acyclic structures. The
N-methyl carbon appeared at about 43–38 ppm, and the signal at
139–136 ppm is attributed to the C]N carbon atom.
3.2. Reaction of nitrilimines 2 with 1-substituted-1-
methylhydrazines 3
Triethylamine (7 mL, 50 mmol) was added at room temperature
to stirred mixture of 1-substituted-1-methylhydrazines 3 (20 mmol)
and the appropriate hydrazonoyl halides
1 (10 mmol) in

8724
H.M.M. Dalloul / Tetrahedron 65 (2009) 8722–8726
tetrahydrofuran (100 mL). The reaction mixture was monitored by
TLC and stirred for 20–30 min at rt, then the precipitated triethyl-
amine salt was filtered off and the solvent was removed under re-
duced pressure. The residue was washed with water (100 mL) and
extracted with chloroform (3ꢂ20 mL) and the combined extracts
were washed with water (50 mL), dried over anhydrous sodium
sulfate. The solvent (CHCl3) was evaporated in vacuo, and the crude
product was triturated with ethanol (5–10 mL). The crude solid
products were collected and recrystallized from ethanol to afford the
desired compounds.
C
21H20ClN5O (393.88) requires: C, 64.04; H, 5.12; N, 17.78%. nmax
(KBr) 3382, 3276, 3240 (NH), 1660 (C]O), 1594 (C]N) cmꢁ1
;
dH
(300 MHz, CDCl3) 10.43 (s, 1H, ArNH), 9.84 (s, 1H, amide), 8.52–7.25
(m, 14H, Ar–H), 6.30 (s, 1H, NH), 3.13 (s, 1H, NCH3) ppm; dC
(300 MHz, CDCl3) 187.1 (C]O), 138.7 (C]N), 141.9, 135.2, 134.7,
132.4, 129.7, 129.2, 128.0, 127.5, 127.1, 124.8, 122.2, 116.5 (Carom.),
ꢀ
39.7 (NCH3) ppm; m/z (393/395 Mþ , chlorine isotopes).
3.2.7. 1-(4-Chlorophenyl)-3-(2-furoyl)-5-methyl-1,2,4,5-tetraaza-2-
hexene (4g). Yield 2.5 g, 78% as a white solid, mp 151–153 ꢃC
(ethanol). Found: C, 55.55; H, 6.11; N, 17.25. C15H19ClN4O2 (322.80)
requires: C, 55.81; H, 5.93; N, 17.36%. nmax (KBr) 3378, 3254 (NH),
3.2.1. 3-Acetyl-1-(4-chlorophenyl)-5-methyl-1,2,4,5-tetraaza-2-hex-
ene (4a). Yield 1.9 g, 75% as a pale yellow solid, mp 146–148 ꢃC.
Found: C, 52.15; H, 6.05; N, 21.90. C11H15ClN4O (254.72) requires: C,
51.87; H, 5.94; N, 22.00%. nmax (KBr) 3385, 3240 (NH), 1690 (C]O),
1655 (C]O), 1597 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.35 (s, 1H,
ArNH), 8.52–7.25 (m, 7H, Ar–H), 6.35 (s, 2H, 2NH), 3.14 (s, 6H,
2NCH3) ppm; dC (300 MHz, CDCl3) 175.3 (C]O),138.8 (C]N),140.9,
136.9, 135.4, 134.9, 128.9, 128.1, 120.6, 114.9 (Carom.), 38.6
1598 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.51 (s, 1H, ArNH), 7.22–
ꢀ
7.05 (m, 4H, Ar–H), 6.20 (s, H, NH), 3.15 (s, 6H, 2NCH3), 2.56 (s, 3H,
CH3) ppm; dC (300 MHz, CDCl3) 193.2 (C]O), 137.9 (C]N), 141.4,
129.3, 126.9, 115.3 (Carom.) 37.9 (NCH3), 24.9 (CH3) ppm; m/z (254/
(NCH3) ppm; m/z (322/324 Mþ , chlorine isotopes).
3.2.8. 1-(4-Chlorophenyl)-3-(2-furoyl)-5-phenyl-1,2,4,5-tetraaza-2-
hexene (4h). Yield 2.8 g, 74% as a white solid, mp 162–164 ꢃC
(ethanol). Found: C, 62.15;H, 5.35; N, 14.72. C20H21ClN4O2 (384.87)
requires: C, 62.42; H, 5.50;N, 14.56%. nmax (KBr) 3375, 3255 (NH),
ꢀ
256Mþ , chlorine isotopes).
3.2.2. 3-Acetyl-1-(4-chlorophenyl)-5-phenyl-1,2,4,5-tetraaza-2-hex-
ene (4b). Yield 2.5 g, 79% as a pale yellow solid, mp 186–188 ꢃC
(ethanol). Found: C, 60.45; H, 5.25; N, 17.80. C16H17ClN4O
(316.79) requires: C, 60.66; H, 5.41; N, 17.69%. nmax (KBr) 3386,
1650 (C]O), 1593 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.42 (s, 1H,
ArNH), 8.52–7.25 (m, 12H, Ar–H), 6.32 (s, 1H, NH), 3.19 (s, 3H,
NCH3) ppm; dC (300 MHz, CDCl6) 175.6 (C]O), 139.4 (C]N), 141.8,
140.2, 137.3, 135.5, 135.1, 129.3, 128.6, 128.3, 127.7, 126.2, 120.1, 115.9
3238 (NH), 1687 (C]O), 1596 (C]N) cmꢁ1
; dH (300 MHz, CDCl3)
ꢀ
10.50 (s, 1H, ArNH), 7.34–7.20 (m, 9H, Ar–H), 6.24 (s, H, NH),
3.25 (s, 3H, NCH3), 2.54 (s, 3H, CH3) ppm; dC (300 MHz, CDCl3)
193.3 (C]O), 138.6 (C]N), 142.2, 137.2, 132.5, 130.4, 129.4, 128.0,
(Carom.) 43.2 (NCH3) ppm; m/z (384/386 Mþ , chlorine isotopes).
3.2.9. 1-(4-Chlorophenyl)-5-methyl-3-(2-thenoyl)-1,2,4,5-tetraaza-
2-hexene (4i). Yield 2.5 g, 75% as a yellow solid, mp 172–174 ꢃC
(ethanol). Found: C, 52.95; H, 5.75; N, 16.70. C15H19ClN4OS (338.86)
requires: C, 53.17; H, 5.65; N, 16.53%. nmax (KBr) 3375, 3260 (NH),
127.3, 115.4 (Carom.), 38.4 (NCH3), 24.9 (CH3) ppm; m/z (316/318
ꢀ
M
þ , chlorine isotopes).
3.2.3. 3-Benzoyl-1-(4-chlorophenyl)-5-methyl-1,2,4,5-tetraaza-2-
hexene (4c). Yield 2.4 g, 76% as a pale yellow solid, mp 159–161 ꢃC
(ethanol). Found: C, 60.40; H, 5.30; N, 17.85. C16H17ClN4O (316.79)
requires: C, 60.66; H, 5.41; N, 17.69%. nmax (KBr) 3365, 3250 (NH),
1665 (C]O), 1596 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.39 (s, 1H,
ArNH), 8.52–7.25 (m, 7H, Ar–H), 6.04 (s, 1H, NH), 3.25 (s, 6H,
2NCH3) ppm; dC (300 MHz, CDCl3) 174.6 (C]O), 138.5 (C]N), 141.9,
136.9, 135.4, 128.9, 128.1, 127.9, 120.6, 115.8 (Carom.), 38.6
ꢀ
1655 (C]O), 1594 (C]N) cmꢁ1
;
dH (300 MHz, CDCl3) 10.30 (s, 1H,
(NCH3) ppm; m/z (338/340 Mþ , chlorine isotopes).
ArNH), 8.12–7.10 (m, 9H, Ar–H), 6.40 (s, 1H, NH), 3.07 (s, 6H,
2NCH3) ppm; dC (300 MHz, CDCl3) 187.8 (C]O), 138.5 (C]N), 141.3,
136.4, 132.2, 130.7, 129.4, 127.9, 127.1, 115.8 (Carom.), 38.8
3.2.10. 1-(4-Chlorophenyl)-5-phenyl-3-(2-thenoyl)-1,2,4,5-tetraaza-
2-hexene (4j). Yield 3.1 g, 77% as a yellow solid, mp 179–181 ꢃC
(ethanol). Found: C, 60.15; H, 5.12; N, 14.10. C20H21ClN4OS (400.93)
requires: C, 59.92; H, 5.28; N, 13.97%. nmax (KBr) 3370, 3265 (NH),
ꢀ
(NCH3) ppm; m/z (316/318 Mþ , chlorine isotopes).
3.2.4. 3-Benzoyl-1-(4-chlorophenyl)-5-phenyl-1,2,4,5-tetraaza-2-
hexene (4d). Yield 2.8 g, 74% as a pale yellow solid, mp 132–134 ꢃC
(ethanol). Found: C, 66.35; H, 4.92; N, 14.90. C21H19ClN4O (378.86)
requires: C, 66.58; H, 5.05; N, 14.79%. nmax (KBr) 3356, 3245 (NH),
1662 (C]O), 1595 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.45 (s, 1H,
ArNH), 8.52–7.25 (m, 12H, Ar–H), 6.07 (s, 1H, NH), 3.18 (s, 3H,
NCH3) ppm; dC (300 MHz, CDCl3) 174.2 (C]O), 139.3 (C]N), 142.5,
137.4, 135.9, 135.2, 134.9, 129.2, 128.4, 128.1, 127.0, 124.7, 120.8, 116.1
ꢀ
1656 (C]O), 1696 (C]N) cmꢁ1
;
dH (300 MHz, CDCl3) 10.33 (s, 1H,
(Carom.) 42.8 (NCH3) ppm; MS m/z (400/402 Mþ , chlorine isotopes).
ArNH), 8.10–7.09 (m, 14H, Ar–H), 6.38 (s, 1H, NH), 3.15 (s, 3H,
NCH3) ppm; dC (300 MHz, CDCl3) 187.2 (C]O), 139.6 (C]N), 141.9,
137.2, 136.7, 132.6, 131.3, 130.9, 130.1, 129.4, 127.9, 127.1, 125.3, 115.9
3.2.11. 1-(4-Chlorophenyl)-5-methyl-3-(2-naphthoyl)-1,2,4,5-tet-
raaza-2-hexene (4k). Yield 2.6 g, 71% as a pale yellow solid, mp
192–194 ꢃC (ethanol). Found: C, 65.75; H, 5.05; N, 15.40.
C20H19ClN4O (366.85) requires: C, 65.48; H, 5.22; N, 15.27%. nmax
ꢀ
(Carom.), 42.3 (NCH3) ppm; m/z (378/380 Mþ , chlorine isotopes).
3.2.5. 1-(4-Chlorophenyl)-5-methyl-3-phenylaminocarbonyl-1,2,4,5-
tetraaza-2-hexene (4e). Yield 2.4 g, 72% as a pale yellow solid, mp
178–180 ꢃC (ethanol). Found: C, 59.15; H, 5.35; N, 21.30.
C16H18ClN5O (331.81) requires: C, 58.92; H, 5.47; N, 21.11%. nmax
(KBr) 3360, 3225 (NH), 1645 (C]O), 1595 (C]N) cmꢁ1
; dH
(300 MHz, CDCl3) 10.46 (s, H, ArNH), 8.65–7.05 (m, 11H, Ar–H), 6.50
(s, H, NH), 3.22 (s, 6H, 2NCH3) ppm; dC (300 MHz, CDCl3) 187.2
(C]O), 137.9 (C]N), 141.1, 135.2, 133.6, 132.7, 132.3, 129.7, 129.4,
(KBr) 3380, 3270, 3235 (NH), 1665 (C]O), 1597 (C]N) cmꢁ1
;
dH
128.2, 127.7, 127.5, 127.0, 126.6, 126.4, 115.9 (Carom.
)
38.9
ꢀ
(300 MHz, CDCl3) 10.41 (s, 1H, ArNH), 9.80 (s, 1H, amide), 8.52–7.25
(m, 9H, Ar–H), 6.24 (s, 1H, NH), 3.05 (s, 6H, 2NCH3) ppm; dC
(300 MHz, CDCl3) 187.1 (C]O), 137.9 (C]N), 141.1, 134.8, 129.4,
129.1, 126.9, 124.3, 119.7, 116.1 (Carom.), 38.3 (NCH3) ppm; m/z (331/
(NCH3) ppm; m/z (366/368 Mþ , chlorine isotopes).
3.2.12. 1-(4-Chlorophenyl)-3-(2-naphthoyl)-5-phenyl-1,2,4,5-tet-
raaza-2-hexene (4l). Yield 3.0 g, 70% as a pale yellow solid, mp 203–
205 ꢃC (ethanol). Found: C, 69.80; H, 5.05; N, 12.95. C25H21ClN4O
(428.93) requires: C, 70.01; H, 4.93; N,13.06%. nmax (KBr) 3365, 3230
ꢀ
333 Mþ , chlorine isotopes).
3.2.6. 1-(4-Chlorophenyl)-5-phenyl-3-phenylaminocarbonyl-1,2,4,5-
tetraaza-2-hexene (4f). Yield 2.8 g, 71% as a pale yellow solid, mp
187–189 ꢃC (ethanol). Found: C, 63.85; H, 4.95; N, 17.90.
(NH), 1644 (C]O), 1592 (C]N) cmꢁ1
; dH (300 MHz, CDCl3) 10.44 (s,
H, ArNH), 8.72–7.10 (m, 16H, Ar–H), 6.47 (s, 2H, 2NH), 3.25 (s, 3H,
NCH3) ppm; dC (300 MHz, CDCl3) 187.4 (C]O), 139.2 (C]N), 141.2,

H.M.M. Dalloul / Tetrahedron 65 (2009) 8722–8726
8725
135.2, 134.2, 133.3, 132.5, 132.4, 130.5, 129.6, 129.4, 129.1, 128.3,
127.8, 127.6, 127.4, 127.1, 126.8, 126.1, 116.3 (Carom.), 43.4
(300 MHz, DMSO-d6) 172.6 (Ar–C]O) 144.0 (C]N), 143.1, 128.9,
128.1, 126.1, 123.8, 121.7, 119.2, 114.9 (Carom.), 60.4 (CH2), 42.5
ꢀ
ꢀ
(NCH3) ppm; m/z (428/430 Mþ , chlorine isotopes).
(CH3) ppm; m/z (329/331 Mþ , chlorine isotopes).
3.3. Thermal cyclization of compounds 5a–l
3.3.6. 4-(4-Chlorophenyl)-2-phenyl-6-phenylaminocarbonyl-1,2,3,4-
tetrahydro-1,2,4,5-tetrazine (5f). Yield 2.8 g, 73% as a white solid,
mp 198–200 ꢃC (benzene/pet. ether). Found: C, 64.60; H, 4.55; N,
18.01. C21H18ClN5O (391.86) requires: C, 64.37; H, 4.63; N, 17.87%.
Acyclic compounds 4a–l (5 mmol) and Pd/charcoal (0.1 w/
w%) or LiH (0.5–1.0 g) in benzene or toluene (50 mL) were
heated to reflux for 2–4 h and monitored by TLC. The reaction
mixture was cooled, then filtered and the solvent was minimized
to one-third amount. Petroleum ether (bp 40–60 ꢃC) was slowly
added to effect complete crystallization of the desired cyclic
compounds 5a–l.
nmax (KBr) 3287, 3230 (NH), 1665 (Ar–C]O), 1594 (C]N) cmꢁ1
; dH
(300 MHz, DMSO-d6) 9.10 (s,1H, amide NH), 8.4–7.2 (m,14H, Ar–H),
6.46 (s, 1H, NH), 4.98 (s, 2H, CH2) ppm; dC (300 MHz, DMSO-d6)
174.5 (Ar–C]O), 144.1 (C]N), 143.4, 141.3, 135.4, 133.9, 131.7, 130.6,
128.9, 128.0, 127.4, 125.1, 122.2, 116.7 (Carom.), 60.6 (CH2) ppm; m/z
ꢀ
The following compounds were synthesized using this method:
(391/393 Mþ , chlorine isotopes).
3.3.1. 6-Acetyl-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5a). Yield 1.9 g, 76% as a yellow solid, mp 138–
140 ꢃC (toluene/pet. ether). Found: C, 52.50; H, 5.08; N, 22.30.
C11H13ClN4O (252.71) requires: C, 52.28; H, 5.19; N, 22.17%. nmax
3.3.7. 4-(4-Chlorophenyl)-6-(2-furoyl)-2-methyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5g). Yield 2.4 g, 76% as off white solid, mp 133–
135 ꢃC (toluene/pet. ether). Found: C, 55.90; H, 5.47; N, 17.35.
C15H17ClN4O2 (320.78) requires: C, 56.17; H, 5.34; N, 17.47%. nmax
(KBr) 3225 (NH), 1695 (C]O), 1596 (C]N) cmꢁ1
;
dH (300 MHz,
(KBr) 3255 (NH), 1656 (C]O), 1597 (C]N) cmꢁ1
; dH (300 MHz,
DMSO-d6) 7.35–7.07 (m, 4H, Ar–H), 6.67 (s, 1H, NH), 5.23 (s, 2H,
CH2), 3.56 (s, 3H, NCH3), 2.61 (s, 3H, CH3) ppm; dC (300 MHz,
DMSO-d6) 8.20–7.18 (m, 7H, Ar–H), 6.58 (s,1H, NH), 5.17 (s, 2H, CH2)
3.51 (s, 3H, CH3) ppm; dC (300 MHz, DMSO-d6) 173.5 (Ar–C]O),
143.9 (C]N), 141.5, 137.3, 135.2, 131.9, 129.1, 128.0, 120.8, 115.5
DMSO-d6) 193.3 (Ar–C]O), 143.7 (C]N), 141.5, 129.5, 127.1, 116.8
ꢀ
ꢀ
(Carom.), 57.3 (CH2), 42.9 (NCH3), 24.5 (CH3) ppm; m/z (252/254 Mþ
,
(Carom.), 61.2 (CH2), 42.2 (CH3) ppm; m/z (320/322 Mþ , chlorine
chlorine isotopes).
isotopes).
3.3.2. 6-Acetyl-4-(4-chlorophenyl)-2-phenyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5b). Yield 2.3 g, 74% as a yellow solid, mp 150–
152 ꢃC (toluene/pet. ether). Found: C, 61.25; H, 4.66; N, 17.91.
C16H15ClN4O (314.78) requires: C, 61.05; H, 4.80; N, 17.80%. nmax
3.3.8. 4-(4-Chlorophenyl)-6-(2-furoyl)-2-phenyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5h). Yield 2.9 g, 75% as off white solid, mp 152–
154 ꢃC (toluene/pet. ether). Found: C, 62.60; H, 4.85; N, 14.76.
C20H19ClN4O2 (382.85) requires: C, 62.75; H, 5.00; N, 14.63%. nmax
(KBr) 3224 (NH), 1698 (C]O), 1598 (C]N) cmꢁ1
;
dH (300 MHz,
(KBr) 3250 (NH), 1652 (C]O), 1593 (C]N) cmꢁ1
; dH (300 MHz,
DMSO-d6) 7.38–7.10 (m, 9H, Ar–H), 6.70 (s, 1H, NH), 5.26 (s, 2H,
CH2), 2.63 (s, 3H, CH3) ppm; dC (300 MHz, DMSO-d6) 193.3 (Ar–
C]O), 143.7 (C]N), 141.3, 133.1, 132.9, 129.7, 129.0, 127.4, 125.2,
DMSO-d6) 8.25–7.20 (m, 12H, Ar–H), 6.60 (s, 1H, NH), 5.19 (s, 2H,
CH2) ppm; dC (300 MHz, DMSO-d6) 173.6 (Ar–C]O), 143.9
(C]N), 141.9, 137.8, 136.7, 134.9, 132.3, 129.4, 128.9, 128.0, 125.2,
ꢀ
ꢀ
116.1 (Carom.), 57.3 (CH2), 24.5 (CH3) ppm; m/z (314/316 Mþ , chlo-
121.6, 116.1, 114.9 (Carom.), 61.2 (CH2) ppm; m/z (382/384 Mþ
,
rine isotopes).
chlorine isotopes).
3.3.3. 6-Benzoyl-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5c). Yield 2.3 g, 72% as a pale green solid, mp 178–
180 ꢃC (toluene/pet. ether). Found: C, 60.85; H, 4.70; N, 17.92.
C16H15ClN4O (314.78) requires: C, 61.05; H, 4.80; N, 17.80%. nmax
3.3.9. 4-(4-Chlorophenyl)-2-methyl-6-(2-thenoyl)-1,2,3,4-tetrahy-
dro-1,2,4,5-tetrazine (5i). Yield 2.6 g, 78% as a pale yellow solid, mp
148–150 ꢃC (toluene/pet. ether). Found: C, 53.25; H, 4.90; N, 16.75.
C15H17ClN4OS (336.85) requires: C, 53.49; H, 5.09; N, 16.63%. nmax
(KBr) 3250 (NH), 1650 (C]O), 1595 (C]N) cmꢁ1
;
dH (300 MHz,
(KBr) 3261 (NH), 1662 (C]O), 1593 (C]N) cmꢁ1
; dH (300 MHz,
DMSO-d6) 7.95–7.16 (m, 7H, Ar–H), 6.52 (s, 1H, NH), 5.12 (s, 2H,
CH2), 3.51 (s, 3H, CH3) ppm; dC (300 MHz, DMSO-d6) 185.3 (Ar–
C]O), 143.5 (C]N), 142.6, 132.9, 129.9, 129.0, 128.2, 125.8, 121.8,
DMSO-d6) 8.25–7.15 (m, 7H, Ar–H), 6.55 (s, 1H, NH), 5.03 (s, 2H,
CH2), 3.55 (s, 3H, CH3) ppm; dC (300 MHz, DMSO-d6) 174.3 (Ar–
C]O), 143.9 (C]N), 141.5, 137.8, 135.6, 133.7, 131.4, 129.6, 124.3,
ꢀ
ꢀ
115.8 (Carom.), 56.2 (CH2), 42.3 (CH3) ppm; m/z (314/316 Mþ , chlo-
115.6 (Carom.), 60.5 (CH2), 42.1 (CH3) ppm; m/z (336/338 Mþ
,
rine isotopes).
chlorine isotopes).
3.3.4. 6-Benzoyl-4-(4-chlorophenyl)-2-phenyl-1,2,3,4-tetrahydro-
1,2,4,5-tetrazine (5d). Yield 2.8 g, 74% as a dirty green solid, mp
154–156 ꢃC (toluene/pet. ether). Found: C, 67.20; H, 4.42; N, 14.75.
C21H17ClN4O (376.85) requires: C, 66.93; H, 4.55; N, 14.87%. nmax
3.3.10. 4-(4-Chlorophenyl)-2-phenyl-6-(2-thenoyl)-1,2,3,4-tetrahy-
dro-1,2,4,5-tetrazine (5j). Yield 2.9 g, 72% as pale green solid, mp
191–193 ꢃC (toluene/pet. ether). Found: C, 60.50; H, 4.92; N, 13.95.
C20H19ClN4OS (398.92) requires: C, 60.22; H, 4.80; N, 14.04%. nmax
(KBr) 3255 (NH), 1655 (Ar–C]O), 1598 (C]N) cmꢁ1
;
dH (300 MHz,
(KBr) 3256 (NH), 1665 (C]O), 1595 (C]N) cmꢁ1
; dH (300 MHz,
DMSO-d6) 7.90–7.12 (m, 14H, Ar–H), 6.57 (s, 1H, NH), 5.19 (s, 2H,
CH2) ppm; dC (300 MHz, DMSO-d6) 185.2 (Ar–C]O), 142.9 (C]N),
142.5, 134.5, 133.7, 132.2, 131.3, 130.2, 129.7, 128.9, 128.3, 126.1,
DMSO-d6) 8.30–7.20 (m, 12H, Ar–H), 6.56 (s, 1H, NH), 5.07 (s, 2H,
CH2) ppm; dC (300 MHz, DMSO-d6) 174.4 (Ar–C]O), 143.9 (C]N),
141.4, 137.8, 136.1, 135.6, 133.7, 131.4, 129.6, 128.6, 128.1, 124.3,
ꢀ
ꢀ
121.4, 116.2 (Carom.), 56.3 (CH2) ppm; m/z (376/378 Mþ , chlorine
121.3, 115.6 (Carom.), 60.5 (CH2) ppm; m/z (398/400 Mþ , chlorine
isotopes).
isotopes).
3.3.5. 4-(4-Chlorophenyl)-2-methyl-6-phenylaminocarbonyl-1,2,3,4-
tetrahydro-1,2,4,5-tetrazine (5e). Yield 2.3 g, 70% as a white solid,
mp 158–160 ꢃC (benzene/pet. ether). Found: C, 58.55; H, 5.00; N,
21.11. C16H16ClN5O (329.79) requires: C, 58.27; H, 4.89; N, 21.24%.
3.3.11. 4-(4-Chlorophenyl)-2-methyl-6-(2-naphthoyl)-1,2,3,4-tetra-
hydro-1,2,4,5-tetrazine (5k). Yield 2.7 g, 73% as a yellow solid, mp
172–174 ꢃC (benzene/pet. ether). Found: C, 66.05; H, 4.55; N, 15.45.
C20H17ClN4O (364.84) requires: C, 65.84; H, 4.70; N, 15.36%. nmax
nmax (KBr) 3290, 3235 (NH), 1660 (C]O), 1592 (C]N) cmꢁ1
;
dH
(KBr) 3232 (NH), 1645 (C]O), 1597 (C]N) cmꢁ1
; dH (300 MHz,
(300 MHz, DMSO-d6) 8.89 (s, 1H, amide NH), 7.8–7.2 (m, 9H, Ar–H),
6.49 (s, 1H, NH), 4.96 (s, 2H, CH2), 3.48 (s, 3H, CH3) ppm; dC
DMSO-d6) 8.60–7.17 (m, 11H, Ar–H), 6.53 (s, 1H, NH), 5.00 (s, 2H,
CH2), 3.52 (s, 3H, CH3) ppm; dC (300 MHz, DMSO-d6) 183.9

8726
H.M.M. Dalloul / Tetrahedron 65 (2009) 8722–8726
7. Tsuda, S.; Manabe, Y.; Tsuji, K. Jpn. Pat. 107,254, 1988.
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Renault, R. Chem.dEur. J. 2005, 11, 5667–5673.
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(Ar–C]O), 143.9 (C]N), 141.3, 135.4, 134.1, 132.4, 132.2, 130.0,
129.6, 129.1, 128.4, 128.2, 127.5, 126.3, 125.8, 115.5 (Carom.), 56.8
ꢀ
(CH2), 42.3 (CH3) ppm; m/z (364/366 Mþ , chlorine isotopes).
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3.3.12. 4-(4-Chlorophenyl)-6-(2-naphthoyl)-2-phenyl-1,2,3,4-tetra-
hydro-1,2,4,5-tetrazine (5l). Yield 3.0 g, 70% as a dirty green solid,
mp 184–186 ꢃC (benzene/pet. ether). Found: C, 70.55; H, 4.40; N,
12.95. C25H19ClN4O (426.91) requires: C, 70.34; H, 4.49; N, 13.12%.
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nmax (KBr) 3235 (NH), 1648 (C]O),1596 (C]N) cmꢁ1
; dH (300 MHz,
DMSO-d6) 8.58–7.15 (m, 16H, Ar–H), 6.58 (s, 1H, NH), 5.02 (s, 2H,
CH2) ppm; dC (300 MHz, DMSO-d6) 184.2 (Ar–C]O), 143.6 (C]N),
141.7, 135.4, 134.3, 132.9, 132.4, 132.2, 131.9, 130.2, 129.7, 129.0,
128.7, 128.7, 127.9, 127.5, 126.7, 125.6, 121.7, 116.2 (Carom.), 56.9
ꢀ
(CH2) ppm; m/z (426/428 Mþ , chlorine isotopes).
4. Conclusion
The reaction of several nitrilimines with 1,1-dimethylhydrazine
or 1-methyl-1-phenylhydrazines leads to formation of 1,3,5-
trisubstituted 1,2,4,5-tetraaza-2-hexene, which underwent ther-
mal cyclization to corresponding 1,2,3,4-tetrahydro-s-tetrazine
derivatives.
Acknowledgements
The author is thankful to the Union Arab Universities, Sup-
porting Box of Palestinian Universities, Amman, Jordan, for partial
finance support.
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