Synthesis, crystal structures and quantum chemical calculations of 3,6-diphenyl-1,2-dihydro- and 1,4-dihydro-1,2,4,5-tetrazine derivatives

Article abstract of DOI:10.3184/174751913X13783040292986

1-Acyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared by treatment of 3,6-diphenyl-1,4- (or 1,2)-dihydro-1,2,4,5-tetrazine and an equimolar amount of an acyl chloride. Further reaction with another equivalent of an acyl chloride yielded 1,4(or

Full text of DOI:10.3184/174751913X13783040292986

586 RESEARCH PAPER
OCTOBER, 586–591
JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis, crystal structures and quantum chemical calculations of
3,6-diphenyl-1,2-dihydro- and 1,4-dihydro-1,2,4,5-tetrazine derivatives
Zhen-Zhen Yanga, Feng Xua*, Zhong-Lu Kea, Hong-Yun Chena, Wei-Xiao Hub and Hai-Bo Lic
aBiopharmaceutical Research and Development Centre, Taizhou Vocational and Technical College, Taizhou 318000, P. R. China
bCollege of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, P.R. China
cLaboratory of Microbiology Nantong Center for Disease Control and Prevention (CDC), Nantong 226007, P.R. China
1-Acyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared by treatment of 3,6-diphenyl-1,4- (or 1,2)-dihydro-1,2,4,5-
tetrazine and an equimolar amount of an acyl chloride. Further reaction with another equivalent of an acyl chloride yielded
1,4(or 1,2)-diacyl-3,6-diphenyl-1,4(or 1,2)-dihydro-1,2,4,5-tetrazines. Their structures are confirmed by 1H NMR, IR, and mass
spectra and by elemental analysis and X-ray diffraction. The experimental results are also validated by calculation of molecular
stabilisation energies with the DFT calculations (B3LPY method). It can be shown that when alkanoyl chlorides are used, the
products are the 1,4-dihydro-1,2,4,5-tetrazines, whereas acylation with aroyl chlorides affords 1,2-dihydro-1,2,4,5-tetrazines.
Keywords: dihydro-1,2,4,5-tetrazine, crystal structure, synthesis, quantum chemical calculation
Compounds containing the 1,2,4,5-tetrazine skeleton have
anti-inflammatory,1 anticancer,2 insecticidal3 and antiviral4
activities. In recent years, some dihydro-1,2,4,5-tetrazine
derivatives have attracted attention due to their good anticancer
activity, especially for 1,4-dihydro- and 1,2-dihydro-1,2,4,5-
tetrazine derivatives For example, N1,N4-bis(o-tolyl)-3,6-
Results and discussion
The synthesis procedures for 1,4 (or 1,2)-diacyl-3,6-diphenyl-
1,4(or 1,2)-dihydro-1,2,4,5-tetrazines are summarised in
Scheme 1. 3,6-Diphenyl-1,4(or 1,2)-dihydro-1,2,4,5-tetrazine
1 (or 1’) was first prepared by the literature procedure.12
Then, compound 1 (or its tautomer 1’) was reacted with 1
equiv. of an acyl chloride in chloroform at 0 °C to yield the
dimethyl-1,4-dihydro-
1,2,4,5-tetrazine-1,4-dicarboxamide
(ZJGDHu-1, Fig. 1), showed excellent anticancer activities
against human P-388, Bel-7402, MCF-7 and A-549 cell lines
with IC50 values 0.6, 0.6, 0.5 and 0.7 μM, respectively.5
1-Chloroacetyl- 3,6-diphenyl-1,2-dihydro-1,2,4,5-tetrazine is a
highly effective compound against human P-388 and A-549 cell
lines at the concentration 10–6 mol L–1.6
1-acyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazines
2
that
were subsequently acylated with an equimolar amount of
the same acyl chloride in dichloromethane in the presence
of 4-(dimethylamino)pyridine (DMAP) as a catalyst. These
Until now, there have been few reports on synthetic routes
to 1,4-disubstituted-1,4-dihydro- or 1,2- disubstituted-1,2-
dihydro-1,2,4,5-tetrazines.5,7–10 Hu et al.5,7 reported the synthesis
of 1,4-diaryl-3,6-dialkyl- 1,4-dihydro-1,2,4,5-tetrazine-1,4-
dicarboamides which were prepared from 3,6-dialkyl-1,6-
dihydro-1,2,4,5- tetrazines and isocyanates. The drawback
of this method is its narrow scope; thus it cannot be readily
extended to obtain 1,4-disubstituted-3,6-diaryl-1,2,4,5-
tetrazines because of the inaccessibility of the requisite starting
materials, namely 3,6-diaryl-1,6-dihydro-1,2,4,5-tetrazines.
Tewari et al.8 have adopted phenacylidenedimethylsulfurane
and diazonium salts to synthesise 1,4-disubstituted-3,6-diaryl-
1,4-dihydro-1,2,4,5-tetrazine derivatives.8 The difficultly of
accessing phenacylidenedimethylsulfurane is also the problem
with this method. Rao et al.9,10 have attempted to synthesise
1,4-disubstituted-3,6-daryl-1,4-dihydro-1,2,4,5-tetrazine-1,4-
dicarboxylates from 1,4-dihydro-3,6-diaryl -1,2,4,5-tetrazines
and chloroformates. Unexpectedly, they only obtained the
N
NH
N
N
N
NH
NH
i
or
CN
HN
1
1'
O
O
N
N
N
R
iv
N
N
N
N
R
HN
R
ii
O
R= a-f
2a-f
3a-f
iii
O
O
isomeric
1,2-disubstituted-3,6-diaryl-1,2-dihydro-1,2,4,5-
N
N
N
Ar
tetrazine-1,2-dicarboxylates.9,10 Motivated by these findings, and
asacontinuationofourresearchinto1,2-or1,4-disubstituted-3,6-
diaryl-dihydro-1,2,4,5-tetrazines,11 we explored the acylation of
3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine with acyl chlorides
to establish whether the reaction affords 1,2-dihydro-1,2,4,5-
tetrazines or 1,4- dihydro-1,2,4,5-tetrazines.
v
N
N
Ar
Ar
HN
N
N
O
Ar= g-j
2g-j
3g-i
H3C
CH3
O
a: Me; b: Et, c: n-Pr; d: n-Amyl; e:C(CH3)3; f: CH(CH3)2;
g: Ph; h: p-CH3-Ph; i: p-Cl-Ph; j: p-NO2-Ph
N
N
N
NH
HN
N
Reagents and conditions: (i) 80% NH2NH2·H2O, S8 powder, 95% EtOH,
reflux; (ii) RCOCl, pyridine, CHCl3, 0 °C; (iii) ArCOCl, pyridine, CHCl3, 0 °C;
ne,(iv) RCOCl, CH2Cl2 DMAP, rt – reflux; (v) ArCOCl, CH2Cl2, DMAP, rt –
reflux;.
O
CH3
CH3
Fig. 1 The structure of ZJGDHu-1.
* Correspondent. E-mail: xufeng901@126.com
Scheme 1 Synthesis of the compounds 2a–j, 3a–i.
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JOURNAL OF CHEMICAL RESEARCH 2013 587
reactions
provided
1,4-diacyl-3,6-diphenyl-1,4-dihydro-
of nitrogen N4 is located at the 4 position, so the compound
belongs to the 1,4-dihydro-1,2,4,5-tetrazine rather than
1,2-dihydro-1,2,4,5-tetrazine (Fig. 2) series. In the tetrazine
ring, atoms N2, C3, N5 and C6 are coplanar within 0.001 Å,
while atoms N1 and N4 deviate from the plane by 0.503 (2)
and 0.363 (2) Å, respectively, so the central tetrazine ring
adopts an unsymmetrical boat conformation. The phenyl rings
C7–C12, C13–C18 and alkyl chain C19–C21 make dihedral
angles of 35.99 (3)°, 27.76 (3)°and 38.56 (3)°, respectively, with
the N2/C3/N5/C6 plane. The crystal packing is stabilised by
intermolecular N–H---O and C–H---O interactions (Table 1).
In the crystal structure of 3a, N2, C3,N5 and C6 are coplanar
within 0.001 Å, while atoms N1 and N4 deviate from the
plane by 0.267 (2) and 0.267 (2) Å, respectively, so the central
tetrazine ring also adopts an symmetrical boat conformation.
The phenyl rings C7–C12, C13–C18, acetyl chains C19–C20
1,2,4,5-tetrazines (3a–f) or 1,2-diacyl-3,6-diphenyl-1,2-
dihydro- 1,2,4,5-tetrazines (3g–i) depending upon whether an
alkanoyl chloride or an aroyl chloride, respectively, had been
employed in the acylation reaction.
There is still confusion as to whether the structure of the
product from the first step of the reaction is a 1,4-dihydro-
or 1,2-dihydro-1,2,4,5-tetrazine. Although Rao et al.2 has
proved the structure of 3,6-dibenzyl-1,4-dihydro-1,2,4,5-
tetrazine by X-ray crystallography, no single crystal structure
of a 3,6-diphenyl-1,4-dihydro-1,2,4,5- tetrazine has ever been
reported.
1
Similar to the above situation, the IR, H NMR, MS and
elemental analysis data for the products 2 and 3 are equivocal
as to whether the structures are 1,2- or 1,4-dihydro-1,2,4,5-
tetrazines. However, this question is easily resolved by single
crystal X-ray diffraction. The crystal structure of 2g has been
reported,11 and the molecular structures of 2b, 3a and 3g are
shown in Figs 2 and 3, respectively. From these, it is apparent that
the compounds 2b and 3a are 1,4-dihydro-1,2,4,5-tetrazines,
whereas 3g is a 1,2-dihydro-1,2,4,5-tetrazine. This is an
unexpected result, because when 3,6-diaryl-1,2,4,5-tetrazines
were reacted with alkyl chloroformates only 3,6-diaryl-1,2-
dihydro-1,2,4,5-tetrazine-1,2-dicarboxylates were isolated,
but their isomers, 3,6-diaryl-1,4-dihydro-1,2,4,5-tetrazine-1,4-
dicarboxylates,9,10 were not obtained.
Table 1 Hydrogen bond lengths (Å) and bond angles (°) for compounds
2b, 3a and 3g
d(D–H)
D–H...A
d(H...A) d(D...A)
∠DHA
Compound 2b
N(4)–H(4’N)---O(1’)i
N(4’)–H(4’N)---O(1)ii
C(12)–H(12)---O(1’)i
Compound 3a
0.91(2)
0.90(2)
0.95(2)
1.97(3)
2.00(3)
2.43(2)
2.85(2)
2.88(2)
3.31(2)
163(2)
167(2)
153(2)
C(9)–H(9)---O(2)iii
0.95(2)
0.95(2)
0.98(2)
2.54(3)
2.45(2)
2.52(2)
3.47(2)
3.39(2)
3.38(2)
167(2)
173(2)
147(2)
C(16)–H(16)---O(2)iv
C(22)–H(22c)---O(1)v
Compound 3g
In the crystal structure of 2b, it is obvious that the hydrogen
C(10”)–H(10”)---O(1’)vi
C(16”)–H(16”)---O(1”)vii
C(23”)–H(23”)---O(1”) viii
C(24)–H(24)---O(2”)vi
C(24”)–H(24”)---O(2’)viii
C(29”)–H(29”)---N(5’)ix
C(11’)–H(11’)---Cg(15)x
C(18)–H(18)---Cg(5)x
C(18’)–H(18’)---Cg(10)x
C(18”)–H(18”)---Cg(15)x
C(30)–H(30)---Cg(4)xi
C(32)–H(32)---Cg(2)xi
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
0.95(2)
2.53(2)
2.44(2)
2.46(2)
2.37(2)
2.50(2)
2.62(2)
2.79(2)
2.71(2)
2.94(2)
2.96(2)
2.89(2)
2.81(2)
3.47(2)
3.26(2)
3.35(2)
3.24(2)
3.40(3)
3.38(2)
3.52(2)
3.45(2)
3.61(2)
3.71(2)
3.75(2)
3.69(2)
174(3)
144(2)
155(2)
151(2)
158(3)
138(2)
135(2)
135(2)
129(2)
137(2)
151(2)
155(2)
Symmetry codes: (i) x,1/2–y,1/2+z; (ii) 1–x,1–y,1–z; (iii) 1–x,1–y,–z; (iv)–
x,1–y,1–z; (v) 1+x,y,z; (vi) 1/2–x,–1/2+y,z; (vii) 1/2–x,1/2+y,z; (viii) 3/2–
x,1/2+y,z; (ix) 1/2+x,y,1/2–z; (x) x, y, z; (xi) 1/2–x,1/2+y, z. Cg(2) is centroid
of phenyl ring (C7–C12) of compound 3g; Cg(4) is centroid of phenyl ring
(C20–C25)of compound 3g; Cg(5) is centroid of phenyl ring (C27–C32) of
compound 3g; Cg(10) is centroid of phenyl ring (C27’–C32’) of compound
3g; Cg(15) is centroid of phenyl ring (C27’’–C32’’) of compound 3g.
Fig. 2 Molecular structure of 2b with atomic labelling scheme at 30%
probability displacement ellipsoids.
Fig. 3 Molecular structure of 3a and 3g with atomic labelling scheme at 30% probability displacement ellipsoids.
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588 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 The calculated molecular stabilisation energies E(HF) of
compounds 3 or their isomers 3’ by DFT method
Cl
R
Ph
H
Ph
Ph
R
N
O
E(HF)
in vacuum/a.u.
E(HF) in
dichloromethane/a.u.
Compoundsa
N
N
N
O
N
N
N
NH
N
R
N
Cl
+
R
3a
3a’
3b
3b’
3c
3c’
3g
3g’
3h
3h’
3i
–1064.894853
–1064.893226
–1143.517224
–1143.516106
–1222.143886
–1222.141715
–1448.353508
–1448.352642
–1526.995665
–1526.987238
–2367.565700
–2367.561584
–1064.897518
–1064.895016
–1143.519543
–1143.517925
–1222.145792
–1222.143230
–1448.355263
–1448.354746
–1526.995938
–1526.989494
–2367.566351
–2367.561910
O
Ph
O
N(CH3)2
A
2
N(CH3)2
Ph
Ph
O
N
N
N
N
R
-HCl
R
O
R=alkyl
3
Ph
O
N
N
N
Ar
H
H
O
3i’
NH
Ar
aCompounds 3a’,3b’, 3c’, 3g’, 3h’ and 3i’ are all isomers of 3a, 3b, 3c, 3g,
3h and 3i, respectively. 3a’, 3b’ and 3c’ belong to the 1,2- dihydro-1,2,4,5-
tetrazine series, and 3g’, 3h’ and 3i’ are 1,4-dihydro-1,2,4,5-tetrazines.
N
N
Ar
Ar
N
N
N
Ph
N
NH
N
N
O
O
Cl
4
H
O
O
N
Ph
Cl
N(CH3)2
N
(H3C)2N
-HCl
Cl
Ph
dichloromethane are lower than those in vacuum for all
compounds, which indicates 3 or 3’ in dichloromethane are more
stable than in vacuum. The values of E(HF) for compounds 3
are all lower than for their isomers 3’ whether in vacuum or
in dichloromethane, which shows that compounds 3 are more
stable than their isomers 3’. Thus the possibly existent structures
for compounds 3a–f are 1,4-dihydro-1,2,4,5-tetrazines, rather
than their 1,2-dihydro-1,2,4,5-tetrazine isomers. The structures
for compounds 3g–i are thus 1,2-dihydro-1,2,4,5-tetrazines,
rather than their isomers 1,4-dihydro-1,2,4,5-tetrazines. The
above results are consistent with the experimental results.
N(CH3)2
C
Ph
Ph
O
O
B
N
N
N
Ar
Ar
N
3
Scheme 2 Proposed reaction mechanism for the synthesis of the
compounds 3.
and C21–C22 make dihedral angles of 26.43 (3)°, 41.89 (3)°,
27.73 (3)° and 32.57 (3)°, respectively, with the N2/C3/N5/C6
plane. The crystal packing is stabilised by intermolecular C–H-
--O interactions (Table 1). In the crystal structure of 3g, there
are three molecules in one crystal unit cell. The atoms N2, C3,
N4 and N5 are almost coplanar within 0.002 Å, while atoms
N1 and C6 deviate from the plane by 0.998 (2) and 0.592 (2)
Å, respectively. The phenyl rings C7–C12, C13–C18, C20–C25
and C27–C32 make dihedral angles of 16.87 (3)°, 2.36 (3)°,
67.30 (2)° and 49.30(2)°, respectively, with the N2/C3/N4/N5
plane. The crystal packing is stabilised by intermolecular C–H-
--O, C–H---N and C–H---π interactions (Table 1). The other
two molecules have the similar situation to the above molecule.
A plausible mechanism for the synthesis of compounds 3
is depicted in Scheme 2. Compound 2 attacks the carbonyl
group of the N-acylpyridinium salt to form the intermediate
(A), and then elimination of hydrogen chloride from A leads
to the formation of 3; Alternatively under the influence of base,
2 could be converted to its isomer 4, which then attacks the
carbonyl group of the N-acylpyridinium salt (as in B) to form the
intermediate (C). The latter may be stabilised by intramolecular
C–H---π interactions between the phenyl rings and the
developing N-aroyl moiety in C. This situation can be proved
by the crystal structure of 3g, in which the intramolecular C–H-
--π interactions (C18–H18---Cg, Cg is centroid of the phenyl ring
from C27 to C32, Fig. 3) are apparent. Finally, elimination of
hydrogen chloride leads to the formation of 3.
Conclusions
Some 3,6-diphenyl-1,2- or 1,4-dihydro-1,2,4,5-tetrazine
derivatives were designed and synthesised. The conformations
of the compounds 2b, 3a and 3g were confirmed by X-ray
diffraction. It was shown that when alkanoyl chlorides were
used to acylate 3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine 1 the
products were the 1,4-dihydro-1,2,4,5-tetrazines 3a–f whereas
acylation with aroyl chlorides afforded 1,2-dihydro-1,2,4,5-
tetrazines 3g–i.
Experimental
All the chemical reagents purchased were of analytical grade
and used without further purification, except for chloroform and
dichloromethane, which were dried by refluxing in the presence of
calcium hydride and distilled prior to use. Melting points were carried
out on a XRC-1 apparatus and are uncorrected (Beijing Technical
Instrument Co.). IR spectra were recorded from KBr discs of solid
materials, on a Nicolex FI-IR-170 instrument. The 1H NMR spectra were
run on Bruker AC500 (500 MHz) or AC400(400 MHz) instruments.
Compounds were dissolved in CDCl3 or DMSO-d6, and chemical shifts
were referenced to TMS. High-resolution mass spectra (HRMS) were
obtained on an Agilent 6210 TOF LC-MS. Mass spectra were obtained
on a Agilent 1260 lon Trap LC-MS 500 analysis system. Elemental
analyses were performed on a Thermo-Finnigan Flash EA 1112
Inordertovalidateaboveresult,weadoptedGaussiansoftware
to calculate molecular stabilisation energies of compounds 3 by
the DFT method. Since the reaction proceeded in a solvent, the
quantisation calculation process should take into account the
solvent effect, i.e. it should calculate the molecular stabilisation
energies in a vacuum and in dichloromethane respectively.
The results are shown in Table 2; compounds 3’ represent the
corresponding isomers of compound 3, namely, 3a’, 3b’ and 3c’
belonging to the 1,2- dihydro-1,2,4,5-tetrazine series, and 3g’,
3h’ and 3i’ are 1,4-dihydro-1,2,4,5-tetrazines (Fig. 4).
O
O
O
N
N
N
N
R
R
N
N
N
N
Ar
Ar
3a': R=Me;
3b': R=Et;
3c': R=n-Pr
3g': R=Ph;
3h': R=4-Me-Ph;
3i': R=4-Cl-Ph
O
From Table 2, it is apparent that the values of E(HF) in
Fig. 4 The structures of compound 3'.
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JOURNAL OF CHEMICAL RESEARCH 2013 589
instrument. TLC was carried out on silica gel UV-254 plates. X-ray
diffraction data were recorded on a Rigaku AFC10 diffractometer.
m/z (%): 355.5(M+H+, 100). Anal. Calcd for C22H18N4O: C, 74.56; H, 5.12;
N, 15.81; O, 4.51. Found: C, 74.57; H, 5.12; N, 15.80; O, 4.51%.
1-(4-Chlorobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2i):
Yield: 31.8%; yellow solid, m.p. 188–190 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.21 (s, 1H, NH), 7.94 (d, 2H, J=7.5 Hz, Ar), 7.65–7.67 (m, 2H,
Ar), 7.60–7.62 (m, 2H, Ar), 7.54–7.57 (m, 1H, Ar), 7.35–7.47 (m, 7H, Ar).
IR(KBr) νmax/cm–1: 3279, 2973, 1635, 1466, 1390, 1144, 1014, 962; ESI-
MS m/z (%): 375.2 (M+H+, 100). Anal. Calcd for C21H15ClN4O: C, 67.29;
H, 4.03; N, 14.95; O, 4.27. Found: C, 67.28; H, 4.02; N, 14.96; O, 4.27%.
Synthesis of compounds (2a–j); general procedure
The appropriate acyl chloride (3.4 mmol) in chloroform (10 mL) under
stirring at 0 °Cwas added dropwise to a solution of 3,6-diphenyl-1,4-
dihydro-1,2,4,5-tetrazine 1 (or 1’) (0.47 g, 3.4 mmol) in chloroform
(20 mL) and pyridine (0.27 g, 3.4 mmol). The mixture was stirred
for 20–30 h during which time the progress of the reaction was also
monitored by TLC (ethyl acetate). After the reaction was complete, the
solvent was distilled off under vacuum and anhydrous ethanol (20 mL)
was added to the residue. The mixture was heated until the residue was
completely dissolved and then cooled to room temperature, filtered, and
the filtrate distilled off under vacuum. The residue was recrystallised
from anhydrous ethanol to obtain the target compounds.
1-(4-Nitrobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine
(2j):
Yield: 55.8%; orange solid, m.p. 195–197 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.30 (d, 2H, J=7.8 Hz, Ar),8.16 (s, 1H, NH), 8.12 (br.s, 2H, Ar),
7.57–7.63 (m, 5H, Ar), 7.46–7.50 (m, 2H, Ar), 7.40–7.42 (m, 3H, Ar).
IR (KBr) νmax/cm–1: 3307, 3109, 2971, 1653, 1466, 1389, 1142, 963; ESI-
MS m/z (%): 386.3(M+H+, 100), 408.1(M+Na+, 47). Anal. Calcd for
C21H15N5O3: C, 65.45; H, 3.92; N, 18.17; O, 12.45. Found: C, 65.47; H, 3.92;
N, 18.16; O, 12.44%.
1-Acetyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2a): Yield:
51.5%; yellow solid, m.p. 168–170 °C(lit.6 164–165 °C). ESI-MS m/z
(%): 279.2(M+H+, 100).
1-Propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2b): Yield:
48.5%; yellow solid, m.p. 141–143 °C (lit.6 145 °C). ESI-MS m/z (%):
293.2(M+H+, 100).
Synthesis of compounds (3a–3i); general procedure
The appropriate acyl chloride (2.0 mmol) in dichloromethane (10 mL)
was added dropwise to a solution of 1-acyl-3,6-diphenyl-1,4-dihydro-
1,2,4,5-tetrazine 2 (2.0 mmol) and DMAP (0.26 g, 2.1 mmol) in
dichloromethane (20 mL) under stirring at room temperature. The
mixture was first stirred for 1 h at room temperature, then heated to
reflux for 30–50 h during which time the progress of the reaction was
monitored by thin-layer chromatography (eluent, petroleum ether-ethyl
acetate=1:1). After the reaction was complete, the solvent was distilled
off under vacuum and the residue was chromatographed on a silica gel
column using petroleum ether-ethyl acetate (6:4) as the eluent to give the
product 3 as a white solid.
1,4-Diacetyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (3a): Yield:
51.5%; white solid, m.p. 143–145 °C. 1H NMR (500 MHz,CDCl3) δ
(ppm); 8.02–8.05 (m, 4H, Ar); 7.50–7.53 (m, 6H, Ar), 2.51(s, 6H, 2CH3).
IR (KBr) νmax/cm–1: 2962, 1696, 1452, 1381, 1252, 980; ESI-MS m/z
(%): 321.2 (M+H+, 5). Anal. Calcd for C18H16N4O2: C, 67.49;H, 5.03;N,
17.49;O, 9.99;Found C, 67.55;H, 5.02;N, 17.51;O, 10.01%.
1-Butyryl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2c): Yield:
1
58.5%; yellow solid, m.p. 142–144 °C. H NMR(500 MHz, CDCl3) δ
(ppm); 8.06 (s, 1H, NH), 7.75–7.77 (m, 2 H, Ar), 7.47–7.59 (m, 5 H, Ar),
7.38–7.42 (m, 3 H, Ar), 2.79 (br.s, 2H, CH2), 1.78 (sext, 2H, J=7.4 Hz,
CH2), 1.05 (t, 3H, J=7.4 Hz, CH3). IR (KBr) νmax/cm-1 3294, 2959,
1653, 1472, 1400, 1148, 1095, 992; ESI-MS (%) 307.2(M+H+, 100),
329.1(M+Na+, 57). Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92; N,
18.29; O, 5.22. Found:: C, 70.59; H, 5.92; N, 18.28; O, 5.21%.
1-Hexanoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2d): Yield:
38.2%; yellow solid, m.p. 179–181 °C. 1H NMR(500 MHz, CDCl3)δ
(ppm); 8.20(s, 1H, NH), 7.74–7.75 (m, 2 H, Ar), 7.47–7.59 (m, 5 H, Ar),
7.38–7.42 (m, 3 H, Ar), 2.79 (brs, 2 H, CH2), 1.78 (sext, 2 H, J=7.4 Hz,
CH2), 1.05 (t, 3H, J=7.4 Hz, CH3). IR (KBr) νmax/cm–1 3281,, 2928, 1686,
1459, 1389, 1147, 1097, 986; ESI-MS m/z (%): 335.2(M+H+, 100). Anal.
Calcd for C20H22N4O: C, 71.83; H, 6.63; N, 16.75; O, 4.78. Found:: C,
71.85; H, 6.62; N, 16.73; O, 4.78%.
1,4-Propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine
(3b):
1-Pivaloyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2e): Yield:
62.2%; yellow solid, m.p. 153–155 °C. 1H NMR(500 MHz, CDCl3)δ
(ppm); 8.16 (s, 1H, NH), 7.76–7.78 (m, 2 H, Ar), 7.46–7.58 (m, 5 H, Ar),
7.38–7.41 (m, 3 H, Ar), 1.48 (s, 9 H, 3CH3). IR(KBr) νmax/cm–1: 3289, 2955,
1631, 1470, 1397, 1147, 1012, 975; ESI-MS m/z (%): 321.2(M+H+, 100).
Anal. Calcd for C19H20N4O: C, 71.23; H, 6.29; N, 17.49; O, 4.99. Found::
C, 71.26; H, 6.29; N, 17.47; O, 4.98%.
1-Isobutyryl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2f): Yield:
45.5%; yellow solid, m.p. 147–149 °C. 1H NMR(500 MHz, CDCl3)δ
(ppm); 8.10 (s, NH), 7.75–7.77 (m, 2 H, Ar), 7.47–7.59 (m, 5 H, Ar), 7.37–
7.42 (m, 3 H, Ar), 3.50 (br.s, 1 H, CH), 1.28 (d, 6 H, J=6.9 Hz, 2 CH3). IR
(KBr) νmax/cm-1: 3296, 2973, 1642, 1469, 1411, 1146, 1085, 989; ESI-MS
m/z (%): 307.3(M+H+, 100). Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92;
N, 18.29; O, 5.22. Found:: C, 70.58; H, 5.92; N, 18.28; O, 5.21%.
Yield: 41.3%; white solid, m.p. 128–130 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.02–8.05 (m, 4H, Ar), 7.49–7.53 (m, 6H, Ar), 2.88 (q, 4 H,
J=6.0 Hz);1.24 (t, 6 H, J=6.0 Hz). IR (KBr) νmax/cm–1: 2971, 1701, 1454,
1373, 1267, 1069, 944; ESI-MS: m/z (%): 349.2 (M+H+, 10). Anal. Calcd
for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08; O, 9.18. Found: C, 68.98; H,
5.77; N, 16.10; O, 9.16%.
1,4-Butyryl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (3c): Yield:
35.3%; white solid, m.p. 111–113 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.03–8.05(m, 4H, Ar),7.50–7.54 (m, 6H, Ar), 2.84 (t, 4 H,
J=7.4 Hz, 2CH2),1.78 (q, 4 H, J=7.4 Hz, 2CH2),1.06 (t, 6 H, J=7.4 Hz,
2CH3). IR (KBr) νmax/cm–1: 2963, 1696, 1381, 1309, 1252, 980; ESI-
MS: m/z (%): 377.2 (M+H+, 51),399.2 (M+Na+, 100). Anal. Calcd for
C22H24N4O2: C, 70.19; H, 6.43; N, 14.88; O, 8.50. Found: C, 70.22; H, 6.45;
N, 14.86; O, 8.48%.
1-Benzoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2g): Yield:
70.2%; yellow solid, m.p. 203–205 °C. 1H NMR (400 MHz,CDCl3)
δ (ppm); 8.17 (s,1H, NH), 7.92 (d, 2H, J=7.1 Hz, Ar), 7.65–7.67 (m, 2H,
Ar), 7.58–7.60 (m, 2H, Ar),7.50–7.54 (m, 1H, Ar), 7.37–7.47(m,5H,Ar),
7.32–7.33 (m, 3H, Ar). IR(KBr) νmax/cm–1: 3290, 3076, 2975, 1637, 1465,
1396, 1147, 962; ESI-MS m/z (%): 341.2(M+H+, 25). Anal. Calcd for
C21H16N4O: C, 74.10; H, 4.74; N, 16.46; O, 4.70; Found: C, 74.12; H, 4.74;
N, 16.44; O, 4.70%.
1,4-Hexanoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-
tetrazine
(3d):
Yield: 30.1%; white solid, m.p. 143–145 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.03–8.05 (m, 4 H, Ar), 7.51–7.54 (m, 6 H, Ar), 2.85 (t,
4 H, J=7.5 Hz, 2CH2),1.72–1.78 (m, 4H, 2CH2),1.36–1.43 (m, 8H,
2CH2CH2),0.94 (t, 6H, J=7.2 Hz, 2CH3). IR (KBr) νmax/cm–1: 2955, 1701,
1382, 1267, 1108, 1051, 962; ESI-MS: m/z (%): 433.1 (M+H+,15). Anal.
Calcd for C26H32N4O2:C, 72.19; H, 7.46; N, 12.95; O, 7.40. Found: C,
72.22; H, 7.45; N, 12.93; O, 7.39%.
1-(4-Methylbenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (2h):
Yield: 51.8%; yellow solid, m.p. 180–182 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.17 (s, 1H, NH), 7.88 (d, 2H, J=7.6 Hz, Ar), 7.68–7.69 (m, 2H,
Ar), 7.60–7.61 (m, 2H, Ar), 7.52–7.55 (m, 1H, Ar), 7.42–7.45(m, 2H,Ar),
7.33–7.36 (m, 3H, Ar), 7.22 (d, 2H, J=7.6 Hz, Ar), 2.40(s, 3H, Me). IR
(KBr) νmax/cm–1: 3276, 2973, 1631, 1466, 1391, 1144, 1010, 961; ESI-MS
1,4-Pivaloyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (3e): Yield:
65.7%; white solid, m.p. 153–155 °C. H NMR (500 MHz, CDCl3) δ
1
(ppm); 7.43–7.52 (m, 10H, Ar), 1.50 (s, 18H, 6CH3). IR (KBr) νmax/cm–1:
2975, 1686, 1398, 1348, 1219, 953; ESI-MS: m/z (%):405.4 (M+H+, 18).
Anal. Calcd for C24H28N4O2: C, 71.26; H, 6.98; N, 13.85; O, 7.91. Found:
C, 71.22; H, 6.98; N, 13.87; O, 7.92%.
JCR1301915_FINAL.indd 589
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590 JOURNAL OF CHEMICAL RESEARCH 2013
1,4-Isobutyryl-3,6-diphenyl-1,4-dihydro-1,2,4,5-
tetrazine
(3f):
Yellow crystals of compound 2b and 2g were recrystallised by slow
evaporation from ethyl acetate at room temperature, and colourless
crystals of 3a and 3g were obtained by similar treatment from anhydrous
ethanol. Diffraction data were collected at 153K by the ψ-ω scans
technique, on a Rigaku AFC10 diffractometer with a Saturn724+
CCD detector using graphite-monochromated MoKα radiation from
rotating anode graphite source (λ=0.71073 Å) using the CrystalClear
program.13 The structures were solved with SHELXS97 and refined
with the full-matrix least-squares procedure on F2 by SHELXL97.14
Scattering factors incorporated in SHELXL97 were used. The function
∑w(|Fo|2–|Fc|2)2 was minimised, with w–1 = [σ2(Fo)2 +(AP)2 +BP],
where P=[Max(Fo2,0)+2 Fc/3].The crystal parameters and selected
bond angles and lengths of 2b, 3a and 3g are listed in Tables 3 and 4,
respectively. All non-hydrogen atoms were located in a difference
Fourier map and refined anisotropically. All hydrogen atoms located
at geometrically calculated positions and treated by a mixture of
independent and constrained refinement. Other details of the structures
have been deposited with the Cambridge Crystallographic Data Centre.
The deposition reference numbers are given in Table 3.
Yield: 32.6%; white solid, m.p. 118–120 °C. 1H NMR (500 MHz,CDCl3)
δ (ppm); 8.03-8.05 (m, 4 H, Ar), 7.51–7.54 (m, 6H, Ar), 3.51 (quint, 2H,
J=6.9 Hz), 1.30 (d, 12 H, J=6.9 Hz). IR (KBr) νmax/cm–1: 2976, 1704,
1385, 1260, 1092, 1010, 966; ESI-MS: m/z (%): 377.3(M+H+,100). Anal.
Calcd for C22H24N4O2: C, 70.19; H, 6.43; N, 14.88; O, 8.50. Found: C,
70.22; H, 6.42; N, 14.87; O, 8.48%.
1,2-Benzoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5- tetrazine (3g): Yield:
26.4%; white solid, m.p. 192–194 °C. 1H NMR (500 MHz,CDCl3) δ
(ppm); 7.66 (d, 4H, J=8.0 Hz, Ar), 7.49–7.51 (m, 4H, Ar), 7.31–7.38 (m,
6H, Ar),7.24–7.27 (m, 6H, Ar). IR (KBr) νmax/cm–1: 2976, 1710, 1487,
1278, 1132, 1077, 949; ESI-MS: m/z (%):445.2 (M+H+, 100). Anal. Calcd
for C28H20N4O2: C, 75.66; H, 4.54; N, 12.60; O, 7.20. Found: C, 75.68; H,
4.54; N, 12.59; O, 7.19%.
1,2-(4-Methylbenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine
(3h): Yield: 25.3%; white solid, m.p. 226–228 °C. 1H NMR (500 MHz,
CDCl3) δ (ppm); 7.60 (d, 4H, J=8.2 Hz, Ar), 7.48–7.51(m, 4H, Ar),7.33
(d, 4H, J=8.2 Hz, Ar), 7.23–7.27 (m, 6H, Ar), 2.47(s, 6H, 2CH3). IR
(KBr) νmax/cm–1: 2924, 1609, 1374, 1299, 1172, 1015, 1003; ESI-MS: m/z
(%):473.2 (M+H+,13). Anal. Calcd for C30H24N4O2: C, 76.25; H, 5.12; N,
11.86; O, 6.77. Found: C, 76.27; H, 5.11; N, 11.85; O, 6.76%.
Calculation methods
The structures of the compounds were optimised by AM1 method, and
further geometric optimisations were performed by using DFT method
with B3LYP hybrid functional and 6-311G basis set. All computations
were finished using the Gaussian 03 program package.15
1,2-(4-Chlorobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-
tetrazine (3i): Yield: 25.3%; white solid, m.p. 258–260 °C. H NMR
1
(500 MHz,CDCl3) δ (ppm); 7.70 (d, 4H, J=8.6 Hz, Ar), 7.48–
7.51(m, 4H, Ar),7.47 (d, 4H, J=8.6 Hz, Ar),7.25–7.27 (m, 6H,
Ar). IR (KBr) νmax/cm–1: 1685, 1322, 1283, 1129, 1093, 929; ESI-MS: m/z
(%):513.3 (M+H+, 14). Anal. Calcd for C28H18Cl N O2: C, 65.51; H,
3.53; N, 10.91; O, 6.23. Found: C, 65.50; H2, 34.53; N, 10.92; O,
6.22%.
Table 4 Selected bond lengths (Å) and bond angles (o) of compounds
2b, 3a and 3g
2b
O1–C19
N1–C6
N1–N2
N4–N5
1.229 (16) N1–C19
1.418 (17) N2–C3
1.428 (15) N4–C3
1.408 (15) N5–C6
1.478( 18) C6–C13
1.363(17)
1.289(17)
1.383(17)
1.275(17)
1.473(19)
120.12(11)
110.41(11)
113.32(11)
118.89(12)
118.88(12)
121.16(12)
123.19(13)
X-ray crystallography
Table 3 Crystal parameters of compounds 2b, 3a and 3g
C3–C7
2b
C17H16N4O
292.34
153(2)
3a
C18H16N4O2
320.35
153(2)
3g
C28H20N4O2
444.48
153(2)
C19–N1–C6
C6–N1–N2
C3–N4–N5
N2–C3–N4
N4–C3–C7
N5–C6–C13
O1–C19–N1
124.52 (11)
115.34 (10)
115.97 (11)
121.63 (12)
119.48 (12)
119.29 (12)
120.05 (12)
C19–N1–N2
Empirical
formula
C3–N2–N1
C6–N5–N4
N2–C3–C7
N5–C6–N1
N1–C6–C13
O1–C19–C20
Formula weight
Temperature/K
Wavelength/Å
Crystal system
Space group
a/nm
0.71073
Monoclinic
P21/c
0.71073
Monoclinic
P21/c
0.71073
Orthorhombic
Pbca
3a
O1–C19
N1–C19
N1–N2
N4–C21
N4–N5
C3–C7
C19–N1–C6
C6–N1–N2
C21–N4–C3
C3–N4–N5
N2–C3–N4
N4–C3–C7
N5–C6–C13
1.216 (13) O2–C21
1.402 (14) N1–C6
1.413 (12) N2–C3
1.391 (15) N4–C3
1.422 (13) N5–C6
1.482 (15) C6–C13
1.217(14)
1.404(15)
1.283(14)
1.409(15)
1.282(14)
1.481(15)
117.66(9)
112.73(9)
117.80(9)
112.26(9)
117.91(10)
120.32(10)
120.43(9)
1.449(3)
1.642(3)
1.428(3)
3.0783(10)
115.065(2)
1.262
1.177(3)
1.456(4)
0.935(3)
1.6005(8)
92.323(4)
1.329
1.465(13)
1.618(14)
5.775(5)
1.3682(2)
90
b/nm
c/nm
Cell volume/
nm3
β/(o)
124.41 (9)
116.43 (9)
125.76 (9)
116.32 (9)
119.87 (10)
121.87 (9)
119.08 (10)
C19–N1–N2
Calculated
C3–N2–N1
C21–N4–N5
C6–N5–N4
N2–C3–C7
N5–C6–N1
N1–C6–C13
1.295
density/gcm–3
Z
8
4
24
F(000)
1232
672
5568
Absorption
coefficient
(μ)/mm–1
0.082
0.090
0.084
3g
Θ range for
data collection
2.00 o <θ< 29.14 o
3.07o <θ<30.02o
3.05o <θ<25.50o
O1–C19
N1–C6
N1–N2
N2–C3
1.213 (4)
1.411 (4)
1.415 (3)
1.430 (4)
1.401 (3)
O2–C26
N1–C19
N2–C26
N4–C3
1.212 (4)
1.412 (4)
1.408 (4)
1.291 (4)
1.294 (4)
110.1 (2)
116.9 (2)
108.1 (2)
116.6 (3)
122.1 (3)
119.0 (3)
119.3 (3)
Reflection
collected/
unique
Refinement
method
27244/8205
14254/4629
[R(int)=0.0329]
83166/12710
[R(int)=0.0695]
[R(int)=0.0401]
Full-matrix least-
squares on F^2
Full-matrix least-
squares on F^2
Full-matrix least-
squares on F^2
N4–N5
N5–C6
C6–N1–C19
C19–N1–N2
C26–N2–C3
C3–N4–N5
N4–C3–N2
N2–C3–C7
N5–C6–C13
129.2 (2)
C6–N1–N2
C26–N2–N1
N1–N2–C3
C6–N5–N4
N4–C3–C7
N5–C6–N1
N1–C6–C13
Goodness of fit
on F 2
1.000
R1=0.0498,
1.001
0.999
116.5 (2)
117.8 (2)
117.8 (3)
118.6 (3)
119.2 (3)
121.3 (3)
Final R index
R1 =0.0436,
R1 =0.0858,
[I>2δ(I)]
wR2 = 0.1146
wR2 =0.0926
wR2 = 0.1708
R index (all
data)
R1 =0.0765,
wR2 = 0.1295
R1 =0.0588,
wR2 = 0.1009
R1 = 0.0957,
wR2 = 0.1771
CCDC ref
846676
859921
846677
JCR1301915_FINAL.indd 590
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JOURNAL OF CHEMICAL RESEARCH 2013 591
5
W.X. Hu, G.W. Rao and Y.Q. Sun, Bioorg. Med. Chem. Lett., 2004, 14,
1177.
G.W. Rao and W.-X. Hu, Bioorg. Med. Chem. Lett., 2005, 15, 3174.
G.W. Rao, Y.M. Guo and W.X.Hu, ChemMedChem, 2012, 7, 973.
R.S. Tewari, A.K. Awasthi and P. Parihar, Synthesis, 1983, 4, 334.
S. Zhang, G.W. Rao, X.G. Mao and W.X. Hu, J. Chem. Res., 2011, 5, 275.
The project was supported by the educational commission of
Zhejiang Province for financial support (Y201225654).
6
7
8
9
Received 28 April 2013; accepted 3 July 2013
Paper1301915 doi: 10.3184/174751913X13783040292986
Published online: 7 October 2013
10 G.W. Rao and W.X. Hu, Chinese J. Org. Chem., 2004, 24, 1622.
11 F. Xu, Z.Z. Yang, J.R. Jiang and G.W. Rao, Chinese J. Struct. Chem., 2010,
29, 1672.
12 N.O. Abdel, M.A. Kira and M.N. Tolba, Tetrahedron Lett., 1968, 9, 3871.
13 Rigaku/MSC, CrystalClear. Rigaku/MSC Inc., The Woodlands, Texas,
USA 2008.
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