1H and 13C NMR spectral characterization of some novel 7H-1,2,4-triazolo[3, 4-b] [1,3,4] thiadiazine derivatives

Article abstract of DOI:10.1002/mrc.1940

Some novel 1, 2, 4-triazolo[3,4-b][1,3,4]thiadiazines derivatives were synthesized. The complete ¹H and ¹³C NMR chemical shift assignments were analyzed on one-and two-dimensional NMR techniques, including DEPT, NOE-DIF, COSY, HMBC,

Full text of DOI:10.1002/mrc.1940

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2007; 45: 265–268
Published online 22 December 2006 in Wiley InterScience
(
www.interscience.wiley.com) DOI: 10.1002/mrc.1940
Spectral Assignments and Reference Data
1H and 13C NMR spectral characterization of
some novel 7H-1,2,4-triazolo[3, 4-b] [1,3,4]
KEYWORDS: NMR; 1H NMR; 13C NMR; 1,2,4-triazolo[3,4-b][1,3,4];
thiadiazines; synthesis
thiadiazine derivatives
Xinxiang Lei, Lixue Zhang, Anjiang Zhang, Xiaoxia Ye2
1
1
1∗
INTRODUCTION
and Jing Xiong1
1,2,4-Triazoles and N-bridged heterocycles are found to be associ-
ated with diverse pharmacological properties.
and pharmacological properties of various thiadiazines fused with a
1
–3
Broad biological
1
Department of Chemistry, Wenzhou University, Wenzhou 325027,
4
–9
China
triazole ring have been extensively studied.
In particular, var-
2
ious substituted 7H-1,2,4–triazolo-[3,4-b][1,3,4] thiadiazines have
been shown to possess diverse pharmacological properties, such
as antimicrobial, bactericidal, anti-inflammatory, antiviral, antihy-
pertensive, antifungal, antihelminthic, and analgesic effects.1
Prompted by the biological properties of 1,2,4-triazole derivatives
and 1,3,4-thiadiazines, and in continuation of our studies on N-
Department of Chemistry, Wenzhou Medical College, Wenzhou
325035, China
0–13
Received 24 September 2006; revised 2 November 2006; accepted 8 November
006
2
1
4–15
bridged heterocycles,
characterization of some 7H-1,2,4-triazolo[3,4-b][1,3,4] thiadiazine
derivatives (Scheme 1), of which compounds 1a, 1b, 1d, 1e, 1f, 1o,
we report here the synthesis and spectral
Some novel 1, 2, 4-triazolo[3,4-b][1,3,4]thiadiazines deri-
vatives were synthesized. The complete 1H and 13
C
1
2,13
and 1q were known.
NMR chemical shift assignments were analyzed on one-
and two-dimensional NMR techniques, including DEPT,
NOE-DIF, COSY, HMBC, and HSQC. Copyright  2006
John Wiley & Sons, Ltd.
Ł
Correspondence to: Anjiang Zhang, Department of Chemistry, Wenzhou
University, Wenzhou 325027, China. E-mail: ajzhang@wzu.edu.cn
Scheme 1. Structure of various 3,6-disubstituted-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines.
Copyright  2006 John Wiley & Sons, Ltd.

266
Spectral Assignments and Reference Data
(TMS). The long-range 1H–13C correlation (HMBC) spectra were
EXPERIMENTAL
Materials
obtained using the hmbcgpndqf program in the Bruker software.
The spectra resulted from a 256 ð 1024 data matrix size with 16 scans
per t1 increment, 200 µs delay for homospoil/gradient recovery
Various
5-substituted-4-amino-2,4-dihydro-3H-1,2,4-triazole-3-
thiones were prepared by methods given in the literature.16–18
All other chemicals and solvents used were of analytical reagent
grade.
13
(D16), 1 ms for homospoil/gradient pulse (P16), and 5 : 3 : 4 gradient
combination using a pulse sequence optimized for 8 Hz. Spectral
widths of 3.5 kHz in f2 and 15.5 kHz in f1 were used. The acquisition
time was 0.57 s, the delay was set to 3.45 ms, the recycle time was
1.50 s, and the Fourier transformation was done on a 2k ð 1k data
matrix. The one-bond heteronuclear correlation (HSQC) spectra were
obtained using the hsqcetgp program in the Bruker software. The
spectra were measured with the same D16 ꢀ200 µs) and P16 (1 ms)
and a different 4 : 1 gradient combination. The acquisition time was
Preparation of various 3,6-disubstituted-7H-
1
,2,4-triazolo[3,4-b][1,3,4]thiadiazines
The mixture of 5-substituted-4-amino-2,4-dihydro-3H-1,2,4-triazole-
-thione (40 mmol), ω-bromoacetophenones (42 mmol), ethanol
70 ml), and water (30 ml) was stirred and refluxed for 3 h. The
3
(
1
solution was cooled and then filtered. The precipitate was washed
with ether and dried. The crude material was recrystallized from
0.14 s, the delay was set to 3.45 ms, and an average J(C, H) of 145 Hz
was used; the recycle time was 1.55 s. The Fourier transformation
7
3
0% ethanol solution to obtain the pure products (1a–1r, 2a–2e, and
was done on a 2k ð 1k data matrix.
a–3d) at a yield of 63–86%.
RESULTS AND DISCUSSION
NMR spectra
All NMR experiments were performed at 293 K using a solution of
In order to unequivocally assign all NMR signals, we used 1D and
2D techniques such as DQF-COSY, HSQC, and HMBC.
2
0 mg of the compound dissolved in 0.5 ml of dimethyl sulfoxide
(
DMSO)-d6 on a Bruker AVANCE-300 instrument with a 5 mm BBFO
In Scheme 1, the structures and numbering of the title com-
1
13
probe head equipped with shielded Z-gradient coil. The gradient
pounds are presented. Their H and C NMR chemical shifts are
given in Tables 1 and 2, respectively. For example, assigning the
spectra of 1k is described as follows. H-7 (υ 4.41), H-11, H-15 (υ 7.90),
H-12, H-14 (υ 7.61), methylene proton (υ 3.98), and methyl (υ 1.05)
ꢀ
4
ꢀ1
1
.
field was 50 ð 10 T cm
H NMR spectra were recorded at a
proton frequency of 300.13 MHz with a spectral width of 4.5 kHz
1
3
and 11 µs (90°) pulse. The C NMR spectra were obtained using a
spectral width of 20 kHz, a 3.9 µs (30°) pulse, and a 1.8 s acquisition
proton were assigned directly, and the H signals of H-18¾H-21 were
1
time; 1024 scans with 32 768 data points each were used. Exponential
multiplication was applied before Fourier transformation in both
cases. The chemical shifts were referenced to tetramethylsilane
determined by the combination of COSY, HSQC, and HMBC experi-
ments. Seven quaternary carbons were observed by DEPT technique
and assigned by HMBC experiments, the assignments were C-3 at
Table 1. 1H NMR data for compounds 1a–2r, 2a–2e, and 3a–3d(Solvent: DMSO-d
)
6
Com-
pound
7
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
R1
R2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3
3
3
3
a
b
c
4.42
4.42
4.30
4.40
4.38
4.50
4.47
4.37
4.50
4.45
4.41
4.52
4.44
4.46
4.44
4.32
4.52
4.47
4.39
4.46
4.41
4.38
4.37
4.46
4.89
4.45
4.48
7.95 7.80
8.01 7.66
7.89
7.80 7.95
7.66 8.01
7.64 7.72
7.39 7.96
7.30 7.95
8.40 8.25
7.90 8.10
7.34 7.77
8.37 8.11
7.85 7.98
7.61 7.90
8.37 8.21
7.38 7.95
7.92 7.12
7.93 7.12
7.92 7.12
7.91 7.12
7.92 7.12
7.94 7.13
7.97 7.13
7.12 7.92
7.12 7.93
7.12 7.92
7.12 7.91
7.12 7.92
7.13 7.94
7.13 7.97
4.12, 1.36
4.12, 1.36
4.12, 1.35
d
e
f
7.96 7.39
7.95 7.30
8.25 8.40
8.10 7.90
7.77 7.34
8.11 8.37
7.98 7.85
7.90 7.61
8.21 8.37
7.95 7.38
4.12, 1.36 2.40
4.12, 1.36 3.67
4.13, 1.37
g
h
i
7.78 7.53 7.43 7.53 7.78 4.13, 1.37
3.98, 1.03 2.36
7.18 7.08 7.54 7.52
7.19 7.11 7.56 7.53
7.20 7.12 7.51 7.48
7.18 7.10 7.55 7.52
6.98 7.42 7.02 7.83
6.98 7.39 7.05 7.99
6.98 7.41 7.04 7.91
6.96 7.42 7.05 7.92
6.95 7.41 7.06 7.88
4.01, 1.05
j
7.75 7.55 7.43 7.55 7.75 4.02, 1.08
k
l
3.98, 1.05
10.30
m
n
o
p
q
r
10.20
2.40
8.07 7.58 7.58 7.58 8.07
10.20
7.99 7.80
7.90
7.80 7.99
7.65 7.73
8.39 8.25
7.89 8.10
10.20
10.30
8.25 8.39
8.10 7.89
8.01 7.67
8.00 7.17
7.67 8.01
7.14 8.00
7.77 7.51 7.40 7.51 7.77
3.85
a
b
c
7.97 7.47 7.52 7.47 7.97 4.74
7.53 7.50 7.85
7.95 7.57 7.60 8.29
7.95 7.57 7.59 8.29
7.96 7.54 7.56 8.27
7.94 7.55 7.58 8.28
7.94 7.55 7.59 8.28
8.21 8.38
7.97 7.14
7.91 7.77
7.88 7.36
7.94 7.40
7.98 7.80
8.02 7.13
7.91
8.38 8.21 4.76
7.14 7.97 4.75
7.77 7.91 4.74
7.36 7.88 4.75
7.40 7.94
7.50 7.47 7.85
7.47 7.44 7.79
7.48 7.45 7.84
7.48 7.44 7.85
3.85
d
e
a
b
c
2.38
2.40
8.73 7.94 8.90
9.32
9.35
9.33
9.34
7.80 7.98
8.79 7.98 8.96
8.74 7.95 8.90
8.74 7.94 8.91
7.13 8.02
3.86
d
7.67 7.74
Copyright  2006 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2007; 45: 265–268
DOI: 10.1002/mrc

267
Spectral Assignments and Reference Data
Copyright  2006 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2007; 45: 265–268
DOI: 10.1002/mrc

268
Spectral Assignments and Reference Data
υ 151.32, C-6 at υ 153.78, C-9 at υ 141.95, C-10 at υ 132.23, C-13 at
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1
υ 136.82, C-16 at υ 115.13, and C-17 at υ 156.85. All the other H and
1
3
C NMR chemical shifts were determined completely by the same
4
5
6
. Soni N, Bhalla TN, Gupta TK, Parmar SS, Barthwal JP. Eur. J.
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. Peter CW, Richard VB, Thomas PK, Palmer DM, Robert CM. J.
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methods. Distinguishing H-18 from H-19 and H-22 from H-25 for
compounds 2a–2e was not easy and NOE difference spectra were
applied. Because of the similarity in structures, we take 2e as an
example. The signals at υ 7.48 and υ 8.28 were increased by 5.5% and
9.6%, respectively, by radiating at υ 4.75 (H-16, methylene proton),
and thus the signals of H-18 (υ 7.48) and H-25 (υ 8.28) were assigned.
From Table 1 it may be concluded that substitution on the
aromatic ring moiety has little effect on the heterocyclic system
H-7 proton. Thus, the H-7 proton resonates in the narrow range
of 4.30–4.52 ppm, with the exception of compound 3b. Generally,
the electron-accepting group on the aromatic ring shifts the signal
downfield, whereas the electron-donating substituents shift the
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The 13C NMR spectra exhibit characteristic signals for C-3, C-6,
10. Prasad AR, Ramalingam T, Rao AB, Daiwan PV, Sattur PB. Eur.
J. Med. Chem. 1989; 24: 199.
C-7, and C-9 of the fused ring at υ 148.41–152.72, 153.15–156.81,
11. El-Daway MA, Omar AMME, Ismail AM, Hazzaa AAB. J. Pharm.
2
2.66–23.33, and 140.48–143.81, respectively. As shown in Table 2,
the signals corresponding to the heterocyclic system are relatively
insensitive to the nature of the substituent on the aryl ring. C-3 in
these systems resonates in the narrow range of 151–152 ppm, with
the exception of compounds 3a–3d.
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Acknowledgements
This work was supported by the Zhejiang Provincial Natural Science
Foundation of China (No. M203149) and Wenzhou University
Natural Science Foundation (No. 2006L001).
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Copyright  2006 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2007; 45: 265–268
DOI: 10.1002/mrc