Investigation on the ring-opening reactions of 3-(1H-1,2,4-triazol-1-yl)1, 5-benzothiazepines with arylonitrile oxides

Article abstract of DOI:10.1080/10426507.2010.509290

Novel ring opening compounds, (Z)-2-((Z)-((E)-1,3-diaryl-2-(1H-1,2,4- triazol-1-yl)allylidene)amino)aryl N-hydroxybenzimidothioates 4a-r, were obtained from the reaction of 2,4-diaryl-3-(1H-1,2,4-triazol-1-yl)-2,5-dihydro- 1,5-benzothiazepines 3a-f and ar

Full text of DOI:10.1080/10426507.2010.509290

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Investigation on the Ring-Opening
Reactions of 3-(1H-1,2,4-Triazol-1-
yl)1,5-benzothiazepines with Arylonitrile
Oxides
Sheng-Qin Chen a , Fei Ding b & Fang-Ming Liu a
a College of Materials and Chemical Engineering , Hangzhou Normal
University , Hangzhou, P.R. China
b Technology Center of Juhua Group , Quzhou, P.R. China
Published online: 07 Mar 2011.
To cite this article: Sheng-Qin Chen , Fei Ding & Fang-Ming Liu (2011) Investigation on the
Ring-Opening Reactions of 3-(1H-1,2,4-Triazol-1-yl)1,5-benzothiazepines with Arylonitrile
Oxides, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:3, 574-581, DOI:
10.1080/10426507.2010.509290
To link to this article: http://dx.doi.org/10.1080/10426507.2010.509290
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Phosphorus, Sulfur, and Silicon, 186:574–581, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.509290
INVESTIGATION ON THE RING-OPENING REACTIONS OF
3-(1H-1,2,4-TRIAZOL-1-YL)1,5-BENZOTHIAZEPINES WITH
ARYLONITRILE OXIDES
Sheng-Qin Chen,1 Fei Ding,2 and Fang-Ming Liu1
1College of Materials and Chemical Engineering, Hangzhou Normal University,
Hangzhou, P.R. China
2Technology Center of Juhua Group, Quzhou, P.R. China
GRAPHICAL ABSTRACT
Abstract Novel ring opening compounds, (Z)-2-((Z)-((E)-1,3-diaryl-2-(1H-1,2,4-triazol-1-
yl)allylidene)amino)aryl N-hydroxybenzimidothioates 4a–r, were obtained from the reaction
of 2,4-diaryl-3-(1H-1,2,4-triazol-1-yl)-2,5-dihydro-1,5-benzothiazepines 3a–f and arylonitrile
oxides. The structure of these products has been elucidated by spectroscopic analysis and, in
one case, X-ray crystallographic analysis. According to the result, it was presumed that this
reaction did not proceeded through 1,3-dipolar cycloaddition reaction.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Arylcarbohydroximinoyl chloride; benzothiazepine; ring-opening; 1,2,4-triazole
Received 30 April 2010; accepted 15 July 2010.
Address correspondence to Fang-Ming Liu, College of Materials and Chemical Engineering, Hangzhou
Normal University, Hangzhou 310036, P.R. China. E-mail: fmliu859@sohu.com
574

RING-OPENING REACTIONS
575
INTRODUCTION
Owing to their remarkable chemotherapeutic applications, 1,5-benzothiazepines1–3
have been the object of intense investigations in medicinal chemistry, and currently some
of them are among the most widely used drugs in the treatment of cardiovascular disorders,
such as diltiazem,4 thiazesim,5 and clentiazem.6 On account of this, a great deal of work has
been done on the synthesis of 1,5-benzothiazepine derivatives aimed at defining their bio-
chemical and pharmacological roles.7–10 Recently, annulated 1,5-benzothiazepine deriva-
tives have attracted increasing attention with the consideration that the addition of a third
ring to bond [d] may be expected to enhance the activity or modify the activity profile.11–14
Jin and colleagues studied the ring-opening reactions of 1,5-benzothiazepines with carbenes
and proposed a mechanism,15–17 but the ring-opening reactions of 1,5-benzothiazepines
with arylonitrile oxides have not been reported in the literature. In addition, 1,2,4-triazole
derivatives represent one of the most interesting and important classes of compounds,
possessing a widespread biological activities such as antimicrobial and antifungal activi-
ties.18–22 Many triazole derivatives, for example, fluconazole and itraconazole, have been
commercially available as antifungal agents.23,24 Meanwhile, the introduction of the 1,2,4-
triazole moiety into the parent compounds may improve the properties and biological
activities of the compounds; it is therefore thought to be of interest to combine these two
potential biologically active units into a single molecule for evaluating their biological
activity.
A literature survey shows that 1,5-benzothiazepines with a 1,2,4-triazole moiety
substituted at the 3-position have not been reported. Taking into consideration the important
biological activity of 1,5-benzothiazepine and 1,2,4-triazole moieties, and as an extension
of our investigations on the synthesis of new 1,5-benzothiazepine derivatives,25,26 we report
here the synthesis of a new series of 1,5-benzothiazepine derivatives with a 1,2,4-triazole
moiety substituted at the 3-position and their reactions with arylonitrile oxides, expecting
to get the desired normal cycloadducts (4ꢁ). Unfortunately, only the ring-opening products
(4) were obtained. The synthetic route is shown in Scheme 1.
RESULTS AND DISCUSSION
The α,β-unsaturated ketones 2 were obtained from 1-aryl-2-(1H-1,2,4-triazol-1-
yl)ethanones 1 and aromatic aldehydes at reflux in dry toluene in the presence of piperidine
under a nitrogen atmosphere; the water generated was removed with a Dean–Stark trap.27,28
Then, the chalcones 2 were reacted with 2-aminobenzenethiol in methanol in the presence
of CF3COOH as an acidic catalyst to give the 1,5-benzothiazepines 3 at 60–90% yield
(Scheme 1).29 The structures of 3a–f were inferred from spectroscopic (IR, 1H NMR, MS)
and elemental analyses data.29 The IR spectra of 3a–f exhibit bands at 1662–1681 cm−1
(C C) and 3217–3244 cm−1(NH). Their 1H NMR spectra exhibited a singlet at δ 5.34–5.43
(NH) and δ 6.03–6.10 (2-CH) besides the expected signals. In the 1H NMR spectra of 3c,
a singlet that appeared at δ 3.73 was attributed to the methoxy protons, a singlet at δ 6.03
due to 2-CH. The remaining 15 aromatic protons resonated as multiplets in the range δ
7.98∼6.47, indicating the formation of 3 instead of 3ꢁ.
The EI mass spectra of compounds 3a–f revealed the existence of molecular ion
peaks, and the characteristic fragmentation pattern of the 1,5-benzothiazepine ring was
also observed. In the mass spectrum of compound 3c, a molecular ion peak was observed

576
S.-Q. CHEN ET AL.
Scheme 1 Synthesis of the triazole derivatives 4.
at m/z 412; an intense peak observed at 343 m/z was due to the loss of trizole. The base
peak observed at m/z 212 was due to the contraction of the 1,5-benzodiazepine ring to
give the stable 2-phenyl-benzothiazole. 1,3-Dipolar cycloaddition reaction of 2,4-diaryl-
3-(1H-1,2,4-triazol-1-yl)-2,5-dihydro-1,5-benzothiazepines 3a–f with a slight excess of
arylonitrile oxides (generated in situ via triethylamine dehydrohalogenation of the cor-
responding benzohydroximinoyl chloride) in methylene chloride, stirring at room tem-
perature for 4 days. Removal of the solvent under reduced pressure and chromatography
over silica gel afforded the products 4a–r, (Z)-2-((Z)-((E)-1,3-diaryl-2-(1H-1,2,4-triazol-1-
yl)allylidene)amino)aryl N-hydroxybenzimidothioate, at 25∼40% yield (Scheme 1). The
structure of products is ring-opened compounds rather than normal cycloadducts (4ꢁ) based
on spectroscopic (IR, 1H NMR, MS, X-ray) and elemental analyses data. IR spectra of 4a–r
displayed absorption bands at 1625–1645 cm−1 for C N stretching, a medium intensity
band appears at 1010–1070 cm−1 due to C S stretching vibrations and the corresponding

RING-OPENING REACTIONS
577
absorption for aromatic and R-substituents. 1H NMR spectra of 4a–r show the absence of
the proton signal adjacent to the sulfur atom of 1,5-benzothiazepine, and the presence of
1
signals in the region of δ 6.12–6.20 were attributed to olefinic proton C CH. In the H
NMR spectrum of 4c, a singlet that appeared at δ 3.72 was attributed to the methyloxy
protons, a singlet at δ 6.16 assigned to C CH. The signal of OH appeared as a broad peak at
δ 8.50. The remaining 21 aromatic protons resonated as multiplets in the range δ 6.60–7.58.
The EI mass spectra of compounds 4a–r revealed the existence of molecular ion peaks and
anticipated fragmentation peaks, which were in good accordance with the given structures
of the products (Table 1). The mass spectrum of compound 4c showed a molecular ion peak
M+ at 531 m/z. The mechanism was proposed as shown in Scheme 2. The reaction was
most probably initiated by a nucleophilic attack of the sulfur atom to the dipolar carbon
of the arylonitrile oxide during the course of reaction,30 as well as accompanied by ring
opening, leading to a dipolar intermediate, which subsequently underwent proton transfer
to form the final products (Scheme 2). Sample spectra for 4c and 3a are shown in the
Supplemental Materials (Figures S1–S7, available online).
Scheme 2 Possible formation mechanism of the triazole derivatives 4.
X-Ray Crystallographic Analysis
In order to confirm the assigned stereochemistry, a single crystal X-ray analysis
was carried out for compound 4c. The crystal structure and data refinement parameters of
compound 4c are illustrated in Figure 1 and Table 2, respectively.
EXPERIMENTAL
All reagents were commercially availabile. The purity of compounds was checked
by TLC on glass plates coated with silica gel G using the solvent system, ethyl ac-
etate:petroleum ether (1:5). Melting points were measured on a Mettler FP-5 capillary
melting point apparatus and were uncorrected. Elemental analyses were performed on
a Perkin-Elmer 2400 elemental analyzer. The IR spectra were determined as potassium
1
bromide pellets on a Bruker Equinox 55 FT-IR spectrophotometer. The H NMR spectra

578

RING-OPENING REACTIONS
579
Figure 1 Molecular structure of the triazole derivative 4c in the crystal.
were recorded on a Varian Inova-400 spectrophotometer using TMS as an internal stan-
dard. EI-MS spectra were recorded with an Agilent 5975 apparatus. X-ray crystal structure
was obtained using R-Axis Spider X-ray diffraction. The starting compounds 1, 2, 3 were
prepared according to the previously reported procedures.27–29
The Synthesis of (Z)-2-((Z)-((E)-1,3-Diaryl-2-(1H-1,2,4-triazol-
1-yl)allylidene)amino)aryl N-Hydroxybenzimidothioate (4a–r)
Benzohydroximinoyl chloride (1.5 mmol) was added under stirring to a solution of
the appropriate 1,5-benaothiazepine derivative (1 mmol) in methylene chloride (30 mL),
and a solution of triethylamine (1.5 mmol) in the same solvent (5 mL) was added dropwise
slowly. The reaction mixture was kept under magnetic stirring at room temperature for
4 days. After the completion of the reaction, the solvent was evaporated off at reduced
pressure, then ether was added and the triethylamine hydrochloride was filtered. After
removal of the solvent, the residue was purified by silica gel column chromatography with
ethyl acetate/light petroleum (v:v = 1:5). Analytical data for compounds 4 are summarized
in Table 3). IR, 1H NMR, and mass spectral data 4a–r are listed (Table 1).

580
S.-Q. CHEN ET AL.
Table 2 Details for X-ray data collection and structure refinement for compound 4c
Compound
4c
C31H25N5O2S
531.62
Triclinic/P-1
9.2396(15)
Empirical formula
Formula weight
Crystal system/space group
a/Å
b/Å
10.6076(18)
13.849(2)
93.170(4)
91.161(4)
99.916(4)
c/Å
α/◦
β/◦
γ /◦
V/Å3
1334.4(4)
Z
2
D calc (Mg/mˆ3)
µ (mm-1)
1.323
0.160
Crystal size (mm)
Color/shape
0.57 × 0.41 × 0.22
Yellow
Temp (K)
288(2)
Theta range for collection
Reflections collected/unique
Max. and min. transmission
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Largest difference peak/hole
3.06◦–27.48◦
12214/5828 [R(int) = 0.0220]
0.9657 and 0.9144
5828/0/357
1.061
R1 = 0.0420, wR2 = 0.1376
R1 = 0.0523, wR2 = 0.1545
0.311 and −0.273 e.Aˆ-3
Table 3 Analytical data for compounds 4
%Analyses, calcd./found
Compound
N
H
C
Formula/mol. wt.
Color/yield% Mp, ◦C/
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
13.96/13.97 4.62/4.61 71.83/71.83 C30H23N5OS 501.60
Yellow 31.6
Yellow 38.8
Yellow 30.8
Yellow 34.9
Yellow 32.3
Yellow 27.2
Yellow 28.9
Yellow 30.5
Yellow 37.4
Yellow 39.7
Yellow 38.9
Yellow 39.2
Yellow 28.0
Yellow 31.8
200–202
173–174
181–183
191–192
150–151
149–150
151–152
181–183
163–165
192–194
187–189
175–178
133–135
189–190
127–128
202–203
186–188
179–180
13.06/13.07 4.14/4.13 67.22/67.22
13.17/13.19 4.74/4.74 70.04/70.03
13.06/13.05 4.14/4.16 67.22/67.22
12.28/12.28 3.71/3.70 63.16/63.18
12.37/12.37 4.27/4.27 65.77/65.78
13.17/13.17 4.74/4.75 70.04/70.02
12.37/12.38 4.27/4.25 65.77/65.78
12.47/12.48 4.85/4.86 68.43/68.43
13.06/13.05 4.14/4.16 67.22/67.23
12.28/12.28 3.71/3.71 63.16/63.16
12.37/12.38 4.27/4.29 65.77/65.78
12.28/12.27 3.71/3.75 63.16/63.16
11.55/11.58 3.33/3.33 59.56/59.56
11.66/11.68 3.86/3.83 62.00/62.03
12.37/12.38 4.27/4.28 65.77/65.77
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
30H22ClN5OS 536.05
31H25N5O2S 531.63
30H22ClN5OS 536.05
30H21Cl2N5OS 570.49
31H24ClN5O2S 566.07
31H25N5O2S 531.63
31H24ClN5O2S 566.07
32H27N5O3S 561.65
30H22ClN5OS 536.05
30H22ClN5OS 570.49
31H24ClN5O2S 566.67
30H21Cl2N5OS 570.49
30H20Cl3N5OS 604.94
31H23Cl2N5O2S 600.52 Yellow 35.3
31H24ClN5O2S 566.07 Yellow 30.5
11.66/11.66 3.86/3.88 62.00/61.18 C31H23Cl2N5O2S 600.52 Yellow 34.1
11.75/11.74 4.40/4.42 64.48/64.50 32H26ClN5O3S 596.10 Yellow 37.8
C

RING-OPENING REACTIONS
581
REFERENCES
1. Mogilnicka, E.; Czyark, A.; Maj, J. Eur. J. Pharmacol. 1987, 138, 413–416.
2. Rampe, D.; Triggle, D. J. Prog. Drug Res. 1993, 40, 191–238.
3. Amblard, M.; Daffix, I.; Bedos, P.; Bergen, G.; Buneau, D.; Paquet, J. L.; Luccarini, J. M.;
Belihard, P.; Dodey, P.; Martinez, J. J. Med. Chem. 1999, 42, 4185–4192.
4. Harovitz, Z. P. Psychosomatics 1965, 6, 281–286.
5. Nygren, Z. P.; Larsson, R.; Slater, L. J. Cell Pharmacol. 1991, 2(4), 202–225.
6. Kikkawa, K.; Murata, S.; Iwasaki, H.; Toriuni, W.; Banno, K.; Naga, T. Arzneim Forsch. 1992,
42, 781–786.
7. Grandolini, G.; Perioli, L.; Ambrogi, V. Eur. J. Med. Chem. 1999, 34, 701–709.
8. Urbanski, M. J.; Chen, R. H.; Demarest, K. T.; Gunnet, J.; Look, R.; Ericson, E.; Murray, W. V.;
Rybczynski, X. Z. Bioorg. Med. Chem. Lett. 2003, 13, 4031–4034.
9. Sanchez-Mateo, C. C.; Darias, V.; Exposito-Orta, M. A.; Albertos, L. M. Il Farmaco 2003, 58,
1–10.
10. Fang Che, X.; Nakajima, Y.; Sumizawa, T.; Ikeda, R.; Ren, X. Q.; Lei Zheng, C.; Mukai, M.;
Furukawa, T.; Haraguchi, M.; Gao, H.; Sugimoto, Y.; Akiyama, S. Cancer Lett. 2002, 187,
111–119.
11. Ambrogi, V.; Grandolini, G.; Perioli, L.; Giusti, L.; Lucacchini, A.; Martini, C. Eur. J. Med.
Chem. 1995, 30, 429–437.
12. Campiani, G.; Nacci, V.; Fiorini, I.; De Filippis, M. P.; Garofalo, A.; Ciani, S. M.; Greco, G.;
Novellino, E.; Manzoni, C.; Mennini, T. Eur. J. Med. Chem. 1997, 32, 241–252.
13. Campiani, G.; Fiorini, I.; De Filippis, M. P.; Ciani, S. M.; Garofalo, A.; Nacci, V.; Giorgi, G.;
Sega, A.; Chiarini, B.; Budriesi, R.; Bruni, G.; Romeo, M. R.; Manzoni, C.; Mennini, T. J. Med.
Chem. 1996, 39, 2922–2938.
14. De Sarro, G.; Chimirri, A.; De Sarro, A.; Gitto, R.; Grasso, S.; Zappala, M. Eur. J. Med. Chem.
1995, 30, 925–929.
15. Wu, C. Z.; Huang, J. X.; Zhang, Q. H.; Xu, J. X. Chem. Res. Chin. Univ. 2006, 22, 36–39.
16. Mi, B. Y.; Jin, S. Chin. Chem. Lett. 1991, 2, 925–926.
17. Xu, J. X.; Lan, R. X.; Jin, S. Chem. J. Chin. Univ. 1998, 19, 1774–1776.
18. Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura, H.; Sugiura, M.; Fukaya,
C.; Kagitani, Y. J. Med. Chem. 1996, 39, 3019–3029.
19. De Clercq, E. J. Clin. Virol. 2004, 30, 115–133.
20. Wadsworth, H. J.; Jenkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark, M. S. G.; Brown, F.; Riley, G.
J.; Graves, D.; Hawkins, J.; Naylor, C. B. J. Med. Chem. 1992, 35, 1280–1290.
21. Burrell, G.; Evans, J. M.; Hadley, M. S.; Hicks, F.; Stemp, G. Bioorg. Med. Chem. Lett. 1994, 4,
1285–1290.
22. Eto, H.; Kaneko, Y.; Sakamotoa, T. Chem. Pharm. Bull. 2000, 48(7), 982–990.
23. Goa, K. L.; Barradell, L. B. Drugs 1995, 50, 658–690.
24. Haria, M.; Bryson, H. M.; Goa, K. L. Drugs 1996, 51, 585–620.
25. Yang, D. B.; Liu, F. M.; Xu, F.; Yang, C.; Ye, J. W.; Shen, S. W.; Zhou, Y. L. Mol. Divers. 2008,
12, 103–109.
26. Liu, F. M.; Wang, B. L.; Li, Y. P. Chem. J. Chin. Univ. 2002, 23, 2097–2101.
27. Mohamed, A. M.; Mohamed, H. E.; Negm, A. M. J. Heterocycl. Chem. 2002, 39, 105–108.
28. Shi, Y. N.; Yang, Y.; Fang, J. X.; Lu, W. S. Chem. J. Chin. Univ. 1996, 17, 1578–1582.
29. Yang, D. B.; Liu, F. M.; Shen, S. W.; Chen, S. Q. Chin. J. Org. Chem. 2010, 30, 244–249.
30. Xu, J. X. Mol. Divers. 2005, 9, 45–49.