A facile method for the synthesis of pyridazino[4,5-b][1,4]thiazine-diones via Smiles rearrangement

Article abstract of DOI:10.1016/j.tetlet.2013.04.026

An efficient one-pot tandem method for the synthesis of pyridazino[4,5-b][1,4]thiazine-diones via Smiles rearrangement was developed. A number of ideal products were obtained with high yields without any byproducts. More specifically, this transition metal-free process is an environmentally friendly, economical, and efficient method for preparation of mixture-based heterocyclic libraries.

Full text of DOI:10.1016/j.tetlet.2013.04.026

Tetrahedron Letters 54 (2013) 3253–3255
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile method for the synthesis of pyridazino[4,5-b][1,4]thiazine-diones via
Smiles rearrangement
⇑
Yongmei Zhao, Yongcheng Bai, Qihui Zhang, Zhi Chen, Qiaoling Dai, Chen Ma
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China.
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot tandem method for the synthesis of pyridazino[4,5-b][1,4]thiazine-diones via Smiles
rearrangement was developed. A number of ideal products were obtained with high yields without any
byproducts. More specifically, this transition metal-free process is an environmentally friendly, econom-
ical, and efficient method for preparation of mixture-based heterocyclic libraries.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 30 December 2012
Revised 27 March 2013
Accepted 8 April 2013
Available online 20 April 2013
Keywords:
Pyridazino[4,5-b][1,4]thiazine-diones
One-pot synthesis
Smiles rearrangement
Tandem reaction
Introduction
diones to find out if they can be considered as ‘drug-like’ mole-
cules,14 so that the risk of pointless synthesis could be avoided.
Small molecules play a key role in modern drug development,
especially in the area of drug discovery, because of their inhibition
of disease-associated molecular interactions and interaction with
proteins.1 For example, the discovery and development of small
molecules that have been used as cancer drugs and have been rev-
olutionized over the last decade.2 Moreover, small mixture-based
heterocyclic molecules and libraries have dramatically different
physical and biological properties from the prime compounds used
as starting materials.3 Heterocyclic-fused thiomorpholin-3-ones
have aroused a considerable interest due to their extensive range
of biological activities, such as bacteriostatic,4 antiarrhythmic5,
and antidiabetic.6 Moreover, 4H-benzo[b][1,4]thiazin-3(4H)-ones
are used as herbicides.7 Pyridazinone derivatives are a kind of
fused heterocyclic compounds that have a number of biological
activities, such as antimicrobial,8 antiarrhythmic,9 bioavailable
inhibitors of Aurora A kinase,10 pesticides,11 and anticancer activi-
ties.12 However, pyridazino[4,5-b][1,4]thiazine-diones has been
studied neither for biological activities nor its synthesis pathway.
Therefore, it is a worthwhile study of pyridazino[4,5-b][1,4]thia-
zine-diones considering that dissimilar compounds generally pro-
duce dissimilar effects.
All of the related properties such as logP (octanol/water partition
co-efficient),15 PSA (polar surface area),16 and molecular volume
were obtained using the Molinspiration online property calculator,
based on group contribution.17 Moreover, for the majority of com-
pounds, the values of logP were between 2 and 3 and all of these
data are provided in our Supporting information Table 2. As a re-
sult, none of these designed molecules violated Lipinski’s rule of
5. Therefore, an efficient method for the synthesis of fused pyridaz-
ino[4,5-b][1,4]thiazine-diones is needed, in order to study their
biological activities in detail.
Considering pressing environmental and energy problems, or-
ganic synthesis toward cleaner and greener chemical processes is
becoming increasingly important today.18 In addition, using a me-
tal catalyst has some drawbacks in industrial applications as it is
expensive, oxygen sensitive, and may leave toxic trace metal con-
taminants. We have been studying the development of economical
syntheses of heterocyclic systems.19 In continuation of our work,
we describe a one pot metal-free synthesis of 7-(tetrahydro-2H-
pyran-2-yl)-2H-pyridazino[4,5-b][1,4]thiazine-3,8(4H,7H)-iones at
mild reaction conditions. The ideal products were obtained by
the reaction of 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyrida-
zin-3(2H)-one with a variety of N-substituted mercaptoacetamides
(Scheme 1).
It is generally acknowledged that molecules whose properties
obey ‘Lipinski’s rule of 5’13 have a high propensity for penetration
into cells and for oral absorption. So, we first calculated the phys-
icochemical properties of fused pyridazino[4,5-b][1,4]thiazine-
Results and discussion
Optimized reaction conditions were found by systematically
investigating the reaction parameters using 4,5-dichloro-2-(tetra-
⇑
Corresponding author. Tel.: +86 531 88364464; fax: +86 531 88564464.
E-mail address: chenma@sdu.edu.cn (C. Ma).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.026

3254
Y. Zhao et al. / Tetrahedron Letters 54 (2013) 3253–3255
R1
N
those of N-aryl substrates (Table 2, entries 8–12), there was no dif-
ference. Additionally, according to the experiments, when the N-
substrate of 2 is 2-propylamine or cyclohexylamine the reaction
did not produce the expected product in spite of trying higher tem-
peratures and longer reaction times. We believe steric hindrance is
responsible for the results. It was also found that the N-aryl sub-
strates with an electron-donating group (Table 2, entries 11 and
12) provided little higher yield than substrates with an electron-
withdrawing group (Table 2, entries 8–10). The structures of de-
sired compounds were shown in Figure 1. In addition, the molecu-
lar structure of the representative product 3j was determined by X-
ray crystallographic analysis (Fig. 2).
Based on reported Smiles rearrangement reaction and our
experimental results, a plausible reaction mechanism was pro-
posed in Scheme 2. The reaction of 1 with 2 yielded compound 4.
Compound 4 could proceed in two paths (I and II). Path II could
produce the direct intramolecular nucleophilic substitution prod-
uct 8. Path I could lead to compound 3 via Smiles rearrangement.
However, we only obtained compound 3.
Cl
Cl
N
N
O
O
Base, Solvent
rt
N
N
HS
R1
THP
N
H
THP
S
O
O
1
2
3
Scheme 1. One-pot synthesis of pyridazino[4,5-b][1,4]thiazine-diones.
hydro-2H-pyran-2-yl)pyridazin-3(2H)-one and N-benzyl-2-mer-
captoacetamide (Table 1). First, different bases such as KOH, NaH,
NaOH, and K2CO3 in DMF were tested at room temperature, which
proved that Cs2CO3 was the most suitable base. Then we probed
into the influence of different solvents on the reaction. DMF was
found to be an effective solvent with a good result, but CH3CN,
DMSO, and THF were less effective.
Then, the optimized reaction conditions were used to explore
the scope of synthesizing 7-(tetrahydro-2H-pyran-2-yl)-2H-
pyridazino[4,5-b][1,4]thiazine-3,8(4H,7H)-diones (Table 2). The
desired 7-(tetrahy dro-2H-pyran-2-yl)-2H-pyridazino[4,5-b][1,4]
thiazine-3,8(4H,7H)-diones were obtained yielding from 78% to
95% (Table 2). As shown in Table 2, for the variation of R1, compar-
ing the yields of N-substrates alkyl (Table 2, entries 1–7) with
Imido nitrogen in compound
5 underwent intramolecular
nucleophilic attack on the carbonium (meta-position to the car-
bonyl group). Migration of the spiro-sulfur, proceeding through
O
O
THP
S
N
THP
S
N
N
N
N
N
Table 1
Optimization of reaction conditions
O
O
O
O
3b
3d
3a
HS
O
Cl
Cl
O
O
N
N
Base
N
S
O
N
N
THP
S
N
HN
THP
S
N
Solvent, rt
N
N
N
N
THP
THP
O
O
3c
1
2
3
Entry
Base
Solvent
Temp/°C
Time/h
Yield/%
1
2
3
4
5
6
7
Cs2CO3
K2CO3
NaOH
NaH
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMSO
CH3CN
THF
rt
rt
rt
rt
rt
80
80
3
7
3
3
3
7
7
86
83
79
52
37
32
36
O
THP
S
N
N
N
O
THP
S
N
N
O
N
O
3f
3e
Table 2
Figure 1. Structures of desired compounds of 3a–l.
Synthesis of Pyridazino[4,5-b][1,4]thiazine-3,8(4H,7H)-diones
R1
Cl
N
N
O
N
O
Cs2CO3, DMF
rt
N
N
HS
R1
THP
Cl
N
H
THP
S
O
O
1
3
2
Entry
R1
Time/h
Product
Yield/%
1
2
3
4
5
6
7
8
2a Me
2b Et
2c Pr
2d Bu
2e Bn
2f b-Phenethyl
2g 3,4-MeOphenethyl
2h 4-FC6H4
2i 4-ClC6H4
2j Ph
2k 4-MeC6H4
2l 4-MeOC6H4
4
4
4
4
6
6
6
10
10
10
10
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
89
90
95
87
83
81
78
87
87
92
87
9
10
11
12
3j
3k
3l
Figure 2. X-ray structure of compound 3j with atomic numbering scheme.

Y. Zhao et al. / Tetrahedron Letters 54 (2013) 3253–3255
3255
O
O
O
THP
Cl
S
THP
Cl
Cl
N
N
N
N
base
base
HS
R1
H
N
+
N
H
R1
O
O
1
2
4
path II
Cl
R1
Cl
N
O
Cl
S
S
O
THP
O
N
O
THP
N
N
path I
O
N
N
N
path I
S
N
N
THP
R1
R1
Cl
7
6
5
path II
Cl
O
O
R1
N
THP
S
THP
O
N
N
N
N
N
O
S
R1
8
3
Scheme 2. A plausible reaction mechanism.
3099; (c) Hann, M. M.; Leach, A. R.; Harper, G. J. Chem. Inf. Comput. Sci. 2001, 41,
856.
2. Hoelder, S.; Clarke, P. A.; Workman, P. Mol. Oncol. 2012, 6, 155.
3. (a) Eichler, J.; Houghten, R. A. Mol. Med. Today 1995, 1(4), 174; (b) Dooley, C. T.;
Houghten, R. A. J. Perspect. Drug. Disc. Design. 1995, 2, 287.
4. Guarda, V. L. M.; Perrissin, M.; Thomasson, F.; Ximenes, E. A.; Galdino, S. L.;
Pitta, I. R.; Luu-Duc, C.; Barbe, J. Eur. J. Med. Chem. 2003, 38, 769.
5. Fujita, M.; Ito, S.; Ota, A.; Kato, N.; Yamamoto, K.; Kawashima, Y.; Yamauchi, H.;
Iwao, J. J. Med. Chem. 1990, 33, 1898.
6. Kawashima, Y.; Ota, A.; Mibu, H. W.O. Patent 9,405,647, 1994.
7. Wuemachu, T.; Oshi, H. K.R. Patent 8,200,849, 1982.
8. Sridhara, A. M.; Reddy, K. R. V.; Keshavayya, J.; Goud, P. S. K.; Somashekar, B. C.;
Bose, P.; Peethambar, S. K.; Gaddam, S. K. Eur. J. Med. Chem. 2010, 45, 4983.
9. (a) Mátyus, P. J. Heterocycl. Chem. 1998, 35, 1075; (b) Bidló-Iglóy, M.; Mátyus, P.
J. Pharm. Biomed. Anal. 1999, 19, 487.
10. (a) Verhelst, T.; Verbeeck, S.; Ryabtsova, O.; Depraetere, S.; Maes, B. U. W. Org.
Lett. 2011, 13, 272; (b) Li, Y. X.; Luo, Y. P.; Xi, Z.; Niu, C. W.; He, Y. Z.; Yang, G. F.
J. Agric. Food Chem. 2006, 54, 9135.
the ‘Meisenheimer complex’ 6, with intramolecular nucleophilic
displacement of the chlorine anion by a sulfur anion of compound
7 yielded the desired cyclization product 3 (Scheme 2).
Also, a theoretical study of this SÀN type Smiles rearrangement
process was done to rationalize the experimental observations.19b
By performing quantum chemical calculations, the molecular
mechanism for the SÀN type Smiles rearrangement was shown.
The theoretical results showed that the Smiles rearrangement
pathway was energetically more favorable than the direct nucleo-
philic substitution pathway.
Conclusions
In conclusion, we developed an operationally simple and eco-
nomic synthesis of a number of pyridazino[4,5-b][1,4]thiazine-
diones based on the Smiles rearrangement. Furthermore, this me-
tal-free method accords with the development of the current or-
ganic synthesis trend toward cleaner and greener chemical
processes which is due to pressing environmental and energy
problems. Therefore, this transition-metal-free process has poten-
tial applications in the synthesis of biologically and medicinally
relevant compounds.
11. (a) Schwartz, A.; Beke, G.; Kovári, Z.; Böcskey, Z.; Farkas, Ö.; Mátyus, P. J. Mol.
Struct: Theochem. 2000, 49, 528; (b) Monsieurs, K.; Krajsovszky, G.; Dunkel, P.;
Maes, B. U. W.; Tapolcsányi, P.; Egyed, O.; Boros, S.; Mátyus, P.; Pieter, L.;
Lemière, G. L. F.; Hajós, G. L. F.; Hajós, G. Tetrahedron 2006, 62, 121.
12. Del Olmo, E.; Barboza, B.; Ybarra, M. I.; Lopez-Perez, J. L.; Carron, R.; Sevilla, M.
A.; Boselli, C.; San Feliciano, A. Bioorg. Med. Chem. Lett. 2006, 16, 2786.
13. (a) Lipinsky, C. et al Adv. Drug Delivery Rev. 1997, 23, 2; (b) Kubinyi, H. et al J.
Med. Chem. 1998, 41, 3325; (c) Murko, M. et al J. Med. Chem. 1998, 41, 3314; (d)
Proudfood, J. R. Bioorg. Med. Chem. Lett. 2002, 12, 1647.
14. (a) Uetrecht, J. Curr. Opin. Drug Disc. Dev. 2001, 4, 55; (b) Uetrecht, J. Chem. Res.
Toxicol. 2008, 21, 84; (c) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. ACS
Comb. Sci. 1999, 1, 55; (d) Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc.
2007, 6(11), 881.
15. Mannhold, R.; Rekker, F. P. Perspect. Drug Discovery Des. 2000, 18, 1.
16. (a) Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714; (b) Ertl, P. In
Molecular Drug Properties; Mannhold, R., Ed.; Wiley-VCH, 2007; pp 111–126.
17. http://www.molinspiration.com.
18. (a) Pereira, C. J. Chem. Eng. Sci. 1959, 1999, 54; (b) Jin, Y.; Wang, D. Z.; Wei, F.
Chem. Eng. Sci. 2004, 59, 1885; (c) Jin, Y.; Wang, D. Z.; Wei, F. J. Chem. Eng. Sci.
1885, 2004.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21172131) for financial support of this research. Thanks
to Dr. Edward C, Mignot, Shandong University, for linguistic advice.
19. (a) Zhao, Y. M.; Dia, Q. L.; Chen, Z.; Zhang, Q. H.; Bai, Y. C. ACS Comb. Sci. 2013,
15, 130; (b) Zhao, Y. M.; Wu, Y.; Jia, J.; Zhang, D. J.; Ma, C. A. J. Org. Chem. 2012,
77, 8501; (c) Zhang, X. H.; Jia, J.; Ma, C. Org. Biomol. Chem. 2012, 10, 7944; (d)
Zhan, C. J.; Jia, J.; Yang, B. C.; Huang, A. P.; Liu, Y. L.; Ma, C. RSC Advances 2012,
2(19), 7506; (e) Liu, Y. L.; Ma, Y.; Zhan, C. J.; Huang, A. P.; Ma, C. Synlett 2012,
23, 255; (f) Huang, A. P.; Qiao, Z.; Zhang, X. H.; Yu, W.; Zheng, Q. Q.; Ma, Y.; Ma,
C. Tetrahedron 2012, 68, 906; (g) Huang, A. P.; Liu, F.; Zhan, C. J.; Liu, Y. L.; Ma, C.
Org. Biomol. Chem. 2011, 9, 7351; (h) Liu, Y. L.; Chu, C. X.; Huang, A. P.; Zhan, C.
J.; Ma, Y.; Ma, C. ACS Comb. Sci. 2011, 13, 547.
Supplementary data
Supplementary data (experimental procedures, physicochemi-
cal properties of 3a–l, and spectral data of compounds 3a–l) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.04.026.
References and notes
1. (a) Knudsen, L. B.; Kiel, D.; Teng, M., et al Proc. Natl. Acad. Sci. U.S.A. 2007, 104(3),
937; (b) Sloop, K. W.; Willard, F. S.; Brenner, M. B., et al Diabetes 2010, 59(12),