Clean synthesis of novel spiro[indene-2,2’-[1,3,5]-oxathiazine]-1,3-diones in water

Article abstract of DOI:10.1016/j.cclet.2016.12.036

In this work, we have designed an efficient and convenient method for the synthesis of novel spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-diones by the one-pot, three component condensation of tetramethyl guanidine, ninhydrin, and isothiocyanates in water. E

Full text of DOI:10.1016/j.cclet.2016.12.036

Accepted Manuscript
Title: Clean<!–<query id="Q1">Please check the dochead and
correct if necessary.</query>–> synthesis of novel
spiro[indene-2,2’-[1,3,5]-oxathiazine]-1,3-diones in water
Author: <ce:author id="aut0005"
author-id="S1001841717300207-
c36f674d3fa3625849de7e46da1561e2"> Mahboobeh
Salehpour<ce:author id="aut0010"
author-id="S1001841717300207-
e9d620f1a4ae1467cae995958e4f4969"> Javad
Azizian<ce:author id="aut0015"
author-id="S1001841717300207-
be3aa3b7eb3d2ce839e699469deecead"> Hassan
Kefayati
PII:
S1001-8417(17)30020-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2016.12.036
CCLET 3947
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Chinese Chemical Letters
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31-10-2016
5-12-2016
7-12-2016
Please cite this article as: Mahboobeh Salehpour, Javad Azizian, Hassan Kefayati, Clean
synthesis of novel spiro[indene-2,2’-[1,3,5]-oxathiazine]-1,3-diones in water, Chinese
Chemical Letters http://dx.doi.org/10.1016/j.cclet.2016.12.036
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Original article
Clean synthesis of novel spiro[indene-2,2'-[1,3,5]-oxathiazine]-1,3-diones in water
a
a,
b

Mahboobeh Salehpour , Javad Azizian , Hassan Kefayati
a Department of Chemistry, Science and Research Branch, Islamic Azad University, P. O. Box 19395-1775, Tehran, Iran
b Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
Corresponding author.
E-mail address: azizian@srbiau.ac.ir
Graphical abstract
An efficient and convenient method for the synthesis of novel spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-diones by the one-pot, three
component condensation of tetramethyl guanidine, ninhydrin, and isothiocyanates in water was reported. Easy purification, green
reaction conditions, easy performance and good yields are some advantages of this procedure.
ABSTRACT
In this work, we have designed an efficient and convenient method for the synthesis of novel spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-
diones by the one-pot, three component condensation of tetramethyl guanidine, ninhydrin, and isothiocyanates in water. Easy purification,
green reaction conditions, easy performance and good yields are some advantages of this procedure.
Keywords:
Spiro[indene-oxathiazine]
Tetramethyl guanidine
Ninhydrin
Oxathiazine
ARTICLE INFO
Article history:
Received 31 October 2016
Received in revised form 5 December 2016
Accepted 7 December 2016
Available online

1. Introduction
Multi-component reactions (MCRs) have gained significant attention due to the one-pot reaction, atom-economy, and the
possibility of introducing maximum diversity in the product in one chemical operation. These types of reactions leading to interesting
heterocyclic scaffolds, are particularly useful for the construction of diverse chemical libraries of drug-like molecules [1].
Heterocycles are a widespread structural motif found as key elements of numerous drugs and designed medicinal agents in
medicinal chemistry. Among them, sulfur containing heterocycles such as, thiomorpholines, thiazepines and thiazines are ubiquitous
compounds and they exhibit a variety of biological properties such as antiarrhythmic, antihypertensive, antibacterial and antidiabetic
[2]. In particular, heterocycles comprising nitrogen, oxygen, and sulfur atoms in one ring are very important in view of their
biological applications. Among these, the oxathiazines have been used for a long time in agricultural and biological applications.
They act as nematicides [3], herbicides, fungicides, plant desiccants and defoliants [4], antifouling agents [5], and wood preservatives
[6]. Due to these properties, many methods have been reported for the synthesis of oxathiazine compounds [7].
Spirocyclic frameworks represent an important class of naturally compounds which have some biological properties [8].
Synthesis of this framework has always been a challenging for organic chemists because it often requires synthetic design based on
specific strategies. Moreover in some cases the products are rearranged to other organic framework [9]. Due to the enormous
importance of this class of compounds, chemists have been much attention to these spiro derivatives and a range of method has been
reported for their synthesis [10-12].
Recently, reactivity and properties of novel heterocyclic compounds were reported using tetramethyl guanidine [13]. Herein, in
the course of our research goal into the synthesis of new heterocyclic compounds [14], according to some work on (O,S)-ketal
synthesis and on-water catalysis-free synthesis [15], we have been interested in this strategy for the synthesis of hitherto unreported
heterocycles including nitrogen, oxygen, and sulfur atoms in one ring with spiro skeleton in water without the catalysts.
2. Results and discussion
Initially, we planned to evaluate the reaction of ninhydrin (1), tetramethyl guanidine (2) and 4-chlorophenyl isothiocyanate (3a)
in order to produce 4'-((4-chlorophenyl)amino)-6',6'-bis(dimethylamino)-6'H-spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione (5a) at
room temperature in ethanol. Surprisingly, it was found that, the spectral data of isolated product was not consistent with the expected
derivative 5a. Indeed, the data was in good agreement with the structure of an unprecedented product 4'-((4-chlorophenyl)imino)-6'-
(dimethylamino)-4'H-spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione 4a (Scheme 1).
The structure of compound 4a was elucidated by their mass, IR and high-field NMR and spectra and elemental analysis. The
mass spectrum of 4a showed a molecular ion peak at m/z 399, which was consistent with the mass of a 1:1:1 condensation product of
the three components having released HNMe2 molecule. The 1H NMR spectrum of the product exhibited a singlet integrating for six
protons at δ 3.59 corresponding to the two methyl groups and clearly indicating that, there is only one –NMe2 group in the product.
The aromatic region of the spectrum displayed separate signals for all the aromatic protons at the expected chemical shifts and with
appropriate integral values. Further support for the structures of compounds 4a was obtained from the 13C NMR spectra of the
product where a downfield resonance (e.g., 110.9 for 4a) was apparent corresponding to the presence of one spiro carbon in the
molecule. Based on these features the product was identified as 4a.
In order to find the optimum conditions, we carried out the above reaction in various solvents and temperatures (Table 1). As
shown in Table 1, the best results were obtained in H2O at room temperature and with the increase of temperature, yield of the 4a
decreased and more spots appeared in TLC, probably due to side reactions and/or conversion of product to other by-products.
After optimizing the conditions, the generality of the method was evaluated by using various isothiocyanate 3 bearing electron-
withdrawing and electron-donating groups. The reactions are performed as clean as the model reaction and the desired products 4a-g
were obtained in good to excellent yields (Table 2).
We have not established the exact mechanism for the formation of 4, however, a reasonable suggestion is offered in Scheme 2.
At first, nucleophilic attack of tetramethyl guanidine to isothiocyanate (3) leads to the formation of intermediate 6. Then nucleophilic
attack of sulfur atom to middle carbonyl group of ninhydrin can afford intermediate 7 (route a) or 8 (route b). It seems the route b is
the main route of reaction due to the higher donating effect of the nitrogen atoms bearing two methyl groups compared to the one
bearing an aromatic moiety. Finally, cyclization of them produced intermediate 5. There is a singlet for six protons at δ 3.59 in the 1H
NMR spectra shows that the reaction has gone a step ahead to produce a more stable products 4.
3. Conclusion

We have reported a novel, clean and efficient synthesis of new spiro[indene-2,2'-[1,3,5]oxathiazine derivatives 4 by a three-
component reaction. Simple procedure for product isolation, lack of problems connected with conventional solvent use, good yields
are the main features of this method. The products described in this article have two important biological active moieties therefore,
synthetic and biological applications of compounds 4 can be considered in the near future.
4. Experimental
All starting materials were purchased from Merck (Germany) and Fluka (Switzerland) and were used without further
purification. All products were identified with the following methods: Melting points: Electrothermal 9100 apparatus; Elemental
analyses for C, H, and N: Heraeus CHN–O–Rapid analyzer; Mass spectra: Finnigan-Matt 8430 mass spectrometer operating at an
1
ionization potential of 70 eV; H NMR and 13C NMR spectra: at 500 and 125 MHz, respextively, on a Bruker Advance DRX-500
MHz in CDCl3; IR Spectra: in KBr on a Shimadzu IR-460 spectrometer.
General procedure for the synthesis of spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-diones 4a-g: A solution of tetramethyl guanindine
(1 mmol) and isothiocyanate derivatives (3a-g) (1 mmol) in water (2 mL) were magnetically stirred for 5 min to obtained
intermediate 6. Then, ninhydrin (1 mmol) was added to reaction mixture and the solution was stirred for appropriate time at room
temperature. The reaction products were monitored using thin layer chromatography (TLC). After completion of the reaction, the
mixture was filtered, and the precipitate was washed with ether (4 mL) to afford the pure product 4a-g.
4'-((4-Chlorophenyl)imino)-6'-(dimethylamino)-4'H-spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione (4a, Table 2, entry a): Yield:
94%. Yellow powder; mp 126-128 °C. IR (KBr, cm-1): max 1171, 1241, 1374, 1496, 1533, 1723; 1H NMR (500 MHz, CDCl3): δ 3.59
(s, 6H, NMe2), 7.39 (d, 2H, 3J = 7.5 Hz, Ar), 7.64 (t, 2H, 3J = 7.5 Hz, Ar), 7.91 (d, 2H, 3J = 7.9 Hz, Ar), 8.04 (d, 2H, 3J = 7.9 Hz, Ar);
13C NMR (125 MHz, CDCl3): δ 44.0, 110.9, 127.4, 127.5, 130.1, 130.7, 130.9, 133.3, 135.7, 164.5, 167.6, 195.8; MS (EI, 70 eV): m/z
(%)= 399 (M+, 48), 354 (25), 255 (43), 191 (69), 144 (100), 111 (80), 77 (95); Anal. Calcd. for C19H14ClN3O3S: C, 57.07; H, 3.53; N,
10.51. Found: C, 57.01; H, 3.44; N, 10.87.
6'-(Dimethylamino)-4'-(p-tolylimino)-4'H-spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione (4b, Table 2, entry b): Yield: 85%.
1
Yellow powder; mp 131-133 °C. IR (KBr, cm-1): max 1170, 1257, 1367, 1461, 1529, 1723; H NMR (500 MHz, CDCl3): δ 2.49 (s,
3H, Me), 3.88 (s, 6H, NMe2), 7.10 (d, 2H, 3J = 7.6 Hz, Ar), 7.30 (t, 2H, 3J = 7.6 Hz, Ar), 7.40 (d, 2H, 3J = 7.8 Hz, Ar), 7.93 (d, 2H, 3J
= 7.8 Hz, Ar); 13C NMR (125 MHz, CDCl3): δ 22.2, 45.7, 110.9, 125.1, 126.1, 127.5, 129.2, 130.0, 130.3, 130.6. 162.5, 166.0, 195.2;
MS (EI, 70 eV): m/z (%) = 379 (M+, 66), 335 (46), 235 (59), 187 (96), 144 (80), 91 (88), 77 (100); Anal. Calcd. for C20H17N3O3S: C,
63.31; H, 4.52; N, 11.07. Found: C, 63.45; H, 4.39; N, 10.83.
Other data of compounds 4c-g are deposited in Supporting information.
Acknowledgement
We gratefully acknowledge financial support from the Research Council of Science and Research Branch, Islamic Azad
University.
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Scheme 1. The reaction leading to the synthesis of spiro[indene-oxathiazine] derivatives 4a.
Scheme 2. Proposed mechanism for preparation of spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione derivatives (4a-g).
Table 1
Optimization of the reaction conditions for the formation of 4a.a
Entry
Solvent
EtOH
MeOH
MeCN
CH2Cl2
THF
DMF
H2O
H2O
Time (h)
Temperature (ºC)
Yield (%)
1
2
3
4
5
6
7
8
6
6
8
9
8
4
4
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
81
80
74
69
62
85
94
70
a Reaction conditions: Tetramethyl guanindine (1 mmol), 4-chlorophenyl isothiocyanate (1 mmol), ninhydrin (1 mmol).

Table 2
Prepared spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-dione derivatives (4a-g).a
Entry Compound 3
Product 4
Time (min) Yield (%)b Mp (oC)
240
94
126-128
a
260
85
131-133
b
c
250
225
83
90
140-142
119-121
d
230
220
88
82
151-153
160-162
e
f
220
84
169-171
g
a Reaction conditions: Tetramethyl guanindine (1 mmol), isothiocyanate derivatives (1 mmol), ninhydrin (1 mmol) in H2O (2 mL), at r.t.
b Isolated yields.