Novel domino reactions for the efficient synthesis of 5,6-dihydro-1,4,2- oxathiazines

Article abstract of DOI:10.1016/j.tetlet.2014.05.062

A facile efficient synthesis of novel 3-aryl-5,6-dihydro-1,4,2-oxathiazin- 6-ols from the reaction of (E)-N-hydroxyarylimidoyl chlorides and 1,4-dithiane-2,5-diol in the presence of triethylamine is described. This transformation presumably proceeds via in situ generation of 2-mercaptoacetaldehyde and nitrile oxide and their concomitant [3+3] annulation.

Full text of DOI:10.1016/j.tetlet.2014.05.062

Tetrahedron Letters 55 (2014) 3761–3764
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel domino reactions for the efficient synthesis
of 5,6-dihydro-1,4,2-oxathiazines
⇑
Sundaravel Vivek Kumar, Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile efficient synthesis of novel 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols from the reaction of (E)-N-
hydroxyarylimidoyl chlorides and 1,4-dithiane-2,5-diol in the presence of triethylamine is described. This
transformation presumably proceeds via in situ generation of 2-mercaptoacetaldehyde and nitrile oxide
and their concomitant [3+3] annulation.
Received 26 February 2014
Revised 13 May 2014
Accepted 14 May 2014
Available online 22 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
(E)-N-Hydroxyarylimidoyl chloride
1,4-Dithiane-2,5-diol
3-Aryl-5,6-dihydro-1,4,2-oxathiazin-6-ol
Low molecular weight heterocycles are among the most preva-
lent pharmacophores.1 In particular, heterocycles comprising
nitrogen, oxygen, and sulfur atoms in one ring are undoubtedly
of great importance in view of their biological applications. Among
these, the oxathiazine and its derivatives have been used for a long
time in agricultural and biological applications. They act as nema-
ticides,2 herbicides, fungicides, plant desiccants and defoliants,3
antifouling agents,4 and wood preservatives.5 Bethoxazine (Betho-
O
O
N
N
O
Y
N
S
S
(O)n
X
S
O
]
[O
S
n
S
n=0,1,2; X= O, S; Y = N,CH
n=0,1,2
Industrial microbicide
Antibacterial and Antifouling agents
O
guard™, Fig. 1) is
a broad spectrum industrial microbicide
introduced by Janssen Pharmaceutica.6 Oxathiazines also serve as
crop protection agents and crop growth regulators,7 anticancer,
antiinfectious, antigastric acid secretion, antiosteoporosic and
anti-inflammatory agents,8 estrone sulfatase inhibitors,9 and in
the treatment of hyperglycemia.10 Oxathiazine derivatives also
serve as key intermediates for the synthesis of thiadiazoles11 and
b-lactam analogues12 as well as artificial sweetener.13
O
N
O
N
N
H
N
S
S
S
X
O
[O]n
[O]n
[O]n
R
n = 0,1,2
n= 1,2
n= 1,2; X = S, SO, SO2
Inhibitors of sulfhydryl - depentent biomolecules
Despite the above biological importance of 1,4,2-oxathiazines,
investigation on their assembly is scarce.6c,d This led us to report
in this Letter a two-component domino reaction for the facile syn-
thesis of 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols, whose retro-
synthetic analysis (Scheme 1) points to simple readily accessible
starting materials, viz. (E)-4-bromo-N-hydroxybenzimidoyl chlo-
ride and 1,4-dithiane-2,5-diol.
Wood perservatives
Figure 1. Selected examples of biologically active 5,6-dihydro-1,4,2-oxathiazine
derivatives.
It is pertinent to note that 2-mercaptoacetaldehyde endowed
with both electrophilic and nucleophilic reaction centers, gener-
ated from 1,4-dithiane-2,5-diol in the presence of base, has the
versatility to combine with reactants possessing both nucleophilic
and electrophilic centers and hence has been used in the synthesis
of important heterocycles such as thiophenes,14 dihydrothiophene
carbaldehyde,15 tetrahydrothiophenes,16 thiacytidine,17 1,4-dith-
iin,18 thienopyrimidine,19 and penicillin analogues.20 This study
forms a part of our research embarked recently on the synthesis
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
http://dx.doi.org/10.1016/j.tetlet.2014.05.062
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3762
S. Vivek Kumar, S. Perumal / Tetrahedron Letters 55 (2014) 3761–3764
Table 2
O
N
Synthesis of 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols 3
OH
O
S
N
O
OH
S
OH
O
S
OH
DCM, Et3N (1 eq)
8-12h, rt
N
N
+
S
HO
S
Cl
Ar
Ar
R
R
3
1
2
Entry
Compd
Ar
Time (h)
Yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
4-ClC6H4
4-BrC6H4
4-PhC6H4
4-MeC6H4
4-EtC6H4
4-PriC6H4
4-tBuC6H4
C6H5
2-MeC6H4
3-FC6H4
3-BrC6H4
1-Naphthyl
2-Naphthyl
2-Thienyl
12
8
9
8
8
8
8
8
10
5
67
74
85
86
84
88
87
82
74
65b
69
81
80
70
72
HO
N
S
S
OH
+
Cl
HO
R
Et3N
Scheme 1. Retrosynthesis of 5,6-dihydro-1,4,2-oxathiazines.
12
9
10
9
of biologically relevant heterocycles employing domino
transformations.21
We started our study with the optimization of the model two-
component reaction between (E)-4-bromo-N-hydroxybenzimidoyl
chloride (1 mmol) and 1,4-dithiane-2,5-diol (0.5 mmol) in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (1 equiv) in etha-
nol at room temperature for 10 h.
2-Benzothienyl
10
a
Isolated yield after purification.
b
The reaction was performed with corresponding (E)-N-hydroxyarylimidoyl
chloride and 1,4-dithiane-2,5-diol in the presence of Et3N in CH3CN at reflux.24
After standard work-up and purification of the reaction mixture
via silica gel column chromatography, product 3b was obtained in
52% yield (Table 1, Entry 1). Then we proceeded with the optimiza-
tion of reaction conditions for maximizing the yield of the product.
As shown in Table 1, various bases such as potassium carbonate,
triethylamine, pyrrolidine, piperidine, pyridine, N,N-dimethylami-
nopyridine, and 1,4-diazabicyc-lo[2.2.2]octane were screened for
their catalytic efficacy in the reaction. Among the above bases, tri-
ethylamine is found to be superior to other bases and the yield of
the desired product could be increased to 65% in ethanol (Table 1,
Entry 12) and 74% in dichloromethane (Table 1, Entry 10) under
mild reaction conditions. Next, the model reaction was
investigated in other solvents, such as N,N-dimethylformamide,
methanol, water, and 1,4-dioxane (Table 1, Entries 10–16). From
the data listed in Table 1, it is clear that triethylamine–dichloro-
methane pair is ideal for obtaining a maximum yield of 3b (74%).
With the above optimized reaction conditions in hand, we pro-
ceeded to investigate the synthesis of a series of 3-aryl-5,6-dihy-
dro-1,4,2-oxathiazin-6-ols
3 (Table 2) employing differently
substituted (E)-N-hydroxyarylimidoyl chlorides (1 mmol) and
1,4-dithiane-2,5-diol (0.5 mmol) in the presence of triethylamine
(1 equiv) in dichloromethane at room temperature for 8–12 h.23
After completion of the reaction (TLC), the solvent was removed
under reduced pressure and the resulting crude product was
purified by flash silica column chromatography using petroleum
ether–ethyl acetate as eluent (4:1 v/v) to obtain a series of novel
3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols 3a–o in 65–88% yields
(Table 2). As shown in Table 2, the (E)-N-hydroxyarylimidoylchlo-
rides bearing moderately electron-releasing groups such as phenyl,
naphthyl, heteroaryl, and alkyl gave better yields in shorter
reaction time than that with mild electron-withdrawing groups.
Table 1
However, this transformation with
1 having either strong
Solvent and base-screen for the synthesis of 3ba
electron-releasing or electron-withdrawing groups such as 4-
NO2, 4-CF3, 3-NO2, 4-OMe, 4-(Me)2N, and 3-OMe failed even at
high temperature. The structure of 3-aryl-5,6-dihydro-1,4,2-oxa-
thiazin-6-ols 3 was deduced from one- and two-dimensional
NMR spectroscopic data as detailed for 3b as a representative
example (Fig. 2).
O
S
OH
OH
N
N
S
OH
DCM, base (1 eq)
8-12 h, rt
+
Cl
HO
S
Br
Br
3b
1b
2
In the 1H NMR spectrum of 3b, the H-6 appears as a doublet of
doublets at 5.64 ppm (J = 2.4, 0.9 Hz). The diastereotopic H-5
hydrogens appear as a doublet of doublets at 3.21 (J = 12.3,
3.6 Hz) and 3.35 ppm (J = 12.3, 2.2 Hz). These H-5 hydrogens show
(i) a C,H-COSY correlation with the carbon signal at 29.1 ppm due
to C-5 and (ii) a HMB correlation with C-6 at 85.3 ppm. The H-20,60
hydrogens appear as a multiplet at 7.57–7.60 ppm and show (i) a
C,H-COSY correlation with the carbon signal at 127.6 ppm assign-
ing it to C-20,60 and (ii) HMB correlations with C-3 and C-40 at
150.0 and 125.1 ppm respectively. Similarly, the H-30,50 appearing
as a multiplet at 7.51–7.55 ppm show a C,H-COSY correlation with
the carbon signal at 131.8 ppm and a HMB correlation with C-10 at
133.8 ppm. The hydroxyl proton gives a broad singlet at 3.95 ppm.
The 1H and 13C chemical shifts of 3b are depicted in Figure 2. The
structure deduced from NMR spectroscopic data is also in accord
with ESI-Mass spectra. Finally, the structure of the product 3d
has been unequivocally determined by X-ray structurallographic
study (Fig. 3).22
Entry
Base (1 equiv)
Solvent
EtOH
DCM
DCM
DCM
DCM
DCM
DCM
Time (h)
Yield of 3ba (%)
1
2
3
4
5
6
7
DBU
DBU
DMAP
Pyridine
Piperidine
Pyrrolidine
10
12
12
12
12
12
10
52
58
60
63
Trace
Trace
b
—
L-Proline
b
8
9
K2CO3
Na2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DCM
DCM
DCM
MeOH
EtOH
10
12
8
8
8
—
—
b
10
11
12
13
14
15
16
74
69
65
68
64
DMF
9
CH3CN
1,4-Dioxane
Water
10
12
12
b
—
—
b
a
Isolated yield after purification.
No reaction occurred.
b

S. Vivek Kumar, S. Perumal / Tetrahedron Letters 55 (2014) 3761–3764
3763
5.64, dd, J = 2.4, 0.9 Hz, 1H
85.3
7.57-7.60, m, 2H
127.6
OH
Cl
N
1
Domino
Reactions
S
OH
H
3.95, brs, 1H
6
O
S
OH
H
H
N
Ar
7.51-7.55, m, 2H
131.8
5
HO
S
2
H
3.21 (dd, J = 12.3, 3.6 Hz, 1H)
3.35 (dd, J = 12.3, 2.2 Hz, 1H)
H
Et3N
O
Br
H
Et3N
150.0
N
O
O
H
4
Ar
5
or
HS
125.1
133.8
S
Et3NH
Et3NH Cl
Et3NH
1
H
2
Et3N
OH
O
OH
H
N
6
H
H
O
3
H
1'
N
S
4
5
Ar
S
3
4'
Br
H
2'
3'
H
Figure 2. Selected 1H and 13C chemical shifts and HMBC correlations of 3b.
Scheme 2. Probable domino mechanistic pathway leading to the formation of 3.
the annulation step. If the anion of mercaptoacetaldehyde reacts
with the nitrile oxide, then for final protonation to give the prod-
uct, the intermediate will abstract a proton from triethylammo-
nium ion (Scheme 2). The fact that one mole of triethylamine is
sufficient to catalyze the reaction discloses that deprotonation
by triethylamine and reprotonation by triethylammonium ion
could happen as equilibrium processes, which could facilitate
the overall transformation even if one mole of triethylamine is
used.
In conclusion, we have disclosed a facile, highly efficient syn-
thesis of novel 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols in good
yields via domino sequence of reactions from simple, readily avail-
able starting materials. This transformation occurs with the forma-
tion of a CAS and a CAO bond in a one pot operation.
In the present study, we also tried to synthesize biologically
important 3-aryl-5,6-dihydro-1,4,2-oxathiazines from the corre-
sponding 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols. Our efforts to
(i) derivatize the hydroxyl group of 3-aryl-5,6-dihydro-1,4,2-oxa-
thiazin-6-ols through tosylation/mesylation or substitution of the
hydroxyl group by halogen by Appel reaction for further reduction
and (ii) deoxygenate through Barton–Mc Combie deoxygenation
did not fructify. Attempted deoxygenation of 3-aryl-5,6-dihydro-
1,4,2-oxathiazin-6-ols using (i) NaBH4 in acetic acid and (ii) AlCl3
or Et3SiH with BF3ꢀOEt2/InCl3/Cu(OTf)2 at ꢁ55 °C in dry dichloro-
methane also failed to afford the corresponding cyclic ethers.
A plausible mechanism for the formation of 3-aryl-5,6-dihydro-
1,4,2-oxathiazin-6-ols is depicted in Scheme 2. Presumably, this
transformation involves (i) the initial formation of the thiolate
anion of 2-mercaptoacetaldehyde 4 from the reaction of 1,4-dithi-
ane-2,5-diol 2 with base, (ii) generation of nitrile oxide 5 via dehy-
drochlorination of (E)-N-hydroxyarylimidoyl chloride 1 in the
presence of triethylamine and (iii) [3+3] annulation of 4 and 5
affording product 3. This mechanism also explains the failure to
obtain the product with 1 bearing both powerful electron-releasing
and the withdrawing substituents on the aryl ring. While strong
electron-releasing groups could diminish the electrophilicity of
the carbon of the nitrile oxide functionality, strong electron-
withdrawing groups on the aryl ring could attenuate the nucleophi-
licity of the oxygen of the nitrile oxide, both of them forbid the
reaction.
Acknowledgements
S.P. thanks DST-SERB and CSIR, New Delhi, for Major Research
Projects, SR/S1/OC-50/2011 and 01(2433)/10/EMR-II, respectively.
S.P. also thanks the UGC, New Delhi for the award of BSR Faculty
Fellowship and DST-IRHPA program for funds for the purchase of
a high resolution NMR spectrometer.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.05.
062.
In this reaction, the mercaptoacetaldehyde and/or its anion
generated from the 1,4-dithiane-2,5-diol could be involved in
Figure 3. ORTEP diagram for 3d.

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S. Vivek Kumar, S. Perumal / Tetrahedron Letters 55 (2014) 3761–3764
20. Martyres, D. H.; Baldwin, J. E.; Adlington, R. M.; Lee, V.; Probert, M. R.; Watkin,
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22. Crystallographic data for the derivative 3d in this manuscript have been
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23. General procedure for the synthesis of 3-aryl-5,6-dihydro-1,4,2-oxathiazin-6-ols at
ambient temperature (3a–i, 3k–o).
A mixture of (E)-N-hydroxyarylimidoyl
chloride (1 mmol), 1,4-dithiane-2,5-diol (0.5 mmol) and triethylamine
(1 mmol) in dichloromethane (6 ml) was stirred for 10–12 h under room
temperature. After completion of the reaction (TLC), the solvent was removed
under reduced pressure and the resultant crude product was purified by flash
silica column chromatography using petroleum ether–ethyl acetate as eluent
(4:1 v/v).
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the solvent was removed under reduced pressure and the resultant crude
product was purified by flash silica column chromatography using petroleum
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representative compounds 3a–c are given below. 3-(4-Chlorophenyl)-5,6-
dihydro-1,4,2-oxathiazin-6-ol (3a): white solid. Yield: 67%; mp = 104–105 °C;
(300 MHz, CDCl3) dH: 3.22 (dd, J = 12.3, 3.6 Hz, 1H), 3.34 (dd, J = 12.4, 1.9 Hz,
1H), 5.64–5.65 (m, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H); 13C
NMR(75 MHz, CDCl3) dc: 29.1, 85.1, 127.4, 128.8, 133.3, 136.8, 149.8; ESI-MS:
m/z. Calcd: 229.00; Found: 230.00 (M+); Anal. Calcd for C9H8ClNO2S: C, 47.06;
H, 3.51; N, 6.10. Found C, 47.18; H, 3.44; N, 6.18. 3-(4-Bromophenyl)-5,6-
dihydro-1,4,2-oxathiazin-6-ol (3b): white solid. Yield: 74%; mp = 173–174 °C;
1H NMR(300 MHz, CDCl3) dH: 3.21 (dd, J = 12.3, 3.6 Hz, 1H), 3.35 (dd, J = 12.3,
2.2 Hz, 1H), 3.95 (br s, 1H), 5.64 (dd, 3.3, 2.4 Hz, 1H), 7.52–7.55 (m, 2H), 7.57–
7.60 (m, 2H); 13C NMR(75 MHz, CDCl3) dc: 29.1, 85.3, 125.1, 127.6, 131.8, 133.8,
150.0; ESI-MS: m/z. Calcd: 272.95; Found: 273.98 (M+), 275.98 (M+3); Anal.
Calcd for C9H8BrNO2S: C, 39.43; H, 2.94; N, 5.11. Found C, 39.30; H, 2.88; N,
5.21. 3-(Biphenyl-4-yl)-5,6-dihydro-1,4,2-oxathiazin-6-ol (3c): white solid. Yield:
85%; mp = 165–166 °C; 1H NMR (300 MHz, CDCl3) dH: 3.24 (dd, J = 12.6, 3.6 Hz,
1H), 3.39 (dd, J = 12.4, 2.2 Hz, 1H), 3.58 (d, J = 4.5 Hz, 1H), 5.66 (br s, 1H), 7.37–
7.40 (m, 1H), 7.43–7.49 (m, 2H), 7.60–7.68 (m, 4H), 7.78–7.81 (m, 2H); 13C
NMR (75 MHz, CDCl3) dc: 29.3, 85.5, 126.6, 127.1, 127.2, 127.8, 128.8, 133.7,
140.1, 143.4, 150.6; ESI-MS: m/z. Calcd: 271.07; Found: 272.08 (M+); Anal.
Calcd for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16. Found C, 66.52; H, 4.70; N,
5.10.
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19. (a) Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5261; (b)
Bugge, S.; Kaspersen, S. J.; Sundby, E.; Hoff, B. H. Tetrahedron 2012, 68, 9226.