Original ring contraction of triazine derivatives to 1,2,4-thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2009.07.144

The oxidation of triazines 1 is described here. While treatment with m-CPBA or DMDO led to formation of a mixture of compounds, [TBA-OX] oxidation led exclusively to thiadiazoles 2 by ring contraction reaction.

Full text of DOI:10.1016/j.tetlet.2009.07.144

Tetrahedron Letters 50 (2009) 5802–5804
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Original ring contraction of triazine derivatives to 1,2,4-thiadiazoles
*
Vincent Kikelj, Karine Julienne, Jean-Claude Meslin, David Deniaud
CNRS, UMR 6230, Université de Nantes, Chimie et Interdisciplinarité: Synthèse Analyse Modélisation, UFR Sciences et Techniques, 2 Rue de la Houssinière, BP92208,
44322 Nantes Cedex 03, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation of triazines 1 is described here. While treatment with m-CPBA or DMDO led to formation of
a mixture of compounds, [TBA-OX] oxidation led exclusively to thiadiazoles 2 by ring contraction
reaction.
Received 7 July 2009
Revised 23 July 2009
Accepted 28 July 2009
Available online 3 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ring contraction
Oxone
Thiadiazole
Oxidation
Triazine
Compounds containing the 1,2,4-thiadiazole ring system have at-
tracted considerable attention in recent years because of their prom-
ising biological properties.1–5 Numerous methods have been
published and reviewed several times for synthesizing this skele-
ton.6–11 We report here the synthesis of 3,5-disubstituted-1,2,4-thi-
adiazoles (2a–c) by ring contraction of easily prepared
triazinethiones (1a–c) in the presence of oxidizing agents (Scheme 1).
1,3,5-Triazinethiones 1a–c were prepared in good yields from
thiourea according to the standard procedures.12,13 Inspired by
previous work on oxidations of heterocycles we decided to inves-
tigate the behavior of triazinethione 1a with m-chloroperoxyben-
zoic acid (m-CPBA) to convert C@S to C@O.14 Unfortunately,
under these conditions, a mixture of thiadiazole 2a and triazinone
3a was isolated (Scheme 2).
undergoes rearrangement into oxathiirane and finally provides the
ketone by sulfur extrusion.15 A possible mechanism for the forma-
tion of thiadiazole 2a might involve the oxidation of the imine
function of 1a by the peroxy acid into oxaziridine. In this case
the mechanism would involve a nucleophilic oxygen-transfer from
the peroxy acid to the electrophilic carbon of C@N bond, followed
by intramolecular displacement leading to the oxaziridine ring
(Scheme 3).
Since m-CPBA can effectively be an electrophile as well as a
nucleophile depending on the substrates, we studied the reaction
with a more electrophilic oxidizing agent (DMDO) and a more
nucleophilic one (OxoneÒ) in order to improve the regioselectivity
of the oxidation step. Of course, our initial target 3a can be easily
obtained selectively by a non-oxidative method through conver-
This result prompted us to study the reaction with other oxidiz-
ing agents such as dimethyldioxirane (DMDO) or OxoneÒ to obtain
selectively thiadiazole 2a. The results are summarized in Table 1.
Oxidation of the triazinethione 1a using 1.2 equiv of m-CPBA in
dichloromethane led to an equimolecular mixture of thiadiazole 2a
and triazinone 3a (Table 1, entry 1). In contrast to literature data
we did not observe oxidation of the sulfide (methyl sulfanyl group
on triazine ring) into sulfoxide or sulfone. Triazinone 3a results
from oxidation of the thiocarbonyl group, while thiadiazole 2a
might arise from a ring contraction. For the formation of triazinone
3a, m-CPBA reacts as an electrophilic oxygen-transfer agent; nucle-
ophilic attack of the thiocarbonyl sulfur atom gives a sulfine which
H
S
R
N
S
N
N
S
[ox]
R
N
N
S N
2a-c
1a-c
a R = Ph, b R = Me, c R = Bn
Scheme 1. General strategy for the synthesis of 1,2,4-thiadiazoles by ring contrac-
tion of 1,3,5-triazinethiones.
H
S
N
S
O
N
S
N
[conditions]
N
S
Ph
+
N
N
N
N
S N
2a
Ph
Ph
1a
3a
* Corresponding author. Tel.: +33 2 51 12 54 06; fax: +33 2 51 12 54 02.
E-mail address: david.deniaud@univ-nantes.fr (D. Deniaud).
Scheme 2. Synthesis of mixture of thiadiazole 2a and triazinone 3a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.144

V. Kikelj et al. / Tetrahedron Letters 50 (2009) 5802–5804
5803
Table 1
Oxidation conditions
O
H
O O O
O
K
O
O
Al Al Al
AlO
O
O O
O
O
H
H
H
S
Entry
Conditions
Ratio 2a
:
3a
50
100
68
43
0
O
OH
+
1
2
3
4
5
6
7
m-CPBA
50
0
32
:
:
:
:
:
:
:
S
N
SMe
(CF3CO)2O
DMDO
N
represents
N
R2 R1
N
N
R2 R1
Ph
OxoneÒ
57a
100
100
100
1a
OxoneÒ/Al2O3
OxoneÒ/TFA
[TBA-OX]
0
0
O
O
K
K
AlO
AlO
a
O
O
H
O
O
O
O
H
O
O
Mixture of sulfide [SMe] and sulfoxide [S(O)Me].
S
S
O
O
O
O
+
+
H
H
N
N
R2 R1
R2 R1
O
S
N
S
S
N
S
S
N
S
N
N
O
N
+
N
N
N
Ph
Ph
Ph
O
O
1a
K
AlO
+
N
R2
R1
O
O
H
O
O
O
S
OH
OH
m-Cl(C6H4)
O
Scheme 5. Possible reaction pathway of the oxidation by Oxone/Alumina.
2a
3a
Scheme 3. Plausible intermediate for thiadiazole 2a and triazinone 3a.
We obtained the same regioselectivity with trifluoroacetic acid
in dichloromethane, and thiadiazole 2a was isolated in 89% yield
(Table 1, entry 6). It can be assumed that TFA ensures the proton-
ation of the imine thus allowing, by anionic counter-ion exchange,
the formation of the iminium peroxomonosulfate, which can lead
to the oxaziridine through precedent way (Scheme 6).
We have also shown that the use of tetrabutylammonium
OxoneÒ (TBA-OX) in dichloromethane was also efficient for the
synthesis of thiadiazole 2a from triazinethione 1a in 96% yield
(Table 1, entry 7). Very mild conditions and very simple work-up
procedure were used. TBA-OX was prepared from potassium per-
oxomonosulfate triple salt by cationic exchange using NBu4Br
and gave a soluble version of the salts mixture, with the ammo-
nium bromide acting as a phase transfer catalyst. We showed that
buffering the reaction with NaHCO3 inhibits the reaction and leads
to a mixture of compounds. This result seems to confirm that the
reaction is acid-catalyzed (protonation of the imine), with the
hydrogen sulfate present in OxoneÒ playing the part of the Brön-
sted acid (Scheme 6).19,20
sion of thiocarbonyl of 1a to a carbonyl group using trifluoroacetic
anhydride in 71% yield (Table 1, entry 2).16 Dimethyl dioxirane is
known to behave as an electrophilic oxidant and it led to triazinone
3a as the major product rather than thiadiazole 2a from triazin-
ethione 1a (Table 1, entry 3). Alternatively, potassium peroxo-
monosulfate triple salt (2KHSO5, KHSO4, and K2SO4) (OxoneÒ and
caroateÒ) is known to behave as a nucleophilic oxidant. In the first
experience using OxoneÒ in CH3CN (heterogeneous system), the
reaction of 1a at room temperature for 24 h gave a mixture of
1,2,4-thiadiazole 2a and triazinone 3a (Table 1, entry 4). This pre-
liminary result encouraged us to investigate further the reaction
conditions for a more effective homogeneous system. We finally
discovered three protocols leading selectively to compound 2a
(Scheme 4).
Recently, it has been reported that a heterogeneous mixture of
wet alumina and OxoneÒ can react with ketones to give the corre-
sponding esters or lactones in quantitative yields.17 The reaction of
compound 1a with OxoneÒ in dichloromethane at room tempera-
ture for 24 h in presence of wet alumina gave only the desired ring
contraction product 2a in 95% yield without any trace of triazinone
3a (Table 1, entry 5). Different parameters were investigated,
including the amount of OxoneÒ used. The optimal molar ratio of
KHSO5/triazine was 2:1. OxoneÒ was mixed in CH2Cl2, dispersed
and probably adsorbed on the surface of the alumina, catalyzing
the oxidation in this way. Indeed, the reaction of triazinethione
1a with non-supported OxoneÒ in dichloromethane at room tem-
perature for 24 h gave only a 5% conversion of the substrate. Potas-
sium peroxomonosulfate was probably adsorbed on the surface by
hydrogen bonding, and acido-basic exchange may activate the
imine by protonation into an iminium salt and thus induce the
nucleophilic transfer of an oxygen atom (Scheme 5).18
The ring contraction mechanism has yet to be elucidated. Acti-
vation of the oxaziridine by protonation, leading to the corre-
S
N
S
N
N
Ph
1a
TFA
HSO4
S
N
N
S
H
S
N
S
N
N
N
Ph
Ph
H
2
SO4
CF3CO2
KHSO5
[TBA-OX]
S
N
S
H
N
N
Ph
H
S
N
S
N
N
S
a or b or c
Oxone(1.1 eq)
CH2Cl2, rt
HSO5
Ph
N
N
S N
2a
Ph
1a
S
N
S
a: wet Al2O3, 95%
b: TFA (1.1 eq), 89%
c: NBu4Br (1.1 eq), 96%
N
N
O
Ph
Scheme 6. Possible reaction pathway of the oxidation by TFA/Oxone and by
Scheme 4. Different protocols for the synthesis of 1,2,4-thiadiazole 2a.
[TBA-OX].

5804
V. Kikelj et al. / Tetrahedron Letters 50 (2009) 5802–5804
Oxone(1.1 eq)
NBu4Br (1.1 eq)
Acknowledgments
H
S
R
N
S
N
N
S
R
N
N
S N
The French Ministry of Education and CNRS are gratefully
acknowledged for financial support.
CH2Cl2, rt
1a-c
2a-c
a R = Ph (96%)
b R = Me (80%)
c R = Bn (89%)
References and notes
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Scheme 7. Synthesis of 1,2,4-thiadiazoles 2a–c by ring contraction of 1,3,5-
triazinethiones 1a–c.
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sponding oxaziridinium salt, may induce a rearrangement result-
ing in the formation of thiadiazole 2a. Unfortunately, all attempts
to isolate the intermediate oxaziridine (or oxaziridinium salt) were
unsuccessful and the mechanism of this unexpected ring contrac-
tion under oxidative conditions remains under investigation. Clas-
sically, imine function is oxidized to oxaziridine (with probably the
formation of nitrone as a competing process in a relatively small
proportion) but another mechanism could be envisaged by hydra-
tion at position 6 of triazine 1a, followed by ring opening. Resulting
acyclic moiety then cyclizes to give a thiadiazole derivative 2a.
Nevertheless, during our previous works we have never observed
the hydration of the imine functions of heterocycles.
By applying the optimal conditions (OxoneÒ, NBu4Br, and
CH2Cl2) to substrates 1b and 1c (Scheme 7) thiadiazoles 2a–c were
isolated in good yields.
In conclusion, this report details an inexpensive and very simple
method for the synthesis of thiadiazoles from triazinethiones un-
der mild oxidative reaction conditions. It is suggested that com-
pounds 1a–c are first oxidized to the corresponding oxaziridines,
followed by a subsequent ring contraction reaction to afford thi-
adiazoles 2a–c. Further applications of this methodology and
investigation of the ring contraction mechanism are now
underway.
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