Synthesis of 1,2,4-dichalcogenazoles by the reaction of 6H-1,3,5-oxachalcogenazines with elemental chalcogen

Article abstract of DOI:10.1016/j.tetlet.2004.05.156

A series of 1,2,4-dichalcogenazoles were synthesized by the reaction of 6H-1,3,5-oxachalcogenazines with elemental chalcogen through the plausible pathway involving in situ generation of 1,3-chalcogenaza-1,3-butadienes and the subsequent reaction with chalcogen species. Synthetic utilities of 1,2,4-dichalcogenazoles were also explored.

Full text of DOI:10.1016/j.tetlet.2004.05.156

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6187–6190
Synthesis of 1,2,4-dichalcogenazoles by the reaction of
6H-1,3,5-oxachalcogenazines with elemental chalcogen
Islam Md. Rafiqul, Kazuaki Shimada, Shigenobu Aoyagi, Yoriko Fujisawa
and Yuji Takikawa*
Department of Chemical Engineering, Faculty of Engineering, Iwate University, Iwate, Morioka 020-8551, Japan
Received 24 March 2004; revised 12 May 2004; accepted 28 May 2004
Available online 6 July 2004
Abstract—A series of 1,2,4-dichalcogenazoles were synthesized by the reaction of 6H-1,3,5-oxachalcogenazines with elemental
chalcogen through the plausible pathway involving in situ generation of 1,3-chalcogenaza-1,3-butadienes and the subsequent
reaction with chalcogen species. Synthetic utilities of 1,2,4-dichalcogenazoles were also explored.
Ó 2004 Elsevier Ltd. All rights reserved.
Studies on heterocyclic compounds containing sulfur
and nitrogen atoms are fascinating areas of current
research due to their versatile applications. In particular,
compounds possessing dichalcogenazole ring offer
increasing interests in the field of pharmaceutical and
fundamental research.1 However, intensive research is
going on in the field of five-membered heterocycles
having nitrogen atom. Although heterocycles having
disulfur-moiety together with nitrogen atom have great
demand due to their frequent appearance in living sys-
tem, but this field has been studied the least. Burger
reported a synthesis of 1,2,4-dichalcogenazoles by tak-
ing the advantage of strong stabilizing functionality,
trifluoromethyl group, using 2H-1,3-thiazetes as pre-
cursors.2a This method suffers from the lack of gener-
ality in respect of substrates and requiring prolonged
reaction period, in some cases, it takes 4–5 weeks. On the
other hand, the synthetic utilities of this novel ring
system still remain to be explored. Therefore, little is
known about the structure and reactivities of 1,2,4-di-
chalcogenazoles due to the lack of a general method of
synthesis.
respectively.2b We obtained 3H-1,2,4-dichalcogenazoles
3 and 5 as byproducts during our studies on 6H-1,3,5-
oxachalcogenazines (1, 2).2b
It was envisaged that 1,2,4-dichalcogenazoles 3–7 would
be synthesized through the reaction of in situ generated
A or B with elemental chalcogen as shown in Scheme 1.
In accordance with the expectation, we succeeded to
synthesize 3–6 in moderate to excellent yields by the
heating of 1 or 2 with elemental chalcogen in toluene.
Now, we wish to report a novel method for the synthesis
of a series of 1,2,4-dichalcogenazoles 3–6 from 1 or 2 via
in situ generation of A or B and will describe some
synthetic utilities of these compounds.
6H-1,3,5-Oxachalcogenazines 1, 2 were prepared by
treating a thioamide or a selenoamide with an aliphatic
aldehyde and BF3ÆOEt2 according to the reported pro-
cedures.2b;3
Screening experiment for the synthesis of 3 from 1 by
using elemental sulfur, P2S5, or Lawesson’s reagent was
suggested to be elemental sulfur (chalcogen) as chalco-
gen source.
In the course of our studies on reactive chalcogenocar-
bonyl building blocks, we reported a generation of 1,3-
chalcogenaza-1,3-butadienes (A, B) through thermal
cycloreversion of 6H-1,3,5-oxachalcogenazines (1, 2),
The reaction of 1a–e with elemental sulfur in toluene
refluxing temperature afforded 3H-1,2,4-dithiazoles 3a–e
in moderate to excellent yields. The physical data
Keywords: 6H-1,3,5-Oxachalcogenazines; 1,2,4-Dichalcogenazoles;
1,3-Chalcogenaza-1,3-butadienes; Chalcogen; Thermal cycloreversion.
* Corresponding author. Tel./fax: +81-19-621-6323; e-mail: takikawa@
iwate-u.ac.jp
1
including MS, IR, H NMR, and 13C NMR, as well as
elemental analysis were fully consistent with the struc-
ture of 3H-1,2,4-dithiazoles 3. The results of thermolysis
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.156

6188
I. Md. Rafiqul et al. / Tetrahedron Letters 45 (2004) 6187–6190
1
1
R
2
R
X
R
X
∆ , Ch
1
R
X
Ch
2
N
O
N
N
2
R
R
2
3 (X=S, Ch=S)
4 (X=S, Ch=Se)
5 (X=Se, Ch=Se)
6 (X=Se, Ch=S)
7 (X=S, Ch=Te)
1 (X=S)
2 (X=Se)
R
A (X=S)
B (X=Se)
Scheme 1.
and thiation reactions of 1a–e are summarized in Table
1. When 1a was heated in the absence of sulfur, only a
trace amount of 3a was afforded along with recovery of
substrate (entry 1). It is thought that thermal cyclo-
reversion of 1a generates heterodiene A, which might
cause further fragmentation to give sulfur species, and
the subsequent reaction of heterodiene A with the re-
leased sulfur species to afford compound 3a. When 1e
having CH3 group at C-2 and C-6 positions was heated
with elemental sulfur, expected compound 3e was
formed in moderate yield along with unidentified com-
pounds (entry 6).
pound 3a was formed by the reaction of 1a with
elemental selenium, via primary formation of 4a
followed by the exchanging reaction of selenium in 4a
ring with sulfur species,4;5 which was assumed to be
generated from A.
The reaction of 2a with elemental selenium in toluene at
98 °C afforded 3H-1,2,4-diselenazoles 5a in 72% yield
(Table 1, entry 11). The physical data including MS, IR,
1H NMR, 13C NMR, 77Se NMR, as well as elemental
analysis were fully consistent with the structure of 3H-
1,2,4-diselenazoles 5a.
The reaction of 1 with elemental selenium in toluene
refluxing temperature afforded the expected 3H-1,2,4-
thiaselenazoles 4 in moderate to excellent yields as
shown in Table 1 (entries 7–10). However, in the case of
entries 8 and 10, the unexpected 3H-1,2,4-dithiazoles 3
were also found along with 4. An independent reaction
of 4a with elemental sulfur (2 mol amt.) at toluene
refluxing temperature for 15 h afforded 3a in quantita-
tive yield. This result might suggest that minor com-
The reaction of 2a with elemental sulfur in toluene at
98 °C afforded an inseparable mixture of 3H-1,2,4-di-
thiazole 3a, 3H-1,2,4-diselenazole 5a and plausible 5H-
1,2,4-thiaselenazole 6a (Table 1, entry 12). The most
likely structure of 6a was suggested through the analysis
1
of H NMR and mass spectral data of the mixture. The
chemical shifts of the likely structure 6a are probably d
1.14 (9H, s) and 6.08 (1H, s). On the other hand,
chemical shifts of those of isomer 4a are d 1.12 (9H, s)
Table 1. Synthesis of 1,2,4-dichalcogenazoles by the reaction of 6H-l,3,5-oxachalcogenazines with chalcogen atom
R1
R1
Chalcogen
(5 mol amt.)
X
R2
3 (X=S, Ch=S)
4 (X=S, Ch=Se)
5 (X=Se, Ch=Se)
6 (X=Se, Ch=S)
7 (X=S, Ch=Te)
X
Ch
N
N
O
Toluene
R2
R2
1 (X=S)
2 (X=Se)
Entry
Substrate
R2
Chalcogen Temperature Time (h)
(°C)
Yield (%)a
R1
3
4
5
6
7
Recovery
1
C6H5
C6H5
t-C4H9
t-C4H9
t-C4H9
t-C4H9
1a
––b
S
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
98
15
15
25
25
15
5
Trace ––
––
––
––
––
––
––
––
––
––
––
72
20c
––
––
––
––
––
––
––
––
––
––
––
––
––
30c
––
––
––
––
––
––
––
––
––
––
––
––
––
––
0
98
0
2
1a
1b
1c
1d
1e
1a
1b
1c
1d
2a
2a
1a
1d
88
91
89
98
48
0
––
––
––
––
––
98
44c
97
63c
––
0
3
p-ClC6H4
p-FC6H4
S
6
4
S
7
5
p-CH3OC6H4 t-C4H9
CH3
S
0
6
C6H5
C6H5
S
0
7
t-C4H9
t-C4H9
t-C4H9
Se
Se
Se
Se
Se
S
15
15
15
15
12
12
15
15
0
8
p-ClC6H4
p-FC6H4
20
0
0
9
0
10
11
12
13
14
p-CH3OC6H4 t-C4H9
15c
––
50c
33
36
0
C6H5
C6H5
C6H5
t-C4H9
t-C4H9
t-C4H9
0
98
Reflux
Reflux
0
Te
Te
––
––
Trace
Trace
p-CH3OC6H4 t-C4H9
0
a Isolated yield.
b In the absence of chalcogen atom.
c NMR yield.

I. Md. Rafiqul et al. / Tetrahedron Letters 45 (2004) 6187–6190
6189
DMAD (10 mol amt.)
Ph
S
CO2Me
CO2Me
Toluene, Reflux, 4 h
N
(Ref. 2b)
t-Bu
11a (71%)
Ph
S8 (5 mol amt.)
EtOH (10 mol amt.)
S8 (5 mol amt.)
Ph
S
S
t-Bu
Ph
HN
DMAD (10 mol amt.)
S
11a (39%)
+
S
N
O
Toluene,
Reflux, 8 h
Toluene, Reflux, 7 h
N
OEt
t-Bu
1a
t-Bu
8a (97%)
t-Bu
3a (48%)
DMAD
(10 mol amt.)
Toluene, Reflux, 8 h
Scheme 2.
and 6.88 (1H, s), but isomer 4a was not observed in the
1H NMR spectrum of this mixture. Moreover, the
coupling constant between the carbon atom at C-3 po-
Moreover, generation of A along with Ph3P@Se in the
reaction of 4 with Ph3P strongly suggests that the loca-
tion of sulfur–selenium unit should be 1,2-position in
3H-1,2,4-thiaselenazole 4 ring system. When compound
5a was treated with Ph3P (1.0 mol amt.) in the presence
of EtOH at room temperature for 1 h gave 10a in 78%
yield, the 1,4-adduct of heterodiene B with EtOH, along
with Ph3P@Se in 68% yield.
1
sition and the selenium atom of 4a was JC–Se ¼ 63 Hz,
implying that the ring system of 4a is 3H-1,2,4-thiasel-
enazole. In addition, the mass spectra of the mixture
containing 6a showed a parent ion peak (m=z) at 285
assigned to 6a, and all of these results suggest the
structure of 6a.
We have already reported that the heating of 1a with an
excess amount of dimethylacetylenedicarboxylate
(DMAD) in toluene refluxing temperature afforded 11a
in 71% yield, [4þ2] cycloadduct of heterodiene A with
DMAD.2b Reaction of 1a with elemental sulfur
(5 mol amt.) in the presence of EtOH in toluene refluxing
temperature resulted in the formation of compound 8a
in 97% yield, the 1,4-adduct of heterodiene A with
EtOH, and no compound 3a was observed. On the other
hand, treatment of 1a with elemental sulfur (5 mol amt.)
in the presence of DMAD gave 3a in 48% yield along
with 11a in 39% yield. However, when 3a was inde-
pendently heated with DMAD in toluene refluxing
temperature for 8 h, no reaction occurred. This result
ruled out the possibility of the opening of 1,2,4-di-
chalcogenazoles ring only by heating (Scheme 2).
Surprisingly, when 1a or 1d was reacted with elemental
tellurium in toluene refluxing temperature, the expected
3H-1,2,4-thiatellurazole 7a or 7d could not be detect,
besides the unexpected product 3a or 3d was formed in
moderate yield (Table 1, entries 13 and 14). However,
the thermolysis of 1 in the absence of sulfur atom only
gave a trace amount of 3a (entry 1), assuming that
compound 7 was transiently formed, followed by the
reaction with liberated sulfur species (from heterodiene
A) to afford compound 3 through tellurium–sulfur
exchanging.
Generally, heterodienes, 1,3-chalcogenaza-1,3-buta-
dienes (A, B), are generated through thermal cyclore-
version of appropriate precursors at elevated
temperature. However, synthesis or generation of such
building blocks at low temperature is of great demand in
synthetic organic chemistry. We found a new route for
the generation of heterodienes A and B at room tem-
perature by using 1,2,4-dichalcogenazoles 3–6 as
potential precursors.
By considering the above results suggesting the genera-
tion of heterodiene A by a series of the trapping experi-
ment of 1a with EtOH or DMAD, it can be rationalized
that the necessity of heterodienes A or B and chalcogen
species for the synthesis of 1,2,4-dichalcogenazoles 3–7
should be essential. A plausible formation pathway of
3–7 involving [4þ1]-type cycloaddition (path a)2a
through the reaction of in situ generated A or B with
chalcogen atom is proposed. However, another pathway
involving transient generation of intermediate C or D or
E or F and their subsequent ring closure (path b)6 can
not exclude out at this time as shown in Scheme 3.
It was expected that 1,3-thiaza-1,3-butadienes A would
be generated through the extrusion of sulfur atom (S-2)
from 3H-1,2,4-dithiazoles 3a ring system. The reaction
of 3a with Ph3P (1.0 mol amt.) in the presence of EtOH
in CH2Cl2 at room temperature afforded 8a in 98%
yield, 1,4-adduct of heterodiene A with EtOH, along
with Ph3P@S in 72% yield.
In conclusion, we have developed a novel method for an
efficient synthesis of a wide range of 1,2,4-dichalcogen-
azoles 3–7 from 6H-1,3,5-oxachalcogenazines 1 and 2
by treating with elemental chalcogen. In addition, a new
method for the generation of heterodienes A and B at
low temperature using 1,2,4-dichalcogenazoles 3–5 as
precursors has also been developed. Further studies on
The reaction of 4a with Ph3P (1.0 mol amt.) in the
presence of EtOH at room temperature for 1 h afforded
8a in 85% yield, the 1,4-adduct of heterodiene A with
EtOH, along with Ph3P@Se in 69% yield. It is demon-
strated that both compounds 3 and 4 are new precursors
for the generation of heterodiene A at low temperature.

6190
I. Md. Rafiqul et al. / Tetrahedron Letters 45 (2004) 6187–6190
1
R
X
Ch
Ch
N
R2
C (X=S, Ch=S)
D (X=S, Ch=Se)
E (X=Se, Ch=Se)
F (X=Se, Ch=S)
path b
R1
R1
R1
R1
X
X
X
X
R2
Ch
∆
Ch
R2
Ch
N
N
[4+1]
path a
N
-R2CHO
N
O
R2
R2
A (X=S)
B (X=Se)
R2
1 (X=S)
3-7
Ph3P/R.T.
(3-5)
2 (X=Se)
R1
X
EtOH
EtOH
1,4-addition
A or B
OEt
R2
HN
8 (X=S)
10 (X=Se)
Scheme 3. Plausible formation pathway of compounds 3–10.
4093–4096; (c) Pandeya, S. N.; Kumar, A.; Singh, B. N.;
Mishra, D. N. Pharm. Res. 1987, 4, 321–326; (d) Heck-
mann, G.; Johan, R.; Kraft, G.; Wolmershaeuser, G. Synth.
Met. 1991, 43, 3287–3290; (e) Duczek, W.; Tiltelbach, F.;
Costisella, B.; Niclas, H.-J. Tetrahedron 1996, 52, 8733–
8738.
the mechanistic approach are in progress in our labo-
ratory.
Acknowledgements
2. (a) Burger, V. K.; Hubl, D.; Huber, E. Chemiker-Zeitung
1986, 110, 87–88; (b) Shimada, K.; Aikawa, K.; Fujita, T.;
Sato, M.; Goto, K.; Aoyagi, S.; Takikawa, Y.; Kabuto, C.
Bull. Chem. Soc. Jpn. 2001, 74, 511–525.
3. Giordano, C.; Belli, A. Synthesis 1975, 789–791.
4. Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada,
K.; Miyoshi, N.; Kambe, N. Tetrahedron Lett. 1991, 32,
3503.
This work was partially supported by a Grant-in-Aid for
Scientific Research (No 14044006) from the Ministry of
Education, Science, Sports, and Culture.
References and notes
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