Synthesis and ring opening reactions of tetrahydroimidazo-[1,5-b][1,2,4]oxadiazol-2(1H)-thiones

Article abstract of DOI:10.1080/10426500307788

1,3-Dipolar cycloaddition of imidazoline 3-oxides 1 with methylisothiocyanate proceeds regio- and diastereoselectively to give tetrahydroimidazo[1,5-b][1,2,4]oxadiazol-2(1H)-thiones 3 in high yields. The cis configuration of the adducts were proved by our double cis elimination test as well as by NOESY experiments. The imidazooxadiazol-2-thiones 3a-e were treated with concentrated HCl in ethanol at 50°C to give the corresponding 4 H-[1,2,4]oxadiazole-5-thione only in the cases where the substituent at C-6 is an aryl.

Full text of DOI:10.1080/10426500307788

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Synthesis and Ring Opening Reactions of
Tetrahydroimidazo[1,5- b ][1,2,4]oxadiazol-2(1 H )-
thiones
a
a
Necdet Coşkun & Fatma Tirli Tat
a
Uludagˇ University , Bursa, Turkey
Published online: 27 Oct 2010.
To cite this article: Necdet Coşkun & Fatma Tirli Tat (2003) Synthesis and Ring Opening Reactions of Tetrahydroimidazo[1,5-
b ][1,2,4]oxadiazol-2(1 H )-thiones, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 881-886, DOI:
10.1080/10426500307788
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:881–886
Copyright �C 2003 Taylor & Francis
1
042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390198048
SYNTHESIS AND RING OPENING
REACTIONS OF TETRAHYDROIMIDAZO-
[
1,5-b][1,2,4]OXADIAZOL-2(1H)-THIONES
Necdet Co s¸ kun and Fatma Tirli Tat
Uluda gˇ University, Bursa, Turkey
(Received August 12, 2002; accepted September 29, 2002)
1
,3-Dipolar cycloaddition of imidazoline 3-oxides 1 with methylisoth-
iocyanate proceeds regio- and diastereoselectively to give tetrahydro-
imidazo[1,5-b][1,2,4]oxadiazol-2(1H)-thiones 3 in high yields. The cis
configuration of the adducts were proved by our double cis elimination
test as well as by NOESY experiments. The imidazooxadiazol-2-thiones
�
3
a–e were treated with concentrated HCl in ethanol at 50 C to give the
corresponding 4 H-[1,2,4]oxadiazole-5-thione only in the cases where
the substituent at C-6 is an aryl.
A number of works either on cycloadditions or incorporating cycloaddi-
1
tions have appeared in recent years. 1,3-Dipolar cycloadditions of ni-
trones with variety of dipolarophiles take an important place among the
methods for the synthesis of five membered heterocyclic compounds.1
� 4
Aryl and alkylisothiocyanates also act as dipolarophiles with respect
to C N bond but in some cases the cycloaddition may occur at C S in
4
the reaction with different nitrones. Nitrones undergo cycloaddition
to the C N double bond of phenylisothiocyanates to give corresponding
oxadiazole-5-thiones, but in reactions with substituted phenylisothio-
cyanates and benzoylisothiocyanate the addition to the C S double
5
,6
bond predominates.
The cycloaddition reactions with alkylisoth-
6
iocyanates are analogous to the reaction with arylisothiocyanates.
The reaction of acyclic nitrones with isothiocyanates was shown to
give mainly oxadiazolidin-5-thiones. We have shown the 1,3-dipolar
7
Uluda gˇ University Research Fund is gratefully acknowledged for the financial support
(
Project No. 200I-2).
Address correspondence to Necdet Co s¸ kun, Uluda gˇ University, Department of
Chemistry, 16059-Bursa, Turkey. E-mail: dcoskun@uludag.edu.tr
8
81

8
82
N. Co s¸ kun and F. T. Tat
cycloaddition reactions of cyclic nitrones 1 with dipolarophiles as
8
,9
10
11,12
13
arylisocyanates, styrene, DMAD,
and �-pinene to proceed re-
gio and in the case of chiral nitrones diastereoselectively. An interesting
1
4
11,12
feature of the adducts from isocyanate and DMAD
and chiral ni-
trones 1 was their different behavior in the presence of secondary and
tertiary amines. A quite reliable chemical way, double cis elimination,
for determination of the relative configuration of the carbons 3a and 6
in the tetrahydroimidazooxadiazol-2-ones, and tetrahydroimidazoisox-
1
1,12,14
azolines was developed.
Here we report on the reaction of cyclic nitrones 1 with twenty-
fold excess of the dipolarophile without solvent, to give a new class of
tetrahydroimidazo[1,5-b][1,2,4]oxadiazole-2(1H)-thiones 3. Methyliso-
thiocyanate was shown to react regio and diastereoselectively with ni-
trones 1d–e, the configuration of their adducts 3d–e was confirmed by
1
1,12,14
our double cis elimination test
experiment. An interesting rearrangement of C-6 substituted adducts
in the presence of HCl to give 4H-[1,2,4]oxadiazole-5-thione was
observed.
Cyclic nitrones 1 were refluxed in acetonitrile in the presence of
to be cis as well as by NOESY
3
phenylisothiocyanate for 48 h but no conversion to the corresponding
imidazooxadiazol-2-thiones was observed; the nitrones were recovered
unchanged. This was in contrast with the reaction of the same nitrones
with arylisocyanates where the reaction proceeds in high yields to
give the corresponding imidazooxadiazole-2-ones.14 However, nitrones
1
convert in high yields to the corresponding 4 using the dipolarophile
as a solvent, (see Table I).
SCHEME 1
The structure of compounds 3 was established on the basis of their
1
13
IR, H, and C NMR spectra and elemental analysis. The absence of
�
1
an absorption in the 1510–1650 cm region of the IR spectra of com-
pounds 3 was indicative for the regioisomer arising from the addition to
C N double bond. Alternative addition to C S bond should give an exo-
cyclic imine having C N stretching vibration in the mentioned region.6
Characteristic pattern of adducts 3a–c are the two proton AB systems

Synthesis and Ring Opening Reactions
883
TABLE I Tetrahydroimidazo[1,5-b][1,2,4]oxadiazole-2(1H)-thiones 3 and
Oxadiazolones 4
R1
R2
m.p. of 3 ( C)
�
Yields of 4
Yields of 3
R
a
b
c
d
e
65
70
70
90
95
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
H
H
H
Ph
Ph
Ph
116.6
155–155.6
98
149.8
146.3–147
0
—
0
56
60
4-MeOC6H4
Ph
Ph
Ph
at 3.73 (JAB = 10.80 Hz) and 4.72 ppm (JAB = 10.76 Hz) assigned to C-4
and C-6 methylenes. The AB system for C-4 protons of 3d–e appears
at nearly 4.20 ppm and the singlet for C-6 proton have � 5.92 and 6.02
for 3d and 3e respectively. These chemical shifts are in good agreement
with the chemical shifts for the same protons in the adducts obtained
from the same imidazoline 3-oxides and phenylisocyanate where the
cis relation of the phenyls at C-3a and C-6 was deduced from NOESY
and the double cis elimination amine test experiments. The thiocar-
bonyl carbon’s shifts in the 1 C NMR spectra of compounds 3 are at �
approximately 183 ppm.
3
We assume that due to the sterical hindrance the dipolarophile
should attack the nitrones 1d–e from the opposite side of the phenyl at
C-2. This will result in cis 3a,6-diphenylimidazooxadiazole-2-thiones
3
d–e. This was the case in all of the tetrahydroimidazo adducts
8
� 13
reported.
The reaction of 3d with aniline (1:2 molar ratio) in ethanol at re-
flux for 24 h gave the corresponding nitrone 1 and N-methyl-N-phenyl-
thiourea. This was in agreement with the reaction of arylisocyanate
adducts with aniline where the products were also nitrone 1 and the
corresponding N,N-diarylurea.
Thermal treatment of adducts 3 in the condensed phase under vac-
uum led to the formation of corresponding imidazoles in high yields.
The same reaction with the adducts of nitrones 1 with arylisocyanates
led to the formation of corresponding nitrones.8
,9
Adducts 3a–c convert to the corresponding imidazole within 30–
0 min in the presence of diethyl- or triethylamine in refluxing ace-
4
tonitrile. Adducts 3d–e were refluxed for 4 h with excess of diethy-
lamine expecting a double cis elimination as in the cases of DMAD and
isocyanate14 adducts and this was the case; the corresponding imida-
zole was the only product formed. However the same adducts remained
unchanged when triethylamine was used at the same conditions. A sim-
ilar behavior of the cis DMAD adducts have been reported recently.1
cis Arylisocyanate adducts also did not give elimination but undergo
1,12

8
84
N. Co s¸ kun and F. T. Tat
FIGURE 1 Selected NOESY correlations for 3e.
retro cycloaddition when treated with triethylamine for a long
time.14
Some selected NOESY correlations for 3e are given in Figure 1 below.
Methyl groop’s protons are in relation with the part of the AB system
at C-4 as shown in the Figure 1. This proton in turn gives cross peak
with the protons of the p-tolyl ring. The proton at C-6 gives also cross
peak with the protons of the aryl at N-5. All these give a quite reliable
base for the assignment of cis configuration for compounds 3d–e.
1
Compounds 3 with R = H converts slowly to the corresponding im-
idazoles when heated gently on a water bath in ethanol in the pres-
ence of 37% HCl or remain unchanged. However at the same reaction
1
conditions adducts 3d having R = Ar was shown to convert to 4H-
[
1,2,4]oxadiazole-5-thione 4. The probable mechanism of the reaction
is outlined in Scheme 2. Protonation of adduct 3 at the bridgehead ni-
trogen led to the formation of an ammonium species 5 which undergoes
retro 1,3-dipolar cycloaddition to give the corresponding azomethine
ylide 6 and oxadiazol-5-thione 4. To our knowledge this is the first ex-
ample of acid induced rearrangement of tetrahydroimidazooxadiazole-
5
-thiones.
SCHEME 2
The azomethine ylide formation was deduced from its hydrolysis
products, namely the aldehyde and corresponding amine. Thus the

Synthesis and Ring Opening Reactions
885
method described serves as an alternative cycloaddition way to the
oxadiazol-5-thiones accessible by the reaction of N-substituted amide
oximes with ethyl chloroformate and thiophosgene.1
8,19
EXPERIMENTAL
Melting points were taken on an Electrothermal Digital melting point
1
apparatus. IR spectra were recorded on a Mattson 1000 FTIR. H and
1
3
C NMR spectra were recorded on a Bruker Dpx 400 MHz spectrome-
ter. All spectra were taken in deuteriochloroform with a little DMSO-d6.
1
5� 17
Freshly prepared imidazoline 3-oxides
lization from either ethanol or acetone.
were used after recrystal-
Tetrahydroimidazo[1,5-b][1,2,4]oxadiazol-2(1H)-thiones
3
a-e: General Procedure
The mixture of imidazoline 3-oxide 1 (2 mmol) and methylisothio-
�
cyanate (20 mmol) was heated for 2 h at 80 C. The excess of isoth-
iocyanate was removed under vacuum and the residue dissolved in
ethanol at heating and left to crystallize at room temperature. The
formed white crystals were separated by filtration and dried under
vacuum.
3
-Methyl-3a-phenyl-5-p-tolyl-tetrahydroimidazo[1,5-b][1,2,4]oxa-
diazol-2(1H)-thione (3a). IR (KBr) No absorption corresponding to
1
�
C
N; H NMR (CDCl3 and DMSO-d6) � ppm 2.27 (3H, s), 3.0 (3H, s),
3
5
7
5
1
1
.46 (1H, d, J = 10.71), 4.2 (1H, d, J = 10.78), 4.36 (1H, d, J = 10.67),
.07 (1H, d, J = 10.78), 6.68 (2H, d, J = 7.7), 7.05 (2H, d, J = 7.6),
1
3
.43–7.54 (5H, m). C NMR (CDCl3 and DMSO-d6) � ppm 20.11; 31.04;
3.94; 75.46; 93.46; 115.02; 126.44; 128.64; 129.16; 129.46; 129.49;
35.51; 142.68; 182.42. Calcd for C18H19N3OS C, 66.43; H, 5.88; N,
2.91; S, 9.85. Found C, 66.84; H, 6.31; N, 12.67; S, 9.47.
3
-Methyl-3a,6-diphenyl-5-(4-methoxyphenyl)-tetrahydroimidazo-
[
1,5 b][1,2,4]oksadiazol-2(1H)-thione (3d). No absorption correspond-
1
ing to �C N; H NMR (CDCl3) � ppm 3.0 (3H, s), 3.7 (3H, s), 4.18 (1H,
d, J = 11), 4.23 (1H, d, J = 11), 5.92 (1H, s), 6.63 (2H, d, J = 8.46),
13
6
(
.73 (2H, d, J = 8.46), 7.2–7.24 (3H, m), 7.31–7.42 (7H, m). C NMR
CDCl3) � ppm 31.94; 55.72; 87.23; 55.87; 92.61; 115.24; 116.88; 126.94;
1
1
27.86; 128.86; 128.99; 129.38; 130.02; 136.19; 136.97; 139.55; 154.11;
83.63. Calcd for C24H23N3O2S C, 69.04; H, 5.55; N, 10.06; S, 7.68.
Found C, 69.70; H, 5.42; N, 9.27; S, 6.83.
The reaction of 3d–e with HCl. To a suspension of adduct 3
0.15 mmol) in ethanol HCl (0.13 mL, 37%) was added and the mixture
(

8
86
N. Co s¸ kun and F. T. Tat
�
heated at 50 C on a water bath for 25 h. The solvent was removed
and the residue extracted with dichloromethane (3 � 15 mL). The com-
bined extracts were dried over anhydrous Na2SO4, filtered, and the
solvent removed under vacuum. The products isolated by recrystalliza-
tion or column chromatography were the corresponding 4-Methyl-3-
�
19
phenyl-4H-[1,2,4]oxadiazole-5-thione, yield 56%. m.p. 117–118 C; lit
m.p. 119–120.
REFERENCES
[
[
[
[
[
[
[
[
[
1] C. P. Dell, J. Chem. Soc. Perkin Trans 1, 3873 (1998).
2] A. Padwa, Angew. Chem. Int. Ed. Engl., 15, 123 (1976).
3] W. Oppolzer, Angew. Chem. Int. Ed. Engl., 16, 10 (1977).
4] D. St. C. Black, R. F. Crozier, and V. C. Davis, Synthesis, 205 (1975).
5] D. St. C. Black and K. G. Watson, Tetrahedron Lett., 41, 4191 (1972).
6] D. St. C. Black and K. G. Watson, Aust. J. Chem., 26, 2473 (1973).
7] G. Zinner and E. Eghtessad, Arch. Pharm. (Weinheim), 312, 907 (1979).
8] N. Co s¸ kun, Tetrahedron Lett., 38, 2299 (1997).
9] N. Co s¸ kun, Tetrahedron, 53, 13873 (1997).
[
[
10] N. Co s¸ kun and M. Ay, Heterocycles, 48, 537 (1998).
¨
¨
¨
11] N. Co s¸ kun, F. T. Tat, O. O. G u¨ ven, D. Ulk u¨ , and C. Arici, Tetrahedron Lett., 41, 5407
2000).
12] N. Co s¸ kun, F. T. Tat, and O. O. G u¨ ven, Tetrahedron, 57, 3413 (2001).
(
¨
¨
[
[
[
[
[
[
[
[
¨
¨
13] N. Co s¸ kun, F. T. Tat, and O. O. G u¨ ven, Tetrahedron: Assym., 12, 1463 (2001).
14] N. Co s¸ kun, Tur. J. Chem., 25, 267 (2001).
15] N. Co s¸ kun and D. S u¨ mengen, Synth. Commun., 23, 1699 (1993).
16] N. Co s¸ kun and O. Asutay, Chim. Acta Turc., 25, 69 (1997).
17] N. Co s¸ kun and O. Asutay, Chim. Acta Turc., 27, 17 (1999).
18] D. S u¨ mengen and A. Pelter, J. Chem. Soc. Perkin Trans, 1, 687 (1983).
19] H. A gˇ ırbas, Y. D u¨ r u¨ st, and D. S u¨ mengen, Phosphorus, Sulfur, Silicon, 66, 321 (1992).