Thiophene-substituted 1,2,4-oxadiazoles and oxadiazines

Article abstract of DOI:10.1080/10426500600919124

Twenty one new thiophene-substituted 1,2,4-oxadiazol-5(4H)-ones, 1,2,4-oxadiazol-5(4H)-thiones, and 1,2,4-oxadiazin-5(6H)-ones were synthesized by the reaction of thiophene-ring substituted amidoximes with ethyl chloroformate, thiophosgene, and chloroacet

Full text of DOI:10.1080/10426500600919124

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Phosphorus, Sulfur, and Silicon
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Thiophene-Substituted 1,2,4-
Oxadiazoles and Oxadiazines
a
Yaşar Dürüst a , Cevher Altuğ & Ferdi Kiliç a
a Department of Chemistry , Abant Izzet Baysal
University , Bolu, Turkey
Published online: 18 Feb 2007.
To cite this article: Yaşar Dürüst , Cevher Altuğ & Ferdi Kiliç (2007) Thiophene-
Substituted 1,2,4-Oxadiazoles and Oxadiazines, Phosphorus, Sulfur, and Silicon and
the Related Elements, 182:2, 299-313, DOI: 10.1080/10426500600919124
To link to this article: http://dx.doi.org/10.1080/10426500600919124
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Phosphorus, Sulfur, and Silicon, 182:299–313, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600919124
Thiophene-Substituted 1,2,4-Oxadiazoles
and Oxadiazines
¨ ¨
Yas¸ar Durust
˘
Cevher Altug
Ferdi Kılıc¸
Department of Chemistry, Abant Izzet Baysal University, Bolu, Turkey
Twenty one new thiophene-substituted 1,2,4-oxadiazol-5(4H)-ones, 1,2,4-oxadiazol-
5(4H)-thiones, and 1,2,4-oxadiazin-5(6H)-ones were synthesized by the reaction of
thiophene-ring substituted amidoximes with ethyl chloroformate, thiophosgene, and
chloroacetylchloride, respectively. Their structure elucidation was performed by
means of spectral measurements (IR, NMR, and MS) and physical data.
Keywords Oxadiazine; oxadiazole; spectroscopy; thiadiazole; thione; thiophene
INTRODUCTION
The amidoximes are versatile in organic synthesis as starting ma-
terials that have been widely used in assembling many heterocyclic
compounds.1−3 In particular, they and their derivatives have been re-
ported to be used as drugs and to have considerable biological activity
(antifungal, antibacterial, and antitumoral).4−10 Synthetic procedures
for substituted amidoximes, oxadiazoles, oxadiazines, and thiadiazoles
have been reported by some of us previously.11−16
Thiophene is the most aromatic of the five-membered ring heterocy-
cles and thus is unique in terms of reactivity, stability, and chemical
and electronic properties that make it the subject of intense study. An
increase in the number of thiophene derivatives was observed in super-
conductor research and clinical applications of potentially therapeutic
products.17 Amidoximes have also found numerous technological appli-
cations, such as uranium recovery and pharmacological uses.18
Received April 5, 2006; accepted June 7, 2006.
Abant Izzet Baysal University Research Fund (BAP Grant No. 2003.03.03.184) is
gratefully acknowledged for financial assistance.
Address correspondence to Yas¸ar Du¨ru¨st, Abant Izzet Baysal University, Department
of Chemistry, Faculty of Arts and Sciences, TR-14280, Bolu, Turkey. E-mail: yasardurust@
ibu.edu.tr
299

300
Y. Du¨ ru¨st et al.
The fact that various oxadiazolones and thiones are known to show
various biological activities19−21 and also because thiophene itself has
a considerable effect to enhance the previously discussed properties
of the various class of potential bioactive compounds, we focused on
synthesizing thiophene bearing 1,2,4-oxadiazol-5(4H )-one and thiones.
Pharmacological and biological activities of the title compounds will be
assayed in a future work.
We have previously reported the first examples of some N-
substituted thiophene-2-carboxamidoximes22 and data related to their
acid–base equilibria.23 In the present study, we report the first exam-
ples, to our best knowledge, of five-and six-membered thiophene substi-
tuted heterocycles (1,2,4-oxadiazol-5(4H )-ones) 1,2,4-oxadiazol-5(4H )-
thiones, and (1,2,4-oxadiazin-5(6H )-ones) derived by the action of
N-substituted thiophene-2-carboxamidoximes with ethyl chlorofor-
mate, thiophosgene, and chloroacetylchloride, respectively.
RESULTS AND DISCUSSION
N-substituted thiophene-2-carboxamidoximes (4a–g), including a new
one, (4e), were obtained according to the procedure described in the
literature22 and were purified by flash chromatography (Scheme 1).
Their structures were identified by means of IR, NMR, MS data, and
melting points.
SCHEME 1
Thiophene substituted-1,2,4-oxadiazol-5(4H )-ones (5a–g) were ob-
tained by reacting amidoximes with ethyl chloroformate in the presence
of triethylamine as a base in refluxing xylene (Scheme 2). Progress of
the ring-closure reaction of amidoximes (4a–g) and ethylchloroformate
was monitored by TLC.

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
301
SCHEME 2
Common features of these compounds are their strong carbonyl ab-
sorptions around 1760–1780 cm−1 in IR spectra and the chemical shift
position of a carbon atom of the carbonyl group at ca 165 ppm, along with
the iminic carbon chemical shifts at around 155 ppm. The proton NMR
spectra of these new compounds also revealed the necessary proof to elu-
cidate their structures providing aromatic protons and methyl protons
in the case of N-p-tolyl substitution. The data obtained are in accord
with the literature values reported previously for similar structures.24
N-substituted thiophene-2-carboxamidoximes (4a–g) were reacted
with thiophosgene in the presence of triethylamine as a base by cooling
initially in an ice-salt bath and then standing to mix at r.t. until all the
starting materials disappeared, which were monitored by TLC. After
the usual workup, the crude reaction products were subjected to flash
column chromatographic separation on silica gel with the specified elu-
ants to give the thiophene substituted 1,2,4-oxadiazol-5(4H )-thiones
(6a–g) (Scheme 3).
The new thiophene substituted 1,2,4-oxadiazol-5(4H )-thiones
(6a–g) were identified based on their spectroscopic and physical data
(IR, NMR, MS, m.p., and Rf). The disappearance of the broad hydrogen-
bonded NOH absorption of the starting amidoxime and the arising of
the N C S absorption in the IR spectra around 1350–1140 cm−1 is
accepted as proof of the title compounds.
Upon a careful investigation of the mass spectra of 6a–g, we can
conclude that a thermal rearrangement process, thione-thiol rear-
rangement, occurred during mass spectral measurement as described
previously.25−27 Since the pure compounds were injected into a GC inlet
of the GC-MS instrument, the account for the appearance of two peaks

302
Y. Du¨ ru¨st et al.
SCHEME 3
in the total ion chromatograms of 6a, 6b, 6c, 6f, and 6g: 4-N substi-
tution with phenyl, 4-methylphenyl, 4-chlorophenyl, 1-naphthyl, and
4-iodophenyl, respectively, is that there has been a thermal rearrange-
ment of oxadiazolone into thiadiazolone (Scheme 4).28
Figures 1 and 2 show the representative total ion chromatogram
of thione (6a) with two peaks showing both thione (retention time
SCHEME 4

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
303
FIGURE 1
21.20 min) and the rearranged product thiadiazol-one (retention time
20.10 min).
The new thienyl substituted six-membered 1,2,4-oxadiazin-5(6H)-
ones (7e) were synthesized by reacting the amidoximes (4a–g) with
chloroacetylchloride in the presence of triethyl amine as a base
(Scheme 5).

304
Y. Du¨ ru¨st et al.
FIGURE 2
Despite the easy conversion of amidoximes into five-membered het-
erocyles, namely oxadiazolones and oxadiazolethiones, the ring closure
leading to six-membered heterocycles, 1,2,4-oxadiazinones (7a–g) did
not occur smoothly even if the various reaction conditions, including
microwave irradiation and catalyst incorporation were tried. In this
regard, we were able to obtain six-membered heterocyclic compounds

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
305
SCHEME 5
(7a–g) in low yields in comparison to the five-membered rings. Their
structures were confirmed by spectroscopic and physical data.
EXPERIMENTAL
Thiophene-2-carbaldehyde, N-chlorosuccinimide, chloroacetylchloride,
triethyl amine, and aromatic primary amines were purchased from
Merck and Fluka. NMR data were recorded on Varian 300 and 400 MHz
instruments (Palo Alto, CA). Mass spectra were recorded by a GC inlet
of a Hewlett-Packard 5790 series instrument. IR spectra were run on
a JASCO 430 FTIR spectrophotometer. Elemental analyses were per-
formed on a LECO CHNS-932 (St. Joseph, MI). Melting points were
determined on a Meltemp apparatus and are uncorrected. Silica gel
(Merck (Darmstadt, Germany) or Fluka (Buchs SG, Switzerland), 230-
400 Mesh ASTM) was used for flash column chromatography and pre-
coated plastic plates with a fluorescent indicator for TLC. The stain
solutions of permanganate, p-anisaldehyde, and iodine were used for
visualization of the TLC spots.
Thiophene-2-carboxaldehyde oxime(2), thiophene-2-hydroximoyl
chloride(3), N-phenyl thiophene-2-carboxamidoxime (4a), N-p-tolyl
thiophene-2-carboxamidoxime (4b), N-(4-chlorophenyl) thiophene-2-
carboxamidoxime (4c), N-(4-methoxyphenyl) thiophene-2-carbox-
amidoxime (4d), N-(4-bromophenyl) thiophene-2-carboxamidoxime
(4e), N-(1-naphthyl) thiophene-2-carboxamidoxime (4f), and N-(4-iodo-

306
Y. Du¨ ru¨st et al.
phenyl) thiophene-2-carboxamidoxime (4g) were obtained according to
the methods described previously,22 and their purity was checked by
means of TLC, spectral, and physical data (NMR, IR and MS).
General Procedure for the Preparation of
1,2,4-Oxadiazol-5(4H )-ones (5a–g)
To a stirred solution of N-substituted thiophene-2-carboxamidoxime 4
(1.0 mmol) in xylene (25 mL) at r.t. was added triethylamine (1.0 mmol),
and then ethyl chloroformate was added dropwise (1.1 mmol) in xylene
(5 mL) to the previously mentioned mixture on an ice-salt bath. Then
the mixture was heated under reflux for 3 h. The reaction mixture was
filtered through filter paper, and the solution was evaporated at re-
duced pressure. The crude reaction product was crystallized from an
appropriate solvent or solvent mixture specified to give pure products
(5a–g).
4-Phenyl-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one (5a)
Yield 62%, m.p. 144–146◦C (Cylohexane). Rf:0.42 (Eluant:hexane:ethyl
acetate; 3:2). IR (KBr) ν (cm−1): 1764 (C O), 1573, 1546 (C N). Anal.
calcd. for C12H8N2O2S: (F.W.244.27): C, 59.00%; H, 3.30%; N, 11.47%;
S, 13.13%. Found: C, 58.62%; H, 3.17%; N, 10.87%; S, 12.58%. 1H NMR
(CDCl3, 300 MHz): δ = 7.56–7.48 (m, 3H), 7.38–7.35 (m, 2H), 7.00–6.95
(m, 2H).
13C NMR (CDCl3,75 MHz): δ = 158.4 (C O), 153.6 (C N), 131.6,
130.9, 130.8, 130.3, 128.2, 128.0, 123.4. MS (m/z, %): 244 (M+, 100),
125 (19), 97 (53), 77 (51), 51 (28).
3-(2-Thienyl)-4-p-tolyl-1,2,4-oxadiazol-5(4H )-one (5b)
Yield 50%, m.p. 125–126◦C (Cyclohexane). Rf:0.67 (Eluant:hexane:ethyl
acetate; 3:2) IR (KBr) ν (cm−1): 1774(C O), 1577, 1516 (C N). 1H NMR
(CDCl3, 300 MHz): δ = 7.50 (s, 1H), 7.32(d, 2H, J= 8.2 Hz), 7.25 (d,
2H, J= 8.2 Hz), 6.98 (s, 2H), 2.45 (s, 3H). 13C NMR (CDCl3, 75 MHz):
δ = 157.7 (C O), 152.9 (C N), 141.2, 130.9, 130.8, 21.6. MS (m/z, %):
258 (M+, 100), 234 (95), 137 (51), 97 (49).
4-(4-Chlorophenyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one (5c)
Yield 42%, m.p. 111–112◦C (Hexane). Rf:0.70 (Eluant:hexane:ethyl ac-
etate; 3/2). IR (KBr) ν (cm−1): 1786 (C O), 1575, 1511 (C N). 1H NMR
(CDCl3, 300 MHz): δ = 7.54–7.49 (m, 3H), 7.32–7.29 (m, 2H), 7.04–7.02

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
307
(m, 2H). 13C NMR (CDCl3, 75 MHz): δ = 158.4 (C O), 153.3 (C N),
136.9, 130.1, 129.4, 128.5, 128.1, 131.1, 130.6, 123.0, 131.0. MS (m/z,
%): 278 (M+, 100), 234 (95), 137 (51), 97 (49).
4-(4-Methoxyphenyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one
(5d)
Yield 60%, m.p. 118–120◦C (Cyclohexane). Rf:0.43 (Eluant:hexane:ethyl
acetate; 3:2). IR (KBr) ν (cm−1): 1769 (C O), 1606, 1576, 1515 (C N).
Anal. calcd. for C13H10N2O3S: (F.W.274.30): C, 56.92%; H, 3.67%; N,
10.21%; S, 11.69%. Found: C, 57.30%; H, 3.33%; N, 9.55%; S, 11.16%.
1H NMR (CDCl3, 300 MHz): δ = 7.49 (d, 1H, J= 6.44 Hz), 7.28(d, 2H,
J= 9.08 Hz), 7.03 (m, 4H), 3.88 (s, 3H). 13C NMR (CDCl3, 75 MHz):
δ = 161.2 (C O), 158.7 (C N), 153.8, 130.9, 130.8, 129.6, 128.0, 124.0,
123.5, 115.5, 55.9 (O-CH3). MS (m/z, %): 274 (M+, 100), 230 (100), 216
(100), 187 (42), 149 (14), 133 (17), 106 (24), 97 (6), 78 (27).
4-(4-Bromophenyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one
(5e)
Yield 63%, m.p. 112–113◦C (Diethylether/hexane). Rf:0.41 (Elu-
ant:hexane:ethyl acetate; 3:1). IR (KBr)ν (cm−1): 1784 (C O), 1574,
1510 (C N). Anal. calcd. for C12H7BrN2O2S: (F.W.323.17): C, 44.60%;
H, 2.18%; N, 8.67%; S, 9.92%. Found: C, 45.16%; H, 1.82%; N, 8.12%;
S, 9.44%. 1H NMR (CDCl3, 300 MHz): δ = 7.67 (d, 2H, J= 9.0 Hz),
7.53 (dd, 1H, J= 6.6, 5.1 Hz), 7.25(d, 2H, J= 5.7 Hz), 7.02 (m, 2H).
13C NMR (CDCl3, 75MHz): δ = 158.0(C O), 153.3 (C N), 131.0, 130.6,
129.7, 128.2, 131.2, 133.6, 125.0, 123.0. MS (m/z, %): 322 (M+, 100), 280
(100), 199 (18), 181 (32), 155 (19), 97 (45).
4-(1-Naphthyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one (5f)
Yield 54%, m.p. 187–188◦C (Cyclohexane). Rf:0.40 (Eluant:hexane:
ethyl acetate; 3:2). IR (KBr) ν (cm−1): 1769 (C O), 1597, 1576, 1555,
1525, 1508 (C N). Anal. calcd. for C16H10N2O2S: (F.W.294.33): C,
65.29%; H, 3.42%; N, 9.52%; S, 10.89%. Found: C, 66.02%; H, 3.66%;
N, 9.31%; S, 10.53%. 1H NMR (CDCl3, 300 MHz): δ = 8.08 (d, 1H,
J= 6.9 Hz), 7.96 (d, 1H, J= 8.4 Hz), 7.67–7.55 (m, 5H), 7.35 (t, 1H),
6.82 (t, 2H). 13C NMR (CDCl3, 75 MHz): δ = 158.6 (C O), 154.4 (C N),
134.7, 131.9, 130.9, 130.5, 130.3, 129.1, 128.7, 128.0, 127.9, 127.8, 127.6,
125.7, 123.2, 121.5. MS (m/z, %): 294 (M+, 100), 250 (76), 205 (19), 153
(68), 97 (14).

308
Y. Du¨ ru¨st et al.
4-(4-Iodophenyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H )-one (5g)
Yield 40%, m.p. 181–183◦C (Cyclohexane). Rf:0.66 (Eluant:hexane:ethyl
acetate; 3:2) IR (KBr) ν (cm−1): 1769 (C O), 1577, 1508 (C N). 1H NMR
(CDCl3, 300 MHz): δ = 8.02 (d, 1H, J= 9.08 Hz), 7.58–7. 45 (m, 3H), 7.25
(m, 1H) 7.01 (s, 2H). 13C NMR (CDCl3, 75 MHz): δ = 157.9 (C O), 153.1
(C N), 140.8, 134.4, 132.8, 131.1, 130.6, 130.4, 128.1, 123.4, 99.5. MS
(m/z, %): 370 (M+ could not be observed), 326 (M+-CO2, 100), 199 (60),
172 (43), 63 (16).
General Procedure or the Preparation
of 1,2,4-Oxadiazole-5(4H )-thiones (6a–g)
To
a solution of N-substituted thiophene-2-carboxamidoxime 4
(0.40 mmol) in chloroform (10 mL) at r.t. was added triethylamine
(0.80 mmol), and thiophosgene (0.40 mmol) in chloroform (5 mL) was
added dropwise on an ice-salt bath. The reaction mixture was stirred
for 5 h at r.t. The solvent was evaporated at reduced pressure. The re-
action mixture was extracted with acetone and filtered. Acetone was
evaporated, and the remaining solid was crystallized from a solvent
specified to give pure products (6a–g).
4-Phenyl-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-thione (6a)
Yield 40%, m.p. 156–157◦C (cyclohexane). Rf:0.72 (Eluant:benzene:
ethyl alcohol; 5:1). IR (KBr) ν (cm−1): 1578, 1556(C N), 1348,
1141cm−1(N C S). Anal. calcd. for C12H8N2O2S: (F.W.244.27): C,
59.00%; H, 3.30%; N, 11.47%; S, 13.13%. Found: C, 58.62%; H, 3.17%; N,
10.87%; S, 12.58%. 1H NMR (CDCl3, 400 MHz): δ = 7.66–7.60 (m, 3H),
7.53 (dd, 1H, J= 4.04, 2.04 Hz), 7.43–7.39 (m, 2H), 7.03 (m, 2H). 13C
NMR (CDCl3, 100 MHz): δ = 187.2 (C S), 154.5 (C N), 133.2, 131.4,
131.1, 130.3, 128.5, 127.9, 121.8. MS (thione) (m/z, %): 260 (M+, 88),
200 (100), 141 (26), 97 (21), 77 (33). MS (thia) (m/z, %): 260 (M+, 94),
186 (56), 141 (100), 77 (47).
3-(2-Thienyl)-4-p-tolyl-1,2,4-oxadiazol-5(4H )-thione (6b)
Yield 59%. m.p. 127–128◦C (Hexane). Rf:0.47 (EtOH:Benzene; 1:6). IR
(KBr) ν (cm−1): 1575, 1512, 1332, 1227, 1144 (N C S). 1H NMR (CDCl3,
400 MHz): δ = 7.54 (d, 1 H, J= 6.9 Hz), 7.42 (d, 2H, J= 8.0 Hz), 7.29
(d, 2H, J= 8.4 Hz), 7.01 (m, 2H), 2.50 (s, 3H). 13C NMR δ = (CDCl3,
100 MHz): 186.4 (C S), 141.3 (C N), 130.7, 130.8, 21.4. MS (thione)

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
309
(m/z, %): 274 (M+, 94), 214 (100), 200 (11), 104 (14), 91 (30), 77 (12). MS
(thia) (m/z, %): 274 (M+, 100), 200 (72), 91 (32), 65 (28).
4-(4-Chlorophenyl)-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-thione
(6c)
Yield 57%, m.p. 160–161◦C (Hexane). Rf:0.74 (Eluant:EtOH:benzene;
1:5). IR (KBr) ν (cm−1): 1575(C N), 1351, 1231, 1157(N C S). 1H NMR
(CDCl3, 400 MHz): δ = 7.61(d, 2H, J= 8.6 Hz), 7.57 (dd, 1H, J= 5.1, 1.4
Hz), 7.36 (d, 2H, J= 8.6 Hz), 7.10 (dd, 1H, J= 3.8, 1.2 Hz), 7.06(t, 1H).
13C NMR (CDCl3, 100 MHz): δ = 187.1 (C O), 154.4 (C N), 137.4, 131.6,
131.6, 131.4, 131.0, 130.3, 129.9, 129.8, 128.3, 128.1. MS (thione) (m/z,
%): 294 (M+, 68), 234 (100), 141 (55), 109 (28). MS (thia) (m/z, %): 294
(M+, 78), 220 (60), 141 (100), 111 (22).
4-(4-Methoxyphenyl)-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-
thione (6d)
Yield 58%, m.p. 136–137◦C (Hexane). Rf:0.73 (Eluant:EtOH:benzene;
1:6). IR (KBr) ν (cm−1): 1578(C N), 1334, 1254, 1148 (N C S). Anal.
calcd. for C13H10N2O2S2: (F.W.290.36): C, 53.77%; H, 3.47%; N, 9.65%;
S, 22.09%. Found: C, 54.30%; H, 3.43%; N, 10.48%; S, 22.09%. 1H
NMR (CDCl3, 400 MHz): δ = 7.54 (dd, 1H, J= 3.8, 0.9 Hz), 7.30 (d, 2H,
J= 8.8 Hz), 7.12 (dd, 1H, J= 3.8, 1.2 Hz), 7.10 8d, 2H, J= 8.8 Hz),
7.04(dd, 1H, J= 4.8, 3.8 Hz), 3.92 (s, 3H). 13C NMR (CDCl3, 100 MHz):
δ = 187.5(C S), 161.4 (C N), 154.8, 131.4, 131.2, 129.7, 127.9, 125.4,
121.9, 115.5, 55.6. MS (thione) (m/z, %) 290 (M+, 88), 216 (83), 149 (52),
141 (100).MS (thia) not observed.
4-(4-Bromophenyl)-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-thione
(6e)
Yield 47%, m.p. 151–152◦C (Hexane). Rf:0.72 (Eluant:EtOH:benzene;
1/5). IR (KBr) ν (cm−1):1575 (C N), 1337, 1297, 1157 (N C S). Anal.
calcd. for C12H7BrN2OS2: (F.W.339.23): C, 42.49%; H, 2.08%; N, 8.26%;
1
S, 18.90%. Found: C, 43.19%; H, 2.11%; N, 8.06%; S, 18.88%. H NMR
(CDCl3, 400 MHz): δ = 7.76 (d, 2H, J= 8.7 Hz), 7.56 (dd, 1H, J= 4.9,
1.3 Hz), 7.28 (d, 2H, J= 8.7 Hz), 7.10 (dd, 1H, J= 3.9, 1.2 Hz), 7.06
(dd, 1H, J= 5.0, 3.9 Hz). 13C NMR (CDCl3, 100 MHz): δ = 186.8 (C S),
154.3(C N), 133.8, 133.7, 131.4, 131.2, 129.7, 127.9, 125.4, 121.9, 115.5,
55.6.MS (thione) (m/z, %), 340 (M+, 52), 266 (36), 199 (13), 183 (35), 155
(21), 141 (100), 97 (24).MS (thia) not observed.

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Y. Du¨ ru¨st et al.
4-(1-Naphthyl)-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-thione (6f)
Yield 48%, m.p. 172–173◦C (Hexane). Rf:0.74 (Eluant:EtOH:benzene;
1:5). IR (KBr) ν (cm−1): 1580, 1503 (C N), 1333, 1149, 1108 (N C S).
Anal. calcd. for C16H10N2OS2: (F.W.310.39): C, 61.91%; H, 3.25%; N,
9.03%; S, 20.66%. Found: C, 61.56%; H, 3.36%; N, 8.48%; S, 19.49%.
1H NMR (CDCl3, 400 MHz): δ = 8.18 (d, 1H, J= 8.1 Hz), 8.05 (d, 1H,
J= 7.8 Hz), 7.70–7.55 (m, 5H), 7.40 (dd, 1H, J= 9.5, 1.2 Hz), 6.91 (dd,
1H, J= 4.7, 1.0 Hz), 6.87 (t, 1H). 13C NMR (CDCl3, 100 MHz): δ = 187.2
(C S), 155.3 (C N), 134.5, 131.9, 131.3, 131.0, 129.5, 129.3, 128.9,
128.5, 127.8, 127.7, 127.6, 127.5, 125.6, 121.6, 121.4. MS (thione) (m/z,
%): 310 (M+, 1), 250 (100), 207 (12), 140 (10). MS (thia) (m/z, %): 310
(M+, 100), 236 (94), 169 (46), 141 (60).
4-(4-Iodophenyl)-3-(2-thienyl)-1,2,4-oxadiazole-5(4H )-thione
(6g)
Yield 74%, m.p. 206–207◦C (Hexane). Rf:0.68 (Eluant:EtOH:benzene;
1:5). IR (KBr) ν (cm−1): 1577(C N), 1334, 1155, 1055 (N C S). 1H NMR
(CDCl3, 400 MHz): δ = 8.07 (d, 1H, J= 8.1 Hz), 7.62 (t, 1H), 7.54(m, 1H),
7.37(t, 2H), 7.11–7.03 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ = 185.9
(C S), 154.0 (C N), 140.8, 135.8, 132.7, 131.5, 130.4, 130.1, 128.0,
121.7, 98.6.MS (thione) (m/z, %): 386 (M+, 36), 326 (69), 259 (71), 245
(48), 231 (100), 109 (38), 90 (48). MS (thia)(m/z, %): 386 (M+, 100), 312
(36), 259 (13), 231 (32), 150 (61), 141 (55), 109 (13).
General Procedure for the Preparation of 1,2,4-oxadiazin-
5(6H )-ones (7a–g)
To
a
solution of N-substituted thiophene-2-carboxamidoxime
(4) (0.5 mmol) in THF (10 mL) at r.t. was added triethylamine
(1.1 mmol), and chloroacetyl chloride (0.6 mmol) in THF(5 mL) was
added dropwise on an ice-salt bath. Then the mixture was stirred
and heated under the reflux for 2 d. The reaction mixture was
filtered, and the solution was evaporated at a reduced pressure.
The residual solid was subjected to flash column chromatography
(eluant:dichloromethane-hexane, 1:1). The column-separated product
was recrystallized from hexane to give pure products (7a–g).
4-Phenyl-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one (7a)
Yield 40%, m.p. 173–174◦C (Hexane). Rf:0.74 (EtOH:Benzene; 1:6). IR
(KBr) ν (cm−1): 1726 (C O), 1551 (C N), 1433, 1346, 1303, 1016. Anal.

Thiophene-Substituted 1,2,4-Oxadiazoles and Oxadiazines
311
calcd. for C13H10N2O2S: (F.W.258.30): C, 60.45%; H, 3.90%; N, 10.85%;
S, 12.41%. Found: C, 60.51%; H, 3.84%; N, 11.19%; S, 11.96%. 1H NMR
(CDCl3, 400 MHz): δ = 7.25–7.41 (m, 6H), 6.76–6.83 (m, 2H), 4.65 (s,
2H, OCH2). 13C NMR (CDCl3, 100 MHz): δ = 163.9 (C O), 150.8 (C N),
135.1, 130.9, 130.5, 129.3, 129.2, 128.8, 128.3, 127.1, 68.4. MS (m/z,%):
258 (M+, 100), 200 (59), 186 (16), 105 (14), 97 (21), 77 (39).
4-(4-Methylphenyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one
(7b)
Yield 43%, m.p. 154–156◦C (Hexane). Rf:0.76 (EtOH:Benzene; 1:6). IR
(KBr) ν (cm−1): 1730 (C O), 1558 (C N), 1440, 1361, 1283. Anal. calcd.
for C13H9ClN2O2S: (F.W.292.74): C, 54.34%; H, 3.10%; N, 9.57%; S,
1
10.95%. Found: C, 54.01%; H, 3.39%; N, 9.58%; S, 10.96%. H NMR
(CDCl3, 400 MHz): δ = 7.32 (d, 1H, J= 1.1 Hz), 7.21 (d, 2H, J= 8.6
Hz), 7.14 (d, 2H, J= 9.0 Hz), 6.78–6.85 (m, 2H), 4.62 (s, 2H), 2.37 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ = 163.5 (C O), 150.3 (C N), 138.4,
131.9, 130.4, 130.1,129.4, 128.8, 127.4, 126.6, 67.9 (O-CH2), 20.6 (CH3).
MS (m/z, %): 272 (M+, 100), 214 (52), 200 (23), 105 (15).
4-(4-Chlorophenyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one
(7c)
Yield 50%, m.p. 124–126◦C (Hexane). Rf:0.80 (EtOH:Benzene; 1:6). IR
(KBr) ν (cm−1): 1732 (C O), 1571, 1522 (C N), 1493, 1306, 1221, 1090,
1
1016. HNMR (CDCl3, 400 MHz): δ = 7.30–6.72 (m, 7H), 4.53 (s, 2H).
13CNMR (CDCl3, 100 MHz): δ = 163.8 (C O), 150.7 (C N), 130.5, 129.4,
129.3, 127.5, 127.1, 114.5, 68.4, 55.4. MS (m/z, %): 292 (M+, 100), 234
(47), 220 (14), 105 (23).
4-(4-Methoxyphenyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-
one (7d)
Yield 53%, m.p. 131–132◦C (Hexane). Rf:0.70 (EtOH:Benzene: 1:6). IR
(KBr) ν (cm−1): 1726 (C O), 1608, 1564, 1511 (C N). Anal. calcd. for
C14H12N2O3S: (F.W.288.32): C, 58.32%; H, 4.20%; N, 9.72%; S, 11.12%.
1
Found: C, 58.32%; H, 3.66%; N, 10.09%; S, 10.86%. H NMR (CDCl3,
400 MHz): δ = 7.31 (d, 2H, J= 3.9 Hz), 7.17 (d, 1H, J= 6.8 Hz), 6.91
(d, 2H, J= 8.6 Hz), 6.85 (t, 1H), 6.65 (dd, 1H, J= 9.3, 1.1 Hz), 4.62 (s,
2H, OCH2), 3.83 (s, 3H, OCH3). 13C NMR (CDCl3, 100 MHz): δ = 164.1
(C O), 159.6 (C N), 150.9, 130.9, 130.5, 129.4, 129.3,127.5, 127.1,

312
Y. Du¨ ru¨st et al.
114.5, 68.4 (OCH2), 55.4 (OCH3). MS (m/z, %): 288 (M+, 100), 230 (45),
215 (100), 135 (17).
4-(4-Bromophenyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one
(7e)
Yield 50%, m.p. 155–156◦C (Hexane). Rf:0.87 (EtOH:Benzene; 1:6).
IR (KBr) ν (cm−1): 1731 (C O), 1570 (C N). Anal. calcd. for
C13H9BrN2O2S: (F.W.337.19): C, 46.31%; H, 2.69%; N, 8.31%; S, 9.51%.
Found: C, 46.52%; H, 1.96%; N, 9.53%; S, 8.9%. 1H NMR (CDCl3,
400 MHz): δ = 7.44 (d, 2H, J= 8.4 Hz), 7.25 (dd, 1H, J= 5.0, 1.1 Hz), 7.04
(d, 2H, J= 8.7 Hz), 6.78 (dd, 1H, J= 8.9, 5.1 Hz), 6.72 (dd, 1H, J= 9.3,
1.1 Hz), 4.50 (s, 2H, OCH2). 13C NMR (CDCl3, 100 MHz): δ = 163.8
(C O), 150.5 (C N), 134.2, 132.5, 131.0, 130.2, 129.6, 127.3, 122.7, 68.4.
MS (m/z, %): 336 (M+, 100), 280 (83), 183 (33), 155 (20), 97 (28).
4-(1-Naphthyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one (7f)
Yield 35%, m.p. 158–159◦C (Hexane). Rf:0.73 (EtOH:Benzene; 1:6).
1
IR (KBr) ν (cm−1): 1726 (C O), 1604, 1572 (C N). H NMR (CDCl3,
400 MHz): δ = 7.89–6.44 (m, 10H), 4.85 (q, 2H, OCH2). 13C NMR (CDCl3,
100 MHz): δ = 164.0 (C O), 148.9 (C N), 135.5, 134.2, 130.4, 130.1,
129.2, 128.4, 128.3, 127.6, 127.0, 126.9, 126.8, 126.7, 126.4, 126.3,
125.3,125.2, 125.1, 122.1, 121.8, 68.5 (OCH2).MS (m/z, %): 308 (M+,
100), 249 (65), 153 (52), 140 (24), 127 (36).
4-(4-Iodophenyl)-3-(2-thienyl)-4H-1,2,4-oxadiazin-5(6H )-one
(7g)
Yield 26%, m.p. 152–154◦C (Hexane). Rf:0.65 (EtOH:Benzene; 1:6). IR
1
(KBr) ν (cm−1): 1730 (C O), 1572 (C N). H NMR (CDCl3, 400 MHz):
δ = 7.91 (d, 1H, J= 1.3 Hz), 7.36–6.83 (m, 6H), 4.69 (q, 2H,OCH2). 13
C
NMR (CDCl3, 100 MHz): δ = 162.7 (C O), 149.6 (C N), 140.2, 137.7,
130.9, 130.8, 130.6, 129.7, 129.5, 129.3, 127.1, 99.5, 68.3 (OCH2). MS
(m/z, %): 384(M+,100), 326 (25), 312 (20), 257 (27), 199 (28), 155 (18),
132 (59), 90 (32), 76 (36).
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