[3+2]-Cycloadditions of nitrilimines with heteroaryl thioketones

Article abstract of DOI:10.1080/17415993.2017.1346103

The in situ generated nitrilimines are trapped efficiently with heteroaryl thioketones bearing thiophen-2-yl or selenophen-2-yl substituents. The exclusive products observed in these reactions are 2,3-dihydro-1,3,4-thiadiazoles formed via regioselective [

Full text of DOI:10.1080/17415993.2017.1346103

Journal of Sulfur Chemistry
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[3+2]-Cycloadditions of nitrilimines with heteroaryl
thioketones
Korany A. Ali, Grzegorz Mlostoń, Katarzyna Urbaniak, Anthony Linden &
Heinz Heimgartner
To cite this article: Korany A. Ali, Grzegorz Mlostoń, Katarzyna Urbaniak, Anthony Linden & Heinz
Heimgartner (2017): [3+2]-Cycloadditions of nitrilimines with heteroaryl thioketones, Journal of
Sulfur Chemistry, DOI: 10.1080/17415993.2017.1346103
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Date: 08 July 2017, At: 04:32

JOURNAL OF SULFUR CHEMISTRY, 2017
https://doi.org/10.1080/17415993.2017.1346103
[3+2]-Cycloadditions of nitrilimines with heteroaryl
thioketones
Korany A. Alia, Grzegorz Mlostońb, Katarzyna Urbaniakb, Anthony Lindenc and
Heinz Heimgartnerc
aApplied Organic Chemistry Department, Center of Excellence for Advanced Science, National Research
Centre, Giza, Egypt; bDepartment of Organic and Applied Chemistry, University of Łódź, Łódź, Poland;
cDepartment of Chemistry, University of Zurich, Zurich, Switzerland
ABSTRACT
ARTICLE HISTORY
Received 19 April 2017
Accepted 18 June 2017
The in situ generated nitrilimines are trapped efficiently with
heteroaryl thioketones bearing thiophen-2-yl or selenophen-2-yl
substituents. The exclusive products observed in these reactions
are 2,3-dihydro-1,3,4-thiadiazoles formed via regioselective [3+2]-
cycloaddition. Competitive head-to-tail dimerization of the interme-
diate 1,3-dipoles was not observed in any of the studied reactions.
KEYWORDS
[3+2]-Cycloadditions;
thioketones; nitrilimines;
1,3,4-thiadiazoles; X-ray
crystallography
X
X
Ph
N N
S
Ph
S
X
N
N
C
Ph
Ph
THF, r.t.
X
yield: X = S or Se (71–73%)
1. Introduction
Nitrilimines 1 belong to the group of classical 1,3-dipoles widely applied in [3+2]-
cycloadditions with diverse dipolarophiles, mainly activated ethenes, and acetylenes [1,2].
Synthetically important diarylnitrilimines 1A are generated in situ by thermal or pho-
tolytical decomposition of 2,5-disubstituted tetrazoles 2 or by dehydrohalogenation of
hydrazonoyl halides 3 in the presence of a base, e.g. triethylamine (TEA, Scheme 1). These
reactive 1,3-dipoles have been characterized in a matrix at 12–85 K by UV and IR spec-
troscopy [3–5], and the structure of the sterically crowded C,N-ditritylnitrilimine was
confirmed by X-ray crystallography [6]. Other relatively stable nitrilimines, bearing silyl
or phosphorus substituents, are also known (e.g. [7–10]).
CONTACT Korany A. Ali
kornykhlil@gmail.com
Applied Organic Chemistry Department, Center of Excellence
gmloston@uni.lodz.pl
for Advanced Science, National Research Centre, 12622 Dokki, Giza, Egypt; Grzegorz Mlostoń
Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, PL-91-403 Łódź, Poland
© 2017 Informa UK Limited, trading as Taylor & Francis Group

2
K. A. ALI ET AL.
Ar1
2
=
R
Ar
Ar2
N
N
C
Ar1
R
D or hn
base
-HCl
N N
N
1A
NHAr1
-N2
N
Ar2
Cl
N
=
Ar1
R
CF3
3
2
N
N
C
F
3C
1B
Scheme 1. Methods for generation of nitrilimines 1.
S
S
Ph
Ph
Ph
THF
x
2
+
CH2N2
Ph
Se
Se
Se
-60 oC
-N2
S
Se
S
H
H
5
4a
6
7
Scheme 2. Head-to-headdimerizationoftheselenophen-2-yl-substitutedthiocarbonylS-methanide6.
Thioketones are known as ‘superdipolarophiles’ [11], and reactions of diarylnitrilimines
1A with aromatic and cycloaliphatic representatives have been reported [12–15]. More-
over, other thiocarbonyl compounds were also used in cycloadditions with 1 [16–18]. In all
cases, 2,3-dihydro-1,3,5-thiadiazoles were obtained in a regioselective manner. In a series
of recent papers, we reported on diverse cycloadditions using heteroaryl thioketones as
dipolaro- and dienophiles [19]. The studies showed that the presence of a heteroaryl sub-
stituent strongly modifies the reactivity of the thioketones. For example, the reaction of
phenyl selenophen-2-yl thioketone (4a) with diazomethane (5) led to the 14-membered
cyclodimer 7 of the intermediate thiocarbonyl S-methanide 6 via a biradical mechanism
[20,21] (Scheme 2).
A very recent study demonstrated that in contrast to diarylnitrilimines 1A, N-aryl-
C-(trifluoromethyl)nitrilimines 1B (Scheme 1), derived from trifluoroacetonitrile, react
=
efficiently with thiochalcones as C S dipolarophiles [22]. The same series of nitrilimines
1B was used for the synthesis of trifluoromethyl-substituted 2,3-dihydro-1,3,4-thiadiazoles
[23]. Considering the importance of these heterocycles [24,25], we have studied [3+2]-
cycloadditions of heteroaryl thioketones with C,N-diphenyl-, C-acetyl-N-phenyl- and
C-ethoxycarbonyl-N-phenylnitrilimines (1a–1c).
2. Results and discussion
The reactions of the hydrazonoyl chlorides 3a–3c with heteroaryl thioketones 4 in the pres-
ence of an equimolar amount of TEA were performed either in boiling benzene or in THF
at room temperature. Characteristically, the reaction times for diphenylnitrilimine (1a)
were shorter than in the case of 1b and 1c. In general, the reactions in boiling benzene
required 5–8 h, whereas the experiments in THF at room temperature were complete after
6 h for 1a and 48 h in the cases of 1b and 1c. In a typical experiment with 1a and phenyl
selenophen-2-yl thioketone (4a) in THF, the green color of 4a disappeared after 6 h. After
typical workup by chromatography, the product formed was isolated as a yellow solid and

JOURNAL OF SULFUR CHEMISTRY
3
Ar2
Hetar
Ar1
TEA
R
C6H6, 80 oC
Ar1
N
N
Ar2
Hetar
S
N
C
N
N
R
R
NHAr1
Cl
or THF, r.t.
-HCl
S
4
1a-c
8a-i
3a-c
x2
Ar1
N
R
N
N
Ar1
R
N
9
Scheme 3. [3+2]-Cycloadditions of the in situ generated nitrilimines 1 with heteroaryl thioketones 4.
Table 1. Synthesis of 2,3-dihydro-1,3,4-thiadiazoles 8 via [3+2]-cycloadditions.
Hydrazonoyl chloride
Heteroaryla thioketone
3
R
Ar1
4
Ar2
Hetar
Thiadiazole 8
Yield (%)b
a
a
a
a
b
b
b
b
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
b
c
d
a
b
c
Ph
Ph
Sel
Thi
Ph
Sel
Thi
Sel
Thi
Sel
Thi
Sel
Thi
Thi
a
b
c
d
e
f
g
h
i
76c
72d
73c
71d
67c
66c
72c
72d
72d
Ph
MeCO
MeCO
MeCO
MeCO
Ph
Sel
Thi
Thi
d
d
EtOCO
4-MeC6H4
aPh, Phenyl; Sel, Selenophen-2-yl; Thi, Thiophen-2-yl.
bYield of isolated product.
cReaction performed in THF at r.t.
dReaction performed in boiling benzene.
characterized by means of spectroscopic methods. The 13C NMR spectrum revealed the
presence of the expected signals at 118.8 and 153.0 ppm attributed to C(2) and C(5), respec-
tively, of the 2,3-dihydro-1,3,5-thiadiazole ring. The molecular formula C24H18N2SSe for
the [3+2]-cycloadduct 8a was confirmed by elemental analysis (Scheme 3).
Similarly, the additional reactions performed with nitrilimines 1a–1c and het-
eroaryl thioketones 4a–4d afforded 2,3-dihydro-1,3,4-thiadiazoles 8b–8i in 66–73% yield
(Table 1). All of these products displayed similar spectroscopic data, which confirmed the
structure 8. In addition, the structures of 8d and 8h were unambiguously confirmed by
X-ray crystallography (Figure 1).
The obtained products 8 were formed via regioselective [3+2]-cycloaddition of the
initially generated nitrilimines 1 with thioketones 4 as dipolarophiles. In none of the
studied cases were 1,3,4,6-tetrasubstituted 1,4-dihydro-1,2,4,5-tetrazines 9 observed, and
this result demonstrated once more that heteroaryl thioketones are ‘superdipolarophilic’
agents. In reactions of 1a with less reactive ethylenic or acetylenic dipolarophiles, the
head-to-tail dimerization leading to 9 was reported as a process competitive with the
[3+2]-cycloaddition [27,28].

4
K. A. ALI ET AL.
Figure 1. ORTEP plots [26] of the molecular structures of (a) 8d and (b) one of the disordered confor-
mations of 8h (50% probability ellipsoids; arbitrary numbering of the atoms).
In contrast to earlier reported formal [3+2]-cycloadditions of heteroaryl thioketones
with thiocarbonyl S-methanides [29] or diazoalkanes [30], in which the sterically more
crowded 1,3-dithiolanes were formed regioselectively, apparently, via an intermediate,
delocalized diradical, the reactions with nitrilimines do not offer an experimental indi-
cation for a stepwise reaction mechanism. However, the structure of the obtained 1,3,4-
thiadiazoles shows that also in this case, the postulated 1,5-diradical as a likely intermediate
could be well stabilized within the delocalized system [23].
3. Conclusions
The study showed that heteroaryl thioketones are excellent trapping reagents for in situ
generated nitrilimines bearing phenyl, acetyl or ethoxycarbonyl groups at the C-atom. The
2,3-dihydro-1,3,4-thiadiazoles are formed in high yields in a regioselective manner, regard-
less of the type of substituents in the transient nitrilimines. In analogy to nitrilimines
derived from trifluoroacetonitrile, the [3+2]-cycloadditions with heteroaryl thioketones
occur without competitive dimerization of the nitrilimines used in this study.
4. Experimental design
4.1. General
Melting points were determined in a capillary using a Melt-Temp. II (Aldrich) apparatus,
and they are uncorrected. The IR spectra were recorded on a Nexus FT-IR spectropho-
tometer as KBr pellets; absorptions in cm−1. The 1H and 13C NMR spectra were measured
in CDCl3 solution on a Bruker Avance III instrument (600 and 150 MHz, respectively),
using the solvent signal as reference. Chemical shifts (δ) are given in ppm and coupling
constants J in Hz. The mass spectra were recorded on a Finnigan MAT-95 spectrometer.
Elemental analyses were performed in the Microanalytical Laboratory of the Chemistry
Faculty in Łódź or of the National Research Centre in Cairo. All crude mixtures were
separated by chromatographic methods.

JOURNAL OF SULFUR CHEMISTRY
5
4.2. Starting materials
Aryl heteroaryl (4a,b) and diheteroaryl thioketones (4c,d) were prepared following the
literature procedures based on thionation of the corresponding ketones with Lawesson’s
reagent [31].
Hydrazonoyl chlorides 3a–3c were prepared either by reaction of the corresponding
hydrazone with N-chlorosuccinimide–dimethyl sulfide complex according to the known
general procedure [32] or by the reaction of aryl diazonium salts with α-chloro-β-
ketoesters [33].
4.3. Reactions of thioketons 4 with hydrazonoyl chlorides 3 - General procedures
To a stirred solution of the corresponding thioketone 4 (1 mmol) in dry THF (5 mL), a
solution of the appropriate hydrazonoyl chloride 3 (1 mmol) and 2.5 mL of triethylamine
in 1 mL of dry THF was added dropwise at room temperature (r.t.) under an argon atmo-
sphere. The resulting mixtures were kept at r.t. until the color of 4 disappeared completely.
Triethylamine hydrochloride was filtered off and the solvent was evaporated under reduced
pressure. The crude mixtures were purified chromatographically on silica gel using a mix-
ture of petroleum ether with an increasing amount of dichloromethane. The obtained
products 8 were additionally purified by crystallization from hexane or petroleum ether
with a small amount of CH2Cl2.
In the alternative procedure (synthesis of 8b,d,h,i), the reaction mixtures were refluxed
in boiling dry benzene for 5–8 h. After completion of the reactions, the solvent was evapo-
rated under reduced pressure and the obtained products were triturated with methanol to
afford solid products (purified by crystallization from EtOH) or yellow-brown oils (purified
by column chromatography (SiO2), using the mixture AcOEt/CH2Cl2 1:9 as the eluent).
4.3.1. 2,3-Dihydro-2,3,5-triphenyl-2-(selenophen-2-yl)-1,3,4-thiadiazole (8a)
Yellow crystals; m.p. 147–149°C (hexane/CH2Cl2); yield: 340 mg (76%). 1H NMR:
6.90–6.94 (m, 1CHarom); 7.11–7.18 (m, 5CHarom); 7.25 (dd, JH,H = 3.8 Hz, JH,H = 1.0
Hz, 1CHarom); 7.36–7.45 (m, 6CHarom); 7.74–7.79 (m, 4CHarom); 8.05 (dd, JH,H = 5.7 Hz,
JH,H = 1.0 Hz, 1CHarom). 13C NMR: 90.3 (C(2)); 118.8, 121.9, 126.7, 127.8, 128.2, 128.3,
128.5, 128.6, 128.9, 129.5, 131.9, 134.0 (18CHarom); 131.2, 141.7, 143.4, 153.0 (4Carom
,
=
C N). IR (KBr): 3063m, 3022m, 1594s, 1553m, 1492s, 1445m, 1328s, 1255s, 1236s, 1122m,
1065m, 967s, 742s, 698s, 685s. Anal. calcd for C24H18N2SSe (445.44): C 64.71, H 4.07, N
6.29, S 7.20; found: C 64.72, H 4.04, N 6.31, S 7.37.
4.3.2. 2,3-Dihydro-2,3,5-triphenyl-2-(thiophen-2-yl)-1,3,4-thiadiazole (8b)
Yellow crystals; m.p. 136–138°C (petroleum ether/CH2Cl2); yield: 286 mg (72%). 1H NMR:
6.76–6.79 (m, 2CHarom); 6.95 (dd, JH,H = 3.7 Hz, JH,H = 1.1 Hz, 1CHarom); 6.96–7.00 (m,
4CHarom); 7.21 (dd, JH,H = 5.1 Hz, JH,H = 1.1 Hz, 1CHarom); 7.24–7.31 (m, 6CHarom);
7.60–7.64 (m, 4CHarom). 13C NMR: 88.3 (C(2)); 118.6, 121.7, 126.2, 126.6, 127.6, 127.9,
128.1, 128.3, 128.4, 128.5, 129.4, 129.8 (18CHarom); 131.2, 141.7, 141.78, 143.4, 145.6
=
(4Carom, C N). IR (KBr): 3079m, 3018m, 1595s, 1553m, 1496vs, 1448m, 1337s, 1325s,
1255s, 1236s, 1125s, 1068m, 967s, 821m, 739s, 720s, 685s. MS m/z (%): 398 [M+] (75),
391 (15), 377 (17), 365 (15), 145 (100), 102 (50). Anal. calcd for C24H18N2S2 (398.54): C
72.33, H 4.55, N 7.03, S 16.09; found: C 72.34, H 4.57, N 7.02, S 15.92.

6
K. A. ALI ET AL.
4.3.3. 2,3-Dihydro-3,5-diphenyl-2,2-di(selenophen-2-yl)-1,3,4-thiadiazole (8c)
1
Yellow crystals; m.p. 115–117°C (petroleum ether/CH2Cl2); yield: 365 mg (73%). H
NMR: 6.98–7.00 (m, 1CHarom); 7.14–7.19 (m, 4CHarom); 7.25–7.27 (m, 2CHarom); 7.34
(dd, JH,H = 3.9 Hz, JH,H = 1.0 Hz, 2CHarom); 7.41–7.46 (m, 3CHarom); 7.75–7.78 (m,
2CHarom); 8.09 (dd, JH,H = 5.7 Hz, JH,H = 1.4 Hz, 2CHarom). 13C NMR: 89.6 (C(2));
120.7, 123.3, 126.8, 128.2, 128.7, 129.2, 129.7, 130.7, 133.8 (16CHarom); 131.1, 142.4, 143.4,
=
153.2 (4Carom, C N). IR (KBr): 3056m, 3015m, 1594s, 1556m, 1489s, 1445m, 1318s,
1252s, 1239s, 1116s, 1059m, 960m, 875m, 758s, 745s, 701s, 691s, 682s. Anal. calcd for
C22H16N2SSe2 (498.36): C 53.02, H 3.24, N 5.62, S 6.43; found: C 53.02, H 3.22, N 5.55,
S 6.38.
4.3.4. 2,3-Dihydro-3,5-diphenyl-2,2-di(thiophen-2-yl)-1,3,4-thiadiazole (8d)
Yellow crystals; m.p. 119–121°C; yield: 287 mg (71%). 1H NMR: 6.92–7.00 (m, 2CHarom);
7.13–7.23 (m, 5CHarom); 7.39 (dd, JH,H = 4.9 Hz, JH,H = 1.0 Hz, 1CHarom); 7.42–7.46 (m,
2CHarom); 7.77 (d, JH,H = 6.7 Hz, 1CHarom). 13C NMR: 86.1 (C(2)), 120.3, 123.1, 126.7,
126.8, 127.8, 128.2, 128.5, 128.7, 129.7 (16CHarom); 131.2, 142.4, 143.4, 146.1 (4Carom
,
=
C N). IR (KBr): 3075m, 3018m, 1591s, 1559m, 1489s, 1448m, 1426m, 1328s, 1249s, 1236s,
1182m, 1122s, 1065m, 1036m, 960s, 878m, 843m, 739s, 701vs, 682s. MS m/z (%): 404 [M+]
(100). Anal. calcd for C22H16N2S3 (404.57): C 65.31, H 3.99, N 6.92, S 23.78; found: C
65.20, H 4.17, N 6.91, S 23.80.
4.3.5. 1-[4,5-Dihydro-4,5-diphenyl-5-(selenophen-2-yl)-1,3,4-thiadiazol-2-yl]
ethanone (8e)
Yellow-brown crystals; m.p. 110–112°C (hexane/CH2Cl2); yield: 275 mg (67%). 1H NMR:
2.63 (s, CH3); 7.00–7.04 (m, 1CHarom); 7.12–7.18 (m, 5CHarom); 7.21 (dd, JH,H = 3.8 Hz,
JH,H = 1.0 Hz, 1CHarom); 7.39–7.45 (m, 3CHarom); 7.66–7.69 (m, 2CHarom); 8.09
(dd, JH,H = 5.8 Hz, JH,H = 1.0 Hz, 1CHarom). 13C NMR: 26.7 (CH3); 91.8 (C(2ꢀ));
119.8, 123.9, 127.2, 128.4, 128.6, 128.7, 129.0, 132.3, 134.9 (13CHarom); 141.6, 141.7,
=
=
=
142.1, 152.2 (3Carom, C N); 191.0 (C O). IR (KBr): 3060m, 3031m, 1666vs (C O),
1591s, 1527s, 1489s, 1439m, 1252vs, 1144vs, 1046s, 932s, 748s, 691s. Anal. calcd for
C20H16N2OSSe (411.38): C 58.39, H 3.92, N 6.81, S 7.79; found: C 58.40, H 3.93, N 6.82,
S 7.87.
4.3.6. 1-[4,5-Dihydro-4,5-diphenyl-5-(thiophen-2-yl)-1,3,4-thiadiazol-2-yl]ethanone
(8f)
1
Yellow crystals; m.p. 113–115°C (hexane/CH2Cl2); yield: 240 mg (66%). H NMR: 2.61
(s, CH3); 6.90 (dd, JH,H = 5.0 Hz, JH,H = 3.7 Hz, 1CHarom); 6.98–7.02 (m, 1CHarom);
7.06 (dd, JH,H = 3.7 Hz, JH,H = 1.1 Hz, 1CHarom); 7.14–7.16 (m, 4CHarom); 7.36
(dd, JH,H = 5.0 Hz, JH,H = 1.1 Hz, 1CHarom); 7.37–7.46 (m, 3CHarom); 7.63–7.65 (m,
2CHarom). 13C NMR: 25.7 (CH3); 89.8 (C(2)); 115.4, 119.6, 123.8, 126.5, 128.4, 128.6, 128.7,
=
=
129.5, 130.2 (13CHarom); 141.6, 141.7, 142.2, 145.0 (3Carom, C N); 191.0 (C O). IR (KBr):
3066m, 3031m, 1670vs (C O), 1591s, 1530s, 1492s, 1442m, 1252vs, 1144vs, 1049s, 932s,
=
821m, 748s, 720s, 691s. Anal. calcd for C20H16N2OS2 (364.48): C 65.91, H 4.42, N 7.69, S
17.59; found: C 65.82, H 4.67, N 7.72, S 17.70.

JOURNAL OF SULFUR CHEMISTRY
7
4.3.7. 1-[4,5-Dihydro-4-phenyl-5,5-di(selenophen-2-yl)-1,3,4-thiadiazol-2-yl]
ethanone (8g)
1
Orange crystals; m.p. 116–118°C (petroleum ether/CH2Cl2); yield: 335 mg (72%). H
NMR: 2.61 (CH3); 7.06–7.10 (m, 1CHarom); 7.17–7.20 (m, 4CHarom); 7.22–7.24 (m,
2CHarom); 7.32 (dd, JH,H = 3.9 Hz, JH,H = 1.0 Hz, 2CHarom); 8.12 (d, JH,H = 5.6 Hz,
2CHarom). 13C NMR: 25.7 (CH3); 91.2 (C(2)); 121.2, 124.9, 128.5, 129.3, 130.8, 134.5
=
=
(11CHarom); 141.5, 142.3, 152.7 (3Carom, C N); 191.1 (C O). IR (KBr): 3107m, 3056m,
=
1670vs (C O), 1593m, 1530s, 1486s, 1239vs, 1223s, 1141s, 1049m, 1021m, 922m, 891m,
761m, 701s. Anal. calcd for C18H14N2OSSe2 (464.30): C 46.56, H 3.04, N 6.03, S 6.91;
found: C 46.75, H 3.03, N 6.07, S 6.92.
4.3.8. 1-[4,5-Dihydro-4-phenyl-5,5-di(thiophen-2-yl)-1,3,4-thiadiazol-2-yl]ethanone
(8h)
1
Yellow crystals; m.p. 130–132°C (EtOH); yield: 265 mg (72%). H NMR: 2.57 (s, CH3);
6.92–6.96 (m, 2CHarom); 7.04–7.08 (m, 1CHarom); 7.12–7.18 (m, 4CHarom); 7.20–7.23 (m,
1CHarom); 7.41 (d, JH,H = 5.0 Hz, 1CHarom); 7.72 (d, JH,H = 5.0 Hz, 1CHarom); 7.94 (d,
JH,H = 3.7 Hz, 1CHarom). 13C NMR: 25.7 (CH3); 87.3 (C(2)); 120.8, 124.7, 126.8, 128.3,
=
=
128.4, 128.6, 141.5, 142.4, 145.6 (11CHarom, 3Carom, C N); 191.1 (C O). IR (KBr): 3085m,
1665s (C O), 1533s, 1490m, 1240s, 1226s, 1137s, 1043m, 925m, 755m, 719s, 696m. MS m/z
=
(%): 370 [M+] (100). Anal. calcd for: C18H14N2OS3 (370.51): C 58.35, H 3.81, N 7.56, S
25.96; found: C 58.32, H 3.85, N 7.51, S 25.94.
4.3.9. Ethyl 4,5-dihydro-5,5-di(thiophen-2-yl)-4-(p-tolyl)-1,3,4-thiadiazole-
2-carboxylate (8i)
Yellow-brown oil (AcOEt/CH2Cl2 1:9); yield: 300 mg (72%). 1H NMR: 1.36 (t,
JH,H = 7.1 Hz, CH3), 2.22 (s, CH3), 4.35 (q, JH,H = 7.1 Hz, CH2O), 6.89–6.92 (m,
3CHarom); 6.95–6.98 (m, 2CHarom); 7.10 (dd, JH,H = 3.7 Hz, JH,H = 1.1 Hz, 1CHarom);
7.18 (dd, JH,H = 4.9 Hz, JH,H = 3.9 Hz, 1CHarom); 7.37 (dd, JH,H = 5.1 Hz, JH,H = 1.1 Hz,
1CHarom); 7.68 (dd, JH,H = 4.9 Hz, JH,H = 1.1 Hz, 1CHarom); 7.90 (dd, JH,H = 3.7 Hz,
JH,H = 1.1 Hz, 1CHarom). 13C NMR: 14.1 (CH3); 20.8 (CH3); 62.3 (CH2O); 87.5 (C(2)),
114.5, 121.3, 126.8, 127.9, 128.3, 128.5, 133.2, 133.4 (10CHarom); 134.8, 139.4, 143.0, 145.7,
=
=
=
160.3 (4Carom, C N); 178.8 (C O). IR (KBr): 2962m, 2923m, 1730s and 1704s (C O),
1541s, 1507s, 1463s, 1261vs, 1090vs, 1073m, 804s, 708m. MS m/z (%): 414 [M+] (100).
Anal. calcd for C20H18N2O2S3 (414.56): C 57.94, H 4.38, N 6.76, S, 23.20; found: C 57.97,
H 4.35, N 6.70, S 23.19.
4.4. X-ray crystal structure determination of compounds 8d and 8h [34]
All measurements were made on Nonius KappaCCD area-detector diffractometer [35]
using MoK α radiation (λ = 0.71073 Å) and an Oxford Cryosystems Cryostream 700 cooler.
The data collection and refinement parameters are given below [34] and views of the
molecules are shown in Figure 1. Data reduction was performed with HKL Denzo and
Scalepack [36]. The intensities were corrected for Lorentz and polarization effects, and
an absorption correction based on the multi-scan method [37] was applied. Equivalent
reflections were merged. Each structure was solved by direct methods using SHELXS97
[38], which revealed the positions of all non-hydrogen atoms. In the case of 8h, one of

8
K. A. ALI ET AL.
the five-membered rings is disordered through a rotation of approximately 180° about the
ring pivot axis, thus interchanging the positions of the S-atom and a C-atom. Two positions
were defined for each of these atoms and the site occupation factor of the major confor-
mation refined to 0.697(2). Similarity restraints were applied to the chemically equivalent
bond lengths involving disordered atoms, while the neighboring disordered atoms were
restrained to have similar atomic displacement parameters. The non-hydrogen atoms were
refined anisotropically. All of the H-atoms were placed in geometrically calculated posi-
tions and refined by using a riding model where each H-atom was assigned a fixed isotropic
displacement parameter with a value equal to 1.2Ueq of its parent atom (1.5Ueq for the
methyl group in 8h). The refinement of each structure was carried out on F2 by using
full-matrix least-squares procedures, which minimized the function ꢀw(Fo2 − Fc2)2. A cor-
rection for secondary extinction was applied in the case of 8h. Neutral atom scattering
factors for non-H-atoms were taken from ref. [39], and the scattering factors for H-atoms
were taken from ref. [40]. Anomalous dispersion effects were included in Fc [41]; the val-
ues for f ꢀ and f ꢀꢀ were those of ref. [42]. The values of the mass attenuation coefficients are
those of ref. [43]. The SHELXL-2016 program [44] was used for all calculations.
Crystal data for 8d: C22H16N2S3, M = 404.55, crystallized from Et2O/hexane, yellow,
¯
prism, crystal dimensions 0.12 × 0.20 × 0.28 mm, triclinic, space group P1, Z = 2, reflec-
tions for cell determination 33,649, 2θ range for cell determination 4–55°, a = 9.0252(2)
Å, b = 10.2253(2) Å, c = 11.6650(3) Å, α = 94.8910(16)°, β = 110.1558(15)°, γ =
108.0826(16)°, V = 938.12(4) Å3, T = 160(1) K, DX = 1.432 g cm−3, μ(MoKα) =
0.405 mm−1, scan type ω, 2θ(max) = 54.9°, transmission factors (min; max) = 0.863;
0.955, total reflections measured 20,152, symmetry-independent reflections 4267, reflec-
tions with I > 2σ(I) 3135, reflections used in refinement 4267, parameters refined
244, R(F) [I > 2σ(I) reflections] = 0.0433, wR(F2) [all data] = 0.1099 (w = [σ2(Fo2) +
(0.0469P)2 + 0.4391P]−1, where P = (Fo2 + 2Fc2)/3), goodness of fit 1.068, final ꢁmax/σ
0.000, ꢁρ (max; min) = 0.38; −0.44 e Å−3
.
Crystal data for 8h: C18H14N2OS3, M = 370.49, crystallized from hexane/CH2Cl2,
yellow, plate, crystal dimensions 0.07 × 0.22 × 0.37 mm, monoclinic, space group
P21/c, Z = 4, reflections for cell determination 61,174, 2θ range for cell determina-
tion 4–55°, a = 10.6525(1) Å, b = 15.9217(2) Å, c = 10.3570(2) Å, β = 104.7834(9)°,
V = 1698.46(4) Å3, T = 160(1) K, DX = 1.449 g cm−3, μ(MoKα) = 0.444 mm−1, scan
type ω, 2θ(max) = 54.9°, transmission factors (min; max) = 0.890; 0.970, total reflections
measured 40,626, symmetry-independent reflections 3892, reflections with I > 2σ(I)
3248, reflections used in refinement 3892, parameters refined 238, restraints 54, R(F)
[I > 2σ(I) reflections] = 0.0352, wR(F2) [all data] = 0.0926 (w = [σ2(Fo2) + (0.0427P)2
+ 0.8503P]−1, where P = (Fo2 + 2Fc2)/3), goodness of fit 1.044, secondary extinction
coefficient 0.006(1), final ꢁmax/σ 0.001, ꢁρ (max; min) = 0.37; −0.48 e Å−3
.
Acknowledgement
Skillful performance of elemental analysis of all new compounds by Ms Agnieszka Cieślińska and
Ms Hanna Jatczak (University of Łódź) is gratefully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the authors.

JOURNAL OF SULFUR CHEMISTRY
9
Funding
G. M., K. U., and H. H. thank the National Science Center (Cracow, Poland) for generous financial
support [grant Maestro-3 (Dec-2012/06/A/ST5/00219)]. K. A. thanks the National Research Centre-
Egypt for supporting the work.
References
[1] Caramella P, Grünanger P. Nitrile oxides and imines. In: Padwa A, editor. 1,3-Dipolar cycload-
dition chemistry. New York: John Wiley & Sons; 1984. p. 291–392.
[2] Sharp JT. Nitrile ylides and nitrile imines. In: Padwa A, Pearson WH, editors. Synthetic appli-
cations of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products. New
York: John Wiley & Sons; 2002. p. 473–537.
[3] Toubro NH, Holm A. Nitrilimines. J Am Chem Soc. 1980;102:2093–2094.
[4] Meier H, Heinzelmann W, Heimgartner H. Direct detection of diphenylnitrilimine in the
photolysis of 2,5-diphenyltetrazole. Chimia. 1980;34:504–506.
[5] Bégué D, Qiao GGH, Wentrup C. Nitrile imines: matrix isolation, IR spectra, structures, and
rearrangement to carbodiimides. J Am Chem Soc. 2012;134:5339–5350.
[6] Réau R, Veneziani G, Dahan F, et al. An easy synthesis of nitrilimine. Crystal structure
analysis of a unheteroatom substituted stabilized nitrilimine. Angew Chem Int Ed Engl.
1992;31:439–440.
[7] Sicard G, Baceiredo A, Bertrand G. Synthesis and reactivity of a stable nitrile imine. J Am Chem
Soc. 1988;110:2663–2664.
[8] Granier M, Baceiredo A, Bertrand G. The first direct proof of a nitrilimine-diaza isomer-
ization. Synthesis of a relatively stable N-silylated nitrilimine. Angew Chem Int Ed Engl.
1988;27:1350–1351.
[9] Arthur MP, Baceiredo A, Fischer J, et al. Substitution reactions at nitrilimine skeletons.
Synthesis. 1992;43–45.
[10] Bertrand G, Wentrup C. Nitrile imines: from matrix characterization to stable compounds.
Angew Chem Int Ed Engl. 1994;33:527–545.
[11] Huisgen R, Fišera L, Giera H, et al. Thiones as superdipolarophiles: rates and equilibra of
nitrone cycloadditions to thioketones. J Am Chem Soc. 1995;117:9671–9678.
[12] Huisgen R, Grashey R, Seidel M, et al. 1,3-Dipolar addition. III. Reaction of diphenylnitrilimine
with carbonyl und thiocarbonyl compounds. Liebigs Ann Chem. 1962;658:169–180.
[13] Dunstan JBF, Elsey GM, Russell RA, et al. Dipolar cycloaddition reactions of nitrilimines. Aust
J Chem. 1998;51:499–510.
[14] Itto MYA, Feddouli A, Boutalib A, et al. Highly diastereoselective cycloaddition of diarylnitril-
imines to the C = S bond of (1R)-thiocamphor as a source of chiral spiro-1,3,4-thiadiazoles. J
Sulfur Chem. 2013;34:250–258.
[15] Katada T, Eguchi S, Sasaki T. Thermal cycloaddition reactions of thiocarbonyl compounds. Part
2. 1,3-Dipolar cycloaddition reactions of adamantanethione with nitrile oxides, nitrilimines,
and diazoalkanes. J Chem Soc Perkin Trans 1. 1984;2641–2647.
[16] Korchevin NA, Usov VA, Voronkov MG, et al. α,β-Unsaturated sulfur compounds. XX. [2 +
3]-Cycloaddition of 3-amino-2-aryl-1-indenethiones to nitrilium betaines and azidobenzene.
Zh Org Khim. 1986;22:1276–1282.
[17] Linden A, Awad EMAH, Heimgartner H. A rhodanine derivative and its cycloadduct with
diphenyl nitrile imine. Acta Crystallogr Sect C. 1999;55:1877–1881.
[18] Caleb AA, Ballo D, Rachid B, et al. Synthesis and antibacterial activity of new spiro[thiadiazoline-
quinoxaline] derivatives. Arkivoc. 2011;2011(2):217–226.
[19] Mlostoń G, Grzelak P, Hamera-Fałdyga R, et al. Aryl, hetaryl, and ferrocenyl thioketones as
versatile building blocks for exploration in the organic chemistry of sulfur. Phosphorus Sulfur
Silicon Relat Elem. 2017;192:204–211.
[20] Mlostoń G, Urbaniak K, Linden A, et al. Selenophene-2-yl-substituted thiocarbonyl ylides – at
the borderline of dipolar and biradical reactivity. Helv Chim Acta. 2015;98:453–461.

10
K. A. ALI ET AL.
[21] McKee ML, Mlostoń G, Urbaniak K, et al. Dimerization reactions of aryl selenophen-2-yl-
substituted thiocabonyl S-methanides as diradical processes: a computational study. Beilstein
J Org Chem. 2017;13:410–416.
[22] Grzelak P, Utecht G, Jasiński M, et al. First (3+2)-cycloadditions of thiochalcones as C = S
dipolarophiles: efficient synthesis of 1,3,4-thiadiazoles via reactions with fluorinated nitrile
imines. Synthesis. 2017;49:2129–2137.
[23] Mlostoń G, Urbaniak K, Utecht G, et al. Trifluoromethylated 2,3-dihydro-1,3,4-thiadiazoles
via the regioselective [3+2]-cycloadditions of fluorinated nitrile imines with aryl, hetaryl, and
ferrocenyl thioketones. J Fluorine Chem. 2016;192:147–154.
[24] Dogan HN, Duran A, Rollas S, et al. Synthesis of new 2,5-disubstituted-1,3,4-thiadiazoles
and preliminary evaluation of anticonvulsant and antimicrobial activities. Bioorg Med Chem.
2002;10:2893–2898.
[25] Hu Y, Li C-Y, Wang X-M, et al. 1,3,4-Thiadiazole. Synthesis, reactions, and applications in
medicinal, agricultural, and materials chemistry. Chem Rev. 2014;114:5572–5610.
[26] Johnson CK. ORTEP II, Report ORNL-5138, Oak Ridge National Laboratory. Oak Ridge,
Tennessee; 1976.
[27] Huisgen R, Seidel M, Wallbillich G, et al. Diphenylnitrilimine and its 1,3-dipolar additions to
alkenes und alkynes. Tetrahedron. 1962;17:3–29.
[28] Spiteri C, Keeling S, Moses JE. New synthesis of 1-substituted-1H-indazoles via 1,3-dipolar
cycloaddition of in situ generated nitrile imines and benzyne. Org Lett. 2010;12:3368–3371.
[29] Mlostoń G, Pipiak P, Linden A, et al. Studies on the reactions of thiocarbonyl S-methanides
with hetaryl thioketones. Helv Chim Acta. 2015;98:462–473.
[30] Mlostoń G, Pipiak P, Heimgartner H. Diradical reaction mechanism in [3+2]-cycloadditions
of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes. Beilstein J Org
Chem. 2016;12:716–724.
[31] Mlostoń G, Urbaniak K, Gębicki K, et al. Hetaryl thioketones. Synthesis and selected reactions.
Heteroatom Chem. 2014;25:548–555.
[32] Patel HV, Vyas KA, Pandey SP, et al. Facile synthesis of hydrazonyl halides by reaction of hydra-
zones with N-halosuccinimide-dimethyl sulfide complex. Tetrahedron. 1996;52:661–668.
[33] Ali KA, Ragab EA, Kamal M, et al. Synthetic access to some new benzothiazole-based 1,3,4-
thiadiazole and 1,3-thiazole derivatives. Turk J Chem. 2016;40:277–282.
[34] CCDC-1544688 and 1544689 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/structures.
[35] Hooft R. KappaCCD collect software. Delft (The Netherlands): Nonius BV; 1999.
[36] Otwinowski Z, Minor W. Chapter. In: Carter Jr CW, Sweet RM, editors. Methods in enzy-
mology, Vol. 276, macromolecular crystallography, Part A. New York: Academic Press; 1997.
p. 307–326.
[37] Blessing RH. An empirical correction for absorption anisotropy. Acta Crystallogr Sect A.
1995;51:33–38.
[38] Sheldrick GM. A short history of SHELX. Acta Crystallogr Sect A. 2008;64:112–122.
[39] Maslen EN, Fox AG, O’Keefe MA. In: Wilson AJC, editor. International tables for crystallo-
graphy. Vol. C. Dordrecht: Kluwer Academic; 1992. Table 6.1.1.1; p. 477–486.
[40] Stewart RF, Davidson ER, Simpson WT. Coherent X-ray scattering for the hydrogen atom in
the hydrogen molecule. J Chem Phys. 1965;42:3175–3187.
[41] Ibers JA, Hamilton WC. Dispersion corrections and crystal structure refinements. Acta Crys-
tallogr. 1964;17:781–782.
[42] Creagh DC, McAuley WJ. In: Wilson AJC, editor. International tables for crystallography. Vol.
C. Dordrecht: Kluwer Academic; 1992. Table 4.2.6.8. p. 219–222.
[43] Creagh DC, Hubbell JH. In: Wilson AJC, editor. International tables for crystallography. Vol.
C. Dordrecht: Kluwer Academic; 1992. Table 4.2.4.3. p. 200–206.
[44] Sheldrick GM. Crystal structure refinement with SHELXL. Acta Crystallogr Sect C.
2015;71:3–8.