An unexpected result of the reaction of benzothioamide derivatives with 2-aryl-2-bromoacetonitriles

Article abstract of DOI:10.1002/hlca.201100110

Unexpectedly, in the reaction of 2-bromo-2-phenylacetonitrile derivatives with 2 mol-equiv. of benzothioamide in DMSO, 3,5-diaryl-1,2,4-thiadiazoles were obtained in excellent yields (83-90%) and in short reaction times (5-10 min). It is found that, in DMF, a quite different reaction takes place and 2,5-diaryl-1,3-thiazol-4-amines are formed as the main products. Copyright

Full text of DOI:10.1002/hlca.201100110

Helvetica Chimica Acta – Vol. 94 (2011)
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An Unexpected Result of the Reaction of Benzothioamide Derivatives with
2-Aryl-2-bromoacetonitriles
by Hassan Zali Boeini* and Mehdi Mobin
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, Iran
(phone: þ 98-311-7932715; fax: þ 98-311-6689732; e-mail: h.zali@chem.ui.ac.ir)
Unexpectedly, in the reaction of 2-bromo-2-phenylacetonitrile derivatives with 2 mol-equiv. of
benzothioamide in DMSO, 3,5-diaryl-1,2,4-thiadiazoles were obtained in excellent yields (83 – 90%) and
in short reaction times (5 – 10 min). It is found that, in DMF, a quite different reaction takes place and
2,5-diaryl-1,3-thiazol-4-amines are formed as the main products.
Introduction. – In continuation of our research in developing novel synthetic routes
for the preparation of sulfur heterocycles using thioamides [1 – 14], we report here on
unexpected and unprecedented results of the reaction of benzothioamide with 2-
bromo-2-phenylacetamide derivatives in DMSO and/or DMF.
Results and Discussion. – It was found that a mixture of benzothioamides 1 and
2 mol-equiv. of an 2-bromo-2-phenylacetamide derivative 2 at 608 in DMSO leads to
the corresponding 3,5-diaryl-1,2,4-thiadiazoles 3 in short time (6 min; Scheme 1) with
an efficient conversion (83 – 90% yield).
Scheme 1
The study was started by examining the reaction of 3-bromobenzenecarbothio-
amide (1a) as a test substrate with 2-bromo-2-phenylacetonitrile (2a) in DMSO.
Fortunately, the course of the reaction could be followed even visually. At the outset of
the reaction, a yellow color is visible due to presence of the benzothioamide in the
mixture. After 2 min heating at 608, the mixture turns orange and then changes to red
within a further 3 min heating. Finally, a rapid and exothermic reaction takes place
within 1 min leading to the corresponding 3,5-bis(3-bromophenyl)-1,2,4-thiadiazole
(3a) in 90% yield.
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
A mechanism for the reaction is proposed based on a report of Takikawa et al. [9]
(Scheme 2). It seems that the bromo(dimethyl)sulfonium ion (5), formed by reaction
of DMSO with 2, is the active intermediate in the reaction. Meanwhile, benzothioamide
1 undergoes an S-bromination with this reactive intermediate to produce, after loss of
Me2S, 6, which, after releasing HBr and sulfur affords the S-brominated compound 7.
Finally, this undergoes intermediate cyclization to the corresponding 3,5-diaryl-1,2,4-
thiadiazole 3, alongside elimination of HBr.
Scheme 2
As shown, DMSO has a vital function in the course of the reaction because it plays
the role as reagent and solvent. The proposed mechanism was supported by isolation of
mandelonitrile as by-product. Fortunately, mandelonitrile was soluble in the reaction
media, and the corresponding thiadiazole precipitated as fine crystals. To isolate the
pure product, cold MeOH was added, and the mixture was filtered. Compounds 2 with
three differently substituted phenyl groups were reacted with benzothioamide 1 to
assess the effect of the substituents on the course of the reaction. The results are
compiled in Table 1.
Six different benzothioamide derivatives, 1a – 1f, were probed to evaluate the scope
of this new synthetic approach. The results are collected in Table 2.
Unexpectedly, a different result was obtained, when the reaction of 4-chloroben-
zenecarbothioamide (1g) with 2-bromo-2-phenylacetonitrile (2a) was carried out in a
small amount of DMF as solvent. In this case, the reaction proceeded at room
temperature leading to 2-(4-chlorophenyl)-5-phenyl-1,3-thiazol-4-amine (8a) as the
major product (84% yield). As shown in the mechanism proposed in Scheme 3,
formation of compound 8a can be attributed to a different pathway followed under this
condition.
Conclusions. – In summary, an unexpected result of the reaction of benzothioamide
derivatives with 2-bromo-2-phenylacetonitrile in different solvents was observed. The
novel reaction could be successfully employed for the mild, rapid, and efficient
conversion of benzothioamide derivatives to the corresponding thiadiazoles or thiazol-

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Table 1. Preparation of Compound 3a from 1a and 2a – 2c.
Entry
2
Ar
Solvent
Yielda) [%]
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
Ph
Ph
DMSO
Dioxane
DMSO
Dioxane
DMSO
Dioxane
90
16
88
17
80
12
4-ClꢀC6H4
4-ClꢀC6H4
4-NO2ꢀC6H4
4-NO2ꢀC6H4
a) Pure isolated products.
Table 2. Oxidative Cyclization of Benzothioamides Using 2-Bromo-2-phenylacetonitrile (2a)
Entry
Ar
1
Time [min]
Product 3a)
Yieldb) [%]
1
2
3
4
5
6
3-BrꢀC6H4
4-BrꢀC6H4
2-ClꢀC6H4
3-ClꢀC6H4
4-FꢀC6H4
1a
1b
1c
1d
1e
1f
6
6
8
7
8
8
3a
3b
3c
3d
3e
3f
90
90
88
89
83
85
2,4-Cl2ꢀC6H3
a) All products were characterized by 1H- and 13C-NMR spectroscopy. b) All yields refer to pure isolated
products.
4-amines depending on the choice of solvent. The significance of the presented method
lies in the simplicity of performing the reaction and the isolation of the product. To the
best of our knowledge, the method also seems to be one of the simplest and the fastest
routes for the preparation of 3,5-diaryl-1,2,4-thiadiazoles and/or 2,5-diarylthiazol-4-
amines so far investigated.

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 3
Experimental Part
General. All solvents were dried and distilled before use according to standard procedures. M.p.: in
sealed capillaries; uncorrected. Anal. TLC: silica gel (SiO2; Merck 60 F254) coated on aluminum plates;
visualization by UV and with aq. KMnO4 soln. IR Spectra: UR-20 spectrometer; KBr pellets; ˜n in cmꢀ1
.
1H- and 13C-NMR spectra in CDCl3 and (D6)DMSO on Bruker AMX-500 spectrometers: d in ppm rel. to
Me4Si as internal standard, J in Hz.
Caution: All experiments should be carried out in an efficient hood to avoid exposure to very
unpleasant Me2S vapors. All 2-bromo-2-phenylacetonitriles are highly lachrymatory, and skin-irritant
compounds should be handled with great care.
General Procedure for the Preparation of 2-Bromo-2-phenylacetonitriles 2. In a 100-ml round-
bottom flask, phnelyacetonitrile derivative (50 mmol) in dry toluene (50 ml) was dissolved and heated to
908. Thereafter, Br2 (52 mmol, 8.32 g, 2.67 ml) was added dropwise during 20 min with vigorous stirring.
Heating was continued for a further 40 min. Then, the mixture was cooled to r.t., washed with NaHCO3
soln. (5%, 2 ꢁ 25 ml), and then with H2O (2 ꢁ 50 ml). The org. phase was dried (MgSO4), and the solvent
was removed under reduced pressure to obtain the 2-bromo-2-phenylacetronitrile derivative.
General Procedure for the Preparation of 3,5-Diaryl-1,2,4-thiadiazoles 3a – 3e. Benzothioamide 1
(3 mmol) and 2 (1.5 mmol) was dissolved in DMSO (1 ml) and heated at 608 for the times noted in
Table 2. After completion of the reaction (TLC) and cooling to ambient temp., the mixture was poured
into MeOH/H2O 85 :15 (4 ml), and the resulting crystals of the product were filtered, washed with
MeOH/H2O 1:1 (2 ꢁ 5 ml), and dried to obtain pure compound as white crystals.
General Procedure for the Preparation of 2,5-Diarylthiazol-4-amines 8. Benzothioamide 1 (3 mmol)
and 2 (3 mmol) were dissolved in DMF (1 ml) and stirred at r.t. for 20 min. Thereafter, the mixture was
poured into H2O (5 ml), and the crude precipitated product was filtered. The product was purified by
crystallization from AcOEt/Et2O to afford compound 8 as deep yellow crystals.
3,5-Bis(3-bromophenyl)-1,2,4-thiadiazole (3a). Yield: 533 mg (90%). White crystals. IR: 2941, 2857,
1
1581, 763. H-NMR: 8.51 (s, 1 H); 8.32 (d, J ¼ 8.7, 1 H); 8.21 (s, 1 H); 7.93 (dd, J ¼ 8.4, 1.5, 1 H); 7.68
(ddd, J ¼ 8.4, 1.5, 0.8, 1 H); 7.60 – 7.68 (m, 2 H); 7.35 – 7.42 (m, 2 H). 13C-NMR: 186.8; 172.4; 134.9; 134.5;
133.4; 130.8; 130.3; 126.9; 126.1; 123.4; 122.9. Anal. calc. for C14H8Br2N2S (396.10): C 42.45, H 2.04, N
7.07, S 8.10; found: C 42.28, H 1.99, N 7.15, S 8.31.
3,5-Bis(4-bromophenyl)-1,2,4-thiadiazole (3b). Yield: 534 mg (90%). White crystals. IR: 2985, 2843,
1593, 775. 1H-NMR: 8.24 (d, J ¼ 8.5, 2 H); 7.90 (d, J ¼ 8.5, 2 H); 7.66 (d, J ¼ 6.9, 2 H); 6.64 (d, J ¼ 6.9,

Helvetica Chimica Acta – Vol. 94 (2011)
2043
2 H). 13C-NMR: 187.2; 172.9; 132.8; 131.6; 129.8; 129.5; 128.8; 126.6; 125.1. Anal. calc. for C14H8Br2N2S
(396.10): C 42.45, H 2.04, N 7.07, S 8.10; found: C 42.30, H 2.01, N 7.10, S 8.25.
3,5-Bis(2-chlorophenyl)-1,2,4-thiadiazole (3c). Yield: 404 mg (88%). White crystals. IR: 2976, 2854,
1
1580, 784. H-NMR: 7.40 – 7.42 (m, 2 H); 7.46 – 7.48 (m, 2 H); 7.55 – 7.60 (m, 2 H); 8.05 (td, J ¼ 7.2, 2.2,
1 H); 8.65 (td, J ¼ 7.2, 2.1, 1 H). 13C-NMR: 126.8; 127.5; 129.6; 130.7; 130.8; 130.9; 132.1; 132.3; 133.3;
133.8; 173.2; 183.1. Anal. calc. for C14H8Cl2N2S (307.20): C 54.74, H 2.62, N 9.12, S 10.44; found: C 54.51,
H 2.45, N 9.05, S 10.55.
3,5-Bis(3-chlorophenyl)-1,2,4-thiadiazole (3d). Yield: 410 mg (89%). White crystals. IR: 2995, 2813,
1590, 751. 1H-NMR: 7.43 – 7.49 (m, 3 H); 7.52 – 7.54 (m, 1 H); 7.90 (d, J ¼ 7.6, 1 H); 8.07 (s, 1 H); 8.27 (d,
J ¼ 7.0, 1 H); 8.39 (s, 1 H). 13C-NMR: 125.7; 126.4; 127.3; 128.5; 130.0; 130.6; 132.0; 132.1; 134.3; 134.8;
135.5; 172.5; 186.9; Anal. calc. for C14H8Cl2N2S (307.20): C 54.74, H 2.62, N 9.12, S 10.44; found: C 54.60,
H 2.51, N 9.10, S 10.61.
3,5-Bis(4-fluorophenyl)-1,2,4-thiadiazole (3e). Yield: 341 mg (83%). White crystals. IR: 2998, 2855,
1
1602, 771. H-NMR: 7.16 – 7.24 (m, 4 H); 8.05 (ddd, J ¼ 11.9, 5.2, 2.8, 2 H); 8.38 (ddd, J ¼ 12.2, 6.7, 3.3,
2 H). 13C-NMR: 115.7; 116.5; 129.6; 130.4; 163.2; 163.9; 165.2; 166.0; 172.8; 187.0. Anal. calc. for
C14H8F2N2S (274.29): C 61.30, H 2.94, N 10.21, S 11.69; found: C 61.21, H 2.80, N 10.02, S 11.80.
3,5-Bis(2,4-dichlorophenyl)-1,2,4-thiadiazole (3f). Yield: 478 mg (85%). White needles. IR: 2971,
2839, 1597, 769. 1H-NMR: 7.40 (dd, J ¼ 8.4, 2.1, 1 H); 7.47 (dd, J ¼ 8.7, 2.1, 1 H); 7.58 (d, J ¼ 2.1, 1 H); 7.62
(d, J ¼ 2.1, 1 H); 8.04 (d, J ¼ 8.4, 1 H); 8.57 (d, J ¼ 8.7, 1 H). 13C-NMR: 120.7; 127.2; 128.1; 130.3; 130.8;
131.4; 133.1; 134.2; 134.4; 136.3; 136.4; 138.0; 173.2; 182.3. Anal. calc. for C14H6Cl4N2S (376.09): C 44.71,
H 1.61, Cl 37.71, N 7.45, S 8.53; found: C 44.60, H 1.54, N 7.37, S 8.74.
2-(4-Chlorophenyl)-5-phenyl-1,3-thiazol-4-amine (8a). Yield: 695 mg (81%). Yellow crystals. IR:
3330, 3276, 3039, 1615, 825. 1H-NMR (400 MHz, (D6)DMSO): 7.85 – 7.87 (d, J ¼ 8.4, 2 H); 7.53 – 7.55 (m,
4 H); 7.38 – 7.42 (t, J ¼ 7.6, 2 H); 7.20 – 7.24 (t, J ¼ 7.6, 1 H); 5.80 (s, 2 H). 13C-NMR (100 MHz,
(D6)DMSO): 160.5; 154.3; 134.8; 132.8; 132.3; 129.7; 129.5; 127.4; 126.3; 126.1; 106.1. Anal. calc. for
C15H11ClN2S (286.78): C 62.82, H 3.87, N 9.77, S 11.18; found: C 62.59, H 4.10, N 9.43, S 10.90.
5-(4-Chlorophenyl)-2-phenyl-1,3-thiazol-4-amine (8b). Yield: 720 mg (84%). Yellow crystals. IR:
1
3337, 3265, 3052, 1617, 761. H-NMR (400 MHz, (D6)DMSO): 7.85 – 7.87 (m, 2 H); 7.54 – 7.57 (m, 2 H);
7.45 – 7.50 (m, 5 H); 4.42 (s, 2 H). 13C-NMR (100 MHz, (D6)DMSO): 132.8; 132.3; 131.1; 129.8; 129.7;
129.5; 129.3; 128.0; 126.1. Anal. calc. for C15H11ClN2S (286.78): C 62.82, H 3.87, N 9.77, S 11.18; found: C
62.48, H 3.99, N 9.55, S 10.81.
2,5-Bis(4-chlorophenyl)-1,3-thiazol-4-amine (8c). Yield: 700 mg (73%). Yellow crystals. IR: 3424,
3341, 3018, 1596, 754. 1H-NMR (400 MHz, (D6)DMSO): 7.86 – 7.88 (d, J ¼ 8.4, 2 H); 7.54 – 7.57 (m, 4 H);
7.45 – 7.48 (d, J ¼ 8.4, 2 H); 6.62 (s, 2 H). 13C-NMR (100 MHz, (D6)DMSO): 162.3; 147.5; 135.5; 132.5;
131.6; 130.3; 129.9; 129.6; 129.5; 127.7; 114.2; Anal. calc. for C15H10Cl2N2S (321.22): C 56.09, H 3.14, N
8.72, S 9.98; found: C 55.89, H 3.36, N 9.43, S 10.90.
We are grateful to the Research Council of the University of Isfahan for financial support.
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Received March 15, 2011