Synthesis and reactivity of benzoxa(thia)zol-2-thiones: New route to 2- alkylthiobenzoxa(thia)zoles

Article abstract of DOI:10.1016/S0040-4039(00)00758-9

The reaction of aromatic primary amines 1 with carbon disulfide in the presence of a catalytic amount of triethylamine followed by treatment with aqueous hydrogen peroxide leads to the corresponding benzoxa-(thia)zol-2- thiones 3a-c which can be transformed with iminoethers into 2- alkylthiobenzoxa(thia)zoles 5a-h in good yields (64-85%). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00758-9

Tetrahedron Letters 41 (2000) 5833±5835
Synthesis and reactivity of benzoxa(thia)zol-2-thiones: new
route to 2-alkylthiobenzoxa(thia)zoles
Abdallah Harizi, Anis Romdhane and Zine Mighri*
Á
Â
Laboratoire de chimie des substances naturelles et de synthese organique, Departement de chimie,
Â
Faculte des Sciences de Monastir, 5019 Monastir, Tunisie
Received 17 March 2000; accepted 10 May 2000
Abstract
The reaction of aromatic primary amines 1 with carbon disul®de in the presence of a catalytic amount of
triethylamine followed by treatment with aqueous hydrogen peroxide leads to the corresponding benzoxa-
(thia)zol-2-thiones 3a±c which can be transformed with iminoethers into 2-alkylthiobenzoxa(thia)zoles 5a±h
in good yields (64±85%). # 2000 Elsevier Science Ltd. All rights reserved.
The 2-alkylthiobenzoxa(thia)zoles 5 are crucial heterocyclic substances which have been used
intensively in medicinal chemistry and prepared by several ways.1 In addition, benzoxazole- and
benzothiazole-based compounds have shown diverse biological activities.2 4 As a part of our
ongoing work on the use of imidates in heterocyclic synthesis,5 we report here a new and
convenient synthesis of 2-alkylthiobenzoxa(thia)zoles 5 from reaction of phenylimidates with
benzoxa(thia)zol-2-thiones 3.
In order to prepare 2-hydroxy(or 2-mercapto)phenyl isothiocyanates 2 and study their
reactivity with imidates, we used the method of Tajima and Li.6 In fact, the reaction of 2-hydroxy
or 2-mercaptophenol with carbon disul®de followed dehydrosulfurization with aqueous hydrogen
peroxide but did not lead to the isothiocyanates 2. These intermediates spontaneously cyclized
and could not be isolated6,7 even on changing the reaction conditions where temperature was less
than 0ꢀC and/or a double quantity of acid was used. In all cases the reaction led directly to the
corresponding benzoxa(thia)zol-2-thiones 3a±c8 known as bactericides.9
It has already been proposed10,11 that there was a tautomeric equilibrium between these
structures and that the thione forms were predominant.
The reaction of benzoxa(thia)zol-2-thiones 3 with iminoethers5 in re¯uxing THF provided the
desired 2-alkylthiobenzoxa(thia)zoles 5 followed by elimination of benzamide. It is conceivable
that the reaction starts by the addition of the SH group on the CˆN double bond of the
* Corresponding author. Fax: 216 03 500 0278; e-mail: zine.mighri@fsm.rnu.tn
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00758-9

5834
iminoether to give the intermediate 4. These species rearranged by an intramolecular s-alkylation
to yield compounds 5. A possible mechanism of this reaction is shown in Scheme 1.
Scheme 1.
In order to ®nd out the best conditions for the synthesis of compounds 5, we examined the
reaction under various conditions by changing the temperature, the solvent and the catalyst; we
found that the best yields were obtained when compounds 3 and phenyl imidate were heated
under re¯ux of THF; we note that the use of a catalytic amount of acid or base did not give
satisfactory results (less than 10%).
The reaction was conducted until TLC indicated that the starting materials have been
completely converted. The puri®cation was performed by silica-gel column chromatography
(chloroform:ethyl acetate, 80:20) to give, after elimination of the benzamide, a light oil identi®ed
as the product 5.
1
The structures of compounds 3 and 5 have been assigned from their analytical data, IR, H
1
NMR, 13C NMR and mass spectroscopy.8,12 In fact, the H NMR spectra of product 5 showed:
(i) the absence of any D2O exchangeable signals; and (ii) the presence of the signals corresponding
to the introduced R0 groups. The IR spectra also revealed the absence of absorbance due to NH
or SH bands. The mass spectra showed essentially the molecular peak (M+Á) and the 13C NMR
spectra of these compounds were also in agreement with the proposed structures.
In conclusion, we present an ecient method for the preparation of benzoxa(thia)zol-2-thiones
3 which react with phenylimidates to give 2-alkylthiobenzoxa(thia)zoles 5 with good yields. The
reaction of compounds 3 with other N-substituted imidates is actually under progress.

5835
References
1. Sidoova, E.; Odlerova, Z. Czech. CS 257, 398 (cl. Co7 D277/74, 15 December, 1988; Appl. 87/926, 12 February,
1987). Chem. Abstr. 1989, 111, 214475t.
2. Arcay, N.; Safak, C.; Abbasoglu, U. Hacettepe. Univ. Eczacilik Fak. Derg. 1992 12, 33±46. Chem. Abstr. 1993, 119,
139159c.
3. Aichaoui, H.; Lesieur, D.; Henichart, J. P. J. Heterocyclic Chem. 1992, 29, 171±175.
4. Maleski, R. I.; Osborne, C. E.; Cline, S. M. J. Heterocyclic Chem. 1991, 28, 1937±1939.
5. (a) Harizi, A.; Hajjem, B.; Zantour, H.; Baccar, B. J. Soc. Chim. Tunisie 1995, 10, 683±691. Chem. Abstr. 1996,
124, 289482v. (b) Harizi, A.; Hajjem, B.; Baccar, B. Revue Roumaine de Chimie 1998, 43, 35±40.
6. Tajima, H.; Li, G. Synlett 1997, 7, 773±774.
7. Somerville, W. T.; Andersen, C. N. J. Org. Chem. 1960, 25, 656±657. Chem. Abstr. 1960, 54, 18476d.
8. Benzoxa(thia)zol-2-thiones: compound 3 are synthesized according to Tajima's porcedure;6 compound 3a: mp
191ꢀC; IR (CHCl3) 1200, 3220 cm^1; H NMR (300 MHz, CDCl3) ꢀ 7.5 (m, 4H), 8.2 (s, 1H, NH); 13C NMR (75
1
MHz, CDCl3) ꢀ 121, 123.5, 125.4, 128.0, 135.5, 138.2, 176.2; compound 3b: mp 148ꢀC; IR (CHCl3) 1180, 3180
1
cm^1; H NMR (300 MHz, CDCl3) ꢀ 7.5 (m, 3H), 8.8 (s, 1H, NH); 13C NMR (75 MHz, CDCl3) ꢀ 120.3, 123.2,
125.1, 127.8, 135.2, 138.4, 168.7; compound 3c: mp 167ꢀC; IR (CHCl3) 1200, 3170 cm^1; H NMR (300 MHz,
1
CDCl3) ꢀ 7.5 (m, 4H), 10.3 (s, 1H, NH); 13C NMR (75 MHz, CDCl3) ꢀ 120.2, 123.2, 124.8, 128.2, 135.3, 138.4,
175.6.
9. Sidoova, E.; Odlerova, Z. Czech. CS 257, 399 (cl. Co7 D277/70, 15 December, 1988; Appl. 87/927, 12 February,
1987). Chem. Abstr. 1989, 111, 214476u.
10. Acharya, T. E.; Dhal, P. N.; Nayak, A. J. Inst. Chem. Calcutta. 1972, 44, 166±169. Chem. Abstr. 1973, 79, 5296s.
11. Durust, Y.; Nohut, F. Synth. Commun. 1999, 29, 1997±2005.
12. Synthesis of 2-alkylthiobenzoxa(thia)zoles 5. Compound 5a: oil; IR (CHCl3) 1640 cm^1; 1H NMR (300 MHz,
CDCl3) ꢀ 2.9 (s, 3H), 7.5 (m, 4H); 13C NMR (75 MHz, CDCl3) ꢀ 22.0, 120.6, 123.3, 125.1, 128.5, 135.3, 138.4,
175.2; MS (70 eV) m/z (%) 165 (100), 150 (20), 132 (90), 122 (82), 63 (21); compound 5b: oil; IR (CHCl3)
1
1640 cm^1; H NMR (300 MHz, CDCl3) ꢀ 1.0 (t, J=6.9, 3H), 1.9 (m, 2H), 3.3 (t, J=6.9, 2H), 7.5 (m, 4H); 13C
NMR (75 MHz, CDCl3) ꢀ 13.5, 22.6, 35.4, 120.3, 123.5, 125.2, 128.4, 135.0, 138.2, 174.8; MS (70 eV) m/z (%) 193
(8), 151 (100), 122 (7); compound 5c: oil; IR (CHCl3) 1635 cm^1; 1H NMR (300 MHz, CDCl3) ꢀ 1.1 (d, J=7, 6H),
2.2 (m, 1H), 7.5 (m, 4H); 13C NMR (75 MHz, CDCl3) ꢀ 19.2, 70.1, 120.5, 123.2, 125.6, 128.3, 135.0, 138.2, 175.2;
MS (70 eV) m/z (%) 193 (5), 151 (100), 122 (8), 41 (10); compound 5d: oil; IR (CHCl3) 1640 cm^1; 1H NMR (300
MHz, CDCl3) ꢀ 1.1 (t, J=7, 3H), 3.2 (q, J=7, 2H), 7.5 (m, 3H); 13C NMR (75 MHz, CDCl3) ꢀ 15.5, 43.0, 119.8,
123.0, 125.6, 128.2, 135.7, 138.2, 174.7; MS (70 eV) m/z (%) 213 (65), 185 (100), 156 (36), 63 (12); compound 5e:
oil; IR (CHCl3) 1635 cm^1; 1H NMR (300 MHz, CDCl3) ꢀ 1.1 (d, J=7, 6H), 2.2 (m, 1H), 7.5 (m, 3H); 13C NMR
(75 MHz, CDCl3) ꢀ 19.2, 70.1, 120.5, 123.0, 125.3, 127.8, 134.9, 138.2, 175.2; MS (70 eV) m/z (%) 227 (4), 185
(100), 156 (8), 41 (12); compound 5f: oil; IR (CHCl3) 1640 cm^1; 1H NMR (300 MHz, CDCl3) ꢀ 2.3 (s, 3H), 7.5 (m,
4H); 13C NMR (75 MHz, CDCl3) ꢀ 22.0, 121.2, 123.7, 125.6, 128.1, 135.5, 138.2, 174.3; MS (70 eV) m/z (%) 181
1
(100); compound 5g: oil; IR (CHCl3) 1640 cm^1; H NMR (300 MHz, CDCl3) ꢀ 1.0 (t, J=6.9, 3H), 1.9 (m, 2H),
3.3 (t, J=6.9, 2H), 7.5 (m, 4H); 13C NMR (75 MHz, CDCl3) ꢀ 13.5, 22.6, 35.4, 120.4, 123.4, 125.5, 128.4, 135.6,
138.6, 174.0; MS (70 eV) m/z (%) 209 (22), 194 (14), 167 (100), 108 (15); compound 5h: oil; IR (CHCl3) 1635 cm^1;
1H NMR (300 MHz, CDCl3) ꢀ 1.1 (d, J=7, 6H), 2.2 (m, 1H), 7.5 (m, 4H); 13C NMR (75 MHz, CDCl3) ꢀ 19.2, 70.1,
120.5, 123.5, 125.3, 128.5, 135.7, 138.3, 173.7; MS (70 eV) m/z (%) 209 (2), 123 (68), 105 (100), 77 (38), 56 (12).