Thiocyanation of alkylanilines. A simple and efficient synthesis of thiosulfonates containing 2-aminobenzothiazole

Article abstract of DOI:10.1016/S0040-4039(00)00591-8

Thiocyanation of anilines was used to introduce a thiol functionality and to construct the aminothiazole ring, all in a single step. A systematic study of thiocyanation of alkyl anilines was investigated to understand the regio-chemistry of the reaction. X-Ray crystal structures of two 2- aminobenzothiazoles were determined to assign the structures without any ambiguity. The intermediates obtained were further expanded to thiosulfonates containing 2-aminobenzothiazoles, which are extremely valuable intermediates to synthesize HIV protease inhibitors. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00591-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4065–4068
Thiocyanation of alkylanilines. A simple and efficient synthesis
of thiosulfonates containing 2-aminobenzothiazole
J. V. N. Vara Prasad,∗ A. Panapoulous and John R. Rubin
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company,
2800 Plymouth Road, Ann Arbor, Michigan 48106, USA
Received 4 February 2000; revised 22 March 2000; accepted 23 March 2000
Abstract
Thiocyanation of anilines was used to introduce a thiol functionality and to construct the aminothiazole ring,
all in a single step. A systematic study of thiocyanation of alkyl anilines was investigated to understand the regio-
chemistry of the reaction. X-Ray crystal structures of two 2-aminobenzothiazoles were determined to assign the
structures without any ambiguity. The intermediates obtained were further expanded to thiosulfonates containing
2-aminobenzothiazoles, which are extremely valuable intermediates to synthesize HIV protease inhibitors. © 2000
Elsevier Science Ltd. All rights reserved.
Recently we described a non-peptide (1, PD 178390) as a lead inhibitor of Human Immunodeficiency
Virus-1 protease possessing a 3-SPh(2-tert-butyl-4-hydroxymethyl-5-methyl) moiety.1 The synthesis of
1 involves the reaction of an appropriately substituted 5,6-dihydropyran-2-one with the corresponding
thiosulfonate (Eq. (1)).2 We have been interested in replacing the 3-SPh(2-tert-butyl-4-hydroxymethyl-5-
methyl) moiety with 3-S-2-alkyl-benzoheterocycle to study the resulting structure–activity relationships.
Though thiosulfonates have been used extensively in the literature,3,4 thiosulfonates containing 2-
aminobenzothiazoles are not yet known. Herein we describe a simple and efficient synthesis of such
thiosulfonates.
(1)
Anilines (3–9) were chosen as the starting materials for the synthesis of these thiosulfonates. It is
known that aromatic hydrocarbons having strong electron-donating groups such as -OH or NH2 groups
∗
Corresponding author. E-mail: josyula.varaprasad@wl.com (J. V. N. Vara Prasad)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00591-8
tetl 16870

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react with thiocyanogen (formed in situ from KSCN and Br2) to yield aryl thiocyanates resulting in ortho
and/or para thiocyanato products.5–10 The thiocyanate functionality was chosen due to the fact that it
could be useful as a masked thiol group and also due to the reactivity of the thiocyanate group with
an amine functionality to form an aminothiazole ring. Thus, thiocyanation of anilines resulted in the
introduction of the thiol functionality and formation of the aminothiazole ring in a single step. Finally,
thiocyanate functionality could be converted to thiol as shown in Scheme 1.
Scheme 1.
Initially, thiocyanation of alkyl-substituted anilines was studied in order to understand the regioselec-
tivity of the reaction, and the results are shown in Table 1. meta-tert-Butyl11 and iso-propyl anilines (3
and 4) yielded products 10 and 11, respectively, in excellent yields. No other regioisomers were obtained.
However, m-toluidine (5) gave a mixture of two regioisomers (12 and 13) in the ratio of 1:4, resulting
from the thiocyanation of both the ortho positions with the respect to the amine group. The structures
and the ratio of the regioisomers were confirmed by 1D-NOE, INEPT and APT experiments. From these
results, it appears that thiocyanation on the other ortho-position with respect to the amino group was
prevented in the case of m-tert-butyl and iso-propylanilines due to the bulkiness of the alkyl groups.
This was further confirmed by the lack of dithiocyanation and/or aminothiazole ring formation when
5-tert-butyl-2-methylaniline (6) was exposed to similar reaction conditions.12 Thus compound 6 yielded
14 as the only product. However, when 5-iso-propyl-2-methylaniline (7) was subjected to thiocyanation
reaction conditions, 15 was formed along with the monothiocyanation product, 16, in a smaller amount.
Interestingly, when p-tert-butylaniline (8) and p-toluidine (9), were subjected to thiocyanation reaction
conditions; 17 and 18, respectively, were isolated resulting from only ortho-thiocyanation at both the
ortho positions of the amine group. The structures of 17 and 18 were confirmed by 1D-NOE, INEPT
and APT experiments. Final conformation of the structures 10 and 15 were obtained by X-ray crystal
structure determination (Fig. 1).
Thiocyanates (10, 11, 15, 17) were converted into the corresponding thiosulfonates in two steps (Eq.
(2)): (a) transformation of the thiocyanate functionality to thiol by treating with dithiothreitol (DTT); (b)
conversion of thiol to the corresponding thiosulfonate by treatment with tosyl bromide13 in the presence
of a weak base like pyridine. In step (b), although the amine functionality of the aminobenzothiazole was
not protected, no sulfonamides arising from the amine were noticed.
(2)

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Table 1
The heterocyclic thiosulfonates (19, 20, 21, 22) prepared were coupled successfully with various 6,6-
disubstituted-5,6-dihydro-pyran-2-ones in the presence of potassium carbonate in DMF as described in
Eq. (1). HIV protease and anti-HIV activities and their pharmacokinetic data of 5,6-dihydropyran-2-ones
containing 3-position aminobenzothiazoles will be published in due course.

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Fig. 1. X-Ray structures of 10 and 15
Acknowledgements
We thank Dr. John M. Domagala for his encouragement and Dr. Brain Tobias for conducting NMR
experiments.
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