Solid-Phase Synthesis of 2-Aminobenzothiazoles
A traceless solid supported protocol for the synthesis of 2-aminobenzothiazoles is described, employing resin-bound acyl-isothiocyanate and a series of anilines. Cyclization of the resulting N-acyl, N\xe2\x80\xb2-phenyl-thioureas generates the 2-aminobenzothiazole scaffold, which can be further elaborated prior to hydrazine-mediated cleavage of the final products from the carboxy-polystyrene resin. A small, focused library of 2-aminobenzothiazoles was prepared.
<p>Libraries of compounds based on diverse heterocyclic scaffolds comprise a key aspect of modern drug discovery. In this context, solid supported synthesis has proved to be a powerful tool leading to a wide-range of heterocyclic compounds.1 However, to the best of our knowledge, a procedure for the solid phase synthesis of 2-aminobenzothiazoles has not been reported. The 2-aminobenzothiazole scaffold is one of the "privileged" structures in medicinal chemistry.2 Indeed, various examples featuring this particular scaffold have been prepared, many exhibiting remarkable biological activities.3,4 Given the importance of this particular chemical entity to the field of medicinal chemistry, the development of improved and/or alternative methods for the rapid construction of libraries of derivatives is desirable. Although examples of solid supported synthesis of benzothiazoles have been reported,5,6 these methods are not applicable to 2-aminobenzothiazoles. We thus undertook a focused study to adapt previously disclosed methods for solution phase synthesis to the solid phase for this particular class of heterocycles.</p><p>The now classical synthesis of 6-substituted 2-aminobenzothiazoles entails treatment of 4-substituted anilines with potassium thiocyanate in the presence of bromine in acetic acid (Scheme 1 A).7 This method, however, is not generally applicable as thiocyanation in the para position of anilines is often the predominant reaction when 4-unsubstituted anilines are employed under these or similar oxidation conditions (Scheme 1 B).8,9 Alternative methods for the syntheses of 4, 5, 6, and 7 substituted 2-aminobenzothiazoles employ phenylthioureas as the synthetic precursors (Scheme 1 C). In these cases, heterocycle ring formation can be carried out, albeit non regioselectively, by treating the phenylthioureas with bromine in chloroform10 or acetic acid.11 Alternatively, regiospecific cyclizations can be performed via SNAri reactions, employing phenylthioureas obtained from the appropriate ortho-fluoroanilines in the presence of sodium methoxide.12 We report here adaptation of these reaction conditions onto solid support beginning with resin-bound isothiocyanate.</p><p>The resin-bound isothiocyanate 3 was prepared as previously described in two steps from carboxy-polystyrene (Scheme 2).13 Conversion of 3 to the N-acyl, N′-phenylthioureas of general structure 4 was then readily achieved upon treatment of 3 with the appropriate aniline at room temperature in N,N-dimethylformamide.14 This reaction can be conveniently monitored by infrared spectroscopy following the disappearance of the characteristic isothiocyanate band at ∼1910 cm-1 (Figure 1). When X = H cyclization of 4 to 2-acylaminobenzothiazole 5 was then performed by treatment with six equivalents of bromine in acetic acid (Scheme 2, Method A14). Alternatively, when X = F or Br, benzothiazoles obtained (e.g., entries e, and h Table 1), were formed by treatment of the corresponding N-acyl, N′-phenylthioureas with sodium hydride (Method B & C14) via an SNAri mechanism.</p><p>Finally, the desired 2-aminobenzothiazoles of general structure 6 were obtained in good overall yield and >85% purity upon treatment of 5 with 4% hydrazine monohydrate in ethanol (Table 1).14 Alternative TFA-mediated cleavage conditions were also investigated, however, the optimized hydrazine cleavage conditions proved more reliable, and generally proceeded with little or no trace of contaminants or by-products (cf., Figure 2).</p><p>As anticipated, when 3-subtituted anilines (e.g., entries c and f, Table 1) were employed, oxidative cyclization conditions (Method A) led to mixtures of two regioisomers (i.e., 5- and 7-substituted 2-aminobenzothiazoles); the relative ratio apparently determined by the steric encumbrance of the substituent in the meta position of the starting aniline. Thus, while 3-bromoaniline furnished a separable 1:1 mixture of 5- and 7-bromo-2-aminobenzothiazoles, under the above reaction conditions, the 3-phenylaniline generated a mixture (95:5) in favor of the 5-substituted-2-amino-benzothiazole (cf., entries c and f, Table 1), which could be readily separated and purified by column chromatography or crystallization. Single crystal X-ray analysis confirmed the structure of 6f (Figure 3).</p><p>Although mixtures of regioisomers are often acceptable in the generation of libraries for HTS, single isomers could be obtained when ring formation was performed via SNAri, as exemplified by entries e (Method B) and h (Method C); each proceeded regiospecifically to furnish the 7-chloro- and the 5-bromo-2-aminobenzothiazole 6e and 6h (Table 1), respectively.</p><p>Finally, in order to exemplify the utility of this synthetic protocol for the construction of libraries of 2-aminobenzothiazole derivatives, we evaluated representative resin-bound bromobenzothiazoles 5c and 5h as possible starting points for further structural elaboration. Thus, 5c and 5h were treated under either Suzuki15 or Buchwald-Hartwig16 conditions to yield products of cross-coupling. Representative examples of C–C, and C–N bond forming reactions are summarized in Table 2.</p><p>Both cross-coupling reactions were carried out under microwave promoted conditions. For these reactions, 0.05-0.1 mol% of Pd(PPh3)4 was found to be the preferred catalyst (cf., Table 3).</p><p>In summary, we have developed an effective method for the solid supported synthesis of 2-aminobenzothiazoles, with an application to the preparation of a focused library of 2-aminobenzothiazole derivatives.</p><p>IR spectra.</p><p>LC/MS Analysis of the crude reaction obtained after hydrazine-mediated cleavage (entry f, Table 1); A: photodiode array detector; B: total ion current; C: mass spectrum.</p><p>X-ray crystal structure of compound 6f (CCDC 753930).</p><p>Commonly employed methods for the solution phase synthesis of 2-aminobenzothiazoles (A and C); thiocyanation of 4-unsubstituted anilines upon treatment with potassium thiocyanate in the presence of bromine in acetic acid (B).</p><p>Reagents and Conditions: (a) oxalyl chloride, DCE, rt, 16 h; (b) Bu4NNCS, DCE/THF, rt, 16 h; (c) aniline, DMF, rt, 16 h; (d) For X = H, Method A: Br2 (6 eq.), acetic acid, rt, 16 h; for X = F, Method B: NaH (6 eq.), DMF, rt, 16 h; for X = Br, Method C: NaH (10 eq.), DMF, 100 °C, 16 h (e) hydrazine monohydrate, EtOH, 150 °C, MW, 30 min.</p><p>Representative examples of 2-aminobenzothiazoles prepared.</p><p>Overall yield after purification.</p><p>Approximately a 50:50 mixture of 5- and 7-bromo-2-aminobenzothiazoles;</p><p>Approximately a 95:5 mixture of 5- and 7-phenyl-2-aminobenzothiazole.</p><p>Representative examples of cross-coupling reactions.</p><p>Approximately a 50:50 mixture of 5- and 7-phenyl-2-aminobenzothiazoles (separable).</p><p>Cross-coupling reaction investigation.</p><p>Conversion of the starting material by LC-MS analysis after cleavage of the product.</p>