Article pubs.acs.org/joc
Synthesis of Imidazo[2,1‑b]thiazoles via Copper-Catalyzed A3‑Coupling in Batch and Continuous Flow Irina V. Rassokhina,† Tatyana A. Tikhonova,† Sergey G. Kobylskoy,‡ Igor Yu. Babkin,‡ Valerii Z. Shirinian,† Vladimir Gevorgyan,§ Igor V. Zavarzin,† and Yulia A. Volkova*,† ‡
Laboratory of High Technologies, Ltd, 86 prosp. Vernadskogo, 119571 Moscow, Russia Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Room 4500, Chicago, Illinois 60607, United States
§
S Supporting Information *
ABSTRACT: A straightforward method for the synthesis of functionalized imidazo[2,1-b]thiazoles starting from benzaldehydes, 2-aminothiazoles, and alkynes under copper(I,II) catalysis was developed. The protocol allows the construction of a variety of aryl-substituted imidazo[2,1-b]benzothiazoles, -[2,1-b]thiazoles, and -[2,1-b][1,3,4]thiadiazoles. The reactions were easy to perform affording most of the desired products in 33−93% yields. The intensification of the process in a continuous-flow reactor increases the products’ yields up to quantitative.
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INTRODUCTION Imidazo[2,1-b]thiazole is one of the most important fused sulfur-containing heterocycle widely found in a variety of biologically active agents (Figure 1),1 including a number of
bromides with 2-aminothiazole toward imidazo[2,1-b]thiazoles.13 Hajra and co-workers reported an elegant Fe/Zncocatalyzed aerobic oxidative cyclization of 2-aminobenzothiazole and chalcones. 14 In another report, Zhu et al. demonstrated a copper(II) acetate-promoted cycloaddition of α-methylenyl isocyanides with 2-methylbenzothiazole.15 The metal-free condensation of 2-aminothiazole with β-nitroacrylates to form imidazo[2,1-b][1,3]benzothiazoles in an ionic liquid was reported by Meshram.16 Despite the impressive progress made in this area, the synthesis of functionalized imidazo[2,1-b]thiazoles from readily available and easily varied starting materials using a simple procedure still remains a great challenge. The known methods suffer from the necessity of using prefunctionalized, commercially unavailable reacting substances and a limited substrate scope. Recently, the transition-metal-catalyzed three-component coupling of aldehyde, alkyne, and amine, commonly called A3-coupling, has been established as a practical tool in modern organic synthesis.17 Since the initial reports in 1998, the A3coupling18 has emerged as the most convenient and general approach for the in situ generation of labile propargylamine intermediates for cascade heterocyclizations.17,19 Numerous protocols using transition-metal catalysis were developed for functionalized five- and six-membered N,O-heterocycles, e.g., quinolines,20 imidazopyridines,21 furans,22 benzofurans,23 1,4dihydropyridines,24 pyrroles,25 and oxazoles.26 However, the use of A3-coupling in constructing sulfur-containing heterocyclic compounds remains strictly limited.27 Only two solitary examples, the syntheses of 2-(4-chlorophenyl)-4-phenylthiazolopyrimidine27a and 5-benzyl-6-phenylimidazo[2,1-b][1,3]-
Figure 1. Representative drug or drug candidates containing imidazo[2,1-b]thiazole moieties.
drugs and drug candidates (e.g., anthelmintic levamisole,1d potent anticancer agent Quizartinib,2 p53 inhibitor antineoplastic drug pifithrin-β,3 antiaging agent SRT2140,4 and anxiolytic agent WAY-181,1875). The prevalence of the imidazo[2,1-b]thiazole motif in medicinally relevant compounds,6 catalysts,7 and phosphorescent emitting8 and electronic9 materials has inspired the development of many novel methods for their preparation.10 However, there are only limited protocols for the one-pot assembly of polyfunctionalized imidazothiazole derivatives.11 Traditional methods include heterocyclizations of 2-aminothiazoles with α-bromoketones.12 Recently, Singh et al. reported a visible-light-triggered procedure in a green medium for the condensation of arylacyl © 2017 American Chemical Society
Received: July 14, 2017 Published: August 11, 2017 9682
DOI: 10.1021/acs.joc.7b01762 J. Org. Chem. 2017, 82, 9682−9692
Article
The Journal of Organic Chemistry thiazole,27b were reported. As part of our ongoing synthetic efforts toward imidazoheterocycles,28 herein we report a general and efficient synthesis of the imidazo[2,1-b]thiazole scaffold by the copper-catalyzed three-component coupling reaction of 2-aminothiazoles with aryl aldehydes and alkynes involving 5-exo-dig cyclization of an in situ generated propargylamine intermediate (Scheme 1). We also demonstrate that the
heterocyclization to 4a, revealed the superior activity of copper salts (Table 1, entries 2−7). Among others, CuCl, CuOTf· C6H6, and Cu(OTf)2 showed promising results, providing the desired product 4a in 61%, 67%, and 55% yields, respectively (Table 1, entries 2−4). However, the best results were achieved by performing the reaction with the homogeneous catalytic system CuOTf·C6H6 (10 mol %)/Cu(OTf)2 (10 mol %) in toluene under an inert atmosphere at 120 °C. Compound 4a was obtained in 75% yield in 2 h (Table 1, entry 8). A sharp decrease in the yield was observed in other solvents tested, at a lower temperature (Table 1, entries 10−12), and under aerobic conditions (Table 1, entry 9). The structure of imidazo[2,1b]thiazole (4a) was confirmed by single-crystal X-ray diffraction (see the Supporting Information, Figure S1). With the optimized conditions in hand, the substrate scope was explored with a variety of aldehydes (Table 2), alkynes
Scheme 1. Proposed Approach toward the Imidazo[2,1b]thiazole Scaffold
Table 2. Scope of Aldehydesa
use of the continuous-flow technique allows for the full implementation of this transformation, thus providing a more convenient and scalable method.
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RESULTS AND DISCUSSION We started our study by optimizing the reaction of 2aminobenzothiazole (1a) with 4-chlorobenzaldehyde (2a) and ethyl propiolate (3a) to prepare imidazo[2,1-b]benzothiazole (4a) (Table 1). In the absence of additives in toluene at 120 °C, the desired transformation did not occur (Table 1, entry 1). The screening of the d-metal catalytic systems (see the Supporting Information), which hold promise for the Table 1. Optimization of the Reaction Conditionsa
entry
Cu species
solvent
T, °C
yield 4a, %b
1 2 3 4 5 6 7 8 9 10 11 12
− CuCl CuOTf·C6H6 Cu(OTf)2 Cu(OAc)2·H2O CuI/Cu(OTf)2 CuCl/Cu(OTf)2 CuOTf·C6H6/Cu(OTf)2 CuOTf·C6H6/Cu(OTf)2 CuOTf·C6H6/Cu(OTf)2 CuOTf·C6H6/Cu(OTf)2 CuOTf·C6H6/Cu(OTf)2
toluene toluene toluene toluene toluene toluene toluene toluene toluene anisole MeCN DMSO
120 120 120 120 120 120 120 120 120 110 82 120
− 61 67 55
