Efficient Solid-Phase Synthesis of 3-Substituted-5-Oxo-5H-Thiazolo[2,3-b]-Quinazoline-8-Carboxamides under Mild Conditions with Two Diversity Positions

Abstract

In continuation of our efforts to develop novel and efficient polymer-supported routes, leading to heterocyclic derivatives with potentially attractive pharmacological properties, we turned our attention to thiazolo [2,3,b]quinazolines. A survey of the literature revealed that a quinazoline ring fused with thiazole exhibits a wide range of biological activities, 1-3 including antifungal 4 and antibacterial activities. [4][5][6]3,b]quinazoline derivatives were also tested for their application as herbicides for the agricultural industry. 7 To date, only solution-chemistry syntheses have been described. Narang et al. 5,8 reported the first synthetic route to thiazoloquinazolines in solution by refluxing the appropriate R-haloketones with 2-carbethoxy-phenylthiourea. Subsequently, Schadev et al. 1 used 2-aminobenzonitrile and 4-chloro-2-aminobenzonitrile with R-thiocyanoketones in the presence of hydrochloric acid to synthesize thiazolo[2,3,b]-quinazolines and Sharma et al. 9 condensed isatin with allyl isothiocyanate in the presence of aqueous alcoholic potassium hydroxide. Dhami et al. 5 condensed anthranilic acid with 2-chlorothiazole. Chern et al. 10 described a multistep route from 2-thioxo-1H,3H-quinazolin-4-one leading to 3-methylthiazolo[2,3-b]quinazolin-5-one, that was further derivatized. Although some of the routes described provided respectable yield, in all reported syntheses the conditions for cyclization of acyclic precursor were severe. The harsh conditions limited the diversity of accessible derivatives. Here we report the first solid-phase synthesis of thiazolo[2,3,b]quinazoline accomplished under mild conditions and amenable to high throughput/combinatorial synthesis.Our solid-phase synthesis of thiazolo[2,3,b]quinazoline is based on the use of anthranilates and bromoketones as key building blocks and diversity elements. Anthranilates are versatile synthons providing access to diverse fused heterocyclic systems. Their application for polymer-supported syntheses of heterocycles is employed frequently and includes the synthesis of quinazolin-4-ones, 11-14 quinazoline-2,4-diones, 15-21 4-hydroxyquinolin-2-ones, 22 2-amino-benzooxazin-4-ones, 23 2-thioxoquinazoline-4-ones, 24 1,4-benzodiazepine-2,5-diones, [25][26][27][28][29] and pyrrolo[2,1-c][1,4]benzodiazepines. 30,31 We have used anthranilates for syntheses of quinazolin-4-ones 32 and recently 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxamides. 33 Our first effort to prepare thiazolo[2,3,b]quinazolines was based on a solid-supported synthesis of 2-thioxoquinazoline-4-ones using anthranilates as the key synthon. This was followed by alkylation with bromoketones and subsequent formation of the six-membered quinazolinone ring. Combination of these two types of building blocks allows for the preparation of thiazolo[2,3,b]quinazolines with two diversity positions: one on the carboxylic benzene ring and the second on position 3 of the thiazolo ring.Briefly, Rink amide resin 1, after cleavage of the Fmoc group, was acylated with commercially avail...

Preparation of Fused Tetracyclic Quinazolinones by Combinations of Aza‐Wittig Methodologies and CuI‐Catalysed Heteroarylation Processes

“…A number of synthetic methods for the preparation of this ring system have been developed. These include reactions between heteroaromatic 2-amino esters and 2-(methylthio)-2-thiazoline, [15] solid-phase methods, [16] condensations of substituted anthranilic acids or esters with methyl 2-chlorothiazole-5-carboxylate, [17] and the electrochemical oxidation of catechols in the presence of 2-mercapto-3H-quinazolin-4-one. [18] Scheme 4.…”

Synthesis, Antibacterial, and Antioxidant Evaluation of Novel Series of Condensed Thiazoloquinazoline with Pyrido, Pyrano, and Benzol Moieties as Five- and Six-Membered Heterocycle Derivatives

“…Considerable research efforts have been devoted to synthesizing thiazole, quinazoline derivatives, and their moieties because of their widespread applications of biological merit [ 1 , 2 , 3 , 4 ]. Thiazole and quinazoline exist in condensed fused systems such as thiazolo[3,2- a ]quinazoline, thiazolo[4,3- b ]quinazoline, thiazolo[2,3- b ]quinazoline, 8 H -thiazolo[5,4- f ]quinazolin-9-ones, thiazolo[4,5- h ]quinazolin, and thiazolo[5,4- c ]quinoline which leads to them exhibiting their properties as important synthetic targets [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] due to their biological and pharmacological efficiency, such as DYRKIA inhibitors [ 15 ], HIV-1integrase inhibition [ 16 ], antimalarial [ 17 ], anticancer [ 18 , 19 , 20 ], anti-inflammatory [ 20 , 21 ], antituberculosis [ 22 ], antidepressant [ 23 ], anticonvulsant [ 24 ], antifungal [ 25 ], antihistamine [ 26 ], and antitumor [ 10 , 27 , 28 , 29 ] activity. In addition, these compounds play an important role by providing a new molecular framework for drug discovery [ 30 ].…”

Organocatalysis in heterocyclic synthesis: DABCO as a mild and efficient catalytic system for the synthesis of a novel class of quinazoline, thiazolo [3,2-a]quinazoline and thiazolo[2,3-b] quinazoline derivatives

“…So, on the basis of the above findings the quinazoline and thiazole are privileged structures, which attracted considerable attention in the designing of biologically active molecules and combining them in one molecule exemplified by the thiazoloquinazoline system it is expected to furnish biologically active molecule with characteristic features. In the last decade numerous methods have been developed for the synthesis of highly substituted thiazoloquinazoline system exemplified by thiazolo[2,3- b ]quinazoline [8,31-33], thiazolo[5,4- f ]quinazoline [34,35], thiazolo[4,5- h ]quinazolin [36], thiazolo[5,4- c ]quinoline [37], thiazolo[4,3- b ]quinazoline [38] and thiazolo[3,2- a ]quinazoline [39]. However, after detailed literature survey it was observed that there were only limited publications devoted to the synthesis of especially thiazolo[3,2- a ]quinazoline which involved reaction of 2-mercaptopropargyl quinazolin-4-one with various aryl iodides catalyzed by Pd-Cu [39] or by condensation of 2-mercapto-4-oxoquinazoline with chloroacetic acid [40], inspite of this procedure was also reported in the literature to afford the thiazolo[2,3- b ]quinazoline.…”