Pd-Catalyzed and Copper Assisted Regioselective Sequential C2 and C7 Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one with Aryl Halides

Abstract

A selective functionalization of thiazolo[5,4-f]quinazolin-9(8H)-one has been developed through sequential activation of C-H bonds to furnish diarylated compounds. This strategy allows the regioselective C2 and C7 arylation by a judicious choice of coupling partners and bases, requiring no additional ligands or directing groups. Differently substituted N(8)-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure was also performed. These protocols provide a synthetically useful route for late-stage functionalization of this highly valuable scaffold, required in drug discovery.

<strong>Late-Stage Sequential </strong><strong>C-H Functionalization of </strong><strong>Thiazolo[5,4-<em>f</em>]quina-zolin</strong><strong>-9(8<em>H</em>)-</strong><strong>one: Synthesis of a Library of Potential Kinase Inhibitors</strong>

“…Increased loading of aryl iodide and longer reaction time afforded the bisphenylated compound 8 in up to 68% yield. 8 With acceptable conditions established, the scope of the bis-arylation reaction was explored with aryl iodides (Scheme 4). When aryl iodide was introduced, the resulting 2-aryl-thiazolo [5,4-f]quinazolin-9(8H)-ones were reactive enough to perform a second arylation, yielding significant amounts of 2,7-bis-arylated products 8a-f.…”

“…Indeed the reaction efficiency was dramatically improved by using 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in the presence of 1.0 equiv of CuI. 8 Longer reaction time and 10 mol% Pd(OAc)2 are also required for a total conversion of 6. Under these conditions, both aryl iodides and bromides are effective as coupling partners to afford exclusively C2-arylated compound 7a-j in a 47-92% range yield (Scheme 5).…”

Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

“…In this context, our group focused its activity on the synthesis of novel angular thiazolo [5,4f]quinazolin-9(8H)-one derivatives [25,26]. Innovative microwave-assisted metal-catalysed chemical reactions were studied [33,34], allowing the synthesis of important arrays of 2-aryl-N8alkylthiazolo[5,4-f]quinazolin-9(8H)-ones which were screened on a panel of five kinases (CDK5/p25, CK1δ/ε (casein kinase 1), GSK-β, CLK1 and DYRK1A, according to standard methods [35,36]. Among the various thiazolo [5,4-f]quinazolin-9(8H)-ones tested, only the 8-cyclopropyl-2-(pyridin-3-yl)thiazolo [5,4-f]quinazolin-9(8H)-one (also called FC162) ( Figure 2) exhibited nanomolar IC50 values (11,18, and 68 nM, against DYRK1A, CLK1, and GSK3, respectively) [27].…”

“…In this context, our group focused its activity on the synthesis of novel angular thiazolo[5,4-f ]quinazolin-9(8H)-one derivatives [25,26]. Innovative microwave-assisted metal-catalysed chemical reactions were studied [33,34], allowing the synthesis of important arrays of 2-aryl-N8-alkylthiazolo[5,4-f ]quinazolin-9(8H)-ones which were screened on a panel of five kinases (CDK5/p25, CK1δ/ε (casein kinase 1), GSK-3α/β, CLK1 and DYRK1A, according to standard methods [35,36].…”

Development of Kinase Inhibitors via Metal-Catalyzed C–H Arylation of 8-Alkyl-thiazolo[5,4-f]-quinazolin-9-ones Designed by Fragment-Growing Studies

“…This article focuses on the design and synthesis of an array of 2-aryl- N8 -alkylthiazolo[5,4- f ]quinazolin-9(8 H )-ones (series 4 ) which were evaluated as potential kinase inhibitors. According to our recent experience in carbon–carbon bond formation [ 31 , 32 ], a regioselective C–H bond activation was planned to provide the corresponding C2-arylated valuable compounds ( Scheme 4 ). Most of the syntheses described in this paper were achieved under microwave irradiation as a powerful alternative to traditional heating with economic and environmental benefits [ 33 ].…”