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

Monoand bis-(hetero)-arylation of thiazolo[5,4-f]quinazolin-9(8H)-one backbone involving sequential activation of C-H bonds has been developed to furnish the corresponding monoor diarylated valuable scaffolds. This strategy allows the regioselective C2-H and C7-H arylation by a judicious choice of coupling partners and bases. Differently substituted N8-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)ones were thereby obtained in a facile manner. A one-pot procedure was also developed. These protocols provide a synthetically useful route for late-stage functionalization of this high valuable scaffold, required in drug discovery.


1-Introduction
Our research group was focused on the synthesis of libraries of thiazolo [5,4-f]quinazolin(on)es as potential kinase inhibitors involved to some extent in Alzheimer's disease. 1 We previously reported that 9-N-alkylated/arylated thiazolo [5,4-f]quinazolines (II) displayed single-digit nanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. 2 Following our effort for the construction of an array of substituted thiazoloquinazolin-4-one derivatives, 3 the synthesis of an array of C2 and/or C7 arylated compounds was further envisioned (Figure 1).In this context, transitionmetal-catalyzed C-C coupling of heteroarene through C-H arylation represents an extremely attractive approach, notably for the late-stage functionalization. 4This methodology has emerged as an important tool for incorporating structural diversity into complex nitrogen containing heterocycles, without the need for prefunctionalized starting materials, useful in drug discovery. 5Since high temperature and long reaction time are often required for the C-H activation, the microwave irradiation appears to be a suitable tool. 6

Microwave-assisted C-H arylation of Quinazolin-4-one-type precursors of bioactive heterocycles: rapid access to biologically relevant 2-arylquinazolin-4-one derivatives Scheme 2. Late-stage functionalization's strategy through a metal catalysed C-H activation 2-Results and discussion
Owing to the importance of DYRK1A inhibitors, structure-activity relationship (SAR) studies were considered.Among the potential chemical transformation, C2 and C7 functionalization of thiazolo[5,4f]quinazolin-9(8H)-one core was investigated.In this context, transition metal-catalyzed intermolecular C-C coupling of this valuable scaffold through direct C-H arylation represents an extremely attractive approach, circumventing tedious multi-step syntheses in SAR studies.Given that selective C-H arylation is an ideal strategy for late-stage functionalization, we opted to use the N 8 -benzylatedthiazolo-quinazolin-9(8H)-one 6 as the model substrate (Scheme 3), a unique scaffold and key structural unit in DYRK1 kinase inhibitor series.When the reaction was conducted under our reported conditions on C2-H arylation of quinazolin-4ones and pyridopyrimidin-ones, 7 a mixture of C2-mono-and C2/C7-bis-phenylated products 7 and 8 respectively was obtained.Increased loading of aryl iodide and longer reaction time afforded the bisphenylated compound 8 in up to 68% yield. 8With 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.

Scheme 4. Scope of the bis-arylation reaction
Since only tBuOLi was effective for the C-H arylation of quinazolin-4-one part, 7a the selective C2-H arylation of the azole moiety has been achieved by switching the base.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).-Bromostyrene was also an effective coupling partner as demonstrated by the alkenylation reaction leading exclusively to the corresponding (E)-isomer in 43% yield.

Scheme 5. Scope of the selective C2-H arylation reactions and alkenylation
The sequential C7-H arylation of compounds 7a-f was performed using our previously reported conditions for C-H arylation of quinazolinones 7a to afford the corresponding diarylated compounds 9a-j in 33-87% yield after 5h (Scheme 6).

Scheme 6. Scope of the C7-H arylation reaction: Synthesis of diarylated compounds
The dual C-H bond functionalization was peformed in a one-pot process, allowing the chromatographic purification step discarded.The first C2-H arylation of 6 with phenyl bromide was complete within 5h, while the second arylation was finally achieved by the in situ addition of tolyl iodide, CuI (50 mol%) and Pd(OAc)2 (5 mol%) to the mixture reaction.The expected C2 and C7 diarylated thiazolo[5,4-f]quinazolin-9(8H)-one 9a was isolated in acceptable yield (Scheme 7).

3-Conclusion
This innovative sequential C-H functionalization tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups.Electron-deficient heteroarenes are also readily introduced at the C2 position, a notable feature with respect to medicinal agent synthesis Differently substituted N 8 -benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner.A one-pot procedure has also been performed.These protocols provide a synthetically useful route for late-stage functionalization of a high valuable scaffold, required in drug discovery.Brief studies of their Structure-Activity Relationships (SAR) as kinase inhibitors are currently under investigation.