2-Aryl-thiazolo[4,5-b]pyridines and their related N-fused het- erocycles are important heterocyclic compounds with promising biological activities,for example,they have been used for metabotropic glutamate receptor subtype 5 antagonist (1,Fig. 1) ^[1] and AMG 369 that is a potential dual S1P₁/S1P₅ agonist with limited activity at S1P₃ and no activity at S1P₂/S1P₄ (2,Fig. 1) ^[2].

Fig. 1

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Fig. 1.The representative 2-aryl-thiazolo[4,5-b]pyridines and their derivatives.

Unlike the synthesis of 2-aryl-benzothiazoles ^{[3, 4]},there are very few synthetic routines of 2-aryl-thiazolo[4,5-b]pyridines in the literature. One typical method was shown in Scheme 1 (route a),acylation of 2-amino-3-bromopyridine derivatives 3 with benzoic acids 4 provided the benzamides 5. Cyclization of 5 was done in the presence of Lawesson’s reagent 6 to produce 2-aryl- thiazolo[4,5-b]pyridines 7. Although the transformation could be achieved in one-pot reaction without metal catalysis,multi-steps were required to prepare key intermediate 3 with use of excess N-bromosuccinimide (NBS) or bromine. In addition,this cycliza- tion reaction also suffered fromhigh reaction temperature and low yields. Another procedure ismore complicated (Scheme 1,route b). Compound 3 was treated with thiophosgene,followed by nucleophic addition with Grignard reagent (prepared with phenyl bromide 9 and BuLi at a strict reaction condition) to provide the key intermediate benzothioamide 10. Thus,new synthetic strategies for the preparation of 2-arylthiazolo[4,5-b]pyridines are strongly desired. Liebeskind and Srogl ^[5] developed a novel C-C cross- coupling protocol,involving the Pd(0)-catalyzed,Cu(I)-mediated coupling of thioether-type species with boronic acids under neutral conditions. Then,the Pd(0)-catalyzed C-S bond activation based on various heteroaryl thioethers,such as 3-chloro-4-arylthiocyclobutene- 1,2-dione ^[6],cyclic thioamides ^[7],2-S-p-methoxybenzyl-pyrazine/ benzothiazole/pyrimidine ^[8],2-(methylthio)benzofuran-3-carboxy- lates ^[9],6-thiophenylpurines ^[10] and 1-(methylsulfanyl)-3,4-dihy- droisoquinoline ^[11] were also reported to allow this desulfitative cross-coupling process. However,to the best of our knowledge,no reports of palladium-catalyzed desulfitative cross-coupling reaction between multisubstituted thiazolo[4,5-b]pyridine thioethers and boronic acids are known.

Scheme.1

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Scheme.1.Methods to synthesize 2-aryl-thiazolo[4,5-b]pyridines.

We have previously reported palladium-catalyzed desulfitative cross-coupling reactions affording 2-thiouracil derivatives ^[12] and 2-aryl-dihydropyrimidines ^[13]. N-fused heterocycles were also synthesized via Csp-S coupling reaction and 5-endo-dig cyclization ^[14]. Recently,a ZnCl2-promoted one-pot synthesis of multisubstituted thiazolo[4,5-b]pyridines 12 from mercaptoni- trile salts 11,a-bromo ketones and ketones was developed ^[15].This approach involved S_N2 alkylation/Thorpe-Ziegler cyclization/ Friedla ¨nder tandem reaction,which allowed the formation of heteroaryl methyl thioethers facilely and efficiently. To continue the exploration of the Liebeskind-Srogl reaction ^[16],the palladium-catalyzed cross-coupling reaction of heteroaryl methyl thioethers 12 and arylboronic acids 13 was investigated here to construct the 2-aryl-thiazolo[4,5-b]pyridines 7 (Scheme 1,route c).

Reagentswere purchased fromOuhe,Aladdin and J&K Scientific without further purification. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AVANCE III-400 spectrometer at ambient temperature with CDC_l3 as solvent. Chemical shifts were referenced to the residual peaks of the solvent [CDC_l3: 7.26 ppm ( ¹H NMR),77.16 ppm (¹³C NMR)]. IR spectra were recorded as KBr pellets on a Nicolet Nexus 470 FTIR spectrometer. High-resolution mass spectra were recorded on Bruker Apex IV Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. All melting points were measured on a melting point apparatus with corrected thermometers. Flash column chromatography was carried out using silica gel (200-300).

General procedure for the synthesis of fused pyridines 7: Thiazolo[4,5-b]pyridine thioether 12 (0.50 mmol),boronic acid 13 (1.0 mmol),copper(I) thiophene-2-carboxylate (1.0 mmol) and Pd catalyst (5 mol%) were placed in a 35 mL sealed tube and flushed with argon. After THF (3 mL) was added,themixturewas stirred at 100 8C for 12 h. The solution was filtered and water was used to wash the solid. The product in water was extracted three times with EtOAc (10 mL ×3). Organic layers were combined,washed with NaHCO3-saturated solution (10 mL ×2) and brine (10 mL ×2), dried with anhydrous Na2SO4,and concentrated under reduced pressure. The residue was purified with flash chromatography (petroleum ether/EtOAc = 5:1). All analytic data of compounds 7a-7w can be found in Supporting Information.

With 12a and 13a as model substrates,effects of metal catalyst precursors were systematically examined. As shown in Table 1, except of PdCl2 (entry 6),a variety of palladium compounds (entries 1-5)were effective. Copper salts also affected the coupling reaction significantly and CuI thiophene-2-carboxylate (CuTC) showed the best result (Table 1,entries 1,7-10).With Pd(PPh3)4 as the palladiumsource,increasing the amount of CuTC improved the yields to some extent. Then three control reactions (Table 1,entries 1,11 and 12) showed that excellent yield was obtained with 2 equiv. of copper salt loadings.

Table 1

Table 1 Optimization of reaction conditions. a

Table 1 Optimization of reaction conditions. a

With the optimized conditions in hand,we next investigated the substrate scope of the reaction by varying arylboronic acids 13. As shown in Table 2,a host of mono-substituted arylboronic acids 13b-13j provided the corresponding 2-aryl-thiazolo[4,5-b] pyr- idines 7b-7j in moderate to good yields. Both electron-donating groups,such as Me and OMe (Table 2,entries 8 and 13),and electron-withdrawing groups,such as CN,CF3 and Cl (Table 2, entries 2,5,and 10),were tolerated. Ortho-,meta- and para- substituted arylboronic acids could allwork in this system. Slightly lower yield was observed in the case of ortho-substituted arylboronic acid in comparison to its para- or meta-analogues, possibly due to steric hindrance (Table 2,entries 13-15). Reactions of 13i and 13j showed that thismethod could tolerate the presence of aryl halides,thus leaving great opportunities for further functionalization via conventional cross-coupling. From di-substi- tuted arylboronic acids,such as 13k and 13l,the corresponding products (7k in 85% yield and 7l in 81%) were obtained, respectively.

Table 2

Table 2 Reaction scope of arylboronic acids. a

Table 2 Reaction scope of arylboronic acids. a

As shown in Table 3,the synthesis of N-fused heterocycles from phenylboronic acid 13a or 13m and different multisubstituted thiazolo[4,5-b]pyridines 12b-i was studied. The results showed that this reaction tolerated various substituents on the 7-phenyl group,such as nitro,methyl,methoxy,chloro,trifluoromethyl. Fromthiazolo[4,5-b]pyridineswith anm-nitrophenyl group 12b to p-substituted phenyl groups (12c-f),desired products were all obtained with good yields (Table 3,entries 1-5). Besides, thiazolo[4,5-b]pyridines with disubstituted phenyl groups (12g, 12h) also gave products with good yields (Table 3,entries 6-7). In contrast,only moderate yield was obtained from thiazolo[4,5- b]pyridine with o-substituted phenyl group 12i,suggesting that steric effect from the phenyl substituents influenced the reaction slightly.

Table 3

Table 3 Synthesis of N-fused heterocycles from phenylboronic acid and different multi-substituted thiazolo[4,5-b]pyridines. a

Table 3 Synthesis of N-fused heterocycles from phenylboronic acid and different multi-substituted thiazolo[4,5-b]pyridines. a

All compounds were confirmed with IR,melting point, ¹H NMR,¹³C NMR and HRMS spectra (see Supporting information).

In conclusion,we have developed a palladium-catalyzed desulfitative cross-coupling reaction of heteroaryl methyl thioethers and arylboronic acids which is simple and facile to synthesize 2-aryl-thiazolo[4,5-b]pyridines. And this approach could also be further used to efficiently synthesize a series of compounds for biological activity screening.

This research was supported by the National Natural Science Foundation of China (No. 21272009).

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2015.05.012.