HETEROCYCLES

Communication | Special issue | Vol. 79, No. 1, 2009, pp. 303-309
Received, 7th July, 2008, Accepted, 1st August, 2008, Published online, 4th August, 2008.
DOI: 10.3987/COM-08-S(D)3

■ Palladium-catalyzed Arylation at C-H and C-C Bonds of Masked Thiazole Derivatives

Hirotoshi Furukawa, Suguru Matsumura, Atsushi Sugie, Daiki Monguchi, and Atsunori Mori*

Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan

Abstract

The differently substituted 2,5-diarylthiazole derivatives are synthesized via palladium catalyzed sequential C-H arylation at the 5-position and C-C bond activation at the 2-positon with masked thiazole.

Since 2,5-diarylated thiazoles show remarkable characteristics in photoluminescence, liquid crystal, and electrochemical redox, development of synthetic protocols for 2,5-diarylthiazoles is our major concern.1 The cross-coupling methodology with a transition metal catalyst is a tool for the introduction of a substituent into the thiazole ring.2 In particular, direct coupling of a thiazole derivative at the carbon–hydrogen bond by the catalysis of palladium is one of the practical way to introduce aryl and alkenyl groups via the carbon–carbon bond formation.3,4 We have reported that the C–H bond at the 2- and 5-positions of thiazole is efficiently substituted by various aryl groups with a palladium catalyst.5
Meanwhile, catalytic reactions via the cleavage of a C–C bond, in which a tertiary alcohol serves as a masked group of the corresponding C–H bond, have attracted much attention as a new class of transition metal-catalyzed carbon–carbon bond formation, and various catalytic processes involving different modes to activate the relatively inert bond have been developed.6,7 Our concern has thus focused on the use of such a reaction to the functionalization of thiazole derivatives. We herein describe that a new synthetic route to introduce an aryl moiety into thiazole at the 5-position and the 2-position with a thiazole derivative masked by a tertiary alcohol 1 via the C–H bond arylation and the arylation through C–C bond activation as shown in Scheme 1.

The masked thiazole 1 was prepared by the reaction of 2-bromothiazole with iPrMgBr to form the intermediate Grignard reagent8 and following addition of benzophenone to afford the corresponding tertiary alcohol 1 in 68% yield. (Scheme 2)

C–H arylation at the 5-position was first examined with masked thiazole 1 and an aryl iodide in the presence of a palladium catalyst and silver(I) nitrate/potassium fluoride as an activating agent. It was found to undergo the reaction affording the 5-arylated product. The reaction proceeded under similar conditions to those of 2-arylthiazole with an aryl iodide despite the presence of a hydroxy group in the molecule. Formation of the C–C bond at the 5-position of thiazole was found to occur.5b Accordingly, the masked thiazole serves as a protective group in the palladium-catalyzed reaction. The reaction with other aryl iodides was examined as shown in Table 1. Iodobenzene and aryl iodides bearing an electron-donating substituent at the 4-position afforded 3 in 39-51% yields (entries 1-3). On the other hand, iodides bearing an electron-withdrawing substituent CF3 (82%, entry 4) or CO2Et (quant, entry 5) resulted in excellent yields.
Deprotection of the masked group was found to take place by treatment of 3e with Cs2CO3 under reflux in xylene to afford the corresponding 5-arylated thiazole in a quantitative yield. (Scheme 3) Since few example on regioselective arylation at the 5-position of unsubstituted thiazole is reported,3b,3k the method would be a practical surrogate for the direct 5-arylation.5b

We then carried out the palladium-catalyzed reaction at the 2-position through the C–C bond activation in the presence of Cs2CO3 to undergo the 2-arylation (Table 2). The reaction of 3e with various aryl halides 2 (Cl, Br, and I) was employed for the reaction to obtain 4a to bring about similar yields (entry 1-3). It should be pointed out that aryl bromides and chlorides reacted similarly to aryl iodides when a bulky phosphine was employed as a ligand of palladium catalyst.7f,10 The masked thiazole bearing a electron-withdrawing substituent was found to undergo the reaction smoothly. Indeed, the reaction of 3e proceeded with both electron-rich iodides 2a,b and those having an electron-withdrawing substituent 2d-e to give 4a-d. The reaction of 3b, which possesses electron-enriched aryl group as a substituent at the 5-position, with electron-deficient aryl iodide 2e proceeded in a good yield (entry 7), while the reaction of electron-enriched 2b resulted in a poor yield (entry 8).

With differently substituted 2,5-diarylthiazole 4b and 4e in hand, we then compared characteristics of these isomers. Figure 1 shows fluorescence spectra of the obtained 2,5-diarylthiazoles. Both compounds showed photoluminescence. The quantum yield of 4e was found to be Φ = 0.56, which was ca. twice higher than that of 4b (Φ = 0.24).

In summary, we showed that palladium-catalyzed arylation reactions of masked thiazole took place at the C-H bond of the 5-position of thiazole and at the C–C bond of the 2-position. The masked group was found to serve as a functional group to promote C–C bond formation via C–C bond activation at the 2-position of thiazole, as well as a protective group in the 5-arylation reaction with a palladium catalyst and a silver salt. The protocols allow the introduction of the substituent in an opposite order, which reacts at the 5-position and then at the 2-position, to our conventional 2-arylation and the following 5-arylation sequence.10

ACKNOWLEDGEMENT
This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas, "Advanced Molecular Transformation of Carbon Resources" by Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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10. Arylation of 3e at the 2-position through the C-C bond activation with 2e (Table 2, Entry 6) To a 25 mL Schlenk tube equipped with a magnetic stirring bar were added Cs₂CO₃ (39.1 mg, 0.12 mmol), Pd(OAc)₂ (1.42 mg, 0.005 mmol), P(biphenylene-2-yl)(^tBu)₂ (2.98 mg, 0.01 mmol), xylene (1.6 mL), ethyl 4-iodobenzoate 2e (33 mg, 20 μL, 0.12 mmol), and 3e (41.6 mg, 0.1 mmol). The reaction mixture was stirred at 150 °C under N₂ atmosphere for 80 h. After cooling to rt, the mixture was poured onto saturated aqueous NH₄Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to leave a crude solid, which was purified by chromatography on silica gel to afford 18.3 mg of 4d (48%).^5a