Unprecedentedly mild direct Pd-catalyzed arylation of oxazolo[4,5-b]pyridine Fedor A. Zhuravlev * Technical University of Denmark, Building 201, Kemitorvet, DK-2800 Kgs. Lyngby, Denmark Received 5 January 2006; revised 9 February 2006; accepted 17 February 2006 Available online 10 March 2006 Abstract—Pd-catalyzed C-2 arylation of oxazolo[4,5-b]pyridine proceeds efficiently at 30 °C and tolerates a variety of aryl halides, including derivatized amino acids for which no racemization was observed during the reaction. Experimental evidence for facile deprotonation of oxazolo[4,5-b]pyridine under the reaction conditions is presented and the nature of the anionic intermediates is computationally examined. Ó 2006 Elsevier Ltd. All rights reserved. Inhibition of fatty acid amide hydrolaze (FAAH) is emerging as a promising therapeutic strategy for pain intervention, anxiety management, and treatment of sleep disorders. 1 Several new classes of reversible FAAH inhibitors based on azole heterocycles have been recently disclosed. 2,3 Among those, oxazolo[4,5-b]pyridines functionalized at C-2 showed exceptionally high levels of potency and selectivity. The introduction of carbon- based substituents at the C-2 position of azoles, however, remains a demanding task often requiring fully stoichio- metric pre-functionalization, such as metalation. This significantly limits functional group compatibility and increases the length of the reaction sequence. The devel- opment of a mild and general methodology allowing for direct catalytic carbon–carbon functionalization of azoles is, therefore, of great importance. In recent years, significant progress has been made toward the develop- ment of direct arylation of a wide variety of substrates, including oxazoles, 4,5 thiazoles, 4–7 imidazoles, 4,6,8,9 indoles, 9–13 pyrroles, 9,12 indolizines, 14 imidazo[1,2-a]pyri- midines, 7,15 imidazo[1,2-b][1,2,4]triazines, 16 and purine. 9 The majority of these reactions use palladium catalysis although some success was also reported with cobalt 5 and rhodium-based 12 catalytic systems. All these exam- ples, however, require forcing reaction conditions with temperatures typically in the range of 100–140 °C. Ex- tended reaction times are often necessary for achieving good yields. This letter reports the first example of the Pd-catalyzed arylation of oxazolo[4,5-b]pyridine, which readily proceeds at ambient temperature and accommo- dates a variety of aryl halides including those with sensi- tive functionalities. Initial attempts to effect the arylation of oxazolo[4,5- b]pyridine with phenyl iodide under conditions most frequently found in the literature (Pd(OAc) 2 /PPh 3 / Cs 2 CO 3 , DMF, 140 °C) indicated rapid consumption of the starting material and the formation of 2-phenyl- oxazolo[4,5-b]pyridine, also prepared independently. 17 Optimization of the reaction temperature revealed that ambient temperatures were adequate for efficient aryl- ation: at 30 °C the product was obtained in 68% isolated yield (Table 1, entry 1). Using this reaction as a platform for further screening, the choice of solvent and base was addressed. In accordance with previous reports polar solvents performed well; acetone, in particular, was found to have an advantage over DMF in terms of yields and ease of work-up. Cesium carbonate proved to be the base of choice as other common inorganic bases, including potassium carbonate failed to give any product. Two equivalents of base were needed since the yield dropped to 32% with 1 equiv of Cs 2 CO 3 . Next, the effect of ligand and Pd source was examined. As expected, the combination Pd(OAc) 2 /PPh 3 worked well giving a 72% yield. A 4:1 molar ratio of PPh 3 / Pd(OAc) 2 was found to be important for maintaining catalytic efficiency as lowering the amount of triphenyl- phosphine from 20 to 10 mol % decreased the reaction 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.02.117 Keywords: Direct Pd-catalyzed arylation; Oxazolopyridine; Oxaz- olo[4,5-b]pyridine; Azole functionalization. * Tel.: +45 45252101; fax: +45 45883136; e-mail: fedorz@kemi.dtu.dk Tetrahedron Letters 47 (2006) 2929–2932