The low reactivity of carboxylic esters toward (trifluoromethyl)trimethylsilane (TMS−CF3) was investigated. A universal cesium fluoride catalyzed procedure for nucleophilic trifluoromethylation was developed. At room temperature (25 °C), with catalytic amounts of cesium fluoride, carboxylic esters were found to react to give the silyl ether intermediates, which afforded the trifluoromethyl ketones after hydrolysis. Sulfonic, sulfinic, and selenic esters also show good reactivity, giving novel trifluoromethylated compounds. The trifluoromethylation method was also applied to aldehydes and ketones, which were transformed to trifluoromethyl silyl ether intermediates and afforded trifluoromethylated alcohols in excellent yields after acid hydrolysis. Ethylene glycol dimethyl ether was used as solvent for solid or high boiling substrates, and benzonitrile was used for the low boiling substrates.

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b S Supporting Information M acrophages, which are derived from monocytes, a subset of leukocytes, are well-characterized mediators of tissue destruction. These cells can be activated to secrete proinflammatory cytokines such as TNFR and IL-1β, tissue-degrading enzymes such as MMPs, and other chemokines that mediate the influx of other inflammatory cells. 1 Excessive recruitment of these cells to sites of inflammation leads to significant tissue destruction and contributes to the morbidity of chronic inflammatory and autoimmune diseases. The trafficking of monocytes/ macrophages to sites of inflammation is believed to be predominantly mediated by monocyte chemoattractant protein-1 (MCP-1, CCL2) through interaction with its specific receptor, CCR2, which is a member of the super family of seven-transmembrane G-protein-coupled receptors (GPCRs) and is predominantly expressed on monocytes. Binding of MCP-1 to CCR2 induces chemotaxis, resulting in directed migration of monocytes/macrophages to disease sites where MCP-1 expression is elevated. 2 Studies in rodent models have demonstrated the critical role of MCP-1/CCR2 in inflammatory and autoimmune diseases and strongly suggest that CCR2 is an attractive therapeutic target. 3 As a result, inhibition of CCR2 has emerged as a novel therapeutic approach for pharmaceutical research, and a number of potent small molecule CCR2 antagonists have been identified. 4À10 We have reported the discovery of a novel series of CCR2 antagonists through rational design. 10 Our structureÀactivity relationship (SAR) studies on that series of compounds led to the identification of INCB3344 (Figure 1), a potent, selective, and orally bioavailable antagonist of human and murine CCR2 (hCCR2 and mCCR2). INCB3344 has been used as a tool compound for target validation in rodent models because of its potent inhibitory activity toward murine CCR2, its selectivity over other homologous chemokine receptors, and its good pharmacokinetics profile but was not suitable as a clinical candidate due to its moderate hERG activity (IC 50 = 13 μM) as assessed using a dofetilide binding assay, which did not meet our criteria in hERG binding activity. In addition, INCB3344 was an inhibitor of CYP3A4.In the course of SAR studies on the INCB3344 series in an attempt to identify a clinical candidate, we discovered that removal of the ethoxy at the 3-position on the pyrrolidine in the INCB3344 series as in 1 (Figure 2) resulted in a significant loss in mCCR2 activity but retained the hCCR2 activity as in 2 (Figure 2). An R configuration at the 3-position on the pyrrolidine as shown in 2 is required for activity as the S enantiomer of 2 displayed an IC 50 of >1 μM in hCCR2 MCP-1 assay. Although this des-ethoxy series is not superior to the INCB3344 series by comparison of 2 with 1 in hCCR2 activity and hERG binding activity, the 1,3-disubstituted pyrrolidine core in this series offers an advantage over the 1,3,4-trisubstituted pyrrolidine core in the INCB3344 series from a synthetic point of view as the former ...