A concise one-pot synthesis of trifluoromethyl-containing 2,6-disubstituted 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines.

5,6,7,8-Tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines with appended trifluoromethyl groups are valuable chemotypes in medicinal chemistry due to the presence of a partially-saturated bicyclic ring and metabolically-stable CF(3) group. (1)H NMR studies were used to optimize the preparation of such compounds, using a three-step/one-pot procedure, to provide novel 2,6-disubstitued derivatives with a tertiary-substituent. Racemic 2,6-disubstituted tetrahydroquinolines were separated by chiral HPLC to provide single enantiomers.

Preparation of heteroaryloxetanes and heteroarylazetidines by use of a Minisci reaction.

Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroaromatic bases was achieved by using a radical addition method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetidine into heteroaromatic systems that have found important uses in the drug discovery industry, such as the marketed EGFR inhibitor gefitinib, a quinolinecarbonitrile Src tyrosine kinase inhibitor, and the antimalarial hydroquinine.

Preparation of aryloxetanes and arylazetidines by use of an alkyl-aryl suzuki coupling.

The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.

Very-low-dose ketamine for the management of pain and sedation in the ICU.

Management of pain in critically ill patients can be very difficult. In the attempt to provide comfort with adequate levels of opioids and sedatives, respiratory depression and cardiovascular instability may become difficult to control in patients with labile hemodynamics and poor cardiopulmonary reserve. The use of medications like ketamine, an anesthetic agent that in subanesthetic doses has been reported to be effective in preventing opioid-induced tolerance and to have analgesic properties, may be of help, especially in patients who develop tolerance, leading to rapidly escalating doses of opioids and sedatives. The case report presented here shows how a very low dose of ketamine can be helpful for the management of pain and sedation in critically ill patients, especially when they are ready to be weaned from mechanical ventilation, and very high doses of opiods and sedatives do not permit it.