Stereoretentive Halogenations and Azidations with Titanium(IV) Enabled by Chelating Leaving Groups

Abstract

Titanium does it again! With the help of nucleophile‐assisting leaving groups (NALGs), alkyl bromides, iodides, and, for the first time, azides are obtained from sulfonates with complete retention of configuration. Critical to the design of these new titanium(IV) reactions has been the use of NALGs which are thought to chelate the Lewis acid reagent in the transition state promoting an SNi‐type mechanism.

A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols

“…The initial inclination to use titanium(IV) fluoride in reactions with chelating leaving groups was based on our desire to develop a stereoretentive fluorination reaction as a follow-up to our success with chlorinations [14] and brominations [9] using the corresponding Ti(IV) halogen reagents. Although currently under study by various groups for use in dental varnishes, [15] titanium(IV) fluoride has received only modest attention from the organic synthesis community [16] probably due to its moderate complexing ability, [17] propensity for oligomer complex formation, and sparing solubility in typical reaction solvents.…”

“…[24] Finally, primary alcohols (table 3, entry 11) reacted very slowly, consistent with our previous work with titanium(IV) mediated reactions. [9] …”

“…[9],[14] However, the recent work of Braddock (Imperial College London) and Burton (Oxford) provide convincing evidence that an S N 1-type mechanism may also be operative in NALG/Ti(IV) reactions. [22] Specifically, the British researchers argue that these Ti(IV)-mediated reactions proceed via carbocation intermediates whose nucleophilic capture is under diastereomeric control.…”

“…[9] Using a designed chelating leaving group, [10] we fortuitously discovered a more direct stereospecific Ritter-type amidation reaction for cyclic alcohols. This initial observation involved the reaction of an 8-quinoline sulfonate (quisylate, QsO) with titanium(IV) fluoride in the presence of alkyl or aryl nitriles (scheme 1).…”

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination

“…We have previously demonstrated that radiofluorination at aliphatic carbon 7 and silicon 8 can be accomplished using metal chelating leaving groups capable of facilitating nucleophilic substitution reactions. We dubbed such groups as “nucleophile assisting leaving groups” (NALGs), arguing that the observed rate enhancements afforded by these nucleofuges are primarily due to stabilizing interactions between substrates and metal-nucleophile pairs to lower transition state energies.…”