A mild chlorination reaction of alcohols was developed using the classical thionyl chloride reagent but with added catalytic titanium (IV) chloride. These reactions proceeded rapidly to afford chlorination products in excellent yields and with preference for retention of configuration. Stereoselectivities were high for a variety of chiral cyclic secondary substrates including sterically hindered systems. Chlorosulfites were first generated in situ and converted to alkyl chlorides by the action of titanium tetrachloride which is thought to chelate the chlorosulfite leaving group and deliver the halogen nucleophile from the front face. To better understand this novel reaction pathway, an ab initio study was undertaken at DFT level of theory using two different computational approaches. This computational evidence suggests that while the reaction proceeds through a carbocation intermediate, this charged species likely retains pyramidal geometry existing as a conformational isomer stabilized through hyperconjugation (hyperconjomers). These carbocations are then essentially “frozen” in their original configurations at the time of nucleophilic capture.
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 series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the metal chelating unit is attached to the aryl ring via an ether linker. These NALGs exhibited significant rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions are facilitated by stabilization of charge in the transition state rather than through strong precomplexation with metal cation. In several cases, a primary substrate containing one of the new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups were used in 18 F-fluorination reactions using no-carrier-added [ 18 F]fluoride ion (t 1/2 = 109.7 min, β + = 97%) in CH 3 CN. Under microwave irradiation and without the assistance of a cryptand, such as K2.2.2, primary substrates with select NALGs led to a substantial improvement (2 to 3 fold) in radiofluorination yields over traditional leaving groups.
Titan in zentraler Rolle: Alkylbromide, ‐iodide und erstmals auch Azide sind unter Konfigurationserhaltung aus Sulfonaten zugänglich. Entscheidend für diese neuen Titan(IV)‐vermittelten Reaktionen ist der Einsatz von Abgangsgruppen mit nucleophilen Substituenten, die eine chelatisierende Bindung an die Lewis‐Säure im Übergangszustand ermöglichen und dadurch einen SNi‐Mechanismus begünstigen.
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