Intermediates (Chemistry)

We report here the development of a Lewis acid catalyzed method for the dehydrative
coupling of cyclic alcohols and nitriles to form amides with retention of configuration.
By contrast, the formation of amides by nitrile trapping of carbocations (Ritter reaction)
usually affords racemic product. The present reaction was accomplished by first
converting alcohol starting materials to their corresponding chlorosulfites in situ. Even
after an extensive search, only copper (II) salts were able to produce the desired
conversion of these chlorosulfites to amides though with low catalytic turnover.
Improving the turnover without deteriorating the stereochemical outcome was eventually
accomplished by a careful selection of the reagent addition sequence and through the
removal of gaseous byproducts. This Ritter-like coupling reaction proceeds in good
yields with secondary cyclic alcohols under mild conditions. The stereochemical outcome likely due to fast nucleophilic capture of a non-planar carbocations (hyperconjomers)
stabilized by ring hyperconjugation.

The synthesis and reactivity of Nucleophile Assisting Leaving Groups was studied in order to assess the rate enhancement of nucleophilic substitution reactions. Various Nucleophile Assisting leaving groups were synthesized, all of them containing a coordinating arm positioned ortho to an electrophilic center on a benzene ring. The various coordinating arms had novel geometries and binding properties. Their reactivity was studied with a variety of metal salts and the kinetics of the reactions was studied with 1H-NMR spectroscopy. This method provided a quantitative measurement of the rate enhancement observed in the substitution reactions from the rate constants obtained. In the case of certain crown ether-containing substrates, NMR experiments suggest that the mechanism of substitution proceeds in two steps, the first being a pre-coordination of the metal salt with the coordinating arm, followed by a conversion of the complex to products.

We report here the development of very efficient aryl- and quinolinyl- sulfonate based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), which substantially accelerate the rate of nucleophilic substitution reactions with metal halides. Detailed synthesis and kinetics study are described herein. Our synthesized NALGs have shown great reactivity towards poor nucleophiles and/or substrates traditionally considered too hindered to undergo nucleophilic attack. The abundant existence of halide, azide and amine in natural products demands new synthetic pathway. To fulfill this requirement, new mild stereoretentive halogenations (chlorination, bromination and iodination) reactions have also been developed for secondary cyclic alcohols using NALGs involving titanium (IV) reagents. The novel methodology can be extended to Azidation reactions as well with titanium (IV) azide, in which Ti (N3)4 is the first time being engaged in organic synthesis. Beased on the NALGs theory we discover the chlorosulfite can be a simplest NALG and applied as the intermediate in mild one-pot stereoretentive halogenations (chlorination and bromination) using titanium (IV) halides as catalysts or stoichiometric reagents. These reactions were found to be particularly efficient for cyclic alcohols. Finally, an efficient mild bromination and iodination reaction for primary and secondary alcohols with Grignard reagents is also reported. This reaction exhibits the generality with substrates with various leaving groups. The important features of this reaction are that, for the first time, bromide formation using Grignard reagents without the Cu (I) catalysts.

We report here the development of very efficient sulfonate based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), to accelerate the rate of nucleophilic substitution reactions involving poor nucleophiles and/or substrates traditionally considered too hindered to undergo nucleophilic attack. Indeed NALGs have shown exceptional ability in improving rate of nucleophilic substitution reactions. New very mild stereoretentive halogenations and azidation reactions have also been developed for secondary cyclic alcohols using NALGs involving titanium(IV) reagents. This reaction is particularly significant since the carbon-halogen bond is found widely in natural products and is used extensively as a synthesis intermediate. Azide is also a synthetically important functional group from which a variety of biologically important functional groups are conveniently obtained. Though stereoretentive chlorination and bromination reactions are known, we have developed, for the first time, a stereoretentive azidation reaction using titanium(IV) azide, a reagent not previously used in organic synthesis. During our development of stereoretentive reactions, we eventually developed very efficient, mild, two-step one-pot stereoretentive halogenations (chlorination and bromination) using titanium(IV) halides as catalysts or stoichiometric reagents. These reactions were found to be particularly efficient for cyclic alcohols. An efficient one pot stereoretentive amidation reaction for secondary cyclic alcohols is also reported. The important features of this reaction are that, for the first time, chlorosulfite (prepared in situ from alcohol using thionylchloride) has been used as a leaving group and titanium(IV) fluoride as an activator.