New Selenium Catalyzed Reactions and Computational Chemistry to Understand Regio- and Diastereoselectivities: Directed C-H Allylic Amination

Abstract

Allylic amines are an important class of nitrogen-containing compounds for use in synthesis or medicinal properties. Direct strategies to make allylic amines involve activation of an allylic C-H bond (allylic C-H amination), but often require expensive transition metals. Our group previously developed an alternative method using organoselenium catalysis on aliphatic alkenes. Herein, we discuss the adaptation of our allylic C-H amination reaction on internal vinylsilanes. The substrate scope features a range of silanes and can incorporate two types of nitrogen nucleophiles, including 4-nitrobenzenesulfonamide (NsNH2) and trifluoroethanol sulfonamide (TfesNH2). We discuss a trend in regioselectivity concerning amination with NsNH2, where activation of the distal allylic C-H bond is preferred. Unexpectedly, the use of TfesNH2 leads to reduced regioselectivity. Terminal vinylsilanes containing activated allylic positions (benzylic, tertiary) are aminated using the same reaction conditions. The utility of the aminated products is shown in two derivatization reactions, including iododesilylation and directed epoxidation. Our amination reaction is demonstrated on a gram scale and is reproducible. Computational chemistry is employed to determine a model that describes regioselectivity in amination of vinylsilanes. The DFT reaction coordinate involving distal or proximal allylic C-H amination are featured using a selenium diimide derived from methanesulfonamide, our model of NsNH2. The distal path exhibits an ene barrier that is 1.2 kcal/mol lower in energy than the proximal path. The ene step has asynchronous character, where positive charge build-up at the internal alkenyl carbon is consequential for regioselectivity. We determine the DFT reaction coordinate involving a selenium diimide derived from methyl sulfamate, a model of TfesNH2. A substantially lower ene barrier is observed (~ 4 kcal/mol) and can justify a loss of regioselectivity. We extend our computational study to focus on diastereoselective outcomes in allylic C-H amination. We investigate how protected alcohols at the homoallylic position of alkenes favor formation of anti-1,2-products. Homoallyl fluorides are used as model substrates, and we evaluate three conformations of the C-F bond (anti, inside, or outside). The magnitude of electron donation into the ? system is correlated with the energy of the [2,3]-sigmatropic rearrangement transition state. The inside alkoxy effect is attributed to the diastereoselectivity, the first time it is implicated in a [2,3]-sigmatropic rearrangement. The rearrangement transition states for a homoallyl acetate substrate are analyzed and formation of the anti-diastereomer is favored by 2.6 kcal/mol. Further studies include the diastereoselective formation of 1,4-products from Z-alkenes containing allylic protected alcohols. We evaluated how conformation of the allylic acetyl group affected the ene transition state energy. We determined the ene transition states leading to the syn or anti products, focusing on how the eclipsing atom group affected the barrier. In the transition states with minimized A1,3 strain, formation of the syn-diastereomer was favored by 0.4 kcal/mol. Diastereoselectivity is rationalized by the preference of the diimide to approach the less sterically hindered side of the alkene. We next investigated how functional groups (X) could act as directing groups for regioselective allylic C-H amination. The ene transition states are determined with electronically diverse X groups near or remote to the allylic site. Enhanced carbocation character is observed in the ene transition states of 1,1- and 1.2-disubstituted alkenes when X is electron-releasing. Statistical analysis is presented with multivariable linear regressions to predict ΔG‡ and ΔΔG‡ in these cases. We also calculate the ene transition states for a range of alkenes containing X groups at the vinylic position. Short Se-C distances and a low ene barrier are generally observed when X is electron releasing. A multivariable linear regression model is presented to predict ΔG‡ in these reactions. Following is a study of the ene transition states for two terpenes (methyl jasmonate and δ-damascone) to propose models that rationalize the regioselective amination.