| Mechanistic studies are described with an aim of better understanding amino alkoxide-mediated asymmetric 1,2-additions, in concurrence with a program to develop practical syntheses of quinazolinone-based non-nucleoside reverse transcriptase inhibitors. Low-temperature 6Li, 13C, 15N, and 19F spectroscopy are utilized in the structural studies described. 19F NMR spectroscopy was used to determine rate constants in the kinetic studies reported.; Mixtures of lithium cyclopropylacetylide (LiCPA), a (+)-carene-derived amino alkoxide (R1*OLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (LiCPA)3(R1*OLi) mixed tetramer, a C2-symmetric and asymmetric (LiCPA)2(R1*OLi) 2 mixed tetramer, and a C3-symmetric (LiCPA)(R1*OLi) 3 mixed tetramer. Analogous mixtures of LiCPA/R1*OLi in Et2O and Me2NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C2-symmetric (LiCPA)2(R1*OLi) 2 mixed tetramer is formed in Et2O, whereas the asymmetric isomer is formed in Me2NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-LiCPA or LiHMDS-R1*OLi mixed aggregates. LiHMDS-LiCPA mixtures form mixed aggregates in Me2 NEt.; Mixtures of LiCPA or lithium phenylacetylide (PhCCLi) and a vicinal amino alkoxide derived from camphor (R2*OLi) in THF/pentane afford an asymmetric (RCCLi)3(R2*OLi) mixed tetramer and a C2-symmetric (RCCLi)2(R2*OLi) 2 mixed tetramer depending on the stoichiometries. The corresponding (RCCLi)(R2*OLi)3 mixed tetramer is not observed. R*OLi-mediated additions of PhCCLi to benzaldehyde proceed with up to an 8:1 enantiomeric ratio that depend on both the choice of R*OLi and the PhCCLi/R*OLi stoichiometries.; The 1,2-addition of PhCCLi to quinazolinones was investigated. Deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with LiHMDS affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi dimer. Although the mixed tetramer dominates at high mixed aggregate concentrations and low temperatures used for the structural studies, the mixed dimer is the dominant form at the low total mixed aggregate concentrations, high THF concentrations, and ambient temperatures used to investigate the 1,2-addition. Rate studies revealed a first-order dependence on mixed dimer, a zeroth-order dependence on THF, and a half-order dependence on the PhCCLi concentration. The rate law is consistent with the addition of a disolvated PhCCLi monomer to the mixed dimer. Investigation of the 1,2-addition of PhCCLi to an O-protected quinazolinone implicates reaction via trisolvated PhCCLi monomers. |
