ABSTRACT
Several procedures were evaluated for the preparation of lithium 4,4'-di-tert-butylbiphenylide (LiDBB, Freeman's reagent) from lithium metal and 4,4'-di-tert-butylbiphenyl (DBB) in THF. Solutions with nominal concentration of 0.4 and 1.0 M were formed. The stability of LiDBB solutions was evaluated over time, and the gradual uptake of lithium metal was observed. At 0 °C the LiDBB solutions were stable for over a week in THF. At 20 °C the LiDBB solution underwent various decomposition pathways, which led to uptake of more lithium metal and the accumulation of side products. These decomposition pathways were studied, and the importance of ethene in the destruction of THF by LiDBB was observed. On a practical note, LiDBB solutions in THF were stable and effective for over a week at 0 °C or for more than 37 weeks when stored under argon at -25 °C. These observations will extend the utility of LiDBB as a reagent in organic synthesis.
ABSTRACT
Reductive lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemical synthesis , Nitriles/chemistry , Organometallic Compounds/chemistry , Spiro Compounds/chemical synthesis , Alkylation , Combinatorial Chemistry Techniques , Cyclization , Heterocyclic Compounds, 2-Ring/chemistry , Molecular Structure , Spiro Compounds/chemistry , Stereoisomerism , ThermodynamicsABSTRACT
A variety of spirocyclic heterocycles have been constructed by a double-alkylation and reductive cyclization approach utilizing α-heteroatom nitriles as trianion synthons. The method provides access to heteroatom-substituted spirocycles in a variety of ring sizes that are found in natural products and are important in pharmaceutical lead development and optimization.
