Generation, Stability, and Utility of Lithium 4,4′-Di-tert-butylbiphenylide (LiDBB)

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.

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine

“…The configuration inversion of allylic alcohol 15 via a sequential one-pot oxidation-reduction process generated the Guillou’s intermediate I 50 in high efficiency. For the crucial hydroamination reaction of I toward the synthesis of (‒)-codeine, we developed an efficient method by using lithium 4,4′-di- tert -butylbiphenylide (LiDBB 51,52 ) in the presence of t -BuOH, which efficiently afforded (‒)-codeine ( 1b ) in 68% yield (50 mg scale). Compared with the classical Birch-type reaction 50 , photocyclization reaction 17 or oxymercuration procedure 19,53 , this methodology showed a remarkable superiority in terms of reproducibility, synthetic scale, and chemical yield (see Supplementary Table 8).…”

Programmable Synthesis of 2-Deoxyglycosides

“…14 Using these as a starting point, we evaluated the reductive lithiation Fig. 2A) with lithium di-tert-butylbiphenylide (LiDBB), 15 followed by the addition of benzyl tetrahydropyranyl monoperoxy acetal (2). Under these conditions, the product 3 was isolated in 6% yield as a single detectable α-diastereomer ( 1 H NMR analysis).…”

Enantioselective Synthesis and Biological Evaluation of Sanglifehrin A and B and Analogs

“…Thus, the ketone 24 was elaborated via a similar sequence as described above to afford the spirolactam 27 (Scheme 3). The spirolactam 27 was subjected to radical‐mediated debenzylation using lithium 4,4′‐di‐ tert ‐butylbiphenylide (LiDBB, Freeman's reagent), [29] followed by Dess–Martin oxidation to smoothly deliver the aldehyde 28 in excellent yields (99 %, 81 %, respectively). The aldehyde 28 was elaborated to install the stereocenters on C30‐C31 using Brown crotylation (65 %, dr 3:1), and the resulting terminal alkene was subjected to cross metathesis with crotonaldehyde using Hoveyda–Grubbs Second Generation (H‐G II) catalyst to afford the α,β‐unsaturated aldehyde 29 in a good yield (78 %).…”

“…Thus,the ketone 24 was elaborated via asimilar sequence as described above to afford the spirolactam 27 (Scheme 3). Thes pirolactam 27 was subjected to radicalmediated debenzylation using lithium 4,4'-di-tert-butylbiphenylide (LiDBB,F reemansr eagent), [29] followed by Dess-Scheme 1. A) Synthesis of the ketone 6.B)Synthesis of the aldehyde 7a.…”