C‐Propargylation Overrides O‐Propargylation in Reactions of Propargyl Chloride with Primary Alcohols: Rhodium‐Catalyzed Transfer Hydrogenation

Abstract

Graphical abstract A Path Less Travelled. The canonical SN2 behavior displayed by alcohols and activated alkyl halides in basic media (O-alkylation) is superseded by a pathway leading to carbinol C-alkylation under the conditions of rhodium catalyzed transfer hydrogenation. Racemic and asymmetric propargylations are described.

Catalytic Enantioselective Carbonyl Allylation and Propargylation via Alcohol-Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier

“…31 The chiral rhodium catalyst generated from [Rh(cod)Cl] 2 and ( R )-BINAP overcomes the requirement of terminally substituted propargyl donors, allowing use of propargyl chloride itself (Scheme 6-C). 32 However, to achieve high levels of asymmetric induction, match-mismatch effects between the catalyst and an enantiomerically enriched chiral α-stereogenic amino alcohol are required. Collectively, these methods provide an alternative to the longstanding use of preformed chiral allenylmetal reagents in carbonyl propargylation.…”

Catalytic Enantioselective Carbonyl Propargylation Beyond Preformed Carbanions: Reductive Coupling and Hydrogen Auto‐Transfer

“…Because the use of optically pure BINAP only led to moderate levels of enantiomeric enrichment (40–55 % ee), match‐mismatch effects in the C ‐propargylation of chiral α‐stereogenic amino alcohols were explored. As we hoped, products of asymmetric C ‐propargylation could be formed with high levels of stereocontrol (Scheme ) . Diastereoselectivities were found to increase with increasing size of the α‐substituent.…”

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

“…The connected continuous process of allene dissolution, lithiation, Li-Zn transmetallation, and asymmetric propargylation provides homopropargyl b-amino alcohol 1 with high regio-and diastereoselectivity in high yield. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. Judicious selection of mixers based on the chemistry requirement and real-time monitoring of the process using process analytical technology (PAT)e nabled stable and scalable flow chemistry runs.…”

“…[1] Recently,wer equired apractical manufacturing process to access chiral homopropargyl bamino alcohol 1. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. Despite these advances,e stablished methods require low reaction temperatures to avoid substrate epimerization when applied to carbonyl substrates with a-stereogenic centers.…”

“…Despite these advances,e stablished methods require low reaction temperatures to avoid substrate epimerization when applied to carbonyl substrates with a-stereogenic centers. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. [5] Theu se of mercury,t he corrosiveness of propargyl bromide,a nd the pyrophoric nature of the allenyl boronic acid raise significant environmental and safety concerns when using these reagents for large-scale applications.T he direct lithiation of allene, ar eadily available and inexpensive starting material, is ap otential alternative to propargyl bromide magnesiation if apractical lithiation/transmetallation process could be developed.…”