Lithium‐Catalyzed anti‐Markovnikov Intermolecular Hydroamination Reactions of Vinylarenes and Simple Secondary Amines

Abstract

Various β‐arylethylamine derivatives were straightforwardly obtained by the lithium‐catalyzed anti‐Markovnikov selective intermolecular hydroamination reaction of secondary aliphatic amines with vinylarenes. The use of only 1.5 mol % LiCH2TMS as a solid base in THF proved to be efficient to deliver the target products at room temperature with up to complete conversions. Both reaction partners were, moreover, used in equivalent amounts; thus, this protocol best respects the concepts of sustainable chemistry for the easy preparation of lead structures for pharmaceutically active compounds.

Ambient Moisture Accelerates Hydroamination Reactions of Vinylarenes with Alkali‐Metal Amides under Air

“…Inspired by these results we also pondered whether sodium alkyl 4 could act as a precatalyst for the hydroamination of styrenes under inert atmosphere conditions (to avoid competing decomposition pathways). While lithium alkyls have shown good promise in catalytic hydroamination of olefins, the use of sodium alkyls has not been investigated. Interestingly, we found that using just 5 mol % of 4 hydroamination of several styrenes [ 1 a , 1 c , and α‐Me‐styrene ( 1 l )] with a range of secondary amines [ 2 a – 2 d , HNBz 2 ( 2 f ), HNMeBz ( 2 g ), HNBu 2 ( 2 h )] is accomplished in excellent yields (72–88 %) at room temperature in just 10 minutes (Scheme ).…”

Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View

“…In their investigation of intramolecular hydroamination reactions, Hannedouche and co-workers found that easily available chiral diamino­binaphthyl ligands in combination with alkali metal derivatives (MeLi, n- BuLi, or LiCH 2 SiMe 3 = Am-3 ) formed efficient precatalysts (diamido­binaphthyl dilithium salts) for the asymmetric cyclohydro­amination of amino-1,3-diene compounds at room temperature with high stereoselectivities and moderate enantioselectivities (Table , Entry 4). , Further studies on lithium-catalyzed intermolecular hydroamination of vinylarenes with secondary amines using chiral diamido­binaphthyl dilithium salts as catalysts (LiCH 2 SiMe 3 8 mol %, ligand 3.2 mol %, C 6 D 6 , 100 °C, 5–24 h) led to the formation of the anti-Markovnikov hydroamination product (Scheme ). Interestingly, higher conversions were obtained in deuterated benzene when using a racemic mixture of the diamino­binaphthyl ligand or even in its absence, which was rationalized in terms of the formation of inactive lithium amide aggregates. Furthermore, a strong solvent effect was also observed.…”

“…70,71 Further studies on lithium-catalyzed intermolecular hydroamination of vinylarenes with secondary amines using chiral diamidobinaphthyl dilithium salts as catalysts (LiCH 2 SiMe 3 8 mol %, ligand 3.2 mol %, C 6 D 6 , 100 °C, 5−24 h) led to the formation of the anti-Markovnikov hydroamination product (Scheme 13). 72 Interestingly, higher conversions were obtained in deuterated benzene when using a racemic mixture of the diaminobinaphthyl ligand or even in its absence, which was rationalized in terms of the formation of inactive lithium amide aggregates. Furthermore, a strong solvent effect was also observed.…”

Strategies for Direct, Transition Metal‐Free Addition of Nitrogen Synthons to Alkenes

“…However, these examples produced good yields for both primary (benzyamine) and secondary (morpholine and piperidine) amines. In 2017, Hannedouche and Schulz disclosed a protocol for using catalytic amounts of a unique alkyl lithium reagent for the addition of secondary amines to styrenes ( Scheme 108 ,C ) [284] . The authors happened upon this discovery while attempting to use a chiral dinaphthyldiamine to effect enantioselective addition of amines to styrene (see Sect.…”

“…In 2017, Hannedouche and Schulz disclosed a protocol for using catalytic amounts of a unique alkyl lithium reagent for the addition of secondary amines to styrenes (Scheme 108,C). [284] The authors happened upon this discovery while attempting to use a chiral dinaphthyldiamine to effect enantioselective addition of amines to styrene (see Sect. 4.2.3 below for the intramolecular variant).…”