Hydroaminoalkylation, amines

Emerging at a fast rate, but not examined in this book, are the syntheses of allylic chiral amines [2] and propargylic chiral amines [3]. In addition, the very recent development of efficient catalytic hydroaminoalkylation, albeit racemic, holds great promise [4]. 

Scheme 16 Inter- and intramolecular hydroaminoalkylation reactions for the atom-economic synthesis of selectively substituted amines...

Scheme 17 Proposed catalytic cycle for the hydroaminoalkylation of secondary amines with tantalum precatalysts...

Scheme 19 intramolecular hydroaminoalkylation of unactivated olefins with secondary amines catalyzed by mono- and bis(amidate) tantalum ami do complexes... 

Complex 9 remains one of the most broadly applicable catalysts for this reaction, catalyzing hydroaminoalkylation with A -arylalkylamines, including controlled monoalkylation of dienes. This reactive catalyst 9 even displays tolerance of oxygen-containing substrates. Most importantly, this remains the only catalytic system capable of the direct C—H alkylation a to N of unprotected heterocyclic amine substrates. Such products are potentially important structural motifs for exploration in medicinal chemistry. In all cases this precatalyst shows regioselective hydroaminoalkylation to generate the branched product, and excellent diastereoselectivity when applicable (Scheme 20). [79]... 

An interesting observation in these investigations is the fact that intermolecular hydroaminoalkylation catalysts are not viable for application in intramolecular reactions. Furthermore, there are no catalysts that are effective for the intramolecular hydroaminoalkylation of secondary aminoalkenes and all high yielding examples of intramolecular hydroaminoalkylation are restricted to primary aminoalkenes. Meanwhile, intermolecular hydroaminoalkylation with primary amines has not yet been reported. 

The formation of such bridged metallaziridine species rationalizes the selectivity for primary amines and suggests that dimeric species may be key catalytic intermediates. This is further supported by experiments that illustrated that increasing catalyst concentration results in an increase in hydroaminoalkylation product versus hydroamination product. [72] Therefore, we proposed that catalyst-controlled chemoselectivity for hydroaminoalkylation (C—C bond formation) versus hydroamination (C—N bond formation), could be achieved by designing catalyst systems that promote the formation of bridged species. 

To this end, a titanium bis(2-pyridonate) complex (17) has been developed. [22c] These catalytic systems promote catalyst-controlled selectivity for hydroaminoalkylation over hydroamination and for the first time amine-substituted cyclopentanes can be prepared preferentially over piperidine hydroamination products (Scheme 25). 

Titanium complexes are known as catalysts for both intra- and inter-molecular hydroaminoalkylations of alkenes by selective carbon-hydrogen bond activation a to amines to form either the branched or the linear product (Scheme 5.2). ° This reaction has attracted much attention in recent years due to it being a 100% atom-economic transformation for carbon-carbon bond formation. 

Hydroamination is an atom-economical process for the synthesis of industrially and pharmaceutically valuable amines. The hydroamination reaction has been studied intensively, including asymmetric reactions, and a variety of catalytic systems based on early and late transition metals as well as main-group metals have been developed." However, Group 5 metal-catalysed hydroaminations of alkenes had not been reported until Hultzsch s work in 2011. Hultzsch discovered that 3,3 -silylated binaphtho-late niobium complex 69 was an efficient catalyst for the enantioselective hydroaminoalkylation of iV-methyl amine derivatives 70 with simple alkenes 71, giving enantioselectivities up to 80% (Scheme 9.30). Enantiomerically pure (l )-binaphtholate niobium amido complex 69 was readily prepared at room temperature in 5 min via rapid amine elimination reactions between Nb(NMe2)5 and l,l-binaphthyl-2-ol possessing bullqr 3,3 -silyl substituents. Since the complex prepared in situ showed reactivity and selectivity identical... 

Another limitation of the cyclopentadienyl-derived catalysts is their illustrated propensity for forming unwanted side products (Scheme 15.7) that result from unexpected C-C bond formation in an intramolecular direct a-aUcylation reaction, otherwise known as the hydroaminoalkylation reaUion [50]. The formation of this side product is problematic when targeting the heterocyclic products however, such reactivity is highly intriguing for the efficient preparation of amine-substituted carbocycles [51]. 

Chong E, Garcia P, Schafer LL (2014) Hydroaminoalkylation early-transition-metal-catalyzed a-alkylation of amines. Synthesis 46 2884—2896... 

Neutral group 4 metal complexes appear to possess a relatively broad scope for catalytic hydroaminations. They have been employed for the intramolecular hydroamination of alkynes [2], allenes [3], and alkenes [4] as well as the inter-molecular hydroaminations of alkynes [5] and allenes [6]. Primary aryl- and alkylamines readily react, but secondary amines have posed a greater challenge for this type of transformation with neutral catalysts [7]. For the reactions of the latter, cationic Zr and Ti complexes have been employed in intramolecular cyclizations of aminoalkenes [8]. Very recent work suggests that substrates that are difficult to hydroaminate may favor hydroaminoalkylations instead (Scheme 13.2) [9]. 

Niobium and tantalum The intermolecular hydroaminoalkylation of unactivated alkenes RCH=CH2 and styrenes with secondary amines ArNHMe to produce amines (229) has been reported to be catalysed by the tantalum and niobium binaphtholate complexes with <98% ee. The reaction has been found to be first order in the amine... 

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