Amines asymmetric hydroamination

As already mentioned, there has been significant progress in the development of chiral catalysts for asymmetric hydroamination reactions over the last decade. However, significant challenges remain, such as asymmetric intermolecular hydro aminations of simple nonactivated alkenes and the development of a chiral catalyst, which is applicable to a wide variety of substrates with consistent high stereochemical induction and tolerance of a multitude of functional groups as well as air and moisture. Certainly, late transition metal based catalysts show promising leads that could fill this void, but to date, early transition metal based catalysts (in particular, rare earth metals) remain the most active and most versatile catalyst systems. 

Hydroamination of prochiral cyclic dienes such as 1,3-cycloheptadiene (19) with aniline gave rise to 3-(A/ -phenylamino)cycloheptene (20) smoothly using Pd-PPh3. This reaction suggests the possibility of asymmetric amination. Actually Hartwig carried out successful asymmetric hydroamination of 1,3-cyclohexadiene with 4-aminobenzoate using (R, 7 )-(XIII-l) as a chiral ligand and obtained N-(3-cyclohexenyl)-4-aminobenzoate (21) in 83 % yield with 95 % ee [7],... 

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... 

Catalytic asymmetric hydroamination is a long-standing challenge for which there are no general solutions to date. However, there have been advances toward realizing this objective that point toward its powerful potential in the synthesis of chiral, substituted heterocycles and amine small molecules. This focused topic has been comprehensively reviewed by Hultzsch [280] and is briefly summarized in the... 

ASYMMETRIC HYDROAMINATION AND REDUCTIVE AMINATION IN TOTAL SYNTHESIS... 

Hydroamination can be defined as the simultaneous addition of the N—H bond across multiple bonds. Based on its 100% atom-economic and side-product-free nature, asymmetric hydroamination (AHA) serves as one of the most efficient strategies for the synthesis of chiral amines. Its easily available starting materials and nonhazardous nature make it a suitable industrial process in the synthesis of various pharmaceutical agents and synthetically important chemicals. 

Synthesis of chiral amines has always been an important goal in organic synthesis. Chiral amines are prevalent in a number of natural products and other biologically active compounds. Many chiral amines are also used as important substrates for the synthesis of various biologically active compounds. Although various methods for the synthesis of chiral amines have been developed, asymmetric hydroamination has been established as a unique method for generation of chiral amines considering its operational simplicity, atom economy, and the easy availability of substrates. 

Intramolecular asymmetric hydroamination (hydro-amination/cyclization)... 

Intermolecular asymmetric hydroamination provides chiral acyclic amines, whereas intramolecular asymmetric hydroamination provides chiral cyclic amines. 

Asymmetric hydroamination has made a significant contribution toward the synthesis of chiral cyclic amines. Intramolecular asymmetric hydroamination of amino alkenes, amino alkynes, and amino allenes has been extensively studied to develop interesting strategies for the synthesis of chiral cyclic amines. 

Substrate 27 was converted into secondary amine 29 using diisobutylaluminum hydride (DIBAL-H) and MeNH2 (Scheme 39.10). The secondary amine 29 upon asymmetric hydroamination/cyclization produces codeine 30 in 57% yield. Codeine can be demethylated to produce morphine 31 using BBr3 in chloroform (Scheme 39.10). ... 

Although hydroamination reactions are regiospecific in most cases, the stereoselective synthesis of pharmaceutically relevant chiral amines via hydroamination remains challenging despite significant progress for asymmetric intramolecular reactions and some initial reports on asymmetric intermolecular hydroamination. Selected examples of asymmetric hydroamination will be covered in this chapter due to the volume limitations, and the reader should refer to available specialized reviews for a more comprehensive coverage of the stereoselective aspects [8-15]. 

The asymmetric hydroamination constitutes a facile and atom-economical approach to chiral amines. The rational design of efficient, configurationally stable and highly selective catalysts has become an area of intense research activity. Significant progress has been made in the area of intramolecular enantioselective hydroamination, while... 

The development of group-4-metal-based catalysts for intramolecular hydro-amination of aUcenes has also led to several advanced systems for asymmetric hydroamination (Fig. 19). Most group 4 metal catalyst systems exhibit inferior reactivity and substrate scope (Table 19) in comparison to most rare earth metaland alkaline earth metal-based catalyst systems. They typically require high catalyst loadings and elevated reaction temperatures. However, the recent development of zwitterionic zirconium catalysts with significantly improved reactivities and selectivities [60, 118] promises to close this gap. 

Thus, early transition metal catalyst systems have yet to reach the nearly perfect degree of stereoselectivity (up to 99% ee) achieved with late transition metal catalysts [263-266] and dithiophosphoric acids [267]. However, it should be noted that these systems are confined to 77-protected (tosylates, ureas, carbamates) amines with reduced nucleophilicity, and the highly selective asymmetric hydroamination of aminoallenes with simple amino groups remains a challenge. 

In tenns of understanding the mechanistic aspects involved in such additimis on vinylic substrates via organometallic catalysts, analogies have been drawn to the hydroamination reactimis [28-30], Chiral metal complex-promoted asymmetric hydroaminations have been proposed to follow two different pathways. The first involves a sequence that commences with the oxidative addition of the N-H bond onto the metal ion followed by the insertion of the olefin and subsequent reductive elimination of the chiral substrate. An alternative pathway has also been proposed which involves the nucleophilic attack by the free amine on a coordinated olefin and a final protonolysis sequence, which leads to the release of the final product. Similar studies on metal irm-induced hydrophosphinations have been reported, and the mechanisms suspected to be in play include those proposed by Glueck and coworkers which basically involves the oxidative addition of a secondary phosphine followed by an olefin insertion [31], Togni and coworkers have also observed in certain scenarios the coordination of the olefin to the catalyst metal center followed by the addition of a secondary phosphine across the C-C double bond [32]. 

Chen K (2011) Application of palladacycles in asymmetric hydrophosphinations, asymmetric hydroamination and tandem allylic aminations/aza-Cope rearrangements. PhD Dissertation, Nanayang Technological University... 

Transition metal complex-catalyzed carbon-nitrogen bond formations have been developed as fundamentally important reactions. This chapter highlights the allylic amination and its asymmetric version as well as all other possible aminations such as crosscoupling reactions, oxidative addition-/3-elimination, and hydroamination, except for nitrene reactions. This chapter has been organized according to the different types of reactions and references to literature from 1993 to 2004 have been used. 

Ruthenium complexes mediate the hydroamination of ethylene with pyridine.589 The reaction, however, is not catalytic, because of strong complexation of the amine to metal sites. Iridium complexes with chiral diphosphine ligands and a small amount of fluoride cocatalyst are effective in inducing asymmetric alkene hydroamination reaction of norbomene with aniline [the best enantiomeric excess (ee) values exceed 90%].590 Strained methylenecyclopropanes react with ring opening to yield isomeric allylic enamines 591... 

The enantioselective hydroaminations of allenes with chiral phosphine catalysts was accomplished with substrates that had a terminal symmetric substitution and with the amines protected as carbamates or sulfonamides. The same symmetric substituents were necessary for the enantioselective transformation nsing chiral counterions. However, very recently, high enantiomeric excesses were reached with trisubstituted asymmetric allenes by a dynamic kinetic enantioselective hydroamination of allenyl carbamates (eqnation 110), even thongh the E/Z ratio of the prodncts was not optimal. 

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