Hydroamination of Aminoalkynes

Interestingly, the reactivity pattern in rare earth metal-catalyzed hydroamination/ cyclization reactions of aminoalkynes with respect to ionic radius size and steric demand of the ancillary ligand follows the opposite trend to that observed for aminoalkenes, namely decreasing rates of cyclization with increasing ionic radius of the rare earth metal and more open coordination sphere around the metal. This phenomenon can be explained by a negligible sterical sensitivity of a sterically less encumbered triple bond, as sterically less open complexes and smaller metal ions provide more efficient reagent approach distances and charge buildup patterns in the transition state [32]. 

Catalyst systems derived from Ln N(SiMe3)2 3 and chelating diamines (e.g., 13a, Fig. 5) are also active in the cyclization of aminoaIk3mes with quite remarkable activity and functional group tolerance (5) [123]. 

The rare earth metal-catalyzed cyclization of aminoalkenes, aminoalkynes, and aminodienes generally produces exclusively the exocyclic hydroamination products. The only exception was found in the cyclization of homopropargylamines leading to the formation of the endocyclic enamine product via a 5-endo-dig hydroamination/cyclization (6) [124], most likely due to steric strain in a potential four-membered ring exocyclic hydroamination product. Interestingly, the 5-endo-dig cyclization is still preferred even in the presence of an aUcene group that would lead to a 6-exo hydroamination product [124]. 

As discussed in Sect. 5, the intermolecular hydroamination of alkynes catalyzed by group 4 metal complexes is a well-documented process. The less challenging intramolecular transformation can be achieved efficiently with various titanium-based catalysts [51, 125-130]. The cyclization proceeds analogously to the rare earth metal-catalyzed process with exclusive ej o-selectivity and often requires elevated temperatures. However, the homoleptic titanium tetraamide Ti(NMe2)4 catalyzes the cyclization of both terminal and internal aminoalkynes at room temperature (7) [126, 127]. 

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Intramolecular addition of amine N-H bonds to carbon-carbon multiple bonds would afford nitrogen heterocycles. To realize catalytic cyclization of a,co-aminoalkenes or aminoalkynes, various catalytic systems have been developed especially with early transition metals such as titanium, zirconium, lanthanide metals, and actinide metals [ 12], Late-transition-metal catalysis based on Ni, Pd, and Rh has also proved to be efficient [ 12], Recently, the ruthenium-catalyzed intramolecular hydroamination of aminoalkynes 15 was reported to afford 5-7-membered ring products 16 in various yields (Eq. 6) [13]. Among... 

Equation 11.9. Palladium catalyzed asymmetric intramolecular hydroamination of aminoalkynes [115]. 

Some of the most active catalysts for the hydroamination of alkynes are based on lanthanides and actinides. The turnover frequencies for the additions are higher than those for lanthanide-catalyzed additions to alkenes by one or two orders of magnitude. Thus, intermolecular addition occurs with acceptable rates. Examples of both intermolecular and intramolecular reactions have been reported (Equations 16.87 and 16.88). Tandem processes initiated by hydroamination have also been reported. As shown in Equation 16.89, intramolecular hydroamination of an alk5me, followed by cyclization with the remaining olefin, generates a pyrrolizidine skeleton. Hydroaminations of aminoalkynes have also been conducted with the metallocenes of the actinides uranium and thorium. - These hydroaminations catalyzed by lanthanide and actinide complexes occur by insertion of the alkyne into a metal-amido intermediate. 

Table 15.26 Asymmetric hydroamination of aminoalkyne using Pd-chiral phosphine complexes.

Enantiomerically pure Norphos derivatives were synthesized and used as chiral bisphosphine ligands for the catalyst system Pd(dba)3 CHCI3/ PhC02H in the intramolecular hydroamination of aminoalkynes. The synthetic approach to the racemic bis(phosphine oxide) precursor of Methyl Norphos is shown in Scheme 7. ... 

The tetrakisamido titanium complex is also efficient in catalysis of intramolecular hydroamination of aminoalkynes and aminoallenes to obtain cycloimines [318]... 

The hydroamination of alkenes and alkynes provides a highly atom-economical method for the preparation of substituted amines and imines. Despite substantial efforts and recent progress, the development of a generally applicable functional group-tolerant catalyst for this reaction remains a challenge, and intense research continues in this field. An interesting example has been reported by means of Rh combined with a bidentate NHC ligand [eqn (8.14)]. Complex 32 was found to catalyse the intramolecular hydroamination of aminoalkynes. However, the turnover rates remained modest with values up to 50 h ... 

Cationic palladium(II) complexes are homogeneous catalysts for both intramolecular and inter-molecular hydroamination reactions.267 Palladium species immobilized on silica can be prepared by the simple addition of alkyl- or hydroxopalladium(II) complexes to partially dehydroxylated silica. The silica-bound species are more stable than their molecular precursors and are efficient catalysts for the cyclization of aminoalkynes.268... 

Access to more simply substituted azepine derivatives 116 and 117 has also been realized by ruthenium-catalyzed intramolecular hydroamination of the aminoalkyne 115 (Equation 16) <2001JOM(622)149>. The isolated yield of 116 was 21% and of 117 was only 13%. 

Scheme 13. Organosamarium-catalyzed hydroamination and cyclization of aminoalkynes...

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

A palladium-catalyzed three-component reaction with 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines to prepare fV-substituted 4-methylene-3,4-dihydro-1 (27/)-isoquinolin-1 -ones was disclosed <02TL2601>. A synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via a Cp2TiMe2-catalyzed, intramolecular hydroamination/cyclization of aminoalkynes was also reported <02TL3715>. Additionally, a palladium-catalyzed one-atom ring expansion of methoxyl allenyl compounds 79 to prepare compounds 80 that can serve as precursors to isoquinolones was reported <02OL455,02SL480>. 

The complexes were used in catalytic intramolecular hydroamination reactions resulting in the intramolecular cyclisation of aminoalkynes [298,299]. 

Scheme 6 Samarocene-catalyzed hydroamination/cycUzation of aminoalkynes [105,106]...

As discussed in the previous sections, hydrosilylation and hydroamination reactions can be catalyzed by essentially the same catalysts under very similar reaction conditions due to the similarity in their reaction mechanisms. Hence, both reactions can be performed in one synthetic procedure as a one-pot sequence. Although less explored than hydrosilylation of C-C multiple bonds, organolanthanide-catalyzed hydrosilylation of imines is a facile straightforward process [172,173]. Imines, in particular cyclic imines, are readily available via organolanthanide-catalyzed hydroamination of alkynes. Roesky and coworkers have demonstrated that A-silylated saturated heterocycles can be smoothly obtained (38) and (39) utilizing the bis(phosphinoamide)methanide complex 12 (Fig. 8) [57,58]. The higher reactivity of aminoalkynes in the hydroamination process makes this method a valuable alternative to aminoalkene hydroamination. 

The sequential hydroamination/hydrosilylation reaction (Scheme 54) catalyzed by 143 and 144 was also investigated. In the first step, aminoalkynes were converted to cyclic imines by hydroamination reaction and the subsequent hydrosilylation led to the corresponding silicon species. Hydrolysis of the products gave cyclic amines similar to the ones obtained from the hydroamination of aminoalkenes. However, the starting materials in the sequential hydroamination/hydrosilylation reaction were aminoalkynes. Therefore, the reactions are faster and easier to perform. 

Intermolecular hydroamination of alkynes, which is a process with a relatively low activation barrier, has not been used for the synthesis of chiral amines, since the achiral Schiff base is a major reaction product. However, protected aminoalkynes may undergo an interesting intramolecular allylic cyclization using a palladium catalyst with a chiral norbomene based diphosphine ligand (Eq. 11.9) [115]. Unfor tunately, significantly higher catalyst loadings were required to achieve better enantioselectivities of up to 91% ee. 

Equation 11.14. Titanium catalyzed tandem hydroamination/hydrosilylation of aminoalkynes [133]. 

The organolanthanide-catalyzed hydroamination of the aminoalkynes 276 gives the nitrogen-containing heterocycles 277 or 278 (in the case of R = H).158 The reaction of primary amines produces the cyclic imines 278, while the reaction of secondary amines gives the cyclic enamines 277 (Scheme 89). The organolan-... 

Scheme 11 Samarocene-catalyzed hydroamination/cyclization of aminoalkynes [28, 29]...

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