Alkenes hydroaminations

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

In 2003, Livinghouse et al. also reported that chelating bis(thiophosphonic amidates) complexes of lanthanide metals, such as yttrium or neodymium, were able to catalyse intramolecular alkene hydroaminations. These complexes were prepared by attachment of the appropriate ligands to the metals by direct metalation with Ln[N(TMS)2]3- When applied to the cyclisation of 2-amino-5-hexene, these catalysts led to the formation of the corresponding pyrrolidine as a mixture of two diastereomers in almost quantitative yields and diastereos-electivities of up to 88% de (Scheme 10.81). 

C-N Ring-forming Reactions by Transition Metal-catalyzed Intramolecular Alkene Hydroamination... 

Alkene hydroamination has been known for many years, but has been little used as a method in organic synthesis. Tobin Marks of Northwestern recently published a series of three papers that will make this transformation much mote readily accessible. In the first (J. Am. Chem. Soc. 125 12584,2003) he describes the use of a family of lanthanide-derived catalysts for intermolecular hydroamination of alkynes (to make imines, not illustrated) and alkenes. With aliphatic amines, the branched (Markownikov) product is observed, 1 — 2. With styrenes, the linear product is formed. When two alkenes are present, the reaction can proceed (3 —> 4) to form a ring, with impressive regioselectivity. 

The products from alkene hydroamination are inherently lightly functionalized. To address this possible deficiency. Professor Marks also reported (J. Am. Chem. Soc. 125 15878, 2003) the cyclization of amino dienes such as 5. The cyclizations proceed with high selectivity for, the cis-2,6-dialkyl piperidines, and with a little lower selectivity for the trans 2,5-dialkyl pyrrolidine. The product alkenes are -95% E, the balance being a little Z alkene and the terminal alkene. 

New catalyst systems for intramolecular alkene hydroamination have also been developed Chem. Comm. 2004, 894 and Angew. Chem. lnt. Ed. 2004, 43, 5542). 

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... 

Addition of ammonia and amines to alkenes (hydroamination) is thermodynamically feasible, but kinetically hindered, hence it requires activation of either of the reactants1,2,51. The intramolecular reaction is generally more easily accomplished than the intermolecular reaction and allows the stereochemistry to be controlled to a certain degree. 

A different catalytic cycle for alkene hydroamination is initiated by the oxidative addition of the N-H bond to the metal, followed by insertion of the alkene into the metal-nitrogen bond and reductive elimination to form the amine. The oxidative addition of unactivated N-H bonds to platinum(O) complexes is thermodynamically unfavorable, so the catalytic cycle cannot be completed17, but the successful iridium(I)-catalyzed amination of norbornene with aniline has been reported18. 

The organolanthanide-catalyzed alkene hydroamination has been reported. With this approach, amino alkenes (not enamines) can be cyclized to form cyclic amines, and amino alkynes lead to cyclic imine. The use of synthesized C-1 and C-2 symmetric chiral organolanthanide complexes give the amino alcohol with good enantioselectivity. 

Figure 20 Catalytic inter- and intramolecular alkyne and alkene hydroamination (A-D)...

Interestingly, by switching from bis(amidate) to bis(ureate) bis(amido) complexes, a broader scope of reactivity can be realized in intramolecular alkene hydroamination. [28] Reactivity studies indicate that the tethered zirconium bis(ureate) precatalysts are more reactive for intramolecular alkene hydroamination than the titanium analogs. 

SCHEME 11.55. Intermolecular alkene hydroamination catalyzed by aldehydes. 

While early efforts in rare earth systems focused on cyclohydroamination, pioneering contributions in group 4 catalyzed hydroamination catalysis focused on intermolecular reactions [8]. However, owing to the aforementioned thermodynamic problems associated with intermolecular alkene hydroamination and mechanistic hmitations (see later discussion), early efforts focused on alkyne hydroamination with a variety of primary amines. 

Figure 15.3 Croup 4 alkene hydroamination catalysts capable of hydroamination of established aminoalkene substrates.

More dramatic achievements in alkene hydroamination have been realized with noncyclopentadienyl ligands that promote the formation of sterically accessible, electrophilic reactive metal centers. For example, the dipyrrolylmethane complex... 

Previously reported bis(amidate)- and tethered-amidate-supported zirconium complexes can be used for alkene hydroamination catalysis, and all substrate scope and mechanistic investigations of these systems are consistent with the [2+2] cycloaddition mechanistic profile [61, 62). However, more recent catalyst systems that can be used with secondary amines show broader substrate scope, similar to that attained by rare earth elements and suggest a mechanistic similarity to that observed for previously intensely investigated rare earth hydroamination catalyst systems [7j. Such complexes are proposed to achieve ring closure via o-bond insertion, and thus, consideration of such a mechanistic profile in this case demanded further investigation. 

Once again, this proton-assisted mechanistic profile allows for previously unattainable reactivity, in that this overall neutral complex is capable of achieving alkene hydroamination at room temperature with standard gem-disubstituted substrates, much Hke rare earth elements. This enhanced reactivity may be attributable to the formally cationic metal center in this zwitterionic species, thereby realizing a catalytic species that is isoelectronic with the more reactive rare earth elements. Interestingly, while previously reported cationic Zr species have had a... 

Table 15.9 Group 4 alkene hydroamination at room temperature.

Although this chapter is formally not covering recent achievements in rare earth chemistry, it must be mentioned that the first examples of asymmetric intermolecular alkene hydroamination have been reported by Hultzsch and coworkers (Scheme 15.13) [85]. Using a bulky binaphtholate yttrium complex at high temperatures with excess alkene substrate, the first examples of this challenging and highly sought after reaction have been realized with unactivated alkenes. 

Scheme 15.13 Y-catalyzed asymmetric intermolecular alkene hydroamination.

Alkene hydroaminations were the first characterized examples of this hydrofunctionalization reaction [86]. Although decades of investigation into hydroamination has broadly resulted in dramatic progress across a range of amine and C-C multiply... 

Key contributions in the development of late transition metal catalysts toward alkene hydroamination, which precede the 2008 comprehensive review [10], focus on contributions using group 9 and 10 metals. Preferred substrates for these transformations include aminoalkenes [230] for intramolecular reactivity or the use of activated alkenes such as styrene [93, 109, 113, 245] or alkenes substituted with electron-withdrawing substituents to generate hydroamination products via aza-Michael-type reactions [246-249]. Au has also been applied to the hydrofunctionalization of alkenes, although these reactions have demanded the use of protected amine substrates such as ureas [250], tosylamides [251], and carbamates [252]. 

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