Alkenes, metal catalyzed hydroamination

Earher mechanistic studies by Milstein on a achiral Ir catalyst system indicated that the iridium catalyzed norbornene hydroamination involves amine activation as a key step in the catalytic cycle [27] rather than alkene activation, which is observed for most other late transition metal catalyzed hydroamination reactions [28]. Thus, the iridium catalyzed hydroamination of norbornene with aniline is initiated by an oxidative addition of aniline to the metal center, followed by insertion of the strained olefin into the iridium amido bond (Scheme 11.4). Subsequent reductive elimina tion completes the catalytic cycle and gives the hydroamination product 11. Unfor tunately, this catalyst system seems to be limited to highly strained olefins. 

The hydroamination of alkenes and alkynes has been of longstanding interest in organometallic chemistry [26]. Much of the early work in this area focused on early transition metal or lanthanide metal catalyst systems. However, much recent progress has been made in late-metal catalyzed hydroamination chemistry, and several interesting hydroamination reactions that afford nitrogen heterocycles have been developed using palladium catalysts. 

General aspects of this reactivity,including theoretical studies,have been reviewed. Particular attention has been paid to reactions with amines to get more information on metal-catalyzed hydroamination of alkenes. A recent DFT theoretical study has evaluated the hydroamination process for different metals, concluding that nucleophilic attack of amine is thermodynamically and kinetically favorable for group 10 metals. " ... 

Huang L, Arndt M, GooBen K, Heydt H, GooBen LJ (2015) Late transition metal-catalyzed hydroamination and hydroamidation. Chem Rev 115(7) 2596-2697 Pirnot MT, Wang Y-M, Buchwald SL (2016) Copper hydride-catalyzed hydroamination of alkenes and alkynes. Angew Chem Int Ed 55(l) 48-57... 

The rare earth metal-catalyzed hydroamination/cyclization of internal and terminal aminoalkynes is a facile process, as shown by experimental [28, 29] and theoretical [32] studies. In general, the reaction proceeds via the same mechanism as amino-alkene hydroamination (Scheme 2) with some notable difference arising from a different insertive reactivity of the triple bond. The insertion of the C-C triple bond proceeds much faster than that of a double bond due to the exothermic nature of the insertion step (Fig. 1). Overall, the cyclization of an aminoalkyne is commonly 1-2 orders of magnitude faster than that of an analogous terminal aminoalkene. However, the insertion step is still considered to be the rate-determining step, based on aforementioned DFT calculations and experimental observations. 

Alkali metal-catalyzed hydroaminations of unactivated higher alkenes is significantly less feasible [148, 152],... 

Although a maximum of 6 turnovers in 3 days (TOP = 0.08 h ) were reached before loss of activity, this is the first successful demonstration of hydroamination of an alkene via a transition metal-catalyzed N-H activation process. 

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

A few examples are known using homogeneous transition-metal-catalyzed additions. Rhodium(III) and iridium(III) salts catalyze the addition of dialkylamines to ethylene.302 These complexes are believed to activate the alkene, thus promoting hydroamination. A cationic iridium(I) complex, in turn, catalyzes the addition of aniline to norbornene through the activation of the H—N bond.303 For the sake of comparison it is of interest to note that dimethylamino derivatives of Nb, Ta, and Zr can be used to promote the reaction of dialkylamines with terminal alkenes.304 In this case, however, C-alkylation instead of /V-alkylation occurs. 

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 (32) [142], 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 alkene group that would lead to a 6-exo hydroamination product [142]. 

The mechanism and scope of rare-earth metal-catalyzed intramolecular hydrophosphination has been studied in detail by Marks and coworkers [147,178-181]. The hydrophosphination of phosphinoalkenes is believed to proceed through a mechanism analogous to that of hydroamination. The rate-determining alkene insertion into the Ln-P bond is nearly thermoneutral, while the faster protolytic o-bond metathesis step is exothermic (Fig. 22) [179,181]. The experimental observation of a first-order rate dependence on catalyst concentration and zero-order rate dependence on substrate concentration are supportive of this mechanism. A notable feature is a significant product inhibition observed after the first half-life of the reaction. This is apparently caused by a competitive binding of a cyclic phosphine to the metal center that impedes coordination of the phosphinoalkene substrate and, therefore, diminishes catalytic performance [179]. 

Synthesis of saturated heterocycles via metal-catalyzed formal cycloaddition reactions that generate a C—N or C—O bond 13THC(32)225. Synthesis of saturated heterocycles via metal-catalyzed alkene carboami-nation, carboalkoxylation diamination, aminoalkoxylation, dialkoxyla-tion hydroamination or hydroalkoxylation reactions 13THC(32)1, 13THC(32)39, 13THC(32)109. 

Examples of the [2+2] cycloadditions and the mechanisms of these processes were presented in detail in Chapter 13 on complexes containing metal-ligand multiple bonds. In short, coordination of the alkyne or allene precedes the [2+2] cycloaddition. This cycloaddition is thermodynamically favorable for aikynes and allenes, but is thermodynamically disfavorable for reactions of alkenes. Studies on the regioselectivity of the stoichiometric [2+2] cycloaddition and of the regioselectivity of zirconocene-catalyzed hydroamination revealed that the [2+2] process is reversible during the hydroaminations catalyzed by zir-conocene complexes. Moreover, it has been shown that addition of an alkyne to an isolated zirconocene azametallacyclobutene leads to exchange. 

One possible way to promote hydroamination is to activate the reacting ammonia or amine.288-291 Alkali metals were found to be useful catalysts. Even in the catalyzed addition of ammonia to simple alkenes, however, drastic reaction conditions are... 

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. 

A different mechanism again is involved in the hydroamination reaction catalyzed by lanthanide complexes, Cpff.nR which is applied to the cyclization of unsaturated amines. The mechanism involves the formation of a metal amide species from both the catalysts (by different routes), followed by the turnover —limiting intramolecular insertion of the alkene to give a cr-complex, from which the decomplexed cyclic amine is obtained after reaction with a second molecule of the unsaturated amine19,20,107. 

Intermolecular additions of primary amines to alkenes have also been reported using lanthanide catalysts. These reactions, although slow, do occur to high conversion. Similar to hydroaminations catalyzed by late transition metal complexes, these reactions form the products from Markovnikov addition of the N-H bond across the olefin. One example of such a reaction is shown in Equation 16.59. ... 

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. 

Hydroaminations occurring by nucleophilic attack on ir-ligands are the oldest class of hydroamination and are discussed first. A mechanism for the hydroamination of alk-enes and alkynes catalyzed by palladium(II) complexes is shown in Scheme 16.16. By this pathway, coordination of the alkene or alkyne through the -ir-system occurs to generate a cationic or electron-poor, neutral metal-olefin or metal-alkyne complex. Nucleophilic attack of the amine on the coordinated olefin or alkyne then occurs. Nucleophilic attack on coordinated olefins and alkynes is presented in detail in Chapter 11. As noted in Chapter 11, this nucleophilic attack occurs at the internal position of an alkene or alkyne. 

As discussed in Chapter 9, the insertion of olefins and alk)nes into metal-amido complexes is limited to a few examples. Such insertion reactions are proposed to occur as part of the mechanism of the hydroamination of norbomene catalyzed by an iridium(I) complex and as part of the hydroamination of alkenes and alkynes catalyzed by lanthanide and actinide metal complexes. This reaction was clearly shown to occur with the iridium(I) amido complex formed by oxidative addition of aniline, and this insertion process is presented in Chapter 9. The mechanism of the most active Ir(I) catalyst system for this process involving added fluoride is imknown. 

The hydroamination of olefins has been shown to occur by the sequence of oxidative addition, migratory insertion, and reductive elimination in only one case. Because amines are nucleophilic, pathways are available for the additions of amines to olefins and alkynes that are unavailable for the additions of HCN, silanes, and boranes. For example, hydroaminations catalyzed by late transition metals are thought to occur in many cases by nucleophilic attack on coordinated alkenes and alkynes or by nucleophilic attack on ir-allyl, iT-benzyl, or TT-arene complexes. Hydroaminations catalyzed by lanthanide and actinide complexes occur by insertion of an olefin into a metal-amide bond. Finally, hydroamination catalyzed by dP group 4 metals have been shown to occur through imido complexes. In this case, a [2+2] cycloaddition forms the C-N bond, and protonolysis of the resulting metallacycle releases the organic product. 

Although Pd-catalyzed intramolecular hydroamination reactions of alkynes have been known for ten years, analogous transformations of unactivated alkenes have only recently been developed [33]. Key to the success of these studies was the use of a cationic palladium complex bearing a pyridine-derived P-N-P pincer ligand (29). For example, treatment of 26 with catalytic amounts of 29, AgB F4, and Cu(OTf)2 led to the formation of pyrrolidine 27 in 88% yield with 4 1 dr (Eq. (1.13)). Detailed mechamstic studies have indicated these transformations proceed via alkene coordination to the metal complex followed by outer-sphere aminopaUadation to provide 28. Protonolysis ofthe metal-carbon bond with acid generated in situ leads to formation of the product with regeneration of the active catalyst. 

Iwasawa has reported the gold(III)-catalyzed reaction of N-(o-ethynylphenyl)imi-nes with electron-rich alkenes to form polycyclic indole derivatives [26]. As an example, reaction of N-[l-(l-pentynyl)phenyl]imine 28 and tert-butyl vinyl ether with a catalytic amount of AuBrs in toluene at room temperature led to isolation of the polycyclic indole 29 in 80% yield as a mixture of diastereomers (Scheme 11.3). Conversion of 28 to 29 presumably occurs via initial intramolecular hydroamination to form the gold carbene containing azomethine ylide 30 that undergoes intermo-lecular [3 + 2] cydoaddition with tert-butyl vinyl ether to form the carbene complex 31. 1,2-Migration of the 7t-propyl group to the metal-bound carbon atom coupled with deauration then forms 29. This transformation is also catalyzed efficiently by PtCl2 [26]. 

---