Aminoalkenes cyclization

Only a limited number of organoactinide catalysts have been investigated for the hydroamination/cyclization of aminoalkenes (Fig. 4, Table 2) [55, 96-98]. The constrained geometry catalysts 11-An (An = Th, U) show high activity comparable to the corresponding rare earth metal complexes and can be applied for a broad range of substrates [55, 96, 97]. The ferrocene-diamido uranium complex 12 was also catalytically active for aminoalkene cyclization, but at a somewhat reduced rate [98]. Mechanistic studies suggest that the actinide-catalyzed reaction occurs via a lanthanide-like metal-amido insertion mechanism and not via an imido mechanism (as proposed for alkyne hydroaminations), because also secondary aminoalkenes can be cyclized [55, 98]. 

Although efficient for the intramolecular hydroamination/cyclization (abbreviated IH below) of aminoalkenes (see below), organolanthanides exhibit a much lower catalytic activity for the intermolecular hydroamination of aUcenes, as exemplified by the reaction of n-PrNH2 with 1-pentene catalyzed by a neodymium complex (Eq. 4.17) [127]. 

The IH of exocyclic alkenes allows the construction of bicyclic amines bearing one methyl group at the ring junction. Although long reaction times (2-7 days) are necessary (Eq. 4.22), amines are obtained in good yield. In contrast, endocyclic aminoalkenes are resistant to cyclization [134]. 

The ring-size dependence of the cyclization rate (TOE) is 5 > 6, as already observed for IH of aminoalkenes and aminoalkynes. 

The bicyclic aminoalkene l-azabicyclo[4.4.4]tetradec-5-ene (32) behaves actually like an enamine96. It is oxidized more readily than its saturated analogues. Protonation does not occur on the nitrogen atom but at the double bond accompanied by transannular cyclization (32 — 33). 

Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe-Ingold effect).56... 

A dimeric proline-derived diamidobinaphthyl dilithium salt has been introduced as the first example of a chiral main group metal-based catalyst for asymmetric hydroami-nation-cyclization reactions of aminoalkenes.256... 

Aminoalkenes, oxidative cyclization, 10, 710-711 Aminoalkoxides, on zinc compounds, 2, 371 a-Aminoalkylallenes, cycloisomerizations, 10, 720 a-Aminoalkylcuprates, preparation, 9, 519-520 -Aminoalkylidynes, diiron carbonyl complexes with cyclopentadienyl ligands, 6, 248 Aminoalkynes, hydroamination, 10, 717 a-Aminoallenes, activation by gold, 9, 574 Amino r]5-amides, in Ru and Os half-sandwich rf3-arenes,... 

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]. 

Insofar as asymmetric synthesis is concerned, some pioneering work was conducted by Marks and co-workers through their demonstration of enantioselectivity in the samarium or lanthanide complex-catalyzed cyclization of aminoalkenes, an analogy of the simple reaction exemplified in Scheme 36. As before, the reaction works best for Se-unsaturated amines where the product of an exocyclic ring closure pathway is a cyclopentylamine. In the most favorable cases, high turnover to the desired product is observed [110] (Scheme 37). 

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... 

Intramolecular hydroamination/cyclization, the addition of an N-H bond across an intramolecular carbon-carbon unsaturated bond, offers an efficient, atom economical route to nitrogen-containing heterocyclic molecules (Equation 8.37). Numerous organolanthanide complexes were found to be efficient catalysts for this transformation [124, 125]. The real active intermediates are organolanthanide amides, which are formed by the rapid protonolysis reactions of precatalysts with amine substrates. The proposed catalytic cycle of hydroamination/cyclization of aminoalkenes is presented in Figure 8.37 [124]. 

Figure 837 The proposed catalytic cycle of hydroamination/cyclization of aminoalkene.

The carbon-carbon unsaturated substrates have now expanded from aminoalkenes to aminoalkynes, aminoallenes, and aminodienes, and the hydroamination/cyclization reactions of these substrates have produced functionalized nitrogen-containing heterocycles. It is worth noting that the aminoallene hydroamination/cyclization reactions are highly diastereoselective, and can provide concise routes to the synthesis of some natural products (Figure 8.38) [126]. 

Ge, S.Z., Meetsma, A., and Hessen, B. (2008) Neutral and cationic rare earth metal alkyl and benzyl compounds with the l,4,6-trimethyl-6-pyrrolidin-l-yl-l,4-diazepane Ugand and their performance in the catalytic hydroamination cyclization of aminoalkenes. Organometallics, 27, 5339. 

The phenylselenenyl chloride induced intramolecular ring closure of ro-aminoalkenes can be utilized in the synthesis of nitrogen heterocycles. Olefinic primary amines do not cyclize readily in this reaction, while urethane derivatives and secondary amines cyclize according to the following scheme55 56. 

Table 8. /V-Heterocycles by Intramolecular Cyclization of oj-Aminoalkenes induced by Phenylselenenyl Chloride55,56...

A -l leterocyclcs by Phenylselenenyl Chloride Induced Intramolecular Cyclization of ro-Aminoalkenes General Procedure56 ... 

Few examples have been reported of the cyclization of 6-aminoalkenes to polysubstituted piperidines, e.g., 1-3, the equatorial disposition of substituents is generally preferred. When mercury(II) acetate was used as an electrophile, the C - Hg bond underwent oxidative treatment with sodium borohydride/oxygen and the corresponding alcohol was obtained in very good yield109-111. 

Constrained-geometry complexes of the type [Me2Si(C5Me4)(NBut)]An(NRR1)2 (An = Th, U R = R1 = Me R = Me, R1 = Et R = R1 = Et) have been reported to be effective precatalysts for intramolecular catalytic hydro-amination/cyclization of aminoalkenes and aminoalkynes.55... 

Fig. 12 Thermodynamics of the elementary steps in rare-earth metal-catalyzed hydroamina-tion/cyclization of aminoalkenes (a), aminoalkynes (b), aminoallenes (c), and aminodienes (d) n = 1-3) [103-108]...

Pioneering experimental findings by Marks and coworkers [97,103,114] followed by theoretical analysis [109] allowed elucidation of the mechanism of aminoalkene hydroamination/cyclization (Fig. 13). The reaction is considered to proceed through a rare-earth metal amido species, which is formed upon protonolysis of a rare-earth metal amido or alkyl bond. As discussed in the previous section, the first step of the catalytic cycle involves insertion of the alkene into the rare-earth metal amido bond with a seven-membered chair-like transition state (for n = 1). The roughly thermoneutral [103,109] insertion step is considered to be rate-determining, giving rise of a zero-order rate dependence on substrate concentration and first-order rate dependence on catalyst concentration. 

Fig. 13 Simplified catalytic cycle for aminoalkene hydroamination/cyclization [103,109]...

Initial studies focused on lanthanocene-based catalyst systems that proofed to be efficient in the exo-specific cyclization of terminal aminoalkenes to form five-, six-, and seven-membered azacycles (Scheme 2). The reactions are predictably faster for the formation of smaller five-membered rings and in the presence of em-dialkyl substituents [117]. An increasing metal ionic radius and a more open coordination sphere, for example, in onra-lanthanocenes, are also beneficial for higher cyclization rates [103]. A further increase in catalytic activity is observed when sterically more open and more electrophilic CGC 17 (Fig. 15) are applied [118]. 

Catalyst systems obtained in situ from rare-earth metal trisamides Ln N-(SiMc3)2 3 and various chelating diamines (Fig. 17) have shown good activity in the cyclization of aminoalkenes (Schemes 3 and 4) [123,125-127]. The more challenging cyclization of the chiral aminoalkene 26 can be accomplished with... 

Scheme 4 Catalytic hydroamination/cyclization of an aminoalkene with an internal double bond [104,125]...

The rare-earth metal-catalyzed hydroamination/cyclization of internal and terminal aminoalkynes is a facile process, as shown by experimental [105,106] and theoretical [110] studies. In general, the reaction proceeds via the same mechanism as aminoalkene hydroamination (Fig. 13) 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 step (Fig. 12). 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. 

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 [110]. 

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]. 

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