Hydroamination of aminoallenes

The kinetic analysis demonstrated an unusual dependence of the cyclization rate on the rare earth metal ion size, with maximum turnover rates observed for the medium-sized yttrium and slower rates for the larger lanthanum and smaller lutetium [137]. As for aminoalkynes, catalysts with more open ligand frameworks are less active. DPT calculations indicate that protonolysis is the rate-determining step of the process [25, 34], although this notion is contrary to some experimental observations [136, 137]. 

The scope of this process has been extended in a more detailed investigation to the synthesis of quinolizidines [21] and the influence of alkyl substituents in various positions of the dialkenylamine substrate on product diastereoselectivity was probed. Neodymium-based catalysts are particularly efficient for six-membered ring formation (12). The methodology has found further application in the synthesis of tri- and tetracyclic alkaloidal skeletons (13) [22]. 

The carbocyclization step needs to be intramolecular in order to afford the desired product while the hydroamination step may also be intermolecular. Thus, a sequence of inter- and mtramolecular hydroaminations and carbocycUzations of the alkenylalkynylamine 40 substrate allows the facile assembly of the tricyclic polyheterocycle 41 with exclusive trans diastereoselectivity (14) [23]. 

Trivinylbenzene may be utilized in a hydroamination/carbocyclization process that is initiated by an intermolecular anft-Markovnikov addition of n-propylamine followed by an intramolecular hydroamination and a highly diastereoselective carbocyclization step (15) [20]. 

More recently the catalyst scope was extended to organolithium species [24] however, the reaction is confined to activated (alkenyl)aminostilbenes and yields pyrrolizidine and indolizidine derivatives. A toluene-THF mixture was used as reaction medium and the presence of excess amount of lithium ferf-butyltritylamide was required to obtain the bicyclization product (16). In the presence of substoi-chiometric amounts of the lithium-amide, only the hydroamination product was observed. 

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Higher levels of chiral induction were achieved with (/ )-xylyl-BINAP(Au-/i-nitrobenzoate)2 or (/ )-ClMeOBIPHEP(Au-p-nitrobenzoate)2 as catalyst (Scheme 4-63). These allow the smooth formation of chiral pyrrolidines or piperidines with up to 99% ee and high chemical yield from the corresponding trisubstituted tosyl-protected y- or 5-aminoallene. Gold catalysts with a chiral counterion can also be employed for the highly enantioselective intramolecular exo-hydroamination of aminoallenes. ... 

Scheme 15.79 Asymmetric hydroamination of aminoallenes using chiral Au(l) catalyst where 72 is resolved using chiral anions such as 71.

Scheme 16.55 Gold-mediated intramolecular hydroamination of aminoallenes to form pyrrolidines and piperidines.

A catalytic asymmetric intramolecular hydroamination of aminoallenes has been carried out in the presence of titanium complexes prepared by the in situ reaction of Ti(NMe3)4 with chiral amino alcohols [319]. The ring-closing reaction of hepta-4,5-dienylamine at 110 °C with 5 mol% catalyst gives a mixture of 6-ethyl-2,3,4,5-tetrahydropyridine (14-33%) and both Z- and T-2-propenylpyrroli-dine (67-86%), whereas the same reaction with 6-methylhepta-4,5-dienylamine under similar conditions gives exclusively 2-(2-methylpropenyl)pyrrolidine with modest enantiomeric excess values (<16%) (Scheme 14.139). 

Table 8 Group-4-metal-catalyzed hydroamination of aminoallenes...

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 the hydroamination of aminoallene, the product of Eq. (9) is comparable to that of Eq. (8) through q -allyl coordination. It should be noted that the reaction of chiral aminoallenes gives racemic products in the case of q -allyl metal system [49] however, high chirality transfer occurs in the case of q -coordination system [57]. 

An interesting example of a gold-catalyzed cycloisomerization of P-aminoallene 168 to tetrahydropyridine 169 is depicted below <06OL4485>. Patil et al. report a similar gold-catalized hydroamination of allenes to produce 2-vinyl piperidine 170 in good yield <06TL4749>. 

Highly regioselective intramolecular hydroamination of a y-aminoallenes has been achieved using a titanium bis (sulfonamide) as a precatalyst (Scheme 16.102) [107]. 

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]. 

Type 4 metallocene complexes catalyze the regioselective mtermolecular addition of primary amines to acetylenic, olefinic, and diene substrates at rates which are = 1/1000 those of the most rapid intramolecular analogues [165]. Variants such as the intramolecular hydroamination/cyclization of aminoallenes [166] and the intra- and intermolecular tandem C-N and C-C bond-forming processes of aminodialkenes, aminodialkynes, aminoallenynes, and aminoalkynes [167] were applied as new regio- and stereoselective approaches to naturally occurring alkaloids. For example, bicyclic pyrrolizidine intermediate E... 

Scheme 11.24 Chiral counteranion effect on the gold catalyzed hydroamination/cyclization of aminoallenes [118],...

We found that the intramolecular hydroamination of the aminoallenes 220 took place in the presence of catalytic amounts of palladium, phosphine, and acetic acid to give the 2-alkenylpyrrolidine and -piperidine 221 in good to high yields (Scheme 71).142 The reaction proceeds through formation of hydri-dopalladium species by the oxidative addition of an N—H bond to palladium(O) and subsequent hydro-palladation of the allene moiety, as mentioned in Scheme 70, type b. 

Krause has shown that gold(III) salts catalyze the intramolecular emJo-hydroamina-tion of N-protected a-aminoallenes [35]. For example, treatment of the diasteromeri-cally pure a-allenyl sulfonamide 44 with a catalytic amount of AUCI3 in dichlor-omethane at 0 °C for 1 h formed the pyrroline derivative 45 in 95% yield with 96% diastereomeric purity (Scheme 11.6). The protocol tolerated aryl and alkyl substitution of the distal allenyl carbon atom and was also effective for the hydroamination of N-unprotected a-allenylamines although these latter transformations required considerably longer reaction time. In a similar manner, Lee has reported the gold (Ill)-catalyzed ewdo-hydroamination of 4-allenyl-2-azetidinone 46 to form bicydic P-lactams 47 (Eq. (11.25)) [36]. 

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

Although hydroamination of allenes can be easily achieved with group 4 and group 5 metal catalysts, the stereoselectivity of these systems is rather limited. Several attempts to perform asymmetric hydroamination/cyclization of aminoallenes employing chiral aminoalcohols [260, 261] and sulfonamide alcohols [262] as chiral proligands for titanium- and tantalum-based catalyst systems have produced vinyl pyrrolidines with low selectivities only. While the titanium catalysts were... 

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]. 

Rare-earth metal complexes have proven to be very efficient catalysts for intramolecular hydroamination reactions involving aminoalkenes, aminoalkynes, aminoallenes, and conjugated aminodienes [88, 97]. They are significantly less efficient in intermolecular hydroamination reactions and only a limited number of examples are known [98-102]. The difficulties in intermolecular hydroamination reactions originate primarily from inefficient competition between strongly binding amines and weakly binding alkenes for vacant coordination sites at the catalytically active metal center. 

Scheme 11.22 Titanium catalyzed asymmetric hydroamination/cyclization of an aminoallene.

Also the hydroamination/cyclization of chiral aminoallenes has been utilized in the synthesis of various alkaloid skeletons [120]. The pyrrolidine alkaloid ( + ) 197B (Scheme 11.25), as well as the indolizidine alkaloid (+) xenovenine (Scheme 11.26),... 

Scheme 11.26 Diastereoselective synthesis of ( + ) xenovenine via hydroamination/bicyclization ofthe aminoallene alkene 77 [120],...

Scheme 11 Proposed mechanism for the organoactinide-catalyzed intramolecular hydroamination/cyclization of terminal and disubstituted aminoalkenes, aminoalkynes, aminoallenes, and aminodienes...

The highly diastereoselective hydroamination catalyzed by 13a/Sc N(SiMe3)2)3 was applied as a key step in a preparation of (zt)-xenovenine (Scheme 8) [100], Xenovenine is also accessible via a bicyclization of an aminoallene-alkene substrate in both racemic and enantiopure form [101]. Both approaches involve hydroamination with a secondary amine, a reaction that often requires a stericaUy more open rare earth metal catalyst [17]. 

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