Hydroamination bicyclization

The above catalyst and Me2Si(C5Me4)2NdCH(SiMe3)2 are also efScient for the intramolecular hydroamination/bicyclization of aminoalkenynes, as exemplified in Eq. (4.26) [137, 138]. 

As in the case of aminodialkenes (see above), hydroamination/bicyclizations of aminoalkenynes allow the regiospecific synthesis of pyrrolizidine skeletons (Eq. 4.87) [138, 303]. 

Hydroamination/bicyclization of aminodialkenes, aminodialkynes, and amino-alkenynes opens a straightforward route to pyrrolizidines and indolizidines in a tandem C-N and C-C bond forming process. An important prerequisite for the success of this reaction sequence is a sufficient lifetime of the rare-earth metal alkyl intermediate formed in the initial insertion process of the alkene/alkyne in the Ln-amide bond in order to permit the carbocyclization step (Scheme 9) [99,174],... 

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

However, some experimental data, in particular the observatimi of sequential hydroamination/bicyclization sequences (see Sect. 4) catalyzed by organolan-thanide [20-23] and organolithium [24] species is in conflict with this scenario, as the sequential reaction requires a finite lifetime for the rare earth metal alkyl intermediate. Therefore, the intermediacy of the metal-alkyl species and its potential lifetime is unclear at present and probably strongly depends on catalyst and substrate structure. Unfortunately, involvement of concerted insertion/protonolysis... 

Scheme 13 Synthesis of pyrrolizidines (n = 1) and indolizidines (n = 2) via hydroamination/ bicyclization [23, 139]...

Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion. 

Intramolecular hydroamination of cyclohexa-2,5-dienes (204) mediated by Bu"Li has been reported to produce the corresponding bicyclic allylic amines (205) with high... 

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... 

This chemistry was extended to a number of bicyclic alkenes and dienes utilizing various chelating axially chiral bisphosphine iridium catalysts (Scheme 11.5) [29]. Further synthetic transformations of the chiral hydroamination product 13 provide access to functionally substituted chiral cyclopentylamines with multiple stereocenters, such as 14 and IS. It should be noted that alkylamines, such as octylamine or N methyl aniline, and sterically encumbered aniline derivatives, such as 0 toluidine or o anisidine did not undergo hydroamination reactions under these conditions. 

Scheme 77). The product 239 was converted to (+)-pyrrolidine-197B 240. The tandem hydroamination/ cyclization of the allenylalkenylamine 241 occurred in the presence of the samarium catalyst 201 to give the bicyclic pyrrolizidine 242 in a high yield (Scheme 78). Hydrogenation of 242 led to (+)-xenovenine 243. 

Alternatively, hooper and Bhonde used an early-stage Ag(I)-initiated hydroamination cascade reaction to assemble first a bicyclic guanidinium core. This elegant cascade reaction assembles two C-N bonds, one C-O bond, and three rings to give... 

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]. 

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. 

---