Hydroamination diastereoselective

A lanthanide-mediated, sequential hydroamination/C-C cyclization reaction served to prepare the benzo[ ]quino-lizine derivative 358 from precursor 357, using a Nd species as a catalyst (Equation 12). This cascade process proceeded in good yield and with high diastereoselectivity <2003T10581>. 

Hydroamination of Allenes Different related amines can also be cyclized. The use of free amino groups led to long reaction times (several days), but sulfonamides, acetyl or BOc as protecting group led to fast conversion (in the latter case, problems of diastereoselectivity were observed). Optimization studies showed that, although cationic gold (I) complexes were not effective for these conversions, AuCI was a very good catalyst for these reactions. 

Very recently, Genet and Michelet developed a diastereoselective reaction that took place by hydroamination of an unactivated alkene followed by a cydization process under very mild conditions. This 1,6-enyne reaction was compatible with electron-poor aromatic amines, including amines bearing chloride atoms (Equation 8.73), which is very useful for further functionalization of the substituted aniline ring [164]. 

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. 

A desymmetrization of cyclohexa-2,5-dienes (22) and (24), obtained by Birch reductive alkylation, through a diastereoselective intramolecular hydroamination led with high selectivity to the corresponding bicyclic allylic amines (23) and (25) (Scheme 6).19... 

The mechanism does not proceed through a direct hydroamination of one of the diastereotopic alkenes, but involves a series of very selective processes including a deprotonation of (22), diastereoselective protonation of (26), intramolecular addition of lithium amide (27) to the 1,3-diene moiety, and final regioselective protonation of the allyl anion (28), all mediated by a substoichiometric amount of n-BuLi. 

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]. 

Examples of the hydroamination of chiral alkenes in which substrate-induced diastereoselectivity would be expected to be observed are lacking in the literature. 

The diastereoselective addition of aniline to norbornene was accomplished using a catalytic amount of iridium(I). As the intermediate azametallacyclobutane 2 could be isolated its stereochemistry was determined by X-ray analysis both iridium and nitrogen occupy the exo position41. However, the scope of the amination method, with respect to the nature of the amine and the structure of the alkene, was not determined. Conversely, the analogous rhodium(I)-cat-alyzed reactions of norbornene and aromatic amines gave mixtures of hydroamination and hydroarylation products106. 

Cyclic Amines by Intramolecular Hydroamination and Carboamination Substrate-Induced Diastereoselectivity... 

A sequence of inter- and intramolecular hydroaminations and carbocyclizations of the aminoalkeneyne 34 substrate allows the facile assembly of the tricyclic polyheterocycle 35 with exclusive trani -diastereoselectivity (43) [99]. 

Trivinyl benzene may be utilized in a hydroamination/carbocyclization process that is initiated by an intramolecular anft -Markovnikov addition of n-propylamine followed by an intramolecular hydroamination and a highly diastereoselective car-bocyclization step (44) [100]. 

Scheme 11.25 Diastereoselective synthesis of pyrrolidine ( + ) 197B via hydroamination/...

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

Organolithium mediated cycloisomerization of chiral aminoalkenes may proceed with high diastereoselectivities when favored by the substrate geometry. The last step ofthe enantioselective synthesis of ( ) codeine (80), reported by Trost and Tang [121], consisted of an intramolecular hydroamination. Treatment of amine 79 with LDA or wBuLi in refluxing THF left the starting material unreacted. However, irradiation of the amine/LDA solution with a 150 W tungsten lamp led to diastereoselective cycloisomerization to form ( ) codeine (80) (Eq. 11.11). 

Recently, an elegant synthesis of hyacinthacine A2 was proposed by Fox and colleagues in which the pyrrolizidine skeleton was elaborated through a trans-annular hydroamination of a 5-aza-trans-cyclooctene such as XIV, in mm obtained via a diastereoselective photoisomerization of a c/s-octene XV (Scheme 24) [32]. The enantiopure cyclooctene was obtained from the chiral ketone 96, prepared via a three steps sequence from sucrose disaccharide [33]. 

Most importantly, this reaction demands control of regioselectivity and can also be carried out asymmetrically (Scheme 15.38). Thus, branched imine or linear allylamine products can be selectively prepared. Diastereoselective and enantiose-lective allene hydroamination can also be targeted with advances in enantioselective catalysis using late transition metals being reviewed in Section 15.3.7. 

More recently, reactivity investigations have explored the scope of reactivity of previously developed catalysts. With respect to advances in group-lO-catalyzed allene hydroamination, Widenhoefer [229] explored Pt(II) neutral and cationic species for the intermolecular hydroamination of allenes with secondary alkylamines to make aUylamine products with excellent regioselectivity and diastereoselectivity (E/Z) (Scheme 15.43). This work builds upon a 2005 report for neutral Pt(II) compleiKs for the intermolecular hydroamination of alkenes with secondary amines [230, 231]. In the 2010 report, a variety of cyclic and acyclic alkylamines can be used as substrates, although neither arylamines nor primary amines are disclosed as substrates. This system is also limited to monosubstituted allenes. Consistent with long-standing proposals [231], outer-sphere addition of the amine to a cationic Pt(II) It-allene complex is proposed [229]. 

In an effort to realize a readily accessible catalyst system capable of mediating allene hydroamination with a variety of substrates, Widenhoefer [239] showed that a commercially available bulky phosphine ligand (P(tBu)2-o-biphenyl) can be complexed to AuCl and activated in situ with AgOTf to generate catalytically active systems. 1,1-Disubstituted allenes react with primary and secondary arylamines to typically give the allylamine products in good to excellent yield at modest reaction temperatures (45 °C) within 24 h (Table 15.18). This same system can also mediate the hydroamination of 1,3-disubstituted allenes with modest to excellent diastereoselectivity (up to >25 1 /Z selectivity). No notable examples of primary or secondary alkylamines have been reported. 

Piperazines are an important drug scaffold in medicinal chemistry and selective approaches for their syntheses have been realized using hydroamination [348]. Using protected diaminoalkene substrates that are readily assembled from enan-tiopure amino alcohol precursors, Pd-catalyzed hydroamination can realize the diastereoselective ring closure to access the trans product selectively in excellent yields (>88% yield) (Scheme 15.113). Steric bulk in the 2-position is not favorable and to date, only terminal alkenes have been reported to be compatible with this hydroamination ring closure step. 

The aminoaUene hydroamination/cyclization reactions are highly diastereoselective and can provide concise routes to synthesize some natural products (Scheme 3). Using chiral organolanthanide complexes as catalysts, enantioselec-tive hydroamination/cychzation reactions are achieved, which provide a convenient route for the synthesis of chiral amines from simple, readily available prochiral substrates in a single step. 

Silver(I) salts are often utilized as catalysts for addition reactions. Kozmin and Sun have recently shown that AgNTf2 is a catalyst of choice for the hydroamination of siloxy alkynes with either secondary amides or carbamates to give silyl ketene am-inals [34]. The addition occurs in a syn selective manner, for instance, the reaction of siloxy alkyne (24) with carbamate (25) produces silyl ketene aminal (26) in 86% yield at room temperature under the influence of 1 mol% of AgNTf2 (Scheme 18.9). A six-membered chelated transition state is proposed to explain the high syn selectivity. Diastereoselective bromohydroxylation and bromomethoxylation reactions of cinnamoyl compounds possessing a chiral auxiliary are also effectively promoted by silver(I) salts such as AgNOs [35]. The asymmetric halohydrin reaction has been successfully applied into stereoselective syntheses of (-)-chloramphenicol and (+)-thiamphenicol. Csp-H iodination [36], hydrosilylation of aldehydes [37], and deprotection of TMS-alkynes [38] are also catalyzed by silver (I) salts. 

A relay catalytic hydroamination/redox reaction for the synthesis of cyclic aminals 83 from tertiary amine-substituted 3-en-l-yne derivatives 81 and various aniline derivatives 82 was recently developed by Gong and coworkers (Scheme 12.40) [43]. The gold carbene complex [(IPrlAuNTfj] and TfOH were found to be optimal cocatalysts for this cascade reaction. In their preliminary studies, the authors found that this reaction could be carried out in a highly enantioselective manner, despite that 2 equiv. of an expensive chiral phosphoric acid are required. Interestingly, the diastereoselectivity for a particular substrate appears to be independent of the catalyst or ee. This suggests that the enantioselectivity may result from the ring-closure step, rather than the hydride shift step. 

Asymmetric hydroamination has served as an important strategy for the synthesis of pyrrolidine and piperidine derivatives. Moreover, it has been found to be useful for the synthesis of other five- and six-membered heterocyclic compounds having more than one hetero atom. Asymmetric hydroamination and diastereoselective hydroamination have been found to be extremely useful for the synthesis of natural products and pharmaceutical agents. It is important to note that diastereoselective hydroamination has been... 

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