Hydroamination mechanisms

Nettekoven U, Hartwig JF (2002) A new pathway for hydroamination. mechanism of palladium-catalyzed addition of anilines to vinylarenes. J Am Chem Soc 124 1166-1167... 

The proposed reaction mechanism involves intermolecular nucleophilic addition of the amido ligand to the olefin to produce a zwitterionic intermediate, followed by proton transfer to form a new copper amido complex. Reaction with additional amine (presnmably via coordination to Cn) yields the hydroamination prodnct and regenerates the original copper catalyst (Scheme 2.15). In addition to the NHC complexes 94 and 95, copper amido complexes with the chelating diphosphine l,2-bis-(di-tert-bntylphosphino)-ethane also catalyse the reaction [81, 82]. 

Scheme 2.15 Postulated mechanism for the copper-catalysed hydroamination of electron-deficient alkenes...

Anfj-Markovnikov products are only observed. The postulated mechanism for these reactions is analogous to the previously discussed for the copper-catalysed hydroamination (Scheme 2.15) with the coordinated thiolate (rather than the amide) acting as nucleophile [82, 85]. 

Kovacs, G., Ujaque, G. and Lledos, A. (2008) The Reaction Mechanism of the Hydroamination of Alkenes Catalyzed by Gold(I)-Phosphine The Role of the Counterion and the N-Nucleophile Substituents in the Proton-Transfer Step. Journal of the American Chemical Society, 130, 853-864. 

Both heterogeneous and homogeneous catalysts have been found which allow the hydroamination reaction to occur. For heterogeneously catalyzed reactions, it is very difficult to determine which type of activation is involved. In contrast, for homogeneously catalyzed hydroaminations, it is often possible to determine which of the reactants has been activated (the unsaturated hydrocarbon or the amine) and to propose reaction mechanisms (catalytic cycles). 

Study of the mechanism of the rhodium-catalyzed hydroamination of ethylene with secondary amines indicated that the piperidine complex trans-RhCl(C2H4)(piperidine)2 can serve as a catalyst precursor [109, 110]. 

The reaction mechanism is believed to involve a domino hydroamination-in-tramolecular arynic condensation. Indeed, the same results are obtained from either 2- and 3-chlorostyrenes [159]. 

Although N-(2-phenylethyl)morpholine is formed in only 14% yield (TOE = 0.3 h ), this is the first example of a transition metal-catalyzed anti-Markovnikov hydroamination of a non-activated olefin. Concerning the reaction mechanism, labeling experiments led the authors to favor activation of the N-H bond over olefin activation [166]. 

Scheme 4-13 Mechanism of the HgCl2-catalyzed hydroamination of terminal alkynes...

Similar to the addition of secondary phosphine-borane complexes to alkynes described in Scheme 6.137, the same hydrophosphination agents can also be added to alkenes under broadly similar reaction conditions, leading to alkylarylphosphines (Scheme 6.138) [274], Again, the expected anti-Markovnikov addition products were obtained exclusively. In some cases, the additions also proceeded at room temperature, but required much longer reaction times (2 days). Treatment of the phosphine-borane complexes with a chiral alkene such as (-)-/ -pinene led to chiral cyclohexene derivatives through a radical-initiated ring-opening mechanism. In related work, Ackerman and coworkers described microwave-assisted Lewis acid-mediated inter-molecular hydroamination reactions of norbornene [275]. 

Based on the established mechanism for titanium-catalyzed hydroamination, the authors propose a reversible reaction between a titanium imide complex and the alkyne to form metalloazacyclobutene 86, which in turn undergoes 1,1-insertion of the isonitrile into the Ti-C bond. The generated five-membered ring iminoacyl-amido complex 87 with the new C-C bond is protonated by the primary amine to afford the desired three-component coupling product, with regeneration of the catalytic imidotitanium species. Very recently, titanium-catalyzed carbon-carbon bond-forming reactions have been reviewed.122... 

In order to account for the high regioselectivities observed in the rhodium-catalyzed hydroboration of styrenes, Hayashi proposed a modified mechanism which proceeds through 73-benzyl-rhodium complex 22 as a key intermediate (Scheme 7). Reductive elimination from this 73-benzyl-rhodium complex 22 produces the secondary alkylborane regioselectively.12 A related 73-benzyl-palladium complex was recently isolated by Hartwig in studies of hydroamination.75... 

The intramolecular hydroamination of substrates 170 is catalyzed by a Pd(0) catalyst which is generated in situ from a Pd(II) precursor and a phosphane. One equivalent of acetic acid has to be added for efficient catalysis this is a hint of a hydropallada-tion mechanism. Meguro and Yamamoto obtained good yields of the vinyltetrahy-dropyrroles or the vinylhexahydropyridines 171 in that way (Scheme 15.53) [109]. 

Scheme 6.4 The proposed mechanism for the intramolecular alkane hydroamination/cyclization reaction (Equation 6.10)...

Chatani s proposed mechanism bears some similarity to that of Jun s reaction (Scheme 9.12). They both begin with hydroamination of the C=C 7t-bond of a rhodium vinylidene. The resultant aminocarbene complexes (71 and 62) are each in equilibrium with two tautomers. The conversion of 71 to imidoyl-alkyne complex 74 involves an intramolecular olefin hydroalkynylation. Intramolecular syn-carbome-tallation of intermediate 74 is thought to be responsible for ring closure and the apparent stereospecificity of the overall reaction. In the light of the complexity of Chatani and coworkers mechanism, the levels of chemoselectivity that they achieved should be considered remarkable. For example, 5 -endo-cyclization of intermediate 72 was not observed, though it has been for more stabilized rhodium aminocarbenes bearing pendant olefins [27]. 

The latter transformation requires the use of a small amount of an acid or its ammonium salt. By using [Cp2TiMe2] as the catalyst, primary anilines as well as steri-cally hindered tert-alkyl- and sec-alkylamines can be reacted.596 Hydroamination with sterically less hindered amines are very slow. This was explained by a mechanism in which equlibrium between the catalytically active [L1L2Ti=NR] imido complex and ist dimer for sterically hindered amines favors a fast reaction. Lantha-nade metallocenes catalyze the regiospecific addition of primary amines to alkenes, dienes, and alkynes.598 The rates, however, are several orders of magnitude lower than those of the corresponding intramolecular additions. 

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 mechanism of polyamine hydrogenation (Fig. 6.8) is believed to involve successive electron transfer (from polyamine to fullerene) - proton transfer (from polyamine radical cation to fullerene radical anion) steps (Briggs et al. 2005 Kintigh et al. 2007). At or near room temperature, aliphatic amines and polyamines are known to hydroaminate [60]fullerene (Miller 2006), likely also involving preliminary electron transfer - proton transfer steps followed by free radical coupling of C and N based radicals (Fig. 6.8). At elevated temperatures in polyamine solution, however, this latter free radical coupling step becomes uncompetitive with... 

Fig. 6.8 Proposed mechanism for the polyamine hydrogenation of [60]fullerene and its relationship to hydroamination (Briggs et al. 2005 Kintigh et al. 2007)...

Hydrido(trialkylsilyl)silyllithiums, preparation, 3, 424 Hydroacylations, olefins, 10, 142 Hydroalkoxylations and etherification, 10, 672 in etherification, 10, 683 Hydroaluminations for C-E bond formation characteristics, 10, 857 chemoselectivity, 10, 859 mechanism, 10, 858 overview, 10, 839-870 stereoselectivity, 10, 861 total synthesis applications, 10, 865 characteristics, 3, 275 process and examples, 9, 268 via Ti(IV) complexes, 4, 658 Hydroaminations actinide-catalyzed, 4, 237 in aminations... 

Scheme 18. Mechanism scheme for organolanthanide-catalyzed hydroamination...

Figure 50. Proposed mechanism for catalytic asymmetric hydroamination/cyclization.

Figure 11 Predicted 13C KIEs for alternative mechanisms of catalysed hydroamination of styrene with aniline in benzene at 80°C (see text).

Figure 9.1 Proposed reaction mechanism for the Zn2+ catalysed hydroamination...

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