Hydroamination intramolecular reactions

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

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

Addition of ammonia and amines to alkenes (hydroamination) is thermodynamically feasible, but kinetically hindered, hence it requires activation of either of the reactants1,2,51. The intramolecular reaction is generally more easily accomplished than the intermolecular reaction and allows the stereochemistry to be controlled to a certain degree. 

The catalytic activity of the chiral complexes [Ln(L)Z2] shown in Scheme 70 was investigated in NMR-scale intramolecular hydroamination/cyclization reactions [135]. The rate dependence on the ionic radii of the center metal was studied by using 5 mol% bisoxazoline L32 and [Ln N(SiMe3)2 3] as precatalysts and 2,2-dimethyl-4-penten-l-amine as substrate (Scheme 71). The reaction rate as well as the enantioselectivities increased with increasing radius of the center metal. Therefore, the lanthanum compound 184 was the most active catalyst among the investigated complexes. 

The reaction involves initial formation of the zirconium-imido species, followed by [2-1-2] cycloaddition with the C—C unsaturation (Scheme 13). This is consistent with the observation that bis(amidate) complexes do not mediate hydroamination with secondary amine containing substrates. The cyclic transition state of the intramolecular reaction determines the regioselectivity of the reaction followed by successive protonation of the intermediate metallacycle and release of product to regenerate the catalyticaUy active imido species. 

Kinetic studies in the intramolecular hydroamination/cyclization reaction show first order dependence on the precatalyst and zero order dependence on the substrate, making the kinetic rate law as described in 14 [104]. 

The insertion approach is very successful in the hydroamination of alkynes and alkenes catalyzed by lanthanide complexes developed by Marks et al. [220]. Thorough mechanistic studies have been undertaken for the intramolecular reaction (hydroamination-cyclization of aminoalkenes), although the intermolecular version of the process is also efficient [222]. The mechanism of the reaction can be represented in a simplified way by Scheme 6.68. The insertion step is almost thermoneutral, but the protonolysis of the M-aminoalkyl bond that follows is exothermic and provides the necessary driving force. The insertion of the alkene into the Ln-N bond is irreversible and rate determining and it goes through a... 

The first hydroaminations by this mechanism were reported by Bergman with zircono-cene complexes and by Livinghouse with monocyclopentadienyl titanium and zirconium complexes. Bergman reported the intermolecular addition of a hindered aniline to an alkyne. The hindrance of the aniline was important to prevent formation of stable dimeric complexes containing bridging imido groups. Livinghouse reported intramolecular reactions that occurred at lower temperatures over shorter times. The intramolecularity of this process allows the [2+2] cycloaddition of the imido complex with the alkyne to be faster than the dimerization. 

The bulk of the studies on intramolecular hydroamination of alkenes catalyzed by lanthanide complexes have been conducted using lanthanocene complexes or half-sandwich lanthanide complexes. The prototypical cyclizations of aminoalkenes to form five- and six-membered rings are shown in Equation 16.61. These reactions occur with exclusive Markovnikov selectivity. These reactions have also been conducted using arylamines, as shown in Equation 16.62. The intramolecular reactions of amines catalyzed by certain lanthanide complexes occur with 1,1- and 1,2-disubstituted olefins (Equation 16.63), although such reactions require high temperatures. 

The hydroamination of alkynes catalyzed by group 4 complexes were some of the first transition-metal-catalyzed hydroamination reactions. One example of these reactions is shown in Equation 16.84. The reactions only occur with hindered amines and are slow. Nevertheless, the reactions occur m high yield and, in the absence of air, the catalysts are stable indefinitely. An early intramolecular reaction catalyzed by CpTiClj to form a cyclic enamine is shown in Equation 16.85. Reactions with internal alkynes occur to form products with Markovnikov regiochemistry. ° As described in more detail below, tliese reactions occur by [2+2] additions of the alkyne to an intermediate metal-imido complex. 

Some of the most active catalysts for the hydroamination of alkynes are based on lanthanides and actinides. The turnover frequencies for the additions are higher than those for lanthanide-catalyzed additions to alkenes by one or two orders of magnitude. Thus, intermolecular addition occurs with acceptable rates. Examples of both intermolecular and intramolecular reactions have been reported (Equations 16.87 and 16.88). Tandem processes initiated by hydroamination have also been reported. As shown in Equation 16.89, intramolecular hydroamination of an alk5me, followed by cyclization with the remaining olefin, generates a pyrrolizidine skeleton. Hydroaminations of aminoalkynes have also been conducted with the metallocenes of the actinides uranium and thorium. - These hydroaminations catalyzed by lanthanide and actinide complexes occur by insertion of the alkyne into a metal-amido intermediate. 

Similar reasons seem to count also for the promising catalytic experiments with the dimeric Rh and Ir complexes 37 and 39 which bear the same CCC pincer ligand in the intramolecular hydroamination of terminal olefins. Up to now, the air- and water-stable catalyst system is limited to the intramolecular reaction of P-disubstituted secondary amines. 

In recent years, several groups have developed enantioselective tandem reactions based on the combination of gold catalysis and organocatalysis. Among them, Gong et al. reported that an achiral gold complex compatibly worked with a chiral phosphoric acid to promote a domino intramolecular hydroamination-reduction reaction, readily transforming... 

Scheme 7.30 Domino intramolecular hydroamination-reduction reaction catalysed by chiral phosphoric acid catalysis and gold catalysis.

Although hydroamination reactions are regiospecific in most cases, the stereoselective synthesis of pharmaceutically relevant chiral amines via hydroamination remains challenging despite significant progress for asymmetric intramolecular reactions and some initial reports on asymmetric intermolecular hydroamination. Selected examples of asymmetric hydroamination will be covered in this chapter due to the volume limitations, and the reader should refer to available specialized reviews for a more comprehensive coverage of the stereoselective aspects [8-15]. 

The Rh and Ir complexes 85-88 (Fig. 2.14) have been tested for the intramolecular hydroamination/cyclisation of 4-pentyn-l-amine to 2-methyl-1-pyrroline (n = 1). The reactions were carried out at 60°C (1-1.5 mol%) in THF or CDCI3 The analogous rhodium systems were more active. Furthermore, the activity of 87 is higher than 85 under the same conditions, which was attributed to the hemilabihty of the P donor in the former complex, or to differences in the trans-eSects of the phosphine and NHC ligands, which may increase the lability of the coordinated CO in the pre-catalyst [75,76]. 

The pincer complexes 89-90 (Fig. 2.14) catalyse the intramolecular hydroamination/ cyclisation of unactivated alkenes, yielding pyrrolidines and piperidines (n = 1,2, respectively). The reactions can be carried out in benzene or water with high... 

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]. 

Cationic palladium(II) complexes are homogeneous catalysts for both intramolecular and inter-molecular hydroamination reactions.267 Palladium species immobilized on silica can be prepared by the simple addition of alkyl- or hydroxopalladium(II) complexes to partially dehydroxylated silica. The silica-bound species are more stable than their molecular precursors and are efficient catalysts for the cyclization of aminoalkynes.268... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Hydroamination of olefins under most catalytic conditions proceed with Markovnikov addition of the N-H bond across the olefin. Shown below is a rhodium-catalyzed intramolecular, anti-Markovnikov, hydroamination developed for the synthesis of 3-arylpiperidines 167 <06JA6042>. Further evaluation of this reaction as a synthesis of multisubstituted piperidines revealed that substrates with substituents a or y to the amino group did not produce the expected piperidine, however, substrates with a substituent (1 to the amino group produce piperidines in high yield. 

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