Markovnikov reactions hydroamination

Nickel catalysts promoted the addition of nitrogen nucleophiles to internal alkynes [138] TMS-protected alkynes are excellent snbstrates for the base-assisted anti-Markovnikov selective hydroamination reaction [143]. No need to remove the protecting group prior to the hydroelementation reaction Tetrahydropyridines have been generated through the treatment of dihydropyrans with aniline precursors [149]... 

Hydroamination of activated alkenes has been reported with complexes 91-93 (Fig. 2.15). For example, 91 catalyses the hydroamination of methacrylonitrile (X = CN in Scheme 2.13) by a range of secondary amines (morpholine, thiomorpholine, piperidine, iV-methylpiperazine or aniline) in good to excellent conversions (67-99%) and anfi-Markovnikov regioselectivity (5 mol%, -80°C or rt, 24-72 h). Low enantioselectivies were induced ee 30-50%) depending on the amine used and the reaction temperature [79]. 

The hydroaminations of electron-deficient alkenes with aniline or small primary alkylamines proceed at high conversions (85-95%, nnder mild conditions, 5 mol%, rt), giving exclnsively the anh-Markovnikov addition product. Secondary dialkyl or bnlky primary amines require longer reaction times. With amines containing P-hydrogens, no imine side-products were observed. 

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]. 

With some secondary amines, especially morpholine, the reaction leads to a mixture of the oxidative amination product and of the hydroamination product, both corresponding to an anh-Markovnikov addition (Eq. 4.39) [166]. 

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]. 

The hydroamination of alkynes with primary and secondary ahphatic amines necessitates the use of higher amounts of catalyst (17%) and higher temperatures, and TOFs are low (<1 h ) [260]. With ahphatic and aromatic terminal alkynes and a 5-fold excess of primary aliphahc amines, the products are the corresponding imines (40-78% yield, TOF up to 0.3 h ). In contrast to the CujClj-catalyzed reaction of phenylacetylene and secondary ahphatic amines (Scheme 4-12), the HgClj-catalyzed reachon is fully regioselechve for the Markovnikov hydroamination products which do not evolve under the reachon condihons (Eq. 4.66) [260]. 

The stoichiometric hydroamination of unsymmetrically disubstituted alkynes is highly regioselective, generating the azametaUacycle with the larger alkyne substituent a to the metal center [294, 295]. In others words, the enamine or imine formed results from an anti-Markovnikov addition. Unfortunately, this reaction could not be applied to less stericaUy hindered amines. 

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. 

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]. 

Iron salts (e.g. FeCls) have been identified as new catalysts for intramolecular hydroamination. A number of olefinic tosylamides underwent the reaction at 80 °C to form the corresponding the N-tosylpyrrolidine derivatives in good yield.63 The same salt can also catalyse Markovnikov addition of electron-rich arenes and heteroarenes to styrenes, giving rise to 1,1-diarylalkanes at 80 °C.64... 

Since more reactive alkenes, such as vinyl arenes or sterically strained polycycles, react more readily in the hydroamination reaction, several asymmetric hydroami nation reactions utilizing these substrates have been disclosed. Weakly basic anilines can react with vinyl arenes to give the Markovnikov addition products 6 and 7 with good yields and enantioselectivities in the presence ofa chiral phosphine ligand Pd complex as demonstrated by Hartwig (Eq. 11.3) [13] and later by Hii (Eq. 11.4) [14]. 

Intermolecular additions of primary amines to alkenes have also been reported using lanthanide catalysts. These reactions, although slow, do occur to high conversion. Similar to hydroaminations catalyzed by late transition metal complexes, these reactions form the products from Markovnikov addition of the N-H bond across the olefin. One example of such a reaction is shown in Equation 16.59. ... 

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. 

Catalysts for tfie additions of amines to vinylarenes have also been developed. These catalytic reactions include some of the first hydroaminations of unstrained olefins catalyzed by late transition metals, as well as examples catalyzed by lanthanide complexes. These additions occur with Markovrukov selectivity with one set of catalysts and with anti-Markovnikov selectivity with several others. These additions occur by several different mechanisms that are presented in Section 16.5.3.2. 

Ruthenium complexes also catalyze the anti-Markovnikov hydroamination of vinylarenes. In this case, the combination of l,5-bis(diphenylphosphino)pentane (DPPPent), triflic acid, and a ruthenium(II) precursor generates a catalyst for the additions of secondary amines to vinylarenes (Equation 16.72). This mixture of catalyst components has been shown to generate a cationic Ti -arene complex of a PCP pincer ligand generated from the DPPPent ligand. The mechanism of this reaction involves nucleophilic attack of the amine on an Ti -vinylarene complex, as described in more detail in the section on the mechanisms of hydroamination. 

Finally, a much different catalyst, a lanthanocene, generates (3-phenethylamines from the anti-Markovnikov hydroamination of vinylarenes and primary alkylamines (Equation 16.73). These reactions occur with vinylarenes containing a range of electronic properties. The reaction is thought to occur by insertion of styrene into a lanthanum-amido complex. 

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. 

Examples of palladium- and rhodium-catalyzed hydroaminations of alkynes are shown in Equations 16.90-16.92 and Table 16.9. The reaction in Equation 16.90 is one of many examples of intramolecular hydroaminations to form indoles that are catalyzed by palladium complexes. The reaction in Equation 16.91 shows earlier versions of this transformation to form pyrroles by the intramolecular hydroamination of amino-substituted propargyl alcohols. More recently, intramolecular hydroaminations of alkynes catalyzed by complexes of rhodium and iridium containing nitrogen donor ligands have been reported, and intermolecular hydroaminations of terminal alkynes at room temperature catalyzed by the combination of a cationic rhodium precursor and tricyclohexylphosphine are known. The latter reaction forms the Markovnikov addition product, as shown in Equation 16.92 and Table 16.9. These reactions catalyzed by rhodium and iridium complexes are presumed to occur by nucleophilic attack on a coordinated alkyne. 

Beller took advantage of simple Zn salts and used Zn(OTf)2 for the hydroamination of terminal aUcynes with arylamines (218). These reactions require similar temperatures as has been reported for other late transition metal catalysts (100-120 °C) and as is most commonly observed for this combination of substrates, the Markovnikov product is preferred (Scheme 15.37). 

Other Pt(II) catalysts in ionic solvent have been disclosed for alkene hydroamina-tion, including ethylene hydroamination (Section 15.3.2) by Brunet and coworkers [109, 112]. This same catalyst system can promote intermolecular hydroamination of unactivated 1-hexene to give a mixture of products, with the Markovnikov product being formed preferentially (Scheme 15.50) [109]. Even in this specialized reaction medium, elevated temperatures and long reaction times are required with these challenging unactivated substrates. 

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