Hydroamination anti-Markovnikov reaction

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]... 

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 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]. 

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. 

Related carbodiphosphoranes of Cu(I)- and Au(I)-t-butoxide complexes (47) have been prepared and rigorously characterized. Both complexes were explored for the anti-Markovnikov hydroamination of acrylonitrile with aniline (Scheme 15.59). The Cu(I) system provided higher conversions to product over the Au(I) complex, and under the reaction conditions explored, only the Cu catalyst yielded high conversions under an argon atmosphere [257]. 

Cationic Ni(II)-pincer complexes have also been exploited for the hydroamination of acrylonitrile with anihne [258]. Stoichiometric reactions in this case suggest that a Lewis acid mechanism promoting the anti-Markovnikov hydroamination is active (Figure 15.7) [258]. 

In 1999, Doye disclosed that dimethyltitanocene is a catalyst widely applicable to intermolecular hydroamination of alkynes with primary aryl- and alkylamines [302]. In the case of unsymmetrically substituted alkynes, the reaction occurs with high re-gioselectivity, forming the anti-Markovnikov products exclusively (Scheme 14.127). Kinetic studies suggest that the reaction mechanism involves the formation of a Ti-imido complex as the catalytically active species. Doye further developed a tandem Ti-catalyzed protocol of alkyne hydroamination and imine reduction, affording secondary amines in a fully catalytic one-pot reaction [303]. 

Schafer found that the bulky bis(amidate) complex is an effective catalyst for intermolecular hydroamination of terminal alkyl alkynes with alkylamines, giving exclusively the anti-Markovnikov aldimine product [309]. The same titanium complexes can also be utilized in the hydroamination of substituted allenes in good yields (Scheme 14.132). Under the catalysis of an imidotitanium complex, the highly strained methylenecyclopropane can undergo hydroamination reaction with either aromatic or aliphatic amines, to give ring-opened imine products in good to excellent yields and chemoselectivities [310]. 

The anti-Markovnikov addition of nitrogen nucleophiles to alkynes has been accomplished using ruthenium catalysts (Scheme 3.125) [137]. During the screening process, the authors discovered that when the reactions were carried out at 80 °C, moderate yields of the hydroamination products were obtained (50%) however, the stereocontrol was poor and a 4 1 ( ratio of the enamines was obtained. When the temperature was increased to 100°C, the Zi-isomer was obtained exclusively. At the higher temperatures, most substrates exclusively generated the E-isomer, although some substrate-specific reactivity was observed. 

Need to carry out an anti-Markovnikov hydroamination reaction (E-selective) between an aniline and a terminal alkyne... 

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 anti-Markovnikov addition (Eq. 4.39) [166]. 

A-Alkylation of amides and amines and dehydrative -alkylation of secondary alcohols and a-alkylation of methyl ketones " have been carried out by an activation of alcohols by aerobic oxidation to aldehydes, with copper(II) acetate as the only catalyst. A relay race process rather than the conventional borrowing hydrogen-type mechanisms has been proposed for the aerobic C-alkylation reactions, based on results of mechanistic studies. A Winterfeldt oxidation of substituted 1,2,3,4-tetrahydro-y-carboline derivatives provides a convenient and efiflcient method for the synthesis of the corresponding dihydropyrrolo[3,2-fc]quinolone derivatives in moderate to excellent yields. The generality and substrate scope of this aerobic oxidation have been explored and a possible reaction mechanism has been proposed. Direct oxidative synthesis of amides from acetylenes and secondary amines by using oxygen as an oxidant has been developed in which l,8-diazabicyclo[5.4.0]undec-7-ene was used as the key additive and copper(I) bromide as the catalyst. It has been postulated that initially formed copper(I) acetylide plays an important role in the oxidative process. Furthermore, it has been postulated that an ct-aminovinylcopper(I) complex, the anti-Markovnikov hydroamination product of copper acetylide, is involved in the reported reaction system. Copper(I) bromide... 

A number of actinide complexes have been investigated with respect to their catalytic activity in the intermolecular hydroamination of terminal alkynes with primary ahphatic and aromatic amines [98, 206-209]. Secondary amines generally do not react and the reaction is believed to proceed via an metal-imido species similar to that of group 4 metal complexes. The reaction of Cp 2UMc2 with sterically less-demanding aliphatic amines leads exclusively to the anti-Markovnikov adduct in form of the -imine (31) [207] however, sterically more demanding amines, e.g., t-BuNH2, result in exclusive alkyne dimerization. The ferrocene-diamido uranium complex 12 (Fig. 4) catalyzes the addition of aromatic amines very efficiently (32) [98]. 

The experiments illustrated in Eqs. (6) and (7) clearly indicate that the reaction proceeds in an irreversible and direct manner. (1) In Eq. (6), the coexistent hydroamination adduct 29 afforded neither free styrene nor crossover products, indicating that the hydroamination is an irreversible process. (2) In the reaction of 2,5-dimethylstyrene (27) with morphorine (28) in Eq. (7), an additive, Markovnikov-type adduct 31, did not isomerize to anti-Markovnikov-type adduct. (3) The kinetic study on the amination process revealed a large negative of —213 J mol s , which is similar to the value of the nitroalkene amination. The first-order rate constant of the arene exchange process is comparable to that of the amination process. (4) The conjugate addition nature was confirmed by using... 

The intermolecular hydroamination reactions of alkynes and alkenes occur with Markovnikov or anti-Markovnikov selectivity. The nucleophilic addition to aUenes occurs at terminal carbon of allenes not at central one. 

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