Markovnikov hydroamination products

It was thought that propionitrile came from dehydrogenation of the anti-Markovnikov hydroamination product, w-PrNHj. Propionitrile can break down to ethylene and HCN, the former reacting with NH3 to generate acetonitrile via ethyl-amine, the latter adding to propene to form the butyronitriles [26, 37]. 

PhNHEt and 1-heptyne afford a N-vinylamine as a stable Markovnikov hydroamination product (Eq. 4.64) [258]. 

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]. 

Under applied conditions (Equation (43)) the Markovnikov hydroamination product 23 was formed in 92% isolated yield.78 Changes in 13C composition were calculated using the aromatic para carbon atom as reference and the experimental KIEs are summarized in Figure 10. 

The range of amines involved may be expanded to more basic alkylamines (Eq. 11.5) [16]. Compound 10 was obtained in moderate yield and enantioselectivity utilizing the R,R) Et FerroTANE ligand. Note that almost stoichiometric amounts of a strong Bronsted acid are required to afford the Markovnikov hydroamination product of the vinyl arene. 

With terminal aUcynes, the direction of the reaction depends on the nature of the substituent, the type of amine and the catalyst Thus, dialkylamines can react with propyne to give 4-dialkylamino-4-methyl-2-pentynes traced from the Hy regioselec-tive formation of 2-dialkylaminopropene, i.e. the Markovnikov hydroamination product (Scheme 4-11) [256]. 

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... 

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. 

The first example of hydroamination of styrene in the presence of an alkali metal appeared in a patent in 1948, albeit with a low catalytic activity (Eq. 4.30) [149]. The anti-Markovnikov addition product was obtained. 

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 zirconium bisamides Cp2Zr(NHAr)2 do not catalyze the hydroamination of alkenes (see above), they are catalyst precursors for the hydroamination of the more reactive double bond of allenes to give the anti-Markovnikov addition product (Eq. 4.96) [126]. 

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]. 

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]. 

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. 

Alkyne hydroamination has been extensively reviewed [3, 4, 10] and important contributions using late transition metals have been realized to give the Markovnikov-type products most typically. Interestingly, in 2007, Fukumoto reported a tris(pyrazolyl borate)rhodium(l) complex for the anti-Markovnikov hydroamination of terminal aUcynes with both primary and secondary amine substrates, although yields with primary amines are always reduced compared to those with secondary amines (Scheme 15.26). Desirable functional group tolerance is also noteworthy for this regioselective hydroamination catalyst [187]. 

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]. 

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]. 

Addition of primary amine to a 1,4- or 1,5-diyne could be accomplished using titanium complex Ti(NMe2)2(dpma), resulting in an imine-yne that can undergo cyclization to the pyrrole derivatives. The Markovnikov hydroamina-tion products of 1,4-pentadiyne could undergo 5-endo-dig cyclization to yield a 2-methylpyrrole. Meanwhile, Markovnikov hydroamination of 1,5-hexandiyne would yield an imine-yne that could undergo 5-exo-dig cyclization to a 2,5-dimethylpyrrole [314] (Scheme 14.135). 

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. 

Rhodium catalysts have also found application in oxidative aminations of styrenes. Beller and co-workers observed that numerous styrenes reacted with various kinds of secondary aliphatic amines in the presence of the cationic rhodium complexe [Rh(cod)2]BF4 and PPhs. Regioselectively the corresponding anti-Markovnikov products ( -enamines) were formed [49], While the Markovnikov product was never observed under such conditions, the target enamine was mostly obtained along with hydrogenated olefin, and in some cases even small amounts of hydroaminated products were detected [50],... 

In fact, catalytic systems which effect solely the hydroamination of 1,3-butadiene and isoprene are rare and usually specific to the diene and to the amine. Thus morpholine adds to 1,3-butadiene in the presence of RhCh.3H20 to give a mixture of 1,2-(Markovnikov) and 1,4-hydroamination products in good overall yield (Eq. 4.42) [171,172). 

Gallium The hydroamination products ArCH(NArR )CH3 have now been obtained from the reaction of alkynes ArC=CH with aromatic amines ArNHR, catalysed by GaCl3, followed by reduction of the imine intermediates ArC(NArR )=CH2 with LiAlH4. DFT calculations suggest that the key step proceeds as a Markovnikov-type iyn-addition of GaCl3 and the amine across the C=C bond. ... 

Reactions of unsymmetric internal alkynes are more challenging, since two hydroamination products can be formed. The feasibility to control regioselectivity depends on the steric properties of both substrate and catalyst and a universal regioselective catalyst remains to be elaborated. When anilines are employed as reactants, high a t/-Markovnikov selectivity is obtained with titanocene catalysts 47 and 48 (Table 11) [182, 183] while aliphatic amines gave poor results. Again, the bis(indenyl)titanium catalyst 49 showed superior a t/-Markovnikov selectivity... 

A catalytic system comprising TiCNMe ), LiNCSilVIej) and IMes has been developed for the intermolecular hydroamination of terminal aliphatic alkynes (1-hexyne, 1-octyne, etc.) with anilines [toluene, 100°C, 10 mol% TiCNMe ) ]. Markovnikov products were dominant. Substituted anilines reacted similarly. High conversions (85-95%) were observed with specific anilines. The optimum Ti/IMes/ LiN(SiMe3)2 ratio was 1 2 1. However, the nature of the active species and especially the role of LiN(SiMe3)2 are unclear [74]. 

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]. 

As previously mentioned [155], PhNHj does not react with styrene under the above conditions. However, Beller et al. discovered that the hydroaminahon of styrene could be achieved in excellent yield by using either a w-BuLi-K2C03 mixture or, better, t-BuOK as catalysts [159]. Using LBuOK (10%) in THE at 120°C (pressure tube), styrene is hydroaminated with aniline (5 equiv.) to give the anh-Markovnikov product in 96% yield (Eq. 4.34), R = = R = R = H, TOE = 0.5 h ]. The scope of... 

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