Amination hydroamination

Two mechanistically plausible scenarios for nucleophilic attack on the q benzyl palladium species seem feasible. Formation of the C N bond could occur either via external attack of the amine through inversion of configuration at the carbon stereocenter, or alternatively the amine could coordinate to palladium followed by an internal attack on the q benzyl ligand. Mechanistic investigations [15] using stoi chiometric amounts ofthe enantio and diastereomerically pure q benzyl palladium complex [ (R) Tol BINAP [q 1 (2 naphthyl)ethyl Pd](OTf) (8) revealed that the re action with aniline produced predominantly (R) N1 (2 naphthyl)ethylaniline R) 9), consistent with external nucleophilic attack (Scheme 11.3) [15]. However, it was noted that the catalytic reaction of [ (1 ) Tol BINAP Pd(OTf)2] with vinyl arenes and amines produced preferentially the opposite enantiomeric (S) amine hydroamination... 

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

The formation of a bis(guanidinate)-supported titanium imido complex has been achieved in different ways, two of which are illustrated in Scheme 90. The product is an effective catalyst for the hydroamination of alkynes (cf. Section V.B). It also undergoes clean exchange reactions with other aromatic amines to afford new imide complexes such as [Me2NC(NPr )2]2Ti = NC6F5. ... 

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]. 

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. 

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]. 

Hydroaminomethylahon of alkenes [path (c)j wiU not be considered [12]. This review deals exclusively with the hydroaminahon reaction [path (d)], i.e. the direct addition of the N-H bond of NH3 or amines across unsaturated carbon-carbon bonds. It is devoted to the state of the art for the catalytic hydroamination of alkenes and styrenes but also of alkynes, 1,3-dienes and allenes, with no mention of activated substrates (such as Michael acceptors) for which the hydroamination occurs without catalysts. Similarly, the reachon of the N-H bond of amine derivatives such as carboxamides, tosylamides, ureas, etc. will not be considered. 

From a thermodynamic point of view, the addihon of NH3 and amines to olefins is feasible. For example, the free enthalpy for the addihon of NH3 to ethylene is AG° -4 kcal/mol [14]. Calculations showed that the enthalpies for the hydroamination of higher alkenes are in the range -7 to -16 kcal/mol and that the exothermicities of both hydrahon and hydroaminahon of alkenes are closely similar [15]. Such N-H addihons, however, are characterized by a high activation barrier which prevents the... 

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). 

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]. 

The first example of acid catalysis appeared in a 1934 patent in which it is claimed that surface catalysts, particularly hydrosilicates of large surface area , known at that time under the trade name Tonsil, Franconit, Granisol, etc. lead to a smooth addition of the olefine to the molecule of the primary aromatic amine . Aniline and cyclohexene were reacted over Tonsil at 230-240°C to give, inter alia, the hydroamination product, N-cyclohexylaniline [47]. 

Hegedus et al. have thoroughly studied the homogeneous hydroamination of olefins in the presence of transition metal complexes. However, most of these reactions are either promoted or assisted, i.e. are stoichiometric reactions of an amine with a coordinated alkene [98-101] or, if catalytic, give rise to the oxidative hydroamination products, as for example in the cyclization of o-allylanilines to 2-alkylindoles [102, 103], i.e. are relevant to Wacker-type chemistry [104]. 

This reaction is restricted to ethylene and to secondary amines of high basicity (nude-ophUicity) and low steric bulk (Me2NH, pyrrolidine, piperidine). No high molecular weight products are formed. However, the same catalysts [107,108] as well as PdQj [108] also exhibit some activity for the hydroamination of ethylene with PhNH2 (Eq. 4.9). 

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]. 

As shown in Eqs. (4.11) and (4.12), some dealkylation of the starting amine and redistribution of alkyl groups occur. Hydroamination of ethylene with PhNHj affords a low-yield mixture of N-ethylaniUne, N,N-diethylaniline, 2-methylquinoUne, 2-(l-butenyl)aniline, and N-ethyltoluidine [113, 114]. 

Using the above preformed catalysts, ethylene can be hydroaminated by primary and secondary amines under much lower pressures (3-55 atm) than those required for the reactions catalyzed by alkali metals (800-1200 atm). The example of N-ethyl-ation of piperidine has been described in full details in Organic Syntheses (Eq. 4.14) [120]. 

Lehmkuhl et al. demonstrated the beneficial effect of TMEDA (N,N,N, N -tetram-ethylethylenediamine) on the addition of n-BuNHj to ethylene catalyzed by n-BuNHIi (from n-BuNH2 and EtLi) [121]. This is also tme for secondary amines. The efficiency of this system is exemplified by the hydroamination of ethylene with EtjNH (Eq. 4.15). 

Nevertheless, hydroamination of ethylene, propene, 1-butene, and the like with NH3, primary and secondary amines using Cp 2Sm(thf)2 (0.5-1%) has been claimed in a patent [128]. 

Lithium alkylamides (in situ generated from the amine and either n-BuLi or sec-BuLi) generally give higher yields under milder conditions. Thus, n-BuLi (5%) catalyzes the addition of primary and secondary amines to styrene to afford (-phenethy-lamines in moderate to good yields (e.g., Bq. 4.32) [155]. NH, and PhNHj, however, do not add to styrene under these conditions. a-Methylstyrene and 1,1-diphenyleth-ylene can also be hydroaminated. 

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]. 

Butadiene and isoprene give rise to mixtures of what are usually called telom-ers, namely 1 1 telomers between the amine and the 1,3-diene (trae hydroamination products), 1 2 telomers and even higher homologs together with oligomers of the diene as exemplified in Eq. (4.41). 

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 RhCf.lHjO to give a mixture of 1,2-(Markoviiikov) and 1,4-hydroamination products in good overall yield (Eq. 4.42) [171,172). 

The same catalytic system has been tested for the hydroamination of 1,3-butadiene with cyclic amines from the three-membered ring aziridine to the seven-mem-bered ring perhydroazepine. Although arizidine does not lead to a hydroamination reaction, all other cyclic amines give rise to a mixture of 1 1 telomers in fair to excellent yields (e.g., Eq. 4.47) [181]. 

Scheme4-5 Intermediates in the hydroamination vs. telomerization ofl,3-dienes 4.4.2.2 Activation ofthe Amine 4.4.2.2.1 Activation by Bases...

The first examples of hydroamination of 1,3-dienes catalyzed by alkali metals appeared as early as in 1928 for the production of pest destroying agents [197]. For example, reacting NH3 with 1,3-butadiene in the presence of sodium for more than 10 days yields 45% tri(butenyl)amine and 55% of high boiling bases rich in carbon (Eq. 4.52). 

Several other examples (50-60% yields) were provided, including hydroamination with primary amines, piperidine, anilines and hexamethylenediamine [197-199]. The special case of aziridine was reported to afford a mixture of isomers in a good yield [200]. 

Under the same conditions, the hydroamination of acetylene with primary or secondary aromatic amines brings about the formation of dimerization-cyclization products since the generated imines or enamines, respectively, are not stable. 

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 hydroamination of phenylacetylene with primary or secondary aromahc amines is also catalyzed by Tl(OAc)3 to give imines or enamines, respectively, in low to good yields (10-89%) with TOF up to 6 h [261]. 

Subshtuted 3-alken-l-ynes can be hydroaminated with primary or secondary aliphahc or aromatic amines at the alkynyl sites or at the alkynyl and at the alkenyl sites in the presence of Hg(ll) salts. However, the reachon is essentially stoichiometric in nature, even if the mercury compound can be recycled without apparent loss of achvity [262-264]. 

CsOH.HjO has also been shown to be a catalyst for the hydroamination of pheny-lacetylene with anihnes (Eq. 4.76) and heterocycUc secondary amines [160]. 

In 1992, Bergman et al. reported that zirconium bisamides Cp2Zr(NHR)2 catalyze the intermolecular hydroamination of alkynes with sterically hindered primary amines to give enamines or their tautomeric imines (e.g., Eq. 4.77) [126]. 

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 terminal alkynes with primary amines has been performed using organoactinides as catalysts [301, 302]. The organouranium complex Cp 2UMe catalyzes the regioselective formation of imines in fair to high yields (Eq. 4.82). 

The [(T -C3H5)PdCl]2/dppf/AcOH catalytic system has been used for the bis(hy-droamination) of 3-alken-l-ynes to alkenic 1,4-diamines (Eq. 4.94), a reaction which seems to be mechanistically related to the hydroamination of allenes since an a-al-lenic amine CH2=C=CH(R )CH2NR2 is believed to be an intermediate [318]. 

A Pd(0) /benzoic acid system has been found to catalyze the hydroamination of certain arylalkynes with secondary amines, a reaction which is also mechanistically related to the hydroamination of allenes, affording high yields of aUyhc amines (Eq. 4.95) [319]. 

The design of a general and efficient process for the hydroamination of alkenes would be a very important (economic) breakthrough for the production of amines. A... 

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