1.4- hydroamination

Catalytic asymmetric hydroamination of alkenes can be achieved using early and late transition metal catalysts and lanthanide-based catalytic 

The most commonly used early transition metal catalysts are 

The intermolecialar hydroamination has also received some attention and studies in this area have focussed on the use of iridium and nickel catalysts. Enan-tioselectivities for the intermolecular process are also generally moderate with ees observed between 60 and 70%. The highest enantioselectivities for this reaction have been obtained during the hydroamination of norbornene (2.145) with aniline in the presence of the iridium complex (2.184) and the fluoride ion source 

The group of Hartwig has shown that dienes imdergo hydroamination with anihnes in the presence of the palladium catalyst formed in situ from [ Pd( 7r-allyl)Cl 2] and Trost s ligand (2.190). Under optimum conditions cyclohexa- 

3- diene (2.191) undergoes conversion into the aUylic amine (2.192) with 95% ee. a,p—Unsaturated enones imdergo highly enantioselective hydroamination in the presence of enantiomerically pure metal catalysts and organocatalysts. However, this process is considered as an enantioselective conjugate addition and is discussed in the appropriate section of this book (Section 11.4). 

Selected examples for hydroamination reactions in which the concept of supported ILs has been applied are summarized in Table 10.4. 

I 70 Supported Ionic Liquids as Part of a Building-Block System for Tailored Catalysts 

Entry Type of Reaction Type of Ionic liquid Support Operation References 

1 Hydroamination Liquid Pd complex Imidazolium salt Silica Batch [43] 

Summaries of results of hydroamination mediated with Rh(I) amide complexes584 and comprehensive reviews giving detailed information of the field are available.585-587 Therefore, only the more important relatively new findings are presented here. In most of the transformations reported transition metals are applied as catalysts. The feasibility of the use of tcrt-BuOK was demonstrated in the base-catalyzed amination of styrenes with aniline.588 

Ruthenium complexes mediate the hydroamination of ethylene with pyridine.589 The reaction, however, is not catalytic, because of strong complexation of the amine to metal sites. Iridium complexes with chiral diphosphine ligands and a small amount of fluoride cocatalyst are effective in inducing asymmetric alkene hydroamination reaction of norbomene with aniline [the best enantiomeric excess (ee) values exceed 90%].590 Strained methylenecyclopropanes react with ring opening to yield isomeric allylic enamines 591 

An efficient hydroamination of vinylarenes with arylamines catalyzed by Pd complexes affords vcc-phenylethylamine products.592 The reaction requires the use of 

The reaction of norbomadiene and secondary amines (morpholine, piperidine, pyrrolidine, N- methylbutylamine) results in the formation of interesting aminated products 593 

A combinatorial approach was applied to evaluate various catalysts for the animation of 1,3-dienes.594 Complexes formed from [(T 3-C3H5)PdCl]2 and PPh3 were the most active to induce the reaction of a broad range of primary and secondary ary-laminesand 1,3-cyclohexadiene, 1,3-cycloheptadiene, or 2,3-dimetyl-1,3-butadiene to give allylamines. The enantioselective version of the transformation is also very effective  

Palladium-catalyzed 1,4-hydroamination of conjugated dienes is usually accompanied by large amounts of 2 1 telomerization product [21,22]. It was shown that the use of an amine hydrochloride as a cocatalyst increased the selectivity for the 1,4-hydroamination product [23]. Thus, 1,3-butadiene and 2-3-dimethylbuta-1,3-diene gave a fair yield in the palladium-catalyzed 1,4-amination shown in [Eq.(5)]. 

High-yielding palladium-catalyzed 1,4-hydroaminations of 1,3-dienes with anilines have more recently been reported by two groups (Eq. (6)) [26]. 

The reaction also works well with acyclic dienes to give hydroamination products in high yields. In one of the studies, trifluoroacetic acid was used in catalytic amounts to increase the rate of the reaction [26aj. In the latter study, the use of chiral ligands in the hydroamination of 1,3-cyclohexadiene afforded products with up to 95% ee. 

As shown by reaction 5.7.1, hydroamination is the addition of an N-H bond across a C=C bond. Intramolecular hydroamination involving ring closures as illustrated by reaction 5.7.2 is also known. In recent years the addition of amides to C=C bonds has also been reported, and these are called hydroamidation reactions. 

Reaction 5.7.3 is an example of a hydroamidation reaction. Hydroamination and hydroamidation reactions are of interest for their potential applications in the syntheses of fine chemicals and pharmaceutical intermediates. 

Many transition metals and lanthanide-based complexes have been shown to catalyze (5.7.2)-type hydroamination reactions. In many cases the catalysts based on lanthanides are found to have significant activity. Structures 5.70 and 5.71 are two typical examples of transition metaland lanthanide-based precatalysts. 

The bridges of 5.70 are easily cleaved by the substrate to give mononuclear catalytic intermediates. For hydroamidation reactions, Ru-based precatalysts are generally required. An effective catalytic system for such reactions is 5.16 (see Section 5.1.2), in combination with phosphines and substituted pyridines. 

Complex 5.71, an analogue of 2.65, is an example of a lanthanide-based constrained geometry catalyst (see Section 6.5.1). Note that it is a half-metallocene complex that has a rather open structure for coordination. 

Preparation of aliphatic amines by direct hydroamination of alkenes with amines is a highly desirable reaction. However, except for the well-established hydroamination of 1,3-dienes via 7r-allylpalladiums, no smooth hydroamination of simple alkenes is known. As a breakthrough, Kawatsura and Hartwig reported that the hydroamination of styrene derivatives with aniline is catalyzed by Pd(TFA)2 and DPPF in the presence of trifluoroacetic acid (TFA) or triflic acid as a cocatalyst to afford the branched amine 24 regioselectively in 99 % yield. Formation of the branched amine 24 offers an opportunity of asymmetric amination. They obtained the (5)-amine 25 in 80 % yield with 81 % ee using (/ )-BINAP as a chiral ligand [14]. The reaction is explained by insertion of styrene to the H-Pd bond and nucleophilic attack of amine on an fj -benzylpalladium complex [15]. Hii and coworkers obtained the amine 24 with 70 % ee in 75 % yield using the dicationic Pd complex, [Pd(MeCN)(H20)(/ -BINAP)](0Tf)2 [16]. 

In addition, they carried out enantioselective Michael-type hydroamination of the alkenoyl-A-oxazolidinone 26 with aniline and obtained the chiral amine 27 with 93 % ee. Furthermore, they reported hydroamination of dihydrofuran (28) and 2,3-dihydropyran (30). Reaction of dihydrofioran (28) with morpholine proceeded at room temperature to give 2-aminotetrahydrofuran 29 regioselectively in high yield. Hydroamination of 2,3-dihydropyran (30) with morpholine proceeded at 80 C to give 2-morpholinotetrahydropyran (31). For this hydroamination, phosphine-free 

K2Pd(SCN)4 was used as an active catalyst. The hydroamination did not appear to be acid-catalyzed since sulfuric and p-toluenesulfoiuc acids failed to induce any reaction even after heating at 60 °C for 24 h [17], 

Although this mechanism is based on known activation of the N-H bond of aniline by Ru3(CO)i2, a mechanism involving the activation of the carbon-carbon triple bond followed by a nucleophilic attack of the amine carmot be discarded. Indeed, typical Lewis acids such as Zn(II) or Cu(I) salts have been shown to be efficient catalysts for the intramolecular hydroamination of alkyne [93], However, contrary to ruthenium(II) complexes, mthenium(O) catalysts are not expected to electrophili-cally activate alkynes. 

For indole synthesis, the best additive both for yield and regioselectivity was found to be the anilinium hydrochloride (PhNH2- HCl). The formation of the indole product can be explained by the isomerization of the hydroamination product, in which it has been clearly shown that the ruthenium catalyst is not involved. 

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The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

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. ... 

B. Hydroamination/cyclization reactions catalyzed by amidinate and guanidinate complexes... 

The guanidinate-supported titanium imido complex [Me2NC(NPr02l2Ti = NAr (Ar = 2,6-Me2C6H3) (cf. Section IILB.2) was reported to be an effective catalyst for the hydroamination of alkynes. The catalytic activity of bulky amidinato bis(alkyl) complexes of scandium and yttrium (cf. Section III.B.l) in the intramolecular hydroamination/cyclization of 2,2-dimethyl-4-pentenylamine has been investigated and compared to the activity of the corresponding cationic mono(alkyl) derivatives. 

Abstract The use of A-heterocyclic carbene (NHC) complexes as homogeneous catalysts in addition reactions across carbon-carbon double and triple bonds and carbon-heteroatom double bonds is described. The discussion is focused on the description of the catalytic systems, their current mechanistic understanding and occasionally the relevant organometallic chemistry. The reaction types covered include hydrogenation, transfer hydrogenation, hydrosilylation, hydroboration and diboration, hydroamination, hydrothiolation, hydration, hydroarylation, allylic substitution, addition, chloroesterification and chloroacylation. 

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]. 

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]. 

Fig. 2.14 Rhodium and iridium cataiysts for the intramolecular hydroamination of alkynes...

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... 

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]. 

Complexes 92 and 93 also show good activity for the hydroamination of methacrylonitrile with morpholine, piperidine or A -methylpiperazine (70-93% conversion at 2.5 mol%, 90°C in 24 h) [80]. 

Fig. 2.16 Copper-amido complexes as catalysts for the intermolecular hydroamination of electron-deficient alkenes...

The well-defined copper complexes 94 and 95 (Fig. 2.16) have been used as catalysts for the intermolecular hydroamination of electron-deficient alkenes [Michael acceptors, X=CN, C(=0)Me, C(=0)(0Me)] and vinyl arenes substituted... 

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]. 

Finally, intramolecular hydroamination/cyclisation of M-alkenyl ureas was catalysed by the well-defined [AuCl(IPr)] complex (Schane 2.16), in the presence of AgOTf (5 mol%, rt, methanol, 22 h). The cationic Au(lPr)+ is presumably the active species [83]. 

Scheme 2.16 Gold-catalysed intramolecular hydroamination of alkenes...

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]. 

Kovacs, G., Ujaque, G. and Lledos, A. (2008) The Reaction Mechanism of the Hydroamination of Alkenes Catalyzed by Gold(I)-Phosphine The Role of the Counterion and the N-Nucleophile Substituents in the Proton-Transfer Step. Journal of the American Chemical Society, 130, 853-864. 

Catalytic Hydroamination of Unsaturated Carbon-Carbon Bonds... 

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). 

The first example of a heterogeneously catalyzed hydroamination of an alkene appeared in a 1929 patent in which it is claimed that NHj reacts with ethylene (450°C, 20 bar) over a reduced ammonium molybdate to give EtNH2 [24]. An intriguing reaction was also reported by Bersworth, who reacted oleic acid with NH3 in the presence of catalysts like palladium or platinum black or copper chromite to give the hydroamination product in quantitative yields [25]. However, this result could not be reproduced [26]. 

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]. 

PhNH2 reacts with ethylene in the presence of alkali metals, e.g., sodium deposited on alumina, to afford the hydroamination product in good yield but with a low turnover frequency (TOP = mol of product synthesized per mol of catalyst in 1 h) (Bq. 4.3) [44]. 

Other catalysts are 20% Na/C, 5% Li/AljOj or 10% Na/8% M0O3-AI2O3 or 10% NaH/Al203 [44]. Similarly, gaseous mixtures of olefins and NH3 have been claimed to give hydroaminated products over a ternary K/graphite/Al203 catalyst [45]. 

Last, McClain disclosed the gas phase hydroamination of ethylene and propene with NH3 over palladium on alumina (Eq. 4.4) [46]. 

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