Palladium-catalyzed 1,4-hydroamination

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]. 

Scheme 11.2 Proposed mechanism for the palladium catalyzed hydroamination of vinyl arenes. 

The palladium catalyzed asymmetric hydroamination of cyclohexadiene with arylamines utilizing a variant of Trost s ligand R,R) 61 proceeds with high enantio selectivities under mild conditions (Scheme 11.19) [21]. The mechanism is believed to follow a similar pathway as proposed for palladium catalyzed hydroamination of vinyl arenes (Scheme 11.2) [17]. 

The hydroamination of cycloheptatriene has also been reported (Equation 16.83). Although the mechanism of this reaction has not been revealed, it is likely to be related to the mechanism of the palladium-catalyzed hydroamination of dienes. TTie overall transformation must involve two hydroaminations one intermolecular hydroamination of the triene unit and one intramolecular hydroamination of the resulting diene. 

Sakai, N., Ridder, A. Hartwig, J. R (2006). Tropene derivatives hy sequential intermolec-ular and transannular, intramolecular palladium-catalyzed hydroamination of cyclohepta-triene. Journal of the American Chemical Society, 128, 8134-8135. 

Lober O, Kawatsura M, Hartwig JF. Palladium-catalyzed hydroamination of 1,3-dienes a colorimetric assay and enantioselective additions. J. Am. Chem. Soc. 2001 123(18) 4366-4367. 

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]. 

Hydroamination of Alkynes The discovery of palladium-catalyzed intramolecular addition of amines to acetylene coupled with the spectacular contribution of Hutchings opened the door for the synthesis of several nitrogen heterocycles. The first study in this field was performed by Utimoto et al., who researched gold catalyzed intramolecular 6-exo-dig hydroamination. Tautomerization of the initial enamines allowed them to obtain imines, which were thermodynamically more stable [111] (Scheme 8.20). 

A palladium-catalyzed three-component reaction with 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines to prepare fV-substituted 4-methylene-3,4-dihydro-1 (27/)-isoquinolin-1 -ones was disclosed <02TL2601>. A synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via a Cp2TiMe2-catalyzed, intramolecular hydroamination/cyclization of aminoalkynes was also reported <02TL3715>. Additionally, a palladium-catalyzed one-atom ring expansion of methoxyl allenyl compounds 79 to prepare compounds 80 that can serve as precursors to isoquinolones was reported <02OL455,02SL480>. 

A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <20040L4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of... 

Palladium-catalyzed regioselective hydroamination of 2,3-dihydrofuran under ligand-free and neutral conditions was found to be general with secondary alkyl amines, as exemplified in Equation (119) <2001T5445>. 

In 2002, Trost and Tang reported the chiral total synthesis of (-)-codeine in short reaction steps using a palladium-catalyzed asymmetric allylic alkylation (AAA) [53] as the key transformation [54], In 2005, a detailed full account of their synthesis was published [55]. The key features of their synthesis are (1) a preparation of an aryl ether with high optical purity by the Pd-catalyzed AAA reaction, (2) the intramolecular Heck reaction to generate the A-C-E benzofuran skeleton, (3) the second intramolecular Heck reaction of Z-vinyl bromide providing the phenan-throfuran core, and (4) the intramolecular hydroamination for the construction of D-ring by the action of LDA and visible light. 

Scheme 11.19 Palladium catalyzed asymmetric hydroamination of cyclohexadiene [21].

Equation 11.9. Palladium catalyzed asymmetric intramolecular hydroamination of aminoalkynes [115]. 

Other examples of microwave-assisted catalysis include allylic alkylation, both palladium catalyzed and molybdenum catalyzed. In the latter case, air stable precursor complexes could be used under non-inert conditions. Microwave-enhanced Pauson-Khand reactions have also been reported, as have hydroamination of alkynes, and metathesis of functionalized alkynes. " Recently, microwave enhancement has been applied to C-H activation reactions, for example, for the formation of functionalized heterocycles, allowing the reaction to be performed with no solvent purification and minimal precautions to exclude air. A solvent-free chelation-assisted hydroacylation... 

Ackermann, L. and Althammer, A. (2006) One-pot 2-arylAinylindole synthesis consisting of a ruthenium-catalyzed hydroamination and a palladium-catalyzed Heck reaction using 2-choroaniUne. Synlett, 3125-9. 

One of the best-characterized examples of intramolecular hydroamidation of an alkene with the tethered activated nitrogen of amide and carbamate groups is shown in Equations 16.66a and 16.66b. This reaction is catalyzed by a dicationic palladium complex ligated by a PNP pincer ligand. Like the rhodium-catalyzed hydroamination, this process occurs to form five- and six-membered rings with or without substituents to bias the system toward cyclization.. 

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. 

The hydroamination of alkenes and alkynes has been of longstanding interest in organometallic chemistry [26]. Much of the early work in this area focused on early transition metal or lanthanide metal catalyst systems. However, much recent progress has been made in late-metal catalyzed hydroamination chemistry, and several interesting hydroamination reactions that afford nitrogen heterocycles have been developed using palladium catalysts. 

Palladium-catalyzed intramolecular hydroamination reactions of alkynes that afford pyrrolidine derivatives were initially reported by Yamamoto in 1998 [27] and have been the subject of detailed investigation over the past ten years [28]. In a... 

Evano and colleagues disclosed a modular indole synthesis via the intramolecular carbocupration of N-aryl-ynamides (124 125) (130L3122).A series of indole derivatives was prepared by Jiao via the palladium-catalyzed aerobic oxidative intramolecular hydroamination and C-H functionalization of N-alkynylanilines (13T4408). Suh reported a microwave-assisted synthesis of 3-functionalized indoles via an intramolecular arene-alkene coupling of o-iodoanilino enamines (13T7211). 

Synthesis of isoindohn-l-one derivatives in phosphonium-based ILs was described by Cao et al. [138]. The palladium-catalyzed caibonylation and hydroamination reaction of l-halo-2-alkynylbenzene with amines afforded the substituted 3-methy-leneisoindolin-1 -ones in good yields and high selectivities in favor of the Z-isomers... 

Kevin et al. [139] reported palladium-catalyzed carbonylation-hydroamination reaction between l-biomo-2-(phenylethynyl)benzene andbenzylamine using phos-phonium-based IL as the reaction solvent (Scheme 4.10). 

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