Palladium hydroamination

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. 

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]. 

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

The palladium salt/dppe combination catalyzes the hydroamination of 1,3-butadi-ene with NH3 to give a mixture of 1 1, bis-(l l) and tris-(l l) hydroamination products (Eq. 4.48) [182]. 

The hydroamination of allene with morpholine or allylamines has been attempted with palladium-based catalysts. Usually, a mixture of 1 1 telomers (hydroamination products) and 1 2 telomers is obtained, the latter being the major [308, 309] or only... 

Cationic palladium(II) complexes are homogeneous catalysts for both intramolecular and inter-molecular hydroamination reactions.267 Palladium species immobilized on silica can be prepared by the simple addition of alkyl- or hydroxopalladium(II) complexes to partially dehydroxylated silica. The silica-bound species are more stable than their molecular precursors and are efficient catalysts for the cyclization of aminoalkynes.268... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

In order to account for the high regioselectivities observed in the rhodium-catalyzed hydroboration of styrenes, Hayashi proposed a modified mechanism which proceeds through 73-benzyl-rhodium complex 22 as a key intermediate (Scheme 7). Reductive elimination from this 73-benzyl-rhodium complex 22 produces the secondary alkylborane regioselectively.12 A related 73-benzyl-palladium complex was recently isolated by Hartwig in studies of hydroamination.75... 

Special dibenzoxazepinones 86, obtained through the general method described in Fig. 16 and containing, as a third additional functionality, a triple bond, have been further cyclized via a palladium-catalysed hydroamination reaction (Fig. 17) [68]. In this way complex polycyclic systems 87 have been assembled in three steps, taking advantage of the three additional functions embedded in the starting component the aryl fluoride, the phenol and the triple bond. 

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 facile intramolecular hydroamination of unactivated alkenes (58), catalysed by the palladium complex (60), has been reported to take place at room temperature. The formation of hydroamination products (59) rather than oxidative amination products is believed to be due to the use of a tridentate ligand, which effectively inhibits -hydride elimination.78... 

Several catalytic systems have been investigated for hydroamination of unsaturated bonds [16]. Takahashi et al. reported the telomerization of 1,3-dienes in the presence of an amine leading to octadienylamine or allylic amines when palladium catalysts are used in association with monodentate or bidentate phosphine ligands, respectively [17]. Dieck et al. demonstrated the beneficial effect of addition of an amine hydroiodic salt in the hydroamination reaction of 1,3-dienes in which the allylic amines are produced via an intermediate Jt-allyl palladium complex [18]. Coulson reported the Pd-catalyzed addition of amines to allenes where dimerization is incorporated [4]. This reaction presumably proceeds via a cyclic palladium intermediate in which the Pd activates the olefinic bond for nucleophilic attack the reactions are therefore different from pronucleophilic additions. 

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>. 

The hydroamination reactions which are assisted or catalyzed by transition metal species can be utilized in the cyclization of unsaturated amines. Palladium(II) is not recommended for such transformations, since low yields were obtained even using stoichiometric amounts of palladium chloride47. Since an enamide is formed by /J-hydride elimination, a reduction step must be performed to obtain the saturated nitrogen heterocycle. A catalytic cyclization reaction, analogous to the Wacker process, was performed from /V-alkenyl tosylamides, such as 1, using... 

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)]. 

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. 

In 2003, O Shaughnessy and Scott reported the first example of rare-earth metal complexes supported by biaryl diamide ligands as the catalysts for the hydroamination reactions [159]. A series of C2 symmetric secondary diamine proligands L37-L40 were prepared by arylations of (7 )-2,2 -diamino-6,6 -dimethybiphenyl under palladium catalysis. L37 reacted with complexes [Ln N(SiHMe2)2 3(THF)2] to form the biaryl diamide complexes [Ln(L37) N(SiHMe2)2 (THF)2] (Ln = Y (190), La (191), Sm (192)). Deprotonation... 

Recent studies on the C—C cleavage reaction of diynes proceeded smoothly with Pd(NO3)3 as the best among all palladium catalysts tested [67]. Substituted benzoxazoles 115 and 116 along with alkanones were derived from C—C bond cleavage of diynes through hydroamination [68]. 

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... 

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]. 

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

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