Hydroamination intermolecular processes

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

The intermolecular process (8 and 9) showed two hydroamination regioselec-tivities depending on the precatalyst. The intermolecular hydroamination catalyzed by the metallocene thorium catalyst yielded the methyl alkyl-substituted imines in... 

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... 

Multiple efficient catalysts were reported for the intramolecular process, while the intermolecular process has been studied predominantly for alkynes. The reactivity of the unsaturated fragment decreases in the order alkyne > allene diene > vinyl arene unactivated alkene with the intermolecular hydroamination of simple alkenes representing the most difficult transformation. The hydroamination of all types of carbon-carbon unsaturated fragments will be covered in this chapter. 

Trivinylbenzene may be utilized in a hydroamination/carbocyclization process that is initiated by an intermolecular anft-Markovnikov addition of n-propylamine followed by an intramolecular hydroamination and a highly diastereoselective carbocyclization step (15) [20]. 

Type 4 metallocene complexes catalyze the regioselective mtermolecular addition of primary amines to acetylenic, olefinic, and diene substrates at rates which are = 1/1000 those of the most rapid intramolecular analogues [165]. Variants such as the intramolecular hydroamination/cyclization of aminoallenes [166] and the intra- and intermolecular tandem C-N and C-C bond-forming processes of aminodialkenes, aminodialkynes, aminoallenynes, and aminoalkynes [167] were applied as new regio- and stereoselective approaches to naturally occurring alkaloids. For example, bicyclic pyrrolizidine intermediate E... 

Organolanthanide-catalyzed intermolecular hydrophosphination is a more facile process than intermolecular hydroamination. The reaction of alkynes, dienes, and activated alkenes with diphenylphosphine was achieved utilizing the ytterbium imine complex 9 (Fig. 8) as catalyst [185-188]. Unsymmetric internal alkynes react regioselectively, presumably due to an aryl-directing effect (48) [186]. 

Intermolecular hydroamination of alkynes, which is a process with a relatively low activation barrier, has not been used for the synthesis of chiral amines, since the achiral Schiff base is a major reaction product. However, protected aminoalkynes may undergo an interesting intramolecular allylic cyclization using a palladium catalyst with a chiral norbomene based diphosphine ligand (Eq. 11.9) [115]. Unfor tunately, significantly higher catalyst loadings were required to achieve better enantioselectivities of up to 91% ee. 

The insertion approach is very successful in the hydroamination of alkynes and alkenes catalyzed by lanthanide complexes developed by Marks et al. [220]. Thorough mechanistic studies have been undertaken for the intramolecular reaction (hydroamination-cyclization of aminoalkenes), although the intermolecular version of the process is also efficient [222]. The mechanism of the reaction can be represented in a simplified way by Scheme 6.68. The insertion step is almost thermoneutral, but the protonolysis of the M-aminoalkyl bond that follows is exothermic and provides the necessary driving force. The insertion of the alkene into the Ln-N bond is irreversible and rate determining and it goes through a... 

The first hydroaminations by this mechanism were reported by Bergman with zircono-cene complexes and by Livinghouse with monocyclopentadienyl titanium and zirconium complexes. Bergman reported the intermolecular addition of a hindered aniline to an alkyne. The hindrance of the aniline was important to prevent formation of stable dimeric complexes containing bridging imido groups. Livinghouse reported intramolecular reactions that occurred at lower temperatures over shorter times. The intramolecularity of this process allows the [2+2] cycloaddition of the imido complex with the alkyne to be faster than the dimerization. 

Some of the most active catalysts for the hydroamination of alkynes are based on lanthanides and actinides. The turnover frequencies for the additions are higher than those for lanthanide-catalyzed additions to alkenes by one or two orders of magnitude. Thus, intermolecular addition occurs with acceptable rates. Examples of both intermolecular and intramolecular reactions have been reported (Equations 16.87 and 16.88). Tandem processes initiated by hydroamination have also been reported. As shown in Equation 16.89, intramolecular hydroamination of an alk5me, followed by cyclization with the remaining olefin, generates a pyrrolizidine skeleton. Hydroaminations of aminoalkynes have also been conducted with the metallocenes of the actinides uranium and thorium. - These hydroaminations catalyzed by lanthanide and actinide complexes occur by insertion of the alkyne into a metal-amido intermediate. 

Organolanthanide complexes are known to be highly active catalysts for a variety of organic transformations, which can be either intramolecular or intermolecular in character. Successful intramolecular transformations include hydroelementation processes, which is the addition of a H-E (E = N, O, P, Si, S, H) bond across unsaturated C-C bonds, such as hydroamination, hydroalkoxylation, and hydrophosphination. Intermolecular transformations include a series of asymmetric syntheses, the amidation of aldehydes with amines, Tishchenko reaction, addition of amines to nitriles, aUcyne dimerization, and guanylation of terminal aUcynes, amines, and phosphines with carbodiimides. 

Almost at the same time, Liu and Che independently applied the same strategy to the synthesis of chiral secondary amines through a domino intermolecular hydroamination-transfer hydrogenation of alkynes using a gold(i) complex in combination with a chiral phosphoric acid." This domino process has a broad substrate scope since a wide variety of aryl, alkenyl, and aliphatic allq nes could be coupled with anilines with different electronic properties to afford chiral amines in excellent enantioselectivities of up to 94% ee, as shown in Scheme 7.31. 

Alkylation. Alkylation of the title compound is also a key transformation to gain access to more elaborated triazoles. It has been shown that alkylation of the N-2 position using methyl iodide is possible by a Sn2 process (eq 3). Both N-1 and N-2 positions can be alkylated with no selectivity for either regioisomer. Various alkylating aromatic or aliphatic agents can be used and yields higher than 80% can be obtained. It is also possible to alkylate via a Mitsunobu reaction to afford a similar alkylation at the N-2 position (eq A)P It has also been shown that it is possible to alkylate both the N-1 and N-3 posihons to form nitrenium ions using an intermolecular hydroamination method (eq 5). ... 

Using a similar Pt-catalyzed intermolecular oxidative dehydrogenation hydroamination followed by intramolecular aryl C(sp )—H fuctionalization process, Poli and coworkers developed a simple protocol for the synthesis of quinaldine 78 from readily available aniline and ethylene (Scheme 12.36) [41]. It was found that the selectivity of the catalytic reaction between aniline and ethylene in the presence of the Brunet catalyst (PtBr2/Br ) shifts from the hydroamination product Af-ethylaniline to the heterocyclization product... 

Almost at the same time, Liu and Che published a cascade intermolecular hydroamination/asymmetric reduction sequence, which included achiral Au complex-catalyzed hydroamination of aryl amines and chiral phosphoric acid-promoted Hantzsch ester reduction to afford secondary aryl amines [70], More recently, the same group reported a tandem one-pot assembly of functionalized tetrahydroquino-lines from amino aldehyde and alkynes by combining Au and chiral phosphoric acid catalysis [71], The reaction was initiated by Au-promotedquinololine 210 generation, followed by an enantioselective HEH-incorporated transfer hydrogenation process (Scheme 9.67). 

The intermolecular hydroamination is significantly less feasible than the intramolecular process as the C-C unsaturated moiety is not tethered in the vicinity of the catalytic center. The mechanism is believed to be analogous to the intramolecular case, with insertion being less favorable [20]. The insertion step was identified to be rate limiting in the intermolecular lithium-amide-catalyzed hydroamination of vinyl arenes by detailed DFT-analysis [40]. 

As discussed in Sect. 5, the intermolecular hydroamination of alkynes catalyzed by group 4 metal complexes is a well-documented process. The less challenging intramolecular transformation can be achieved efficiently with various titanium-based catalysts [51, 125-130]. The cyclization proceeds analogously to the rare earth metal-catalyzed process with exclusive ej o-selectivity and often requires elevated temperatures. However, the homoleptic titanium tetraamide Ti(NMe2)4 catalyzes the cyclization of both terminal and internal aminoalkynes at room temperature (7) [126, 127]. 

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