Intermolecular Alkyne Hydroamination

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]. 

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 intermolecular hydroamination of alkynes catalyzed by late transition metals was reported for the first time in 1999. Ruthenium carbonyl catalyzes the Markovnikov hydroamination of terminal alkynes with PhNHMe to give enamines (Eq. 4.88) [305]. 

Organometallic complexes of the /-elements have been reported that will perform both intra-and intermolecular hydroamination reactions of alkenes and alkynes, although these lie outside of the scope of this review.149-155 Early transition metal catalysts are not very common, although a number of organometallic systems exist.156-158 In these and other cases, the intermediacy of a metal imido complex LnM=NR was proposed.159,160 Such a species has recently been isolated (53) and used as a direct catalyst precursor for N-H addition to alkynes and allenes (Scheme 35).161,162... 

Intermolecular hydroamination of 1-alkynes with anilines has recently been performed using [Rh(COD)2]+ in combination with three equivalents of tricyclohexylphosphine (1.5 mol. % catalyst) at 50 °C to yield the corresponding imines (Equation (16)) 172... 

Alkene hydroamination has been known for many years, but has been little used as a method in organic synthesis. Tobin Marks of Northwestern recently published a series of three papers that will make this transformation much mote readily accessible. In the first (J. Am. Chem. Soc. 125 12584,2003) he describes the use of a family of lanthanide-derived catalysts for intermolecular hydroamination of alkynes (to make imines, not illustrated) and alkenes. With aliphatic amines, the branched (Markownikov) product is observed, 1 — 2. With styrenes, the linear product is formed. When two alkenes are present, the reaction can proceed (3 —> 4) to form a ring, with impressive regioselectivity. 

The intermolecular hydroamination of alkynes, catalysed by the aquapalladium complex [(dppe)Pd(H20)2](0Tf)2, has been reported. The reaction is believed to proceed through the equilibrium between the hydroxopalladium and the amidopalladium complexes, followed by aminopalladation of alkynes.76 Regioselective 1,2-diamination of 1,3-dienes by dialkylureas, catalysed by (MeCN)2PdCl2 in the presence of 1 equiv. of / -benzoquinone, has been developed as a highly efficient method.77... 

Mononuclear complexes [U(C5Me5)2(NHR)2] (R = 2,6-dimethylphenyl, Et, or Bu) have been synthesized and structurally characterized. It was shown that in the presence of terminal alkynes and amines these complexes catalyze the intermolecular hydroamination of terminal alkynes [453]. Complex formation reactions of U(VI) with neutral N-donors in DMSO were reported [454]. 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

Later, Arcadi showed that /J-keto-imines react with alkynes intramolecularly to give pyrroles. The intermolecular animation with aniliaes was later developed by Hayashi and Tanaka using a cationic Au(I) catalyst to form imines (equation 27). More recently, Arcadi etal. developed an intramolecular version for the cyclization of o-alkynylanilines to form indoles (equation 28) and Li reported a double intra- and intermolecular hydroamination to obtain A-vinylindoles. " O-Substituted hydroxylamines can also undergo this type of transformation to dihydroisoxazole derivatives. " " Tandem sequences that involve a first alkyne-hydroamination step with anilines have been recently developed " " and are similar to the previonsly discnssed additions with phenols that access isoflavone skeletons. 

The first intermolecular hydroamination of an alkyne was reported by Uchimaru in 1999 [92]. It was found that Ru3(CO)i2 catalyzes the reaction of N-methylaniline derivatives with phenyl-substituted acetylenes in good yields (76-88%)(Scheme 8.31). 

The intermolecular hydroamination of alkynes can be catalyzed by Cp2TiMe2 (Scheme 759). It is assumed that metal imido intermediates are formed.1948,1949 Cp2TiMe2 is an efficient catalyst for the hydroamination of... 

Synthesis of A-alkynyl-substituted indolyzidines, and pyrrolizidines by Ti-cataly-zed intermolecular hydroamination of alkynes 04SL1653. 

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]. 

While intermolecular hydroamination of simple alkenes remains a great challenge as of now, addition of amines to alkynes, allenes, and dienes proceeds more easily. However, the addition of an amine to a polyene moiety may not necessary result in the formation of a new stereocenter, if an imine is generated (Scheme 11.18). 

Scheme 11.18 Intermolecular hydroamination of alkynes, allenes, and dienes.

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. 

Development of the Ti-Catalyzed Intermolecular Hydroamination of Alkynes Dove. S. Svnlett 2004. 1653. 

Intermolecular Hydroamination of Terminal Alkynes Catalyzed by Neutral Organoactinide Complexes... 

The organoactinide complexes Cp 2AnR2 (An = Th, U R = Me, NHR R = alkyl) and the bridge complexes 3-6 were found to be excellent precatalysts for the intermolecular hydroamination of terminal aliphatic and aromatic alkynes in the presence of primary aliphatic amines to yield the corresponding imido compounds [56, 99]. The reactivity exhibited for the thorium complexes was different, depending on the alkynes, from that for organouranium complexes. 

Scheme 5 Pathways proposed for the organoactinide-catalyzed intermolecular hydroamination of terminal alkynes with primary amines. For Thorium the approach of some alkynes was inverted before insertion...

Scheme 8 presents a plausible mechanism for the intermolecular hydroamination of terminal alkynes promoted by the organothorium complex 1. The first step in the catalytic cycle involves the N-H a-bond activation of the primary amine by the organothorium complex yielding the bisamido-amine complex Cp2 Th(NHR )2 (H2NR ) (28) and two equivalents of methane (step 1). Complex 22 was found to be in rapid equilibrium with the corresponding bis(amido) complex 18 (step 2) [57, 60]. An additional starting point involved a similar C-H activation of the terminal alkyne with complex 1 yielding methane and the bis(acetylide) complex 17 (step 3). 

Scheme 8 Plausible mechanism for the intermolecular hydroamination of terminal alkynes and primary amines promoted by Cp 2ThMe2...

Quinoline and indole derivatives were also synthesized by cyclocondensation reactions of aniline derivatives with alkynes (Eqs. 42,43) [108]. These protocols involve the ruthenium-catalyzed intermolecular hydroaminations of terminal alkynes as the initial steps. 

Phenyl-1-propyne (55) underwent facile formal intermolecular hydroamination, affording the allylic amine 56 in high yield at 0 "C in the presence of AcOH or benzoic acid. In this reaction, at first, Pd-catalyzed isomerization of 55 to pheny-lallene (57) occurs by addition-elimination of H-Pd-OAc to internal alkyne 55, and then the allene 57 is converted to jr-allylpalladium intermediate 58 by hydropal-ladation. The final step is a well-known amination to produce the allylic amine 56. As an intramolecular version, 2-(2-phenylpropenyl)pyrrole (60) was obtained from l-phenyl-7-amino-l-hexyne 59 [16,16a]. Similarly Pd/benzoic acid-catalyzed hydroalkoxylation of 55 with (—)-menthol (61) afforded the allylic ether 62 [17]. 

Synthesis of enantiomerically enriched secondary amines (168) with excellent ee values, through the tandem, intermolecular hydroamination with primary amines (166) /transfer hydrogenation of alkynes (167), using a the gold(I) complex-chiral phosphoric acid (127) protocol, has been developed by Che and Liu (Scheme 44). A wide variety of aryl, alkenyl, and aliphatic alkynes as well as anilines with different electronic properties were tolerated. 

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. 

Li has reported that cationic gold(III) complexes also catalyze the intermolecular hydroamination of terminal alkynes with aniline derivatives [17]. For example, reaction of a neat 1 1.5 mixture of phenylacetylene and aniline catalyzed by AUCI3 at room temperature followed by reduction with sodium borohydride led to isolation... 

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