Terminal alkynes hydroamination

Barluenga et al. have extensively studied the hydroamination of alkynes catalyzed by mercury compounds, especially mercury(II) chloride. Terminal alkynes and... 

The hydroamination of alkynes with primary and secondary ahphatic amines necessitates the use of higher amounts of catalyst (17%) and higher temperatures, and TOFs are low (<1 h ) [260]. With ahphatic and aromatic terminal alkynes and a 5-fold excess of primary aliphahc amines, the products are the corresponding imines (40-78% yield, TOF up to 0.3 h ). In contrast to the CujClj-catalyzed reaction of phenylacetylene and secondary ahphatic amines (Scheme 4-12), the HgClj-catalyzed reachon is fully regioselechve for the Markovnikov hydroamination products which do not evolve under the reachon condihons (Eq. 4.66) [260]. 

Scheme 4-13 Mechanism of the HgCl2-catalyzed hydroamination of terminal alkynes...

Hydroamination of terminal alkynes with primary amines has been performed using organoactinides as catalysts [301, 302]. The organouranium complex Cp 2UMe catalyzes the regioselective formation of imines in fair to high yields (Eq. 4.82). 

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]. 

Table 13 Rhodium-catalvzed hydroamination of terminal alkynes with anilines (catalyst system = fRh-...

Similarly, Vasudevan and Verzal have found that terminal alkynes can be hydrated under neutral, metal-free conditions using water as solvent (Scheme 4.15) [41], While this reaction typically requires a catalyst such as gold(III) bromide, employing microwave-superheated distilled water allowed this chemistry to proceed without any catalyst. Extension of this methodology led to a one-pot conversion of alkynes to imines (hydroamination). 

Chatani and coworkers published an efficient method for the Rh(I)-catalyzed anti-Markovnikov hydroamination of terminal alkynes using either primary or secondary amines [58]. This reactivity had been observed earlier in the course of their studies on hydrative alkyne dimerization (Equation 9.8). 

Laurel Schafer of the University of British Columbia reports (Organic Lett. 2003,5,4733-4736) that terminal alkynes undergo smooth hydroamination with a Ti catalyst. The intermediate imine 4 can be hydrolyzed to the aldehyde 5 or reduced directly to the amine 6. The alkyne to aldehyde conversion has previously been carried out by hydroboration/oxidation (J. Org. Chem. 1996, 61, 3224), hydrosilylation/oxidation (Tetrahedron Lett. 1984,25, 321), or Ru catalysis (J. Am. Chem. Soc. 2001, 123, 11917). There was no previous general procedure for the anti-Markownikov conversion of a terminal alkyne to the amine. 

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]. 

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 inter molecular hydroaminations of terminal alkynes as the initial steps. 

The hydroamination of terminal alkynes with NaAuCLi was developed in 1987. In 1991, Utimoto described the preparation of tetrahydropyridines from 5-alkynylamines with Au(III) catalysts. This idea was further extended by Muller to give the corresponding iminium compounds. ... 

Catalytic hydroamination of imsaturated carbon-carbon bonds has a strong potential for the access to a large variety of amines, enamines or imines [90]. The first addition of a N-H bond to alkynes catalyzed by a ruthenium catalyst was described in 1995 by Watanabe et al. [91], and involved a ruthenium-catalyzed addition of the N-H bond of N-formyl anilines to terminal alkyne (Scheme 8.29). 

Scheme 9 Regioselective hydroamination of terminal alkynes promoted by precatalyst 13...

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

Fischer indolization. Odom and coworkers performed this chemistry with 1,1-disubstituted hydrazines a selection is shown in Table 4 (entries 1-4) [94, 95]. In a similar approach to aryl hydrazones and indoles, Seller and colleagues anployed a titanium catalyst to hydroaminate terminal alkynes leading to indoles (Table 4, entries 5-7) [96-98]. Seller s protocol is particularly valuable for the synthesis of tryptamines, tryptophols, and their homo-logues. Interestingly, Seller found that 1-alkyl-l-phenylhy-drazines react with acetylenedicarboxylates in the absence of titanium to give the corresponding indole-2,3-dicarbox-ylates and 2-arylindole-3-carboxylates after treatment with zinc chloride [99]. This reaction was apparently first discovered by Diels and Reese in 1935 [100] and by others subsequently [101, 102]. Some examples of Seller s work are shown in Scheme 11 (equations 1-3) [99]. 

The direct Au-catalyzed synthesis of 2-arylindoles from aryl alkynes and o-iodoanilines was reported by Wang (eqnation 3) [17]. The An-catalyzed double hydroamination of o-alkynylanilines and terminal alkynes was fonnd by Li to give A-vinylindoles [18], Patil used a Au-catalyzed one-pot reaction between o-alkynylanilines and alkynols to give various 3-substituted indoles [19]. Zhang fonnd that both A-arylhydroxylamines [20] and... 

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 Au(III)-catalyzed double hydroamination cascade reaction of ortho-alkynyla-nilines 167 with terminal alkynes 168 affording N-vinylindoles 169 was reported by li (Scheme 9.63) [221]. In the case of alkyl-substituted acetylenes, this protocol provided mixtures of isomeric N-vinylindoles with both terminal and internal double bonds. This transformation is believed to occur via the Au(III)-catalyzed cydoisomerization of transient key alkynyl imines, similar to 162 utilized by Yamamoto, which were generated via the initial Au(111)-catalyzed hydroamination of the corresponding anilines 167 with alkynes 168. 

Carbamates are also effective nucleophiles for the gold(I)intramolecular hydroamination of alkynes [12]. For example, treatment of O-propargylic carbamate 10 with a catalytic 1 1 mixture of (PPh3)AuCl and AgOTf in dichloromethane at room temperature led to isolation of 2,5-dihydroisoxazole 11 in 88% yield (Eq. (11.8)). The transformation was effective for alkyl-, alkenyl- and aryl-substituted internal alkynes and terminal alkynes and for N-Boc, Cbz, and Ts derivatives. A similar... 

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... 

Che has reported the tandem hydroamination/hydroarylation of aromatic amines wirh terminal alkynes to form dihydroquinolines in which 1 equiv of aniline combines with 2 equiv of alkyne [23]. For example, reaction of 3-methoxyanilme with pheny-lacetylene (5 equiv) and a catalytic 1 1 mixture of the gold(I) N-heterocydic carbene complex (IPr)AuCl (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgOTf at 150 °C under microwave irradiation led to isolation of dihydroquinoline 21 in 82 % yield (Eq. (11.15)). Alternatively, reaction of o-acetylaniline with pheny-lacetylene catalyzed by a mixture of (IPr)AuCl and AgOTf at 150 °C led to isolation of the quinoline derivative 22 in 93% yield via incorporation of a single equivalent of alkyne (Eq. (11.16)). Arcadi has reported the gold(IlI)-catalyzed hydroamination/ hydroarylation of 2-alkynylanilines with a,p-enones to form C3-alkyl indoles [24]. As an example of this transformation, treatment of 2-(phenylethynyl)aniline with 4-phenyl-3-buten-2-one and a catalytic amount of sodium tetrachloroaurate dihydrate in ethanol at 30°C formed 1,2,3-trisubstituted indole 23 in 88% yield (Eq. (11.17)). 

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