Hydroamination of alkyne

Hydroamination of Alkynes Catalyzed by Group 4 Metal Complexes 

The hydroamination of alkynes catalyzed by group 4 complexes were some of the first transition-metal-catalyzed hydroamination reactions. One example of these reactions is shown in Equation 16.84. The reactions only occur with hindered amines and are slow. Nevertheless, the reactions occur m high yield and, in the absence of air, the catalysts are stable indefinitely. An early intramolecular reaction catalyzed by CpTiClj to form a cyclic enamine is shown in Equation 16.85. Reactions with internal alkynes occur to form products with Markovnikov regiochemistry. ° As described in more detail below, tliese reactions occur by [2+2] additions of the alkyne to an intermediate metal-imido complex. 

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. 

Acetonitrile can be obtained in 50-90% yield on passing mixtures of NH3 and acetylene at 300-500°C over mixtures of oxides or nitrates of thorium and zinc on 

Nearly quantitative yields of acetonitrile can be obtained by passing mixtures of NH3 and acetylene over zircon at 400-500°C [225], over CviOy on Y-alumina at 360°C [226] or by passing mixtures of NH, acetylene and hydrogen at 400-420°C over a mixture of zinc and thorium oxides on silica [227] or at 300-450°C over zinc oxide or zinc sulfate or zinc chloride on silica [228, 229], In such reactions, the role of traces of water has often been questioned. However, acetonitrile could be obtained under rigorously anhydrous conditions, thus demonstrating the direct amination of acetylene with NH,. It was also reported that ethyUdeneimine can be obtained in up to 26% yield [225], However, in the Ught of more recent work [230, 231] the product was most probably 2,4,6-trimethyl-l,3,5-hexahydrotriazine. 

Propionitrile can be obtained as the major product (70%) on passing mixtures of propyne and NH, over ZnClj/sUica gel at 360-380°C [229]. 

Nicodemus obtained mixtures of ethylamines on passing mixtures of NH3 and acetylene at 280-290°C over zinc chloride on pumice [232, 233] or at 350°C over a mixture of zinc nitrate, tin chloride, siUca and charcoal on diatomaceous earth (Eq. 4.56) [234]. 

EtNH2 + pt2NH + Et3N +CH3CN + pyridinic bases 10% 14% 39% (4.56) 

EtNH2 + Et2NH + Et3N +CH3CN + pyridinic bases 

A variety of catalyst systems have been developed for the facile intermolecular hydroamination of alkynes, in particular employing early transition metal catalysts based on group 4 metals (Fig. 13). Important issues such as reactivity, reaction 

Reactions of unsymmetric internal alkynes are more challenging, since two hydroamination products can be formed. The feasibility to control regioselectivity depends on the steric properties of both substrate and catalyst and a universal regioselective catalyst remains to be elaborated. When anilines are employed as reactants, high a t/-Markovnikov selectivity is obtained with titanocene catalysts 47 and 48 (Table 11) [182, 183] while aliphatic amines gave poor results. Again, the bis(indenyl)titanium catalyst 49 showed superior a t/-Markovnikov selectivity 

Terminal alkynes are in general more reactive than their internal analogs, and even Ti(NMe2)4 can serve as a catalyst in some cases providing high regioselectivity under relatively mild reaction conditions (Table 12) [196, 197]. However, the di(pyrrolyl) amine complex 50 (Fig. 13) was a more generally applicable 

The increased Markovnikov selectivity in the hydroamination of aliphatic terminal alkynes with aniline derivatives seems to be universal for a number of titanium-based hydroamination catalysts, such as Ind2TiMe2 (49) [184], the di-(pyrrolyl) amine complex 50 [186, 187], and the di(pyrrolyl)methane complex 51 [188]. The bis(amidate) titanium complex 43 exhibited enhanced catalytic activity compared to titanocene catalysts, thus combining high a ri-Markovnikov selectivity with high catalytic activity [191]. 

It is noteworthy that all group -metal-based catalysts described above can only be used for primary amines, as opposite to most late transition metal-based systems. While the stoichiometric reaction of Ti(NMe2)4 with phenylacetylene was shown to produce some enamine hydroanunation product [196], a catalytic process was only facilitated using the tethered zirconium bis(ureate) complex 35 (29) [57]. 

---

The formation of a bis(guanidinate)-supported titanium imido complex has been achieved in different ways, two of which are illustrated in Scheme 90. The product is an effective catalyst for the hydroamination of alkynes (cf. Section V.B). It also undergoes clean exchange reactions with other aromatic amines to afford new imide complexes such as [Me2NC(NPr )2]2Ti = NC6F5. ... 

The guanidinate-supported titanium imido complex [Me2NC(NPr02l2Ti = NAr (Ar = 2,6-Me2C6H3) (cf. Section IILB.2) was reported to be an effective catalyst for the hydroamination of alkynes. The catalytic activity of bulky amidinato bis(alkyl) complexes of scandium and yttrium (cf. Section III.B.l) in the intramolecular hydroamination/cyclization of 2,2-dimethyl-4-pentenylamine has been investigated and compared to the activity of the corresponding cationic mono(alkyl) derivatives. 

Fig. 2.14 Rhodium and iridium cataiysts for the intramolecular hydroamination of alkynes...

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]. 

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]. 

Hydroamination of alkynes offers a straightforward preparation of a variety of amines, enamines, and imines.79 Numerous reports have appeared in the literature on this process. However, almost all these reactions have been carried out in organic solvents, which usually require the protection of functional groups or harsh conditions. Recently, Marinelli et al. have reported an Au(III)-catalyzed hydroamination of alkynes in... 

The cationic imidazolium rhodium complex (56) has been found to catalyze the intramolecular hydroamination of alkynes in refluxing THF. In the case of 2-ethynylaniline, indole is formed in 100% yield over 9h at 55 °C (Scheme 38).173 One of the earliest examples of late transition metal-catalyzed hydroamination involved the use of the iridium(I) complex [Ir(PEt3)2(C2H4)Cl] as... 

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). 

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 hydroamination of alkynes is an efficient way to obtain aldimines with the advantage of avoiding formation of by-products. As shown in Scheme 8.65, the method has been developed into a multicomponent synthesis of a-branched amines. Aldimines 154 are formed using a titanium derivative as catalyst and reacted in situ with an organolithium reagent [141]. 

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... 

A sequence involving a titanium-catalyzed hydroamination of alkynes, followed by an intramolecular N-arylation of the resulting imines, has been implemented in an approach to indoles, allowing, for example, efficient conversion of the substrate 472 into the indole 473, which incorporates a masked amine functionality (Equation 131) <2003AGE3042>. 

Although this mechanism is based on known activation of the N-H bond of aniline by Ru3(CO)i2, a mechanism involving the activation of the carbon-carbon triple bond followed by a nucleophilic attack of the amine carmot be discarded. Indeed, typical Lewis acids such as Zn(II) or Cu(I) salts have been shown to be efficient catalysts for the intramolecular hydroamination of alkyne [93], However, contrary to ruthenium(II) complexes, mthenium(O) catalysts are not expected to electrophili-cally activate alkynes. 

Whereas the catalytic hydrosilylation of alkynes was one of the first methods of controlled reduction and functionalization of alkynes, the ruthenium-catalyzed hydroamination of alkynes has emerged only recently, but represents a potential for the selective access to amines and nitrogen-containing heterocydes. It is also noteworthy that, in parallel, the ruthenium activation of inert C-H bonds allowing alkyne insertion and C-C bond formation also represents innovative aspects that warrant future development. Among catalytic additions to alkynes for the production of useful products, the next decade will clearly witness an increasing role for ruthenium-vinylidenes in activation processes, and also for the development of ruthenium-catalyzed hydroamination and C-H bond activation. 

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. 

As discussed in the previous sections, hydrosilylation and hydroamination reactions can be catalyzed by essentially the same catalysts under very similar reaction conditions due to the similarity in their reaction mechanisms. Hence, both reactions can be performed in one synthetic procedure as a one-pot sequence. Although less explored than hydrosilylation of C-C multiple bonds, organolanthanide-catalyzed hydrosilylation of imines is a facile straightforward process [172,173]. Imines, in particular cyclic imines, are readily available via organolanthanide-catalyzed hydroamination of alkynes. Roesky and coworkers have demonstrated that A-silylated saturated heterocycles can be smoothly obtained (38) and (39) utilizing the bis(phosphinoamide)methanide complex 12 (Fig. 8) [57,58]. The higher reactivity of aminoalkynes in the hydroamination process makes this method a valuable alternative to aminoalkene hydroamination. 

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. 

The metallocene complex 27 containing a M=X double bond undergoes overall [2 + 2] cycloaddition with an internal alkynes to give heterometallacyclobutenes (28) [77], A formal [2 + 2] cycloaddition of CpjZr (=N Bu)(thf) with imine affords a 2,4-diazametallacyclobutane, whose further reaction with imines results in an imine metathesis reaction [78] azametallacyclobutene is an intermediate in the Cp2Zr(NHR)2-assisted hydroamination of alkynes and allene [79],... 

---