Rhodium hydroaminomethylation

Hydroaminomethylation of alkenes occurred to give both n- and /. so aliphatic amines catalyzed by [Rh(cod)Cl]2 and [Ir(cod)Cl]2 with TPPTS in aqueous NH3 with CO/H2 in an autoclave. The ratio of n-and /.soprimary amines ranged from 96 4 to 84 16.178 The catalytic hydroaminomethylation of long-chain alkenes with dimethylamine can be catalyzed by a water-soluble rhodium-phosphine complex, RhCl(CO) (Tppts)2 [TPPTS P(m-C6H4S03Na)3], in an aqueous-organic two-phase system in the presence of the cationic surfactant cetyltrimethy-lammonium bromide (CTAB) (Eq. 3.43). The addition of the cationic surfactant CTAB accelerated the reaction due to the micelle effect.179... 

Given the previous discussion on reductive amination, it is surprising that the potentially more complicated domino hydroformylation-reductive amination reactions have been more thoroughly developed. The first example of hydroaminomethylation was reported as early as 1943 [83]. The most synthetically useful procedures utilize rhodium [84-87], ruthenium [88], or dual-metal (Rh/Ir) catalysts [87, 89, 90]. This area was reviewed extensively by one of the leading research groups in 1999 [91], and so is only briefly outlined here as the second step in the domino process is reductive amination of aldehydes. Eilbrachfs group have shown that linear selective hydroaminomethylation of 1,2-disubstituted alkenes... 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

Hydroaminomethylation is a simple, efficient and atom-economic method to synthesize various amines. This one-pot reaction consists of three consecutive steps in the first step a hydroformylation of an olefin is performed followed by the reaction of the resulting aldehyde with a primary or secondary amine to give the corresponding enamine or imine. Lastly, this intermediate is hydrogenated to the desired secondary or tertiary amine (Fig. 11) [33-39]. In most cases rhodium salts or complexes are used as the homogeneous catalyst in the hydroaminomethylation. 

A rhodium catalyst [Rh(cod)Cl]2 was applied at 140°C and 100 bar to achieve a yield of 99% in hydroaminomethylation of ethyl oleate and morpholine. Several amines were tested in the reaction with fatty compounds hexylamine, benzylamine, aspartic diethyl acid, valinol, and diisopropylamine are further amines which can be employed in hydroaminomethylation. The conversion with primary amines showed that hydroaminomethylation can proceed twice on the amine. The dimer fatty acid ester bridged with an amine is a highly functionalized molecule with various applications. An excess of the primary amine during the reaction prohibits the reaction of the hydroformylation product with a secondary amine which is the product of hydroaminomethylation with the primary amine (Scheme 19). 

Limonene is used as a starting material for growth regulators of tobacco plants. Hydroaminomethylation is able to reduce the number of reactions steps for their production to one. The reaction takes place with yields up to 93% after 20 h with a rhodium dimer as a catalyst (Scheme 20). 

An interesting variation of hydroformylation with a great potential for the industrial preparation of primary amines is hydroaminomethylation. In this process two catalytic reactions are combined, a hydroformylation and a reductive amination of the resulting aldehyde. Although first described more than 60 years ago a really successful procedure was only published recently [78]. To ensure the success of this sequence a rhodium catalyst for the hydroformylation was combined with an iridium catalyst for the imine reduction in a two-phase system, similar to the Ruhrchemie/Rhone-Poulenc process for the hydroformylation. It was demonstrated that less polar solvents such as toluene in combina-... 

For hydroaminomethylation, homogeneous rhodium complexes are preferentially used as catalysts, for example, [Rh(cod)Cl]2. 

Originally discovered by Reppe and co-workers, hydroaminomethylation of olefins has attracted attention as an economical, one-pot synthesis of amines. Alper and co-workers have demonstrated that zwitterionic rhodium complex [Rh (q -cyclooctadiene)(q -CgH5BPh3)-] 74 is an excellent catalyst for hydroaminomethylation of phenylalkenes 75 to afford the corresponding branched methylated amines 76 with high regioselectivity (Scheme 22) [42]. 

Rische T, Eilbracht P (1999) One-pot synthesis of pharmacologically active secondary and tertiary l-(3,3-diarylpropyl)amines via rhodium-catalysed hydroaminomethylation of 1,1-diarylethenes. Tetrahedron 55 1915-1920... 

Ahmed M, Buch C, Routaboul L, Jackstell R, Klein H, Spannenberg A, Beller M (2007) Hydroaminomethylation with novel rhodium-carbene complexes an efficient catalytic approach to pharmaceuticals. Chem Eur J 13 1594-1601... 

Briggs JR, Klosin J, Whiteker GT (2005) Synthesis of biologically active amines via rhodium-bisphosphite catalyzed hydroaminomethylation. Org Lett 7 4795-4798... 

Whiteker GT (2010) Synthesis of fexofenadine via rhodium-catalyzed hydroaminomethylation. Top Catal 53 1025-1030... 

Vieira TO, Alper H (2007) Rhodium(I)-catalyzed hydroaminomethylation of 2-isopropeny-lanilines as anovel route to 1,2,3,4-tetrahydroquinolines. Chem Commun 2710-2711... 

Specific examples of the hydroaminomethylations of olefins with secondary amines are shown in Equations 17.19-17.21. Cyclic and acyclic secondary amines occur in high yield with linear-to-branched ratios exceeding 50 to 1 in most cases when catalyzed by the rhodium complex generated from [Rh(COD)JBF and xantphos. The reaction of pen-tene with piperidine is shown in Equation 17.19. These reactions are also compatible with alcohol (Equation 17.20) and acetal functional groups (Equation 17.21). 

In hydroformylation reactions coupled with a hydrogenation step (e.g., hydroaminomethylation. Section 5.4), the simultaneous use of Rh(acac)(CO)2 and [Rh(COD)2l BF, together with a single modifying ligand can be advantageous [66]. The first rhodium complex forms the active hydroformylation catalyst A, whereas the second is a precursor of the hydrogenation catalyst B. Both are in equilibrium (Scheme 1.27). 

Karakhanov and coworkers [41] incorporated hydroformylation with methyl-formate in a hydroaminomethylation tandem reaction by using a dual metal catalyst consisting of homogeneous Ru and Rh complexes (Scheme 3.19). In contrast to rhodium, the ruthenium catalyst was used in excess. The transformation is exemplified in the scheme with 1-pentene as substrate. Also, other terminal and internal olefins could be converted with dimethylamine into the corresponding amines. High temperatures enhanced the formation of the desired amines and lowered the degree of olefin hydrogenation. The reaction proceeded also well. 

Figure 5.10 Ligands for highly n-regioselective rhodium-catalyzed hydroaminomethylation of internal olefins.

In 2013, the rhodium-based protocol was extended to a ruthenium catalyst modified with a monodentate 2-phosphino-substitued imidazole ligand in the hydroaminomethylation of2-octene (Scheme 5.32) [150]. 

Wittmann K, Wisniewski W, Mynott R, Leitner W, Kranermann CL, Rische T, Eilbracht P, Kluwer S, Emsting JM, Elsevier CJ (2001) Supercritical carbon dioxide as solvent and temporary protecting group for Rhodium-catalyzed hydroaminomethylation. Chem Eur J... 

The unmodified rhodium-catalyzed hydroaminomethylation of 1-octene and morpholine was investigated in ternary thermophoric solvent systems [26]. Therefore, hexane or dodecane, together with propylene carbonate and a mediator solvent, provided complete miscibility at the desired reaction temperature of 125 °C. N- and iso-N-nonylmorpholine products adopted the nonpolar phase after cooling and could be separated (Scheme 5.8). Applying a 1-octene/morpholine ratio of 1.5,96% amine selectivity was the highest achieved in the PC/dodecane/l,4-dioxane (1 0.55 1.3, volume ratio) polar/nonpolar/mediator solvent system. Rhodium loss was measured by ICP-OES to be less than 1.5% and was correlated to the mediator solvent polarity. 

Hydroaminomethylation of 1 -dodecene with dimethylamine using a water-soluble rhodium-phosphane complex, RhCl(CO)(TPPTS)2 in an aqueous-organic two-phase system in the presence of cetyltrimethylammonium bromide was investigated. High reactivity and selectivity for tertiary amine were achieved at 130 °C and 30 bar pressure [163]. 

The rhodium-catalyzed hydroaminomethylation of 1-octene with morpholine was studied using temperature-dependent solvent systems consisting of propylene carbonate, an alkane, and a semipolar mediator such as N-octylpyrrolidone. The conversion of 1-octene and the selectivity to the corresponding amine is 92%. After the reaction, the catalyst can be easily recovered by a simple phase separation with only a negligible loss of rhodium [167]. 

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