Selective hydroaminomethylation

Larock RC (1989) Comprehensive organic transformations. VCH, New York MobaUigh A, Seayad A, Jackstell R, Beller M (2003) Amines made easily a highly selective hydroaminomethylation of olefins. J Am Chem Soc 125 10311-10318... 

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... 

The improvements made in hydroaminomethylation technology suggest that certain variants of this reaction are sufficiently developed for the potential production of amines. The synthesis of linear tertiary and secondary amines from terminal alkenes shows promise in this regard. Belief s recent contributions towards hydroaminomethylation using ammonia to produce linear primary amines, which are of industrial significance due to their abundance, suggest a bright future for this reaction. Branched selective hydroaminomethylation remains relatively underdeveloped and needs further study. 

Figure 2.70 Selective hydroaminomethylation of mixtures using Rh complexes. Source adapted from Seller et af. [345].

Scheme 2 Selective hydroaminomethylation of alkenes catalyzed by a new Rh/lr system.

Hydroaminomethylations with ammonia are difficult to develop because the product amine is more nucleophilic than ammonia and preferentially condenses with the aldehyde to form the precursor to the final amine product. Thus, hydroaminomethylations with ammonia tend to form dialkyl- and trialkylamines. To overcome this problem in selectivity, hydroaminomethylations of ammonia have been conducted with a water-soluble catalyst in a biphasic system. Under these conditions, the reaction occurs preferentially with ammonia in the aqueous phase, because it is more soluble than the alkylamine product, and the reactions favor formation of the primary amine. The use of a water-soluble version... 

The recent improvements described above suggest that hydroaminomethylation is approaching use as a practical process for preparing a range of amines with good linear selectivity, and good catalytic activity. 

In this survey, selected synthetic applications of tandem hydroformylation sequences are described and complementing the more comprehensive reviews covering the literature up to 1998/99 [27], and up to 2003 [28,29]. The material is ordered according to the type of the additional transformation involving heterofunctionalization of the aldehyde group to form acetals, aminals, imines and enamines, as well as reduction of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C,C-bond formation at the carbonyl group or at the acidic... 

Hydroaminomethylation is also be used for the construction of den-drimers [64], Here divergent and convergent strategies with wide variabilities can be used. A selected example is shown in Scheme 17. 

In a similar manner, polymers with unsaturated chains or side chains can be converted to polyamines [66-69]. Conjugated diolefins usually undergo hydroformylation with low selectivities [70]. Mostly hydrogenation of at least one double bond occurs and mixtures of various saturated and unsaturated amines and diamines are obtained [71]. Similar to alkenes also alkynes may serve as unsaturated compounds in hydro aminomethylation reaction sequences. Although synthetically attractive, only a few investigations towards hydroformylation and hydroaminomethylation of alkynes in the presence of N-nuclcophilcs are known. Usually a preferred transformation to furanonic derivatives is observed under hydroformylation conditions [27]. 

However, morpholine-4-carboxylic acid 2-hydroxy-1-methyl-ethyl ester is formed by the reaction of PC and the substrate morpholine in an undesired side reaction. By use of 1.4-dioxane or the pyrrolidones as mediator s3 about 30 to 45% of the morphoUne is consumed by this side reaction. The by-product is contained in the PC phase and can not be extracted to the non-polar product phase. The selectivity to the desired amines is lowered, because of the consiunption of the morphoUne. Thus, PC has to be substituted by another polar solvent (e.g. water, methanol or ethylene glycol) in future experiments. The lactates react with the morphoUne, too resulting in the corresponding amide. Overall, the hydroaminomethylation in the TMS systems PC/dodecane/lactate results in a conversion of 1-octene of about 80%, but in selectivities to the amines of only 50 to 60%. 

This hydroaminomethylation has only been applied in homogeneous one-phase systems until now. The reaction will mostly lead to secondary and tertiary amines, because the intermediate primary amines will further react with the aldehyde formed to secondary amines. The synthesis of the technically important primary amines from ammonia and alkenes via hydroaminomethylation was investigated, but only low selectivities (32 %) and TOFs (9 h ) to primary amines could be achieved, despite the high excess of ammonia. Other side products, e. g., via aldo-lization, are also observed. 

Aliphatic amines are amongst the most important bulk and fine chemicals in the chemical and pharmaceutical industry [13]. Hydroaminomethylation of alkenes to amines presents an atom-economic, efficient and elegant synthetic pathway towards this class of compounds. In hydroaminomethylation a reaction sequence of hydroformylation of an alkene to an aldehyde with subsequent reductive amina-tion proceeds in a domino reaction (see Eq. 4) [14]. Recently, the highly selective hydroamination of alkenes with ammonia to form linear primary and secondary aliphatic amines with a new Rh/Ir catalytic system (] Rh(cod)Cl 2], ] Ir(cod)Cl 2], aqueous TPPTS solution) has been described (see Scheme 2) [15]. The method is of particular importance for the production of industrially relevant, low molecular weight amines. 

The hydroaminomethylation of 1-pentene and ammonia, with a Rh/Ir/TPPTS catalyst in an aqueous/organic two-phase system, was developed by BeUer et al. [14]. Under standard hydroformylation conditions (130°C, 12 MPa) amines could be isolated in 75% yield. By increasing the ammonia/olefin ratio and by using the extraction effect of the organic solvent as in Ref. [10], the selectivity for primary amines could reach more than 90%. This method could also be used for propene and 1-butene to give butylamine and pentylamine as main products. 

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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