Hydroformylation-amination-reduction Hydroaminomethylation

The hydroaminomethylation of aUcenes was originally discovered by Reppe [94] and consists of the hydroformylation of an alkene, followed by reaction of 

This reaction is general and preserves the regioselectivity observed imder normal hydroformylation conditions, although variations are observed as a function of the amine. Thus, hydroaminomethylation of styrene leads to the branched derivative 164 with both secondary (R = R =alkyl) and primary amines (R-aUcyl, R H), although in this case more drastic conditions are needed. The piperazines give the iso, iso-diamine 165 as the major product in 90% yield. 

The reaction is compatible with the presence of carbonyl groups in the molecnle, which remains unaltered, and only the aldehyde function reacts in the reaction conditions (see also Fignre 32). 

Diamines are also obtained from allyl chlorides by initial halogen substitution to give the aUylamine and subsequent hydroaminomethylation [99]. With primary amines or diamines this method can also be nsed in the synthesis of heterocyclic systems. 

Different y- and d-aminofrmctionalized ethers, amines and silanes 169 are obtained from aUcenes 168. Branched derivative is the main product obtained when X=OR, NR. The alkylation of the primary amines leading to secondary or tertiary amines can be controlled by the alkene/amine ratio [100]. Nitro derivatives can be used instead of amines, since they are rednced to amines in the reaction conditions [101]. Selective monoalkylation or dialkylation of nitro compounds is achieved depending on the alkene/nitro compound ratio. 

---

The hydroformylation reaction strategy has recently been extended, in a novel way, to the manufacture of primary amines by hydroaminomethylation of olefins with ammonia in a two-phase system. Thus, 1-pentene was reacted with ammonia here hydroformylation to an aldehyde, with CO and H2, with subsequent reductive amination occurs in a domino reaction. The catalyst was Rh/Ir/TPPS (Zimmermann et al., 1999). 

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]. 

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-... 

Another one-step route to amines is hydroaminomethylation, which is a sequence of hydroformylation and reductive amination of the intermediate aldehyde in a one-pot reaction (Scheme 1). 

Reductive amination of aldehydes prepared from hydrofonnylation is a useful route to amines. Botteghi, et al. reported the synthesis of racemic Tolterodine by sequential hydroformylation-reductive amination [18]. Hydroaminomethylation (tandem hydroformylation/reductive amination) has recently been used to prepare a wide variety of pharmaceutical compounds [19]. Representative examples are shown in Fig. 5. Hydroaminomethylation of 1,1-diarylethenes leads to l-(3, 3-diaiylpropyl)amines, such as fenpiprane [20, 21]. Heterocyclic aUyUc amines undergo hydroaminomethylation to form pharmaceutically active diamines, such as etymemazine [22]. Ibutilide and fexofenadine have been prepared by hydroamino-methylatiOTi of 1-aiylallyl alcohols in the presence of the requisite amines [23,24]. Although none of these reactirais has been developed into a commercial process, the widespread utility of the hydroaminomethylation reaction makes it likely that it will be used commercially... 

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... 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

General Procedure for the Stepwise Hydroformylation/Reductive Amination on Allylated Hyperbranched Polyglycerols (PG). Synthesis of Hydroaminomethylated Hyperbranched PG-dendrimers. PG-Allyl, Rh(acac)(CO)2 and XANTPHOS were dissolved in dry toluene and placed in an autoclave. The autoclave was pressurized with CO/H2 (1 1, 30 bar), heated at 70 °C for 5d. After cooling, the amine was added to the crude PG-aldehyde (1H NMR was used to confirm full conversion) and stirred for 1-2 h. After stirring, Rh(acac)(CO)2 was added and the autoclave was pressurized with CO/H2 (1 6, 70 bar) and heated at 85 °C for 2-5 days. After cooling, the solvent was removed in vacuo and the crude mixture was purified by dialysis (benzoylated cellulose tubing) to give the re-... 

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. 

Carbonylative hydroaminomethylation (hydroformylation-reductive amination) [109-115] has only been reported for mono-olefin reactants, as hydroformylation of dienes and allenes suffers from poor regioselectivity and over-hydroformylation ... 

Several synthetic approaches toward 3,3-diarylpropyl- or 4,4-diarylbutylamines (Figure 12.2) comprise hydroformylation as the key step. One possible route involves the reaction of the (D.co-diarylalkylhalide, obtained in a few steps from the hydroformylation product linear aldehyde, with an appropriate amine [19]. On the contrary, the aldehydes can be converted directly into the amines via a transition metal catalyzed reductive amination reaction [20]. Although these methods have heen employed efficiently for the synthesis of compounds 10,11 [19], and 12 [20], the most elegant solution is the direct hydroaminomethylation where the initial hydroformylation of the alkene is followed by the condensation of the intermediate aldehyde with the amine present in the reaction mixture and a final hydrogenation to give a saturated secondary or tertiary amine. 

---