Hydroformylation/imine/enamine

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. 

Hydroformylation in the presence of nucleophiles such as alcohols or amines leads to 0,0- or N,O-acetals, aminals, imines or enamines (Scheme 2). 

Imines and enamines under hydroformylation conditions can also be reduced to give saturated amines. With or without additional reduction, these conversions can be used in synthesis of various types of heterocycles. 

Similar to the formation of AT.A/ -acetals under hydroformylation conditions attack of the carbonyl carbon by primary or secondary amines can lead to imines and enamines, respectively (Scheme 11). 

Scheme 11 Basic principle for imine and enamine formation under hydroformylation conditions...

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. 

Rhodium oxide,200 cobalt carbonyl,201 rhodium and ruthenium carbonyls,202 and rhodium compounds203,204 were later found to be effective catalysts. A three-step mechanism with hydroformylation of the alkene to yield an aldehyde in the first step can be written [Eq. (7.24)]. Condensation to form an imine [Eq. (7.25)] (or enamine) and hydrogenation of this intermediate leads to the product amine ... 

Hydroaminomethylation is a promising reaction to functionalize unsaturated compounds with an amino group [13, 48, 49], The tandem reaction was discovered by Reppe in 1949 and has been further developed in recent years by Eilbracht and Beller. Hydroaminomethylation consists of three consecutive reactions which are carried out in the same reaction vessel [48], The first reaction is hydroformylation which is followed by the condensation with an amine. Hydrogenation of the generated enamine/imine to the amine is the last step. The conditions for hydroaminomethylation are related to the hydroformylation reaction but are not similar due to the two other reactions. The reaction is called an auto-tandem reaction because two of the three reactions need the same catalyst [9] (Scheme 16). 

If hydroformylation is carried out in the presence of primary or secondary amines, condensation with the initially formed aldehyde and subsequent hydrogenation of the resulting imine or enamine can occur under suitable conditions. The overall reaction sequence is referred to as hydroaminomethylation. The intramo-... 

Many reactions can be conducted in tandem with hydroformylation, but the most extensively developed process is the combination of hydroformylation and reductive ami-nation. The combination of tttese reactions catalyzed by a single complex is called hydroaminomethylation and is shown in Equation 17.18. These reactions formally add tihe C-H bond of an aminomethyl group aaoss an olefin. Hydroaminomethylation reactions were discovered in the mid-twentieth century, but have been developed into more practical processes in recent years. These reactions rely on a complex that can simultaneously catalyze the hydroformylation of an aUcene and the reduction of an imine or enamine. 

Hydroaminomethylation can be considered to be a sequence of two catalytic processes linked by an uncatalyzed process, as summarized in Scheme 17.16. First, catalytic hydroformylation of an alkene occurs by the steps described in the previous section on hydroformylation. This process is then followed by an uncatalyzed condensation of the amine with the aldehyde. When this reaction is conducted with a secondary amine, an enamine results and when the reaction is conducted with a primary amine, an imine results. This condensation process is then followed by hydrogenation of the resulting enamine or imiiie by the mechanisms described in Chapter 15, the chapter on hydrogenation. 

Intermolecular and intramolecular HAMs are known. The transformation can be considered as a tandem reaction [2,3] consisting of three consecutive steps (i) hydroformylation, (ii) formation of an imine or an enamine, and (iii) reduction. Finally, the Af-alkylated amine is produced [4]. Clearly, these reactions can also be carried out in separate steps, but the application of uniform reaction conditions offers considerable advantages, such as the use of a single catalyst for the hydroformylation and the hydrogenation steps. Moreover, the equihbrium of the formation of the intermediate imine or enamine can be advantageously shifted by the irreversible hydrogenation in the last step [5]. 

---