Amines from hydroaminomethylation

A more recent report thoroughly investigates hydroaminomethylation of terminal alkenes to give high yields of linear (linear branched=99 1) tertiary amines from secondary amines and terminal alkenes or linear secondary... 

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. 

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. 

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... 

From an economical and environmental point of view, one pot synthesis of amines from alkenes is a superior pathway over conventional multistep pathways. Hydroaminomethylation is an attractive tool for the synthesis of amines and has been used in the pharmaceutical and chanical industries. Blum developed a heterogeneous system based on [Rh(cod)Cl]2 immobilized within a sol-gel matrix as a highly efficient, regioselective, and recyclable catalyst for hydroaminomethylation reaction of vinylarenes with aniline derivatives (anilines or nitrobenzenes) under mild conditions. 

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... 

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. 

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 reactions can be accomplished by addition of nucleophilic a-amino alkyl radicals (generated from amines) onto electron-deficient alkenes [7, 21], Amines have a low oxidation potential, and are easily oxidized by excited aromatic ketones bearing electron-donating substituents (e.g., Michler s ketone) or... 

The hydroaminomethylation reaction catalyzed by 74 has been found to be rather general with regard to amines and possesses many advantages that stem from the relatively mild reaction conditions. 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

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). 

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. 

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. 

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