Hydroaminomethylation

The term hydroaminomethylation (HAM) describes the one-pot reaction of olefins with syngas, ammonia, and primary or secondary amines to afford secondary or tertiary amines with one carbon atom more than in the starting 

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]. 

It has been known for some time that the last two steps, namely the formation of the unsaturated nitrogen compound and subsequent hydrogenation, can be carried out in one pot, known as reductive amination [6-8], for which even some asymmetric versions exist [9]. Alternatively, with the proper choice of the conditions (e.g., Rh(acac)(CO)2 (acac = acetylacetonate), NAPHOS, C0/H2 = 1 1, 10 bar 65 °C, 16 h), the reaction of an olefin, syngas, and secondary amines can be stopped at the stage of the enamine, which is then called hydroaminomethylenation [10]. 

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- 

Indeed hydroaminomethylation is part of a new route to e-caprolactam. Starting with readily available butadiene it enables the first carbon-carbon bond formation, extending the carbon chain and introducing the aminogroup. In a sub- 

Several factors are needed to realize the tandem process. First, the catalyst should not be poisioned by the high concentration of amine. Tlie use of bidentate ligands helps to retard catalyst decomposition by this route. Second, the catalyst must be sufficiently electron rich to catalyze hydrogenation of the relatively electron-rich enamine, while not being too electron rich to prevent hydroformylation. These properties have been achieved with a number of systems, many of which have been outlined in a review on tandem processes initiated by hydroformylation. Some of these catalysts lack phosphine ligands, while others contain PPhj or more modern bisphosphine or bisphosphite ligands shown by the examples in the equations above. 

The less polar the mediator was the more of it dissolved in the product containing nonpolar phase and the more rhodium was lost. 

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Abstract This chapter focuses on carbon monoxide as a reagent in M-NHC catalysed reactions. The most important and popular of these reactions is hydro-formylation. Unfortunately, uncertainty exists as to the identity of the active catalyst and whether the NHC is bound to the catalyst in a number of the reported reactions. Mixed bidentate NHC complexes and cobalt-based complexes provide for better stability of the catalyst. Catalysts used for hydroaminomethylation and carbonyla-tion reactions show promise to rival traditional phosphine-based catalysts. Reports of decarbonylation are scarce, but the potential strength of the M-NHC bond is conducive to the harsh conditions required. This report will highlight, where appropriate, the potential benefits of exchanging traditional phosphorous ligands with iV-heterocyclic carbenes as well as cases where the role of the NHC might need re-evaluation. A review by the author on this topic has recently appeared [1]. 

Hydroaminomethylation allows for the direct synthesis of key pharmaceuticals, agrochemicals, and natural products (Scheme 9.4) [32]. Synthesis of 3,3-diarylpro-pylamines is an excellent application of hydroaminomethylation [33, 34]. 

Hydroaminomethylation is hydroformylation coupled to amine-aldehyde condensation followed by hydrogenation. The hydroformylation reaction establishes... 

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). 

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... 

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... 

Hydroaminomethylation of Alkenes (Domino Hydroformylation-Reductive Ami nation) 439... 

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... 

Scheme 15.12 Synthesis of fenpiprane using hydroaminomethylation of diphenylethene.

Scheme 15.13 Hydroaminomethylation of terminal alkenes to linear amines.

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 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. 

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. 

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. 

Homogeneously catalyzed tandem reactions Hydroaminomethylation Hydroformylation... 

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]. 

More recently macrocycles with rigid and flexible aromatic and chiral binaphthyl systems with interesting fluorescence properties have been synthesized via hydroaminomethylation (Scheme 16) [62,63]. 

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. 

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-... 

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]. 

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. 

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