Direct reductive aminations, aldehydes

Aldehydes cannot undergo direct enantioselective reduction due to the formation of an achiral product, but List s group discovered an interesting variation on this theme with the direct reductive amination of a-branched aldehydes via an efficient dynamic kinetic resolution (DKR) [56]. Under the reductive amination conditions, an a-branched aldehyde undergoes a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then have to be faster than that of the other, resulting in an enantiomerically enriched product via a dynamic kinetic resolution (Figure 15.6). TRIP once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine product in 50%... 

The direct reductive amination of aromatic aldehydes has been achieved with excellent yields using a gold(I) catalyst along with a Hantzsch ester as the hydrogen source under mild reaction conditions [154]. In another example, B(C6F5)3- is shown to act as a catalyst for the transfer of hydrogen from a Hantzsch ester to an imine [155]. 

A carbene derived from triazole was used in IPA with K2CO3 as base, for direct reductive amination of aldehydes with primary amines to form secondary amine products [179]. Other recent examples include (1) a base-free catalyzed reduction of a series of C=0 bonds and of the C=N bond of benzylideneaniline (>99 % conversion was achieved in 48 h, with 0.1 mol% catalyst) [180] (2) heteroditopic dicarbene Rh(I) and Ir(I) complexes containing 1,2,3-triazolylidene-imidazolyli-dene ligands, mostly tested on acetophenone but with one imine example [181] (3) Ir complexes of A-benzyl-substituted A-heterocyclic carbenes where 0.5 mol% catalyst is used with 5 % KOH in IPA in reductions to give products in >99 %... 

Sc(OTf)3 was used in direct reductive amination reactions using one of Hantzsch dihydropyridines as a reducing reagent [88]. In particular, the selective reaction of the aldehyde-derived imine was carried out with the coexistence of other reducible functional groups including ketones [89]. Intramolecular hydroamination could also finely be performed using Sc complexes [90]. 

The direct reductive amination of aldehydes with primary or secondary amines using a catalytic amount of Pd(PhCN)2Cl2 and 2,2 -biquinoline-4,4 -dicarboxylic acid dipotassium salt (BQC) in water under 200 psi of H2 afforded secondary or tertiary amines. In some cases, primary alcohols were formed as byproducts (eq 168). ... 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

For the solution-phase preparation of functionalized tropanylidenes, the authors simply dispensed solutions of the bromo N-H precursor in 1,2-dichloroethane (DCE) into a set of microwave vials, added the aldehydes (3 equivalents) and a solution of sodium triacetoxy borohydride in dimethylformamide (2 equivalents), and subjected the mixtures to microwave irradiation for 6 min at 120 °C. Quenching the reductive amination with water and subsequent concentration allowed a microwave-assisted Suzuki reaction (Section 6.1.2) to be performed directly on the crude products [295]. 

Abdel-Magid, A. F. Carson, K. G. Harris, B. D. Maryanoff, C. A. Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triace-toxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures, J. Org. Chem. 1996, 67, 3849. 

With the aim of developing new analogues of the cyclic AMP phosphodiesterase inhibitor lixazinone (554), the synthesis of agents 553 and 555-557 was undertaken (Scheme 167) (88JMC2136). Thus, all possible 1,2-related N-r-Boc aldehydes 551 were prepared by directed metalation on isomers 549, with the exception of that which required the use of a metal-halogen exchange reaction on the bromo precursor 550 (attempts to metalate 4-TMS-3-N-f-Boc pyridine proved inefficient). As exemplified for one particular isomer, conversion of 551 into 552 by reductive amination... 

The aldehydes 58 which are obtained in hydro-formylations can also be directly converted to further products in the course of the reaction. For example, in the presence of a secondary amine, a reductive amination to 59 can be added onto the hydroformylation reaction (amino-methylation. Scheme 8) [23]. Especially elegant seems the possibility to add onto the hydroformylation another carbonylation reaction. If dicobalt octacarbonyl is used as the catalyst and the aldehyde 58 is trapped with a primary amide to give 60, a second carbonylation occurs, resulting in a... 

The first consideration when setting up an AlphaScreen assay is the choice of an assay format In most cases, the decision will depend on the interaction partners under investigation and on the biological tools available for their detection. The interaction partners can be coupled to the beads directly via reductive amination of reactive aldehyde groups, similar to the immobilization on a Biacore sensor chip (see above). The usefulness of this approach is limited by the reaction conditions, which may not be appropriate for maintaining the biologically active conformation of the biomolecule. Therefore the biomolecule of interest is usually not coupled to the beads directly, but instead captured via an antibody, also preventing steric hindrance. While not strictly necessary, it is often convenient to use a biotinylated molecule which can be captured by streptavidin-coated donor beads. 

Bis(N-inethylpiperazinyl)aluniinum hydride (li. This hydride was originally prepared from aluminum hydride and N-methylpiperazine, and was used to reduce carboxylic acids directly to aldehydes. It can be prepared more conveniently from lithium aluminum hydride and the amine. It is useful for reduction of aliphatic and aromatic acids to aldehydes (80-95% yield). Significantly, it reduces a,p-unsaturated acids to aldehydes without reduction of the double bond (70-80% yield). ... 

To use reductive amination in synthesis, you must be able to determine what aldehyde or ketone and nitrogen compound are needed to prepare a given amine—that is, you must work backwards in the retrosynthetic direction. Keep in mind the following two points ... 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

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