Reductive amination protocol

The reductive amination protocol for coupling these types of small tags to glycans can be found in the previous section. 

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

In order to place later chapters in proper context, the first chapter offers a comprehensive overview of industrially important catalysts for oxidation and reduction reactions. Chapters 2 and 3 describe the preparation of chiral materials by way of the asymmetric reduction of alkenes and ketones respectively. These two areas have enjoyed a significant amount of attention in recent years. Optically active amines can be prepared by imine reduction using chiral catalysts, as featured in Chapter 4, which also discloses a novel reductive amination protocol. 

A popular and effective method for converting aldehydes to amines is through a reductive amination protocol. Typically, the aldehyde and amine react to fonn an intermediate imine or iminiiim ion and tlien a reducing agent (i.e., sodium triacetoxyborohydride) is added to carry out the reduction of the intermediate species to afford the amine. The reaction is accelerated in the presence of acetic acid (0.1 -3 equivalents). Reviews (a) Baxter, E. W. Reitz, A. B. Org. React. 2002, 59, 1-714. (b) Hutchins, R. O. In Comprehensive Organic Synthesis Trost, B. M. Fleming, L, Eds. Pergamon Press Oxford, U. K., 1991 Vol. 8, Chapter 1.2 Reduction of C=N to CHNH by Metal Hydrides, pp. 25-54. 

Solvent-free reductive amination protocol for carbonyl compounds using sodium borohydride supported on moist montmorillonite KIO clay is facilitated by MW irradiation (Scheme 10). ° Clay serves the dual purpose of a Lewis acid and also provides water from its interlayers that enhances the reducing ability of NaBIL. 

The concept of selective sequestration of non-product species was first demonstrated using solid-supported scavengers with electrophilic and nucleophilic character in amine acylation, amine alkylation, and reductive amination protocols [46]. Since then, a wide range of scavenger reagents has become commercially available from various suppliers. The structures and functions of these scavenger resins are shown in Table 1. 

P chiral amines are not included in this review, but we remind the reader that List has extended his TRIP/p anisidine system to an elegant dynamic kinetic reductive amination protocol for a branched aldehydes, which provides p chiral amines [18]. A computational investigation of the stereochemical pathway for p chiral amine formation has been reported on and is noteworthy [19]. 

The outlined Nugent reductive amination protocol with (R) or (S) PEA and prochiral alkyl alkyl and aryl alkyl ketones (acydic or cyclic) allows higher yields and shorter reaction times than the previously practiced two step strategy via isolated (R) or (S) PEA, see Moss, N., Gauthier, J., and Ferland, J. M., (1995) Synlett, 142 144 ... 

Polymer-supported sodium cyanoborohydride (PSCBH), now available commercially, has become more widely used. It is stable and effective even in the presence of oxidants, such as manganese dioxide, shown in this one pot oxidation-reduction amination protocol (eq 38). ... 

The Hmb-substituted amino acids of non-functional and side-chain r-butyl/ Boc-protected derivatives are readily prepared from commercially available 2-hydroxy-4-methoxybenzaldehyde and amino acid residues by reductive amination Protocol 1). To date the following Hmb residues have been prepared Ala, Arg(Pmc), Asn(Trt), Asp(O Bu), Cys(Acm), Glu(O Bu), Gln(Trt), Gly, lie. Leu, Lys(Boc), Phe, Ser( Bu), Thr( Bu), Tyr( Bu), and Val. 

In this way, the desired metallated phthalocyanines remained on the solid support, while the unwanted by-products such as the symmetrically substituted B4-type moieties were formed in solution and could easily be discarded. After an acid-mediated cleavage from the resin using a TFA/TIPS/DCM mixture at ambient temperature, the e-amine of the lysine moiety of the metallated phthalocyanine was used for the attachment of suitable oligonucleotides connected with aryl aldehydes or acids (Scheme 8.9). Interestingly, both the reductive amination and the amidation reaction could be dramatically sped up using microwave irradiation, carrying out the reactions at 70-75°C for a mere 30 min. The reductive amination protocol was found to provide a far superior yield, owing to the competitive ester formation and hydrolysis observed in the microwave-assisted amidation protocol. 

The AMEBA linker " was installed upon NaH-mediated alkylation of Merrifield resin with 4-hydroxy-2-methoxy-benzaldehyde in DMF at 120°C for 5 min under microwave irradiation (Scheme 8.20). The authors then chose to attach 4-methyl-3-nitroaniline to the linker through a previously established two-step reductive amination protocol, involving the imine formation mediated by Ti(0 Pr)4 followed by reduction of the imine using NaBH (OAc)3 (Scheme 8.20). The free amino group was then acylated with 4-(chloromethyl) benzoyl chloride using DIPEA in DMF to form the corresponding amide. 

MacMillan et al. published a similar reductive amination protocol providing better results shortly afterwards. A more bulky triphenylsilyl substituted TRIP derivative 20 was used to achieve enantiomeric excesses up to 94% (Scheme 32.22). ... 

Very recently, Strotman and co-workers from Merck revealed the upgradation of the previous methodology by exploiting asymmetric reductive amination protocol. This transformation could be made possible by using a novel Ru-based transfer hydrogenation catalyst that... 

Over the years, stereoselective synthesis with the help of chiral auxiliaries has emerged as an important synthetic tool for synthesizing chiral molecules. This methodology allows for enantioselective synthesis of a target molecule via a diastereoselective reaction with a chiral auxiliary. The two major counterparts in reductive amination protocol are the carbonyl compound and the amine. So, enantioselective synthesis can be made possible by either taking a chiral ketone or a chiral amine as the chiral auxiliary. Both methodologies have been reported in the literature, and they are of immense synthetic importance. 

C2-symmetrical secondary amines by applying the stereoselective reductive amination protocol using chiral amines as the source of chirality. In 2005, Nugent et al. published a novel method for the asymmetric reductive amination of prochiral aliphatic ketones116 where the (/ )- or (5)-a-methylbenzylamine (MBA) were employed as the cheap chiral ammonia equivalent. Ti(0 Pr)4/Raney Ni/H2 were employed as the catalyst system for the one-pot conversion of the prochiral ketones 116a-e to the corresponding chiral amines 117a-e with excellent dia-stereoselectivity (Scheme 39.33). 

It has been known for a long time that nature has employed a reductive amination protocol in biological systems. Transferase enzymes use hydrogen bonding to activate pyruvate-derived ketimines selectively toward hydride delivery from NADH, thereby ensuring the enantiocontroUed formation of naturally occurring amino acids. 

SCHEME 39.43. One-pot ozonolysis—reductive amination protocol for the total synthesis of (—)-acutumine. 

SCHEME 39.44. Synthesis of (+)-lyconadin A via reductive amination protocol. 

SCHEME 39.46. Asymmetric total synthesis of (—)-deoxoprosophylline employing a reductive amination protocol. 

SCHEME 39.49. Coupling by reductive amination protocol en route pyrinodemin A 166. 

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