Reduction reaction imines

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

In an attempt to prepare alkylamines by asymmetric reduction of imines with chiral hydride reagents, diphenylphosphinyl imines (38), prepared by reaction of ketoximes (39) with chlorodiphenylphosphine [(Cg 115)2 PCI], were reduced in the presence of a variety of chiral aluminum and boron hydride reagents43. Among the most promising reagents was BINAHL-H44 (40), a chiral hydride compound prepared by the modification of lithium... 

The reductive amination reaction (Scheme 12.10) has two steps the formation of imine and the reduction of imine. The single bead FTIR results (Fig. 12.14) show the combined result of both steps. The aldehyde IR bands at 1682 and 2769 cm disappeared in the final product. However, this did not suggest that the... 

In the reduction of imines and enamines with hydrogen telluride and sodium hydrogen telluride, hydrolysis leading to primary amines and carbonyl compounds is frequently competitive with the reduction. This undesired side reaction is minimized by the addition of triethylamine, in the case of hydrogen telluride. ... 

A number of organic species, including amides, oximes, and nitriles, undergo reductive amination, a variety of reduction reactions that produce cimines. In general, these processes involve imines, R=N-R, or related species. Reduction processes include hydrogenation using Raney nickel as the catalyst (for nitriles), the reaction with sodium/EtOH (for oximes), and the use of lithium aluminum hydride, LiAlH (for amides or nitriles). Figure 13-16 illustrates the preparation of amphetamine by reductive amination. 

The reduction of imines can be performed with zinc powder in 5% aq. NaOH solution without any organic solvents under mild conditions (Tsukinoki et al., 1998). In comparison with other conventional methods, some advantages of this method are the fact that, since the reaction can be done in water at room temperature under atmospheric pressure, it is safe, and that hydrogen gas is not necessary because the proton source is water. Furthermore, Zn powder is cheap compared with metal hydrides, hydrogenation catalyst, and lanthanides, and is not sensitive to oxygen and water. 

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. 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

Reduction reactions, which usually convert imine to secondary amine functions, are also metalion specific and usually most successful for the Ni" complexes. Reductions can be by electrochemical means or by chemical reductants such as NaBH4, NiAl/OH, H2/Pt or H2/Ni. H3P02 is specific for conversion of an a-diimine group to a monoimine. Examples of imine complexes which have been reduced to form cyclic amine complexes include (1), (3), (4), (9), (16) and (20). 

The corrinoid-mediated reduction of polyhaloethenes has been the subject of a recent study, which reports reaction via homolytic C-halogen bond fission. The elimination of a further halogen radical affords haloalkynes, which lead to acetylene itself.56 The electron transfer-induced reductive cleavage of alkyl phenyl ethers with lithium naphthalenide has been re-examined in a study which showed that it is possible to reverse regioselectivity of the cleavage (i.e. ArOR to ArH or ArOH) by introduction of a positive charge adjacent to the alkyl ether bond.57 A radical intermediate has been detected by ESR spectroscopy in the reduction of imines to amines with formic acid58 which infers reacts takes place via Lukasiewicz s mechanism.59... 

Electrochemical reduction of imines (25 Schiff bases) in acidic media proceeds via the iminium species, i.e. the protonated imine (26) (Scheme 5)29. Since 26 bears a positive charge, it is very easily reduced, so much so that the resulting neutral radical (27) is formed at a potential positive of its reduction potential. The products are therefore derived from 27 rather than the corresponding carbanion (28). This stands in contrast with the electrochemical behavior of imines in neutral media, where 27 is immediately reduced to 2830. Thus, cathodic reduction of /u. s-irnincs of 1,2-diamines (29) in DMF containing methanesulfonic acid affords tetrahydropyrazines (equation 13)31. A similar reaction can... 

Lithium aminoborohydrides, which are readily obtained by reaction of n-BuLi with amine-boranes327,328, are excellent reagents for the reduction of imines to their corresponding secondary amines (equation 80)329. If the substrate possesses chirality, then there is considerable diastereoselectivity in this reaction (up to 90%). 

Oxazaborolidines were developed for reduction of carbonyls and were shown to be of value in the reduction of imines. 8 5-Hydrogen oxazaborolidines were prepared in situ from 1 and BH3 THF (tetrahydrofuran), whereas stock solutions of 5-methyl oxazaborolidines were obtained by reaction with trimethylboroxinc. ... 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

In 1993, Bolm reported that these reactions could be performed using catalytic quantities (10 mol%) of the chiral P-hydroxy sulfoximine.132 The enantiomeric purities of the product alcohols ranged from 52% (1-indanone) to 93% (PhCOCHjOSiRj). In many cases the enantiomeric purities were enhanced using sodium borohydride as reductant in the presence of chlorotrimethylsilane.133 These methods have been extended to the asymmetric reductions of imines.134 /V-SPh-substituted imines gave the highest enantioselectivities and these reductions proceeded in the same stereochemical sense as the reductions of ketones. 

Another recent innovation regarding the use of imine chemistry in DCC relies on an original way to freeze the equilibrating mixture by Ugi reactions [27]. In other words, this consists in conjugating a reversible reaction of imine condensation with an irreversible Ugi reaction. The latter step therefore represents an alternative to the more widespread reduction of imines with borohydrides. Wessjohann and coworkers recently prepared a library of macrocyclic oligoimines by condensation... 

From halides. Halides are easily converted into selenides. Since halides are also suitable radical precursors, this transformation is usually done when side reactions of halides with nucleophiles can occur. An example of this type is reported in Eq. (1). The bromide 5 was converted into a phenyl selenide, which could stand DIBALH reduction and imine formation. Tin mediated cyclization of 6 afforded the cyclopentylamine 7 in 72% yield [5]. 

Enantioselective Reduction of Imines. Oxazaborolidine (3) also enantioselectively reduces A-substituted ketimines to the corresponding A-substituted amine in low to moderate ee (eq 8, Table 3). In this case the enantioselectivity is the same as the reduction of ketones thus the (5)-oxazaborolidine catalyst gives (R)-amines. Oxazaborolidine (3) is reported to provide higher enantioselectivity than oxazaborolidine (6). An interesting application of this reaction is the preparation of a (a/ 5,5) diastereomerically enriched (63% de) sample of the more active atropisomers of the herbicide Metalochlor (eq 9)... 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

The reduction of imines to amines (equation 21) by dissolving metals is usually carried out using active metals in a protic solvent, typically Na-alcohol, Zn-NaOH and A1 or Mg in alcohols. - ""- Although the mechanism of these reductions has not been investigated in detail it is almost certainly analogous to that of the reduction of ketones (Section 1.4.2). It has been established that radical anions are intermediates in these reductions and in the absence of a proton donor reductive dimerization is the principal reaction path. ... 

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