Imines synthetic applications

There is an experimental variation in which an W-phenacylpyridinium salt is heated with an aniline[4]. This reaction can also be readily accommodated to the mechanism involving an imine intermediate. There are a few examples of use of other types of a-halokctoncs[5,6] but most of the synthetic applications have been to 2-arylindoles. 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

In this survey, selected synthetic applications of tandem hydroformylation sequences are described and complementing the more comprehensive reviews covering the literature up to 1998/99 [27], and up to 2003 [28,29]. The material is ordered according to the type of the additional transformation involving heterofunctionalization of the aldehyde group to form acetals, aminals, imines and enamines, as well as reduction of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C,C-bond formation at the carbonyl group or at the acidic... 

Titanium ylides are generated from imine esters with titanium isopropoxide chlorides and amines or by transmetalation of the N-lithiated ylides (90,91). The regioselectivity of their reactions with methyl acrylate is opposite to that normally observed (90). A transition state is proposed in Scheme 11.13 to explain this alternative regioselectivity. Intramolecular cycloadditions of the titanium ylides offer a synthetic application of this regioselectivity. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

Thiruvazhi et al. [112] have shown interest in the area of (3-tum mimetics and the synthetic application of d- and L-proline for asymmetric synthesis of proline-derived spiro-(3-lactams. It has been shown that the asymmetric Staudinger reaction of optically active acid chloride of d- and L-proline with achiral imines is impossible due to the loss of stereochemistry at C-2. The authors have developed a strategy in which a chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of the reaction and is sacrificed later to obtain optically active spiro-(3-lactams (Scheme 38). 

Meanwhile, Nikolay had started his new research on the preparation, reactions, and synthetic applications of p-chloro vinyl ketones and related compounds (p-aminovinyl ketones, p-kctoacetals). Efficient synthetic methods were developed and improved, including C-ketovinylation (introduction of the RCOCH = CH group), and a number of useful heterocyclic compounds (pyrazoles, triazoles, pyridines, and so on) were synthesized. The discovery of enamine-imine tautomerism in p-aminovinyl ketones was another remarkable achievement by Nikolay at that time. For these studies he received in 1953 the degree of Doctor of Science in chemistry. He continued as a lecturer and supervisor of postgraduates at the University, becoming docent (associate professor) in 1951 and full professor in 1955. 

Since the rearrangement of silicon azides is known, we looked for some synthetic applications in organometallic chemistry. For example, ring extension reactions involving sila.imines intermediates can be described ... 

Aza Diels-Alder reactions of nonactivated imines have been investigated with regard to the effects of electronically neutral substituents and the influence of Lewis acids [179, 180]. Some of the synthetic applications described below nevertheless take use of the higher reactivity of iminium ions or imines activated by electron-withdrawing substituents, respectively. 

Dizocilpine] (dibenzocycloheptene imine) Synthetic NMDA-Glu-R non-competitive antagonist [anti-excitatory, attention deficit disorder application]... 

A variety of imine reductions using NaBHsCN in acidic media (where the actual species reduced are protonated iminium ion intermediates) are presented in Table 2 and illustrate the versatility of this mild reagent for synthetic applications. Thus, esters (entries 1, 7, 11, 15), amides (entries 3, 13, 15), cyano (entry 6), nitro (entry 12) and even such normally sensitive moieties as ketones (entry 4 however, see entry 5) and azide (entry 11) remain immune to this exceptionally tolerant reagent. 

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 regiochemistry of deprotonation of imines derived from unsymmetrical ketones is of special significance for the synthetic applications of these anions for carbon-carbon bond formation. This selectivity is sensitive to both the amine moiety and the base used. With imines derived from cyclohexyl- or r-butyl-amine, deprotonation with either Grignard reagents or lithium dialkylamide bases will result in high selectivity (>98 2) for removal of the proton on the less substituted a-carbon as in equations (39) and (40). 3i... 

The two major synthetic applications of imine derivatives of ketones and aldehydes are (i) for reduction to amines and (ii) for formation of carbon-carbon bonds at the a-position to the original carbonyl group. Both topics are covered extensively in other volumes in this series and thus will be treated only briefly here. 

Asymmetric hydrosilylation of prochiral carbonyl compounds, alkenes, 1,3-dienes, and imines has been extensively studied and remains one of the most important subjects in the field. This reaction is strongly affected by the nature of the catalyst (metal, type of chiral ligand) and the substrate as well as the reaction conditions (solvent, temperature, etc.). In recent years, many papers have been published on asymmetric hydrosilylation, describing new catalytic systems (mainly new optically active ligands) and new synthetic applications of the reaction [4, 24]. 

Matsuoka, T., Harano, K., Uemura, T., Hisano, T. Hetero Diels-Alder reaction of N-acyl imines. I. The reaction of N -thiobenzoyl-N,N-dimethylformamidine with electron-deficient dienophiles. Stereochemical and mechanistic aspects. Chem. Pharm. Bull. 1993, 41, 50-54. Mikami, K., Motoyama, Y., Terada, M. Asymmetric Catalysis of Diels-Alder Cycloadditions by an MS-Free Binaphthol-Titanium Complex Dramatic Effect of MS, Linear vs Positive Nonlinear Relationship, and Synthetic Applications. J. Am. Chem. Soc. 1994, 116, 2812-2820. 

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

A series of aromatic imines are applicable to the present substitution reactions (Scheme 3.8). para Substituted aromatics showed excellent enantioselectivities irre spective of their electronic properties. Ortho and meta substitutions as well as fused ring systems were also applicable. Thus obtained p amino a diazoester products could be transformed into common synthetic intermediates, that is, p amino add derivatives, via simple reduction or oxidation of the diazo moiety. 

Other synthetic applications derive from various cyclizations that occur during reduction of the substrates that contain a reactive function at a specific position. These cyclizations proceed through the intermediate imine or amine to the cyclic amine. Various functional units such as olefins, heterocyclic rings, ketones, acids, amides, amines, nitrile, and nitro have been involved. Palladium, Rh, and finely divided Ni (Raney Ni) under more vigorous conditions are commonly used. Reductive cyclization of ketonitrile 1 over Raney Ni gives myosmine 2 along with some nomicotine 3 as overreduced product ... 

The Mannich reaction has been reviewed comprehensively by Blicke (1942), Reichert (1959), Hell-mann and Opitz (1960), and Tramontini (1973). These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968). Some variants of the Mannich reaction have been covered as subtopics in other reviews for example. Layer (1963) and Harada (1970) have reviewed general additions of stabilized carbanions to imines, while Bdhme and Haake (1976) have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984) have summarized stabilized carbanion additions to 3,4-dihy-droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober-berines and phthalide isoquinolines, and Evans et al. (1982) " have analyzed the stereochemical aspects of ester enolate and silyl ketene acetal additions to imines. 

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

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