Imines stereoselective reactions

Synthesis and chemistry of substituted l-azabicyclo[1.1.0]butanes 97SL1029. Synthesis of aziridines via stereoselective reactions with imines 99PAC1033. 

In 1999, Bob Atkinson wrote [1] that aziridination reactions were epoxida-tion s poor relation , and this was undoubtedly true at that time the scope of the synthetic methods available for preparation of aziridines was rather narrow when compared to the diversity of the procedures used for the preparation of the analogous oxygenated heterocycles. The preparation of aziridines has formed the basis of several reviews [2] and the reader is directed towards those works for a comprehensive analysis of the area this chapter presents a concise overview of classical methods and focuses on modern advances in the area of aziridine synthesis, with particular attention to stereoselective reactions between nitrenes and al-kenes on the one hand, and carbenes and imines on the other. 

Since alkenes are relatively impotent precursors to aziridines, especially with regard to stereoselective reactions, substantially greater advances have been made in this field by means of the addition reactions between imines and a range of car-bene equivalents. 

Particularly noteworthy is the discovery of a new type of the active catalyst 99,103,104 a crystalline, air-stable yellow-orange solid, which can serve as a highly enantioselective tool in the titanium-catalyzed hydrosilylation of imines. The reaction can be highly stereoselective for both acyclic and cyclic imines under a wide range of hydrogen pressures (Scheme 6-46). 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Compared to the rhodium-catalyzed stereoselective reactions, studies on the iridium-catalyzed reactions have been limited until recently. Usually lower selectivities have been observed in the Ir(i)-catalyzed reactions.459,460 The asymmetric hydrosilylation of imines affords optically active secondary amines. These are very valuable compounds, but the studies on that reaction are quite limited.461 Close examinations of these reactions revealed that they proceed via a transfer hydrogenation. Other conditions such as the 2-propanol/base system in the presence of an appropriate metal complex have been employed as well, but only low selectivities were obtained.462... 

In Ugi s four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [5, 6] a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, 5f. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-... 

A new methylseleno-promoted ketene-imine cycloaddition reaction between 151 and 152 (86JOC4737) gave the bicyclic product 153 in an extremely high stereoselective fashion and in fairly good yield (36-92%) (Scheme 27). 

Lopez, R., Suarez, D., Ruiz-Lopez, M. F., Gonzalez, J., Sordo, J. A., Sordo, T. L. Solvent effects on the stereoselectivity of ketene-imine cycloaddition reactions. J. Chem. Soc., Chem. Common. 1995,1677-1678. 

An interesting and highly stereoselective reaction of dimethoxy cyclopropane derivative 81 with some aromatic N-tosyl imines was recently described by Saigo and coworkers [41] (Scheme 16). In the presence of TiCl4, compound 81 condenses with N-sulfonyl imines to stereoselectively produce lactams 84 and 85, with the cis isomer being the predominant product. It is likely that the dimethoxy cyclopropane initially opens to zwitterionic ester enolate 82, which adds to the imine to yield intermediate 83. The rationale presented for the stereoselectivity in condensation of enolate 82 with the imines is similar to that described for the reactions in Schemes 14 and 15, cf. Fig. (1). 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

Benzylideneanilines have been added across 2,3-dihydrofurans to produce bicyclic azetidines regio- and stereoselectively a zwitterionic mechanism is proposed. An extensive range of reaction parameters have been calculated for the Mannich reaction of benzoxazole with formaldehyde/dimethylamine. A molybdenum bis(imide) has been used to catalyse C=N bond formation in imine-imine metathesis reactions of synthetic interest the approach has been extended to alkylidene-imine, imide-imine, and imide-imide metatheses. 1-Substituted 1-phenyl-... 

Extension of this methodology to a triple stereoselective process is reported in reaction D. This completely stereoselective reaction takes advantage of the matching combination between the enolate and the imine chiral auxiliary, which, in its turn is also internally matched with the other imine stereocenter [37]. 

Enantioselective addition of C-nucleophiles to imines and hydrazones has been reviewed (1998-2009) another review describes the synthesis of a-branched amines by nucleophilic addition of unstabilized carbanions, including application in stereoselective reactions. ... 

Purpose. Tbe third intermediate on the pathway to the target photochromic imine is synthesized. A heterocyclic three-membered ring, an aziridine derivative, is formed. This is the first ring of the diazabicyclohexene system that you will ultimately convert into the photochromic imine. You will study a process that involves three reactions and the formation of two intermediates en route to the final product. You will study a number of interesting stereoselective reactions. You wfll work with organic reactions that require several days to come to completion. 

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