Subject reaction with imines

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

To demonstrate the feasibility of organic synthesis using this support, the authors immobilized a N-Boc protected glycin (22) on the support (Scheme 7.5). After deprotection imine formation readily occurs with an excess of benzaldehyde. The product was then subjected to a Staudinger reaction with phenoxyacetylchlor-ide to yield the polymer supported / -lactam (26) which could be released to give the yS-lactam (27) with TEA in methanol. 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

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). 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

When the norditerpenoid alkaloid imine 360 was subjection to reaction with MeI-NH40H and MCPBA, oxaziridine 361 was formed in 50% overall yield <2002H(57)2357>. Key steps in the proposed mechanism for the formation of 361 involve formation of a quaternary ammonium salt with Mel and peracid oxidation through a Baeyer-Villiger-type process. 

Asymmetric hydrosilylation of imines affords synthetically useful optically active sec-amines, but study on this subject is still quite limited [8 c]. Uemura and co-workers applied their Rh(I)-2 catalytic system to two imines [6]. A good result was obtained from N-phenyl-l-phenylpropanimine (up to 53% ee), but the reaction with the M-benzyl analogue gave low selectivity (up to 11 % ee). 

The Mannich reaction is an aldol reaction with an imine. It has been the subject of many excellent reviews. For example, see Arend, M. Westerman, B. Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Asymmetric variants have also been reported see, for example, Notz, W. Tanaka, E Barbas, C. E, III Acc. Chem. Res. 2004, 37, 580-591. 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

In addition to alkenes, imines are tremendously popular aziridine precursors via an aza-Darzens approach. For example, a stereoselective synthesis of C-sulfonylated aziridines was reported via an aza-Darzens approach employing bromomethyl phenyl sulfbne, NaHMDS, and a series of N-tert-butanesulfinyl imines (14MI969). Likewise as shown below, chiral tert-butane- and mesitylsulfinimines were subjected to an aza-Darzens reaction with substituted 2-bromoesters to provide a host of aziridines in good yield with excellent stereocontrol (14OL6920). In turn, these aziridines could be subsequently converted to chiral A/-H aziridines in a total of three steps starting with a wide range of commercially available aldehydes. 

M-unsubsituted thiohydantoin 29 was prepared from the ketone with anhydrous ammonia and trimethylsilyl cyanide (Scheme 2). The 1-amino carbonitrile 27 was treated with isothiocyanate to form thiohydantoin-4-imine 28, followed by hydrolysis to produce M-unsubsituted thiohydantoins 29. These intermediates were subjected to an SnAt reactions with several 4-halo-aromatic derivatives, such as 4-fluorocyanobenzene, to afford a series of M-aromatic group-substituted thiohydantoins 30. 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

The immediate product from the reaction of the hydride complex with ketone has been a subject of debate. Some have proposed that an alkoxide complex is formed and that proton transfer between the coordinated amine and the alkoxide then forms the alcohol that is ultimately released. Others have supported a direct transfer to form free alcohol (or amine) and then coordination of this species to the open To accommodate the isotope effect data and the absence of an open coordination site for coordination of the ketone, the formation of the alkoxide from the hydride has been proposed to occur by hydride transfer assisted by hydrogen bonding of the amine in the case of the reactions with [Ru(BINAP)(diamine)(H)j], or by ring slip to allow coordination of the ketone (or imine) in the case of the reactions with the Shvo catalyst. ... 

The conversion of a-bromoacyl compounds into a-acylimines has been the subject of two recent publications/ In one, conversion into the corresponding azide and treatment with lithium ethoxide in ethanol gave a quantitative yield of the a-imino-ester (28), isolated by careful removal of the solvent, or characterized by hydrolysis or acetylation. This procedure offers advantages over previously reported procedures for the preparation of (28). In the other, N-phenyl-a-keto-imines result from the base-induced elimination of trifluoromethanesulphinic acid from sulphonamidoketones (29). The imines were not isolated, but directly converted into pyrazines by reaction with ethy-lenediamine. 

Alternative routes to pyrimidines, that avoid the later hydrogenation steps, were developed at Hoffmann-La Roche [46]. This alternative synthetic strategy is shown in Fig. 36. An amino-imine can be prepared in the same way, but this time it is not reacted with a substituted phenylmalonate. Instead an alkoxybenzaldehyde is subjected to a Wittig reaction with the phosphorus ylide of chloromethoxymethane to yield l-(4-al-koxyphenyl)-2-methoxyethane. Treatment with triethoxymethane in the presence of a Lewis acid such as boron trifluoride ether-ate gives the tetraethoxy derivative. Hydrolysis produces 2-(4-alkoxyphenyl)-3-me-thoxypropenal, reaction of this material with the imine results in the pyrimidine being formed directly. 

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