Imine, neutral, cycloaddition

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). 

Since the initial report in 1962 by Merten and Muller of the cycloaddition of an -acyl imine with a conjugated diene,a number of examples of this type of reaction have appeared. In general, IV-acyl im> ines are highly reactive, unstable species which are rarely isolated, but rather are generated in situ from stable precursors. Depending upon the method of formation of the particular dienophile and the reaction conditions, a neutral A -acyl imine or a protonated (or Lewis acid complexed) IV-acyl immonium ion may be involved in the Diels-Alder reaction. 

Simple, neutral electron-rich imines are generally not useful dienophiles unless q>propriately reactive dienes are used. Thus it is possible to effect cycloadditions of neutral imines with some electron-deficient dienes. - In a series of p rs, Langlois and coworkers have described Diels-Alder reactions of cyclic imines and methyl 2,4-pentadienoate to afford adducts used in alkaloid synthesis. For example, the cycloadditicMi shown in equation (IS) was used in a total synthesis of the indole alkaloid vincamine (45). 

Neutral imines also add to o-quinodimethanes. Kametani s group has reported several cycloadditions of the type shown in equation (16). 

Another type of reactive electron-deficient diene which combines with neutral imines is disulfone (46) (equation 17). Interestingly, this diene rearranges under the reaction conditions to isomer (47) which undergoes regioselective [4 + 2] cycloadditions with neutral imines to give initial adducts such as (48). However, this product suffers a subsequent 1,3-hydrogen shift to provide isolable adduct (49). Independent synthesis and cycloaddition of (47) provided good evidence for the overall reaction padiway shown. 

Direct irradiation of amino substituted azirines leads to neutral nitrile ylides which can be trapped with electron-deficient double bonds. H. Heimgartner described the synthesis of triazolines and oxazolines via trapping of a nitrile ylide with diethylazodicarboxylate and methyl trifluoroacetate, respectively. An elegant application of 1,3-dipolar cycloaddition chemistry is the photolysis of a tetrazole leading to a reactive nitrile imine which is trapped in an intramolecular fashion. 

One other isolated example of a neutral imine which was reported to undergo a [4 + 2] cycloaddition is shown in Eq. (18). ... 

Cycloadditions of iminium compounds with 1,3-dienes to afford Diels-Alder adducts seems to be a reaction of general applicability.46 On the other hand, simple electron-rich imino species are less reliable dienophiles. Some electron-rich imines will undergo Diels-Alder reactions under acid catalysis and thus are probably actually reacting as iminium salts. However, inverse electron demand [4 + 2] cycloadditions of neutral imines with electron-deficient dienes have been reported, as have additions to exceptionally reactive dienes (vide infra). 

The Danishefsky group has examined the uncatalyzed and Lewis adic-catalyzed cycloadditions of highly oxygenated dienes with simple imines in preparation of yohimbine50b analogs and the indolizidine alkaloid ipalbi-dine (Scheme 2-VII).50c What is quite interesting is that some of these dienes are sufficiently reactive that catalysis was not necessary with neutral imines. Also, the reaction seems to show excellent facial stereoselectivity with respect to the imine. 

In an analogous system, it was found that a phenanthrene o-quinodimethane, generated by a reductive process, acted as a diene in [4 + 2] cycloadditions with two neutral imines to give pentacyclic adducts, although yields were rather low [Eq. (17)].68... 

Azirines constitute another class of neutral, electon-rich imines which will undergo [4 + 2] cycloadditions with certain types of dienes. As can be seen in the following discussion, the initial adducts of these reactions are often not isolable and that a Diels-Alder reaction has, in fact, occurred is sometimes inferred by mechanistic reasoning. 

In addition to the photo-generation, Carell and coworkers showed that the hydrazonyl chloride (13) could also serve as a precursor to the reactive nitrile imine (17a) in neutral aqueous buffer [23]. Intrigued by these results, Liu and coworkers conducted a mechanistic study of the hydrazonyl chloride-mediated cycloaddition by examining the effects of pH and chloride concentration on the rates of nitrile imine formation and subsequent cycloaddition reactions [24]. They concluded that... 

The aza-Diels-Alder reaction of imines with diene of Danishefsky is an important route to 2,3-dihydro-4-pyridones. A number of Lewis acids have been used to catalyze the reaction in organic solvents. In water the reaction was realized by acid catalysis via iminium salts or by Bronsted acids. The montmorillonite K-10 catalyzed this cycloaddition in water or in aqueous acetonitrile in excellent yield. Recently Kobayashi has performed the reaction in water at room temperature under neutral conditions in two (imine - - diene) or three (aldehyde -b amine -b diene) component versions by using sodium triflate as catalyst. Imine intermediates from the indium-mediated reaction, in aqueous medium at 50° C, between aromatic nitro compounds and 2,3-dihydrofuran undergo aza-Diels-Alder cycloadditions to give tetrahydroquinoline derivatives in good overall yields. ... 

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