1,3-dipoles azomethine ylides

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Like other 1,3-dipoles, azomethine ylides were mostly utilized in the ring construction of five-membered nitrogen heteroaromatics by a sequence of cycloadditions to acetylenes and formal oxidation. Thus, azomethine ylides were employed as the synthetic equivalents of nitrile ylides. Other synthetic applications of azomethine ylides, especially the intended utilization of stereochemical characteristics of the azomethine ylide cycloadditions, were quite rare. 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

Indole Pyrrole Ring as the Dipole, Azomethine Ylides... 

Azomethine ylides are also frequently obtained by ring opening of aziridines, and the analogous carbonyl ylides from oxiranes. These aspects are dealt with in Section 3.03.5.1. A variety of five-membered heterocycles can also function as masked 1,3-dipoles and this aspect is considered in Section 3.03.5.2. 

As the sp nitrogen atom in many heterocycles can be alkylated and aminated, the construction of an azomethine ylide or azomethine imine dipole is readily attainable as shown in Scheme 13. These ylides are very reactive and undergo cycloaddition with a... 

There are at least two mechanisms available for aziridine cis-trans isomerism. The first is base-catalyzed and proceeds via an intermediate carbanion (235). The second mechanism can be either thermally or photochemically initiated and proceeds by way of an intermediate azomethine ylide. The absence of a catalytic effect and interception of the 1,3-dipole intermediate provide support for this route. A variety of aziridinyl ketones have been found to undergo equilibration when subjected to base-catalyzed conditions (65JA1050). In most of these cases the cis isomer is more stable than the trans. Base-catalyzed isotope exchange has also been observed in at least one molecule which lacks a stabilizing carbonyl group (72TL3591). 

For the reactions of other 1,3-dipoles, the catalyst-induced control of the enantio-selectivity is achieved by other principles. Both for the metal-catalyzed reactions of azomethine ylides, carbonyl ylides and nitrile oxides the catalyst is crucial for the in situ formation of the 1,3-dipole from a precursor. After formation the 1,3-di-pole is coordinated to the catalyst because of a favored chelation and/or stabiliza-... 

For azomethine ylides and carbonyl ylides, the diastereoselectivity is more complex as the presence of an additional chiral center in the product allows for the formation of four diastereomers. Since the few reactions that are described in this chapter of these dipoles give rise to only one diastereomer, this topic will not be mentioned further here [10]. 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

It is well known that azomethine ylides, which are usually formed in situ, are very good substrates for 1,3-dipolar cycloadditions. The group of Novikov and Khlebnikov [328] generated such a 1,3-dipol by reaction of difluorocarbene formed from CBr2F2 (2-626) with the imine 2-627. Cycloaddition of the obtained 2-629 with an ac-... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

It is well known that the use of a synthetic equivalent of azomethine ylide, the thiazolium ylide, a known synthon for the simple azomethine dipole, undergoes cycloadditions with higher regioselectivity than the parent ylide <1994JOC4304, 1994JOC2773>. In order to control the enantioselectivity of the reaction, an Evans oxazolidionone was incorporated into the acrylate dipolarophile as in Scheme 71. The cycloaddition was carried out by reaction of 4 equiv of the acrylate with the thiazolium salt to afford the diastereomeric tricyclic adduct 27 (Scheme 71) <2002BMC3509>. 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

Azomethine ylides such as 412 react with triafulvenes again by analogy with cyclopropenones. (3 + 2) Cycloaddition of the 1,3-dipole to the CVC2 bond and subsequent loss of C02 produces l,4-dihydro-4-methylene-N-alkyl pyridines 559, which as merocyanines show marked solvatochromic and thermochromic effects260. ... 

The 3 + 2-cycloaddition of 1,2-dithiophthalides with nitrilimines yields benzo[c]thio-phenespirothiadiazoles regioselectively. The azomethineimines isoquinolinium-iV-aryllimide and A-(2-pyridyl)imide readily undergo 1,3-dipolar cycloaddition with electron-deficient dipolarophiles, dimethyl fumarate and dimethyl maleate, to yield tetrahydropyrazolo[5,l-a]isoquinolines in high yield. ° The 1,3-dipolar cycloadditions of electron-poor 1,3-dipoles, bicyclic azomethine ylides (27), with ( )-l-A,A-dimethylaminopropene to yield cycloadducts (28) and (29) are examples of non-stereospecific cycloadductions (Scheme 9). The synthesis of protected... 

A final class of dipole shown to be effective in iminium ion catalysed [3+2] cycloadditions are azomethine ylides derived from 35 [71] (Scheme 12). Vicario showed that 20 mol% of diarylprolinol 33 catalysed the cycloaddition between a,P-unsaturated aldehydes 34 and imines 35 (THE, 4 °C, 72 h) to give the densely... 

Dipoles can also be generated from rearrangements that take place after the formation of an initial rhodium carbenoid product ]40, 70, 71]. One example of this type of transmutation, also known as a dipole cascade process, involves the formation of an azomethine ylide via the initial formation of a carbonyl ylide [72]. This process was... 

Azomethine ylides can be generated in situ from various readily accessible starting materials. One of the easiest approaches to produce 1,3-dipoles involves the decarboxylation of immonium salts derived from condensation of a-amino acids with aldehydes or ketones [3, 204—206]. For example, the azomethine ylide 203, obtained by decarboxylating the condensation product of N-methylglycine and paraformaldehyde in refluxing toluene, reacts with Cjq to give the N-methyl-pyrrolidine derivative 204 in 41% yield (Scheme 4.32) [204]. 

In the examples presented in CHEC-II(1996) in which a pyridazin-3(2//)-one is the 1,3-dipolarophile, two types of 1,3-dipoles are used nitrile oxides and diazoalkanes. Two other 1,3-dipoles have to be mentioned now. The 1,3-dipolar cycloaddition of the azomethine ylide 95 generated in situ by thermal ring opening of dimethyl trans- -(A-methoxyphenyl)aziridine-2,3-dicarboxylate 94 to some 4- or 5-substituted 2-methylpyridazin-3(2//)-ones has been... 

An exhaustive series of reports by Grigg et al. (28) outlined two basic methods for the generation of azomethine ylides proceeding via either a 1,2-prototropic shift, or by a decarboxylative approach (29). The decarboxylative route to azomethine ylides can be exemplified by the condensation of benzaldehyde with the cyclic amino acid tetrahydroisoquinoline (108) (30), in DMF at 120 °C, to generate the intermediate awfi-dipole 109, which underwent subsequent cycloaddition with N-methyl maleimide to furnish a 1 1 endo/exo mixture of adducts 110 (R = Ph), in 82% yield (Scheme 3.30). 

However, the highly stereoselective nature of the dipole intermediate, which was observed in the preceding cases, did not translate to azomethine ylide cycloadditions of 113 and 114, both of which formed mixtures of products derived from endo... 

Modem synthetic chemistry is increasingly focused on the formation, control, and induction of asymmetry in molecular stmcture. As the complexity of synthetic targets increases, in particular those derived from natural sources, the demands of the chemist for new and efficient methods for the introduction of new stereogenic centers has generated many elegant solutions. Since azomethine ylides are inherently achiral, the induction of stereocontrol has to be performed by attachment of a suitable stereodirecting unit onto either the dipole, or more recently onto the ylide, and latterly many elegant solutions have been developed. 

Due to the increased reactivity of the reaction in the presence of a Lewis acid, the reaction scope was extended to singly activated alkenes. Previous results had shown either no reaction or extremely poor yields. However, under the Lewis acid catalyzed conditions, acrylonitrile furnished a 1 1, endo/exo mixture of products. The addition of the catalyst gave unexpected regiochemistry in the reaction, which is analogous with results described in Grigg s metal catalyzed reactions. These observations in the reversal of regio- and stereocontrol of the reactions were rationalized by a reversal of the dominant, interacting frontier orbitals to a LUMO dipole-HOMO dipolarophile combination due to the ylide-catalyst complex. This complex resulted in a further withdrawal of electrons from the azomethine ylide. 

In an extensive study into the application of the decarboxylative approach to azomethine ylides, Giigg reported the construction of numerous, complex polycyclic systems via an intramolecular protocol. Thiazolidine-4-carboxylic acid (263) was shown to react with 264 in refluxing toluene to furnish a 2 1 mixture of 265 and 266 in 63% yield (81). The reaction is assumed to occur via condensation of the aldehyde and amino acid to generate the imine 267, followed by cyclization to 268. Subsequent thermal decarboxylation of the ester generates either a syn dipole leading to 265 from an exo transition state, or an anti dipole and endo transition state generating adduct 266 (Scheme 3.90). 

The desilylation methodology for the generation of 1,3-dipoles, developed by Vedejs and West (29) with regard to azomethine ylides, was successfully applied by Achiwa and co-workers (30) to the field of thiocarbonyl ylides. This approach allowed the generation of the parent thioformaldehyde (5)-methylide (la) and its use for preparative purposes (31,32). Generation of la in the presence of C=C dipolarophiles led to tetrahydrothiophenes (19) in high yield (Scheme 5.4). 

N-Metalated azomethine ylides (44) are probably the most synthetically useful of these dipoles, since they can be generated from readily available N-alkylide-neamino esters or nitriles through a simple activation method. The resulting 1,3-dipoles show high reactivity with a,p-unsaturated carbonyl acceptors to provide excellent stereo- and regioselectivities. A variety of asymmetric versions have been reported. 

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