Azomethines electron-deficient

Domino reactions of imines with difluorocarbene in the presence of electron-deficient alkynes lead to 2-fluoropyrroles. For instance, reaction of A-benzylideneaniline (18) with difluorocarbene yields an intermediate azomethine ylide 19 capable of undergoing 1,3-... 

Azomethine ylides. The reaction of 1 with the oxime of an aldehyde results in an iminium salt 2. Desilylation of 2 (CsF) gives rise to an azomethine ylide (a) that undergoes 1,3-dipolar cycloaddition with electron-deficient alkenes (equation I). 

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... 

In the thermal cyclization of 3-alkoxyphenyl A -(l-aryl-2,2,2-trifluoroethylidene)carbamates 287, obtained from 3-alkoxyphenols 285 and l-aryl-l-chloro-2,2,2-trifluoroethyl isocyanates 286, 2-aryl-2-trifluoromethyl-2,3-dihydro-477-l,3-benzoxazin-4-ones 290 were formed instead of the regioisomeric l,3-benzoxazin-2-ones 288 (Scheme 53). The formation of 290 was explained by a thermal isomerization of 287 involving a skeletal 1,3-rearrangement of the electron-rich aryloxy group to the azomethine carbon, which is electron deficient due to the electron-withdrawing CF3 group <2002JFC(116)97>. 

The highly effective desilylation routes to nonstabihzed azomethine ylides have provided the basis for much of this chemistry. Thus, the reaction of A-(silylmethyl)-thioimidates (30) with AgF in the presence of a range of dipolarophiles (electron-deficient alkenes and alkynes, and aldehydes) led to the isolation of nitrile ylide adducts in generally high yields (20,21). Differences in reactivity and regioselectivity... 

Af-(Silylmethyl)thioimidates (34) also undergo water-induced desilylation leading to the N-protonated azomethine ylides (38). These ylides react with a range of electron-deficient alkenes and alkynes, aldehydes, and ketones followed by elimination of methane thiol to give formal nitrile ylide adducts (e.g., 40) (23,24). The reactivity of these species is rather dependent on the nature of R (e.g., good for R = Ph but less so for R=Et or i-Pr), which may be due to competition from tautomerization to give the A -methylthioimidate (39). 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

Husson and co-workers (84) investigated the 1,3-dipolar cycloaddition of acyclic chiral azomethine ylides derived from (—)-Af-cyanomethyl-4-phenyl-l,3-oxazoli-dine with electron-deficient alkenes, and in some cases de >95% were obtained. 

Another approach employing chiral acyclic azomethine ylides was published in two recent papers by Alcaide et al. (85,86). The azomethine ylide-silver complex (51) was formed in situ by reaction of the formyl-substituted chiral azetidinone (50) with glycine (or alanine) in the presence of AgOTf and a base (Scheme 12.18). Azomethine ylides formed in this manner were subjected to reaction with various electron-deficient alkenes. One example of this is the reaction with nitrostyrene, as illustrated in Scheme 12.18 (86). The reaction is proposed to proceed via a two step tandem Michael-Henry process in which the products 52a and 52b are isolated in a... 

Other chiral azomethine ylide precursors such as 2-(ferf-butyl)-3-imidazolidin-4-one have been tested as chiral controllers in 1,3-dipolar cycloadditions (89). 2-(ferf-Butyl)-3-imidazolidin-4-one reacted with various aldehydes to produce azomethine ylides, which then were subjected to reaction with a series of different electron-deficient alkenes to give the 1,3-dipolar cycloaddition products in moderate diastereoselectivity of up to 60% de. 

Other 1,3-dipolar cycloadditions of chiral azomethine ylides with Cgo (98) and reactions of chiral azomethine ylides derived from l-benzyl-4-phenyl-2-imidazoline with different electron-deficient alkenes have been performed (99). 

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). 

Gamer et al. (90,320) used aziridines substituted with Oppolzer s sultam as azomethine ylide precursors. The azomethine ylide generated from 206 added to various electron-deficient alkenes, such as dimethyl maleate, A-phenylmalei-mide, and methyl acrylate, giving the 1,3-dipolar cycloaddition product in good yields and up to 82% de (for A-phenylmaleimide). They also used familiar azomethine ylides formed by imine tautomerization (320). Aziridines such as 207 have also been used as precursors for the chiral azomethine ylides, but in reactions with vinylene carbonates, relatively low de values were obtained (Scheme 12.59) (92). 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

Calculations have shown that the HOMO in the [3,4-c]-annelated A,B-diheteropen-talenes is closely related to the nonbonding MO, thereby allowing ready reaction with electron-deficient dipolarophiles. In the case of the systems with two discrete ylide moieties as in thieno[3,4-c]pyrrole derivatives, it is not only the nature of the HOMO which directs the mode of addition, but also the thermodynamic stability of the adduct, leading to addition across the thiocarbonyl ylide at elevated temperatures and to the azomethine ylide at low temperatures (Section 3.18.4.2.1) (77T3203). 

Hydrazones have also been used as azomethine imine precursors to achieve cycloadditions.157 Proto-nated hydrazones act under suitable conditions as quasi-azomethine imines in polar [3+ + 2] cycloadditions. Thus, r.cetaldehyde phenylhydrazone (201) was found to react with styrene in the presence of sulfuric acid in a regiospecific manner to give pyrazolidine (203 Scheme 47) as a diastereomeric mixture.157 The most commonly used azomethine imine has a phenyl group attached to one end of the dipole and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl group does not lower the energy of the LUMO as much as it raises the energy of the HOMO. With electron-deficient di-polarophiles like methyl acrylate, the reaction is dipole HOMO-controlled, and mixtures can be expected. In fact, a 1 1 mixture of regioisomers was obtained in the reaction of (201) with acrylonitrile (equation 9).157... 

Houk has suggested that unsymmetrically substituted azomethine ylides such as munchnones will react readily with both electron-deficient and electron-rich dipolarophiles due to the narrow frontier orbital... 

A large variety of silylmethylamino derivatives have been shown to be excellent starting materials for the in situ generation of non-stabilized azomethine ylids. Combined with a number of electron-deficient olefinic or acetylenic molecules that have been recognized as good dipolarophiles, ready access to diversely substituted five-membered ring nitrogen heterocycles has consequently been opened. 

It has been demonstrated that TMS iodide (in combination with cesium fluoride) or TMS triflate in various solvents (THF, MeCN, HMPA) are excellent reagents to promote the generation of azomethine ylids from A-methoxymethyl-A-(trimethylsilylmethyl)aIkyl-amines and their cycloaddition to electron deficient alkenes with yields ranging from moderate to nearly quantitative. The geometry of the double bond in the alkene is preserved in the cycloadduct.410... 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

As early as 1967, Huisgen and coworkers [37] had shown that, upon photolysis, certain aziridines of type 96 undergo C—C bond fragmentation stereospecifkally to produce octet-stabilized azomethine ylides which, on cycloaddition with electron-deficient dipolarophiles, produce pyrrolidine ring systems (Scheme 8.29). 

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