Cycloadditions with imine dienophiles

As far as catalytic enantioselective cycloadditions to imines are concerned, the only non-Zr-catalyzed process is a Cu-catalyzed protocol reported by Jorgensen (Eq. 6.22) [112]. It should be noted, however, that high enantioselectivities are attained only with highly substituted versions of the Danishefsky diene. 

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Amidines formed by condensation of 4-aminouracils with dimethylformamide dimethyl acetal are effective dienophiles, and form pyrimido[4,5-rflpyrimidines by [4-I-2] cycloaddition with isocyanates, isothiocyanates (Equation 83) <2005TL1433> and imines (Equation 84), A similar process has also been reported, using a nitrone as the dienophile (Equation 85) <2006BMCL3537>. 

The formation of tetrahydropyridines by reaction of a suitable diene with an imino dienophile is a reaction known since more than half a century [177] and has been intensively studied. In general, the imines react as the electron-deficient component and their reactivity strongly depends on the electron density which may be tuned by activating or deactivating moieties. However, exceptions from this rule are possible as found by Padwa et al. [178]. They described cycloadditions of imines to bis(phenylsulfonyl)-1,3-butadienes. 

As noted in. Section 2.1.1.6.2.2.2. the imine bond of fluoroulkyl imines can be involved in [4 + 2] cycloaddition reactions with active dienes and. depending on the N-substitution, tri-fluoromethyl imines can also react as dienes with various dienophiles. 

Immmium salts constitute a class of generally reactive hetero dienophiles. During the past several years a number of examples have been describe of [4 + 2] cycloadditions of imines with oxygenated dienes under Lewis acid catalysis. - These reactions probably involve intermediate immonium salts which react regio- and often stereo-selectively with these electron-rich 1,3-dienes. Danishefsky and coworkers have provided several instances of this type of process. Equation (18) shows an approach to... 

The protic acid and Lewis acid-catalyzed [4 + 2] cycloaddition reactions of electron-rich alkenes with imines derived from anilines and aryl aldehydes constitute an extensively explored class of 2-azadienes capable of providing the products of a formaJ Diels-Alder reaction (equation 9).i5.27.i77 a useful extension of these studies and in efforts to increase the rate of the Att participation of simple 2-aza-1,3-buta-dienes in [4 + 2] cycloaddition reactions, Mariano and coworkers have examined the Lewis acid-catalyzed intermolecular reactions of (l ,3 )-l-phenyl-2-aza-l,3-pentadiene with electron-rich dienophiles, including enol ethers. Reductive work-up of the cycloaddition reactions provided the pro-... 

Silicon-based Lewis acids are also used to activate dienophiles [299-303]. TBSOTf effectively catalyzes the endo-selective cycloaddition of a l,3-bissiloxy-l,3-diene wifh an acrylamide, whereas non-catalyzed thermal reaction or Eu(fod)3-catalyzed reaction is exo-selective (Scheme 10.112) [299]. In the cycloaddition to mefhyl acrylate fhe catalytic activity ofTMSNTf2 is much higher than that ofTMSOTf [301]. Silyl triflates are useful for fhe HDA reaction with imines catalytically or stoichiometrically [302, 303]. 

Azirines with an ester group on the imine carbon, will take part in cycloadditions, with the imine unit as the dienophile, as illustrated below. ... 

The 1-azadiene and the dienophilic character of 2-alkenyl-5,6-dihydro-4//-l,3,4-oxadiazines (150 Section 6.17.6.2) have been explored (Scheme 21) <93TL457>. Attempts to effect cycloaddition with DMAD, dimethyl fumarate, and acrylonitrile failed, whereas with maleic anhydride and A-methylmaleimide unexpected noncyclic adducts (e.g. 151) are obtained. The alkenyl oxadiazines also fail to give cycloadducts with l-methoxy-3-trimethylsilyloxy-l,3-butadiene with or without the presence of a Lewis acid catalyst. However, with methyl penta-2,4-dienoate mixtures of diastereo-isomeric products (e.g. 152) are formed, albeit slowly, by [4 + 2] cycloaddition at the alkenyl side chain, rather than at the C2—N3 imine bond. 

The methods for generating acyl ketenes (Scheme 7-V) and their subsequent in situ participation in [4 + 2] cycloadditions with a wide range of hetero- or olefinic and acetylenic dienophiles (Scheme 7-VI), including acyl ketenes,185 186,197 carbonyl compounds, 86-188 nitriles,1874,189,191 isocyanates and isothiocyanates,1864,190,191 ketenes,191 imines,1864,1874,191,192 carbo-diimides,l87c 190,191,193 ynamines,194 ketene acetals,1864,195 enol ethers,1864,191,196 and V-sulfinylamines197 have been extensively reviewed.5,9,12 Two reports have detailed the 4-n- participation of allenic ketones in [4 + 2] cycloaddition reactions [Eq. (51)].198,199... 

Imines derived from anilines and arylaldehydes are a class of widely recognized and extensively studied 2-aza-1,3-diene systems that have been shown to participate in a range of [4 + 2] cycloadditions with electron-rich olefins in the presence of protic or Lewis acid catalysts [Eq, (31)].4,9,63 64 These systems failed to participate in Diels-Alder reactions with typical electron-deficient dienophiles.1-9... 

This functional group is known as a nitrone. You could think of it as the N-oxide of an imine. The nitrone gets its four electrons in this way there are two jc electrons in the N=C double bond and the other two come from one of the lone pairs on the oxygen atom. The two-electron component in each of these reactions is an alkene which, in a Diels—Alder reaction, would be called a dienophile. Here it is called a dipolarophlle. Simple alkenes (which are bad dienophiles) are good dipolarophiles and so are electron-deficient alkenes. The difference between dienes and 1,3-dipoles is that dienes are nucleophilic and prefer to use their HOMO in cycloadditions with electron-deficient dienophiles while 1,3-dipoles, as their name implies, are both electrophilic and nucleophilic. They can use either their HOMO or their LUMO depending on whether the dipolarophlle is electron-deficient or electron-rich. 

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

The other recent examples of asymmetric syntheses involving Danishefsky s diene focused on hetero Diels-Alder reactions. Shibasaki and Feng separately reported asymmetric reactions with carbonyl dienophiles. Shibasaki demonstrated successful asymmetric reactions of ketones using a chiral Cu(I)-Walphos catalyst. Feng used a chiral A,iV -dioxide/In(OTf)3 catalyst in asymmetric cycloaddition reactions of aldehydes. Imine dienophiles are also amenable to asymmetric Diels-Alder reactions with Danishefsky s diene. Wulff reported enantioselective reactions using a VAPOL-B(OPh)3 catalyst system, while Snapper and Hoveyda disclosed silver-catalyzed enantioselective aza Diels-Alder reactions. ... 

From the numerous ir-systems investigated, nitrogen-containing dienophiles are the most typical carbonyl derivatives for hetero Diels-Alder reactions. Simple imines, however, are quite unreactive and require highly reactive dienes as counterparts. - In contrast, electron-deficient species, such as iminium salts (134 Scheme 63) or N-acylimines (137 Scheme 64), do undergo [4 -t- 2] cycloadditions with normal nonactivated dienes. Thus, the intramolecular Diels-Alder reaction of the iminium species (134), created in situ from the aldehyde (133) and ammonia, gives the octahydroquinoline (135), which can be hydrogenated to afford the 8a-epimer of pumiliotoxin C (Scheme 63). ... 

In a recent publication, Perumal and coworkers [441] described the condensation of an aldehyde 2-863 with an aniline 2-864 to give an imine which is trapped by a dienophile. However, when using this approach an intermolecular cycloaddition takes place as the reaction is performed as a three-component process using enol ethers or cyclopentadiene as dienophiles (Scheme 2.192). When using enol ether 2-... 

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