Inverse-electron-demand ketones

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Hetero-Diels-Alder reactions of other a, -clhylenic trifluoromethyl ketones provide a good alternative access to trifluoromethyl-substitutcd dihydropyrans (Tabic 7). These cycloadditions occur with inverse electron demand with electron-rich heterodienophiles such as vinyl ethers. They are performed under mild thermal conditions or at room temperature and are chemoselective and rcgioselective. but generally not stereoselective. 

Enamino ketones, e.g. 1. react with various enol ethers in hetero-Diels Alder reactions, with inverse electron demand - yields are high. Reactions are regioselective, but not stereoselective. Although the endo approach is favored, stereoselectivity also depends on the EjZ configuration of the heterodiene. The use of high pressure (3.75 MTorr) improves the endo selectivity. ... 

The [4 + 2] cycloaddition of a,p-unsaturated aldehydes and ketones (1-oxa-1,3-dienes) to enol ethers (Diels-Alder addition with inverse electron demand) has been an attractive route for the synthesis of 3,4-dihydro-2 -pyrans [143-146], which can be converted into deoxy- and dideoxypyranosides [147,148]. 

Simple a,/3-unsaturated aldehydes, ketones, and esters participate preferentially in inverse electron demand (LUMOdlcne controlled) Diels-Alder reactions with electron-rich, strained, or simple olefinic and acetylenic dienophiles.3 5 The thermal reaction conditions for promoting the [4 + 2] cycloadditions of simple 1-oxabutadienes (R = H > alkyl, aryl > OR), cf. Eq. (1), are relatively harsh (150-250°C), and the reactions are characterized by competitive a,/3-unsaturated carbonyl compound dimerization or polymerization. Usual experimental techniques employed to compensate for poor conversions include the addition of radical inhibitors to the reaction mixture and the use of excess 1-oxabutadiene for promoting the [4 + 2] cycloaddition. Recent efforts have demonstrated that Lewis acid catalysis and pressure-promoted reaction conditions28-30 may be used successfully to conduct the [4 + 2] cycloaddition under mild thermal conditions (25-100°C). 

Early extensive accounts of the 4v participation of a,/)-unsaturated carbonyl compounds in [4 + 2] cycloadditions detailed their reactions with electron-deficient dienophiles including a,/3-unsaturated nitriles, aldehydes, and ketones simple unactivated olefins including allylic alcohols and electron-rich dienophiles including enol ethers, enamines, vinyl carbamates, and vinyl ureas.23-25 31-33 Subsequent efforts have recognized the preferential participation of simple a,/3-unsaturated carbonyl compounds (a,/3-unsaturated aldehydes > ketones > esters) in inverse electron demand [4 + 2] cycloadditions and have further explored their [4 + 2]-cycloaddition reactions with enol ethers,34-48 acetylenic ethers,48 49 ke-tene acetals,36-50 enamines,4151-60-66 ynamines,61-63 ketene aminals,66 and selected simple olefins64-65 (Scheme 7-1). Additional examples may be found in Table 7-1. 

Synthesis of Oxygen Heterocycies. Alpha, beta-unsatu-rated ketones can cycloadd dienophiles of sufficient reactivity (thus with inverse electron demand). This is the case in the reaction in Scheme 5.13 where a pyran derivative is formed. 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

Pyrrolidine has been the common organocatalyst used by Boger and coworkers for the synthesis of highly substituted pyridines based on the inverse-electron-demand Diels-Alder reaction of in situ formed enamines and 1,2,4-triazines. Barbas and coworkers have described the amine-catalysed direct self-Diels-Alder reaction of a,p-unsaturated ketones. The inverse-electron-demand hetero-Diels-Alder reaction of nitrosoalkenes and in situ formed enamines as dienophiles was also shown to be possible. ... 

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

Inverse-electron-demand DA cycloaddition reactions retain the top position in synthetic research on 1,2,4-triazines (12CHC1153). There are several new examples of the use of the reaction for 1,2,4-triazine ring transformation. Thus, a new route to prepare pyridine derivatives 23 and 24 based on inverse-electron-demand DA/retro-DA reactions of ketones with 1,2,4-triazines 25 using the enolates of methyl ketones direcdy as a dienophile without enamine intermediates is reported, which is complementary to the classical Boger procedure (14RSCA59218). 

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