Aza-Diels-Alder cycloaddition

Then the potential for asymmetric induction of some of these chiral ionic liquids was investigated. The aza Diels-Alder cycloaddition between the enantiomericaUy pure (/ )-imine 31 and the Danishefsky s diene 32 was chosen as model asymmetric reaction (Scheme 8). The reaction was performed at room temperature for 5 h using 0.5 equiv. of ionic liquid and 1.5 equiv. of diene. In the absence of chiral ILs, the same coupling required a Lewis acid catalyst (0.1 equiv. of ZnC ) and afforded the main product 33 in 60% yield and low diastereoselectivity (32% de). 

Fig. 2 Other chiral reaction media for the aza Diels-Alder cycloaddition shown in Scheme 8...

Kobayashi examined the efficacy of various silver salts (e.g., AgOTf, AgC104, Ag2C03) as catalysts for the aza-Diels-Alder cycloaddition of 195 to imines formed in situ in a 9 1 THF/water mixture (Scheme 2.51).84 The silver salts with basic anions (e.g., Ag2CQ3) were unable to catalyze the reaction, but the silver salts with nonbasic... 

The polymer-supported Zr catalyst (12) is useful for asymmetric aza-Diels-Alder cycloaddition of benzaldehyde imine to Danishefsky diene [9]. The 6-substituted BINOL-Zr(IV) catalyst is useful for the enantioselective anft -preferred aldol reaction of benzaldehyde with ketene silyl thioacetal (15) (Scheme 5.5) [ 10]. The calculated charge densities on the oxygen atoms of the BINOL derivatives revealed that there is a good correlation between the charge density and the reactivity of 6-substituted BINOL [ 10]. 

Highly stereoselective aza Diels-Alder cycloadditions have been observed in reactions of chiral A-acylimines bearing two chiral moieties with cyclopentadiene (matched pair) and 1,3-butadienes in the presence of trifluoroacetic acid. 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have also been developed. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, the reaction of benzaldehyde with aniline and Danishefsky s diene produces the tetrahydropyridine derivative in 83% yield, while the reaction with cyclopentadiene instead of Danishefsky s diene produces the tetrahydroquinoline derivative. Various combinations of aldehydes, amines, and alkenes are possible in these reactions to produce diverse tetrahydroquinoline derivatives in high yield. Moreover, the three-component coupling reactions proceed smoothly in aqueous solution, and commercial formaldehyde-water solution can be used directly (eq 19). Sc(OTf)3-catalyzed three-component aza Diels-Alder cycloadditions also proceed smoothly in an ionic liquid. ... 

More recently (2004), Joule proposed a novel synthetic route to access the akuammiline scaffold with reports from his group s synthetic efforts toward realizing this plan. Retrosynthetically, they envisioned akuammiline (1) to result from late stage imine formation of ketone 247 (Scheme 32). The functionality at position 16 would then be elaborated from a carbonyl contained in diketone 248, which in turn was planned to be obtained via an intramolecular Claisen condensation and double bond isomerization of enamine 249, the latter the product of an aza-Diels—Alder cycloaddition involving cyclic 1-aza-1,3-diene 250 and an acrylate 251. To access azadiene 250 they planned an oxidative ring opening of bicyclic pyrrole 252. 

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. ... 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

In 2010, Gong et al. reported a highly enantioselective three-component domino reaction, consisting of an enantioselective aza-Diels-Alder cycloaddition catalysed by a chiral phosphoric acid and a subsequent intramolecular hydroamination catalysed by a gold complex. The domino reaction occurred between aldehydes, an enamide, and 2-(2-propynyl)aniline... 

Also of interest is a synthesis of (ih)-lasubine I (wr-1341) by Furman and Lipner in which the first step of importance was the aza-Diels—Alder cycloaddition between imine 1469 and Danishefsky s diene 1415, which was catalyzed by ytterbium(III) triflate to give the 2,3-dehydro-4-piperidinone... 

Another general approach towards imino sugars is based on the formation of cyclic imines and their subsequent reactions. The versatility of imines results from a number of possible transformations they can undergo reduction to amines/ nucleophilic addition/ and aza-Diels-Alder cycloadditions are among the most common. 

In Section 5.3.1, an example of the typical reactivity of a-oxo-ketenes as 1-oxa-dienes in inverse demand oxa-Diels-Alder reactions was presented. It was recently discovered that in the presence of 1-aza-dienes, a-oxo-ketenes can also react as dienophiles in microwave-assisted aza-Diels-Alder cycloadditions, and this reactivity was exploited for the diastereoselective synthesis of a series of a-spiro-8-lactams (Scheme 5.4). Paralleling the three-component approach presented in Section 5.3.1, the microwave irradiation at 140 °C for 15 minutes of a 1 1 1 mixture of the 5,5-dimethyl-2-diazocyclohexan-l,3-dione 1, benzyl-amine, and cinnamaldehyde furnished the a-spiro-8-lactam... 

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

The aza Diels-Alder cycloaddition of 1-azadienes 139 with alkenes 138 also lead to the synthesis of piperidines skeletons 140 with the creation of three stereogenic centers (Scheme 41.30). If the N-1 position is substituted with an electron donating group, the 1-azadiene react with electron poor dienophiles in a normal electron demand Diels-Alder reaction. However, an electron-withdrawing group at N-1, allowed for the inverse electron demand Diels-Alder cycloaddition to occur with electron-rich dienophiles. ... 

Makino K, Henmi Y, Terasawa M, Hara O, Hamada Y. Remarkable effects of titanium tetrachloride in diastereoselective aza Diels-Alder cycloaddition synthesis of (S)-piper-azic acid. Tetrahedron Lett. 2005 46 555-558. 

The ionic aza-Diels-Alder cycloaddition reactions of cyclopentadiene and pro-tonated glyoxylate imines possessing two chiral auxiliaries, N-(R) or N-(S)-l-phenylethyl and 8-phenylmenthyl or 8-phenyln omenthyl, yielded optically pure... 

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