Imine - diene hetero-Diels-Alder reaction

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

Whiting and co-workers (231) reported that the chiral diamine 341Cu(OTf)2 complex is moderately effective in inducing the hetero-Diels-Alder reaction between glyoxylate imine (339) and Danishefsky s diene (334). In acetonitrile as solvent, this reaction provides cycloadduct 340 in 58% yield and 86% ee, Eq. 190. 

Jprgensen and co-workers (253) adapted this catalyst system to the hetero-Diels-Alder reaction between Danishefsky s diene and glyoxylate imine. The Tol-BINAP CuC104 proved to be the optimal catalyst for this reaction, affording the... 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

Although several Lewis acids are known to catalyze the hetero-Diels-Alder reaction involving imino-dienes or imino-dienophiles (aza-Diels-Alder reaction), a large amount of the catalyst is often necessary. Bi(0Tf)3-xH20 showed higher activity than lanthanide triflates in catalyzing the reactions of imines with Danishefsky s diene (Scheme 15) [72]. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Hetero-Diels-Alder reactions provide an attractive means of rapidly constructing complex heterocyclic ring systems. Cycloaddition of pyrazolyl imines with a variety of electron-deficient dienophiles has been used to assemble pyrazolo[3,4,1 ]pyridines in a focused microwave reactor under solvent-free conditions53. The reactions proceeded in modest to excellent yield, depending upon the choice of diene and dienophile (Scheme 3.32). 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

Hetero-Diels-Alder reactions starting with unsaturated compounds with heteroatom-carbon or heteroatom-heteroatom multiple bond(s) are also enhanced by Lewis acids [374-381]. Aldehydes and imines work as dienophiles under the influence of TiCU- Electron-rich dienes are generally a preferable partner, as shown in Eq. (149), in which the product was obtained virtually as a single isomer [382,383]. The importance of the choice of the Lewis acid in determining the stereochemical outcome of the reaction is illustrated in Eq. (150) [384]. The notion of chelation and of Felkin-Anh models, respectively, is valid for these Diels-Alder reactions. Diastereoi-somers other than those shown in Eq. (150) were not detected. The stereochemistry of the product in Eq. (149) could be also explained by the chelation model. 

The enantioselective total synthesis of the Securienega alkaloid (-)-phyllanthine by S.M. Weinreb et al. involved a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction between a cyclic imine dienophile and Danishefsky s diene This was the first example of using an unactivated cyclic imine in this type of cycloaddition. Commonly used Lewis acid catalysts (e.g., SnCb, TiCU, etc.) produced only low yields of the desired cycloadduct. However, it was discovered that ytterbium triflate catalyzed the cycloaddition and afforded the product in 84% yield. Later they also found that the cyclization could occur at high pressure and in the absence of the catalyst, although a slightly lower yield (71%) of the product was obtained. 

BINOL complexed to Et2Zn shows catalytic activity in the hetero-Diels-Alder reaction of Danishefsky s diene and imine derived from ethyl glyoxylate. ... 

The Lewis acidity of lanthanide complexes has been known for a long time. It was exploited extensively in their use as NMR shift reagents, mainly Eu(fod)3. They show strong affinity toward carbonyl oxygens and, therefore, have been widely used as catalysts for cycloaddition of dienes with aldehydes [25]. Moreover, the ability of catalytic amounts of lanthanide compoimds to activate coordinating nitriles as well as imines has also been recognized [26]. In recent years lanthanide (III) complexes have demonstrated clear effectiveness in catalyzing not only hetero-Diels-Alder reactions, but also Michael, aldol, Strecker and Friedel-Crafts acylation reactions [27]. 

Hetero-Diels-Alder reaction. The condensation of Danishefsky s diene with imines to generate TV-substituted 2-aryl-2,3-dihydro-4-pyridones at room temperature is effected by this salt. A mixture of aldehydes, amines, and the dehydrant MgS04 can be employed instead of imines. 

Hetero-Diels-Alder reactions. The cycloaddition of Danishefsky s diene (and analogs) to chiral imines catalyzed by boronates derived from commercially available BINOL ligands proceeds with good diastereoselectivity. The double asymmetric induction operates for matching pairs, which exhibit fast reaction rates. On the other hand, the reaction of achiral substrates in the presence of chiral binol-boronates gives rise to products in good ee. ... 

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). ... 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

The Zr-BINOL complexes were effectively utilized for asymmetric aza- and hetero Diels-Alder reactions [lb]. The reaction of imine (27) with Danishefsky diene (113) afforded optically active dihydropyridone (114) in high yield (Equation 52) [7, 57]. A similar reaction was also possible for benzaldehyde and diene (115) (Equation 53), [7, 58] and the corresponding dihydropyranone was obtained in excellent yield with excellent enantioselectivity. In addition, the reaction was applied for total synthesis of natural products [58b]. 

Hetero Diels-Alder reaction of Danishefsky s diene with imines is a powerful method for the preparation of dihydropyridone derivatives. HBF4 also catalyzed this reaction using aromatic and aliphatic imines that were prepared in situ from the corresponding aromatic or aliphatic aldehydes and aromatic amines (Scheme 3.5). 

The Frost group has demonstrated the use of indium(III) triflate as a catalyst for hetero Diels-Alder reactions. In the presence of just 0.5 mol % of catalyst, the imino Diels-Alder reaction of an imine and Danishefsky s diene provides the product in excellent yields (eq 16). A three-corrponent coupling of an aldehyde, amine, and diene was also reported. 

In(III) salts were used in many studies in the area of hetero Diels-Alder reactions. Frost et al. worked on using In(OTf)3 to catalyze the reactions of aromatic aldehydes and imines with Danishefsky diene [177]. The group found that the use of In(OTf)3 not only gave good yields of the Diels-Alder products in a short time, but also required the least catalyst load. Further competitive studies revealed that the imine is much more reactive than the aldehyde and the group proceeded to... 

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