Cycloaddition reactions inverse electron demand

Apparently, 3 undergoes [4 + 2] cycloadditions with inverse electron demand more readily than normal Diels-Alder reactions (see Sect. 2.1.1). This is in accord with the high lying HOMO of bicyclopropylidene [12]. Several attempts to trap the monomeric 173, which should be in equilibrium with 174 [42], as a cycloadduct with a second molecule of 3 were unsuccessful even at elevated temperatures in chloroform (70 °C) or toluene-d8 (150°C) [13b]. 

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

The Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

Where no assistance can be expected from intramolecularity, or from a reactive rearomatizing o-qui-nodimethane system as above, [4 + 2] cycloadditions with inverse electron demand are required. Thus, reaction of the 2-aza-1,3-butadiene (146) with the electron-rich enamine (147) at room temperature affords the octahydroisoquinoline (148) in high regio- and diastereo-selectivity (Scheme 68). ... 

Substituted 1,2,4-triazines and 1,2,4,5-tetrazines are known to undergo [2-1-4] cycloaddition with inverse electron demand when reacted with alkenes. The primary bicyclic product loses nitrogen to give dihydropyridines and dihydropyridazines, respectively. The reaction of methylenecyclopropane with dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate at room temperature gave the spiro-dihydropyridazine 2 in 80% yield. ... 

For A-acyliminium ions that (can) adopt the s-cis conformation, the mechanistic picture is quite different. Now the /V-acyliminium intermediate reacts as a 4ir-electron component in a Diels-Alder cycloaddition with inverse electron demand (equation 28). " This process also shows high regio- and stereo-selectivity in most cases. A nice illustration of high stereospecificity is found in recent work on the intramolecular Diels-Alder reaction of A-acyliminium species (equations 29 and 30). The bis-amides (50) and (51) serve as precursors to the reactive intermediates, which cycloadd to the alkenes with high selectivity to give r/a s-fused bicyclic 5,6-dihydro-1,3-oxazines. 

This chapter will mainly describe new developments in the area of theoretical methods and experimental structural methods, and in the rapidly growing field of inter- and intramolecular Diels-Alder reactions of these electron-poor azadienes. Quantitative data for the reactivity of dienes and dienophiles in these (4 -1- 2) cycloadditions with inverse electron demand will be discussed. The synthesis and reactions of dihydro, tetrahydro, and hexahydro tetrazines cannot be discussed broadly beyond the scope of <84CHEC-I(3)53l>. Verdazyls, a well-known class of compound, cannot be treated in detail within the frame of this contribution (see Section 6.21.5.9). 

The initial product 2 loses N2 in a retro-DiELS-Alder reaction forming the 3,4-dihydropyridine 3, which aromatizes giving the pyridine derivative 4 by elimination of amine or alcohol. The geometry of the transition state of this [4+2] cycloaddition with inverse electron demand follows from the reaction of 3- or 6-phenyl-1,2,4-triazine 5 or 8 with enamines of cyclopentanone. It is apparently influenced by the secondary orbital interaction between the amino and phenyl groups. 3-Phenyl-1,2,4-triazine 5 favours the transition state 11. It leads first to the 3,4-dihydropyridine 6 which, on oxidation followed by a Cope elimination, affords the 2-phenyldihydrocyclopenta[c]pyridine 7. However, 6-phenyl-1,2,4-triazine 8 favours the transition state 12 leading to 3,4-dihydropyridine 9. Elimination of amine yields 5 -phenyldihydrocyclopenta[c]pyridine 10 ... 

Even more so than 1,2,4-triazines (see p 441), 1,2,4,5-tetrazines display heterodiene activity in their reactions towards electron-rich, multiply-bonded systems. Enol ethers, enamines, ketene acetals, imido esters, alkynylamines and nitriles undergo [4+2] cycloadditions with inverse electron demand across the ring positions C-3 and C-6 [176]. Olefinic dienophiles lead to diverse products depending on their substituents ... 

An interesting and important reaction of oxepines is their participation as dienophiles in [2 -I- 4] cycloaddition with inverse electron demand. Using 1,2,4,5-tetrazines or 1,2,4-triazines bearing electron-withdrawing substituents as dienes, this reaction leads to dihydrooxepino[4,5-d]pyridazines (7) or dihydrooxepino[4,5-c]pyridines (8), each of which can be oxidized to corresponding oxepino[4,5-d]pyridazines (9) or oxepino[4,5-c]pyridines (10) the latter are converted by the treatment with an acid to cyclopenta[. 

Some aspects concerning the transition state of this (4 + 2)-cycloaddition with inverse electron demand follow from the reaction of 3- or 6-phenyl-l,2,4-triazine 5 or 8 with cyclopentanone enamines [323]. 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Most reactions discussed can be classified into two types of [n s+iAs cycloadditions, the normal and inverse electron-demand cycloaddition reactions, based on the relative energies of the frontier molecular orbitals of the diene and the dieno-phile (Scheme 4.2) [4]. 

The normal electron-demand reaction is a HOMOdiene-LUMOdienophUeelectron-rich dienes and electron-deficient dienophiles (Scheme 4.2, left dotted line). The inverse electron-demand cycloaddition reaction is primarily controlled by a LUMOdiene HOMOdienophiie inter-... 

INVERSE-ELECTRON DEMAND LUMO(jjend dienephile controliGd cycloaddition reactions... 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

Our development of the catalytic enantioselective inverse electron-demand cycloaddition reaction [49], which was followed by related papers by Evans et al. [38, 48], focused in the initial phase on the reaction of mainly / , y-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a (Scheme 4.34). 

The absolute configuration of products obtained in the highly stereoselective cycloaddition reactions with inverse electron-demand catalyzed by the t-Bu-BOX-Cu(II) complex can also be accounted for by a square-planar geometry at the cop-per(II) center. A square-planar intermediate is supported by the X-ray structure of the hydrolyzed enone bound to the chiral BOX-copper(II) catalyst, shown as 29b in Scheme 4.24. 

The inverse electron-demand 1,3-dlpolar cycloaddition reaction... 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Honk et al. concluded that this FMO model imply increased asynchronicity in the bond-making processes, and if first-order effects (electrostatic interactions) were also considered, a two-step mechanisms, with cationic intermediates become possible in some cases. It was stated that the model proposed here shows that the phenomena generally observed on catalysis can be explained by the concerted mechanism, and allows predictions of the effect of Lewis acid on the rates, regioselectivity, and stereoselectivity of all concerted cycloadditions, including those of ketenes, 1,3-dipoles, and Diels-Alder reactions with inverse electron-demand [2],... 

In an investigation by Yamabe et al. [9] of the fine tuning of the [4-1-2] and [2-1-4] cycloaddition reaction of acrolein with butadiene catalyzed by BF3 and AICI3 using a larger basis set and more sophisticated calculations, the different reaction paths were also studied. The activation energy for the uncatalyzed reaction were calculated to be 17.52 and 16.80 kcal mol for the exo and endo transition states, respectively, and is close to the experimental values for s-trans-acrolein. For the BF3-catalyzed reaction the transition-state energies were calculated to be 10.87 and 6.09 kcal mol , for the exo- and endo-reaction paths, respectively [9]. The calculated transition-state structures for this reaction are very asynchronous and similar to those obtained by Houk et al. The endo-reaction path for the BF3-catalyzed reaction indicates that an inverse electron-demand C3-0 bond formation (2.635 A... 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

The other catalytic approach to the 1,3-dipolar cycloaddition reaction is the inverse electron-demand (Fig. 8.17, right), in which the nitrone is coordinated to the Lewis acid, which for the reaction in Scheme 8.7 was found to be deactivated compared to the uncatalyzed reaction. In order for a 1,3-dipolar cycloaddition to proceed under these restrictions the alkene should be substituted with electron-donating substituents. 

---