Diels-Alder reaction dienophile reactivity

In stereoselective reactions, Zn11 Lewis acids work well to achieve high selectivities (Scheme 54). Chiral complexes of Zn11 with chiral bis(oxazoline) ligands act as effective catalysts in Diels-Alder reactions of reactive dienes with dienophiles having bidentate chelating moieties such as... 

Diels-Alder reactions. Both 3,4-dimethoxy- and 3,4-dibenzyloxyfuran undergo Diels-Alder reactions with reactive dienophiles in refluxing benzene. This cycloaddition can be markedly catalyzed by Znl2, which also enhances enrfo-selectiv-... 

An extremely useful enantioselective Diels-Alder reaction which uses a super-reactive cationic oxazaborinane catalyst was recently reported by Corey and co-workers (Eq. 25) [25]. This strong chiral Lewis acid promotes the Diels-Alder reaction between reactive and unreactive dienes and dienophiles. With tetrabromoborate as a counter-ion, good enantioselectivities were achieved in the reaction of cyclopenta-diene with several a,/3-enals. With tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as a counter-ion, the reaction of isoprene and a-bromoacrolein at -94 °C gave the desired cycloadduct in 90 % yield and 96 % ee. 

For some early reviews that the author (DJH) has found useful when teaching the fundamentals of the Diels-Alder reaction see Sauer, J. Diels-Alder Reactions. II. Reaction Mechanism Anpfcwandte Chem. Int. Ed. Enp[. 1967, 6, 16-33. Sauer, J. Lang, D. Wiest, H. Diels-Alder Reaction. II. The Addition Capacity of Cis-Trans Isomeric Dienophiles in Diene Additions Chem. Ber. 1964, 97, 3208-3218. Sauer, J. Wiest, H. Mielert, A. Diels-Alder Reaction. I. Reactivity of Dienophiles Towards Cyclopentadiene and 9,10-Dimethylanthracene Chem. Ber. 1964, 97, 3183-3207. 

Fortunately, azachalcone derivatives (2.4a-g, Scheme 2.4) turned out to be extremely suitable dienophiles for Lewis-add catalysed Diels-Alder reactions with cyclopentadiene (2.5). This reaction is outlined in Scheme 2.4 and a large part of this thesis will be devoted to the mechanistic details of this process. The presence of a chromophore in 2.4 allows kinetic studies as well as complexation studies by means of UV-vis spectroscopy. Furthermore, the reactivity of 2.4 is such that also the... 

Interestingly, the rate constants for Diels-Alder reaction of the ternary complexes with 3.9 are remarkably similar. Only with 2,2 -bipyridine and 1,10-phenanthroline as ligands, a significant change in reactivity is observed. It might well be that the inability of these complexes to adopt a planar geometry hampers the interaction between the copper ion and the dienophile, resulting in a decrease of the rate of the catalysed Diels-Alder reaction. 

The simplest of all Diels-Alder reactions cycloaddition of ethylene to 1 3 butadi ene does not proceed readily It has a high activation energy and a low reaction rate Substituents such as C=0 or C=N however when directly attached to the double bond of the dienophile increase its reactivity and compounds of this type give high yields of Diels-Alder adducts at modest temperatures... 

Vinylboranes are interesting dienophiles in the Diels-Alder reaction. Alkenylboronic esters show moderate reactivity and give mixtures of exo and endo adducts with cyclopentadiene and 1,3-cyclohexadiene (441). Dichloroalkenylboranes are more reactive and dialkylalkenylboranes react even at room temperature (442—444). Dialkylalkenylboranes are omniphilic dienophiles insensitive to diene substitution (444). In situ formation of vinyl-boranes by transmetaHation of bromodialkylboranes with vinyl tri alkyl tin compounds makes possible a one-pot reaction, avoiding isolation of the intermediate vinylboranes (443). Other cycloadditions of alkenyl- and alkynylboranes are known (445). 

Maleic anhydride has been used in many Diels-Alder reactions (29), and the kinetics of its reaction with isoprene have been taken as proof of the essentially transoid stmcture of isoprene monomer (30). The Diels-Alder reaction of isoprene with chloromaleic anhydride has been analy2ed using gas chromatography (31). Reactions with other reactive hydrocarbons have been studied, eg, the reaction with cyclopentadiene yields 2-isopropenylbicyclo[2.2.1]hept-5-ene (32). Isoprene may function both as diene and dienophile in Diels-Alder reactions to form dimers. 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

It has long been known that the Diels-Alder reaction is particularly efficient and rapid when the dienophile contains one or more electron-attracting groups. These substituent effects are illustrated by the data in Table 11.3. In the case of the diene, reactivity is increased by electron-releasing substituents. Some illustrative data are given in Table 11.4. 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

Bis(trifluoromethyl)-l,l-dicyanoethylene is a very reactive dienophile. It undergoes facile and high-yield [2+4] cycloadditions with 1,3-dienes, cyclopen-tadiene, and anthracene [707] (equation 86). It is reactive enough in a Diels-Alder reaction with styrene [702] (equation 86). 

Chiral 3-alkenoyl-l,3-oxazolidin-2-ones have been developed and used in highly diastereoselective Diels-Alder reactions by Evans et al. [26] (Scheme 1.34). In this reaction these dienophiles are highly reactive compared with the corresponding... 

The 2n component 2, the so-called dipolarophile (analogously to the dieno-phile of the Diels-Alder reaction) can be an alkene or alkyne or a heteroatom derivative thereof. Generally those substrates will be reactive as dipolarophiles, that also are good dienophiles. 

For the ordinary Diels-Alder reaction the dienophile preferentially is of the electron-poor type electron-withdrawing substituents have a rate enhancing effect. Ethylene and simple alkenes are less reactive. Substituent Z in 2 can be e.g. CHO, COR, COOH, COOR, CN, Ar, NO2, halogen, C=C. Good dienophiles are for example maleic anhydride, acrolein, acrylonitrile, dehydrobenzene, tetracya-noethylene (TCNE), acetylene dicarboxylic esters. The diene preferentially is of the electron-rich type thus it should not bear an electron-withdrawing substituent. 

The Diels-Alder reaction with triple bond dienophiles gives access to cyclo-hexa-1,4-diene derivatives. Further reaction of a reactive intermediate thus produced or a subsequent oxidation step can then lead to a six-membered ring aromatic target molecule. 

Amino-subsdnued dienes are also important dienophiles in Diels-Alder reactions Recently, chiral and achiral 2-amino-l,3-dienes have been prepared to snidy their reactivity Csee also asymmetric Diels-Alder reaction Section 8 1 2 The reaction of 2,3-diamino-l,3-butadienes v/ith nitrostyrene gives unusual [3t-2 carbocyclization products, 2-aminocyclopentanones, which are not formed by the direct cycloaddidon but derived from the Michael addidon products fsee secdon discussing the Michael addidon Secdon 4 1 3 "... 

In contrast to those unreactive dienes that can t achieve an s-cis conformation, other dienes are fixed only in the correct s-cis geometry and are therefore highly reactive in the Diels-Alder cycloaddition reaction. 1,3-Cyclopentadiene, for example, is so reactive that it reacts with itself. At room temperature, 1,3-cycIopentadiene dimerizes. One molecule acts as diene and a second molecule acts as dienophile in a self Diels-Alder reaction. 

Rank the following dienophiles in order of their expected reactivity in the Diels-Alder reaction. 

Cyclo butadiene is highly reactive and shows none of the properties associated with aromaticity. In fact, it was not even prepared until 1965, when Rowland Pettit of the University of Texas was able to make it at low temperature. Even at —78 °C, however, cyclobutadiene is so reactive that it dimerizes by a Diels-Alder reaction. One molecule behaves as a diene and the other as a dienophile. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

---