Diels-Alder reactions orientation selectivity

An interesting phenomenon has been observed in the high pressure Diels-Alder reactions of the l-oxa[4.4.4]propella-5,7-diene (117) with 1,4-naphthoquinone, maleic anhydride and N-phenylmaleimide, where the diene 117 undergoes a rearrangement to the diene isomer 118 which, although thermodynamically less favored, exhibits a greater reactivity [40]. The reactivities of the three dienophiles differed since maleic anhydride and N-phenylmaleimide reacted only in the presence of diisopropylethylamine (DIEA) and camphorsulfonic acid (CSA), respectively (Scheme 5.15). The distribution of the adduct pairs shows that the oxygen atom does not exert a consistent oriental dominance on TT-facial selectivity. 

Helmchen and co-worker investigated the use of phosphinooxazolines as ligands for copper(II) catalyzed Diels-Alder reactions (Scheme 19) (214). Optimal selectivities are found for a-naphthyl-substituted phosphinooxazoline (299). These catalysts require 2.5 h to induce complete conversion to cycloadduct, compared to 18 h using the triflate complex 269c under identical conditions. Helmchen invokes a square-planar metal geometry to explain the stereochemistry of the adducts, similar to the model proposed by Evans. He suggests that the bulky phosphine substituents are required to orient binding of the dienophile in such a way as to place the olefin directly below the terf-butyl substituent on the oxazoline. 

In recent years, supramolecular chemistry has produced a number of systems which have been shown to be able to effectively catalyze a Diels-Alder reaction. Most systems selectively afforded only one diastereomer because of a pre-organized orientation of the reactants. These systems include cyclodextrines, of which applications in Diels-Alder chemistry have recently been reviewed89. Some other kinds of non-Lewis acid catalyzed Diels-Alder reactions, including catalysis by proteins and ultrasound, have been discussed by Pindur and colleagues90. 

Metal complexes of bis(oxazoline) ligands are excellent catalysts for the enantioselective Diels-Alder reaction of cyclopentadiene and 3-acryloyl-l,3-oxa-zolidin-2-one. This reaction was most commonly utilized for initial investigation of the catalytic system. The selectivity in this reaction can be twofold. Approach of the dienophile (in this case, 3-acryloyl-l,3-oxazolidin-2-one) can be from the endo or exo face and the orientation of the oxazolidinone ring can lead to formation of either enantiomer R or S) on each face. The ideal catalyst would offer control over both of these factors leading to reaction at exclusively one face (endo or exo) and yielding exclusively one enantiomer. Corey and co-workers first experimented with the use of bis(oxazoline)-metal complexes as catalysts in the Diels-Alder reaction between cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 the results are summarized in Table 9.7 (Fig. 9.20). For this reaction, 10 mol% of various iron(III)-phe-box 6 complexes were utilized at a reaction temperature of —50 °C for 2-15 h. The yields of cycloadducts were 85%. The best selectivities were observed when iron(III) chloride was used as the metal source and the reaction was stirred at —50 °C for 15 h. Under these conditions the facial selectivity was determined to be 99 1 (endo/exo) with an endo ee of 84%. 

In striking contrast with these two previous examples of 1,3-dipolar cycloaddition catalyzed by encapsulation, the EMs calculated for particular examples of Diels-Alder reactions catalyzed by Rebek s softball [25] or by Sanders [26] cyclophane, which was selected from a dynamic combinatorial library (DCL), are lower than the actual reactant concentration calculated from the volumes of the molecular cavities. Probably, the Diels-Alder reactions have more stringent orientational requirements than the 1,3-dipolar cycloaddition. The reactants of the Diels-Alder reactions, when encapsulated or included, spend a significant amount of time in ternary complexes displaying a non-productive mutual orientation. 

Butadienes with alkyl substituents in the 2-position favor the formation of the so-called para-products (Figure 15.25, X = H) in their reactions with acceptor-substituted dienophiles. The so-called mefa-product is formed in smaller amounts. This regioselectivity increases if the dienophile carries two geminal acceptors (Figure 15.25, X = CN). 2-Phenyl-1,3-butadiene exhibits a higher para -selectivity in its reactions with every unsymmetrical dienophile than any 2-alkyl-1,3-butadiene does. This is even more true for 2-methoxy- 1,3-butadiene and 2-(trimethylsilyloxy)-l,3-butadiene. Equation 15.2, which describes the stabilization of the transition states of Diels-Alder reactions in terms of the frontier orbitals, also explains the para "/"meta "-orientation. The numerators of both fractions assume different values depending on the orientation, while the denominators are independent of the orientation. 

Fig. 15.26. Frontier orbital coefficients and energy difference of the H0M0-LUM0 gaps in orientation-selective Diels— Alder reactions (cf. Figure 15.25, X = H).

Diels-Alder reactions with symmetrically substituted dienophiles and/or with symmetrically substituted dienes afford cycloadducts that must be constitutionally homogeneous. In contrast, Diels-Alder reactions between an asymmetrically substituted dienophile and an asymmetrically substituted diene may afford two constitutionally isomeric cycloadducts. If only one of these isomers is actually formed, the Diels-Alder reaction is said to be orientation selective. 

Fig. 12.24. Orientation-selective Diels-Alder reactions with a 2-substituted 1,3-diene I comparison of the effects exerted by one or two dienophile substituents.

We can customize these general statements specifically for the case of the orientation selectivity of Diels-Alder reactions with normal electron demand and make the following statement right away ... 

The consequences thereof for the orientation selectivity of Diels-Alder reactions can be summarized as follows. 

What has just been stated regarding the LCAO coefficients of the dienophile LUMO combined with the rules for the orientation selectivity of any one-step cycloaddition leads to the following consequences for the Diels-Alder reactions of isoprene ... 

The increase in orientation selectivity of Diels-Alder reactions upon addition of Lewis acid has a second cause aside from the one which was just mentioned.The reaction conditions described in Figure 12.27 indicate that A1C13 increases the rate of cycloaddition. The same effect also was seen in the cycloaddition depicted in Figure 12.20. In both instances, the effect is the consequence of the lowering of the LUMO level of the dienophile. According to Equation 12.2, this means that the magnitude of the denominator of the first term decreases and the first term therefore becomes larger than the second term. II) in addition, the numerators of these terms differ by a certain amount for the para and meta transition states (as determined by the combinations of the LCAO coefficients), the effect is further enhanced. This also increases the para selectivity. 

Finally, the examples of the two Diels-Alder reactions in Figure 12.27 lead us to a general statement in Diels-Alder reactions with normal electron demand, the addition of AICI3 increases the reaction rate and the orientation selectivity. This situation marks one of the most notable exceptions from the reactivity-selectivity principle (Section 1.7.4), which is otherwise so often encountered in organic chemistry. 

Fig. 12.28. Orientation selectivity and simple diastereoselectivity of a Diels-Alder reaction with a 1-substituted diene selectivity increase by way of addition of a Lewis acid.

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