Kinetic control Diels-Alder

Marchand and coworkers102 reported a difference in site selectivity between the thermodynamically and kinetically controlled Diels-Alder reactions of cyclopentadiene with 2,3-dicyano-p-benzoquinone (126) (equation 37). Under kinetic conditions, the more reactive double bond of 126 reacted with cyclopentadiene affording 127, whereas the less substituted double bond reacted under thermodynamic conditions affording 128. Both reactions proceeded with complete endo selectivity. These findings were in agreement with ab initio HF/3-21G calculations. 

Marchand and coworkers reported a difference in site selectivity between the thermodynamically and kinetically controlled Diels-Alder reactions of cyclopentadiene with... 

Limited quantitative data on orientation of unsymmetrical dienes and dienophiles in kinetically controlled Diels-Alder reactions are available. Most of the work in this field is preparative, and a discussion based on relative yields... 

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

Stereochemistry of Diels-Alder Reactions. Thermodynamic vs. Kinetic Control... 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

Cycloaddition of 125 with buckminsterfullerene (Ceo) at 3 kbar allowed the adduct [48] to be obtained, preventing a retro Diels-Alder process (Scheme 5.19). Cycloadditions of tropone (125) with furans 134 gave mixtures of 1 1 endo-dcad exo-monocycloadducts 135 and 136, respectively [49a], together with some bisadducts. In this case furan reacts solely as the 27t component in spite of its diene system. Whereas 2-methoxy furan gave mainly the kinetically controlled product 135 (R= OMe Ri =R2 =H), under the same conditions 3,4-dimethoxy furan afforded the thermodynamically controlled cycloadduct 136 (R=H Ri =R2 =OMe) as the major product (Scheme 5.19). 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

Despite the fact that the exo adduct is likely to be the more stable of the two thermodynamically, it is often (though not universally) found in Diels-Alder reactions that the endo adduct is the major, if not the sole, product. To explain this, it has been suggested that in endo addition stabilisation of the T.S. can occur (and the rate of reaction thereby speeds up) through secondary interaction of those lobes of the HOMO in, e.g. (32) and of the LUMO in (33) that are not themselves involved directly in bond-formation, provided these are of the same phase. Such interaction would not, of course, be possible in the T.S. for exo addition because the relevant sets of centres in (32) and (33) will now be too far apart from each other the endo adduct is thus the kinetically controlled product. It is significant in this connection that the relative proportion of exo... 

Actually one orientation predominates (called high regioselectivity) and only one diastereoisomer is produced (called high stereoselectivity). The Diels-Alder reaction is reversible and may be carried out under thermodynamic or kinetic controlled conditions. 

The asymmetric Diels-Alder cycloadditions of enantiopure (5)-5-(/ -tolylsulfinyl)-1,4-benzoquinones with Dane s diene under thermal and Lewis acid conditions produce tetracyclic quinones after spontaneous elimination of the sulfinyl group.The Diels-Alder reaction of barrelene with o-benzoquinone produces tetracyclo[6.2.2.2 .0 ]tetradeca-9,ll,13-triene-4,5-dione. Under kinetic control, the Diels-Alder cycloaddition of 2,3-dicyano-p-benzoquinone (98) with cyclopentadiene in MeOH produces the single cycloadduct (99) (Scheme 38). ... 

The situation may be markedly different for reactions under kinetic control. Here, the lowest-energy conformer(s) of the reagent(s) may not be the one(s) involved in the reaction. A simple but obvious example of this is provided by the Diels-Alder cycloaddition of 1,3-butadiene with acrylonitrile. 

Ketyls, 218 Kinetic aridity, 280 Kinetic control, 42, 151 addition to 0=0, 235 addition to dienes, 195 Diels-Alder, 350... 

Because of the strong rr-deficiency of most six-membered heteroaromatic compounds, cycloadditions of this type belong to Diels-Alder reactions with inverse electron demands in other words, they are LUMO -HOMOp, controlled reactions (for review see (B-87MI 502-08)). Acceptor substituents in the heterocyclic diene and donor substituents in the dienophile accelerate the reaction, as shown by kinetic data (83TL1481,84TL2541,90TL6851). 

When cyclic 1,3-dienes were employed, the reactions were found to be exo selective [Eq. (28)]. In contrast, the Diels-Alder reactions of free thio-and selenoaldehydes with cyclopentadiene occur with a preference for the endo isomer.235 Thus, coordination of thio- and selenoaldehydes to a penta-carbonylmetal fragment resulted in a reversal of the endo selectivity. The exo/endo product ratio of [W(CO)5 E = C(Ph)H ] was 7.3 1 (E = S) and 2.6 1 (E = Se), whereas the kinetically controlled exo/endo ratio of the cycloadducts obtained by trapping of the free heterobenzaldehyde with cyclopentadiene was reported to be 1 7236 and 1 4235 237 (E = S) and 1 2.6238 and 1 4239 (E = Se), respectively. 

There are exceptions to favored endo stereochemistry of Diels-Alder additions. Some of these exceptions arise because the addition reaction is reversible, dissociation being particularly important at high temperature. The exo configuration is generally more stable than the endo and, given time to reach equilibrium (cf. Section 10-4A), the exo isomer may be the major adduct. Thus endo stereospecificity can be expected only when the additions are subject to kinetic control. 

However, Diels-Alder reactions are well known to be exceptional, with maleic anhydride reacting with cyelopentadiene by way of an endo transition structure 2.110 to give what is called the endo adduct 2.111 as the major product. The exo adduct 2.112 is a very minor product, unless the mixture is heated for a long time, when reversal of the Diels-Alder reaction and readdition establish the thermodynamic equilibrium in its favour. The endo adduct is evidently the product of kinetic control, and the preference for it is called Alder s rule. 

Here we are primarily concerned with the fact that this ortho -adduct may occur in the form of two diastereomers. The diastereomers are formed as a 57 43 cis/trans-mixtme in the absence of A1C13, but a 95 5 cis/trans-mixture is obtained in the presence of A1C13. In the latter case, thus, one is dealing with a Diels-Alder reaction that exhibits a substantial simple diastereoselectivity (see Section 11.1.3 for a definition of the term). Here, the simple diastereoselectivity is due to kinetic rather than thermodynamic control, since the preferentially formed ds-disubstituted cyclohexene is less stable than its irans-isomer. 

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