Kinetically controlled cycloadditions

FIGURE 4.26 Pettus one-pot methods kinetically controlled cycloaddition of o-QMs. 

In order to form the activated complex required for the formation of product D, rotational changes of the less dipolar anti-form A to the more dipolar s jn-conformer B are necessary, to give an activated complex C with more parallel bond dipoles, which is thus more dipolar and better solvated than the reactant molecule. In agreement with this explanation is the observation that the reverse refro-Diels-Alder reaction exhibits no large solvent effect, since the activated complex C is quite similar to the reactant D [807], A very subtle solvent effect has been observed in the Diels-Alder addition of methyl acrylate to cyclopentadiene [124], The polarity of the solvent determines the ratio of endo to exo product in this kinetically controlled cycloaddition reaction, as shown in Eq. (5-43). The more polar solvents favour endo addition. 

A small effect by the oxygen substitution on the distribution of the Diels-Alder adducts is observed. The stereochemical preference observed with the free hydroxy compound is reversed when the hydroxy group is protected either as the acetate or as the tert-butyldimethylsilyl ether. The roughly 60 40 distribution of adducts at 80 °C indicates that any differences in the two transition states must amount to less than 1 kcal/mole. The stereochemical preferences observed are the result of a kinetically controlled cycloaddition, rather than equilibration after an initial, fast cycloaddition process. 

Early work established that S4N4 forms di-adducts with alkenes such as norbornene or norbomadiene. Subsequently, structural and spectroscopic studies established that cycloaddition occurs in a 1,3-S,S"-fashion. The regiochemistry of addition can be rationalized in frontier orbital terms the interaction of the alkene HOMO with the low-lying LUMO of S4N4 exerts kinetic control. Consistently, only electron-rich alkenes add to S4N4. 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

H-Azepines 1 undergo a temperature-dependent dimerization process. At low temperatures a kinetically controlled, thermally allowed [6 + 4] 7t-cycloaddition takes place to give the un-symmetrical e.w-adducts, e.g. 2.231-248-249 At higher temperatures (100-200°C) the symmetrical, thermodynamically favored [6 + 6] rc-adducts, e.g. 3, are produced. These [6 + 6] adducts probably arise by a radical process, since a concerted [6 + 6] tt-cycloaddition is forbidden on orbital symmetry grounds, as is a thermal [l,3]-sigmatropic C2 —CIO shift of the unsym-metrical [6 + 4] 7t-dimer. 

The effect of substitutents at the C3 and C6 positions of the azepine ring is much more dramatic in that they force the 1//-azepine into a competing [6 + 2] Tt-cydoaddilion at the Cl —Cl positions.6 1 In fact, at room temperature [6 + 2] cycloaddition by a kinetically controlled, non-concerted, ionic process appears to be dominant, since on treating a mixture of ethyl 3,6-dimethyl- and ethyl 2,5-dimethyl-l//-azepine-l-carboxylate with less than a molar equivalent of ethenetctracarbonitrile, only the [6 + 2] cycloadduct 10 of the 3,6-dimethyl-l//-azepine is formed. 

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). 

Interestingly, the cycloaddition of 2-azadiene 44 with N-methylmaleimide in 2.5m LT-DE gave predominantly exo-adduct in contrast to the thermal cycloaddition that is mainly enJo-selective (Scheme 6.27). A similar but not so dramatic increase in cxo-selectivity was also observed [47] for the cycloaddition of 44 with N-phenylmaleimide. The reaction is kinetically controlled, but the origin of the high cxo-selectivity observed in LT-DE is unclear the polar medium probably favors the more polar exo transition state. 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

When ene-nitrile oxidoisoquinolium betaine 131 was heated as a dilute solution in toluene to 120 °C (Scheme 1.15), near quantitative conversion to the cycloadduct 133, resulting from the undesired regioselectivity, was observed. While the near complete conversion to cycloadduct 133 of oxidoisoquinolinium betaine 131 indeed demonstrated complete avoidance of the conjugate addition pathway in favor of cycloaddition, initial production of undesired isomeric cycloadduct 133 (instead of 136) was disappointing. Notably, cycloadduct 133 is expected to be less kinetically favored based on frontier molecular orbital (FMO) analysis (assuming dipole HOMO-controlled cycloaddition) of the putative transition state. This result stands in contrast to the cycloaddition of nitroalkene oxidoisoquinolinium betaine... 

In an attempt to explain the different behaviour of azomethinic ylides and N-methylnitrones in 1,3-DC reactions with porphyrins and chlorins, a theoretical study has been carried out. The results obtained showed that while in the cycloadditions of porphyrins and chlorins with azomethinic ylides the processes are irreversible and consequently are kinetically controlled, the cycloadditions of such macrocycles involving JV-methylnitrone are clearly reversible, showing that the products from such reactions should be thermodynamically controlled <07MI1>. 

Langa et al. [26, 59, 60], while conducting the cycloaddition of N-methylazo-methine ylide with C70 fullerene, proposed a rather similar approach. Theoretical calculations predict an asynchronous mechanism, suggesting that this phenomenon can be explained by considering that, under kinetic control, microwave irradiation will favor the more polar path corresponding to the hardest transition state . 

The 1,3-dipolar cycloadditions of nitrones (551), (595), (614), (615) and their enantiomers (595 ent), (614 ent), (615 ent) (Fig. 2.40) to a.p-unsaturated y-lactones, such as achiral D7 g and D-glycero D7 h, provide an interesting example of double asymmetric inductions. The reactions are kinetically controlled. However, on heating and at longer reaction times, the reversibility of the cycloaddition (595 + D7 h) was observed, and the presence of a more stable thermodynamic product (620) was detected. Moreover, in the case of lactone D7 h, a... 

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). ... 

Diazo compounds also undergo cycloaddition with fullerenes [for reviews, see (104),(105)]. These reactions are HOMO(dipole)-LUMO(fullerene) controlled. The initial A -pyrazoline 42 can only be isolated from the reaction of diazomethane with [60]fullerene (106) (Scheme 8.12) or higher substituted derivatives of Ceo (107). Loss of N2 from the thermally labile 42 resulted in the formation of the 6,5-open 1,2-methanofullerene (43) (106). On the other hand, photolysis produced a 4 3 mixture of 43 and the 6,6-closed methanofullerene (44) (108). The three isomeric pyrazolines obtained from the reaction of [70]fullerene and diazomethane behaved analogously (109). With all other diazo compounds so far explored, no pyrazoline ring was isolated and instead the methanofullerenes were obtained directly. As a typical example, the reaction of Cgo with ethyl diazoacetate yielded a mixture of two 6,5-open diastereoisomers 45 and 46 as well as the 6,6-closed adduct 47 (110). In contrast to the parent compound 43, the ester-substituted structures 45 and 46, which are formed under kinetic control, could be thermally isomerized into 47. The fomation of multiple CPh2 adducts from the reaction of Ceo and diazodiphenylmethane was also observed (111). The mechanistic pathway that involves the extrusion of N2 from pyrazolino-fused [60]fullerenes has been investigated using theoretical methods (112). 

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. 

Dimerization of lff-azepines is an extensively studied phenomenon and involves a temperature dependent cycloaddition process. At low (0°C for 1 R = Me) or moderate (130 °C for 1 R = C02R or CN) temperatures a kinetically controlled, thermally allowed [6 + 4] dimerization to the exo -adduct (73) takes place, accompanied by a small amount (<10%) of symmetrical dimer (74). The latter are thermodynamically favored and become the major products (83%) when the Iff-azepines are heated briefly at 200 °C. The symmetrical dimers probably arise by a non-concerted diradical pathway since their formation from the parent azepines by a concerted [6+6]tt cycloaddition, or from dimer (73) by a 1,3-sigmatropic C-2, C-10 shift are forbidden on orbital symmetry grounds. Dimerization is subject to steric restraint and is inhibited by 2-, 4- and 7-substituents. In such cases thermolysis of the lif-azepine brings about aromatization to the correspondingly substituted JV-arylurethane (69JA3616). 

Whether cis or trans fusion is observed in nitrone cycloadditions can depend on reaction conditions as first determined by LeBel et al.9 At lower temperature where cycloaddition is irreversible, kinetic control prevails and this usually favors cis fusion. However, at higher temperature equilibration can occur through retrocycloaddition and the more stable product will predominate (i.e. thermodynamic control). The nitrone may also undergo ( )/(Z) isomerization, particularly at elevated temperature, and this complicates the analysis a different kinetically favored ratio might prevail. A recent example of temperature dependence involves formation of isoxazolidines (18) and (19) from aldehyde (17a Scheme 4). At 90 C ds-fused (18) and rrans-fused (19) were formed in 74% and 9% yield, respectively. At 140 C, however, (18) and (19) were formed in 31% and 34% yield. 

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