Cycloaddition reactions relative stabilities

The use of lithium amides to metalate the a-position of the N-substituent of imines generates 2-azaallyl anions, typically stabilized by two or three aryl groups (Scheme 11.2) (48-62), a process pioneered by Kauffmann in 1970 (49). Although these reactive anionic species may be regarded as N-lithiated azomethine ylides if the lithium metal is covalently bonded to the imine nitrogen, they have consistently been discussed as 2-azaallyl anions. Their cyclization reactions are characterized by their enhanced reactivity toward relatively unactivated alkenes such as ethene, styrenes, stilbenes, acenaphtylene, 1,3-butadienes, diphenylacetylene, and related derivatives. Accordingly, these cycloaddition reactions are called anionic [3+2] cycloadditions. Reactions with the electron-poor alkenes are rare (54,57). Such reactivity makes a striking contrast with that of N-metalated azomethine ylides, which will be discussed below (Section 11.1.4). 

Ab initio molecular orbital calculations, coupled with activation energies and entropies from experimental data, have been employed to determine the nature of the intermediates in the reaction of singlet oxygen with alkenes, enol ethers, and enamines.214 Allylic alkenes probably react via a perepoxide-like conformation, whereas the more likely pathway for enamines involves a zwitterionic cycloaddition mechanism. The reactions of enol ethers are more complex, since the relative stabilities of the possible intermediates (biradical, perepoxide, and zwitterionic) here depend sensitively on the substituents and solvent polarity. 

In contrast to cycloaddition reactions of phosphaalkenes, cycloaddition reactions between phosphaalkynes and other unsaturated systems are comparatively rare. Indeed, there are only a limited number of reports for monophos-phacyclobutadiene) complexes, which are obtained from the corresponding phosphaalkyne. Relatively recently, the reaction of phosphaalkynes with highly electron deficient alkynes was reported <19990M4838>. Treatment of a CF3C=CGF3-coordinated dimeric rhodium complex with phosphaalkynes in hexane at — 20°C followed by warming to room temperature afforded the red air- and moisture-stable phosphete complexes 60 in ca. 50% isolated yields. When phosphaalkynes are allowed to react with a kinetically stabilized cyclobutadiene, 2-Dewar-phosphinines, for example 93 (Equation 30), are obtained <1998S1305>. 

With acyclic dienes, the success of the cycloaddition is dependent on the relative stability of the cisoid form of the diene and on the steric hindrance affecting the trifluoromethyl-sub-stituted carbon. Examples arc given by the reactions of 1, 2, and 4. ... 

Diradical intermediates may occur in other types of cycloadditions and cycloreversions. Kinetic data for the thermal transformation of ci5,ci5-l,5-cyclooctadiene to butadiene and 4-vinylcyclohexene are consistent with a diradical intermediate the same intermediate may be involved in the reaction of butadiene leading to [2 + 2] adducts and to the Diels-Alder product 4-vinylcyclohexene. - That a Diels-Alder product may arise from a stepwise path is not as unimaginable today as may have been the case just a few years ago. In more elaborate contexts as well, regiochemistry may be successfully rationalized through estimations of the relative stabilities of diradical intermediates. ... 

Molecular mechanics calculations have recently been used to assist in explaining the stereochemical course of several intramolecular cycloaddition reactions. - In one case, calculations were carried out to determine the relative energies of four diastereomeric products which could have been produced in the intramolecular azomethine cycloaddition reaction displayed (equation 23). A single product was isolated, though in only 25% yield, llie assumption was made that the calculated difrerences in product stability were reflected by similar, but smaller, energy difrerences in the transition states. 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

The synthesis and relative stability of 3,5-diacyl-4,5-dihydro-l//-pyrazoles prepared by dipolar cycloaddition of enones and a-diazoketones has been published <2004JOC9085>. 3-Acyl-4-aryl-2-pyrazolines have been synthesized by the reaction of a,/3-unsaturated ketones with diazomethane <1996IJB1091>. Ethyl diazoacetate added to 1,3-diarylpropenones in a regioselective fashion to give the intermediate 4,5-dihydto-3//-pyrazole derivative 1,3-hydride shift in the latter led to the formation of the isomeric ethyl 4-aryl-5-aroyl-4,5-dihydro-l//-pyrazole-3-carboxylate and ethyl 4-aryl-3-aroyl-4,5-dihydro-l/7-pyrazole-5-carboxylate in a ratio of 5 1 <2001RJ01517>. 1,3-Dipolar cycloaddition of 2-diazopropane with diarylideneacetones afforded diastereomeric bis-A -pyrazolines <1999T449>. 

Arylnitroso compounds of various types react with both electron-rich and electron-deficient dienes under mild conditions (usually 0-l(X)°C) to produce dihydrooxazines. As mentioned in the preceding section, Kresze s group has looked in considerable detail at orientational preferences and kinetics of [4 + 2] cycloadditions with various phenylnitroso compounds and substituted 1,3-dienes. Table 3-1 contains some of the results of cycloadditions of aromatic nitroso dienophiles with representative unsymmetrical 1- and 2-substituted dienes." Scheme 3-1 shows the subtle regiochemical trends that can be observed in a series of these reactions. These results were rationalized based on consideration of putative dipolar and nonpolar transition states and their relative stabilization by aromatic electron-donating and -withdrawing substituent groups. 

The entropic assistance provided by the intramolecular cycloaddition, the inability of the dienes to tautomerize, and the relative stability of the product (acyl versus alkyl enamine) contribute to the success of this process. A total synthesis of (-)-deoxynupharidine based on the implementation of the in situ generation and subsequent intramolecular Diels-Alder reaction of an A-acyl-l-aza-l,3-butadiene has been detailed [Eq. (13)].32c... 

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