Cycloreversions -Cycloaddition

Considerations of this kind, that were not emphasized in connection with the unimolecular reactions dealt with in the preceding chapter, attain crucial importance when the geometric requirements of cycloadditions and cycloreversions are compared. Like the isomerizations previously discussed, cycloreversions are unimolecular a non-totally symmetric vibrational motion that may be called for by the correspondence diagram will ordinarily be opposed by a restoring force. Cycloadditions, at least the prototypical ones, are bimolecular the two reactants can approach each other in a variety of ways, their reorientation in space costing no energy at all. It then becomes reasonable to ask how the conclusions which may be reached by the orbital symmetry analysis depend on the initial geometry assumed for the approach of the reactants towards one another. 

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Treatment of 467 with more than 2 molar equiv of the corresponding aldehyde gives bicyclic products 468 in good yields. These compounds are useful intermediates in the tandem cycloreversion-cycloaddition process (Equation 58) <2000S1170, 2002S 1885>. 

A sequential cycloaddition, tandem cycloreversion-cycloaddition process is more efficient than the direct cycloaddition, especially in case of aliphatic aldehydes, where the corresponding ylides are rather unstable. The cycloreversion strategy lowers the concentration of the free ylide in the reaction mixture and avoids side reactions such as self-condensation of this reactive species. In some cases, this tandem cycloreversion-cycloaddition sequence provides improved chemical yields without any loss of diastereoselectivity. For example, compound 476 treated with methyl fumarate, methyl maleate, and methyl acrylate provides acceptable yields of compounds 477-479 (Scheme 80) <2000S1170, 2002S1885>. 

Finally, the reversibility of the nitrone/alkene [3+2] cycloaddition, mainly used to access the hexahydro-isoxa-zolo[2,3- ]pyridine ring system (see Section 11.10.3.7), can be used to functionalize these heterocycles. Accordingly, Holmes et al. found that a cycloreversion-cycloaddition reaction could be performed from 65 by simple heating in toluene at 190 °C. Under these conditions, the product of the reaction was found to be the exo-adduct 67 (Scheme 21) <2002J(P1)1494>. 

Selenoacylamidines also take part in Diels-Alder reactions yielding 4W-selenopyrans through a cycloaddition-cycloreversion-cycloaddition sequence (95TL237). 5,6-Dihydro-27/-selenopyrans have also been obtained by hetero-Diels-Alder protocol (95JA10922). 

Highly substituted 4-dimethylamino-4/7-thiopyrans result from a cycloaddition-cycloreversion-cycloaddition sequence commencing with the heterodiyne 417 and dimethyl acetylenedicarboxylate (DMAD) <1996J(P2)2623, 1997MI2185>. Activated alkynes cycloadd to 3-aryl-2-cyanothioacrylamides yielding 4-aryl-477-thiopyrans 418 (Scheme 127) <1994J(P1)989>. 

The nitrone protection strategy has also been used in the total synthesis of (-)-histrionicotoxin (84) and some related alkaloids. The bicyclic isoxazolidine 82 underwent the cycloreversion-cycloaddition reaction at 190 °C to give the key intermediate 83 in high yield (82%) <02JCS(P1)1494>. 

Silica gel catalyzed the m-/ra j -isomerization of some 4-nitroisoxazolidines through a cycloreversion/cycloaddition process <1999TA77> (see also Section 4.03.6.3.4). 

Thermal fragmentation of imidazolidines in the presence of dipolarophiles causes a tandem cycloreversion-cycloaddition reaction which leads to cycloadducts <89T4649>. 

Phenylperhydro-l,3,4-oxadiazin-2-ones 151 react with aliphatic or aromatic aldehydes or ethyl 2-oxoacetate to give the intermediates 152. The azomethine imine ylides 152 yield primary oxazolidines 153 <200081170, 2002S1885, 2004TL3127>. These compounds can be synthesized also by treatment of 151 with ethyl oxoacetate or aldehydes in the presence of magnesium bromide etherate. The tandem cycloreversion-cycloaddition of 153 with various electron-poor dipolarophiles then leads to pyrazolidines 154-156 (Scheme 22). 

R. L. Zuckerman, R. G. Bergman, Mechanistic investigation of cycloreversion/cycloaddition reactions between zirconocene metallacycle complexes and unsaturated organic substrates. Organometallics 20, 2001 1792. 

Ozonation ofAlkenes. The most common ozone reaction involves the cleavage of olefinic carbon—carbon double bonds. Electrophilic attack by ozone on carbon—carbon double bonds is concerted and stereospecific (54). The modified three-step Criegee mechanism involves a 1,3-dipolar cycloaddition of ozone to an olefinic double bond via a transitory TT-complex (3) to form an initial unstable ozonide, a 1,2,3-trioxolane or molozonide (4), where R is hydrogen or alkyl. The molozonide rearranges via a 1,3-cycloreversion to a carbonyl fragment (5) and a peroxidic dipolar ion or zwitterion (6). 

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 ... 

In addition to the formation of the pyridine framework by de novo approaches (see section 8.1) or by the cycloaddition/cycloreversion sequence (see section 8.2), one can employ reactions that proceed through a rearrangement pathway. The Boekelheide reaction (see section 8.3.1) involves the rearrangement of an existing pyridine skeleton to a more functionalized scaffold, while the Ciamician-Dennstedt reaction (section 8.3.2) generates the pyridine nucleus by rearrangement of an alternative heterocycle. 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

An interesting perspective for synthesis is offered by the reaction sequence cycloaddition/cycloreversion. It often does not lead to the initial reactants, but to a different pair of dipole and dipolarophile instead ... 

Interestingly, in the inverse-electron-demand Diels-Alder reactions of oxepin with various enophiles such as cyclopentadienones and tetrazines the oxepin form, rather than the benzene oxide, undergoes the cycloaddition.234 236 Usually, the central C-C double bond acts as dienophile. Oxepin reacts with 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dienone to give the cycloadduct 6 across the 4,5-C-C double bond of the heterocycle.234 The adduct resists thermal carbon monoxide elimination but undergoes cycloreversion to oxepin and the cyclopenta-dienone.234... 

In a sequence of cycloaddition and cycloreversion, 3-phenyl-l, 2,4-triazine 1-oxides react with benzyne, generated from 2-aminobenzoic acid (see Houben-Weyl, Vol. 5/2 b, p 622 ff), to give 2-phenyl-l, 3-benzoxazepines in moderate yield.419... 

The bicyclic system 5 can also be used to prepare annulated systems by cycloaddition-cycloreversion processes. With 2//-pyran-2-one (6) a mixture of cycloadducts is formed on... 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

The possibility of being involved in olefin metathesis is one of the most important properties of Fischer carbene complexes. [2+2] Cycloaddition between the electron-rich alkene 11 and the carbene complex 12 leads to the intermediate metallacyclobutane 13, which undergoes [2+2] cycloreversion to give a new carbene complex 15 and a new alkene 14 [19]. The (methoxy)phenylcar-benetungsten complex is less reactive in this mode than the corresponding chromium and molybdenum analogs (Scheme 3). 

The Diels Alder reaction is reversible and the direction of cycloaddition is favored because two n bonds are replaced by two cr-bonds. The cycloreversion occurs when the diene and/or dienophile are particularly stable molecules (i.e. 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-... 

The reaction of furan with 2,5-dihydrothiophene-3,4-dicarboxylic anhydride is remarkable (Scheme 6.19). Furan is a poor diene and requires high pressure to affect cycloadditions [39]. On the other hand, high temperatures are forbidden because cycloaddition products derived from furan undergo cycloreversion under these conditions. In 5.0m LP-DE, the Diels-Alder reaction of furan with 2,5-dihydrothiophene-3,4-dicarboxylic anhydride proceeds at room temperature and atmospheric pressure in 9.5 h with 70 % yield and with the same diastereos-electivity found when the reaction is carried out under high pressure [40]. 

Scheme 6. Photochemical [2 + 2] cycloreversion of the dodecadehydro[18]annulene in furan as the solvent, followed by [4 + 2] Diels-Alder cycloaddition, gives the oxanorbornadiene adducts 38-40 [66]...

Goti, Brandi and coworkers developed an effective synthesis of (-)-rosmarinecine (4-357) via a domino cycloreversion-intramolecular nitrone cycloaddition of 4-355, which led to 4-356 (Scheme 4.79) [125]. 

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