Cycloaddition reactions stereospecificity

Cycloaddition reactions of aziridines with a wide assortment of dipolarophiles have been studied. The reaction of dialkyl azodicarboxylates with the cf5-aziridine (27) is stereospecific... 

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 ... 

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

Direct photochemical excitation of unconjugated alkenes requires light with A < 230 nm. There have been relatively few studies of direct photolysis of alkenes in solution because of the experimental difficulties imposed by this wavelength restriction. A study of Z- and -2-butene diluted with neopentane demonstrated that Z E isomerization was competitive with the photochemically allowed [2tc + 2n] cycloaddition that occurs in pure liquid alkene. The cycloaddition reaction is completely stereospecific for each isomer, which requires that the excited intermediates involved in cycloaddition must retain a geometry which is characteristic of the reactant isomer. As the ratio of neopentane to butene is increased, the amount of cycloaddition decreases relative to that of Z E isomerization. This effect presumably is the result of the veiy short lifetime of the intermediate responsible for cycloaddition. When the alkene is diluted by inert hydrocarbon, the rate of encounter with a second alkene molecule is reduced, and the unimolecular isomerization becomes the dominant reaction. 

Mechanistically the observed stereospecificity can be rationalized by a concerted, pericyclic reaction. In a one-step cycloaddition reaction the dienophile 8 adds 1,4 to the diene 7 via a six-membered cyclic, aromatic transition state 9, where three r-bonds are broken and one jr- and two cr-bonds are formed. The arrangement of the substituents relative to each other at the stereogenic centers of the reactants is retained in the product 10, as a result of the stereospecific y -addition. 

The Diels-Alder cycloaddition reaction (Section 14.4) is a pericvclic process that takes place between a diene (four tt electrons) and a dienophile (two tr electrons) to yield a cyclohexene product. Many thousands of examples of Diels-Alder reactions are known. They often take place easily at room temperature or slightly above, and they are stereospecific with respect to substituents. For example, room-temperature reaction between 1,3-butadiene and diethyl maleate (cis) yields exclusively the cis-disubstituted cyclohexene product. A similar reaction between 1,3-butadiene and diethyl fumarate (trans) yields exclusively the trans-disubstituted product. 

It must be emphasized once again that the rules apply only to cycloaddition reactions that take place by cyclic mechanisms, that is, where two s bonds are formed (or broken) at about the same time. The rule does not apply to cases where one bond is clearly formed (or broken) before the other. It must further be emphasized that the fact that the thermal Diels-Alder reaction (mechanism a) is allowed by the principle of conservation of orbital symmetry does not constitute proof that any given Diels-Alder reaction proceeds by this mechanism. The principle merely says the mechanism is allowed, not that it must go by this pathway. However, the principle does say that thermal 2 + 2 cycloadditions in which the molecules assume a face-to-face geometry cannot take place by a cyclic mechanism because their activation energies would be too high (however, see below). As we shall see (15-49), such reactions largely occur by two-step mechanisms. Similarly. 2 + 4 photochemical cycloadditions are also known, but the fact that they are not stereospecific indicates that they also take place by the two-step diradical mechanism (mechanism... 

Cycloaddition reactions can occur with retention of configuration in the pseudoexcitation band (Sect 1.1) whereas [2jt H-2jtJ reactions are symmetry-forbidden in the delocalization band. Experimental evidence is available for the stereospecific [2-1-2] cycloaddition reactions between A and olefins with retention of configuration (Scheme 14) [82]. A perepoxide intermediate was reported to be trapped in the epoxide form [83] in the reaction of adamantylideneadamantane with singlet oxygen affording dioxetane derivatives [84]. 

The 2+2 cycloadditions of benzyne to cis- and trani-propenyl ether gave cis- and fran -benzocyclobntanes as the main products, respectively [ 117,118], Stereospecific [2+2] cycloaddition reactions were observed between the benzyne species generated by the halogen-Uthium exchange reaction of ort/io-haloaryl triflates and the ketene silyl acetals (Scheme 23) [119],... 

Scheme 23 Stereospecific [2+2] cycloaddition reaction of a benzyne 3.2.2 Reactions of Cycloalkynes...

Cycloaddition reactions with the Si(lOO) surface have been investigated for the purpose of designing microelectronics, nonlinear optical materials, sensors, and biologically active surfaces. The features of the [2+2] cycloadditions characteristic of the reactions in the pseudoexcitation band [133] predicts that [2+2] cycloadditions of electron-donating alkenes with Si(100)-2 x 1 surface could proceed with retention of configurations, in agreement with the observation [134]. Such stereospecific functionalizations of surfaces are of potential use for specific applications. 

Cycloadditions with the Si(lOO) surface were theoretically [133] concluded to be reactions in the pseudoexcitation band. The conclusion is applicable to thermal [2+2] cycloaddition reactions of unsaturated bonds between heavy atoms. In fact, Sekiguchi, Nagase et al. confirmed that a Si triple bond underwent the stereospecific reactions with alkenes [137] along the path typical of [2+2] cycloaddition in the pseudoexcitation band. The stereospecific [2+2] cycloadditions of were designed by Inagaki et al. (Scheme 28) [138]. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

Isatin derivatives and proline react to give stereospecific formation of an azo-methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-... 

A cycloaddition reaction produces a ring of atoms by forming two new G-bonds, for example the formation of a cyclobutane dimer from two alkene molecules. The direct photoreaction involves the concerted reaction of the singlet Jtpt ) excited state of one alkene with the ground state of the other. Stereospecific reactions in which the dimers preserve the ground-state geometry occur when liquid cis- or trans-but-2-ene are irradiated at low temperature ... 

Berberinium chloride (45) also undergoes stereospecific cycloaddition reactions with vinyl ethers or cyclopentadiene. ... 

If the motion had been disrotatory, this would still have been evidence for a cyclic mechanism. If the mechanism were a diradical or some other kind of noncyclic process, it is likely that no stereospecificity of either kind would have been observed. The reverse reaction is also conrotatory. In contrast, the photochemical cyclobutene—1,3-diene interconversion is disrotatory in either direction.368 On the other hand, the cyclohexadiene—1,3,5-triene interconversion shows precisely the opposite behavior. The thermal process is disrotatory, while the photochemical process is conrotatory (in either direction). These startling results are a consequence of the symmetry rules mentioned in Chapter 15 (p. 846).Vl,As in the case of cycloaddition reactions, we will use the frontier-orbital and Mdbius-HQckel approaches.37"... 

Several cycloaddition reactions of vinylthiophene and vinylbenzo[6]thiophene are known. 2-Vinylthiophene easily adds 4-phenyI-l,2,4-triazoline-3,5-dione to give (308) (74JA5591). 2-Vinyl-thiophenes also undergo stereospecific cycloaddition with singlet oxygen to produce the corresponding endoperoxides (Scheme 87) (75TL4471). 

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