Cyclo-addition reactions 8-electron

The chemistry of dehydrobenzene, the parent aryne, has become well established during the past almost twenty years 4>. It is essentially the chemistry of a short lived (half-life ca. 10-4 sec.), and highly electrophilic intermediate. It reacts with a large number of nucleophiles, and undergoes cyclo-addition reactions with a wide variety of compounds. A number of observations have led us, and others, to concentrate our efforts on the tetrahalogenobenzynes. It seemed reasonable to predict that the presence of four electron withdrawing substituents on the aryne (1) would result in a significant increase in the electrophilicity compared with that of benzyne. 

An approach very closely related to that of Woodward and Hoffmann is the so-called Hiickel-Mobius approach 35> based on the rule An +2 electron systems prefer Hiickel geometries and An electron systems prefer Mobius geometries 36>. When no symmetry exists and there is no cyclic orbital array the allowedness or forbiddenness of a reaction can be determined by following the form of the MO s during the reaction 37>. A detailed quantum mechanical study of the stereochemistry of thermal and photo cyclo-addition reactions has been reported38), and a quantum mechanical discussion of the applicability of the Woodward-Hoffmann rules can be found in a paper by George and Ross 39>. 

Thermal (2 + 2)-cycloaddition reactions have never been reviewed so far, although occasionally a few reactions have been discussed in other review articles.20,21 The literature on this subject is summarized here in four subsections. First the mechanistic aspects of thermal (2 + 2)-cyclo-addition reactions are dealt with and subsequently a review is given of (2 + 2)-cycloadditions of heterocycles with olefins and compounds having other double bonds, with acetylenes, and with heterocumulenes. The reactions with acetylenes are discussed under two separate headings, covering (1) reactions with nonaromatic heterocycles and (2) reactions with heteroaromatics. The reactions included are exclusively inter-molecular (2 + 2)-cycloadditions. No examples are known of intramolecular thermal (2 + 2)-cycloadditions of two isolated -electron systems or of thermal electrocyclizations of conjugated 4/r-electron systems of heterocyclic compounds (Appendix). 

More recent views on the theory of (2 + 2)-cycloaddition, in particular with respect to the question whether the two novel o-bonds are formed via a concerted or a stepwise mechanism, have been presented by Epiotis.28 He predicts that, if in the reaction of two n -electron systems one of the reactants has an electron-donating and the other an electron-accepting character, the activation energy of the concerted non-allowed 1 2 + n2s]-cycloaddition will be lowered, so that such a reaction may occur in a concerted manner under relatively mild conditions. As this condition is satisfied in most of the reported thermal (2 + 2)-cyclo-addition reactions of heterocyclic compounds, care must be taken in drawing any conclusions as regards the reaction pathways followed. 

Cycloadditions and cycUzadon. 2-Alken-7-ynones undergo a [2 + 2 + 2]cyclo-addition with electron-deficient alkenes to give cyclohexene derivatives. This process is complementary to the Diels-Alder reaction. 

The twisted shape of the heptafulvalene is ideally set up for antara-facial addition to its 14 ir-electron system. Heptafulvalene takes part in similar [14+2] cyclo-addition reactions with W-phenyl-triazolidinedione and with singlet oxygen, the latter reaction providing tropone as the isolated product [252]. In the reaction with the triazolidinedione the trarzg-isomer is the predominant (90°o) but not the sole product. 

Although [14]annulene supports a diamagnetic ring current and appears to have significant delocalisation of its ir-electrons, it undergoes a cyclo-addition reaction with maleic anhydride [46]. 

The two-component cyclo-addition reactions are conveniently classified as [m + pi reactions, where m and p represent the maximum number of participating ir-electrons on each of the two components. Likewise the general three component cyclo-addition becomes an [m + p + <7] process. On this basis, reactions (3.5) and (3.6) are respectively classified as [4 + 2] and [2 + 2 + 2] cyclo-addition reactions. 

The three possible topological interactions in [ 2 + 2] cyclo-addition reactions are shown in Fig. 5.2 again the basis molecular orbitals of the ethylene components are considered. In the supra-supra and i v antara-antara combinations there are no out of phase orbital overlaps (or two if the signs are reversed on one ethylene component). In the supra intara mode there is one out of phase overlap. Since there are four electrons involved, the Mobius type interaction (i.e. supra-antard) should be preferred the other combinations should therefore be possible under photochemical control. These results accord with the previous findings of orbital symmetry theory. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

The fact that complex 38 does not react further - that is, it does not oxidatively add the N—H bond - is due to the comparatively low electron density present on the Ir center. However, in the presence of more electron-rich phosphines an adduct similar to 38 may be observed in situ by NMR (see Section 6.5.3 see also below), but then readily activates N—H or C—H bonds. Amine coordination to an electron-rich Ir(I) center further augments its electron density and thus its propensity to oxidative addition reactions. Not only accessible N—H bonds are therefore readily activated but also C—H bonds [32] (cf. cyclo-metallations in Equation 6.14 and Scheme 6.10 below). This latter activation is a possible side reaction and mode of catalyst deactivation in OHA reactions that follow the CMM mechanism. Phosphine-free cationic Ir(I)-amine complexes were also shown to be quite reactive towards C—H bonds [30aj. The stable Ir-ammonia complex 39, which was isolated and structurally characterized by Hartwig and coworkers (Figure 6.7) [33], is accessible either by thermally induced reductive elimination of the corresponding Ir(III)-amido-hydrido precursor or by an acid-base reaction between the 14-electron Ir(I) intermediate 53 and ammonia (see Scheme 6.9). 

Pericyclic reactions are concerted reactions that take place in a single step without any intermediates, and involve a cyclic redistribution of bonding electrons. The concerted nature of these reactions gives fine stereochemical control over the generation of the product. The best-known examples of this reaction are the Diels-Alder reaction (cyclo-addition) and sigmatropic rearrangement. 

Although the resonance structures of benzene show it as a cyclo-hexatriene, because of its fully delocalized n system and the closed shell nature of this n system, benzene does not undergo addition reactions like ordinary unsaturated compounds. The destruction of the n electron system during addition reactions would make the products less stable than the starting benzene molecule. However, benzene does undergo substitution reactions in which the fully delocalized closed n electron system remains intact. For example, benzene may be reacted with a halogen in the presence of a Lewis acid (a compound capable of accepting an electron pair) to form a molecule of halobenzene. 

The second reaction unique to conjugated dienes is Diels-AIder cyclo-addition. Conjugated dienes react with electron-poor alkenes (dienophiles)... 

Only one thiophene has been reported to undergo (2 + 2)-cyclo-addition with carbonyl compounds, viz., 2,5-dimethylthiophene.210 In this reaction, too, only one type of isomer (180) was obtained, in 50-60% yield. N-Benzoyl-l//-pyrrole reacted with two molecules of ketone to give cycloadduct 181.211 Similarly, JV-acyl-1//-indoles reacted with certain ketones to produce adducts 182.212 The lack of reactivity of other heterocycles, such as 1//-pyrroles, oxazoles, and isoxazoles, has been attributed to a quenching effect on the excited ketone of the non-bonded electrons on the heteroatom.212... 

In a large number of carbene and carbenoid addition reactions to alkenes the thermodynamically less favored jjyn-isomers are formed The finding that in the above cyclopropanation reaction the an/i-isomer is the only product strongly indicates that the intermediates are organonickel species rather than carbenes or carbenoids. Introduction of alkyl groups in the 3-position of the electron-deficient alkene hampers the codimerization and favors isomerization and/or cyclodimerization of the cyclo-propenes. Thus, with methyl crotylate and 3,3-diphenylcyclopropene only 16 % of the corresponding vinylcyclopropane derivative has been obtained. 2,2-Dimethyl acrylate does not react at all with 3,3-dimethylcyclopropene to afford rranj-chrysanthemic acid methyl ester. This is in accordance with chemical expectations since in most cases the tendency of alkenes to coordinate to Ni(0) decreases in the order un-, mono-< di- tri- < tetrasubstituted olefines. 

This classification, valid for concerted cis-cis (or supra,supra) processes, confirmed that thermal Diels-Alder reactions (m-f-/i = 6) can be (but not, must be) one-step reactions, while predicting that photochemical 1,4-cyclo-additions should be multistep reactions 1,3-cycloadditions should behave analogously, since 1,3-dipoles are four 7r-electron systems. Common 1,2-... 

The additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained, or even simple olefins as dienophiles. Substitution of the heterocyclic azadiene with strongly electron-donating substituents in many instances is sufficient to overcome the electron-deficient nature of the azadiene and permits the use of conventional electron-deficient dienophiles in normal (HOMOdiene controlled) Diels-Alder reactions The entropic assistance provided by the intramolecular Diels-Alder reaction is sufficient in most instances to override the reluctant azadiene participation in Diels-Alder reactions. The incorporation of the heterocyclic azadiene, or the dienophile, into a reactive system, e.g., heterocumulene, allows a number of specialized [4 -I- 2] cycloaddition processes which are best characterized as stepwise addition-cyclization [4 -I- 2] cyclo-additions. ... 

The magnesium and copper bis-oxazoline catalysts used in the asymmetric Diels-Alder reaction (see Section 8.1) display high levels of selectivity in the nitrone cyclo addition with bidentate, electron-deficient dipolarophiles. The magnesium bis-oxazoline catalysts effect moderate to good ee in the cycloaddition with oxazolidines such as (8.51), while copper bis-oxazoline complexes show good selectivity in the addition to bidentate pyrazolidinones rather than oxazo-lidinones and also a-hydroxyenones such as (8.75) used as substrates in the copper bis-oxazoline-catalysed Diels-Alder reaction. ... 

Dienes and dienophiles react regiospecifically, the former by a [4 + 2] cyclo-addition across the 2,3-bond and the latter by a [8 + 2] cyclo-addition across the 4,5 bond, reactions taking place respectively at a localised double bond in the more electron-poor ring and at a localised single bond in the more electron-rich ring [180]. 

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