Reaction -Cycloaddition

A cycloaddition reaction involves the concerted formation of two ct-bonds between the termini of two tt-systems. The reverse reaction involves the concerted cleavage of two ct-bonds to produce two TT-systems. The simplest example being the hypothetical combination of two ethene molecules to give cyclobutane. This does not occur under normal heating, but the cycloaddition of 1,3-butadiene to ethene does, and this is an example of the Diels-Alder reaction. 

A cycloaddition reaction [18] is the joining together of two independent jt-bonding systems to form a ring with two new a bonds. The reverse is called a retrocycloaddition reaction, and the selection rules apply in both directions of a given reaction. 

If butadiene and an appropriately substituted ethylene approach and begin to overlap as in Equation 5.2, there is a favorable phase relationship using the HOMO of the diene and the LUMO of ethylene (the frontier molecular orbitals) for a face-to-face joining. This is, of course, the familiar Diels-Alder reaction, and it is thermally allowed. With respect to both components of the reaction, the reaction occurs from the same face, termed suprafacial addition. Because there are four % electrons in butadiene and two % electrons in ethylene, the Diels-Alder reaction is named as a [ 4 -i- 2 ] reaction. The stereochemical consequences of this approach are further illustrated in Section 8.6. 

The same is true when donor and acceptor are on alkene and diene, respectively. A donor on carbon 2 of a diene enlarges the HOMO coefficient at carbon 1, and an acceptor on carbon 2 enlarges the LUMO coefficient at carbon 1. This favors a 1,4-disubstituted cyclohexene product. The increase in regioselectivity brought about with Lewis acid catalysis is a result of coordination of the catalyst with a receptor substituent, making it a stronger receptor. The stereochemistry of the Diels-Alder reaction is discussed further in Section 8.6. 

Photons generally excite an electron from the HOMO to the next-higher molecular orbital. This higher orbital was the LUMO, but it becomes the highest singly occupied molecular orbital (HSOMO). In butadiene, for example, the ground-state HOMO was but alter photoexcitalion, the HSOMO is (Fig. 5.6). The phase relationship of the HSOMO will be the opposite of the 

Turning now to cycloadditions in which there are four ji electrons, we can see that if two ethylenes are brought together suprafacially, the HOMO—LUMO phase relationship is unfavorable for bond formation (Eq. 5.5), thus the reaction is symmetry forbidden in the 

The cycloaddition of keteniminium triflates 195, formed from tertiary amides by the action of triflic anhydride, with imines formed the azetidine iminium salts 196 (Equation 51) 1996JOC8480 . 

3-dipolar cycloaddition reaction has been investigated on a sohd support primarily toward the construction of diverse small molecule libraries, as the reachon is capable of preparing a variety of privileged five-membered heterocycles. TypicaUy, chemoselectivity is high, and the sohd support provides only a mechanism for the rapid preparation of pure compounds in a parallel fashion however, in select cases the sohd support has been demonstrated to enhance both the chemo- and the regioselechvity of the reachon.  

CHEMO- AND REGIOSELECTIVITY ENHANCEMENT IN SOLID-SUPPORTED REACTIONS 

Diels-Alder cycloadditons have been explored on solid supports, and Winkler and Kwak have demonstrated a chemoselective variant that affords a single reaction of a dienophile containing two reactive double bonds with a bis-diene. Utilizing bis-reactive Diels-Alder reagents in the absence of a solid support is problematic as competing oligomerization can occur. Thus, a dienophile was immobilized as 8 and reacted with the 

Cycloaddition reactions in which anions are involved, have not been studied extensively to date as evidenced by the small number of publications which have appeared over the last few years. 

Indications of the occurrence of cycloaddition were first obtained from reactions of specifically deuterated allyl anions with tetrafluoroethylene. Assuming that no hydrogen/deuterium exchange occurs in the collision complex as shown for the allyl anions themselves (Dawson el al., 1979a), the results obtained (Nibbering, 1979) may be interpreted as indicating that 65% of the allyl anions react by a linear addition (51), 20% by a [2 + 2] atom cycloaddition (52) and 15% by a [2 + 3] atom cycloaddition. (53). It should be noted here that the precise mechanistic details of the losses of HF molecules from the collision complexes in eqns (51)—(53) are not known. However, in view of the nucleophilic aromatic substitution discussed in the previous section, it is quite likely that they occur in a stepwise fashion in which complexes solvated by fluoride anions play a role. 

The observations described prompted a study of the reaction between the 2-cyanoallyl anion and tetrafluoroethylene, since this system has the merit that the charge may be accommodated in the nitrile group of the reaction intermediate in the [2 + 3] atom cycloaddition (54). Elimination of two HF molecules indeed occurs, presumably in a consecutive way, although the product ions resulting from loss of one molecule of HF from the collision complex have not been observed (Dawson and Nibbering, 1980). However, reaction (54) has not yet been studied with specifically deuterated 2-cyanoallyl anions, so that at present an end-on addition process (55) cannot be excluded. 

It is interesting to note here that the ring-closed isomer of the 2-cyanoallyl anion, i.e. the (M — H) ion of cyanocyclopropane, reacts with tetrafluoro-ethylene with expulsion of two molecules of hydrogen fluoride as well, albeit to a minor extent. Most of the corresponding collision complexes, however, appear to eliminate a molecule of ethylene, for which (56) represents the most satisfactory mechanism so far presented (Dawson and Nibbering, 1980). 

A specifically deuterated allyl anion with an electron-withdrawing substituent in the 2-position, which has been allowed to react with some unsaturated substrates for the aimed [2 t+ 3] atom cycloaddition, has been the 2-formyl-1,1-dideuteroallyl anion. This ion has been found to react with the 

Cycloaddition reactions were illustrated in CHEC-I by, for example, reactions of benzyne with pyridazine A -oxides and A -acetylimides (to give 2-hydroxy- and 2-acetylaminophenylpyridazines), inverse electron demand cycloaddition reactions of pyridazinecarboxylates with electron rich acetylenes (to give pyridines and benzenes) and dipolar cycloaddition reactions of a pyridazinone with 

2-diazopropane and of triphenylcyclopropene with pyridazinium and phthalazinium dicyanmethyl-ides 84CHEC-i(3B)i . There has been a significant extension of the cycloaddition chemistry of (benzo)pyridazine derivatives. 

There are a variety of reactions whereby rings are formed through addition to double or triple bonds. An especially simple example is the addition of ethene to 1,3-butadiene to give cyclohexene  

This is the prototype Diels-Alder reaction, which has proved so valuable in synthesis that it won its discoverers, O. Diels and K. Alder, the Nobel Prize in chemistry in 1950. 

The Diels-Alder reaction is both a 1,4 addition of ethene to 1,3-buta-diene and a 1,2 addition of butadiene to ethene. It can be called a [4 + 2] cycloaddition and as such results in the formation of a six-membered ring. Many other cycloadditions are known, such as [2 + 1], [2 + 2], [3 + 2], [4+1], [2 + 2 + 2], and so on, which give different sizes of rings. Some specific examples follow  

The synthetic importance of these reactions is very great and, because many of them often involve dienes, we will discuss their general characteristics in this chapter. The most valuable cycloaddition reaction almost certainly is the [4 + 2], or Diels-Alder, reaction and will be discussed in detail. 

There is one very important point you should remember about the Diels-Alder reaction The reaction usually occurs well only when the [2] component is substituted with electron-attracting groups and the [4] component is sub-, stituted with electron-donating groups, or the reverse. The most common arrangement is to have the alkene (usually referred to as the dienophile) 

Staudinger s Ketene-imine Reactions This is the most fundamental and versatile 

Cycloaddition of diverse types of ketenes and imines leading to the formation of P-lactams is reported. The reactions of chiral ketenes with achiral imines, chiral imines with achiral ketenes, chiral imines with chiral ketenes, and catalytic asymmetrical Staudinger reactions have been investigated. In general, a higher level of asymmetric induction is achieved using either chiral ketenes or chiral imines derived from chiral aldehydes in comparison to the use of a chiral imine derived from an achiral aldehyde with an achiral ketene. Both carboxylic acid chlorides and carboxylic acids themselves have been used as ketene precursors. 

Selenoalkyl- and selenoaryl-substituted ethanoic acids have been used to synthesize P-lactams having selenoalkyl and selenoaryl groups at C-3 position. Phosphoryl chloride [30-32], N,N-dimethyl iminium salt [33-35], and triphosgene [36] have been used in these reactions as acid activators. A detailed review of the literature on such reactions is beyond the scope of this chapter and hence selected recent examples are described in the succeeding paragraphs. 

Asymmetric synthesis of P-lacams through the ketene-imine [2+2]-cycloadditions has been achieved employing N-heterocychc carbenes (NHCs) as 

R = 4-NO2PI1, 4-CIPh, 4-MeOPh, 4-MePh R2 = 4-EtOPh, 4-MeOPh 

The theory of electrocyclic reactions has had a dramatic impact on synthetic and physical organic chemistry. It will not be possible to develop the theory in detail here, and the interested reader is referred to 

It will be helpful to construct a state diagram from the orbital diagram. 

The state symmetries are derived from the product of the orbital symmetries using the following rules  

We have been discussing a cycloaddition where bonds are made or broken on the same face (suprafacial process). The alternative process is one where the bonds are made or broken on opposite faces of the reacting system (antarafacial)  

Without going through the relevant correlation diagrams, two 2 + 2 and three 4 + 2 additions are shown below  

1 [2+2] Cycloaddition Reactions Across C=N Bonds. Cycloaddition reactions of heterocumulenes are well known reactions. Like many of the other heterocumulenes carbodiimides form cyclodimers and cyclotrimers (see Section 2.4.1). The obtained dimeric 

Cycloadducts derived from macrocyclic carbodiimides and diphenylcarbodiimide are also known (see Section 11.3.3). 

Aliphatic carbodiimides often react with heterocumulenes to form six-membered ring 1 2 cycloadducts. For example, DCC reacts with N-p-toluenesulfonyl-N -cyclohexylcarbodiimide to give the 1 2 cycloadduct 207, mp 123-124 °C in 93 % yield. The initially formed polar intermediate 206 reacts with a second sulfonylcarbodiimide molecule to give the final product.  

Similar [2+2+2] cycloadducts 208 are obtained in the reaction of arenesulfonyl isocyanates with aliphatic carbodiimides 

Similar six-membered ring 1 2 cycloaddncts are obtained from aliphatic carbodiimides and aliphatic isocyanates, arenesulfonyl isocyanates and chlorosulfonyl isocyanates. 

Cycloadditions are the most useful of all pericyclic reactions in organic synthesis. This chapter describes the wide range of known cycloadditions, identifies the conditions under which they take place, draws attention to their regio- and stereochemistry, and gives the simple rules for which of them take place and which do not. The explanations for most of these features, based on the molecular orbitals involved, will then be covered in the following chapter. 

The most important type of cycloaddition is the Diels-Alder reaction. Stripped down to its essential components, it is the reaction between butadiene 2.1 and ethylene 2.2 to form cyclohexene 2.3. The ethylenic component is called the dienophile. In practice this reaction is unbearably 

if you look at the different dienophiles in Fig. 2.1, the dimerization of butadiene 2.1 is slower than its reaction with acrolein 2.4. Methyl acrylate and methyl vinyl ketone have electron-withdrawing substituents Z of comparable power, and react at a similar rate, but cyclohexenone 2.5, which has a (5-alkyl substituent, is considerably less reactive. Nitroethylene has one of the most powerful electron-withdrawing groups, and is a very good 

Most impressive of all, cyclic dienes like cyclopentadiene 2.13 are significantly more reactive than open-chain dienes. A diene can participate in a Diels-Alder reaction only when it is in the s-cis conformation. If it were to 

Diels-Alder reactions are, of course, reversible, and the pathway followed for the reverse reaction (2,3 arrows) can sometimes be as telling as the pathway for the forward reaction. The direction in which any pericyclic reaction takes place is determined by thermodynamics, with cycloadditions, like the Diels-Alder reaction, usually taking place to form a ring because two n-bonds on the left are replaced by two j-bonds on the right. A Diels-Alder reaction can be made to take place in reverse when the products do not react with each other rapidly, as in the pyrolysis of cyclohexene 2.3 at 600°. It helps if either the diene or the dienophile has some special stabilization not present in the starting material, as in the formation of the aromatic ring in anthracene 2.15 in the synthesis of diimide 2.16 from the adduct 2,14, and in 

Acetylenes with electron-withdrawing substituents such as Me02C = CC02Me or NCC s CCN have a rich cycloaddition chemistry. As alkynyliodonium salts are highly electron-deficient acetylenes they are expected to undergo a variety of electrocychc processes. 

In Part A, Chapter 10, the relationship of 1,3-dipolar cycloaddition reactions to the general topic of concerted cycloaddition reactions was discussed briefly. It is useful to discuss this reaction in somewhat more detail at this point, since it constitutes a useful method for the synthesis of heterocyclic rings. Table 7.2 lists some classes of molecules that are capable of dipolar cycloaddition. These molecules, which are called 1,3-dipoles, are isoelectronic with allyl anion and each has at least one charge-separated resonance structure with opposite charges in a 1,3-relationship. It is this structural feature which leads to the name 1,3-dipolar cycloaddition reactions as the general name for the particular class of reaction which 

Mechanistic studies have shown that the transition state for cycloaddition of 1,3-dipoles to carbon-carbon multiple bonds is not very polar. The rate of reaction is not strongly sensitive to solvent polarity, and this is in agreement with viewing the addition as a concerted process. The formal destruction of charge that is indicated is more apparent than real, because most 1,3-dipoles are not highly polar 

A comprehensive review of 1,3-dipolar cycloaddition reactions is that of G. Bianchi, C. DeMicheli, and R. Gandolfi, in The Chemistry of Double Bonded Functional Groups Part i. Supplement A, S. Patai (ed.), John Wiley and Sons, New York (1977), pp. 369-532. For a review of intramolecular 1,3-dipolar cycloaddition reactions, see A. Padwa, Angew. Chem. Int, Ed. Engl. 15, 123 (1976). 

Two questions are of principal interest for predicting the structure of reaction products of 1,3-dipolar addition (1) Is the reaction stereospecific (2) Is the reaction regioselective The answer to the first question is yes with respect to the dipolarophile. Many specific examples demonstrate that the cyclic product results from a stereospecific syn addition to olefins. The stereospecific addition that is observed is exactly what would be expected on the basis of a concerted mechanism. 

With some 1,3-dipoles, two possible stereoisomers can be formed by syn additions differing in the relative orientation of the reacting molecules. For example, when diazoalkanes add to unsymmetrical alkenes, mixtures of diastereomers are obtained. ° This is comparable to the competing endo and exo stereoselectivities which characterize Diels-Alder cycloadditions. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) 1996CHEC-II(6)1 . This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

As an extension of intermolecular reactions described earlier, some intramolecular lEDDA reactions of electron-deficient pyridazines with alkyne dienophiles have been presented 1998MOL10, 2001TL7929 . 

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. 

Cycloaddition reactions also have important applications for acyclic chalcogen-nitrogen species. Extensive studies have been carried out on the cycloaddition chemistry of [NSa] which, unlike [NOa] , undergoes quantitative, cycloaddition reactions with unsaturated molecules such as alkenes, alkynes and nitriles (Section 5.3.2). ° The frontier orbital interactions involved in the cycloaddition of [NSa] and alkynes are illustrated in Fig. 4.13. The HOMO ( Tn) and LUMO ( r ) of the sulfur-nitrogen species are of the correct symmetry to interact with the LUMO (tt ) and HOMO (tt) of a typical alkyne, respectively. Although both 

Non-stereospecific photochemical [2+2]-cycloadditions occur in the dimerization of phenyl cyclohexene 23 in the presence of a sensitizer to produce 24 and 25 [17], and in reactions of Z/E-2 butene with cyclohexenone 26 to give 27 and 28 [18] through the formation of intermediate diradicals. The photoaddition of cyclohexene to an enolised form of 1,3 diketone 29 gives 30 in a concerted process via the formation of an unstable cycloadduct [18]. 

The Diels-Alder reactions and 1,3-dipolar cycloaddition reactions are known as [4 +2]-cycloaddition reactions because four electrons from diene or 1,3-dipole, and two electrons from the dienophile or dipolarophile are involved in these reactions. The 1,3-dipolar cycloaddition reactions are also called [3H-2]-cycloaddition 

In the presence of a catalyst consisting of Ni(C104)2-6H20 and the chiral binaphthyldiimine (BDSflM) ligand 141, the first chiral Lewis acid-catalyzed dipole-HOMO/dipolarophile-LUMO-controlled asymmetric 1,3-DC reactions of azomethine imines 138 and 3-acryloyl-2-oxazolidinone 139 were achieved by Suga and 

Carmona and coworkers applied their rhodium catalysts 153 in 1,3-DC of 3,4-dihydroisoquinoline M-oxide 150 and methacrylonitrile 151. The existence of two isomeric catalyst-substrate complex, (5rj, and / c)-L, arising 

The higher order cycloaddition represents a highly valuable strategy for the preparation of medium-sized ring systems. In the construction of five-membered rings, [3 -I- 2] reactions have been widely applied. However, as a direct method to construct 7,5-fused heterocyclic compounds, the asymmetric [8 -I- 2] cycloaddition was less studied. Feng and coworkers developed the first catalytic asymmetric [8 -I- 2] 

The poly-Diels-Alder-adduct 19 of 1,4-benzoquinone and 1,2,4,5-tetra-methylenecyclohexane has only very limited solubility, for example in hexa-fluroisopropanol, that results from high crystallinity of the linear cycloaddition product which consists exclusively of double-stranded linked six-membered rings [37]. 

Stoddard and co-workers [45-47] describe the synthesis of cyclic and linear ribbon-type oligomers starting from the monomers 21 [39] and 23 [42]. The double stranded macrocycles, e.g. 27, generated are intermediates in the preparation of cyclic oligoarenes (cycloacenes) - attractive compounds with two dimensional cyclic J7-systems of the Huckel-type. Synthetic approaches to remove the oxo-bridges reductively and to generate the final fully unsaturated hydrocarbons, lead only to intermediates, e.g. 28, which are partially hydrogenated [46]. 

An improved solubility of the Diels-Alder-adduct 32 can be achieved by the introduction of solubilizing alkyl sub-units into the 9- and 10-positions of the anthracene-bisdienophile used (23, R -alkyl). High molecular weight products (32), consisting of up to 120 six-membered rings, have been observed [2]. 

A spiro-type ladder polymer is produced when l,4,5,8-tetrahydro-l,4,5,8-diepoxyanthracene (23), as the bisdienophile component, is reacted with the bicyclic silaspirodiene 33 [111]. The products formed (34) in the repetitive cycloaddition (under high pressure conditions) possess number average molecular weights of up to 11000 (Dp = 13). Polymers 34 are promising candidates for 

The Diels-Alder-route to ladder polymers is clearly a powerful method for the formation of the primary cycloaddition products. The key problem, however, is the polymer-analogous transformation of the primary macromolecules. 

3-relationship. It is this structural feature that leads to the name 1,3-dipolar cycloadditions for this class of reactions.77 78 The other reactant in a dipolar cycloaddition, usually an alkene or alkyne, is referred to as the dipolarophile. Other multiply bonded functional groups such as imine, azo, and nitroso groups can also act as dipolarophiles. The transition states for 1,3-dipolar cycloadditions involve four n electrons from the 1,3-dipole and two from the dipolarophile. As in the Diels-Alder reaction, the reactants approach one another in parallel planes. 

Mechanistic studies have shown that the transition state for 1,3-dipolar cycloaddition is not very polar. The rate of reaction is not strongly sensitive to solvent polarity. In most 

Nitrile ylide Nitrile imine Nitrile oxide Azomethine ylide Nitrone 

The alternating electronic properties of the Co, and Cp atoms in the vinylidene ligand enable dipolar molecules to enter into cycloaddition reactions. Intramolecular [2 + 2]- 

The role of sulfur functionalities in such processes has received much attention in the recent general literature [482-484] as well as in a number of reviews (inter alia [120, 485]). The tt bond of a thiocarbonyl group can be directly involved in (2 + 2), (3 + 2) and (4 + 2) cycloadditions (see [120] and references therein). 

In view of their very high reactivity with 1,3-dipoles, thiocarbonyl compounds were designated as supcrdipolarophiles [517]. Adducts were obtained with a large variety of dipoles and led to useful synthetic transformations. A few examples are given here (see [120] for references). 

Cycloreversion of adducts with nitrile oxides provides one of the most convenient routes from thiocarbonyl to carbonyl compounds. 

Nitronate esters have been used for the same purpose of C=S to C=0 conversion, and the procedure was notably applied in a (+)-methynolide total synthesis [518], 

The cleavage of adducts from thiocarbonyl compounds with azides or nitrile imines yielded imines. 

The copper-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes (click chemistry) has been the subject of intense research due to wide functional group tolerance, operational ease, and clean formation of the 1,2,3-triazoles. These reactions are particularly amenable to microwave heating, and a host of new compounds and materials have been created using this methodology. -  

If the substrate contains both azide and alkyne functional groups, intramolecular and intermolecular cycloaddition reactions are possible. While the former 

Cycloadditions are useful for the preparation of cyclic ompounds. Several thermal and photoactivated cycloadditions, typically [4+2] (Diels-Alder reaction), are known. They proceed with functionalized electronically activated dienes and monenes. However, various cycloaddition reactions of alkenes and alkynes without their electronical activation, either mediated or catalysed by transition metal complexes under milder conditions, are known, offering a useful synthetic route to various cyclic compounds in one step. Transition metal complexes are regarded as templates and the reactions proceed with or without forming metallacycles [49]. 

These metallacycles are converted further to various acyclic and cyclic products. Trapping of the metalacycles with X—Y affords acyclic compounds 97. Cyclic 

The [2 + 2] photodimerization is a well-known photochemical reaction, for which many examples have been reported, in particular for arylalkenes and a, 3-unsatu-rated carbonyl or carboxyl derivatives. In solution, EjZ isomerization competes with the bimolecular reaction in the solid state, on the other hand, cycloaddition may be quite effective, as has long been known.Relations between the arrangement of the molecules in the crystal lattice and the reaction occurring have 

Only a moderate excess of allyl alcohol is required (ca. 1.5 equiv.) and the reaction is complete within 2 h with the concomitant formation of a lactone moiety in a stereoselective fashion. 

Another synthetically important photochemical reaction is the Paterno-Buchi reaction, i.e., the photocycloaddition of ketones and aldehydes to olefins. This is a milestone in organic photochemistry and involves attack of the n,ji triplet of the carbonyl compounds to an alkene in the ground state, mostly in the triplet multiplicity, although reactions via the singlet are well known. With nucleophilic olefins, the reaction occurs through the initial formation of a CO bond, in the opposite case, formation of a C-C bond occurs first. The use 

Maringgele, in The Chemistry of Inorganic Homo- and Heterocycles, ed. I. Haidue and D. B. Sowerby, Vol. 1, Academie Press, London, 1987, pp. 17-101. 

Gilchrist, Heterocyclic Chemistry, Pitman Publishing, London, 1985, pp. 79-100. 

Inorganic Rings and Polymers of the p-Block Elements From Fundamentals to Applications 

Electron diffraction experiments provide valuable information about structures in the gas phase. Consequently, this method of structural determination is important for inorganic ring systems that are volatile liquids or gases at room temperature. For example, the essentially planar structures of borazine (3.1, E = NH) and the isoelectronic boroxin ring (3.1, E = 0), ° the monomeric structure of the radical [CFgCNSSN] (3.2), and the all-cw arrangement of the 

Photodimerization involves 1 1 adduct formation between an excited nd a ground state molecule. Olefinic compounds, aromatic hydrocarbons, conjugated dienes, oc-unsaturated compounds are known to dimerize when Cxpdsed to suitable radiation. Photodimerization of olefinic compounds Can occur by either (a) 1,2-1,2 addition, (b) 1,2-1,4 addition or 

It is a 1, 4-1, 4 addition reaction forming dianthracene as the single product 

The reaction proceeds from the Sj (ic, rc ) state. The reaction is not quenched by oxygen. 9-substituted anthracenes can be dimerized but 9, 10 compounds do not dimerize because of steric hindrance (Table, 6.3). 

In polyenes, dimerization occurs from the triplet states. The direct and photosensitized reactions are likely to give different products because 

But for molecules whose triplet energy lies between 226 kJ and 251 kJ compound (3) is formed in large amounts. Et of cis-butadiene is 226 kJ. This suggests that since rotation around the central bond in the excited state is a slow process it will not effectively compete with dimerization. 

Schulich Faculty of Chemistry, Technion—Israel Institute of Technology, Haifa, Israel 

Silver in Organic Chemistry Edited by Michael Harmata Copyright 2010 John Wiley Sons, Inc. 

In the 2001 book Cycloaddition Reactions in Organic Synthesis, the use of silver salts as mediators or catalysts was conspicuous only by its absence. The catalytic effects of silver were briefly mentioned in the chapter on [3 + 2] cycloadditions. It is refreshing that in 7 years the field has progressed so far as to warrant a number of reviews, each covering various aspects of silver-mediated synthesis.2 5 This chapter seeks to afford the reader with a comprehensive survey of the field from its inception to the end of 2008. 

Masamune reported that reaction of 10 with AgC104 in the presence of 3 equiv of maleic anhydride resulted in CO evolution and formation of cycloadduct 11 in 85% 

3- dimethylcyclobutadiene. In support of this hypothesis, in situ generation of free 

Build a model of Dewar benzene. Then replace the connector for the bond that is part of both rings with two separate connectors. Do a conrotation and a disrotation to see the strain that is incurred in each process. Also build a model of 1,2,4-tri-t-butylben-zene and the Dewar benzene formed from it and examine the steric strain that is present in each compound. 

Explain why the following Dewar benzene is not produced in the photochemical reaction of 1,2,4-tri-t-butylbenzene  

A cycloaddition reaction most commonly involves two molecules reacting to form two new sigma bonds between the end atoms of their pi systems, resulting in the formation of a ring. The product has two more sigma bonds and two fewer pi bonds than the reactants. The reactions are classified according to the number of pi electrons in each of the reactants. Thus, the reaction of two alkenes to form a cyclobutane derivative is termed a [2 + 2] cycloaddition reaction, and the reaction of a diene with an alkene to form a cyclohexene derivative is termed a [4 + 2] cycloaddition reaction  

Cycloaddition reactions can be viewed as involving the flow of electrons from the HOMO of one reactant to the LUMO of the other. Therefore, examination of the interaction of these MOs is used to determine whether the reaction is favorable. For a cycloaddition to be allowed, the overlap of the orbitals of the HOMO of one component and the LUMO of the other must be bonding where the new sigma bonds are to be formed. Some examples will help make the application of this rule clear. 

Let s consider first the thermal [2 + 2] cycloaddition. The overlaps between the HOMO of one component (it) and the LUMO of the other (u ) are as follows  

For more practical reasons, concentrated acetone or EtgO solutions of LiNTfg (2.5-4.0 m) is used as a similar medium. Under identical conditions (room temperature, 1 h), comparable results were obtained for 4.0 m LiNTfg-acetone and 5.0 m LPDE. Of interest is that the reaction of 2-azadiene 52 with N-methylmaleimide or MA in 2.5 M LiNTfa-EtgO gave rise to preferential or predominant exo selectivity. The 

A clearly apparent disadvantage of such reaction media is the environmental problem associated with disposal of excess catalyst and the possibility of perchlorate explosions. To address these problems, Reetz and co-workers utilized a catalytic amount of LiC104 (ca 7-30 mol %) suspended in CH2CI2. Nevertheless, the amount of acceleration is modest (22 °C, 18 h, 100 % conversion, endoiexo = 6.0) in the reaction of CP and MA (Sch. 25). This compares favorably with the result obtained by performing the reaction in 5.0 m LPDE (room temperature, 5 h, yield 93 %, endo exo = 8.0). In these catalytic versions it has also been suggested by the authors that the effect of internal pressure—compression of the reactants and confined solute movement—is not operating [72]. 

Another alternative, LiNTfa, was also employed as Lewis acid catalyst (1 mol %) in the Diels-Alder reaction of CP with MVK in CH2CI2. The rate enhancement was moderate compared with that obtained with the other alkali earth and lanthanide metal imides Mg(NTf2)2, La(NTf2)3.H20, and Zn(NTfa)2 (Sch. 25) [73]. 

A similar rate enhancing effect was observed for intramolecular Diels-Alder reactions using 5.0 M LPDE, which, after room temperature for 24 h, resulted in a poor (3 1) cis. trans ratio of the two diastereomers (Sch. 26) [74]. In contrast, the reaction was dramatically further accelerated by addition of ca 1.0 mol % of camphorsulfonic 

The product distribution in these intramolecular reactions using LPDE-CSA seems to depend not only on the substitution pattern of both the dienoic and dienophilic moieties in the starting materials but also on the relative capability of cyclization (Sch. 27). For example, the formation of 58 undoubtedly arises via competitive protonation of the terminal diene and subsequent loss of a proton leading to the migrated diene 57 which undergoes very facile cyclization compared with 56 (Sch. 28) [75]. Taking into consideration the use of Me2AlCl, which necessitates slow addition of the substrate, the LPDE-CSA medium seems more convenient. 

Unfortunately, no control experiments in DM SO with conventional heating and in with microwave activation were performed to enable unambiguous 

In contrast, reaction with dimethyl maleate (91) gave only the [4+2] product both by conventional heating and with microwave irradiation. Under the action of 

In 2013, the group discovered that the chiral NHC catalyst J2 was an efficient catalyst for the formal [3 -F 2] annulation of enals and 

Recently, the Glorius group developed the NHC-catalysed formal [3 -I- 2] annulation of enals with aza-aurones or aurone to provide valuable enantioenriched substituted spiro-heterocycles 64. Several different classes of enals proved suitable for the reaction, and the desired products were 

With this system two isomers can be formed 58 (endo) and 59 (exo). With the QUIPHOS ligand and copper catalysis, Buono and co-workers obtained very high endo/exo ratios and excellent conversion and enantioselectivity if the reagents were mixed at — 78 °C and slowly warmed to 25 °C. Imamoto and co-workers used the oxide, the 1-Ad-BisP ligand and iron catalysis at 0°C with modest results of diastereo- and enantioselectivity. Other BisP and MiniPHOS ligands led to inferior results. 

The cycloisomerisation of the ene-diene 60 produced the bicyclic product 61 with excellent diastereo- and enantioselectivity. 

Buono and co-workers showed that palladium(II) complexes of secondary phosphine oxide 63 catalyse the 2-1-1 cycloaddition between norbornadiene and phenylacetylene, affording benzylidienecyclopropane (62). This compound shows what is called cis-trans enantiomerism, also called geometrical enan-tiomorphic isomerism. Using optically pure 63, moderate enantioselectivity was found. 

Zheng and co-workers employed the ferrocenylphosphine-phosphor-amidite 66 in the Ag-catalysed enantioselective 3-1-2 cycloaddition of 64 with dimethyl maleate. Very good yields and impressive enantioselectivities were found. 

Racemic dienophiles and 1,3-dienes have been resolved in [44-2] cycdoadditions where one of the reacting species is chiral and enantiopure. 

Winterfeldt [57] resolved some butenolides such as 53 or cycloalk-2-enones 54 and 55 by a Diels-Alder process, with 56 as a chiral diene. In order to perform the reactions under mild conditions, Lewis-acid catalysis (ZnCl2) and high pressure were used at room temperature. 

Reaction of the chiral diene 56 with 53b afforded a single cycloadduct 57, in a totally endo-, regio- and stereoselective way. 

A thermal retro Diels-Alder reaction dehvered the (S)-isopropylbutenolide 53b. Only one cycloadduct was also obtained from 4-methyIcyclohexenone 54. The desired (S) enantiomer of 55 could not be obtained properly through lipase-catalysed hydrolysis of racemic 55. The totally selective Diels-Alder reaction with 56 proceeded with the preferential reaction of (R)-55 which was the enantiomer predicted to react from a consideration of the mechanism. As the stereochemical result of the cycloaddition is completely predictable, it could help for the configurational assignment of further dienophiles. 

KR of racemic semicyclic 1,3-dienes was observed in their Diels-Alder reaction with enantiomerically pure (S)-(2-p-tolylsulfinyl)-l,4-naphthoquinone (4-)-58 [58]. As an example, [4-t-2] cycloaddition of (+)-58 with ( )-59 (1 equiv) afforded (3-)-anti-60 as the sole stereoisomer, showing 94% ee. The recovered unreacted diene (S)-59 showed 50% ee. The initial cycloaddition thus occurred in a highly endo and jt-facial diastereoselective manner with an efficient resolution of the diene partner. 

Predict the product of cycloaddilion of ethylene and cis-2-butene, addition being suprafacial on both the component. Is the reaction symmetry-allowed under thermal or photochemical condition  

Draw correlation diagram for the cycloaddition of two ethylene molecules. 

Suggest structure of anticipated products of the reaction of isotetralin with dimethyl acetylene dicarboxylate. 

Classify the following reaction and predict whether reaction is thermally or photochemically allowed  

Cycloaddition of two molecules of cis-2-butene may produce different stereoisomers. Write the structures of (i) supra-supra (ii) supra-antara and (iii) antara-antara products alongwith reaction conditions. 

MgCl2(10mol%) EtsN (2 equiv) TMSCI(1.5 equiv) 

---

ACIEE 1984, 23,876 ACJEE 1977, 16, 10 Organic Reactions 1984, 32, 1 W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990... 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

Sulfonium ylides may be added to C N double bonds to yield aziridines in a formal [1 -t-2]-cycloaddition. Alkyl azides are decomposed upon heating or irradiating to yield ni-trenes, which may also undergo [ 1 + 2 -cycloaddition reactions to yield highly strained hetero-cycles (A.G. Hortmann, 1972). 

Ulrich, H. (ed.) 1967, Cycloaddition Reactions of Heterocumulenes, Academic Press New York - London... 

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

Synthetic Elaboration of Indole Derivatives using Cycloaddition Reactions... 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

Acylisocyanates or isothiocyanates undergo cycloaddition with 5-hydroxy-THISs under so mild conditions that isolation of the initial adducts becomes possible (23). In cycloaddition reactions the 5-hydroxy-THISs can be replaced by their precursors (23). 

In contrast to oxazole, thiazole does not undergo the Diels-Alder cycloaddition reaction (331). This behavior can be correlated with the more dienic character of oxazole, relative to thiazole, as shown by quantochemical calculations (184). 

The alkene that adds to the diene is called the dienophile Because the Diels-Alder reaction leads to the formation of a ring it is termed a cycloaddition reaction The prod uct contains a cyclohexene ring as a structural unit... 

Contrast the Diels-Alder reaction with a cycloaddition reaction that looks superfl cially similar the combination of two ethylene molecules to give cyclobutane... 

Refer to the molecular orbital diagrams of allyl cation (Figure 10 13) and those presented earlier in this chapter for ethylene and 1 3 butadiene (Figures 10 9 and 10 10) to decide which of the following cycloaddition reactions are allowed and which are forbidden according to the Woodward-Floffmann rules... 

Isocyanates are Hquids or soHds which are highly reactive and undergo addition reactions across the C=N double bond of the NCO group. Reactions with alcohols, carboxyUc acids, and amines have been widely exploited ia developiag a variety of commercial products. Cycloaddition reactions involving both the C=N and the C=0 double bond of the NCO group have been extensively studied and used for product development (1 9). 

The dimeri2ation and trimeri2ation of isocyanates are special cases of the cycloaddition reaction ia that they iavolve reageats of the same type. The uacataly2ed carbodiiaiidi2atioa of isocyanates likely iavolves a labile 2 + 2 cycloadduct (12) which Hberates carboa dioxide. 

The reaction of dihalocarbenes with isoprene yields exclusively the 1,2- (or 3,4-) addition product, eg, dichlorocarbene CI2C and isoprene react to give l,l-dichloro-2-methyl-2-vinylcyclopropane (63). The evidence for the presence of any 1,4 or much 3,4 addition is inconclusive (64). The cycloaddition reaction of l,l-dichloro-2,2-difluoroethylene to isoprene yields 1,2- and 3,4-cycloaddition products in a ratio of 5.4 1 (65). The main product is l,l-dichloro-2,2-difluoro-3-isopropenylcyclobutane, and the side product is l,l-dichloro-2,2-difluoro-3-methyl-3-vinylcyclobutane. When the dichlorocarbene is generated from CHCl plus aqueous base with a tertiary amine as a phase-transfer catalyst, the addition has a high selectivity that increases (for a series of diolefins) with a decrease in activity (66) (see Catalysis, phase-TRANSFEr). For isoprene, both mono-(l,2-) and diadducts (1,2- and 3,4-) could be obtained in various ratios depending on which amine is used. 

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). 

A shippable but somewhat less reactive form of diketene is its acetone adduct, 2,2,6-trimethyl-4JT-l,3-dioxin-4-one (15) (103,104). Thermolysis of this safer to handle compound provides acetylketene, a reactive intermediate that can be used for acetoacetylation and cycloaddition reactions. The diketene—acetone adduct as weH as / fZ-butylaceto acetate [1694-31 -1] (also used for aceto acetylations by the trans aceto acetylation reaction) (130), are offered commercially. 

H. Ulrich, Cycloaddition Reactions ofHeterocumu/enes, Academic Press, Inc., New York, 1967, pp. 89—94. 

The success of the cycloaddition reaction of maleic anhydride varies gready depending on which heterocyclic diene is used. The cycloaddition of maleic anhydride to furan [110-00-9] occurs ia a few seconds under ambient conditions (42,43). Although the endo adduct (14) is favored kiaeticaHy, the exo adduct (13) is isolated. 

Cycloaddition Reactions. Methacrylates have been widely used as dienophiles in Diels-Alder reactions (22—24). 

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Methacrylates have also found use in diastereoselective -ene reactions. Although not a cycloaddition reaction, this reaction is mechanistically related to the Diels-Alder reaction (37). 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

Polymerization by Gycloaddition. Bisimides and oligoimides capped with reactive unsaturations such as maleimide, acetylene, and xylylene groups, can be chain-extended by a cycloaddition reaction with proper bisdienes. 

The quiaones have excellent redox properties and are thus important oxidants ia laboratory and biological synthons. The presence of an extensive array of conjugated systems, especially the a,P-unsaturated ketone arrangement, allows the quiaones to participate ia a variety of reactioas. Characteristics of quiaoae reactioas iaclude nucleophilic substitutioa electrophilic, radical, and cycloaddition reactions photochemistry and normal and unusual carbonyl chemistry. 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Although the most general cycloaddition reaction of diazo compounds is that they react as 1,3-dipoles, recently some reactions have been reported in which they react as 1,2-dipoles,... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

Furan has the greater reactivity in cycloaddition reactions compared with pyrrole and thiophene the latter is the least reactive diene. However, A -substituted pyrroles show enhanced dienic character compared with the parent heterocycle. 

Thiophene fails to undergo cycloaddition reactions with common dienophiles under normal conditions. However, when thiophene is heated under pressure with maleic anhydride, the exo adduct (136) is formed in moderate yield (78JOC1471). 

---