Stepwise reactions cycloadditions, thermal

In contrast to the [4 + 2] cycloaddition, thermal [2 + 2] cycloadditions seldom are observed, and when they are observed, they are not stereospecific and evidently are stepwise reactions (see Section 21-11) ... 

Since stepwise reactions are not subject to the rules of pericyclic reactions, they are often invoked to explain how reactions in which the rules have been subverted take place. However, there is a small group of thermal [2+2] cycloadditions that seem to be disobeying the rules, and yet may well be pericyclic. One is the reaction of ketenes with electron-rich alkenes, illustrated by the reaction of diphenylketene 2.167 with ethyl vinyl ether 2.166 giving the cyclobutanone 2.168. Another is a group of electrophile-... 

Now are there such reactions as [2 + 2] cycloadditions Can, say, two molecules of ethylene combine to form cyclobutane The answer is yes, but not easily under thermal conditions. Under vigorous conditions cycloaddition may occur, but step-wise—via diradicals—and not in a concerted fashion. Photochemical [2 + 2] cycloadditions, on the other hand, are very common. (Although some of these, too, may be stepwise reactions, many are clearly concerted.)... 

While photocycloadditions are typically not concerted, pericyclic processes, our analysis of the thermal [2+2] reaction from Chapter 15 is instructive. Recall that suprafacial-suprafacial [2+2] cycloaddition reactions are thermally forbidden. Such reactions typically lead to an avoided crossing in the state correlation diagram, and that presents a perfect situation for funnel formation. This can be seen in Figure 16.17, where a portion of Figure 15.4 is reproduced using the symmetry and state definitions explained in detail in Section 15.2.2. The barrier to the thermal process is substantial, but the first excited state has a surface that comes close to the thermal barrier. At this point a funnel will form allowing the photochemical process to proceed. It is for this reason that reactions that are thermally forbidden are often efficient photochemical processes. It is debatable, however, whether to consider the [2+2] photochemical reactions orbital symmetry "allowed". Rather, the thermal forbiddenness tends to produce energy surface features that are conducive to efficient photochemical processes. As we will see below, even systems that could react via a photochemically "allowed" concerted pathway, often choose a stepwise mechanism instead. 

The synthetic potential of such transformations for the preparation of medium-size heterocycles172 has been discussed elsewhere2. It is generally accepted that the reaction between thiirene dioxides and enamines is a stepwise (nonconcerted) thermal [2 -I- 2] cycloaddition. However, a concerted [4 + 2] cycloaddition, in which the lone pair of the enamine nitrogen atom participates, cannot be excluded. 

Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cycloadditions have to be antarafacial on one component and the geometrical and orbital constraints thus imposed ensure that this process is encountered only in special circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise pathway involving diradical or zwitterionic intermediates [la]. Considerably fewer studies have been performed regarding the application of microwave irradiation in [2+2] cydoadditions than for other kinds of cydoaddition (vide supra). Such reactions have been commonly used to obtain /1-lactam derivatives by cycloaddition of ketenes with imines [18-20,117,118],... 

Diazo compounds generally do not undergo [3 + 2] cycloaddition with unactivated nitriles under purely thermal, noncatalyzed conditions. The formation of 4-R-5-trimethylsilyl-l//-l,2,3-triazoles from the reaction of diazo(trimethylsilyl)-methyl lithium and a broad range of nitriles [RCN R = alkyl, aryl, SEt, OPh, PO(OEt)2] appears to be an exception, but this reaction most likely occurs in a stepwise manner with initial nucleophilic attack at the nitrile (275). 

The reaction of a-diazocarbonyl compounds with nitriles produces 1,3-oxazoles under thermal (362,363) and photochemical (363) conditions. Catalysis by Lewis acids (364,365), or copper salts (366), and rhodium complexes (367) is usually much more effective. This latter transformation can be regarded as a formal [3 + 2] cycloaddition of the ketocarbene dipole across the C=N bond. More than likely, the reaction occurs in a stepwise manner. A nitrilium ylide (319) (Scheme 8.79) that undergoes 1,5-cyclization to form the 1,3-oxazole ring has been proposed as the key intermediate. 

This method is by far the most successful and most widely used in the synthesis of four-membered heterocycles with two heteroatoms. In principle these formal additions can be envisioned to occur by (a) two displacements, (b) thermal concerted [2 + 2] cycloadditions, (c) photoinduced [2 + 2] additions, (d) stepwise zwitterionic intermediates or dipolar reactants, and (e) radical intermediates. In some cases the mechanisms have been elucidated but in many others the actual mode of addition is not known. For this reason, no attempt has been made to formally divide the latter four (b-e) into categories and only the first [(a), two displacement reactions] is covered separately. 

Unlike thermal [2 + 2] cycloadditions which normally do not proceed readily unless certain structural features are present (see Section 1.3.1.1.), metal-catalyzed [2 + 2] cycloadditions should be allowed according to orbital symmetry conservation rules. There is now evidence that most metal-catalyzed [2 + 2] cycloadditions proceed stepwise via metallacycloalkanes as intermediates and both their formation and transformation are believed to occur by concerted processes. In many instances such reactions occur with high regioselectivity. Another mode for [2 + 2] cyclodimerization and cycloadditions involves radical cation intermediates (hole-catalyzed) obtained from oxidation of alkcnes by strong electron acceptors such as triarylammini-um radical cation salts.1 These reactions are similar to photochemical electron transfer (PET) initiated [2 + 2] cyclodimerization and cycloadditions in which an electron acceptor is used in the irradiation process.2 Because of the reversibility of these processes there is very little stereoselectivity observed in the cyclobutanes formed. 

The highly strained double bond in methylenecyclopropane displays enhanced reactivity in cycloaddition reactions. In addition to normal [4+2] cycloaddition to 1,3-dienes (e.g. equation 13)32, methylenecyclopropane and its derivatives have a pronounced tendency to undergo thermal [2+2] cycloaddition reactions. For example, thermal dimerization of methylenecyclopropane in the gas phase results in formation of isomeric dispirooctanes 16 and 17 (equation 14)33. This unusual cyclization is considered to proceed via a stepwise radical mechanism involving the intermediacy of biradical 18 (equation 15)34. Equation 15 demonstrates that methylenecyclopropanes possessing substituents capable of stabilizing intermediate radicals undergo efficient [2+2] dimerization even... 

We have not given you much evidence to decide why it is that some thermal [2 + 2] cycloadditions occur but not others. What is special about fluoroalkenes, allenes, and ketenes in these reactions One possibility is that Mobius rather than the Hiickel transition states are involved, but the Mobius transition states are expected to suffer from steric hindrance (Section 21-10B). It is also possible that [2 + 2] cycloadditions, unlike the Diels-Alder additions, proceed by stepwise mechanisms. This possibility is strongly supported by the fact that these reactions generally are not stereospecific. Thus with tetrafluoroethene and trans,trans-2,5-bexadiene two products are formed, which differ in that the 1-propenyl group is trans to the methyl group in one adduct, 45, and cis in the other, 46 ... 

In the thermal reaction the [4 + 2] or Diels-Alder adduct is the major product, whereas in the photochemical reaction [2 + 2] cycloadditions dominate. Because the photochemical additions are sensitized by a ketone, C6H5-COCH3, these cycloadditions occur through the triplet state of 1,3-butadiene and, as a result, it is not surprising that these cycloadditions are stepwise, nonstereospecific, and involve diradical intermediates. 

The [2+2] cycloadditions can be concerted under thermal conditions provided that the interaction between the Ji-systems takes place in a supra-antara mode (Fig. 1). This [27is + 27+] mechanism [20] is sterically very demanding and, therefore, it should be facilitated by cumulenes possessing s/ -hybridized electrophilic carbon atoms. This makes ketenes and isocyanates suitable candidates for concerted symmetry-allowed thermal [2+2] cycloadditions. However, the presence of heteroatoms in both possible [2+2] reactions leads in turn to different stepwise mechanisms in which the electrophilic nature of the v/ -hybridized carbon atoms of ketenes and isocyanates plays a crucial role (Scheme 2). According to these mechanisms, zwitterionic intermediates (6) and (7) are plausible via formation of C-N or C-C bonds, respectively. 

As in the case of the reaction between ketenes and imines, the [2+2] cycloaddition between isocyanates and alkenes [106, 107] can take place via concerted and stepwise mechanisms. However, with the exception of highly nucleophilic alkenes (vide infra), concerted mechanisms were postulated, since isocyanates are suitable candidates to act as antarafacial partners in thermal [2+2] cycloadditions (Fig. 1). Aside from the [n2s + n2J mechanism, in principle [n2s + (A + A) [108] and [A + (A + A s)] [109] mechanisms can be envisaged (Fig. 5). 

Four-membered rings can be synthesised by [2 + 2] cycloadditions. However, thermal [2 + 2] cycloadditions occur only with difficulty they are not concerted but involve diradicals. Photochemical [2 + 2] reactions are common and although some of these may occur by a stepwise mechanism many are concerted. An example of a [2 + 2] reaction is the photodimerisation of cyclopent-2-enone. This compound, as the neat liquid, or in a variety of solvents, on irradiation with light of wavelength greater than 300 nm (the n - n excited state is involved) is converted to a mixture of the head-to-head (48) and head-to-tail (49) dimers, both having the cis,anti,cis stereochemistry as shown. It is believed that the reaction proceeds by attack of an n - n triplet excited species on a ground state molecule of the unsaturated ketone (Section 2.17.5, p. 106). In the reaction described (Expt 7.24) the cyclopent-2-enone is irradiated in methanol and the head-to-tail dimer further reacts with the solvent to form the di-acetal which conveniently crystallises from the reaction medium as the irradiation proceeds the other dimer (the minor product under these conditions) remains in solution. The di-acetal is converted to the diketone by treatment with the two-phase dilute hydrochloric acid-dichloromethane system. 

The cyclic /J-dicarbonyl iodonium ylides can undergo [3 + 2] cycloaddition reactions with various substrates under catalytic or photochemical conditions, presumably via a stepwise mechanism [153-156]. In a recent example, iodonium ylide 211, derived from dimedone, undergoes dirhodium(II) catalyzed thermal [3+ 2]-cycloaddition with acetylenes 212 to form the corresponding furans 213 (Scheme 75). Under photochemical conditions ylide 211 reacts with various alkenes 214 to form dihydrofuran derivatives 215 [156]. 

The formation of diazetidines by [2+2] cycloaddition can be achieved by a thermal or photoinduced reaction. The reaction may proceed stepwise, either by dipolar or radical intermediates. A large number of 1,2-diazetidine derivatives have been prepared by [2+2] cycloaddition of an alkene to an azo compound. A large number of syntheses involving these types of fragments have been complied by Richter and Ulrich <1983HC(42)443> and also by Timberlake and Elder <1984CHEC(7)449>. 

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