Intramolecular cycloadditions multiple bond reactions

Enyne metathesis is unique and interesting in synthetic organic chemistry. Since it is difficult to control intermolecular enyne metathesis, this reaction is used as intramolecular enyne metathesis. There are two types of enyne metathesis one is caused by [2+2] cycloaddition of a multiple bond and transition metal carbene complex, and the other is an oxidative cyclization reaction caused by low-valent transition metals. In these cases, the alkyli-dene part migrates from alkene to alkyne carbon. Thus, this reaction is called an alkylidene migration reaction or a skeletal reorganization reaction. Many cyclized products having a diene moiety were obtained using intramolecular enyne metathesis. Very recently, intermolecular enyne metathesis has been developed between alkyne and ethylene as novel diene synthesis. 

Apart from some special cases, the ring-closure step in the course of the synthetic pathway is often condensation reaction and, thus, these transformations can be considered as cyclocondensations . Reactions following a few other mechanisms like cycloaddition, electrocyclization, and intramolecular nucleophilic addition of electron pair of an atom to a multiple bond also occur relatively often. Because of the fairly large complexity of the ring systems belonging to this chapter, the treatment according to the heteroatomic combinations seemed the most straightforward. Thus, the fused... 

As discussed in Section 6.9 1, 3-dienes and dienophiles in which multiple bonds are not activated by electron-withdrawing or electron-releasing substituents fail to undergo cycloaddition except under the most severe conditions. Particular difficulty is encountered in the cycloaddition of two unactivated species since homodimerization can be a competitive and dominant reaction pathway. The use of transition-metal catalysts, however, has proved to be a valuable solution. Complexation of unactivated substrates to such catalysts promotes both inter- and intramolecular cycloadditions. Consequently, the cycloaddition of such unactivated compounds, that is, simple unsubstituted dienes and alkenes, catalyzed by transition metals is a major, important area of study.655 In addition, theoretical problems of the transformation have frequently been addressed in the more recent literature. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

The term intramolecular enyne metathesis describes two types of processes. One involves a [2+2] cycloaddition of a multiple bond and a transition-metal carbene complex and the other is an oxidative cyclization catalyzed by low-valent transition-metal complexes, for example, Pt, Pd and Ru. The latter reaction is also called a skeletal reorganization. Both processes lead to similar products (Eq. 84). 

The catalytic [2 + 2 + 1]-cycloaddition reaction of two carbon—carbon multiple bonds with carbon monoxide has become a general synthetic method for five-membered cyclic carbonyl compounds. In particular, the Pauson-Khand reaction has been widely investigated and established as a powerful tool to synthesize cyclopentenone derivatives.110 Various kinds of transition metals, such as cobalt, titanium, ruthenium, rhodium, and iridium, are used as a catalyst for the Pauson-Khand reaction. The intramolecular Pauson-Khand reaction of the allyl propargyl ether and amine 91 produces the bicyclic ketones 93, which bear a heterocyclic ring as shown in Scheme 31. The reaction proceeds through formation of the bicyclic metallacyclopentene intermediate 92, which subsequently undergoes insertion of CO to give 93. 

One of the two reaction types which dominate the synthetic utility of arynes as reactive intermediates is cycloaddition. Cycloadditions can be subdivided into several categories. For example, benzynes undergo [4+2] and [2+2] cycloadditions as well as 1,3-dipolar cycloadditions, the ene reaction, and miscellaneous others. These reactions may occur in an inter- or intramolecular mode. Further, multiple and tandem aryne reactions can be used for multiple-bond construction in a single step. Each of these reaction types, as well as a few miscellaneous reactions, is discussed in the following sections. 

The [3-1-2] cycloaddition is mostly catalyzed by Ni or Pd catalysts. The MCPs can have substituents on the olefin or cyclopropane, and the two-atom partners can be electron neutral or deficient alkenes, alkynes, and carbon-heteroatom multiple bonds. Since there are different reaction courses of MCP in cycloaddition, introducing substituents on either MCP or the two-atom reaction partners complicates the reaction even more, considering the associated selectivity issues. Consequently, cycloaddition with multi-substituted substrates often gives mixtures though sometimes good selectivity can be achieved by adjusting reaction conditions and substituents. The intramolecular version of [3-1-2] cycloaddition, mainly developed by Motherwell [81], Nakamura [82], Lautens [83], and Mascarenas [87-91], may address the issues of selectivity to some extent, and leads to polycyclic structure meanwhile. AU these have been summarized by several excellent reviews [1, 84—86] and herein we will only update the [3-1-2] cycloaddition of MCP for synthesis of carbocycles with some recent representative examples. 

The tandem cycloaddition of nitroalkenes is a very complex process consisting of a number of elementary reactions. Multiple bonds, stereogenic centers, and rings are created. The connection between the starting materials and the final product is often not obvious. To simplify the retrosynthetic analysis, summary charts (e.g.. Figure 16.8) for most of the modes of the tandem cycloaddition of nitroalkenes were provided. Illustrations of how these charts can be used for retrosynthetic analysis (e.g.. Scheme 16.54) were also provided. For the most complex modes, such as double intramolecular cycloadditions, a similar chart would be too complex and of limited utility because of the myriad of theoretically possible tether lengths and placements. Moreover, only a handful of variants have been realized in practice. 

The mechanism of the [3 + 2] cycloaddition is summarized in Scheme The first intermediate results from charge transfer interaction between the eli tronically excited aromatic compound at its singlet state S1 with the alkene w] leads to the formation of the exciplexes K. A more stable intermediate is generated by the formation of two C-C bonds, leading to the intermediates These intermediates have still singlet multiplicity and therefore possess zwii ionic mesomeric structures mainly of type M. In most cases and especially intramolecular reactions, chiral induction occurs during the formation of L. final products are then obtained by cyclopropane formation in the last step. 

Carbene reactions provide a versatile approach to the synthesis of five-membered nitrogen-containing rings. Of particular importance here are intramolecular insertion of a carbene into C — H and N — H bonds, addition onto multiple carbon-carbon bonds, intermediate formation of ylides as a result of carbene addition onto the heteroatom followed by rearrangement, cycloaddition, and cyclization. 

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-4, 6-dihydrofuro[3,4-b]-furan-3-carboxylates 146 and 147. The results give further evidence of the potential of intramolecular Diels-Alder based multiple processes [129], 2-Substituted furans and thiophenes 148 and 149, heated in the presence of 3,6-di(pyridin-2 -yl)-,y-tetrazine, underwent intramolecular and intermolecular cycloadditions. The cycloadducts underwent double cycloreversion reactions with the loss of a nitrogen and dipyridyldiazine as illustrated in Scheme 2.55. The electron-deficient dipyridyltetrazine reacts with the isolated, electron-rich olefinic bond rather than with the bond conjugated with the methylcarboxylate. 

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