Pericyclic reactions 1 cycloadditions

Making six-membered rings by the Diels-Alder reaction 

Making five-membered rings by 1,3-dipolar cycloaddition 

Most organic reactions are ionic. Electrons move from an electron-rich atom towards an electron-poor atom anions or cations are intermediates. Formation of a cyclic ester (a lactone) is an example. The reaction involves five steps and four intermediates. The reaction is acid-catalysed and each intermediate is a cation. Electrons flow in one direction in each step— towards the positive charge. This is an ionic reaction. 

This chapter is about a totally different reaction type. Electrons move round a circle and there are no positive or negative charges on any intermediates—indeed, there are no inter- 

Otto Diels (1876-1954) and his research student Kurt Alder (1902-58) worked at the University of Kiel and discovered this reaction in 1928. They won the Nobel Prize in 1950. Diels also discovered carbon suboxide, C2O3 (see p. 420). 

---

J. Jurczak, T. Bauer, C. Chapuis, D. Craig, M. Cinquini, F. Cozzi, W. Sander, P. Binger, D. Fox, B. B. Snider, J. Mattay, R. Conrads, H.-U. ReiBig, Formation of C-C Bonds by Pericyclic Reactions—Cycloadditions, in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21c, 2735, Georg Thieme Verlag, Stuttgart, 1995. 

There are four major classes of pericyclic reactions cycloaddition, electrocyclic, sigmatropic and ene reactions. All these reactions are potentially reversible. A general illustration of each class is given below. 

Pericyclic reactions have cyclic transition states and electron flow paths that appear to go around in a loop. There are three main types of pericyclic reactions cycloaddition... 

The Alder ene reaction is like a Diels Alder reaction in which one Jt-bond in the diene has been replaced by a C-H bond 121. It does not therefore form a ring and does not fit easily into any of the three classes of pericyclic reaction (cycloaddition, electrocyclic, and sigmatropic). Since a hydrogen atom is transferred from one component to the other it is best described as a group transfer reaction.21 The regioselectivity is determined by the interaction 123 with the Jt-bond of the ene (the HOMO) with the LUMO of the enophile. ... 

Pericyclic reactions Cycloadditions are found in spiropyrans, spirooxazines, chromenes, hexa-1, 3, 5-triene, diheteroarylethenes, cyclohexa-1, 3-diene, and spirodihydroindolizines systems... 

Among the numerous reactions that have been developed to date, a certain class, namely the pericyclic reactions, especially stands out for several reasons. Originally termed no-mechanism reactions, these transformations have occupied one of the most prominent positions in organic synthesis. Beside ionic and radical reactions, they constitute the third distinct class of reaction mechanisms. In all kinds of pericyclic reactions - cycloadditions, sigma tropic rearrangements, electrocyclizations, and ene reactions - one can observe cyclic transition states. No intermediates are formed, and all bond-forming and bond-breaking processes take place in concert [1]. 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van... 

The Diels-Alder cycloaddition is one exanple of a pericyclic reaction, which is a one-step reaction that proceeds through a cyclic transition state. Bond formation occurs at both ends of the diene system, and the Diels-Alder transition state involves a cyclic ariay of six carbons and six tt electrons. The diene must adopt the 5-cis conformation in the transition state. 

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 mechanism of the Diels-Alder cycloaddition is different from that of other reactions we ve studied because it is neither polar nor radical. Rather, the Diels-Alder reaction is a pericyclic process. Pericyclic reactions, which we ll discuss in more detail in Chapter 30, take place in a single step by a cyclic redistribution of bonding electrons. The two reactants simply join together through a cyclic transition state in which the two new carbon-carbon bonds form at the same time. 

A pericyclic reaction is one that takes place in a single step through a cyclic transition state without intermediates. There are three major classes of peri-cyclic processes electrocyclic reactions, cycloaddition reactions, and sigmatropic rearrangements. The stereochemistry of these reactions is controlled by the symmetry of the orbitals involved in bond reorganization. 

The polyene character of 1 /7-azcpines makes them susceptible not only to a variety of electro-cyclic reactions, but also to cycloaddition with a variety of dienophiles, and to dimerization by [6 + 4] 7i-pericyclic reactions. 

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-... 

Keywords Diels-Alder reactions, dipolar cycloadditions, electrocyclic reactions, ene reactions, pericyclic reactions, sigmatropic rearrangements... 

The rule may then be stated A thermal pericyclic reaction involving a Hiickel system is allowed only if the total number of electrons is 4n + 2. A thermal pericyclic reaction involving a Mobius system is allowed only if the total number of electrons is 4n. For photochemical reactions these rules are reversed. Since both the 2 + 4 and 2 + 2 cycloadditions are Hiickel systems, the Mdbius-Hiickel method predicts that the 2 + 4 reaction, with 6 electrons, is thermally allowed, but the 2 + 2 reaction is not. One the other hand, the 2 + 2 reaction is allowed photochemically, while the 2 + 4 reaction is forbidden. 

Chapter 6 looks at concerted pericyclic reactions, including the Diels-Alder reaction, 1,3-dipolar cycloaddition, [3,3]- and [2,3]-sigmatropic rearrangements, and thermal elimination reactions. The carbon-carbon bond-forming reactions are emphasized and the stereoselectivity of the reactions is discussed in detail. 

The thermo- and photocycloaddition of alkenes will be discussed in Chapter 12, on pericyclic reactions. On the other hand, transition-metals have effectively catalyzed some synthetically useful cycloaddition reactions in water. For example, Lubineau and co-worker reported a [4 + 3] cycloaddition by reacting a,a-dibromo ketones with furan or cyclopen-tadiene mediated by iron or copper, or a-chloro ketones in the presence of triethylamine (Eq. 3.48).185... 

As pericyclic reactions are largely unaffected by polar reagents, solvent changes, radical initiators, etc., the only means of influencing them is thermally or photochemically. It is a significant feature of pericyclic reactions that these two influences often effect markedly different results, either in terms of whether a reaction can be induced to proceed readily (or at all), or in terms of the stereochemical course that it then follows. Thus the Diels-Alder reaction (cf. above), an example of a cycloaddition process, can normally be induced thermally but not photochemically, while the cycloaddition of two molecules of alkene, e.g. (4) to form a cyclobutane (5),... 

The combination of pericyclic transformations as cycloadditions, sigmatropic rearrangements, electrocydic reactions and ene reactions with each other, and also with non-pericyclic transformations, allows a very rapid increase in the complexity of products. As most of the pericyclic reactions run quite well under neutral or mild Lewis acid acidic conditions, many different set-ups are possible. The majority of the published pericyclic domino reactions deals with two successive cycloadditions, mostly as [4+2]/[4+2] combinations, but there are also [2+2], [2+5], [4+3] (Nazarov), [5+2], and [6+2] cycloadditions. Although there are many examples of the combination of hetero-Diels-Alder reactions with 1,3-dipolar cycloadditions (see Section 4.1), no examples could be found of a domino all-carbon-[4+2]/[3+2] cycloaddition. Co-catalyzed [2+2+2] cycloadditions will be discussed in Chapter 6. 

In this section are described those domino reactions which start with a retro-pericy-clic reaction. This may be a retro-Diels-Alder reaction, a retro-l,3-dipolar cycloaddition, or a retro-ene reaction, which is then usually followed by a pericyclic reaction as the second step. However, a combination is also possible with another type of transformation as, for example, an aldol reaction. 

---