Mechanism of 1,3-Dipolar Cycloadditions

Huisgen s general concept was not only fruitful for synthetic applications after 1960, but also for thorough evaluations of the mechanism of 1,3-dipolar cycloadditions, carried out simultaneously. Within three years, Huisgen came to quite remarkable conclusions (1963 a, b) with respect to stereochemistry and orbital control of these reactions they fitted very well to the principle of conservation of orbital symmetry (Hoffmann and Woodward, 1965). 

We will discuss this and subsequent mechanistic work on 1,3-dipolar cycloadditions in Sect. 6.3. 

There are numerous reviews on 1,3-dipolar cycloadditions. We will mention only those published since 1984, first of all the two-volume handbook, edited by Padwa (1984), then reviews by Drygina and Garnovskii (1986), Samuilov and Konovalov (1986), Huisgen (1988), Tsuge et al. (1989), Carruthers (1990), Padwa and Schoffstall (1990), Padwa (1991a, 1991b), Wade (1991) and Rank (1994). This extensive literature clearly demonstrates the current interest in these cyclization reactions. 

See the additional reviews discussing diazoalkane cycloadditions only, in Sect. 6.5. 

The answer to this dilemma was provided by Huisgen et al. (1962 a, 1962 b) by the cycloaddition reaction of C-methyl-A-phenylsydnone (6.10) with styrene, which yields, via the bicyclic intermediate 6.11 and elimination of CO2, 4,5-dihydro-5-methyl-l,3-diphenyl-li/-pyrazole (6.12). As mentioned briefly in Section 6.2 (Table 6-1, footnote a), sydnones are cyclic azomethine imines. As Huisgen (1968) demonstrated later, sydnone and azomethine imine cycloadditions are kinetically very similar with respect to solvent effects and in the sequence of reactivity with a series of 11 dipolarophiles. 

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The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

R. Huisgen, Steric Course and Mechanism of 1,3-Dipolar Cycloadditions, in Advances in Cycloaddition (D. P. Curran, Ed.) 1988,1, 11-31, Jai Press, Greenwich, CT. 

Furthermore, E) and (Z)-substituted alkenes will, depending on the actual mechanism of cycloaddition, yield stereochemically different triazolines or products in equilibrium. These stereochemical considerations are important for the elucidation of the mechanism of 1,3-dipolar cycloadditions involving azides as 1,3-dipoles (see Sect. 6.3 and the reviews by Huisgen, 1984, and Lwowski, 1984). 

CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Dennis P. Curran. Steiic Course and Mechanism of 1,3-Dipolar Cycloadditions, Rolf Huisgen. Nonstabilized Azomethine Ylides, Edwin Vedejs. Molecular Rearrangements Occurring from Products of Intramolecular 1,3 Dipolar Cycloadditions Synthetic and Mechanistic Aspects, Arthur G. Schultz. Dipolar Cycloadditions of Nitrones with Vinyl Ethers and Silane Derivatives, Philip DeShong, Stephen N. Lander, Jr., Joseph M. LeginusandC. Michael Dickson. The Cycloaddition Approach to b-Hydroxy Carbonyls An Emerging Alternative to the Aldol Strategy, Dennis P. Curran. Index. 

Studies on the mechanism of 1,3-dipolar cycloaddition reactions have shown that the reaction proceeds in a concerted fashion and is controlled not only by the frontier molecular energy gap between the two reactants, but also by the energy needed to distort the 1,3-dipole and dipolarophile to the transition state geometry [23]. The reactivity of dipoles and dipolarophiles can be effectively tuned by the structure and the substitution pattern, allowing modulation of the reaction kinetics. 

R. Huisgen, Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew. Chem. Int. Ed Engl. 1963, 2, 633-645. 

Scheme 9.1 Discussed mechanism of 1,3-dipolar cycloaddition reaction (I) concerted (2)...

The electron-spin theory which is appropriate for the increased-valence mechanism of 1,3 dipolar cycloaddition is (iescribed in some detail in Ref 11, where the importance of the long-bond structures (such as (26)) for the electronic stracture and reactivity of any 1,3 dipolar molecule has also been stressed. The latter conclusion has received support from a number of valence-bond calculations and Goddard and Walch have used structure (26) alone to represent the electronic structure of CHjNj. 

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