Huisgen’s 1,3-dipolar cycloaddition

In this context, click chemistry has been explored as a method for rapid synthesis of compound libraries. In click chemistry, compounds are rapidly synthesized through heteroatom links by a set of powerful, highly reliable, and selective reactions, such as Huisgen s 1,3-dipolar cycloaddition reactions. Click chemistry uses chemical building blocks with built-in high-energy content to drive a spontaneous and irreversible linkage reaction with appropriate complementary sites in other blocks. 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

For comprehensive reviews of 1,3-dipolar cycloaddition reactions, see R. Huisgen, R. Grashey and J. Sauer in The Chemistry of Alkenes, S. Patai, ed., Interscience London, 1965, pp. 806-878 G. Bianchi, C. DeMicheli, and R. Gandolfi, in The Chemistry of Double Bonded Functional Groups, Part I, Supplement A, S. Patai, ed., Wiley-Interscience, New York, 1977, pp. 369-532 A. Padwa, ed., 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, 1984. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

S. Dedola, S. A. Nepogodiev, and R. A. Field, Recent applications of the Cul-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry, Org. Biomol. Chem.., 5 (2007) 1006-1017. 

Cho S, Oh S, Um Y, Jung JH, Ham J, Shin WS, Lee S. (2009) Synthesis of 10-substituted triazolyl artemisinins possessing anticancer activity via Huisgen 1,3-dipolar cycloaddition. Bioorg Med Chem Fett 19 382-385. 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

The controversy between Huisgen and Firestone concerning the mechanism for 1,3-dipolar cycloaddition is longstanding.9,11 For nitrile oxide cycloadditions, experimental data have been interpreted either as supportive of a concerted mechanism9 or in favor of a stepwise mechanism with diradical intermediates.11 Theory has compounded, rather than resolved, this problem. Ab initio calculations on the reaction of fulmonitrile oxide with acetylene predict a concerted mechanism at the molecular otbital level,12,13 but a stepwise mechanism after inclusion of extensive electron correlation.14 MNDO predicts a stepwise mechanism with a diradical intermediate.13 The existence of an extended diradical intermediate such as (4 Scheme 2) has been postulated by Firestone in order to account for the occasional formation of 1,4-addition products such as the oxime (5).11 Of course, the intermediates (4) and (5) for the Firestone mechanism do not correspond to the initial transition states in Firestone s theory. These are attained prior to the formation of, and at higher energy than, the intermediates. 

Recently, Huisgen and coworkers have reported on the first unequivocal example of a nonconcerted 1,3-dipolar cycloaddition.27 Sustmann s FMO model of concerted cycloadditions envisions two cases in which the stepwise mechanism might compete with the concerted one.21 Two similar HOMO-LUMO interaction energies correspond to a minimum of rate and a diradical mechanism is possible, especially if stabilizing substituents are present. A second case is when the HOMO (l,3-dipole)-LUMO (dipolarophile) is strongly dominant in the transition state. The higher the difference in rr-MO energies of reac-... 

R. Sustmann, Rolf Huisgen s contribution to organic chemistry, emphasizing 1,3-dipolar cycloadditions, Heterocycles 1995, 40, 1-18. 

This section deals with the comparatively new anhydro-4-hydroxyoxazolium hydroxides (217), the isomeric 5-hydroxy compounds (218) and the amino analogues (219). The chemistry of the munchnones (218) has been intensively studied as a result of the pioneering research of Huisgen s school in Munich on 1,3-dipolar cycloaddition reactions of these compounds (B-67MI41800). There have been so many publications in this area that only the bare outlines can be presented here the reader is referred to recent reviews (76AHC(19)1, 81MI41800) for fuller accounts. 

This class of compounds has been prepared only as the S-oxides. In most cases thionyl chloride serves as the cyclization agent. Thus the first A3-thiatriazoline (129) was prepared by Huisgen et al. from diphenylbenzamidrazone and SOCl2, and from 1,3-dipolar cycloaddition between diphenylnitrileimine and thionylaniline (equation 78) (62LA(658)169>. 

Huisgen s studies of 1,3-dipolar cycloadditions leading to a great variety of heterocyclic systems (61MI41203, 8ORCR88O) are applicable to the synthesis of triazoles and derivatives. Nitrilimines (171) formed by dehydrohalogenation of C-halobenzylidenephenylhydrazones (172) react with C=N, C=N (as in CNO) to afford triazoles and triazolines in yields of... 

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