Huisgen synthesis

Dihydroisoxazole has also been known as A" -isoxazoline or 4-isoxazoline. Its standard synthesis is via the 1,3-dipolar cycloaddition of nitrones to alkynes Huisgen synthesis) ... 

The classical synthesis of 4-isoxazolines is the 1,3-dipolar cycloaddition of nitrones (4) to aUcynes Huisgen synthesis) [324]. Unsymmetrical alkynes give mixtures of regioisomers. 

Heumann-Pfleger synthesis (indigo) 145 Hinsberg synthesis (thiophene) 98 Hoffmann-Loffler reaction 158 Huisgen synthesis... 

Dipolar cycloaddUions. Interest in 1,3-dipolar cycloadditions increased dramatically during the past 20 years, largely because of the pioneering studies of Huisgen [7, 2] The versatility of this class of pericychc reactions in the synthesis of five-membered-ring heterocyclic compounds is comparable with that of the Diels-Alder reaction in the synthesis of six-membered-ring carbocyclic systems (equation 1)... 

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-... 

Intramolecular arylations can also be carried out photochemically. Huisgen and Zahler (1963 a) prepared fluoren-9-one by irradiation of benzophenone-diazonium salts in dilute sulfuric acid. The classical Pschorr synthesis of phenanthrene-9-carb-... 

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. 

H. Isobe, K. Cho, N. Solin, D. B. Werz, P. H. Seeberger, and E. Nakamura, Synthesis of fullerene glycoconjugates via a copper-catalyzed Huisgen cycloaddition reaction, Org. Lett., 9 (2007) 4611-4614. 

Examples of [3 + 2]- (or 1,3-dipolar) cycloaddition reactions have been known for many years. However, only after the main principles of this type of transformations have been formulated by Huisgen (333), [3+ 2]-cycloaddition became one of the most important tools in organic synthesis (334, 335). Actually, the simultaneous formation of two new bonds makes it possible to efficiently assemble a complex molecule from simple and readily available precursors. Due to... 

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. 

During the synthesis of 436, Muraoka and colleagues produced the diazobi-cyclo[4.3.1]decane 435 via the classical ring expansion (equation 184). Huisgen-White rearrangement of the cyclic lactam leads to 436, a key synthetic intermediate for piperidine alkaloids. 

Fig. 41 Synthesis of cyclic PCL by click copper-catalyzed Huisgen s cycloaddition...

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

Kawase (127,128) reexamined the reaction of mtinchnones with oxygen. Not only is this a powerful method for the synthesis of imides, but, based on labeling experiments, the mechanism of this autoxidation is different from that originally proposed by Huisgen and co-workers (129). This reaction is particularly useful for the preparation of tetrahydroisoquinolones and tetrahydrocarbolones. 

See. for example, Martin Gott Goodlett Hasek /. Org. Chem. 1965,30, 4175 Brady O Neal /. Org. Chem. 1967,32, 2704 Huisgen Feiler Otto Tetrahedron Lett. 1968,4491, Chem. Ber. 1969,102, 3475. For indirect methods of the 1,4 addition of the elements of ketene to a diene see Freeman Balls Brown /. Org. Chem. 1968, 33, 2211 Corey Ravindranathan Terashima /. Am. Chem. Soc. 1971, 93, 4326. For a review of ketene equivalents see Ranganathan Ranganathan Mehrotra Synthesis 1977, 289-296. 

Synthesis of Heterocycles with 1,4-Dipolar Cycloadditions R. Huisgen, Z. Chem., 1968, 8, 290-298. 

Huisgen s group488 have described a new synthesis of pyrroles (26) from oxazol-5-ones (azlactones) (25) with DMAD and MP. The pyrrole derivatives formed in situ from 2,4-dimethyl- and 4-benzyl-2-methyloxazolone with DMAD underwent nucleophilic addition to a second mole of the acetylenic ester to give the Michael adducts 27 and 28... 

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