Huisgen-type cycloaddition

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Up to now, a variety of heterogeneous Cu-catalyzed cycloaddition reactions for the assembly of bioactive heterocycles have been reported. Most examples are the Huisgen-type 1,3-dipolar cycloadditions, but there are rare reports on the heterogeneous Cu-catalyzed synthesis of heterocycles through other types of cycloaddition reactions. 

Huisgen-type 1,3-dipolar cycloaddition of azides to alkynes... 

Oh and coworkers successively developed a series of highly efficient methods for the construction of various types of fused polycyclic heterocycles from enynals with a pendant unsaturated bond [72]. Enynals with a benzyloxy substituent at the propargylic position 155 were successfully cyclized via platinum-catalyzed Huisgen-type cycloaddition to form polycyclic Pt-carbene complex intermediate 156, which undergo insertion into a C-H bond to afford various types of fused polycyclic heterocycles 157 (Scheme 12.68) [73]. 

Scheme 1-235. Huisgen-type [3+2]-cycloadditions between arynes and aryl azides.

This type of reaction is represented by 1,3-dipolar cycloadditions, corresponding to one of the Huisgen categories (69MI1). The 1,3-dipolar cycloaddition corresponds to the interaction between a 1,3-dipole and a multiple system five-membered ring closure (Scheme 1). 

For a system of classification of cycloaddition reactions, see Huisgen, R. Angew. Chem. Int. Ed. Engl., 1968, 7, 321. For a review of certain types of cycloadditions leading to three- to six-membered rings involving 2, 3, or 4 components, see Posner, G.H. Chem. Rev, 1986, 86, 831. See also the series Advances in Cycloaddition. 

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... 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

Although it has been established that the HOMO (diazoalkane)-LUMO (alkene) controlled concerted cycloaddition occurs without intervention of any intermediate for the reactions of simple diazoalkanes with alkenes, Huisgen once proposed a mechanistic alternative 4 namely an initial hypothetical nitrene-type 1,1-cycloaddition reaction of phenyldiazomethane to styrene followed by a vinylcyclopropane-cy-clopentene-type 1,3-sigmatropic rearrangement Control experiments, however, excluded this hypothesis for the bimolecular 1,3-dipolar cycloaddition reaction of diazomethane (Scheme 60).204... 

As early as 1967, Huisgen and coworkers [37] had shown that, upon photolysis, certain aziridines of type 96 undergo C—C bond fragmentation stereospecifkally to produce octet-stabilized azomethine ylides which, on cycloaddition with electron-deficient dipolarophiles, produce pyrrolidine ring systems (Scheme 8.29). 

The formation of triazole rings by the reactions of azides and acetylenes was first described by Huisgen and coworkers [48,49] and has recently been promoted as dick chemistry by Sharpless et al. [50,51]. This versatile [3 + 2] dipolar cycloaddition proved to be useful for the synthesis of hyperbranched polytriazoles via 1,3-dipolar polycydoaddition of AB2-type monomers 28 and 29 (Scheme 14) [52], The monomers exhibited very high reactivity the... 

A 1,3-dipole is a compound of the type a—Het—b that may undergo 1,3-dipolar cycloadditions with multiply bonded systems and can best be described with a zwitter-ionic all-octet Lewis structure ( Huisgen ylid ). An unsaturated system that undergoes 1,3-dipolar cycloadditions with 1,3-dipoles is called dipolarophile. Alkenes, alkynes, and their diverse hetero derivatives may react as dipolarophiles. Since there is a considerable variety of 1,3-dipoles—Table 12.2 shows a small selection—1,3-dipolar cycloadditions represent not only a general but also the most universal synthetic approach to five-membered heterocycles. 

The cationic site is of the immonium type, and is relatively iinreactive, but the radical site is reactive toward electron deficient alkenes such as acrylonitrile, yielding a 50 50 mixture of the diastereoisomeric pyrrolines, after being neutralized by back electron transfer from the sensitizer anion radical. The net result is an interesting example of a net 1,3-dipolar cycloaddition which, in the Huisgen method of classification of cycloadditions, is of the [3 -l- 2] type. The same general reaction had previously been carried out by Padwa, using direct photochemical excitation, a procedure which, in contrast, was highly diastereoselective (90 10, in favor of the trans isomer) [92]. 

Huisgen defined a 1,3-dipoleas a species that may be described (as in Equation 1) by zwitterionic octet structures 6a <- 6b, and which may undergo cycloaddition reactions of the type 3 + 2 -> 5 with suitable multiple bonds (dipolarophile d=e) to give a neutral five-membered ring 7. 

There are numerous other 1,3-dipoles of the S2une type, from azides ( —N3) to ozone (O3). Huisgen (1963 a, 1984, p. 5) lists 18 examples, which lead to an enormous variety of heterocyclic and other compounds. Previously, these compounds were either unknown or difficult to obtain. No wonder that a book of two volumes (1623 pages) was published on 1,3-dipolar cycloadditions by Padwa in 1984 This development is one of the most remarkable examples in organic chemistry that application of the principles of physical organic chemistry can lead to a complete and very diverse framework of synthetic methods. We agree with Padwa s statement that Huisgen s work in this area was monumental. We will discuss 1,3-dipolar cycloadditions of diazoalkanes in Sections 6.2-6.4. 

In the late 1950 s, Huisgen developed the general concept of 1,3-dipolar cycloadditions — again at the University of Munich, where Buchner and von Pechmann had found the first cyclizations of this type 70 years earlier. 

This mechanism is, however, difficult to apply to the fast cycloaddition of diazoacetates (Alder et al., 1931) and 3-diazobutane-2-one (Diels and Konig, 1938) with alkenes of the bicyclo[2.2.1]heptene type, because alkene C-atoms without electron-withdrawing substituents show no electrophilic character. The reverse sequence of steps in (6-4), i. e., first an additon of N at the central C-atom of the acrylate, would also be unusual, as the N ()ff)-atom of diazoalkanes is only a weak electrophilic center. Fleischmann (in Huisgen s group, 1958) showed that, in such cyclization reactions, the rate of reaction of diazomethane with bicyclic alkenes relative to that of )ff-diazo ketones and 2-diazo-l,3-diketones is higer by a factor of 10" -10. ... 

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