Typical 1,3-dipolar cycloaddition reactions

Cyclopropanones are also reactive toward cycloadditions of various types. It is suspected that a dipolar species resulting from reversible cleavage of the cyclo- 

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The typical 1,3-dipolar cycloaddition reaction of nitrones with alkenes involves a dominant interaction of HOMO (nitrone) and LUMO (alkenes). The inverse-electron demand of the... 

The authors have also elaborated a microwave-enhanced one-pot procedure [90] for the Huisgen 1,3-dipolar cycloaddition reaction. In a typical procedure, a pyrazinone with a triple bond connected to the core via C - O linkage, was reacted with a suitable benzylic bromide and NaNs in presence of the Cu(I) catalyst in a t Bu0H/H20 system under microwave irradiation (Scheme 26). The cycloaddition was found to proceed cleanly and with full regioselectivity. As the azide is generated in situ, this procedure avoids the isolation and purification of hazardous azides, which is especially important when handling the ahphatic ones, which are known to be toxic and explosive in nature. 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

Dichloroacetamido)-l-methyl-5-nitroimidazole undergoes a 1,3-dipolar cycloaddition reaction with diazomethane to give (dichloroacetimino)tetrahydroimidazo[4,5-c]pyrazoles in about 10% each (Scheme 5). The failure to observe cycloaddition with l,2-dimethyl-5-nitroimidazole underlines the role of the N- methylated imidazole intermediate (184), a typical non-aromatic a, j6-unsaturated nitro compound acting as a dipolarophile (80TL4757). 

In behaviour that is typical of a 1,3-dipolar cycloaddition reaction, 0s04 reacts almost as well with electron-poor as with electron-rich alkenes. 0s04 simply chooses to attack the alkene HOMO... 

Examples of 1,3-dipoles include diazoalkanes, nitrones, carbonyl ylides and fulminic acid. Organic chemists typically describe 1,3-dipolar cycloaddition reactions [15] in terms of four out-of-plane 71 electrons from the dipole and two from the dipolarophile. Consequently, most of the interest in the electronic structure of 1,3-dipoles has been concentrated on the distribution of the four Jt electrons over the three heavy atom centres. Of course, a characteristic feature of this class of molecules is that it presents awkward problems for classical valence theories a conventional fashion of representing such systems invokes resonance between a number of zwitterionic and diradical structures [16-19]. Much has been written on the amount of diradical character, with widely differing estimates of the relative weights of the different bonding schemes. 

The third typical reaction of carbenes is combination with a nucleophile. Carbenes are electron-deficient species, so they combine with nucleophiles that have reactive lone pairs. Addition of a carbonyl O to a carbene gives a carbonyl ylide, a reactive compound useful for making furan rings by a 1,3-dipolar cycloaddition reaction (see Chapter 4). 

As you have surely noted, several examples of 1,3-dipolar cycloaddition reactions have been discussed throughout the course of the Classics series due to the amazing library of products that result from their employment. Among the 1,3-dipoles typically employed in these events, of which a representative collection is shown in Scheme 5, oxidopyrylium species (whose resonance form is a carbonyl ylide) constitute a relatively unexplored tool... 

The dipolarophile typically is an olefin, but diversity in the structure of the dipolarophile is one of the synthetically important features of 1,3-dipolar cycloaddition reactions. Many different types of unsaturated compounds have been employed as dipolarophiles. Likewise, structural diversity is the rule rather than the exception for compounds capable of acting as 1,3-dipoles. Variation in structure in both the 1,3-dipole and dipolarophile makes this a very versatile and useful reaction, particularly in the synthesis of heterocyclic compounds. The most significant structural feature of 1,3-dipolar compounds is that they possess a 7r-system containing four electrons over three atoms, and are isoelectronic with the allyl anion. Some typical 1,3-dipolar species are shown in Scheme 10.1. 

The concept of (3 -I- 2)-dipolar cycloadditions, pioneered by Rolf Huisgen, dates back to the early 1960s [19]. Over the years, this reaction has found widespread utility in heterocyclic chemistry, natural product synthesis and medicinal chemistry [20-22]. These elegant chemical transformations facilitate the construction of products with high complexity where two new tj-bonds are formed in a single step. In a typical (3 -I- 2)-dipolar cycloaddition reaction, a 1,3-dipole reacts with a... 

Figure 4 Typical concentration versus time profiles for the comparison of the native and doped 1,3-dipolar cycloaddition reaction of a minimal replicator, reciprocal replicator, and an AB system.

A large number of peptidomimetics are currently entering clinical trials, typically protease inhibitors and anti-cancer agents, which emphasizes the importance of developing reactions which efficiently modify peptides or peptide-like structures to increase their drug-like properties. Azides are important dipoles in 1,3-dipolar cycloaddition reactions and react with dipolarophiles such as alkynes and nitriles, to afford [l,2,3]-triazoles and tetrazoles, respectively. 

Nitrile oxides are considerably more reactive than nitrones, and nitrile oxide dimerization is a prominent side reaction that can effectively compete with dipolar cycloaddition. To overcome this obstacle, nitrile oxides are typically generated in situ under conditions that lead to their participation in 1,3-dipolar cycloaddition reactions. The resulting isoxazolines constitute a versatile class of heterocycles, which are amenable to extensive manipulation. Confalone s synthesis of biotin (16) includes clever use of an intramolecular nitrile oxide cycloaddition reaction [46] that sei-ves to install the requisite relative configuration as well as the necessary side chain (Scheme 18.4) [47]. 

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