1.3- dipolar cydoaddition

I 6 Asymmetric Metal-catalyzed 1,3-Dipolar Cydoaddition Reactions... 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

A new type of rigid polymer of 1,1-binaphthols was developed recently [41-43]. The 3,3 -crosslinked polymeric binaphthol ligand 18 in combination with AlMe3 was applied as the catalyst for the 1,3-dipolar cydoaddition (Scheme 6.16) [44]. Very high selectivities were obtained when the aluminum catalyst of 18 (20 mol%) was applied to the 1,3-dipolar cydoaddition reaction between nitrone la and al-kene 8a. The only observable diastereomer resulting from the reactions was exo-9a... 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

Compound 976 c, however, gives, after addition of allyltrimethylsilane 82, via exclusive 1,3-dipolar cydoaddition of allyltrimethylsilane 82, only 5-trimethylsilyl-methylisoxazohdine 979c [71, 72] (Scheme 7.22). 

Besides the combination of an anionic with a Diels-Alder reaction, a combination with a 1,3-dipolar cydoaddition is also possible. There are hundreds of examples of this type, since 1,3-dipoles are usually always prepared in situ in the presence of a dipolarophile. Here, only a few more recent publications are pre-... 

Recently published examples of continuous-flow organic microwave synthesis include, for example, 1,3-dipolar cydoaddition chemistry in the CEM CF Voyager system (see Figs. 3.23 and 3.24). The cycloaddition of dimethyl acetylenedicarboxy-late with benzyl azide in toluene was first carefully optimized with respect to solvent, temperature, and time under batch conditions. The best protocol was then translated to a continuous-flow procedure in which a solution 0.33 m in both build-... 

In heterocyde synthesis these conditions have been particularly used in 1,3-dipolar cydoadditions and Diels-Alder reactions (Chapt. 9). These conditions are, in fact, ideal for green chemistry . 

The thermal hydrazone-azomethine imine isomerization can be easily performed under microwave irradiation in the absence of solvent. The subsequent 1,3-dipolar cydoadditions with electron-defident dipolarophiles occur in only a few minutes to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones 205 leads to valuable compounds, such as bipyrazoles 213, in good yields and this provides a new approach to the preparation of these heterocyclic derivatives [116] (Scheme 9.67). Reactions undertaken with dassical heating under comparable reaction conditions (time and temperature) lead to cydoadduct yields that are considerably lower and, indeed, several dipolarophiles do not react at all. 

Dipolar cycloadditions to electron-deficient allenes are not regioselective, taking place at the electron-poor C=C bond, in all cases. For example, the reaction of 372 with nitrile oxide 378 furnishes a mixture of products 379-383 [356], Obviously, 379, 380 and 381 result from different [2 + 3]-cycloadditions followed by tautomer-ism, whereas 382 and 383 are formed from the primary products of the 1,3-dipolar cydoaddition via addition of a second equivalent of 378 to the remaining exocyclic C—C bond. 

Intramolecular 1,3-dipolar cydoadditions to acceptor-substituted allenes are rare [357]. The synthesis of triazole 386 from the precursor 384 is one of the few examples [120]. 

Dipolar cydoaddition of ethyl 2-(ethoxycarbonyl)-4,4-diphenyl-2,3-butadieno-ate 518 with CH2N2 or Ph2CN2 afforded bicyclic or monocyclic products 519 and 520, respectively. The possibility of extra cydopropanation depends on the steric effect of the diazo compound [234]. 

The 1,3-dipolar cydoaddition reactions ([3-1-2]) are often used to synthesize five member aza- or azoxaheterocycles. Depending on the nature of the 1,3-dipoles employed in the transformation, different types of heterocycles such as isoxaza-zoles [270], isoxazolines (Scheme 3.22) [110], hydantoins [271], pyrrolidines [272], indolizines [273] or pyrazoles [274] are obtained. 

Scheme 3.22 1,3-Dipolar cydoaddition step for the solid-phase synthesis of isoxazolocyclobuta-nones (171) [110],...

Regitz, M, Heydt, H In 1 3-Dipolar Cydoaddition Chemistry, Padwa A, Ed, Wiley New York, 1984, p 393 and literature cited therein... 

This 1,3-dipolar cydoaddition not only gave excellent results but was also found to be very general with regard to the nitrone component. Several types of aryl- and alkyl-substituted nitrone have been applied successfully. Irrespective of the substitution pattern, high diastereomeric ratios and enantioselectivity were obtained (see Scheme 8.9, products 35a,d,f,g). Variation of the N-alkyl group is also possible. As can be see from Scheme 8.9 (see, e.g., products 35a-c), the reactions also proceed well when an N-allyl and N-methyl-substituted nitrone is used. Acrolein, 32b, and crotonaldehyde, 32a, were used as the aldehyde component. It is noteworthy that this reaction is also suitable for use on a larger scale, as has been demonstrated by the 25 mmol-scale preparation of endo-35a (98% yield, 94% ee) starting from nitrone 31a and crotonaldehyde. 

Scheme 22 Rapid 1,3-dipolar cydoaddition of nitrile oxides to olefins and acetylenes...

The expected intramolecular 1,3-dipolar cydoaddition product 171 was only a minor product (3%). The formation of major product 169 was explained through an intramolecular Michael reaction of the enolate ion. 

It is assumed that, after the initial formation of the oxime 2-634, a Michael addition occurs to give 2-635 with formation of a nitrone moiety which then can undergo a 1,3-dipolar cydoaddition to give 2-636. 

Enantioenriched (-)-rosmarinedne, which belongs to the group of pyrrolizidine alkaloids [413], has been synthesized by Goti, Brandi and coworkers applying an intramolecular 1,3-dipolar cydoaddition as the key step [414], The required nitrone was obtained in situ from L-malic acid. Moreover, 1,3-dienes as precursors for a cy-... 

Since the number of domino processes which start with a Diels-Alder reaction is rather large, we have subdivided this section of the chapter according to the second step, which might be a second Diels-Alder reaction, a 1,3-dipolar cydoaddition, or a sigmatropic rearrangement. However, there are also several examples where the following reaction is not a pericydic but rather is an aldol reaction these examples will be discussed under the term Mixed Transformations . 

The key step in the synthesis of4-354 is the retro-1,3-dipolar cydoaddition of the isoxazolidine 4-351 to give the nitronate 4-352, which underwent an intramolecular 1,3-dipolar cydoaddition. The obtained cydoadduct 4-353 can be transformed in a few steps into the desired target 4-354 (Scheme 4.78). 

The indazol-3-yl homo C-nucleoside 81 was obtained by 1,3-dipolar cydoaddition of benzyne to the 2,5-anhydro-D-allonoyldiazomethane derivative 80 (79JHC81) (Scheme 25). 

Although 1,3-dipolar cydoaddition of benzyne or 4,6-dichlorobenzyne to the D-ribouronoyIdiazomethane glycoside 83 afforded a single isomer (82) of this category of C-nucleosides, monosubstituted benzyne provided a mixture of the two isomers 84 and 85 in most cases (76JHC1241 79JHC81) (Scheme 26). 

An unusual influence of water on the rate of 1,3-dipolar cydoadditions was first observed when 2,6-dichlorobenzonitrile N-oxide was allowed to react with 2,5-di-methyl-p-benzoquinone [50]. Likewise, bromonitrile oxide, generated in water at acidic pH, gave cycloadducts effidendy with water-soluble alkenes and alkynes [51]. In highly aqueous media remarkable accelerations for the cycloaddition of phenyl azide to norbomene were observed [52]. 

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