1,3 Dipolar cydoadditions

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. 

Although beyond the scope of the present discussion, another key realization that has shaped the definition of click chemistry in recent years was that while olefins, through their selective oxidative functionalization, provide convenient access to reactive modules, the assembly of these energetic blocks into the final structures is best achieved through cydoaddition reactions involving carbon-het-eroatom bond formation, such as [l,3]-dipolar cydoadditions and hetero-Diels-Al-der reactions. The copper(i)-catalyzed cydoaddition of azides and terminal alkynes [5] is arguably the most powerful and reliable way to date to stitch a broad variety... 

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-... 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

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. 

Holmes et al. used another interesting pericyclic domino reaction in the synthesis of (-)-histrionico-toxine 116 (scheme 23).1631 In a not fully understood sequence 113 at 190 °C generates the cydoadduct 115 in 80% yidd with loss of styrene. It can be assumed that the process consists of a retro-13-dipolar and a 13-dipolar cydoaddition with the intermediary formation of the nitrone 114. Overall, three new stereogenic centers, necessary for the natural product, have been efficiently created. An... 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

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. 

Coldham, I. and Hufton, R. (2005) Intramolecular dipolar cydoaddition reactions of azomethine ylides. Chemical Reviews, 105, 2765-2810. 

It is well known that azomethine ylides, which are usually fonned in situ, are very good substrates for 1,3-dipolar cycloadditions. The group of Novikov and Khlebnikov [328] generated such a 1,3-dipol by reaction of difluorocarbene formed from CBr2F2 (2-626) with the imine 2-627. Cydoaddition of the obtained 2-629 with an ac-... 

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-... 

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