1,3-Dipolar cycloaddition reactions Intramolecular

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

Figure 6.54 A domino DKR-intramolecular 1,3-dipolar cycloaddition reaction.

The pyrimidines 62 undergo cyclisation on refluxing in dioxane to yield not only the pyrazolopyrimidines 63, but the novel pyrazolo[3, 4 4,5]pyrido[2,3-rflpyrimidines 64 by an intramolecular 1,3-dipolar cycloaddition reaction (Scheme 9)<96JCS(P1)1999>. 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

An intramolecular nitrone 1,3-dipolar cycloaddition reaction to give 46 from 45 followed by reductive N-O bond cleavage afforded a stereoselective synthesis of the tetrahydro 177-1-benzazepines 47 the nitrone precursors 44 were prepared in turn by a Claisen rearrangement from an IV-allylamine <06SL2275>. 

More recently, some examples of intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloaddition reactions of especially designed 1,3,4-oxadiazole derivatives have been described (Scheme 3). The... 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

Dipolar cycloaddition reactions are of main interest in nitrile oxide chemistry. Recently, reviews and chapters in monographs appeared, which are devoted to individual aspects of these reactions. First of all, problems of asymmetric reactions of nitrile oxides (130, 131), including particular aspects, such as asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions (132, 133), development of new asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (134), and stereoselective intramolecular 1,3-dipolar cycloadditions (135) should be mentioned. Other problems considered are polymer-supported 1,3-dipolar cycloaddition reactions, important, in particular, for combinatorial chemistry... 

Intramolecular 1,3-dipolar cycloaddition reactions of N -(3-alkenyl)nitrones, as presented in Scheme 2.21 le, led to the synthesis of polyhydroxy derivatives of quinolizidine (474) and indolizidine (475) (Scheme 2.234) (732). 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

For comprehensive reviews of 1,3-dipolar cycloaddition reactions, see G. Bianchi, C. DeMicheli, and R. Gandolfi, in The Chemistry of Double Bonded Functional Groups, Parti, Supplement A, S. Patai, ed., John Wiley Sons, New York, 1977, pp. 369—532 A. Padwa, ed., 1,3-Dipolar Cycloaddition Chemistry, John Wiley Sons, New York, 1984. For a review of intramolecular 1,3-dipolar cycloaddition reactions, see A. Padwa, Angew. Chem. Int. Ed. Engl. 15 123 (1976). 

The alternating electronic properties of the Co, and Cp atoms in the vinylidene ligand enable dipolar molecules to enter into cycloaddition reactions. Intramolecular [2 + 2]-... 

Alcaide et al. (68,69) recently published their smdies of the intramolecular 1,3-dipolar cycloaddition reactions of alkynyl-p-lactams in which they found that the desired cycloaddition was in competition with a reverse-Cope elimination. The reaction of alkynyl aldehydes 37a-c with Al-methylhydroxylamine afforded a mixture of products depending on the reaction conditions and the chain length separating the alkyne and the lactam (Scheme 1.8). Thus, up to three separate... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

Second, the formation of the diazobenzazocine derivatives 264a-e represents an unprecedented reaction for intramolecular 1,3-dipolar cycloaddition reactions of diazo compounds. Note that diazo compounds such as 247a (305) and 248 (307) also give bridged diazabicyclo[n.2.1]alkenes rather than fused diazabi-cyclo[ .3.0]aUcenes upon treatment with Bp3-etherate, but these transformations... 

In a series of papers, Laude and co-workers (144-149) examined 1,3-dipolar cycloaddition reactions of mtinchnone imines derived from Reissert compounds. For example, mtinchnone imine 241 undergoes a smooth intramolecular 1,3-dipolar cycloaddition with the tethered alkyne unit to afford pyrrole 242 after extrusion of HNCO (144). 

Although Maier achieved the first intramolecular 1,3-dipolar cycloaddition reaction of an isomtinchnone, it has been Padwa who has unleashed the synthetic... 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

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