1.3- dipolar cycloaddition reactions intramolecular generation

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. 

An isoxazoline intermediate generated by the intramolecular [3 + 2] dipolar cycloaddition reaction of a nitrile oxide has served as a valuable intermediate in the preparation of biotin... 

A one-pot, double intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides was developed by reaction of 4 equiv of an O-allyl salicyl-adehyde with a fluorous amino ester under microwave heating to generate a novel hexacyclic ring system 13 that contains seven stererocenters (Scheme 15) [45]. 

Modifying the aldehyde function in the pyrroles 1162 into 1,3-dipoles 1163 (nitrone) and 1167 (nitrile oxide) furnished tricyclic heterocycles 1164 and 1168 via intramolecular 1,3-dipolar cycloaddition reactions (Scheme 226) <2000T3013>. None of the isomeric bridged product 1165 is produced despite the preference for that regiochem-istry in the intermolecular reaction. Generated in situ (from the oximes 1166) nitrile oxides 1167 cyclized spontaneously to the dihydroisooxazole 1168 in quantitative yield at room temperature. 

There are two examples of these syntheses, collected in CHEC-I <84CHEc-I(6)973), one by reaction of an imidazolium JV-ylide with ethyl propiolate <68JA3830>, and another by reaction of imidazole-2-carbaldehyde with vinyltriphenylphosphonium bromide in presence of NaH in THE <76JHClii>. In the early 1990s, the intramolecular 1,5-dipolar cycloaddition reaction of the imidazolium N-allylides (48) to give the pyrrolo[l, 2-a]imidazole (49) has been described. Compound (48) is generated... 

Although Maier achieved the first intramolecular 1,3-dipolar cycloaddition reaction of an isomunchnone, it was Padwa who unleashed the synthetic utility of this reaction. Thus Padwa and co-workers also found that isolated 7t-bonds can successfully and efficiently capture the in situ-generated isomunchnones, as shown by the examples 518 519 (Fig. 4.156). The alkene can also be tethered adjacent to the nitrogen atom (not shown). The indole double bond in 520 intercepts an isomunchnone 1,3-dipole to give the single diastereomer 521, the stmcture of which is supported by X-ray crystallography. 

In the full account of this rhodium-catalyzed isomunchnone generation and intramolecular 1,3-dipolar cycloaddition reaction, followed by a terminal Mannich... 

Intramolecular 1,3-dipolar cycloaddition reactions normally proceed efficiently to give bicyclic products and these reactions do not require the presence of an electron-withdrawing group on the dipolarophile. Thus, in an approach to the alkaloid sarain A, the aziridine 221 was heated to generate the intermediate azomethine ylide 222, and hence, after intramolecular cycloaddition, the pyrrolidine 223 (3.143). " An alternative method for the formation of the required azomethine ylide, and which avoids the need for the prior synthesis of an aziridine ring, uses the simple condensation of an aldehyde and a primary or secondary amine. Thus, in another approach to sarain A, addition of formaldehyde to the amine 224 resulted in the formation of the cycloadduct 226 (3.144). Notice that in both cases the... 

Surprisingly, treatment of 1 with Ag20 does not decompose the diazo ester but rather leads to the silver pyrazolate 6. A related observation has been made recently [6], Similary, a thermally induced intramolecular 1,3-dipolar cycloaddition reaction generates pyrazole 7. This reaction mode is limited, however, to specific substitution patterns. In other cases, an intermolecular rather than the intramolecular [3+2] cycloaddition comes into play (see next section). 

In a similar manner,benzo[6]pyrido[3,2 [l,4]oxazepinones 115 were prepared using a ligand-free, copper-catalyzed process (14RA55640). An intramolecular 1,3-dipolar cycloaddition reaction of 6-azido-4-0-propargyl glucopyranosides generated aryl-substituted hexahydro-4H-pyrano[2,4 [l,2,3]triazolo[5,l-c][l,4]oxazepines 116 (14RA63962). 

Particularly significant contributions have been made by Padwa and Schmid in the photochemical generation of benzonitrile methylides from 2//-azirines. For example (Scheme 21), photolysis of (67) in the presence of carbon dioxide as dipolarophile leads to 4-phenyl-3-oxazolin-5-ones (68), whereas the intramolecular dipolar cycloaddition reaction of (69) can afford a useful synthesis of the bicyclic product (70). ... 

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]. 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

Chiacchio and co-workers <97T13855> reported a stereoselective synthesis of 133 via an intramolecular 1,3-dipolar cycloaddition. Intermediate 132 was generated in situ by the reaction of tra .v-/V-(2-formylphenyl)-i -methyl-2-phcnylcthenc- l -sulfonamide 131 with N-methylhydroxylamine and afforded a tricyclic benzothiazine 133 in 51% yield (Scheme 36). 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

Malacria and coworkers346 prepared phyllocladane and kaurane types of diterpenes by means of [3 + 2]/[2 + 2 + 2]/[4 + 2] cascade reaction sequences. A representative example of such a reaction sequence has been outlined in equation 171. The five-membered ring of 598 was built by a 1,3-dipolar cycloaddition between 596 and an all-carbon 1,3-dipole generated from 597. The reaction of 598b with 568h afforded benzocyclobutene 599. The intramolecular [4 + 2] cycloaddition afforded diastereomers 600 and 601 in a 5 1 ratio. It is noteworthy that the exocyclic double bond in 598b neither participates in the [2 + 2 + 2] cycloaddition reaction nor isomerizes under the reaction conditions applied. 

The first successful generation and trapping of isomiinchnones using this strategy was described independently by Maier et al. (36,37) and Padwa et al. (38,39). Maier and Evertz (36) were the first workers to report the intramolecular dipolar cycloaddition of isomiinchnones to alkenes, the reaction that Padwa would later exploit so spectacularly. Thus, diazo imide 62 was readily prepared from... 

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