Dipolar cycloaddition of alkenes

Chiral aluminium complexes have been used as catalysts for inverse electron-demand 1,3-dipolar cycloadditions of alkenes with nitrones, and the first contribution to this field was pubhshed in 1999 (344). The chiral AlMe-BEMOL (BINOL = 2,2 -bis(diphenylphosphino)-l,l -binaphthyl) complexes 235 were excellent catalysts for the reaction between nitrone 225a and vinyl ethers 232 (Scheme 12.68). The diastereo- and enantioselectivities are highly dependent on the chiral ligand. An exo/endo ratio of 73 27 was observed, and the exo-product was... 

The use of TiCl2-TADD0Late and Mg(II)-phenanthroline catalysts in asymmetric 1,3-dipolar cycloadditions of alkenes with nitrones has been reviewed.62 The 1,3-dipolar cycloaddition of 3-acryloyloxazolidin-2-one with nitrones catalysed by [TiX2(TADDOLato)] complex shows high regio-, diastereo-, and enantio-selectivity.63... 

Dipolar cycloaddition of alkenes with carbonyl ylides generated in situ is a versatile method for tetrahydrofuran synthesis. The synthetic potential of such transformations has been reviewed <2005JOM(690)5533, 2003BMI6-253>. In addition, the stereoselective [3 + 2] annulation of allyl silanes has become a reliable protocol for the synthesis of tetrahydrofurans as demonstrated in several total syntheses . Such a [3 + 2] annulation, for example, affords the tetrahydrofuran product 11 as a single stereoisomer (Scheme 15) <2002OL2945>. Lanthanide salts serve as efficient Lewis acid catalysts in similar [3 + 2] cycloaddition reactions . 

The 1,3-dipolar cycloaddition of alkenes to nitrile oxides is a fundamental reactions because the resulting isoxazolines are very useful building blocks ... 

Qiu G, Kuang Y, Wu J (2014) N-imide ylide-based reactions C-H functionalization, nucleophilic addition and cycloaddition. Adv Synth Catal 356(17) 3483-3504 Menon RS, Nair V (2014) 4.21 Intramolecular 1,3-dipolar cycloadditions of alkenes, alkynes, and allenes. Compr Org Synth 11 4 1281-1341... 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

Intramolecular and intermolecular 1,3-dipolar cycloadditions of aziridine-2-car-boxylic esters with alkenes and alkynes have been investigated [131, 132]. Upon heating, aziridine-2-carboxylates undergo C-2-C-3 bond cleavage to form azome-... 

Syntheses of fluoro-substituted pyrazoles continue to be of interest. Both 3- and 5-fluoropyrazoles (44 and 45, respectively) can be prepared from 43 <96JOC2763>. Treatment of 43 with hydrazine followed by N-alkylation provides 44, whereas reactions with monosubstituted hydrazines afford 45. The 4-(trifluoromcthyl)pyrazoles 47 are obtained from J-trifluoromethyl vinamidinium salt 46 <96TL1829>. The 5-trifluoromethyl-3-carboethoxypyrazoles 49 are obtained from the 1,3-dipolar cycloadditions of trifluoromethyl alkenes 48 with ethyl diazoacetate <96T4383>. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Scheme 29 1,3-Dipolar cycloaddition of l-diazo-2-silyloxy-l-alkene and thermolysis of the cycloadduct...

Pyranopyrrolothiazoles can be prepared in a similar way to certain pyrano- and thiopyrano-pyrrolizines and pyrrolizinopyridines as discussed earlier. Thus, thiazolidine-4-carboxylic acid reacts with the aldehyde 179 to give a 2 1 mixture of 180 and 181 (Equation 16). This reaction is a 1,3-dipolar cycloaddition of the alkene to the 1,3-dipole formed from reaction of the amino acid amine with the aldehyde <1988T4953, 1990T2213>. The alkyne analogue of 179 is similarly converted into 182 (Equation 17). 

Isoxazolidinoindolizines and pyrazolidinoindolizines, 268, can be prepared from the oximes or hydrazones 267. 1,3-Dipolar cycloadditions of oxime or hydrazone on to the adjacent alkene occur cleanly by heating the substrate in acetonitrile, or in the case of the basic aliphatic hydrazones, under acidic conditions <1987JOC226> (Equation 40). 

Hu and co-workers reported a facile synthesis of pyrrolo[2,l-n]phthalazine 205 by a 13-dipolar cycloaddition of phthalazium N-ylides generated from 203 with electron deficient alkenes to give 204, followed by treating 204 with tetrakispyridine cobalt(II) dichromate [Py4Co(HCr04)2, TPCD] to complete the aromatization <00JHC1165>. 

Moffett and coworkers203 reported the synthesis of several 4-/3-D-ribofuranosylpyrazoles, such as 284(a-c), by 1,3-dipolar cycloaddition of diazoalkanes to the alkenic C-glycosyl compound 283, followed by dehydrogenation of the resulting pyrazolines. In view of the known biological activities of several nucleosides containing the... 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

Macrocycles containing isoxazoline or isoxazole ring systems, potential receptors in host—guest chemistry, have been prepared by multiple (double, triple or quadruple) 1,3-dipolar cycloadditions of nitrile oxides, (prepared in situ from hydroxamoyl chlorides) to bifunctional calixarenes, ethylene glycols, or silanes containing unsaturated ester or alkene moieties (453). This one-pot synthetic method has been readily extended to the preparation of different types of macrocycles such as cyclophanes, bis-calix[4]arenes and sila-macrocycles. The ring size of macrocycles can be controlled by appropriate choices of the nitrile oxide precursors and the bifunctional dipolarophiles. Multiple cycloadditive macrocy-clization is a potentially useful method for the synthesis of macrocycles. 

A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator protein has been identified. These 3-(2-benzy-loxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines have been synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles (490). 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

A diastereoselective dipolar cycloaddition of chiral nitrone 80 with alkene dipolarophiles afforded imidazo[ 1,2-3]-isoaxazole (Scheme 9). The conversion via N-O reduction of this ring system with Raney-Ni in methanol gave the corresponding pyrrolo[l,2-A imidazole in 66% yield. The structure has been confirmed by X-ray diffraction crystal stmcture analysis <2000SL967>. 

The 1,3-dipolar cycloaddition of imidazolinone 123 with ethyl m-4,4,4-trifluorocrotonate 124 provided, after 36 h at reflux, the regio- and stereoisomer 125 (90%), accompanied with traces of three other unidentified cycloadducts (10%) <2001JFC275>. Compound 125 was isolated in 70% yield (Scheme 15). The structures of the final product were elucidated by nuclear Overhauser effect (NOE) experiments. This high selectivity is the result of a preferred ///////-orientation of both ester and CF3 groups in the transition state and of an impeded ////////-approach of the CFj-substituted terminus of the alkene to the sterically hindered ct-site of 123. 

Other approaches including 1,3-dipolar cycloadditions of azomethine ylides or nitroxides to alkene or alkyne dipolarophiles have been applied to the synthesis of these ring systems. 

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