Nitrile oxides regioselectivity

Isothiazolylphosphonate 29 (Section II.B.2) reacted with 1,3-dipoles such as diazomethane and nitrile oxides, affording regioselectively 30a,b or 32. By reacting 30b and 32 with bases, pyrazolylphosphonate 31 and isoxazolylsulfonamide 33 were obtained (01T(57)5453). 

In 2000, it was proposed that the regioselectivity of the [3 + 2] cycloaddition of fullerenes could be modified under microwave irradiation. Under conventional heating, N-methylazomethine yhde and fullerene-(C7o) gave three different isomeric cycloadducts because of the low symmetry of C70 vs. Ceo. Using microwave irradiation and o-dichlorobenzene as a solvent, only two isomers were obtained, the major cycloadduct 114 being kinetically favored (Scheme 39) [75]. The same authors had previously reported the 1,3-dipolar cyclo addition of pyrazole nitrile oxides, generated in situ, to Geo under either conventional heating or microwave irradiation. The electrochemical characteristics of the cycloadduct obtained with this method made this product a candidate for photophysical apphcations [76]. 

The addition of mesityl nitrile oxide to stable derivatives of a germanethi-one21 and a germaneselone22 is closely related to the addition of nitrones. The reaction is regioselective again, with formation of the germanium-oxygen bond. 

Several strategies have been proposed to improve the regioselectivity of nitrile oxide cycloaddition. Kanemasa and coworkers have reported high-rate acceleration and regioselectivity in nitrile oxide cycloadditions to the magnesium alkoxides of allylic and homoallylic alcohols (Eq. 8.64)."... 

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

Albeit nitrile oxides are more regioselective than nitrones towards MCP, in cycloadditions with alkylidenecyclopropanes they show a lower regiocontrol than nitrones. The same trend, however, on passing from electron-donating to electron-withdrawing substituents is observed. Benzylidenecyclopropane (156) gives (entry 1, Table 28) only a 1 4 mixture (compared with 1 19 with nitrone... 

Reaction yields and regioselectivity were comparable, or better, than those obtained with more simple nitrile oxides. Examples of the use of an optically active (R)-4-chloro-valeronitrile JV-oxide for the synthesis of non-racemic isoxa-lines 371d and 371e are also reported [93]. 

Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides (and nitrones) derived from uracyl-5-carbaldehyde 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06T1494>. 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>. 

The application of microwaves to the cycloaddition reactions of allyl alcohols 180 with nitrile oxides not only achieved a substantial reduction of the reaction time and an improvement of the adduct yields, but also altered the regioselectivity of the cycloaddition in favor of the nonhydrogen bond-directed cycloadduct 182 (Scheme 9.55) [105]. 

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

Dioxolanes 39 derived from a, 3-unsaturated aldehydes react with nitrile oxides R2CNO to give the corresponding isoxazolines 40 with the 1,3-dioxolan-2-yl substituent in position 4 as main products, and their 5-isomers as minor products with good regioselectivity and synthetically useful yields. The corresponding... 

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

Baker s yeast catalyzed the regioselective cycloaddition of stable aromatic nitrile oxides ArCNO [Ar = 2,6-C12C6H3, 2,4,6-Me3C6H2, 2,4,6-(MeO)3C6H2] to ethyl cinnamate, ethyl 3-(p-tolyl)acrylate, and tert-butyl cinnamates (218). Reactions of dichloro- and trimethoxybenzonitrile oxides with all three esters proceeded regio- and stereoselectively to form exclusively alkyl tran.v -3,5-diary 1 -... 

Allenes add nitrile oxides either to one or two double bonds. For mono- and 1,1-disubstituted allenes, relative activity of the two bonds depends on the nature of substituents. The reaction (Scheme 1.18) of N-propadienylanilines 54 with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide proceeds site- and regioselectively to give 5-substituted 4-methylene-4,5-dihydroisoxazoles 55, which add a second molecule of nitrile oxide to afford 4,5/-spirobi-(4,5-dihydroisoxazoles) 56. Dihy-droisoxazoles 55 isomerize to 4-(2-aminobenzyl)isoxazoles 57 via a Claisen-type rearrangement (224). 

Regio- and diastereoselectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones was studied (238, 239). The reactions are always regioselective, while the diastereofacial selectivity depends on the nature of the substituents. Thus, 4-hydroxy-4-methylcyclopent-2-enone (75) gives preferably adducts 76a, the 76a 76b ratio warying from 65 35 to 85 15 (Scheme 1.22). 

The cycloaddition of nitrile oxides RCNO (R = alkyl, alkenyl, aryl), generated in situ from either RCH2NO2/PI1NCO or RCH=NOH/NaOCl to (R)-( + )-limonene, proceeds regioselectively at the extracyclic double bond, but not stereospecifically, to form (5R/S )-isoxazoles 78 in 64% to 81% isolated yield (241). 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

There are a few communications concerning cycloadditions of nitrile oxides to unsaturated oxa and aza cage systems. Benzo- and mesitonitrile oxides RCNO give, with five substituted 7-oxanorbomenes 106, mixtures of the corresponding exo-adducts 107 and 108 in nearly quantitative yields. No traces of compounds resulting from the endo-face attack was detected (274). Substituents at positions 5 and 6 of 106 render the process highly regioselective. 

Dipolar cycloaddition reaction of trimethylstannylacetylene with nitrile oxides yielded 3-substituted 5-(trimethylstannyl)isoxazoles 221. Similar reactions of (trimethylstannyl)phenylacetylene, l-(trimethylstannyl)-l-hexyne, and bis (trimethylsilyl)acetylene give the corresponding 3,5-disubstituted 4-(trimethyl-stannyl)isoxazoles 222, almost regioselectively (379). The 1,3-dipolar cycloaddition reaction of bis(tributylstannyl)acetylene with acetonitrile oxide, followed by treatment with aqueous ammonia in ethanol in a sealed tube, gives 3-methyl-4-(tributylstannyl)isoxazole 223. The palladium catalyzed cross coupling reaction of... 

Pyrrolyl)-4,5-dihydroisoxazole derivatives 402 have been synthesized (Scheme 1.48) in good yields (66%-78%) by regioselective 1,3-dipolar cycloaddition of nitrile oxides to 1-phenylsulfony 1-1,3-dienes, followed by Barton-Zard pyrrole annulation using ethyl isocyanoacetate anion (444). 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

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. 

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