Isoxazolines annulation

Reactions with participation of the C=C bond are the most studied of INOCs. Normal products of such reactions are annulated isoxazolines. A synthesis of bicyclic isoxazolines via sequential Michael and intramolecular 1,3-dipolar additions (403) are mentioned as an example. Michael addition of 1-nitroalkadiene, R1R2C=CH(CH2) CH=CHN02 to allylic stannane R3R4C=C(R5)CH2SnR63... 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

Isoxazolines with an Annulated Five-Membered Ring... 

Another related synthesis made use of the intramolecular cycloaddition of co-nitroalkene 243, also derived from geraniol epoxide 237. Generation of the expected nitrile oxide dipole using p-chlorophenyl isocyanate and triethylamine quantitatively gave the annulated isoxazoline 244 as a 2 1 mixture of diastereo-isomers (Scheme 6.94). Reductive hydrolysis of the cycloadduct to the aldol product followed by dehydration provided enone 245, which was used to prepare the sesquiterpene nanaimoal 246 (242). 

An interesting application of the photochemical reactivity of isoxazolin-5-ones (see also Section 12.3) has been reported for the synthesis ofa series of annulated imidazole derivatives of general structure 72, which are obtained in almost quantitative yield. The methodology consists of an initial N-functionalization of the isoxazolin-5-one with a a-chloro-azaheterocycle, leading to 2-(azahetaryl)isoxazol-5(2H)-ones 71. 

The [3 + 2] stereoselective annulations using allylsilanes were also applied to the syntheses of furans (equation 59)156-162 7V-acylpyrrolidines163,164, a 2-thiabicyclo[2.2.1] hept-5-ene-3-spiro-2/-indan-l/-one165 and A2-isoxazoline derivatives166,167. 

The nitrile oxide cycloaddition has been performed on 83 under Mukaiyama conditions giving the isoxazoline 84 in about 50% yields with high stereocontrol of the annulation reaction. 

Carbohydrate-integrated isoxazolines have been synthesized from 2-nitroglycals and sulfur ylides, with 1-phenylthiourea as catalyst. The reactions proceed via [4 - -l]-annulations and subsequent rearrangement gives the isoxazolines with high diastere-oselectivity (Scheme 83). ... 

The 1,3-dipolar cycloaddition of a variety of nitrile oxides, nitrones, ethyl diazoacetate, and azomethine ylide to the chiral furanone 174a was studied with respect to the present regio- and diastereoselectivity (93T8899). In the case of the azomethine ylide addition, three stereoisomeric adducts were obtained. However, in the case of the other dipoles only two stereoisomeric adducts were isolated the major product proved to be the an//-facial isomer. In this way, a number of multifunctional (lactone-annulated) isoxazolines 241 and 242, isoxazolidines 243 and 244, pyrazolines 245a,b, and pyrrolidines 248a,b,c could be synthesized (Scheme 65) (93T8899). 

On the other hand, Zhong and coworkers found that the 62-catalyzed system was effective for enantioselective [4-)-l]-annulation using 2-nitroacrylates and a-iodoaldehydes, to form crs-isoxazoline N-oxide derivatives in high yields and in high diastereo- and enantioselectivity (Scheme 1.25) [266]. 

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