1.3- Dipolar cycloaddition reactions ketone

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

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). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

Sneider et al. (27,28) applied a familiar nitrone for the synthesis the immunosuppressant (—)-FR901483 (14) in a recent study (Scheme 12.7). The nitrone 12 is generated in situ from ketone 10 and the optically pure hydroxylamine 11 at 25 °C. The resultant nitrone 12 underwent a 1,3-dipolar cycloaddition reaction with ethyl acrylate in refluxing toluene to give the diastereomer 13 with 71 % diastereomeric excess (de). In 22 synthetic steps including the 1,3-dipolar cycloaddition, the target molecule 14 was obtained. 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

Fused aziridines are interesting compounds owing to the fact that the strained three-membered ring can easily open and cause dipolar cycloaddition reactions as well as their photochromic properties. Therefore, most of this chapter covers the chemical and photochemical properties of bi- and tricyclic aziridines. Some properties of aziridinyl ketones are also reviewed, in particular, reactions leading to aziridinyl anils. 

Kerth and Maas have reported reactions of 2-acyl-l,2,3-diazaphospholes 73 with diazo ketones 71 to form bicyclic compounds 74, the products of a 1,3-dipolar cycloaddition reaction of diazoalkenes 72, which are in equilibrium with diazo ketones 71 (Scheme 3) <1999EJ02633>. 

Dipolar cycloaddition reactions are interesting processes for the preparation of several heterocyclic systems due to the generally mild reaction conditions and the simultaneous formation of several bonds in a single operation. The preparation of pyrrolidines via cycloaddition reactions of azomethine ylides is a well known process and has been extensively studied. A strategy based on the reaction of azomethine ylides with a,P-unsaturated ketones was selected by Hollinshead... 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

Hashimoto has reported the enantioselective domino carbonyl yUde formation/l,3-dipolar cycloaddition reaction of a range of a-diazo ketones 185 with various aromatic aldehydes 92, promoted by the chiral Rh(II)-tetrakis[N-benzene-fused-phthaloyl-(S)-valinate] complex (184). The present reaction afforded the corresponding bicyclic cycloadducts 186 in good yields and enantioselectivities. The exo diastereomer 186 was diastereoselectively generated as a single product in almost all the cases (Scheme 11.40) [61]. 

Dipolar Cycloaddition. The principal use of p-bromobenzenesulfonyl azide is in 1,3-dipolar cycloaddition reactions with functionally substituted alkenes. The reagent has been used at ambient temperature and pressure to convert simple trimethylsilyl and methyl enol ethers of cyclic ketones to ring-contracted p-bromobenzenesulfonimidates, and thence to the corresponding amides, esters, or acids (eqs 1 and 2). 

A common problem occurring with ketenes is their polymerization. Diaz-Ortiz et al. [80] reported hetero-Diels-Alder reaction and 1,3-dipolar cycloaddition of ketone acetals under microwave irradiation which was completed in 3 min. The product was isolated directly through cmde reaction mixture without the polymerization of ketene (Scheme 11.27). 

Dipolar cycloaddition reactions with stable and easily prepared azomethine imines, for the synthesis of a diverse array of heterocycles, have attracted considerable attention [125]. The complex RhjldS-MPPlM) (47) catalyzes the highly diastereoselective [3-l-2-l-l]-cycloaddition reaction between a diazo ketone and azomethine imines [126]. The final products are multi-functionalized bicyclic pyrazolidinone derivatives isolated in moderate to high yields (Scheme 9.12). 

The 1,3-dipolar cycloaddition reaction of pyridinium ylides (40) with 3-alkenyl oxindoles (41) yielded spiro-cycloadducts (42) related to oxindole alkaloids, such as strychnofoline (Scheme 12). The one-pot 1,3-dipolar cycloaddition of 3-arylsydnones with a,/ -unsaturated ketones formed 1,3,4-trisubstituted pyrazoles in refluxing dry dimethylbenzene. ... 

An effective way for introduction of a variety of heterocyclic fragments in the position 7 of the fluoroquinolone skeleton is the methodology of 1,3-dipolar cycloaddition reactions [164-167]. Indeed, the reaction of 7-azido derivative of 6-fluoroquinolone 39 with enamines of cyclic ketones and norbomene proceeds rather smoothly with the formation of the corresponding exo-l,2,3-triazolines 40 which undergo the cationic rearrangements into amidines 41 or aminonorbomane 42 [164, 165]. 7-Azido derivatives 39 are capable of reacting with heterocyclic amines to form new 7- fluoroquinolones (Scheme 20) [168]. 

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