Nitronates cycloadditions, isoxazolines

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

The use of alkynes has been investigated in the context of intramolecular nitronate cycloadditions (130). In this case, the starting material is consumed in 24 h at room temperature, however, the corresponding isoxazoline is not isolated (Table 2.41). Instead, the intermediate cycloadduct undergoes a fragmentation which, following the loss of the nitroso moiety, leads to an a,p-unsaturated aldehyde. 

Exceptions do exist, however, and one must be particularly alert to substituent-induced changes in the direction of polarization, as well as to their affect upon the energy of the frontier molecular orbitals. For example, nitrone cycloaddition regiochemistry is generally LU controlled, leading to the production of C-S substituted isoxazolines in excellent yield. However, as the ionization potential of the nitrone decreases or the electron affinity of the dipolarophile increases, there exists an increased propensity for formation of the C-4 regioisomer. Eventually, a switch from LU to HO control occurs and substantial amounts of the C-4 isomer are produced (equation 14). 

Scheme 10.7 gives some other examples of 1,3-DPCA reactions. Entries 1 to 3 are typical intermolecular 1,3-DPCA. The 1,3-dipoles in each instance are isolatable compounds. Entries 4 and 5 are intramolecular nitrone cycloadditions. The product from Entry 5 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxyl group is ensured by the structure of the isoxazoline from which it is formed. 

Hoveyda and co-workers employed nitroolefinic silanes 249 possessing a chiral center that bears a silicon substituent for the diastereoselective synthesis of isoxazolines 251 (Scheme 59) [160]. While the silyl nitronate cycloaddition provided the diastereomeric isoxazolines 251 in >20 1 ratio, the nitrile oxide route was much less selective (dr 1 2), in agreement with the findings by Hassner as shown in Scheme 49. The greater selectivity observed in the ISOC reaction was attributed to a possible 1,3-aUylic strain in the transition state leading to the minor isomer while no such strain was expected for nitrile oxides that have near-linear geometry. The authors also observed greater... 

Recent advances and applications of strain-promoted alkyne-nitrone cycloaddition reactions in bio-orthogonal labeling (14COCB81) and of natural isoxazoline derivatives in the field of anticancer research (14EJM121) were reviewed. 

Both nitrile oxide (eq 3) and silyl nitronate (eq 4) cycloadditions are highly diastereoselective processes. The use of either approach enables access to A -isoxazolines in good yield. Unfortunately, the corresponding nitrone cycloadditions are only slightly selective (dr = 78 22) The enantiomeric sultam was implemented effectively in azomethine ylide cycloadditions to gain access to bridged p)rrolidines with high levels of diastereos-election (eq 5). ... 

The strained isoxazolines 420, formed by nitrone cycloaddition to cyclo-propyUdenecyclobutane, undergo ready ring expansion to give the hexahy-droazepinones 421 upon FVP at 600 °C (Scheme 88 2001EJ03789). 

Tufariello s implementation of nitrone cycloaddition and retrocycloaddi-tion reactions in the total synthesis of cocaine (8) is another striking classic (Scheme 18.2) [44], Isoxazoline 5 had been designed in the synthesis as an effective precursor of nitrone 6. After installation of the a,/3-unsaturated butyrate side chain, heating of 5 readily unmasked nitrone 6, which underwent... 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Because of the relative instabihty of many trimethylsilyl nitronates 1036, 1037, they should be reacted in situ with olefins 1053 [103-105] or acetylenes [127] to generate the isooxazolidines 1054 [103-105, 107-117, 119-133] or isoxazoles [127] (Scheme 7.37) The isoxazolidines 1054 with R2=H readily ehminate trimethylsilanol 4 in the presence of acids such as TsOH to form the isoxazolines 1055 in high yields [104, 105] (Scheme 7.37 cf. also the cycloadditions with acrylonitrile in Scheme 7.42). 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

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>. 

In particular, the reactions of electrophilically activated benzonitrile A-oxides with 3-methylenephthalimidines with formation of 2-isoxazolines and oximes and the cycloaddition between alkynyl metal(O) Fischer carbenes and nitrones leading to 4-isoxazolines have been investigated by density functional theory methods <06JOC9319 06JOC6178>. 

In the frequency of their use in 1,3-dipolar cycloadditions to nitrones, alkynes constitute the second group of dipolarophiles after alkenes. They are of particular interest due to the fact that isoxazolines, the products of initial cycloadditions,... 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Complexes of nickel(II) or magnesium(II) with the chiral ligand DBFOX (Scheme 8) catalyze the DCR of nitrones with a-alkyl- and arylacroleins rendering preferentially the 5-carbaldehyde cycloadducts. However, the reactions with a-bromoacrolein catalyzed by the zinc(II) complex of the same ligand afford isoxazoline -carbaldehydes. The corresponding cobalt(II) complex is also active for the cycloaddition between cyclopenten-l-carbaldehyde and diphenylnitrone. 

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