Nitrones reversible cycloaddition reactions

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Finally, the reversibility of the nitrone/alkene [3+2] cycloaddition, mainly used to access the hexahydro-isoxa-zolo[2,3- ]pyridine ring system (see Section 11.10.3.7), can be used to functionalize these heterocycles. Accordingly, Holmes et al. found that a cycloreversion-cycloaddition reaction could be performed from 65 by simple heating in toluene at 190 °C. Under these conditions, the product of the reaction was found to be the exo-adduct 67 (Scheme 21) <2002J(P1)1494>. 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

The Lewis acid ATPH 97 was effective both in rate enhancement and in control of the regiochemistry i n the cycloaddition reactions b etween C,A-diphenyl nitrone (94) and catalytic amount (10 mol%) of 97, the regiochemistry of the 1,3-DC of 94 and 92 was reversed and the isoxazolidine-4-carbaldehyde 95 was obtained as the major cycloadduct in high yield <02TL657>. 

Nitrone cycloaddition reactions are reversible, thereby offering the opportunity to change stereoselection from that of kinetic to thermodynamic control, should the selectivities associated with these path-... 

Dipolar cycloaddition reactions occurreadily even with non-activated dipo-larophiles, such as isolated alkenes. This contrasts with the Diels-Alder reaction, particularly for intermolecular reactions, in which an activated alkene as the dienophile is required. Like the Diels-Alder reaction, [3+2] cycloaddition reactions of 1,3-dipoles are reversible, although in most cases it is the kinetic product that is isolated. For the intermolecular cycloaddition of nitrile oxides or nitrones, two of the most frequently used 1,3-dipoles, to monosubstituted or 1,1-disubstituted alkenes (except highly electron-deficient alkenes), the oxygen atom of the 1,3-dipole becomes attached to the more highly substituted carbon atom of the alkene double bond. Hence the 5-substituted isoxazolidine 206 is generated from the cycloaddition of the cyclic nitrone 205 with propene (3.136). Reductive... 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

The 1,3-dipolar cycloadditions of nitrones (551), (595), (614), (615) and their enantiomers (595 ent), (614 ent), (615 ent) (Fig. 2.40) to a.p-unsaturated y-lactones, such as achiral D7 g and D-glycero D7 h, provide an interesting example of double asymmetric inductions. The reactions are kinetically controlled. However, on heating and at longer reaction times, the reversibility of the cycloaddition (595 + D7 h) was observed, and the presence of a more stable thermodynamic product (620) was detected. Moreover, in the case of lactone D7 h, a... 

Nitrones derived from cyclic acetals of D-erythrose (479) and (689) and of D-threose (480) and (690), reacted with N -phenylmaleimide D15a to afford the corresponding diastereomeric isoxazolidines (691-706) (Scheme 2.295). The stereoselectivity is dependent on the substituents in the nitrone. In the case of nitrones (479) and (689) the cycloaddition is exo-selective. It was observed that microwave irradiation decreased the reaction times of the cycloadditions dramatically. For example, for nitrone (689) and dipolarophile D15a the reaction time decreased from 11 h to 8 min and for nitrone (690) and D15a it decreased from 3 h to 10 min. Moreover, microwave irradiation reversed the ratio of erythro-frans/erythro-r/.v adducts from 63 37 to 39 55, see compound (689). Cycloadditions of the chiral maleimides D15b and D15c are less stereoselective (817). 

Initially, a complex of nitroalkene (42) with LA (A) is reversibly formed. The efficient concentration of the latter is determined by the reaction conditions and the nature of heterodiene (42) and LA. This complex acts as a Michael substrate and adds alkene (43) to give bipolar adduct B, which undergoes cycliza-tion to give cationic intermediate C. The latter eliminates LA to yield target nitronate (35). In the case of nonconcerted cycloaddition, ionic intermediate B can undergo different isomerization reactions, some of which are considered below. The stereoselectivity of the process depends on the reactive conformation... 

Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (7 )-(-i-)-BINOL, and d5 -l,2,6-trimethylpiperidine. The reaction of benzylbenzylide-neamine A-oxide with 3-(2-butenoyl)-l,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99 1) (Sch. 8) [31,46], It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (i )-(-i-)-BINOL, and cd-l,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. 

Enantioselective cycloadditions of nitrones with alkylidene malonates were catalyzed by the complex of Go(ll) with trisoxazoline 528. The cycloaddition was reversible and the diastereoselectivity could be controlled by reaction temperature. For example, A, C-diphenyl nitrone and diethyl 2-benzylidenemalonate reacted at —40°C under kinetic control, affording mainly the m-adduct 530, but at 0°C the thermodynamically more stable /ra r-isomer 529 was the major product (Equation 85) <20040L1677>. 

Occasionally, the reverse orientation is obtained. The reaction of a trans-disubstituted nitrone, a-phenyl-W-methylnitrone (10a), with nitroethylene gives the 4-substituted isoxazolidine (II).23 With N-t-butylnitrone (11a), however, the same olefin gives the 5-substituted isomer (I).23 Each reaction is regiospecific in that, of the two possible orientations, only one is produced in the reaction. The reaction of phenyl vinyl sulfone with nitrones is one of the rare examples where regiospecificity is lost. Thus, both nitrones 10a and 11a give a mixture of adducts I and II (31 68), and (70 30), respectively.23 Recently, the regioselectivity of 1,3-dipolar cycloadditions have been interpreted by... 

Several examples of the 1,3-dipolar cycloaddition of nitrones using the heterochiral Yb(III) catalyst in the absence of MS 4A are shown in table 38. The reactions were performed by adding one equivalent of the corresponding nitrone to the Yb(III) catalyst and then, successively, the same nitrone and a dipolarophile. In all cases, reverse enantiofacial selectivities compared with those obtained in the presence of MS 4A were observed. When N-acryloy 1-1,3-oxazo lidin-2-one was used as a dipolarophile, the desired isoxazolidine derivative was obtained in 88% ee. Other substrates also gave high diastereo- and enantioselectivities in most cases. In the reaction of an aliphatic nitrone, low diastereoselectivity was observed, albeit the endo adduct was obtained in good yield and ee. 

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