Nitrones 1,3-dipolar

The 1,3-dipolar nitrone character of dibenz[c,e]azepine N-oxide (161) is apparent in its cycloadditions with phenyl isocyanate, JV-phenylmaleimide (74ZN(B)425> and JV-sulfinylaryl-sulfonamides (ArS02NS0) (81TL2141). 

Azine approach. Bicyclic ring formation results if the 1,3-dipolar nitrone-alkene cycloaddition is intramolecular such a reaction is shown for (93) (70TL1117). 

The rhodium carbenoid (55) generated from diazocompound (50) has been shown to react efficiently with 1,3-dipolar nitrones in a formal [3 + 3] manner to produce heterocyclic cycloadducts (56) in high yields. Using chiral dirhodium catalysts such 0 as (51) or equivalent (R = methyl instead of adamantyl), the process exhibits a very high level of enantioinduction. 

Scheme 4.19 Synthesis of pynolo[l,2-a]azepine by 1,3-dipolar nitrone-alkene cycloaddition.

A"-Octadienylatiori, rather than 0-octadienylation, of aldehyde oximes takes place to give the nitrone 37 as an intermediate, which undergoes 1.3-dipolar addition to butadiene, yielding the isoxazolidine 38[39],... 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

Isoxazolidines sometimes undergo retro 1,3-dipolar cycloaddition to give back alkenes and nitrones (77AHC(2D207). 

A" -Isoxazolines, which are readily accessible by 1,3-dipolar addition of nitrones and nitronic esters to activated alkynes, undergo facile rearrangement upon warming (<110 °C)... 

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

Dipolar cycloadditions of five-member cyclic nitrones to a,(3-unsaturated acid derivatives 99H(50)1213. 

Recently the synthetic method involving formation of the 1—5 and 3—4 bonds has been extended to the preparation of the completely hydrogenated system of A -substituted isoxazolidines (42). This interesting reaction results from 1,3-dipolar addition of nitrones (41) to olefins. " ... 

The use of chiral dipolarophiles, such as the nitrile oxide additions to chiral furanones, have received much interest. The cycloaddition of various 1,3-dipolar reagents to the enantiomeric ally pure furanones 170 and 227 showed excellent diastereofacial control by the menthyloxy substituent, especially in nitrone and nitrile oxide additions (cf. Table II) (88TL5317). 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

In a more recent work the same research group has applied cyclic and acyclic vinyl ethers in the oxazaborolidinone-catalyzed 1,3-dipolar cycloaddition reaction with nitrones [30]. The reaction between nitrone 5 and 2,3-dihydrofuran 6 with 20 mol% of the phenyl glycine-derived catalyst 3c, gave the product 7 in 56% yield as the sole diastereomer, however, with a low ee of 38% (Scheme 6.9). 

In an analogous study by Meske, the impact of various oxazaborolidinone catalysts for the 1,3-dipolar cycloaddition reactions between acyclic nitrones and vinyl ethers was studied [31]. Both the diastereo- and the enantioselectivities obtained in this work were low. The highest enantioselectivity was obtained by the application of 100 mol% of the tert-butyl-substituted oxazaborolidinone catalyst 3d [27, 32] in the 1,3-dipolar cycloaddition reaction between nitrone la and ethyl vinyl ether 8a giving endo-9a and exo-9a in 42% and 27% isolated yield, respectively, with up to 20% ee for endo-9a as the best result (Scheme 6.10). 

As for boron catalysts, the aluminum catalysts have exclusively been applied for the inverse electron-demand 1,3-dipolar cycloaddition between alkenes and nitrones. The first contribution to this field was published by j0rgensen et al. in... 

A model for the mechanism of the highly enantioselective AlMe-BINOL-cata-lyzed 1,3-dipolar cycloaddition reaction was proposed as illustrated in Scheme 6.13. In the first step nitrone la coordinates to the catalyst 11b to form intermediate 12. In intermediate 13, which is proposed to account for the absolute stereoselectivity of this reaction, it is apparent that one of the faces of the nitrone, the si face, is shielded by the ligand whereas the re face remains available... 

The above described reaction has been extended to the application of the AlMe-BINOL catalyst to reactions of acyclic nitrones. A series chiral AlMe-3,3 -diaryl-BINOL complexes llb-f was investigated as catalysts for the 1,3-dipolar cycloaddition reaction between the cyclic nitrone 14a and ethyl vinyl ether 8a [34], Surprisingly, these catalysts were not sufficiently selective for the reactions of cyclic nitrones with ethyl vinyl ether. Use of the tetramethoxy-substituted derivative llg as the catalyst for the reaction significantly improved the results (Scheme 6.14). In the presence of 10 mol% llg the reaction proceeded in a mixture of CH2CI2 and petroleum ether to give the product 15a in 79% isolated yield. The diastereoselectiv-ity was the same as in the acyclic case giving an excellent ratio of exo-15a and endo-15a of >95 <5, and exo-15a was obtained with up to 82% ee. 

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