Nitrone Regioselectivity

Prior to 1973, nitrones were believed to add to monosubstituted dipolarophiles in a unidirectional fashion, giving 5-substituted adducts exclusively (Fig. 7). An exception to this behavior was reported by Huisgen a mixture of 4- and S-substituted isoxazolines form in the reaction of methyl propiolate with C-phenyl-N-methylni-trone19, as shown in Fig. 7. 

In the course of a general investigation of the electronic structures of 1,3-dipoles20, we rationalized this behavior according to the reasoning shown schemati- 

There is not a quantitative relationship between the nitrone IP s and the amount of 4-substituted isomer formed, but there is a general trend of increasing percentage of 4-substituted adduct as the IP of the nitrone decreases23, or the electron affinity (EA) of the dipolarophile increases. In Table 1, the first two n IP s of the nitrone 

Theoretical and Experimental Insights Into Cycloaddition Reactions 

Although the arguments given above are based only on orbital energies, donor substituents on the nitrone carbon have an additional influence on the nitrone HOMO, causing the oxygen coefficient to increase at the expense of the carbon23. This also reinforces the preference for 4-substituted adduct as the nitrone IP decreases. 

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Dipolar cycloadditions. Nitrones such as 1 combine with alkenes to form isoxazolidines. Tufariello has employed these 1,3-dipolar cycloadditionS as key steps in the synthesis of several alkaloids. Monosubstituted olefins react with nitrones regioselectively to afford 5-substituted iSoxazolidines thus addition of 2 to 1-pyrroline-l-oxide produces the cycioadduct 3, which serves as an intermediate in a total synthesis of elaeocarpine (4). ... 

The TiX2-TADD0Late-catalyzed 1,3-dipolar q cloaddition reactions were extended to include an acrylate derivative [66]. In the absence of a catalyst, the reaction between nitrones 1 and acryloyl oxazolidinone 19b proceeded to give a mixture all eight regio-and stereoisomers (Scheme 6.23). However, application of in this case only 10 mol% of Ti(OTs)2-TADDOLate 23d as catalyst for the reaction of various nitrones 1 with alkene 19b, led to complete regioselectivity and high endo selectivity in the reaction and the endo products 21 were obtained with 48-70% ee (Scheme 6.23) [66]. 

Allylation of acyloyl-imidazoles and pyrazoles61 with allyl halide mediated by indium in aqueous media provides a facile regioselective synthesis of P, y-unsaturated ketones (Scheme 11.1), which has been applied to the synthesis of the monoterpene artemesia ketone. The same product can be obtained by indium-mediated allylation of acyl cyanide (Eq. 11.35).62 Samarium, gallium, and bismuth can be used as a mediator for the allylation of nitrones and hydrazones to give homoallylic hydroxylamine and hydrazides in aqueous media in the presence of Bu4NBr (Scheme 11.2).63 The reaction with gallium and bismuth can be increased dramatically under microwave activation. 

The addition of mesityl nitrile oxide to stable derivatives of a germanethi-one21 and a germaneselone22 is closely related to the addition of nitrones. The reaction is regioselective again, with formation of the germanium-oxygen bond. 

The influence of substituents on regioselectivity was studied by using a model nitrone 3,4-dihydro-2,2-dimethyl-2/f-pyrrole 1-oxide (DMPO, 256) with different alkylidenecyclopropanes substituted with phenyl (156), electronreleasing (270 and 271) and electron-withdrawing groups (52, 272 and 4) [67,... 

Table 22. Regioselectivity of the cycloadditions of nitrone 256 to alkylidenecyclopropanes substituted with phenyl, electron-releasing and electron-withdrawing groups [67,68]...

These experimental findings, as well as earlier data on alkylidenecyclopropanes, clearly disclose a peculiar effect of a cyclopropylidene system both on reaction rates and regioselectivity. In fact, the parent MCP as well as its derivatives exhibit a high reactivity in 1,3-dipolar cycloadditions with nitrones. In contrast, the related open chain isobutene and its derivatives are well known to enter 1,3-dipolar cycloadditions sluggishly [51c-d, 70]. For example, there is no chance to obtain a cycloadduct from 256 and an open chain trialkyl or tetraalkylethylene, as was obtained in the reaction of 256 with 270 and 271. 

As for the regioselectivity of the nitrone cycloaddition to MCP and its alkyl or aryl derivatives, a tendency of the three-membered ring to end up at the 4-position of the final isoxazolidine ring clearly emerges from the experimental findings. This result is particularly noteworthy if compared to regiospecific formation of the 5,5-disubstituted isoxazolidines in the reactions of nitrones, not... 

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

The question of regioselectivity of the cycloaddition with alkylidenecyclo-propanes was also addressed, in analogy with nitrones, and afforded somewhat different results (Table 28) [91, 67b]. 

Albeit nitrile oxides are more regioselective than nitrones towards MCP, in cycloadditions with alkylidenecyclopropanes they show a lower regiocontrol than nitrones. The same trend, however, on passing from electron-donating to electron-withdrawing substituents is observed. Benzylidenecyclopropane (156) gives (entry 1, Table 28) only a 1 4 mixture (compared with 1 19 with nitrone... 

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>. 

Under suitable conditions, oxidation of /V-alkyl-a-amino acids, accompanied by decarboxylation, has made it possible to carry out regioselective syntheses of nitrones which were utilized in the synthesis of 1-azabicyclic alkaloids (Scheme 2.6) (48, 49). 

Oxidative ring opening of isoxazolidines leads to nitrones. Thus, bicyclic isox-azolidines (50) and (51), treated with m-CPBA, afford nitrones (52), (53), (54), and (55) (Scheme 2.19). Conformational analysis has confirmed the key role of the nitrogen lone pair with respect to regioselectivity of the reaction and of the intramolecular kinetic deprotonation of the intermediate oxoammonium derivative (125). 

Formation of nitrones can be achieved in the first stage of a Krohnke type reaction in which p-n trosodi methy 1 an dine reacts with 2-oo-bromoacetylphenoxathiin in alkaline medium (336). The synthesis of a series of cyclic nitrones of structure (182) has been achieved by regioselective, and by an unusual [3 + 2] cycloaddition of a-nitrosostyrenes (181) to 1,3-diazabuta-l,3-dienes (180) (Scheme 2.64) (337a). Theoretical studies of the substitution effect at the imine nitrogen on the competitive [3 + 2] and [4 + 2] mechanisms of cycloaddition of simple acyclic imines with nitrosoalkenes have been reported (337b). 

Asymmetric syntheses of (3- amino acids result from the addition of chiral enolates (399) to nitrone (400) via A-acyloxyiminium ion formation (642, 643). Regioselective convergence is obtained in the reactions of chiral boron- and titanium- enolates (399a,b), (401), and (402). This methodology was used in preparing four stereoisomers of a-methyl- 3-phenylalanine (403) in enantiomeric pure form (Scheme 2.179) (644). 

Addition of allylic zinc bromides to nitrones, generated in situ from allylbro-mides and zinc powder in THF (670), allyltributylstannane (671) and lithiated allyl ferf-butyldimethylsilyl ether (672), proceeds regioselectively in good yields and is used to synthesize homoallyl hydroxylamines (Scheme 2.189). The latter were subjected to an iodo cyclization reaction (see Scheme 2.186). 

As shown in Scheme 2.21 Id, starting with N-allyl carbohydrate-nitrones (469), a series of chiral six- (470) and seven-membered(471) TV-heterocycles were synthesized (Scheme 2.227). A very interesting and useful aspect of this cycloaddition is the control of regioselectivity by the substitution at the nitrogen atom. Therefore, it is possible to direct reactions towards the syntheses of preferred six- or seven-membered heterocycles from carbohydrate derivatives (722). 

Dipolarophiles D1 and D2. In the study of steric and electronic factors on regioselectivity and stereoselectivity of 1,3-cycloaddition of nitrones to olefins, 1-decene (734) and styrene derivatives (735) have been used. By comparative analyses of the kinetic and thermodynamic parameters in the 1,3-cycloadditions... 

Under similar reaction conditions the D-threose derived nitrone (480) is converted in high regioselectivity to diastereomeric cycloadducts (485-488) in an overall yield of 84% (Scheme 2.238). 

It has been reported that diiron acyl complexes (564) undergo stereo- and regioselective 1,3- cycloadditions with a variety of nitrones (Scheme 2.260). These complexes are then oxidatively converted to synthetically useful thio esters (769). 

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