Nitrones functionality

Dipolarophiles D4. 1,3-Dipolar cycloaddition between acrylonitrile (D4) and chiral nonracemic nitrones is a key step in an efficient synthetic route to isoxa-zolidinyl analogs of thiazofurin (540) (Scheme 2.253). Opposite diastereofacial induction was observed when the chiral group was placed at either the carbon or the nitrogen atom of the nitrone function (753). 

The observed C=N stretching frequencies for aromatic nitronates are very similar to those of the corresponding nitrones, which appear at 1550-1600 cm (27). The observed absorbances for aliphatic nitrones are between 1600 and 1620 cm which is slightly lower that the corresponding nitronates. Moreover, the resonances observed for the nitronate function are slightly lower than those observed for oximes (1650-1685 cm ) (28). This data suggests a decrease in the C=N bond character in the order of oximes > nitronates > nitrones. 

The H NMR data for HC(5) of five-membered, cyclic nitronates is presented in Table 2.18 (60-62). Though there are no reported examples with a hydrogen at C(3), the influence of the nitronate function can be observed at the second point of connection. The presence of electron-withdrawing groups at R provides a... 

The nitrone functionality has also found a number of applications as acceptor of nucleophilic addition, as recently reviewed134. The reaction of nitrone 82 with Id directly affords isoxazolidin-5-ones 83, as shown in equation 51135. 

An oxadiazolium inner salt was found to be an intermediate in the rearrangement of a nitrone (106) to an amide (108). The red salt (107) was isolated. In accord with the mechanism as shown, only when the nitrone function was substituted at C-3 did the rearrangement occur (79JHC1477). 

Spin traps come in basically two types nitroso compounds and nitrone compounds. Reactive free radicals react with the carbon of the nitrone functional group to form a radical adduct that always has a nitroxide group, which is an unusually stable type of free radical. Nitrones are the most useful spin traps for the in vivo detection of free radical metabolites because of the stability of the resulting radical adduct. However, identification of the parent radicals can be difficult because adducts derived from different radicals often have very similar EPR spectra. A comprehensive review of this area through 1992 has recently been published [48]. 

Fig. 5. Structure of the NO-releasing vasodilators. The nitroso and nitrone functional groups are shown in the dotted boxes. Reproduced from ref. [116], with permission.

Daphnezomines C (39) and D (40), possess the secodaphniphylline-type skeleton with a nitrone functionality, while daphnezomine E (41) is the first N-oxide of a daphniphylline-type alkaloid, though the N-oxides of several yuzurimine-type alkaloids have been reported [45]. 

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

Cycloaddition/cycloreversion processes were also employed to temporarily mask the reactive nitrone functionality <2002J(P1)1494, 2002EJ01941>. For example, nitrone 208 was protected by cycloaddition with styrene. The isoxazolidine ring remained unaffected during all the reaction steps used to introduce a pendant dipolarophile and obtain the derivative 209. By heating in a sealed tube at 190 °C, isoxazolidine 209 underwent cycloreversion restoring the nitrone moiety which was directly trapped by an intramolecular 1,3-dipolar cycloaddition to afford 210 with complete regio- and diastereoselectivity (Scheme 47). 

TRIFLUORO-2-BUTYNOATE. C-Acylation of an enolate using methyl cyanoformate provides a convenient source of the a-carbometh-oxyoctalone, METHYL (la,4Ap,8Aa)-2-OXO-DECAHYDRO-l-NAPH-THOATE and represents a good example of generating jS-keto esters under mild conditions. The nitrone functionality is featured in a procedure which makes it in a single step from secondary amines and 6-METHYL-2,3,4,5-TETRAHYDROPYRIDINE N-OXIDE is the example described. Finally, the synthesis of phospholes l-PHENYL-2,3,4,5-TETRAMETHYLPHOS-PHOLE is described as an example of the versatility of zirconocene chemistry. 

The formation of 265, R = CH3, is rationalized as the addition of the C=N of phenyl isocyanate across the formal nitrone function of the oxazole V-oxide (261), followed by opening of the oxazole ring, decarboxylation, and recyclization (Scheme 14).421... 

The reaction of the triazole (323) with carbon disulphide does not yield the expected triazolopyrimidine (325) the triazolothiazine (324) is formed instead (Scheme 125). Derivatives of pyrrolo[3,2- f]pyrimidine (327) are obtained, in 54—64% yield, from pyrimidotriazines (326), the initial step being one of cycloaddition of the alkyne to the nitrone function (Scheme 126)/ ... 

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