Nitroso dienophiles, cycloaddition reactions

Lewis acid catalysis, apparently dispensible due to the very high reactivity of nitroso dienophiles, has not yet been investigated although such a study has been suggested by Streith and Defoin [8]. Thus, examples of asymmetric catalysis lack completely in this area of hetero Diels-Alder chemistry. Nevertheless, cycloadditions involving nitroso dienophiles have reached an advanced level concerning stereoselectivity and therefore much attention has been paid towards the preparation and application of chiral, enantiopure dienophiles and dienes for these reactions. 

An asymmetric Diels-Alder reaction of a chiral nitroso dienophile has been employed by Ganem et al. in order to open an elegant access to enantiomerical-ly pure (-t-)-mannostatin A 7-57 and several derivatives thereof [519], The cycloaddition of the heterodienophile 7-54 derived from mandelic acid to 1-me-thylthiocyclopentadiene 7-55 proceeded only in moderate diastereoselectivity, however, the desired product 7-56 was easily separated from its diastereomer. 

A unified picture of the mechanism of this cycloaddition for various structural types of nitroso dienophiles is not available. Depending upon the electronic and steric nature of the particular nitroso compound, the reaction apparently may vary from a concerted pericyclic process to one involving discrete dipolar intermediates. The net result of this mechanistic diversity is a few anomalous regiochemi-cal results in the cycloaddition. 

Enders, D., Meyer, O. Diastereo- and enantioselective Diels-Alder reaction of 2-amino-1,3-dienes. Liebigs Annalen 1996, 1023-1035. Streith, J., Defoin, A. Aza sugar syntheses and multi-step cascade rearrangements via hetero Diels-Alder cycloadditions with nitroso dienophiles. Synlett 996, 189-200. 

A four-component [4 + 2]/[4 + 2]/[3 + 2] cycloaddition reaction, reported by Scheeren et is another application of multicomponent reactions. The interaction of 2-methoxy-l,3-butadiene (92) (1 equiv.) with p-nitrostyrene (81a) (3 equiv.) at 1.5 GPa led to a mixture of nitroso-acetals 93-95. In this reaction, p-nitrostyrene (81a) first reacts as a dienophile in the normal electron-demand Diels-Alder reaction, it then reacts as a heterodiene in the inverse electron-demand hetero-Diels-Alder reaction and, finally, it acts as a dipolarophile in the [3 + 2] cycloaddition (Scheme 7.23). 

W-Acylsultams of glyoxylic acid 1.134 (R = CHO) and nitroso compound 1.134 (R = NO) are valuable dienophiles. Cycloadditions of 1.134 (R = CHO) with 1-methoxybutadiene mediated by Eu(fod)3 are highly selective [466] (Figure 9.36), and take place via a chelated complex. The reactions of the nitroso compound 1.134 (R = NO) with cyclopentadiene and cydohexadiene give useful results [467], though heterodienes 9.65 do not. The observed results ware interpreted in a fashion similar to that shown in Figure 9.32. 

Arylnitroso compounds of various types react with both electron-rich and electron-deficient dienes under mild conditions (usually 0-l(X)°C) to produce dihydrooxazines. As mentioned in the preceding section, Kresze s group has looked in considerable detail at orientational preferences and kinetics of [4 + 2] cycloadditions with various phenylnitroso compounds and substituted 1,3-dienes. Table 3-1 contains some of the results of cycloadditions of aromatic nitroso dienophiles with representative unsymmetrical 1- and 2-substituted dienes." Scheme 3-1 shows the subtle regiochemical trends that can be observed in a series of these reactions. These results were rationalized based on consideration of putative dipolar and nonpolar transition states and their relative stabilization by aromatic electron-donating and -withdrawing substituent groups. 

Work has recently appeared on the synthesis and cycloaddition reactions of vinylnitroso compounds. - Although these compounds are capable of acting either as heterodienes or as nitroso dienophiles, their reactivity is critically dependent on their structure. In general, if the vinylnitroso system contains any )8 substituents, the compounds will react as dienophiles if there is no /3 substituent, the system prefers to act as the 4tt component of a Diels-Alder reaction and will react with dienophiles. 

Intramolecular cycloaddition reactions with nitroso dienophiles have been used in a number of syntheses of alkaloids. For example, cycloaddition of the acyl nitroso compound formed from the hydroxamic acid 31 gave the dihydro-oxazine 32, which was converted to the alkaloid gephyrotoxin 223AB (3.31). ... 

The normal demand hetero Diels-Alder cycloaddition between nitroso reagents 171 and dienes 172 leads to the formation of 3,6-dihydro-1,2-oxazines 173 via the concomitant stereoselective formations of a C—N and a C O bonds (Scheme 41.36). Several nitroso dienophiles like the a-chloronitroso, arylnitroso, or acylnitroso compounds are known to react efficiently in cycloadditions. Chiral nonracemic chloronitroso and acylnitroso compounds have been developed to achieve diastereoselective nitroso Diels-Alder reactions, and recently Yamamoto and co-workers reported on the first enantioselective-catalyzed cycloaddition with a pyridylnitroso dienophile. ° ... 

Aliphatic and aromatic nitroso compounds are powerful dienophiles and react with a variety of acyclic, cychc and heterocyclic 1,3-dienes producing cyclic hydroxylamines. The reaction proceeds with a high regioselectivity at room temperature (equation 99 291-293 Asymmetric variation of the reaction with chiral copper-BINAP catalyst has been reported ". The cycloaddition is reversible and some amounts of diene and nitroso components may be observed in reaction products. 

Readily available a-chloro nitroso compounds have been used on a number of occasions as hetero-dienophiles since the first report appeared in 1947. The initial adduct of this reaction is unstable and if alcohol solvent is used a dihydrooxazine hydrochloride (89) is produced (equation 33). The cycloadditions proceed under very mild conditions with most 1,3-dienes and, as outlined in Scheme 13, Ae regio-selectivity is excellent. - ... 

The use of acyl nitroso compounds as dienophiles was first described by Kirby. The primary method for generating these highly reactive, unstable species is by periodate oxidation of hydroxamic acids. The acyl nitroso compounds can be trapped in a Diels-Alder reaction with 9,10-dimethylanthracene to give adduct (95) (equation 36) which can act as an alternative source of the dienophile, since retro [4 + 2] cycloaddition occurs under mild thermal conditions. 

Vinyl nitroso compounds have proven to be rather interesting species since they can act as either lit or 4ir components in Diels-Alder cycloadditions. The particular reaction which occurs is dependent upon the structure of the vinyl nitroso compound and the diene which are used. For example, vinyl nitroso compound (112), prepared from oxime (111), reacts as a dienophile (equation 44). On the other hand, nitroso compound (113) (equation 45) reacts with cyclopentadiene to give oxazine (114). Not enough data are presently available to interpret these results satisfactorily. 

Methods for the reductive cleavage of the N—O bond in hydroxylamines have assumed increasing importance in synthesis because it is a key step in routes based on cycloaddition of nitrones and nitroso compounds. Inter- and intra-molecular cycloadditions of nitrones lead to the formation of tetrahydroisox-azoles (Scheme 25) these compounds are then converted into amino alcohols by reductive cleavage of the N—-O bonds. This type of reaction sequence has been exploited in the synthesis of a number of alkaloids.Nitroso compounds, particularly those activated by electron-withdrawing substituents, act as dienophiles in the Diels-Alder reaction (Scheme 26) and the cycloadducts can be used as synthetic intermediates by cleaving the N—O bonds. 

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