Nitrones with acid

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

Because of their higher oxidation level with respect to both amides and nitrones, hydroxamic acids have been sought from either by oxidative processes. 

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. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

The theoretical investigations of Lewis acid-catalyzed 1,3-dipolar cycloaddition reactions are also very limited and only papers dealing with cycloaddition reactions of nitrones with alkenes have been investigated. The Influence of the Lewis acid catalyst on these reactions are very similar to what has been calculated for the carbo- and hetero-Diels-Alder reactions. The FMOs are perturbed by the coordination of the substrate to the Lewis acid giving a more favorable reaction with a lower transition-state energy. Furthermore, a more asynchronous transition-structure for the cycloaddition step, compared to the uncatalyzed reaction, has also been found for this class of reactions. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

Scheme 10.7 1,3-Dipolar cycloadditions of nitrones with 1,1-diethoxypropene catalysed by oxazaborolidines derived A-tosyl-L-a-amino acids.

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

The electron-donor N -oxide oxygen atom of a nitrone makes it suitable for com-plexation and protonation. Such properties of nitrones have been widely used to influence their reactivity, using Lewis acids and protonation in nucleophilic addition reactions (see Section 2.6.6). In this chapter, the chemistry of nitrones with various metal ions [Zn (II), Cu(II), Mn (II), Ni (II), Fe (II), Fe (III), Ru (II), Os (II), Rh (I), UO2 2 ] (375, 382, 442-445), and diarylboron chelates is described (234—237, 446). Accurate descriptions of the structures of all complexes have been established by X-ray analysis. 

Rearrangements of nitrones due to migration of the A-oxide oxygen can be induced both, photochemically and by various reagents, but in specific conditions it can proceed spontaneously. On one hand, such transformations are caused by the O-nucleophilic character of nitrones able to react easily with acid anhydrides, their halo anhydrides, sulfonyl chloride and other agents on the other hand, by a significant CH-acidity of a-alkyl groups. 

In most cases, the stereochemical course of heterocyclic addition can be altered by pre-complexation of nitrones with Lewis acids. In the absence of complexation agents (Et2AlCl, TiCLi), addition of lithio-hetaryl derivatives to chiral 3-alkoxy nitrones (292a-d) gives P-alkoxy-a-hydroxylamino-2-alkylhetaryls (346a-d) in good yields with. vy/i-selectivity. In the presence of diethylaluminum chloride the reaction leads to the same adducts, but with anti-selectivity (Scheme 2.150) (Table 2.12) (581). 

Nucleophilic Perfluoroalkylation of Nitrones The reaction of a,N-diaryl nitrones with (trifluoromethyl)trimethylsilane (TMSCF3) gives O-trimethylsilyl ethers of a-(trifluoromethyl)-hydroxylamines. This reaction is initiated by potassium ten -butoxide. Removal of the trimethylsilyl group on acid treatment leads to a-(trifluoromethyl)hydroxylamines, whereas catalytic hydrogenation gives a-(trifluoromethyl)amines (Scheme 2.194). 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

Finally, the catalytic enantioselective 1,3-dipolar cycloaddition reaction has recently been developed to be a highly selective reaction of nitrones with electron-deficient alkenes activated by chiral Lewis acids. High levels of regio-, diastereo-, and enantioselectivities can now be reached using catalysts 89 <2000JOC9080>, 90 <2002JA4968>, or 91 <2005JA13386> (Scheme 29). 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

The enantioselective inverse electron-demand 1,3-dipolar cycloadditions of nitrones with alkenes described so far are catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminium complexes. However, the glyoxylate-derived nitrone 256 favors abidentate coordination to the catalyst, and this nitrone is an interesting substrate, since the products that are obtained from the reaction with alkenes are masked ot-amino acids (Scheme 12.81). 

The synthetic approach used in this work is shown in Scheme 9. Two known solution pathways were used to convert shikimic acid to an epoxide intermediate. In fact, both the (-)35 and the (+)36 enantiomers were formed. After minor synthetic transformations, these epoxides were linked to Ten-tagel S aminomethyl resin with an o-nitrophenyl-derived photocleavable linker 7437 via amide bond formation to give intermediate 75. The first point of variation was added via various iodo-benzyl nitrone carboxylic acids 76 via 1,3-dipolar addition/esterification reactions. Highly constrained resin-bound tetracyclic hydrooxazoles 77 were thereby produced. 

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