Silyl nitronates 1,3-dipolar cycloaddition

One-pot tandem sequences involving 1,4-addition and ISOC as the key steps have been developed for the construction of N and 0 heterocycles as well as of carbocycles [44]. In this sequence, the nitronate arising from 1,4-addition to an a, -unsaturated nitro alkene is trapped kinetically using trimethyl silyl chloride (TMSCl). The resulting silyl nitronate underwent a facile intramolecular 1,3-dipolar cycloaddition with the unsaturated tether (e.g.. Schemes 20-22). 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Eguchi and Ohno have used silyl nitronate induced 1,3-dipolar cycloaddition for functionalization of fullerene C60 (Eq. 8.76).127a Nitrile oxides also undergo 1,3-dipolar cycloaddition... 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

Theoretical calculations at DFT level agree that the reactions of nitrones with silyl ketene acetal proceeds via 1,3-dipolar cycloaddition followed by the transfer of the silyl group, yielding an open-chain product (641). 

Synthesis of Dialkylboryl Nitronates Approaches to the synthesis of boryl nitronates are similar to the strategy for the synthesis of silyl nitronates developed in more detail (see Section 3.2.3). However, only four studies have dealt with the synthesis of boryl nitronates (217, 229-231). The absence of interest in this class of compounds is apparently attributed to the fact that they are not involved in 1,3-dipolar cycloaddition reactions and, consequently, are unlikely to find use in organic synthesis. 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Several years later, Ioffe et al. (16) demonstrated that silyl nitronates also could be engaged in the dipolar cycloaddition with alkenes. These silylated isoxazolidine cycloadducts were then converted to the corresponding isoxazolines by treatment with sodium methoxide (Scheme 2.2). 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

TABLE 2.32. DIPOLAR CYCLOADDITIONS OF MONOSUBSTITUTED SILYL NITRONATES WITH METHYL ACRYLATE... 

TABLE 2.35. EFFECT OF STERIC BULK ON THE DIPOLAR CYCLOADDITION OF SILYL NITRONATES... 

TABLE 2.36. DIPOLAR CYCLOADDITIONS OF A SILYL NITRONATE WITH HETERODIPOLAROPHILES... 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

The wide variety of methods for the preparation of alkyl nitronates, gives rise to a broader diversity of structures compared to silyl nitronates. Alkyl nitronates can be grouped into two subclasses, acyclic and cyclic. Both subclasses participate in dipolar cycloadditions with similar reactivity, however, minor differences are manifest in their stability and stereoselectivity. Additionally, the ability to prepare cyclic nitronates allows access to a wide variety of novel, multicyclic ring stractures. 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

The reaction mechanism involves silylation of a nitro group oxygen followed by deprotonation to give the intermediate silyl nitronate 137, which undergoes 1,3-dipolar cycloaddition to give the product 136 in excellent yields and with diastereomeric excess ratios often exceeding 99 1 (Scheme 15). 

Heteroatomic dipolarophiles are competent in the dipolar cycloaddition of nitronates. The in situ generated thioaldehydes and thioketones react with silyl nitronate 120 to afford the 1,4,2-oxathiazolidine in good yield (Table 2.36) (113-116). 

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