Cycloaddition reactions alkyl nitronates

Alcohol derivatives 1.155 (Y = CHOHR) are useful as auxiliaries in a-keto-ester reductions [540] or [4+2] cycloadditions of aciylates [548]. 6-Lactams are obtained from imines 1.155 (Y = CH=NAr) with a high enantiomeric excess after reaction with ester enolates and decomplexation [549]. Alkylations of benzylimine 1.155 (Y = Ph2N=CH) give interesting results [539], and some 1,3-dipdar cycloaddition reactions with nitrones have been described [550],... 

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy-clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized. 

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... 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

I. Intermolecular [3+2]-Addition of Nitronates to Olefins Of all known types of nitronates (see Section 3.2), alkyl- and silyl nitronates as well as cyclic C5-C6 nitronates are involved in [3+ 2]-cycloaddition reactions. Detailed comparative kinetic studies for different types of nitronates have not been reported. However, a few data (162, 336, 337) allow one to deduce some sequences (Chart 3.10). 

Silyl Nitronates The characteristic features of the behavior of SENAs in [3+ 2]-addition reactions (75, 133, 175-177, 185, 186, 189, 201a, 203, 205, 206, 216, 355-362c) are virtually identical to those of acyclic alkyl nitronates considered in the previous section. As mentioned above, minor but more reactive Z-tautomers of SENAs derived from primary AN can be detected by cycloaddition reactions (see Section 3.3.4.1 and Scheme 3.128). 

Other Types of Nitronates in [3 + 2]-Cycloaddition Reactions with Olefins As mentioned above, of all known types of nitronates, only alkyl and silyl nitronates can be involved in [3 + 2]-cycloaddition reactions with olefins. However, furoxans (161), which can also be considered as cyclic nitronates, can react with active dipolarophiles under extreme conditions to give nitrosoacetals (162) (Scheme 3.131, Eq. 1). 

The reactions of alkyl nitronates (164) or (165) derived from a-functionalized primary AN with monosubstituted acetylenes produce mixtures of diastereomeric aziridines (166) in moderate to high yields. Most probably, the first step of this process involves normal concerted cycloaddition to give the corresponding intermediates A, which were not detected due to their fast rearrangement to give acyl-substituted aziridines (166). The reaction is regioselective and stereospecific. The latter fact was demonstrated by French researchers (95). 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

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. 

The intermolecular alkylation of metallo nitronates with various alkyl halides is limited. The addition of methyl iodide to the silver salt of an aryl nitro-methane provides the corresponding methyl nitronate in moderate yield (Eq. 2.13) (150), which has also been extended to the silver salt of trinitromethane (Scheme 2.16) (151-153). However, in the case of primary halides, both O- and C-alkylation are observed. For secondary and tertiary halides, only O-alkylation is observed, but in low yields. Unfortunately, under the reaction conditions, the starting alkyl halide can undergo dehydrohalogenation to provide the corresponding alkene, which then undergoes [3+2] cycloaddition with the alkyl nitronate. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

The use of mediators to improve reactivity or selectivity in nitrone cycloaddition chemistry begins with the nitrone generation step. As is well known, the N-alkyla-tion of oximes provides one of the most direct and convenient synthetic routes to N-alkylated nitrones from readily available aldehydes and ketones. Electrophilic mediators have been employed to activate alkenes for N-alkylation, both in intramolecular and intermolecular reactions. They include activation of the internal alkene function by the action of (a) strong nonmetallic electrophiles such as phenyl-selenenyl sulfate (159), and (b) metallic catalysts such as Ag(I) (160) and Pd(II) ions... 

The reactions of chiral cychc alkyl nitronates have been described (62-64). These nitronates are intermediates in a tandem[4- -2]/[3- -2] cycloadditions. 

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

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