Cyclic nitronates alkylation

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

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. 

This reaction is characterized by very high yields of target products (35a) and the almost complete absence of side reactions, including C-alkylation. It should be noted that the six-membered cyclic nitronate (35b), in which the C-4 atom is involved in the carbonyl group, was synthesized only according to this scheme. 

The latter is involved in the intramolecular alkylation of one of the nitro groups accompanied by elimination of the nitronium cation. It was not rigorously established whether the reaction afforded six-membered cyclic nitronate (35 d) or... 

Synthesis ofSeven-membered Cyclic Nitronates Cyclic nitronates containing more than four carbon atoms in the ring remain virtually unknown. Convenient procedures for the synthesis of these compounds are lacking. In particular, intramolecular alkylation of 5-bromo-l-nitropentane affords nitrocy-clopentane rather than the corresponding seven-membered cyclic nitronate (169) (Scheme 3.48). 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

Stability of Cyclic Nitronates For steric reasons, fragmentation of five-and six-membered cyclic nitronates cannot follow pathways presented in Scheme 3.72. Hence, stability of these compounds can be substantially higher than that of alkyl nitronates. These compounds generally exist in the crystalline state and can be purified by recrystallization or liquid chromatography. Selected melting points of nitronates are given in Table 3.8. 

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). 

Silylation of 3-alkyl-substituted five-membered cyclic nitronates remains virtually unknown, although one example of the successful synthesis of the corresponding nitroso acetal was documented (Scheme 3.203) 475. 

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. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

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. 

In six-membered, cyclic nitronates, the H NMR resonance for HC(3) appears in a similar range to that of HC(a) for alkyl-substituted, acyclic nitronates (Table 2.19) (14,58,65,68,69). Interestingly, there is an downfield shift of HC(6), when there is a ring fused at C(5)/C(6), as opposed to the attachment of an ether or methyl group. 

Brandi and co-workers (271) applied the familiar a,p-unsaturated esters 158 and 159 in reactions with cyclic nitrones. In these reactions, the isoxazolidine products were formed as intermediates, which immediately underwent N-alkylation to give tricyclic compounds. The reactions proceeded in both cases with moderate selectivities of 39% de for 158 and 57% de for 159. Most remarkably, the reactions proceeded with opposite face selectivity. 

Cyclic nitrones 1490 (A -imidazoline 3-oxides) react regioselectively with alkyl phenylpropiolates 1491 (or with dimethyl acetylenedicarboxylate) to give the corresponding 2-phenyl-3a,4,5,6-tetrahydroimidazo[l,5- ]isoxazole-3-carboxylic acid alkyl esters 1492. Subsequent thermal, base (piperidine, triethylamine, or alkoxide) induced ringopening reactions led to imidazoles 1493 (Scheme 385) <2004SC1617, 2000TL5407>. 

---