Alkyl nitronates intramolecular

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 combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

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... 

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). 

Treatment of 2- 5//-dibenz[i>,/]azepin-5-yl acetaldehyde (16), prepared in 68% yield by /V-alkylation of 5/7-dibenz[A,/]azepine with bromoacetaldehyde diethyl acetal followed by acid hydrolysis, with methyl hydroxylamine yields the isolable nitrone 17, which in refluxing toluene undergoes intramolecular 1,3-dipolar cycloaddition at the CIO —Cl 1 alkene bond to give 2,3,3a, 12b-tetrahydro-2-methyl-3,8-methano-8//-dibenz[i>,/]isoxazolo[4,5-r/]azepine (18).235... 

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. 

C-Alkylation has also been observed in intramolecular reactions where the O-alkylation is not favoured.76 This property has been recently exploited in a stereocontrolled intramolecular cyclization of nitronate of nitro sugar 101 (Scheme 32), that provided the novel bicyclic nitrolactone 102, a synthetic precursor of tripeptide 103, that includes the first reported polyhydroxylated cyclopentane (3-amino acid.77... 

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. 

The intramolecular oxime-alkene cycloaddition (lOAC) proceeds via N—H nitrones, in contrast to most other nitrone syntheses, which afford N-alkylated 1,3-dipoles. This process was used by WUdman and co-worker (332) in the synthesis of 6-hydroxybuphanidine and 6-hydroxypoweUine, and since then by... 

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