Cyclization nitrone

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

This series is punctuated by several unusual synthons, one the reaction of tropone (567) with aniline to give (568). The cyclization of (569) with sodium hydroxide gave (570) (67AHC(8)277, 69M602). The reaction of in situ generated benzyne with the nitrone (571) produced (572) (67AHC(8)277). 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

A one pot synthesis of isoxazolines 78a-f involves base mediated 1,4-addition of malonate or alcohol 76 possessing an allylic substituent, conversion of the resulting nitronate to the a-chloroaldoxime (hydroxymoyl chloride 77) and its subsequent dehydrohalogenation to the nitrile oxide intermediate which cyclizes to isoxazoline 78 (Eq. 7, Table 6) [32]. 

Thioethers 210 are smoothly formed upon cyclization of silyl nitronates 209, generated in situ from the nitro compounds 208, on treatment with N,0-bis(trimethylsilyl)acetamide (BSA, Scheme 24) [57]. Fluorodesilylation of 210 gave the AT-oxide 212, presumably via highly reactive aldehyde 211, which was reduced to the target compound actinidine 213 in an overall 27% yield. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

N-donor ligand. The reaction appears to proceed via an acyclic iminoplatinum(II) intermediate that undergoes a subsequent intramolecular cyclization. Some mechanistic aspects of this versatile reaction have been elucidated.225,226 A4-l,2,4-oxadiazolines have been prepared by the [2+3] cycloaddition of various nitrones to coordinated benzonitrile in m-[PtCl2( D M SO)(PhCN)] precursors.227,228 Racemic and chiral [PtCl2(PhMeSO)(PhCN)] complexes have also been used in order to introduce a degree of stereoselectivity into the reaction, resulting in the first enantioselective synthesis of A4-l,2,4-oxadiazolines, which can be liberated from the complexes by the addition of excess ethane-1,2-diamine. 

Nitrocycloalkanones can be successfully C-allylated by Pd(0)-catalyzed reaction with various allyl carbonates and 1,3-dienemonoepoxides under neutral conditions, as shown in Eqs. 5.56 and 5.57, respectively.801 The product of Eq. 5.56 is converted into cyclic nitrone via the reduction of nitro group with H2-Pd/C followed by hydrolysis and cyclization.80b... 

Conjugated nitrones are formed by intramolecular reductive cyclizations of nitro groups onto ketones the resulting nitrones give starting materials for preparing azasteroids. An example is shown in Eq. 8.43.66... 

Another approach to cyclic nitronates has been developed by Rosini et al. in which nitro-aldol and subsequent cyclization is used as a key step. For example, 2,3-epoxy aldehydes react with ethyl nitroacetate on alumina surface in the absence of solvent to give 4-hydroxyisoxazoline 2-oxides in good yields (Eq. 8.80).130... 

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare 3,y-epoxyhydroxylamines, 46, and oxazetidine, 47 <06OL3923>. Upon deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the P,y-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional nitrones were examined as well and all provided similar yields of the 3,y-epoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines from the 5-endo-tet cyclization were formed in this cyclization. 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

Cyclization of oximes containing y-,d-, or oo-alkenyl substituents, upon treatment with /V-bromosuccinimide (NBS) or iodine leads in good yields to the corresponding cyclic nitrones or their dimeric H- bonded hydriodide salts (290). 

In the case of 3,y-enoximes (104) an unusual N -enJo-cyclization occurs. This results in the formation of bromomethylpyrroline-IV-oxide (106) rather than in the expected four-membered nitrone (105) (Scheme 2.42) (291). 

As a result of Ag (I) catalyzed cyclization of allenic oximes (124) and (125), stable five- (126) and six-membered (127) cyclic nitrones were obtained (Scheme 2.46) (298a). Recently, a novel method of pyrroline-type nitrone formation via P-allenyl-oxime cyclization has been described (298b). 

High diastereoselectivity occurs in the addition of lithiated methoxyallene to chiral cyclic nitrones. The hydroxylamines obtained can be easily transformed into derivatives of 1,2-oxazine hydroxylamine, which are products of a novel [3 + 3] cyclization reaction (Scheme 2.182) (646, 647). 

Reactions of Allylation and Propargylation Allylation of prochiral and chiral nitrones (292) with allylmagnesium chloride leads to homoallylic hydroxylamines (416), which via an iodo cyclization step are converted to 5-(iodomethyl)isoxazolidines (417) (Scheme 2.186) (202, 213, 666-668). 

Addition of allylic zinc bromides to nitrones, generated in situ from allylbro-mides and zinc powder in THF (670), allyltributylstannane (671) and lithiated allyl ferf-butyldimethylsilyl ether (672), proceeds regioselectively in good yields and is used to synthesize homoallyl hydroxylamines (Scheme 2.189). The latter were subjected to an iodo cyclization reaction (see Scheme 2.186). 

The formation of derivatives of 2,3,6,8-tetraazabicyclo-[3.2.1]3-octene (425) arises from an intramolecular nucleophilic addition to the nitrone group of hydra-zone (424). Compound (424) was prepared by reaction of 2-acyl-3-imidazoline-3-oxides (423) with hydrazine. From the cis- and frans-derivatives (424), exo- and enr/o-isomers (425) were obtained (Scheme 2.197). The reaction of intramolecular cyclization does not occur in cases with monosubstituted hydrazones (316). 

Nucleophilic addition of primary o.-R -allylamine to nitrone followed by a reverse Cope cyclization and Meisenheimer rearrangement gives the oxadiazi-nanes (426a-h) (Scheme 2.198). These reactions have found use for the preparation of oxadiazines, vicinal aminohydroxylamines, and diamines the latter are of particular interest as chiral ligands (683, 684). 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

Intramolecular Cyclization of y-Functionalized AN The most commonly used procedure for the synthesis of five-membered cyclic nitronates (5) is... 

Yet another approach to the synthesis of five-membered cyclic nitronates (5) is based on the Henry condensation of a-halo-substituted aldehydes (9) with primary AN followed by cyclization of nitroaldols (Scheme 3.14, Eq. 4) to give five-membered nitronates containing the hydroxy group at the C-4 atom. 

When discussing the specific features of various leaving groups in the synthesis of nitronates presented in Scheme 3.12, the possibility of the use of the OH group as the leaving group should be separately discussed. As in the synthesis of acyclic nitronates, the Mitsunobu procedure (10) is apparently suitable for intramolecular cyclization of acyclic y-nitro alcohols (Scheme 3.17). 

Unfortunately, only two attempts were made to use this approach in the synthesis of five-membered cyclic nitronates (5), and only one of them could be considered as successful. In the latter case, isomeric nitrocyclopropane was obtained as the major product. Only a-functionalized nitro alcohols are readily involved in the Mitsunobu cyclization. However, the possibility of isomerization of by-products, nitrocyclopropanes, which was mentioned in the discussion of Scheme 3.16, caused the revision of this process as a procedure for the synthesis of five-membered cyclic nitronates. (A new approach to the synthesis of initial y-nitro alcohols from readily available AN was documented in Reference 64)... 

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