Oximes intramolecular cyclization

The cyclohexa-fused isoxazoloquinolizine 466 can be prepared (as a 1 1 mixture of diastereomers, each racemic) by intramolecular cyclization of the oxime 465 using sodium hypochlorite (Equation 194) <1996T4133>. 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

Marchand and co-workers ° synthesis of 5,5,9,9-tetranitropentacyclo[5.3.0.0 .0 °.0 ] decane (52) reqnired the dioxime of pentacyclo[5.3.0.0 .0 °.0 ]decane-5,9-dione (49) for the incorporation of the four nitro groups. Synthesis of the diketone precursor (48) was achieved in only five steps from cyclopentanone. Thus, acetal protection of cyclopentanone with ethylene glycol, followed by a-bromination, and dehydrobromination with sodium in methanol, yielded the reactive intermediate (45), which underwent a spontaneous Diels-Alder cycloaddition to give (46). Selective acetal deprotection of (46) was followed by a photo-initiated intramolecular cyclization and final acetal deprotection with aqueous mineral acid to give the diketone (48). Derivatization of the diketone (48) to the corresponding dioxime (49) was followed by conversion of the oxime groups to gem-dinitro functionality using standard literature procedures. 

Synthesis of novel bicyclic heterocyclic systems involving aziiidine ring formation has been described. The sodium salts of tosylhydrazones 11 decomposed by heating in benzene and gave aziridinopyrroloindoles 12 in yields up to 73% (equation 5) . Intramolecular cyclization of oxime ether 13 in the presence of base (for example, DBU) in acetonitrile afforded aziridinopyrrolidine 14 in yields up to 51% (equation 6) °. 

The intramolecular cyclization of oximes with alkene substituents to dihydropyrroles in the presence of radical initiator or by heating was also describedThus, oxime 83 underwent a tandem 1,2-prototropy-cycloaddition sequence and gave an unstable cycloadduct 84, which on treatment with NaOH afforded indolizine 85 (equation 36). ... 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

In many of these cases, the nucleophile is a C=C double bond (usually an alkenic group and less frequently an aromatic group). Alkenic oxime mesylates enable intramolecular cyclization by an electrophihc addition of the double bond to the electrophilic intermediate. These reactions are terminated by a proton loss. 

Cycloaddition of Nitroalkanes/Nitroalkenes to Unsaturated Compounds. 9.2 Inter- and Intramolecular Cyclization of Oximes... 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

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). 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Intramolecular cyclization of the chiral oxime ether 993 in the presence of isopropyl iodide and triethylborane affords the 3,4,5-trisubstituted tetrahydropyran-2-one 994 in poor yield but with good diastereoselectivity (Equation 388) <2003JOG5618>. Similarly, a triethylborane-induced atom transfer radical cyclization of 3-butenyl 2-iodoacetate leads to 4-(iodomethyl)tetrahydropyran-2-one. Higher yields are achieved when conducting the reaction at lower concentrations (Equation 389) <2000JA11041 >. 

An exceptionally high influence of the C-substituent at the C=N bond on the cyclization direction has been observed (89KGS927) in a large series of derivatives 80. In the solid state and in solution in several solvents, these compounds exist solely as the isomer 80B. Independently of the mutual disposition of the oxime and hydrazone moieties—i.e., for either X = NCOR, Y = O or for X = O, Y = NCOR and for X = Y = NCOPh—the intramolecular cyclization proceeds only along the path involving nucleophilic XH or YH group addition to the more reactive and less hindered aldoxime or aldohydrazone C=N bond. However, in the gas phase, the presence of small amounts of the isomers 80A and 80B was detected. 

The intramolecular oxime-alkene cyclizations, also known as tandem 1,2-prototropic-cycloadditions, with nonactivated alkenes was first reported by Oppolzer and Keller in 1970 <70TLiii7> but their use for the heterocycles of this chapter was first reported in the 1990s <91T4007>. The methodology is shown in Schemes 46 and 47 in an expedient synthesis of chiral, unfunctionalized... 

Intramolecular cyclization of the ry -isomer of iV-chloroacctyI oxime 99 produced l//-bcnzo[z/][ l, 2,6]oxadiazocin-2(3//)-one 100 only in 3% yield, while the major intermolecular macrocyclic product 101 was obtained in 41% yield (Equation 14 <2001MI140>). 

Nitrosoalkenes.1 Nitrosoalkenes are usually generated by reaction of a-halo oximes with bases, and have been used for [4 + 2] cycloadditions. They are also generated efficiently from a-chloro silyloximes by fluoride ion. This elimination is used to effect an intramolecular cyclization of the nitrosoalkene generated from 1 to give a mixture of the dihydrooxazines 2 and 3. The choice of the metal fluoride is critical for acceptable yields. Highest yields are obtained when the nitrosoalkene is generated slowly by a... 

Anodic oxidation of azomethine, hydrazone, oxime, formazane, and semicarbazone structures has been used to initiate the intramolecular cyclization [119] under formation of heterocycles like triazoles [126,127], oxadiazoles [128,129], triazolinones [129], benzoxa-zoles [130,131], benzimidazoles [130,131], pyrazoles [132], indazoles [133], furoxanes [134], and tetrazolium salts [135] (see Chapter 18). Some of these reactions can be performed advantageously by indirect electrolysis using tris(4-bromophenyl)amin or 2,3-dihydro-2,2-dimethylphenothiazine-6(l/7)-one as mediators [119,136]. Two examples are given in Eqs. (19) and (20). 

First, the intramolecular cyclizations between carbonyl compounds and olefins will be described. This field can be classified into three types as illustrated in O Fig. 13. One is a type of cyclization between carbonyl compounds and a, 8-unsaturated esters (type [A]), the next is a type of cyclization between carbonyl compounds and simple olefins (type [B]), and the last is a type of cyclization between carbonyl compounds and oximes (type [C]) (O Fig. 13). 

The efficient activation of oxime sulfonates by organoaluminum reagents enables the intramolecular cyclization of alkenic oxime mesylates, which involves the electrophilic addition of the intermediate ni-trilium ion to the double bond. This results in the direct formation of a wide variety of structurally diverse carbocyclic and heterocyclic systems. Four distinct cyclization modes, i.e. endo(B)-endo, endo(B)-exo, exo(B)-endo and exo(B)-exo are possible, as shown in Scheme 4P The values in parentheses refer to the yields obtained using SnCU. 

A further example of a one-bond-forming pyridine synthesis is provided by the intramolecular cyclization of 0-alkyl-oximes such as (3) under conditions of flash vacuum pyrolysis. Cyclization occurs as a result of the generation of conjugated iminyl radicals (4) (Scheme 1). ... 

The Naito group has also prepared pyrrolidines [23] on solid phase by a combination of intermolecular radical addition to alkene 43 (Scheme 10) followed by intramolecular oxime ether cyclization to yield 44. These reactions proceeded sluggishly with triethylborane at room temperature, while the analogous solution-phase process was kinetically much faster. Radical additions to the phenylsulfonyl oxime ether 45 were reported by Jeon et al. [24]. Yields were better with primary and secondary alkyl iodides, and the tandem cyclization sequence with iodide 46 to afford bicyclic 47 was also accomplished, albeit in modest yield. 

The radicals can also be trapped efficiently by oxime ethers this is a useful approach to intramolecular cyclization . 

Fig. (6). A simple and enantioselective synthesis of (+)-albicanol (66) is desccribed. The hydroxy-ketone (60), prepared from the (-) Wieland-Miescher ketone, undergoes ring cleavage with lead tetra-acetate in methanol. The resulting product on ketalization leads the formation of the product (61) which is converted to oxime (63) by the standard reactions. Intramolecular cyclization followed by reductive hydrolysis and methylenation afforded (+)- albicanol (66).

Structurally similar compound 99 with trifluoromethyl group in isoxazole ring is prepared by the intramolecular cyclization of alkynyl oxime 98 (Scheme 12.14). °... 

Since oximes of erythromycin are less prone to intramolecular cyclization than the parent compound, a structure-activity study was conducted on a series of 9-(0-alkyl)oxime derivatives of erythromycin [84]. From this work, roxithromycin, the 9-[D-(2-methoxyethoxy)methyl]oxime (12), was selected for further development. The isomer with E stereochemistry (oxime substituent syn to C-8 of lactone) is more active than the Z isomer [84]. The X-ray crystal structure of roxithromycin reveals a conformation of the lactone similar to that of erythromycin [85]. The similarity was also established by solution NMR studies, which suggested that the orientation of the oxime substituent helped to explain the increased hydrophobicity of roxithromycin and its greater penetration into certain tissues [86, 87]. 

The allenic oxime (135) undergoes a silver-catalyzed cyclization to form the nitrone (136) (Equation (10)) which may be trapped as the dipolar adduct (137) with vV-methylmaleimide <91JCS(Pl)659>. Azepinonitrones have also been prepared by the spontaneous intramolecular cyclization of alky-nylhydroxylamines, prepared by the reduction of the corresponding oximes <92TL742l, 92TL7425>. 

Oximes can react with triflic anhydride to afford amidines or enamines after a nucleophUic capture of the iminocarhocation formed (111). The activated oxime can also eliminate to form the corresponding nitrile in the presence of imidazole or he converted into henzisoxazoles through an intramolecular cyclization process. ... 

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