Enantioselective addition of nitrones to activated cyclopropanes

In this paper, we demonstrate the first examples of chiral Lewis acid catalysis in the formation of tetrahydro-1,2-oxazines with very high enantioselectivity starting with diactivated cyclopropanes and nitrones (>90% yields and ee). Reactions with racemic substituted cyclopropanes provide approximately 1:1 diastereomeric tetrahydro-1,2-oxazine products with high enantioselectivity. Mechanistic information for the formation of the tetrahydro-1,2-oxazines is also detailed.     

Expedient synthesis of pyrrolo[1,2-a]indoles: preparation of the core of yuremamine

Pyrrolo[1,2- a]indoles are conveniently prepared from tetrahydro-1,2-oxazines, which in turn are generated through the reaction of nitrones with 1,1-cyclopropanediesters. The synthetic route proves to be highly diastereoselective and provides access to the core of the recently discovered pyrrolo[1,2- a]indole natural product yuremamine.     

Three-component homo 3 + 2 dipolar cycloaddition. A diversity-oriented synthesis of tetrahydro-1,2-oxazines and FR900482 skeletal congeners

[reaction: see text] The reaction of nitrones, formed in situ by reaction of hydroxylamines with aldehydes, with 1,1-cyclopropanediesters results in the formation of tetrahydro-1,2-oxazines via a homo 3 + 2 dipolar cycloaddition. This three-component coupling allows for the formation of a diverse array of cycloadducts with excellent diastereoselectivity (>95%) and yields (66-96%). The procedure has been used in the two-step preparation of congeners of the FR900482 skeleton.     

Magnesium iodide promoted reactions of nitrones with cyclopropanes: a synthesis of tetrahydro-1,2-oxazines

Anhydrous magnesium iodide (MgI(2)) is shown to be an effective promoter of the "homo 3+2" dipolar cycloaddition of nitrones with 1,1-cyclopropane diesters. In almost all cases the products tetrahydro-1,2-oxazines are formed in excellent yields. The reactions are highly diastereoselective for a cis relationship between the substitutents at the 3- and 6-positions on the tetrahydrooxazine ring. As an alternative to using a preformed nitrone, the reaction may be performed in a 3-component sense by combining an aldehyde, an hydroxylamine, and the cyclopropane in the presence of catalytic MgI(2).     

Retro-ene reactions in heterocyclic synthesis,III. A new route to 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines

Methyl (E)-4,4-dimethyl-5-oxo-2-pentenoate ( 1 , X = O) reacted with 1,2- or 1,3-aminoalcohols 3 to yield oxazolidines 4a-c or tetrahydro-1,3-oxazines 4d,e. The corresponding imino ester 1 (X = NBu-t) also gave 4 on reaction with 3 . Compounds 4 on heating at 230° yielded 4,5-dihydrooxazoles 5a-c or 5,6-dihydro-4H-1,3-oxazines 5d,e along with methyl 4-methyl-3-pentenoate ( 6 ).     

Synthesis of phosphodiesterase IVb inhibitors 2. Stereoselective synthesis of hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one derivatives

The total stereoselective synthesis of two highly potent phosphodiesterase IVb inhibitors from nitroethane, isovanillin, and ethyl vinyl ether was developed. The compounds obtained are the derivatives of hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one. The strategy proposed involves silylation of six-membered cyclic nitronates as a key step leading to 5,6-dihydro-4H-1,2-oxazines with the group CH₂FG (FG = N₃ or OH) at the C(3) atom.     

Recent Applications of α-Metalated Isocyanides in Organic Synthesis

Being both nucleophilic and electrophilic, α-metalated isocyanides can add to polar double bonds, forming heterocycles. They are also synthons for α-metalated primary amines. This article describes recent or improved procedures for their use in organic synthesis: (1) In heterocyclic syntheses to give 2-oxazolines, 2-imidazolines, 2-thiazolines, oxazoles and oligooxazoles, thiazoles, triazoles, imidazolinones, pyrroles, 5,6-dihydro-1,3-oxazines and -thiazines, and (via cycloaddition with nitrones) 2-imidazolidinones. (2) In the field of formylaminomethylenation, for example transformation of estrone methyl ether and a keto sugar into the corresponding α-formylaminoacrylic esters, and the conversion of aldehydes and ketones by 3- and 4-pyridyl-methyl isocyanides into N-(1-pyridyl-1-alkenyl)formamides and their hydrolysis to 3- and 4-acylpyridines. (3) In connection with the use of α-metalated isocyanides as synthons for α-metalated primary amines, the author demonstrates how they may be used for preparation of 1,2- and 1,3-amino alcohols, 1,2-diamines, 2,3-diaminoalkanoic acids and for synthesis of higher amino acids starting from simple amino acids.     

Asymmeric formal [3 + 3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates

With metal carbene access to dipolar intermediates, 3,6-dihydro-1,2-oxazines are produced in high yields by dirhodium(II) carboxylate catalyzed reactions between nitrones and a β-TBSO-substituted vinyldiazoacetate. High enantiocontrol occurs with catalysis by N-phthaloyl-(S)-(amino acid)-ligated dirhodium carboxylates for [3 + 3]-cycloaddition reactions with both acyclic and cyclic nitrones.     

A highly stereoselective organocatalytic tandem aminoxylation/aza-Michael reaction for the synthesis of tetrahydro-1,2-oxazines

A facile stereoselective synthesis of multifunctionalized tetrahydro-1,2-oxazines (THOs) has been achieved by the organocatalyzed asymmetric tandem alpha-aminoxylation/aza-Michael reaction for the C-O/C-N bond formations in moderate to good yields with excellent diastereo- (>99:1 dr) and enantioselectivities (92% to >99% ee).     

Synthesis of derivatives of dihydro-1,2-oxazine and tetrahydro-1,2-diazine from (4-chlorobutanoyl)-alkoxybenzenes

The reaction of (4-chlorobutanoyl)alkoxybenzenes with hydroxylamine and 2,4-dinitrophenylhydrazine gave dihydro-1,2-oxazines and tetrahydro-1,2-diazines, respectively.Institute of Petrochemical Processes, Academy of Sciences of the Republic of Azerbaijan, 370025 Baku. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 7, pp. 1685–1687, July, 1992.     

Hetero-Diels-Alder reaction of phosphinyl and phosphonyl nitroso alkenes with conjugated dienes: an aza-Cope rearrangement

Phosphorylated nitroso alkenes react with cyclic dienes such as cyclopentadiene or cyclohexadiene to afford hetero Diels-Alder-type cycloadducts where the nitroso alkene participates as dienophile component and the cyclic olefin acts as the 4π-electron (diene) system. Subsequent aza-Cope rearrangement affords highly functionalized 5,6-dihydro-4H-1,2-oxazines. Conversely, the reaction of TMS-substituted cyclopentadiene (dienophile) with nitroso alkenes as heterodienes leads directly to bicyclic 1,2-oxazines. Theoretical studies are in agreement with the experimental results and with the new aza-Cope rearrangement proposed.     

Reduction and hydrolysis of substituted 5-oxa-6-azaspiro[2.4]heptane-1,2-dicarboxylic acid esters

Substituted 5-oxa-6-azaspiro[2.4]heptane-1,2-dicarboxylic acid esters synthesized by reaction of nitrones with dimethyl 3-methylidenecyclopropane-1,2-dicarboxylate were reduced with lithium tetrahydridoaluminate to the corresponding bis(hydroxymethyl)cyclopropanes. Alkaline hydrolysis of the title compounds gave substituted cyclopropane-1,2-dicarboxylic acids. In both cases, the 5-oxa-6-azaspiro[2.4]heptane fragment remained intact.     

Synthesis of 6-hydroxymethyl-5,6-dihydro-4H-1,2-oxazines by one-pot-cyclization of dilithiated oximes with epibromohydrin

6-Hydroxymethyl-5,6-dihydro-4H-1,2-oxazines were regioselectively prepared by one-pot cyclization of dilithiated oximes with epibromohydrin.     

Regioselective synthesis of 6-halomethyl-5,6-dihydro-4H-1,2-oxazines based on cyclizations of arylalkenyl-oximes

6-Iodo- and 6-bromomethyl-5,6-dihydro-4H-1,2-oxazines were prepared by condensation of dilithiated acetophenone-oximes with allylbromide and subsequent regioselective iodine- or NBS-mediated cyclization.     

Rearrangement of 3-alkylidene-2-siloxy-tetrahydro-1,2-oxazines (ASENA). A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines

A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1 from available 5,6-dihydro-4H-1,2-oxazine N-oxides 2 has been described. The key step of the process—the rearrangement of 3-alkiliden-2-siloxy-tetrahydro-1,2-oxazines 3 (ASENA)—was thoroughly investigated. Optimal experimental conditions were developed. A possible pathway of the ASENA rearrangement was proposed.     

Synthesis of thieno[2,3-d]thia[1]pyrano[4,3-b]pyrrole derivatives

It is shown that 2-methyl-3-carbethoxy-4H,8H,5,6-dihydrothieno[2,3-d]thia[1]pyrano [4,3-b]pyrrole and 8-methyl-9-carbethoxy-10H,5,6-dihydrothieno[2,3-d]thia[1]chromeno[4,3-b]pyrrole and their S,S-dioxides, respectively, are obtained in the reaction of 2-methyl-3-carbethoxy-4-thienylhydrazine with tetrahydro-4-thiopyrone, tetrahydro-4-thiopyrone S, S-dioxide, 4-thiochromanone, and 4-thiochromanone S,S-dioxide in the presence of an acid catalyst.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 195–196, February, 1979.     

Reactions of nitrosonium hexafluorophosphate with some olefinic compounds in acetonitrile: one step synthesis of 4H-5,6-dihydro-1,2-oxazines

Reactions of nitrosonium hexafluorophosphate or tetrafluoroborate with olefins having aryl groups at an olefinic carbon atom at low temperature in acetonitrile afforded 4H-5,6-dihydro-1,2-oxazines with two aryl groups at C-4 and C-6 in fair to good yields.     

Synthesis of 5,6-trimethylenetetrahydro-1,3-oxazine-4-spirocyclopentanes and their acyclic precursors

Tricyclic tetrahydro-1,3-oxazines-5,6-trimethylenetetrahydro-1,3-oxazine-4-spirocyclopentanes IV, V, and VII — were synthesized on the basis of 2-(1-isothiocyanatocyclopentyl)cyclopentanone (I). The reductive cyclization of the latter by the action of sodium borohydride leads to oxazinethione V; the acidic hydrolysis of I with subsequent reduction of amino ketone hydrochloride II with sodium borohydride and the reaction of isothiocyanato ketone I with lithium aluminum hydride make it possible to obtain 1,3-amino alcohols III and VI, respectively, which are converted to tetrahydro-1,3-oxazines IV and VII by cyclization with formaldehyde. Pyrimidinethione VIII was synthesized from isothiocyanato ketone I and methylamine. Compounds III–VII are mixtures of stereoisomers with predominance of the cis isomer.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1256–1259, September, 1990.     

A new ring transformation: Synthesis of 5,5-dimethyl-3-oxo-1-pyrroline 1-oxides from 6,6-dimethyl-4-oxo-5,6-dihydro-1,2,4h-oxazines

The nitrosation of some γ,δ-unsaturated β-diketo compounds affords the 3-substituted 4-oxo-5,6-dihydro-1,2,4H-oxazines. These compounds are converted to the isomeric 3-oxo-1-pyrroline 1-oxides by a facile thermal rearrangement.     

2-Etroxy-5,6-dihydro-1,3-oxazines from triethyl azomethinetricarboxylate

Inverse demand Diels-Alder reactions of triethyl azomethinetricarboxylate with electron-rich olefins lead to 2-ethoxy-5,6-dihydro-1,3-oxazines using the CNCO moiety as the diene only.