Brønsted acid-promoted domino reactions: a novel one-pot three-component synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazines

An efficient and novel one-pot synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazine from alkynoates, anilines, and formaldehyde is described. The six-membered N,O-heterocyclic skeleton was constructed via Brønsted acid-promoted domino hydroamination/Prins reaction/cyclization/dehydration reactions.     

Diversity oriented synthesis of fused-ring 1,3-oxazines from carbohydrates as biorenewable feedstocks

Microwave enhanced diversity oriented synthesis (MEDOS) of various N- and O-heterocyclic systems fused with 1,3-oxazine ring is reported. The synthesis represents a new montmorillonite K-10 clay-catalyzed green protocol, which utilizes d-glucose/d-xylose as biorenewable feedstocks. d-Glucose/d-xylose-derived 1,3-oxazin-2-ones(thiones) either directly undergo K-10 clay-catalyzed cyclization to yield pyrano-/furo-1,3-oxazine systems under solvent-free microwave irradiation conditions or afford azolo-/azino-1,3-oxazines when subjected to Malaprade reaction followed by cyclization with appropriate reagents, viz. phenylhydrazine, hydroxylamine, acetamidine, phenylurea and semi(thiosemi)carbazide.     

Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides

A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phenyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence. The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates including 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-nucleophiles.     

Ring size and substituent steric effects in cyclic ketene-N,O/S-acetal trifluoroacetylations

Trifluoroacetylations of cyclic ketene-N,O/S-acetals exhibit a ring size effect. The five-membered rings 2,4,4-trimethyl-2-oxazoline, 2-methyl-2-oxazoline, and 2-methyl-2-thiazoline, each form cyclic ketene-N,O/S-acetal intermediates which then react with trifluoroacetic anhydride to give β-monotrifluoroacetylation products. Conversely, the six-membered ring 2-methyl-2-oxazine gives its β,β-bistrifluoroacetylation product. In situ-generated five-membered ring N-Me cyclic ketene-N,O-acetals, 3,4,4-trimethyl-2-methylene-oxazolidine, and 3-methyl-2-methylene-oxazolidine, and six-membered ring 3-methyl-2-methylene-1,3-oxazinane were each β,β-bistrifluoroacetylated. However, 3-methyl-2-methylene-oxazolidine also afforded a γ-lactam by an iodide-catalyzed rearrangement of its β,β-bistrifluoroacetylated derivative. In situ-generated 3-methyl-2-methylene-thiazolidine gives both β-mono- and β,β-bistrifluoroacetylation products and no lactam, in contrast to its N,O-analog 3-methyl-2-methyleneoxazolidine.     

A facile microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclohex-1-en-1-yl)ethyl)amides

A mild and efficient methodology has been developed for the synthesis of spiro-1,3-oxazine derivatives by the microwave assisted cyclization of N-2-(1′-cyclohexenyl)ethyl-acetamides/benzamides. The reaction was catalyzed by in situ generated trimethylsilyl iodide and featured by its very short reaction time. The starting materials were easily obtained by the condensation of substituted acetic/benzoic acids with 2-(1′-cyclohexenyl)ethyl amine.     

Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.     

Reaction of N,N-diarylamidines with 3,4,5,6-tetrachloro-1,2-benzoquinone

A synthesis of 5,11b-dihydro-1H-dibenzo[d,f][1,3]diazepin-1-ones was found in the reaction of nitro-substituted N¹,N²-diarylamidines with 3,4,5,6-tetrachloro-1,2-benzoquinone. In contrast, 6,7,8,9-tetrachlorodibenzodioxins were obtained from reaction of N¹,N²-diphenylpropionamidine and N¹,N²-di-(4-tert-butylphenyl)acetamidine with 3,4,5,6-tetrachloro-1,2-benzoquinone.     

Synthesis of benzo-annulated 1,3-oxazine derivatives through the multi-component reaction of arynes with N-heteroaromatics and aldehydes or ketones

A multi-component reaction involving arynes, N-heteroaromatic compounds (including pyridine, quinoline, and isoquinoline), and aldehydes or ketones for the synthesis of benzo-annulated 1,3-oxazine derivatives has been described. The whole process is carried out under mild conditions and furnishes the desired products in 35–85% yields. Furthermore, regioselectivity and diastereoselectivity can be observed when using 3-OMe aryne precursor in this reaction.     

Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.     

N,N-Dimethylethylenediamine in direct and direct template syntheses of Cu(II)/Cr(III) complexes

Four new heterometallic Cu(II)/Cr(III) complexes with N,N-dimethylethylenediamine (dmen) and its novel Schiff-base derivatives, N′-[(1Z)-3-amino-1,3-dimethylbutylidene]-N,N-dimethylethane-1,2-diamine (dmenac) and N′-((1Z)-3-{[2-(dimethylamino)ethyl]amino}-1,3-dimethylbutylidene)-N,N-dimethylethane-1,2-diamine (dmen₂ac), have been easily prepared by self-assembly and characterized by spectroscopic methods and single crystal X-ray analysis. The structures of all the complexes are assisted by numerous hydrogen bonds that provide a web of interactions and mould the supramolecular architectures of the compounds. Variable-temperature (1.8–300 K) magnetic susceptibility measurements reveal Curie-Weiss paramagnetic behavior of all the compounds, supported by EPR studies.     

Synthesis of 1,5-naphthylethynyl nanostructure networks with extended π-conjugation. Effective heterocoupling catalyzed by palladium under a compatible CO2 atmosphere

The synthesis of a new extended π-conjugated 5-N,N-dimethylaminonaphthyl family was undertaken by palladium-catalyzed cross-coupling reaction between a protected 5-iodonaphthylethynyl and 1-ethynyl-5-(N,N-dimethylamino)naphthalene. Under an argon atmosphere, only the homocoupling product 1,4-(N,N-dimethylamino)naphthyl-1,3-butadiyne was isolated, in excellent yield. However, under a compatible and pure carbon dioxide atmosphere, the cross-coupling product was obtained in excellent yield.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

Divergent and solvent dependent reactions of 4-ethoxycarbonyl-3-methyl-1-tert-butoxycarbonyl-1,2-diaza-1,3-diene with enamines

Starting from 1-tert-butyloxycarbonyl-3-methyl-4-ethoxycarbonyl-1,2-diaza-1,3-diene and β,β,β and α,β-substituted enamines a careful choice of solvents and temperatures allows the divergent synthesis of 5,6-dihydro-4H-pyridazines, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester, and 1-amino-pyrroles. Moreover, some interesting conclusions about the mechanism(s) of the reaction have been drawn by careful analysis of products' structure and distribution. Thus, the reaction may proceed through a stereospecific [4+2] cycloaddition mechanism giving rise to 5,6-dihydro-4H-pyridazines or by simple addition or domino addition/cyclization pathways affording, respectively, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester and 1-amino-pyrroles (formally the [3+2] cycloaddition product).     

Asymmetric synthesis of α-amino aldehydes from sulfinimine (N-sulfinyl imine)-derived α-amino 1,3-dithianes. Formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline

Hydrolysis of sulfinimine-derived N-sulfinyl α-amino 1,3-dithianes with aqueous 1,3-dibromo-5,5-dimethylhydantoin affords the corresponding N-tosyl α-amino aldehydes in good yield and high enantiomeric purity. These aldehydes can be reduced to amino alcohols and undergo the Wittig reaction to give allylic amines without epimerization. The utility of this methodology is illustrated in a formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline.     

Selective syntheses of 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones via temperature-dependent Rh(II)-carbenoid-mediated 2H-azirine-ring expansion

The Rh(II)-catalyzed reaction of 2-carbonyl-substituted 2H-azirines with ethyl 2-cyano-2-diazoacetate or 2-diazo-3,3,3-trifluoropropionate provides an easy access to 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones. These compounds can be selectively prepared from the same starting material using temperature as the only varied parameter. The 2-azabuta-1,3-diene intermediate, a common precursor for both heterocyclic products, isomerizes into 2H-1,3-oxazine under kinetic control, while 1H-pyrrol-3(2H)-one is the sole product of the reaction at elevated temperatures. According to DFT-calculations a one-atom oxazine ring contraction involving ring-opening to a 2-azabuta-1,3-diene intermediate, followed by a 1,5- and 1,2-prototropic shift leads to the consecutive formation of imidoylketene and azomethine ylide, which then further undergo cyclization to the pyrrole derivative.     

Stereospecific synthesis of conjugated (1E,3E)- and (1Z,3Z)-1,4-di(n-N,N-dimethylaminophenyl)-1,3-butadienes from 2-chloro-1-(n-N,N-dimethylaminophenyl)ethenes: fluorescence properties

The conjugated 1,4-di(n-N,N-dimethylaminophenyl)-1,3-butadienes (n=o-, m-, p-) were efficiently synthesised by homocoupling of the appropriate 2-chloro-1-(n-N,N-dimethylaminophenyl)ethene (n=o-, m-, p-) with stoichiometric amounts of zerovalent nickel complexes. The 1,3-butadienes were obtained as a mixture of stereoisomers, with independence of the starting E or Z chlorovinyl isomer. Moreover, the stereospecific (Z,Z) stereoisomer was obtained by partial hydrogenation of the corresponding 1,3-butadiyne, while the stereospecific (E,E) stereoisomer was obtained by exposure to the sunlight radiation of the (Z,Z) or the (Z,E) compound in ethanol.     

Pd-Catalyzed asymmetric transformations involving P*-mono- and P*,N-bidentate diamidophosphites derived from (2S,3S)-N 2,3-dimethyl-N 1-phenylpentane-1,2-diamine

The synthesis of new P*-mono- and P*,N-bidentate diamidophosphites, containing 1,3,2-diazaphospholidine rings formed starting from (2S,3S)-N ²,3-dimethyl-N ¹-phenylpentane-1,2-diamine, is described. Comparison of their efficiency in the Pd-catalyzed enantioselective allylation with (E)-1,3-diphenylallyl acetate showed that up to 97% ee was reached in the reaction involving dimethyl malonate as a C-nucleophile. The Pd-catalyzed desymmetrization of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate gave up to 61% ee.     

N,N,N,N-Tetramethyl-1,3-propanediamine as the catalyst of choice for the Baylis-Hillman reaction of cycloalkenone: rate acceleration by stabilizing the zwitterionic intermediate via the ion-dipole interaction

N,N,N^′,N^′-Tetramethyl-1,3-propanediamine (TMPDA) can be used as an efficient catalyst for the Baylis-Hillman reaction of cycloalkenones. The increased reaction rate was thought be derived from the stabilizing effect of the zwitterionic intermediate via the ion-dipole interaction.     

One-pot synthesis of aliphatic and aromatic 2H-indazolo[2,1-b]phthalazine-triones catalyzed by N-halosulfonamides under solvent-free conditions

N, N, N′, N′-Tetrabromobenzene-1,3-disulfonamide and poly(N-bromo-N-ethylbenzene-1,3-disulfonamide) were used as efficient catalysts for the one-pot synthesis of aliphatic and aromatic 2H-indazolo[2,1-b]phthalazine-triones in excellent yields from aldehydes, phthalhydrazide, and dimedone at 80-100 °C under solvent-free conditions.     

Rational use of substituted N-allyl and N,N-diallylanilines in the stereoselective synthesis of novel 2-alkenyltetrahydro-1-benzazepines

Two new series of 1,4-epoxy-2-exo-vinyl(isopropenyl)tetrahydro-1-benzazepines and cis-2-vinyl(isopropenyl)-4-hydroxytetrahydro-1-benzazepines were prepared by an efficient three/four-step route from available substituted N,N-diallylanilines and mono N-allylanilines. The amino-Claisen rearrangement and the sequential oxidation/intramolecular 1,3-dipolar cycloaddition reactions were used as the key steps in this synthesis. All the synthesized compounds were fully characterized by IR, GC-MS and NMR techniques.