Synthesis of 4,6-diaryl-1-benzyl-6-hydroxy-5,5-dimethyl-2-oxopiperidine-3-carbonitriles and their analogs via a modified Reformatsky reaction

Organozinc compounds obtained from 1-aryl-2-bromo-2-methylpropanone and zinc react with N-benzyl-3-aryl-2-cyanoacrylamides or N-[6-(2-cyano-1-oxo-3-phenylprop-2-enylamino)hexyl]-2-cyano-3-phenylacrylamide to give 4,6-diaryl-1-benzyl-6-hydroxy-5,5-dimethyl-2-oxopiperidine-3-carbonitriles or 1,6-bis(6-aryl-3-cyano-6-hydroxy-5,5-dimethyl-2-oxo-4-phenylpiperidyl)hexanes as a single isomer with trans-located piperidine hydrogen atoms.     

Condensation of 2-naphthylamine or N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexane-3-carboxylate

Condensation of 2-naphthylamine with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate afforded depending on the reaction conditions methyl 9,9-dimethyl-11-oxo-8,9,10,12-tetrahydro-7H-benzo[a]acridine-10-carboxylate or 4-alkoxymethyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??Hspirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylate. The condensation of N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate provided with the quantitative yield the corresponding methyl 4-benzyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??H-spirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylates.     

Three-component condensation of methoxyarenes with isobutyraldehyde and α-substituted benzyl cyanides

Three-component condensation of anisole with isobutyraldehyde and substituted benzyl cyanides gives 1-benzyl-3,3-dimethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones which undergo dienone-phenol rearrangement during the reaction. Analogous condensation of 1-methoxynaphthalene leads to the formation of 2′-benzyl-5′,5′-dimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-ones.     

Synthetic access of new 6-purineselenyl and 8-(1,3,4-thiadiazolyl)-7-benzyl-1, 3-dimethyl-1H-purine-2,6-(3H,7H)-dione derivatives

Abstract

New 6-purineselenyl, 1, 3, 4-thiadiazols bearing 7-benzyl-1,3-dimethyl-1H-purine-2,6-(3H,7H)-diones and (8-[2-(3-phenyl-5-substituted-1,3,4-thiadiazol-2(3H)-ylidene) hydrazinyl)-7-benzyl-1,3-dimethyl-1H-purine-2,6-(3H,7H)-diones derivatives were synthesized. The structures of the newly synthesized compounds were elucidated by spectroscopic methods (1H-NMR, 13C-NMR, and MS spectrometry) and elemental analysis.     

Five-membered 2,3-dioxo heterocycles: LXIII. Cascade recyclization of isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates with cyclic enamines. Crystalline and molecular structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone

Isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates reacted with N-substituted 3-amino-5,5-dimethylcyclohex-2-en-1-ones to give the corresponding 1′-substituted (Z)-6′,6′-dimethyl-3-[phenyl(arylamino)methylidene]-6′,7′-dihydro-3H-spiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraones. The structure of 1′-benzyl-6′,6′-dimethyl-3-[(Z)-phenyl(phenylamino)methylidene]-6′,7′-dihydro-3Hspiro[furan-2,3′-indole]-2′,4,4′,5(1′H,5′H)-tetraone was proved by X-ray analysis.     

Synthesis of 4,7-dihydro-4-oxopyrrolo[2,3-b]pyridine-5-carboxylic acid derivatives as potential antimicrobial agents

Synthetic approaches to 1-benzyl-7-alkyl-2,3-dimethyl-4,7-dihydro-4-oxopyrrolo[2,3-b]pyridine-5-carboxylic acids from 1-benzyl-2-amino-3-t-butoxycarbonyl-4,5-dimethylpyrrole are reported.     

Controlling stereoselectivity by enzymatic and chemical means to access enantiomerically pure (1S,3R)-1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline derivatives

A chemoenzymatic strategy for the synthesis of enantiomerically pure novel alkaloids (1S,3R)-1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinolines is presented. The key steps are the biocatalytic stereoselective reductive amination of substituted 1-phenylpropan-2-one derivatives to yield chiral amines employing microbial ω-transaminases, and the diastereoselective reduction of a Bischler–Napieralski imine intermediate by catalytic hydrogenation in the presence of palladium on charcoal, leading exclusively to the desired cis-isomer.     

Sterically Encumbered 2,3-Dihydrophosphindole and Its Chalcogenides

Reduction of 2-benzyl-1-mesityl-5,7-dimethyl-2,3-dihydrophosphindole 1-oxide ( 2-O ), which was prepared by catalytic addition of dimesitylphosphane oxide across phenylacetylene via dimesityl-phenylethenylphosphane oxide ( 1 ), with excess of trichlorosilane in toluene yielded 2-benzyl-1-mesityl-5,7-dimethyl-2,3-dihydrophosphindole ( 2 ). Straightforward oxidation of 2 with sulfur and selenium in toluene at 110 °C allowed the isolation of crystalline colorless 2-benzyl-1-mesityl-5,7-dimethyl-2,3-dihydrophosphindole 1-sulfide ( 2-S ) and 1-selenide ( 2-Se ). The hindered rotation of the P-bound mesityl group around the P–C bond is indicative of significant intramolecular steric strain. Despite this strain, the P–E bond lengths (E = S, Se) lie in expected ranges.     

New photochromic symmetrical and unsymmetrical bis(heteroaryl)maleimides: A spectrokinetic study

The photochromic behavior of two newly synthesized diarylethenes is here presented. The compounds studied are the symmetrical (1-benzyl-3,4-bis(2-methylbenzo[b]thiophen-3-yl)-[1H]-2,5-dihydropyrrol-2,5-dione) and the unsymmetrical (1-benzyl-3-(2-methylbenzo[b]thiophen-3-yl)-4-(2,5-dimethyl-3-thienyl)-[1H]-2,5-dihydropyrrol-2,5-dione). Upon stimulation with UV or violet light, these compounds become red-colored due to photocyclization and cyclorevert to the light yellow open form upon irradiation with visible light. In this work, absorption and fluorescence spectra, molar absorption coefficients of the ethenic and cyclized forms, fluorescence quantum yields and photochemical quantum yields of both the forward and back photoreactions were determined. Temperature, excitation wavelength and solvent effects were explored. The symmetrical compound was found to be a bistable photochrome. In contrast, the unsymmetrical molecule resulted unsuitable as photochrome because of side degradation processes occurring in competition with cyclization.     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Dissociation energies of O–H bonds in 3-pyridinols

The O?H bond dissociation energy (D _O?H) has been estimated for 20 substituted 3-pyridinols and a substituted 3-pyrimidinol from experimental kinetic data by the intersecting parabolas method using α-tocopherol and 4-methoxyphenol as reference compounds. The following D _O?H values (kJ/mol) have been obtained: 363.7 for 3-pyridinol, 365.3 for 2-alkyl-3-pyridinols (five compounds), 358.8 for 2-alkyl-6-methyl-3-pyridinols (six compounds), 378.1 for 5-benzyl-3-pyridinol, 353.2 for 2,4,6-trimethyl-3-pyridinol, 340.9 for 2-benzyl-6-methoxy-3-pyridinol, 345.8 for 2,6-dimethoxy-5-benzyl-3-pyridinol, 381.7 for 2-ethyl-4-nitro-6-methyl-3-pyridinol, 376.8 for 2-isopropyl-4-nitro-6-methyl-3-pyridinol, 318.3 for 2,4-dimethyl-6-dimethylamino-3-pyridinol, 357.3 for mexidol, and 322.2 for 2,4-dimethyl-6-dimethylamino-3-pyrimidinol. The substituent effect on the O?H bond dissociation energy in 3-pyridinols is considered. The stabilization energies of pyridinoxyl and phenoxyl radicals are compared. The activation energies and rate constants have been calculated for a series of reactions of various radicals with 3-pyridinols.     

Asymmetric cycloaddition reactions of diazoesters with 2-alkenoic acid derivatives catalyzed by binaphthyldiimine-Ni(II) complexes

The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2)·6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3-proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2)·6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1-benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5-dimethyl-1-naphthylmethyl-3-pyrazolidinone and an α-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid.     

Syntheses of benzomorphan and related compounds. Part III. An alternate synthesis of 3-substituted-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine

Reduction of the appropriate Schiff bases gave 5-benzylamino-3-methyl-2-pentene (XVII) and l-benzylamino-3-methylpentane (XVIII), the condensation of which with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate afforded a mixture of the isomeric 1-benzyl-2-(4-methoxy-benzyl)-3,4-dimethyl-4-hydroxypiperidines (XIXa and XIXb). The piperidinols were heated with hydrobromic acid, respectively, to afford 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine (II). Since the conversion of II to pentazocine (Ic) had already been accomplished, an alternate synthesis of Ic was achieved.     

Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2-vinyl-1H-pyrroles

The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to 2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied. Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole derivative.     

Asymmetric Diels–Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic β-amino acid (1S,2R,3R,4R)-trans-β-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic route by using the chiral auxiliary (R)-1.     

Synthesis and alkylation of new functionally substituted 4,4-dimethylpiperidin-2-ones

The reaction of ethyl isopropylidenecyanoacetate with ethyl 3-amino-3-thioxopropanoate gave rise to ethyl 4,4-dimethyl-6-oxo-2-thioxo-5-cyanopiperidine-3-carboxylate whose alkylation provided ethyl 2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, ethyl 5-benzyl-2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, and ethyl 7,7-dimethyl-5-oxo-6-cyano-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]pyridine-8-carboxylate.     

Diastereoselective atom transfer radical cyclization reactions of unsaturated α-bromo oxazolidinone imides catalyzed by Lewis acids

A new Lewis acid-catalyzed atom transfer radical cyclization reaction of unsaturated α-bromo oxazolidinone imides is reported. In the presence of Lewis acids such as Mg(ClO₄)₂ and Yb(OTf)₃, a series of trans cyclic products was obtained in high yield (up to 87%) between 0°C and room temperature. The loading of strong Lewis acids, such as Yb(OTf)₃, can be reduced to 0.1 equiv. without significantly compromising the yield. Excellent diastereoselectivity could be achieved by using 1,2-stereocontrol or a chiral oxazolidinone auxiliary. For substrates 1e and 1f bearing a β-methyl substituent and the chiral auxiliary, (S)-(−)-4-benzyl-5,5-dimethyl-2-oxazolidinone, respectively, the diastereomeric ratio of the products was greater than 50:1.     

New thiourea organocatalysts and their application for the synthesis of 5-(1H-indol-3-yl)methyl-2,2-dimethyl-1,3-dioxane-4,6-diones a source of chiral 3-indoylmethyl ketenes

The stereoselective properties of modified thiourea organocatalysts were tested in the Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones, which produces chiral 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones. Based on a tentative reaction mechanism for ((S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethylbutanamide organocatalysts, modifications were applied in four selected regions. Systematic structure-stereoselectivity relationship study allowed designing the best efficient organocatalyst for the investigated Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones.     

Synthesis of piperidinones incorporating an amino acid moiety as potential SP antagonists

Substituted (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxamides (type I) and the acylated derivatives of (±)-trans-5-amino-1-benzyl-6-phenylpiperidin-2-one (type II) were prepared by the reaction of (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid and some common reagents to provide the products in satisfactory yields. Newly synthesized compounds share the same moiety with common SP antagonists and thus similar activities might be expected.     

Five-membered 2,3-dioxoheterocycles: LXXIX. Three-component condensation of 1<Emphasis Type="Italic">H</Emphasis>-pyrrol-2,3-diones with acetonitriles and dimedone. Crystal and molecular structure of substituted spiro[chromene-4,3′-pyrrole]

5-Phenyl-4-ethoxycarbonyl-1H-pyrrole-2,3-diones react with acetonitriles and dimedone to form ethyl 2-amino-7,7-dimethyl-2′,5-dioxo-5′-phenyl-1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-pyrrole]-4′-carboxylates. The crystal and molecular structure of ethyl 2-amino-1′-benzyl-7,7-dimethyl-2′,5-dioxo-5′-phenyl-3-cyano-1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-pyrrole]-4′-carboxylate was proved by XRD analysis.