A new pyridine-2,6-bis(oxazoline) for efficient and flexible lanthanide-based catalysts of enantioselective reactions with 3-alkenoyl-2-oxazolidinones

A new pyridine-2,6-bis(oxazoline) (4) has been easily synthesised from the reaction of (1S,2S)-2-amino-1-phenylpropane-1,3-diol (1) and dimethyl pyridine-2,6-dicarboximidate (2), followed by TIPS (TIPS=triisopropylsilyl) protection of the 4'-CH2OH group. The catalysts derived from 4 and eight lanthanide(III) triflates have been tested over three reactions involving 3-acryloyl- and 3-crotonoyloxazolidinones (5 a,b): the Diels-Alder (DA) reaction with cyclopentadiene, the 1,3-dipolar cycloaddition with diphenyl nitrone and the Mukaiyama-Michael reaction with 2-trimethylsilyloxyfuran. Several reactions exhibit very good enantioselectivity (ee>90 %), and the opposite enantiomers can be easily obtained simply by changing the cation. This specific feature of the ligand can be appreciated in the DA reaction of 5 a, since the catalyst [Sc(III)4] gives the adduct (2'S)-9 a with 99 % ee, whereas the catalyst [Y(III)4] gives the opposite enantiomer with 95 % ee. A rationale of the enantioselectivity is proposed on the basis of the NMR spectra of La-based complexes involving 4 and 5 as ligands.     

Synthesis of diverse novel compounds with anticipated antitumor activities starting with biphenyl chalcone

The chalcone as (E)-1-([1,1′-biphenyl]-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one ( 3 ) was reacted with various active methylene compounds via Michael addition reaction under different conditions. In one hand, chalcone 3 reacted with isatin and glycine in one pot reaction via 1,3-dipolar cycloaddition reaction. On the other hand, chalcone 3 was also reacted with different N-nucleophiles via direct addition on the carbonyl group to award cyclic and/or acyclic products. Meanwhile, the reaction of chalcone 3 with S-benzylthiuronium chloride afforded the thio-Michael addition product. Chalcone 3 and 10 novel synthesized compounds were screened against two cell lines (HepG2 and MCF-7). Among of them, thiosemicarbazone 16 , oxime 14 and pyrimidine-2(1H)-thione 19 derivatives revealed an excellent activity against both cell lines (IC₅₀ values = 6.79-12.91 μM), whereas thiosemicarbazone 16 (6.79 ± 0.5 and 7.58 ± 0.6 μM) showed the highest activity.     

The diels-alder reaction of 5-aminopyrazole-4-carbonitrile with dmad: Synthesis and structural determination of dimethyl 2-(p-toluenesulfonylamino)-3-cyano-4-imino-1,4-dihydropyridine-5,6-dicarboxylate

The Diels-Alder reaction of 5-amino-1-(p-toluenesulfonyl)pyrazole-4-carbonitrile with dimethyl acetylenedi-carboxylate was carried out in the presence of potassium carbonate in dimethyl sulfoxide. The reaction gave dimethyl 2-(p-toluenesulfonylamino)-3-cyano-4-imino-1,4-dihydropyridine-5,6-dicarboxylate. The product was formed by transformation of the original Diels-Alder adduct followed by rearrangement of the p-toluenesul-fonylamino group into the 2-position of the pyridine ring. The structure of the product was irrefutably established by X-ray crystallography. This reaction is the first example of a pyrazole ring serving as the diene in a [4 + 2] cycloaddition reaction.     

Cp*Rh complexes with pyridyloxazolines: synthesis, fluxionality and applications as asymmetric catalysts for Diels-Alder reactions

Half-sandwich complexes [RhCl(pymox)Cp*][SbF(6)](1-7)(pymox = pyridyloxazoline) have been synthesised as single diastereomers. Treatment of these with AgSbF(6) generates dications [Rh(OH(2))(pymox)Cp*](2+) which are fluxional at room temperature and which are enantioselective catalysts for the Diels-Alder reaction of methacrolein and cyclopentadiene. Treatment of the dication [Rh(OH(2))((i)Pr-pymox)Cp*](2+) with [X](-) gives [RhX((i)Pr-pymox)Cp*][SbF(6)](X = Br, I) as single diastereomers whilst reaction with 4-Mepy (4-methylpyridine) gives [Rh(4-Mepy)((i)Pr-pymox)Cp*][SbF(6)] as a mixture of diastereomers. Two complexes, [RhCl((i)Pr-pymox)Cp*][SbF(6)](3) and [RhCl(Bz-pymox)Cp*][SbF(6)](6) have been characterised by X-ray crystallography.     

Mass spectra of substituted uracils

The mechanisms for the major fragmentations obtained with selected substituted uracils are discussed. Interpretation of data was facilitated by use of metastable peaks, high-resolution data, and low-voltage spectra. The major fragmentation obtained with N-alkyl substituted uracils, when the alkyl group contains 2 or more carbons, is due to cleavage of the alkyl substituent. This cleavage is accompanied by a rearrangement of 1 or 2 hydrogens from the alkyl group to the uracil ring. Possible mechanisms for the rearrangements are discussed. It was found that the molecular ion of 1- and 3-alkyl substituted uracils (where the alkyl group has 2 or more carbons) does not undergo the expected ‘retro Diels-Alder Reaction’. Instead, the odd-electron ion formed by loss of the alkyl substituent with a single hydrogen rearrangement undergoes this reaction (loses HNCO). Since it is formed as a secondary reaction product, the relative abundance of the ‘retro Diels-Alder’ fragment is low compared to what is obtained in the spectra of the simple uracils. The ‘retro Diels-Alder Reaction’ can be used to differentiate between 2- and 4-thiouracils, and between 1- and 3-methyl and phenyl substituted uracils. It was found that 1- and 3-alkyl substituted uracils (alkyl group of 2 or more carbons) can be differentiated by the mass of the M-alkyl fragment since the 3-substituted compounds give predominantly a double hydrogen rearrangement and the 1-substituted compound gives mainly a single hydrogen rearrangement. In addition the intensity of the molecular ion, relative to the M-alkyl ion, is considerably stronger in the 1-substituted uracils.     

Stereoselectivity of the Diels-Alder Reaction of (E)-γ-Oxo-α,β-Unsaturated Thioesters with Cyclopentadiene

The stereoselectivity of the Diels-Alder reaction of (E)-γ-oxo-α,β-unsaturated thioesters 3a-3d with cyclopentadiene is greatly enhanced in the presence of Lewis acids favoring the endo acyl isomers 4a-4d . In the absence of Lewis acid, Diels-Alder reaction of 3a-3d with cyclopentadiene at 25 °C gave two adducts 4a-4d and 5a-5d in a ratio of 1:1 respectively. In the presence of Lewis acids, Diels-Alder reaction of 3a-3d with cyclopentadiene gave 4a-4d and 5a-5d in ratios of 75-94:25-6 respectively. The stereoelectivity was enhanced to ratios of 95-98:5-2 with lowering the reaction temperature. The stereochemistry of the cycloadducts 4 and 5 was confirmed by iodocyclization. Reaction of the endo-thioester 5c with I₂ in aqueous THF at 0 °C gave the novel methylthio group rearranged product 6c in 80% yield, the first example of iodo-lactonization of endo-thioesters. Reaction of the endo-acyl isomer 4b with I₂ under the same reaction conditions gave an isomeric mixture of 7b and 8b in 1:2 ratio. The stereochemistry of the thioester group in 8b was proved by X-ray single-crystal analysis. The solvent effect on the endo selectivity of (Z)-γ-oxo-α,β-unsaturated thioester 2b was also examined.     

一种主链含光敏基团聚酰亚胺的合成与表征

通过4,4′-二羟乙基查尔酮与1,2,4-苯三酸酐酰氯反应,得到了一种新型的主链含查尔酮的二酐单体,通过二酐和2,2-双(3(-氨基-4(-羟基苯基)六氟丙烷缩聚并高温亚胺化,得到了一种新型的主链含查尔酮,侧链含羟基的光敏聚酰亚胺,并通过1H-NMR、FTIR、GPC及热分析表征了得到的聚酰亚胺的结构和热性能.这种聚酰亚胺在极性溶剂中具有较好的溶解性,并具有较高的热稳定性,在紫外光照射下,能进行[2+2]的环加成反应.     

Optimization of the antioxidant activity of hydroxy-substituted 4-thiaflavanes: a proof-of-concept study

The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (k(inh)), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of k(inh) up to 4.0×10(6) M(-1) s(-1) and BDE((OH)) of 77.2 kcal mol(-1). This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles.     

Synthesis of (±)-kuwanon V and (±)-dorsterone methyl ethers via Diels-Alder reaction

The mulberry Diels-Alder adducts, the pentamethyl ethers of kuwanon V 1a and dorsterone 2a were synthesised via a biomimetic intermolecular [4+2] cycloaddition reaction between a highly electron-rich dienophile and a Lewis acid sensitive diene derived from chalcone. Cycloaddition under thermal conditions afforded 1a and 2a (in 3:2 ratio). Cycloaddition catalysed by AgOTf/Bu₄NBH₄ gave higher yields of the adducts.     

Substituent-controlled domino-Knoevenagel-hetero Diels-Alder reaction—a one-pot synthesis of polycyclic heterocycles

The reaction of 2-(N-alkenyl-N-aryl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde with dimedone/Meldrum’s acid/4-hydroxycoumarin by heating in ethanol in the presence of pyridine produces polycyclic heterocycles bearing pyridine and pyran rings in a one-pot reaction. The effect of substituents on N-atom of the amino function controls the mode of reaction. Terminal alkenes prefer intramolecular Michael type reaction, but non-terminal alkenes favour Diels-Alder reaction, whereas, under similar condition, 2-(N-alkyl-N-allyl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde undergoes domino-Knoevenagel-hetero Diels-Alder reaction.     

Viscosity dependence of intra- and intermolecular Diels-Alder reactions

The kinetics of the bimolecular Diels-Alder reaction between anthracene-9-carbinol and N-ethyl maleimide have been studied in a series of pyridinium-based ionic liquids with the tetrafluoroborate ([BF(4)](-)) and the bis(trifluorosulfonimide) ([NTf(2)](-)) anions and the viscosity dependence of the rate constants have been compared with the results for the intramolecular Diels-Alder reaction of (E)-1-phenyl-4-[2-(3-methyl-2-butenyloxy)benzylidene]-5-pyrazolone. The comparison leads to the surprising observation that the intermolecular reaction is less susceptible to viscosity variations of the ionic liquids as compared to the intramolecular reaction. The observed similarities and differences emphasize the complicated nature of solvent friction on the kinetics of cycloaddition reactions. The results are explained by considering the bimolecular and intramolecular processes as cases of translational and rotational diffusion, respectively. Plausible indicators of microviscosity consistent with the kinetic data for the Diels-Alder reactions are briefly discussed along with the constraints involved in designing a general microviscosity scale.     

Diels-Alder reactions between dienamides and quinones: stereochemistry of the cycloadditions and cytotoxic activity of the adducts

Tetrahydronaphthoquinones and tetrahydroanthraquinones bearing an amido group have been prepared by Diels-Alder reactions between (E)-1-(N-carbobenzyloxyamino)-1,3-butadiene (2) or (E)-1-(N-benzoyl-N-benzylamino)-1,3-butadiene (5) and benzoquinone or 5-substituted naphthoquinones. The stereochemistry of the cycloadditions was investigated. A high regioselectivity was observed in the reaction of the diene carbamate 2 with 5-methoxy and 5-acetoxy naphthoquinones. This latter gave the unexpected 1,8-regioisomer 3d. The cycloadditions of the dienamide 5 with naphthoquinones 1 (R = OH, OMe, OAc) are regiospecific. Assignment of the structure of the tetrahydroanthraquinone 6b is in good agreement with the known directing effect of the 5-hydroxy group of juglone 1b in analogous Diels-Alder reactions. With 5-methoxy and 5-acetoxy naphthoquinones, the opposite regiochemistry observed is consistent with the electron-donating influence of the methoxy or acetoxy group, making the C-3 carbon atom more electron deficient. Aromatization of the adducts 6b and 7c was accompanied by an unusual elimination of the amido moiety. Thus, 1-hydroxy and 1-methoxy anthraquinones were obtained. Reactions of the dienes 2 and 5 with benzoquinone gave the tetrahydronaphthoquinones 9 and 10 with an endo stereospecificity. Oxidation of 9 by activated manganese dioxide gave the naphthoquinone 11. These compounds were submitted to in vitro cytotoxic assays towards murine L 1210 leukemia cells and clonogenic human tumor cell line MDA-MB 231. The naphthoquinone derivatives 9, 10 and 11 had significant activities with IC50 less than or equal to 0.4 microgram/ml towards these two tumor cell systems.     

Diels-alder reactions of 3-(2-nitrovinyl)indoles: Formation of carbazoles and bridged carbazoles

The Diels-Alder reactions of 1-substituted-3-(2-nitrovinyl)indoles 3 with quinones and acetylenes give aromatized 1:1 adducts (- nitrous acid) ( 1 ) or (- nitrous acid, -2 hydrogens) 2,5 . Likewise, dimerization (-2 nitrous acids) of 3 gives aromatized 2-(3-indolyl)carbazoles 4 . In contrast, 3 reacts with maleimides 6 to give 1:2 adducts (- nitrous acid or -2 hydrogens) 10 and 11 , respectively, along with smaller amounts of 1:1 adducts (- nitrous acid, -2 hydrogens; or -4 hydrogens) 12 and 13 , respectively. A mechanism for formation of the nitro products 11 and 13 is discussed. A 1:2 adduct (-2 hydrogens) 19 was also obtained from a Diels-Alder reaction between maleimide and the vinylindole produced in situ by condensing 1-methylindole with acetone. The stereochemisty of this 1:2 adduct has been determined by X-ray crystallography.     

Total synthesis of munchiwarin, a triprenylated chalcone from Crotalaria medicagenia

An efficient method is developed for the synthesis of the modified triprenylated chalcone, munchiwarin (1), isolated from the roots of Crotalaria medicagenia. The synthesis of 1 utilizes a Claisen-Schmidt condensation between 2,4-dihydroxy-3,5-C-diprenyl acetophenone and 4-methoxy benzaldehyde in the presence of Ba(OH)2 to yield the unusual chalcone 5 that contains a nine-membered ether ring. Further prenylation of 5 with 1-bromo-3-methylbut-2-ene and its subsequent demethylation with BBr3 gave munchiwarin (1).     

Synthesis of 2,4-disubstituted 3-chlorofurans and the effect of the chlorine substituent in furan Diels-Alder reactions

2,4-Disubstituted 3-chlorofurans were synthesized in 42-69% overall yields by CuCl/bpy-catalyzed halogen atom transfer radical cyclization of 1-substituted 2,2,2-trichloroethyl allyl ethers to 2-substituted 3,3-dichloro-4-(1-chloroalkyl)tetrahydrofurans followed by base promoted dehydrochlorination. Diels-Alder reactions of 4-substituted 2-(2-furyl)-, 2-styryl-, and 2-crotyl-3-chlorofurans with dimethyl acetylenedicarboxylate occurred exclusively on the chlorofurano diene moieties and not on the non-chlorinated furano diene or the chlorinated exocyclic diene alternatives, demonstrating the predominance of the halogen effect in the furan Diels-Alder reaction.     

Towards organo-click chemistry: development of organocatalytic multicomponent reactions through combinations of aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions

Here we report on our studies on combinations of amino acids and copper(I) for catalyzing multicomponent reactions (MCRs). We aimed to prepare both diene and dienophiles simultaneously, under very mild and environmentally friendly conditions, thus giving the constituents for a stereocontrolled Diels-Alder reaction, which in turn yields compounds 4 to 8. A diversity-oriented synthesis of polysubstituted spirotriones 4 to 6 were assembled from simple substrates like 1-(triphenylphosphanylidene)-propan-2-one, two aldehydes, and cyclic-1,3-diketones through Wittig/Knoevenagel/Diels-Alder and aldol/Knoevenagel/Diels-Alder reaction sequences in one pot under stereospecific organocatalysis. Chemical diversity libraries of polysubstituted spirotrione-1,2,3-traizoles 8 were assembled from simple substrates by means of Wittig/Knoevenagel/Diels-Alder/Huisgen cycloaddition reaction sequences in one pot under stereospecific organo/Cu(I) catalysis. Functionalized dispirolactones such as 6 are biologically active antioxidants and radical scavengers, and spirotrione-1,2,3-traizoles 8 have found wide applications in chemistry, biology, and materials science. Experimentally simple and environmentally friendly, organocatalytic, asymmetric four-component Diels-Alder (AFCDA) reactions of 1-(triphenylphosphanylidene)- propan-2-one, two different aldehydes, and cyclic-1,3-diketones produced diastereospecific and highly enantioselective substituted spirotriones 4 by means of a Wittig/Knoevenagel/Diels-Alder reaction sequence in one pot. Additionally we have developed an organocatalytic, asymmetric three-component Michael (ATCM) reaction of 1-(triphenylphosphanylidene)-propan-2-one, aldehyde, and cyclic-1,3-diketones that produced Michael adducts 15, 16 through a Wittig/Michael reaction sequence in a highly enantioselective one-pot process.     

Synthesis and structure of asymmetric zirconium-substituted silicotungstates, [Zr6O2(OH)4(H2O)3(beta-SiW10O37)3]14- and [Zr4O2(OH)2(H2O)4(beta-SiW10O37)2]10-

The reaction of ZrCl4 with [gamma-SiW10O36]8- in a potassium acetate buffer results in two different products depending on the reactant ratios. The trimeric species [Zr6O2(OH)4(H2O)3(beta-SiW10O37)3]14- (1) consists of three beta23-SiW10O37 units linked by an unprecedented Zr6O2(OH)4(H2O)3 cluster with C1 point group symmetry. The dimeric species [Zr4O2(OH)2(H2O)4(beta-SiW10O37)2]10- (2) consists of beta22- and beta12-SiW10O37 units sandwiching a Zr4O2(OH)2(H2O)4 cluster, which also has C1 symmetry. Polyanion 1 contains more zirconium centers than any other polyoxometalate known to date.     

Synthesis of (+/-)-bakkenolide-A and its C-7, C-10, and C-7,10 epimers by means of an intramolecular Diels-Alder reaction

(+/-)-bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi- and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition, using dimethyl malonate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the corresponding alpha-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro center by a radical cyclization resulted chiefly in reductive deselenization.     

Catalyzed Diels-Alder reaction of alkylidene- or arylideneacetoacetates and Danishefsky's dienes with lanthanide salts aimed at selective synthesis of cis-4,5-dimethyl-2-cyclohexenone derivatives.

The first successful example of the catalyzed Diels-Alder reaction of 1-methoxy-3-trimethylsiloxy-1,3-diene (Danishefsky's diene, 2a), giving the corresponding carbocyclic adducts, is described. The reaction of (Z)-ethylideneacetoacetate 1a with 2a is catalyzed with lanthanide salts such as Yb(OTf)(3) at 0 degrees C, affording the corresponding 2-cyclohexenone 3a in good yield with complete integrity of the starting geometry of 1a. The thermal version of the same cycloaddition results in a decrease in the cis arrangement of the 5-methyl and the 4-alkoxycarbonyl groups on 2-cyclohexenone. The catalyzed reaction of (E)-1a unexpectedly affords the cis-arranged 3a. The reaction path for the catalyzed Diels-Alder reaction is postulated on the basis of these results.     

Critical assessment of two classical synthetic methods for preparation of thiophene-substituted isoxazoles

Formation of thiophene-substituted isoxazoles by reaction of chalcone dibromides and 1,3-diketones with hydroxylamine hydrochloride has been examined under different conditions. Use of KOH as base in the reaction of dibromide chalcone analogs with hydroxylamine hydrochloride yields mixtures of isomeric isoxazoles in modest yields. Replacement of KOH with pyridine affords negligible amounts of isoxazoles only, the intermediate 2-bromoprop-2-en-1-one being isolated from the reaction as the major product. Substitution of the β-bromine atom from a chalcone dibromides with a methoxy group by solvolysis occurred when no base was used. Mixtures of isomeric isoxazoles in which the isoxazole that had a 2-thienyl group at position 5 were always major components, were obtained in good yields from reaction of thiophene-containing 1,3-diketones with hydroxylamine hydrochloride, irrespective of reaction pH. At low pH, regioselectivity was poorer than that observed for reaction of chalcone dibromides with hydroxylamine hydrochloride, but yields were substantially better. At high pH, yields were comparable with those at low pH and regioselectivity for 3-aryl-5-(2-thiophenyl)isoxazole was slightly enhanced, but the dioxime corresponding to the initial 1,3-diketone was also produced in low yields as a mixture of stereoisomers.