Alkylation of complementary ribonucleotides by 1,2‐dodecyl‐epoxide in a micellar environment: a liquid chromatography—electrospray ionization—sequential mass spectrometry investigation

Alkylation of a pair of complementary ribonucleotides, adenosine monophosphate (AMP) and uridine monophosphate (UMP), was accomplished by 1,2‐dodecyl‐epoxide (DE) in a oil‐in‐water microemulsion based on the cationic surfactant Cetyl‐trimethyl‐ammonium‐bromide, providing a suitable catalytic interface for the reagents. Several, often isomeric, alkylation products, bearing one or two hydroxy–dodecyl moieties on their structures, were identified in the reaction mixtures by high‐performance liquid chromatography coupled to electrospray ionization ion trap mass spectrometry. In particular, mass spectrometry (MS)/MS spectra, implemented by extracted ion chromatograms obtained for peculiar MS/MS product ions, indicated alkylation to occur on uracil and on uracil/phosphate OH groups in singly and doubly alkylated UMP, respectively. Adenine NH₂ group and phosphate or ribose OH groups were found to be involved as such (single alkylation) or in combination, in the case of alkylated derivatives of AMP. The reaction of both endocyclic N and C?O groups (tautomerized to C? OH groups) of uracil and the predominance of nucleophilic attack to the more accessible carbon of the DE epoxydic bridge (the only exception being the reaction by the NH₂ group of adenine) were inferred from MS³ spectra with the help of extracted ion chromatograms for specific fragment ions, after their structural characterization. Interestingly, alkylation on one of the uracil C?O groups and, partially, on the adenine NH₂ group, both potentially involved in AMP/UMP base pairing in the micellar environment, were found to be hindered when both ribonucleotides were present in the reaction mixtures. Copyright © 2009 John Wiley & Sons, Ltd.     

Detailed Studies of the Alkylation Sides of Pyridin‐2‐yl and 4,6‐Dimethylpyrimidin‐2‐yl‐cyanamides

Pyridin‐2‐yl‐ and 4,6‐dimethylpyrimidin‐2‐yl‐cyanamides entered into an alkylation reaction in the form of sodium salts. Pyridin‐2‐yl cyanamide 2 was alkylated at endo‐nitrogen atom of pyridine ring, while 4,6‐dimethylpyrimidin‐2‐yl cyanamide 1 was effectively alkylated at exo‐nitrogen atom of amino cyanamide group. The alkylation of cyanamides 1 and 2 with phenacylbromide gave the corresponding acetophenone derivatives. As a result of their intramolecular cyclization reactions 3‐(4,6‐dimethylpyrimidin‐2‐yl)‐5‐phenyloxazol‐2(3H )‐imine in the case of cyanamide 1 and 2‐amino‐3‐benzoylimidazo[1,2‐a ]pyridine in the case of cyanamide 2 were formed. The alkylated derivatives of pyridin‐2‐ylcyanamide 2 possess visible blue fluorescence with the main peak at 421 – 427 nm.     

Synthesis and Irradiation of Vitamin‐B12‐Derived Complexes Incorporating Peripheral G⋅C Base Pairs

The vitamin‐B₁₂ derivative 11 , incorporating a peripheral N⁴‐acetylcytosine moiety, was alkylated under reductive conditions with 2‐(iodomethyl)‐2‐methylmonothiomalonate 8 bearing the complementary guanine moiety. The reaction yielded a mixture of vitamin‐B₁₂‐derived complexes with variations in the cytosine moiety: products 16 – 18 with a cytosine, a N⁴‐acetylated cytosine, and a N⁴‐acetylated reduced cytosine moiety were formed (see Scheme 5). The complexes were photolyzed in CHCl₃/MeCN to yield the dimethylmalonate derivative 22 (Scheme 6) but not the rearranged succinate, in contrast to the results obtained earlier with complexes incorporating the A⋅T base pair (see Scheme 1).     

棉宝中常见单磷酸核苷酸的高效 液相色谱分离与测定

建立了以浓度为 0.05mol/L 的 KH     

Semiempirical studies on the interactions of dialkyldi(aquo)tin cations, [R2Sn(H2O)2]2+, with selected nucleotides

Semiempirical calculations have been carried out on the interactions of [R₂Sn(H₂O)₂]²⁺, [R = H(CH₂)_n: n = 1–8], mainly with five nucleotides, 5′‐adenosine monophosphate (5′‐AMP), but also with guanosine 5′‐monophosphate (5′‐GMP), cytidine 5′‐monophosphate (5′‐CMP), uridine‐5′‐monophosphate (5′‐UMP) and inosine 5′‐monophosphate (5′‐IMP). The preferred sites of interaction were calculated to be the ribose O2 and O3 hydroxyl oxygens and/or the phosphate oxygens, with the nitrogen sites in the bases the least attractive to the tin compounds. This is in general agreement with experimental findings. Structures of the 1:1 coordination complexes vary from distorted tetrahedral, to distorted trigonal pyramidal to distorted octahedral geometries. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of New Furo[2,3‐d]pyrimidines and Pyrimido[4′,5′:4,5]furo[2,3‐d]pyrimidines

Sodium salt of 4‐hydroxy‐6‐methyl‐2‐phenylpyrimidine‐5‐carbonitrile ( 3 ) was subjected to alkylation with different a‐halo compounds, where the corresponding O‐alkylated products 4_a‐g were obtained. Ring closure of the O‐alkylated product 4_a‐c performed using sodium ethoxide in refluxing ethanol afforded furo[2,3‐d]pyrimidines 5_a‐c The latter compounds on reaction with a variety of reagents gave other new furopyrimidines as well as a number of furodipyrimidines.     

离子色谱法测定婴幼儿配方奶粉中的核苷酸

建立了婴幼儿配方奶粉中5种核苷酸的离子色谱检测方法。分离柱为IonPac AS16柱,以KOH为流动相,梯度洗脱,流速为1.0 mL/min,柱温为25 ℃,检测波长为260 nm,进样量为25 μL。在上述条件下,胞嘧啶核苷酸(CMP)、腺嘌呤核苷酸(AMP)、尿嘧啶核苷酸(UMP)、次黄嘌呤核苷酸(IMP)、鸟嘌呤核苷酸(GMP)的质量浓度分别为0.09～50、0.06～50、0.06～50、0.09～50、0.06～50 mg/L时与对应色谱峰面积之间的线性关系良好,检出限分别为0.03、0.02、0.02、0.03和0.02 mg/L,回收率为92.5%～104.0%。该方法简便、快速、准确,可用于实际样品的测定。     

Ruthenium‐catalyzed synthesis of quinolines via reductive heteroannulation of nitroarenes with 3‐amino‐1‐propanols

Nitroarenes are reductively cyclized with 3‐amino‐1‐propanols in dioxane/H₂O in the presence of a ruthenium catalyst and tin(II) chloride dihydrate together with isopropanol to afford the corresponding quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines, propanol group transfer from 3‐amino‐1‐propanols to anilines, N‐alkylation of anilines by 3‐anilino‐1‐propanols and heteroannulation of 1,3‐dianilinopropanes is proposed.     

Studying the synthesis of 4‐tert‐butyl‐1,3‐dihydroimidazol‐2‐ones and their corresponding thiones

4‐tert‐Butyl‐1,3‐dihydroimidazol‐2‐ones and 1,3‐dihydroimidazol‐2‐thiones were synthesized from 1‐amino‐3,3‐dimethylbutanone and subjected to alkylation reactions. The latter compounds were S‐alkyl‐ated with iodoacetamide under alkaline conditions. The N¹ N³‐unsubstituted derivative was iodinated and subsequently alkylated with alkylation reagents which previously have been used for the synthesis of anti‐HTV active imidazoles. Unfortunately, the present products were devoid of activity against HTV.     

Palladium‐Catalyzed Alkylation with Alkyl Halides by C(sp3)−H Activation

Utilizing halogens as traceless directing goups represents an attractive strategy for C−H functionalization. A two C−H alkylation system, initiated by the oxidative addition of organohalides to Pd⁰, has been developed. The first reaction involves an intermolecular alkylation of palladacycles to form C(sp³)−C(sp²) bonds followed by C(sp²)−H activation/cyclization to deliver alkylated benzocyclobutenes as the final products. In the second reaction, two C−C bonds are formed by the reaction of palladacycles with CH₂Br₂, and provides a facile and efficient method for the synthesis of indanes. The alkylated benzocyclobutene products can be transformed into tricyclic hyrocarbons, and the indane derivatives are essential structural motifs in bioactive and odorant molecules.     

Functionalization of Quinazolin‐4‐ones Part 1: Synthesis of Novel 7‐Substituted‐2‐thioxo Quinazolin‐4‐ones from 4‐Substituted‐2‐Aminobenzoic Acids and PPh3(SCN)2

4‐(Nitro, amino, acetylamino)‐2‐aminobenzoic acid were allowed to react with PPh₃(SCN)₂ and gave the crossholding 7‐nitro, 7‐acetylamino‐ and 7‐amino‐2‐thioxo quinazolin‐4‐ones respectively. The nature of the substituent at position 4 of the 2‐aminobenzoic acids has significant influence on the outcome of the cyclisation reaction with PPh₃(SCN)₂. Similarly, the nature of the substituent at position 7 of the 2‐substituted quinazolin‐4‐ones significantly affected the ease with which alkylation reactions could be performed. The alkylation selectivity of the 7‐ substiuted‐2‐thioxo quinazolin‐4‐ones was found to depend on the nature of the alkyl halide and the nature of the substituent at position 2.     

Solvent effects on complexation of thallium(I) with guanosine 5′‐monophosphate in methanol–water mixtures

The interaction of guanosine 5′‐monophosphate, GMP, with the thallium(I) ion was studied by UV–vis and potentiometric titration methods and ³¹P NMR spectroscopy. Both NMR spectra and UV–vis titration data have shown that GMP coordinates via guanine to the thallium(I) ion in the pH range 1.5–10. Our study of the system Tl(I) + GMP was performed in water–methanol mixtures with different volume ratios of methanol. The complexation equilibrium in the pH range of study led to the following mononuclear species: TlH₂(GMP)⁺, TlH(GMP) and Tl(GMP)^?, where (GMP)^2? represents the fully dissociated ligand. The formation constants of the species were calculated in the various media at constant temperature (25 °C) and constant ionic strength of sodium perchlorate (0.1 mol dm^?3) using a suitable computer program. The formation constants were analyzed in terms of Kamlet and Taft's parameters. A single‐parameter correlation of the formation constants, β₁₂₁, β₁₁₁ and β₁₀₁ vs α (hydrogen‐bond donor acidity), β (hydrogen‐bond acceptor basicity) and for π* (dipolarity/polarizability) are relatively poor in all solutions, but multi‐parameter correlations represent significant improvements with regard to the single‐parameter model. In this work, we have also used the normalized polarity parameter, E_T^N, alone and in combination with some of the Kamlet–Taft parameters to find a better correlation of the formation constants in different methanol–water mixtures. Copyright © 2007 John Wiley & Sons, Ltd.     

C9 Fraction Alkylation Desulfurization over Amberlyst 36 Resin:The Kinetics of 2‐Ethylthiophen, 2,5‐Dimethylthiophene,and 2‐n‐Propylthiophene with Isoamylene

C₉ fraction is the by‐products of catalytic reforming and ethylene cracker; it is considered as a kind of petroleum resin raw material. Recently, it was studied for the use as a gasoline additive to enhance the economic benefits. However, C₉ fractions are getting higher in sulfur contents. As conventional hydrotreating technology leads to significant octane number loss and processing costs, the alkylation desulfurization process, which could reduce the sulfuric compounds to hydrogen sulfide by catalytic alkylation with olefins and distillation followed by, is a rather attractive way of reducing the sulfur of C₉ fraction. In this paper, different kinds of thiophenic compounds, including 2‐ethylthiophen, 2,5‐dimethylthiophene, and 2‐n‐propylthiophene, were selected as the model compounds. Thiophenic compounds were studied first by the alkylation reaction over macroporous sulfonic resin Amberlyst 36, and the octane number of C₉ fraction was measured. It was found that isoamylene and Amberlyst 36 resin had a significant effect on the alkylation desulfurization of thiophenic compounds with the conversion, reaching to above 99%. And the octane number of C₉ fraction was increased by alkylation desulfurization over Amberlyst 36 resin. Moreover, the alkylation of thiophenic sulfurs could be described as a pseudo–first–order reaction as well as the reaction rate constant, and the activation energy of alkylation reactions was calculated.     

Bifunctional Heterogeneous Catalysis of Silica–Alumina‐Supported Tertiary Amines with Controlled Acid–Base Interactions for Efficient 1,4‐Addition Reactions

We report the first tunable bifunctional surface of silica–alumina‐supported tertiary amines (SA–NEt₂) active for catalytic 1,4‐addition reactions of nitroalkanes and thiols to electron‐deficient alkenes. The 1,4‐addition reaction of nitroalkanes to electron‐deficient alkenes is one of the most useful carbon–carbon bond‐forming reactions and applicable toward a wide range of organic syntheses. The reaction between nitroethane and methyl vinyl ketone scarcely proceeded with either SA or homogeneous amines, and a mixture of SA and amines showed very low catalytic activity. In addition, undesirable side reactions occurred in the case of a strong base like sodium ethoxide employed as a catalytic reagent. Only the present SA‐supported amine (SA–NEt₂) catalyst enabled selective formation of a double‐alkylated product without promotions of side reactions such as an intramolecular cyclization reaction. The heterogeneous SA–NEt₂ catalyst was easily recovered from the reaction mixture by simple filtration and reusable with retention of its catalytic activity and selectivity. Furthermore, the SA–NEt₂ catalyst system was applicable to the addition reaction of other nitroalkanes and thiols to various electron‐deficient alkenes. The solid‐state magic‐angle spinning (MAS) NMR spectroscopic analyses, including variable‐contact‐time ¹³C cross‐polarization (CP)/MAS NMR spectroscopy, revealed that acid–base interactions between surface acid sites and immobilized amines can be controlled by pretreatment of SA at different temperatures. The catalytic activities for these addition reactions were strongly affected by the surface acid–base interactions.     

Synthesis of N‐Alkylated Indolines and Indoles from Indoline and Aliphatic Ketones

A survey of redox aminations of indoline with aliphatic ketones using bismuth nitrate as catalyst is described. A reaction of an equivalent amount of indoline and aliphatic cyclic and acyclic ketones provides a mixture of excessive alkylated indole derivatives over typically redox isomerization and reductive alkylation pathways while using of the five equivalent of indoline provides N‐alkylated indolines as a reductive alkylation product. The desired N‐alkyl indoles from the oxidation of N‐alkyl indolines were obtained in excellent yields.     

New Synthesis of 7‐(3‐chloropropoxy)‐4‐hydroxy‐6‐methoxyquinoline‐3‐carbonitrile,a Key Intermediate to Bosutinib

A new and convenient synthesis of 7‐(3‐chloropropoxy)‐4‐hydroxy‐6‐methoxyquinoline‐3‐carbonitrile, the key intermediate to bosutinib, is described on a hectogram scale. 5‐Bromo‐2‐methoxyphenol is adopted as the starting material via the simple chemical process including Friedel‐Crafts reaction, alkylation, bromination, cyano substitution, and so on to give the 3‐amino‐2‐(2‐bromobenzoyl)acrylonitrile compound 25 , which underwent key intramolecular cyclization at K₂CO₃/DMF condition; the title product was obtained in 36.9% yield over 7 steps and 98.71% purity (HPLC).     

Ruthenium‐Catalyzed Alkylation of Indoles with Tertiary Amines by Oxidation of a sp3 C?H Bond and Lewis Acid Catalysis

Ruthenium porphyrins (particularly [Ru(2,6‐Cl₂tpp)CO]; tpp=tetraphenylporphinato) and RuCl₃ can act as oxidation and/or Lewis acid catalysts for direct C‐3 alkylation of indoles, giving the desired products in high yields (up to 82 % based on 60–95 % substrate conversions). These ruthenium compounds catalyze oxidative coupling reactions of a wide variety of anilines and indoles bearing electron‐withdrawing or electron‐donating substituents with high regioselectivity when using tBuOOH as an oxidant, resulting in the alkylation of N‐arylindoles to 3‐{[(N‐aryl‐N‐alkyl)amino]methyl}indoles (yield: up to 82 %, conversion: up to 95 %) and the alkylation of N‐alkyl or N‐H indoles to 3‐[p‐(dialkylamino)benzyl]indoles (yield: up to 73 %, conversion: up to 92 %). A tentative reaction mechanism involving two pathways is proposed: an iminium ion intermediate may be generated by oxidation of an sp³ C? H bond of the alkylated aniline by an oxoruthenium species; this iminium ion could then either be trapped by an N‐arylindole (pathway A) or converted to formaldehyde, allowing a subsequent three‐component coupling reaction of the in situ generated formaldehyde with an N‐alkylindole and an aniline in the presence of a Lewis acid catalyst (pathway B). The results of deuterium‐labeling experiments are consistent with the alkylation of N‐alkylindoles via pathway B. The relative reaction rates of [Ru(2,6‐Cl₂tpp)CO]‐catalyzed oxidative coupling reactions of 4‐X‐substituted N,N‐dimethylanilines with N‐phenylindole (using tBuOOH as oxidant), determined through competition experiments, correlate linearly with the substituent constants σ (R²=0.989), giving a ρ value of ?1.09. This ρ value and the magnitudes of the intra‐ and intermolecular deuterium isotope effects (k_H/k_D) suggest that electron transfer most likely occurs during the initial stage of the oxidation of 4‐X‐substituted N,N‐dimethylanilines. Ruthenium‐catalyzed three‐component reaction of N‐alkyl/N‐H indoles, paraformaldehyde, and anilines gave 3‐[p‐(dialkylamino)benzyl]indoles in up to 82 % yield (conversion: up to 95 %).     

Nucleotides and nucleolipids derivatives interaction effects during multi-lamellar vesicles formation

In this paper a micellar interface, constituted by the cationic surfactant CTAB, in presence of 1,2-epoxydodecane and nucleotides was used for catanionic multi-lamellar vesicles (MLVs) formation. The micellar solution of CTAB is able to disperse the 1,2 epoxydodecane in the micellar core promoting the reaction of this reagent with the nucleotide attracted by the positive surface charge of the micellar aggregates. The alkylation of AMP and UMP nucleotides leads to the synthesis of nucleolipids. The behaviour of the supramolecular structures formed depends on the starting reagents (AMP, UMP and AMP+UMP) and on the assembly capabilities of the products. In particular nucleotides and nucleotides derivatives interaction effects are evaluated during the multi-lamellar vesicles formation. NMR spectroscopy and UV-vis measurements performed on MLVs showed strong aryl interactions. Interestingly, NMR spectra revealed prevailing stacking interactions between complementary nucleolipids. The assembly of complementary nucleotides affects the course of the reaction during the MLVs formation. Moreover the MLVs supramolecular stability has been tested by means of turbidity and UV-vis measurements. In particular, an enhanced stability has been found in systems prepared with complementary nucleotides confirming that in these systems the self-assembly process is influenced by nucleolipids interactions. Furthermore by following the hypocromic effect during the micellar catalysis, we showed that even in the earlier stages of the reaction significant differences are detectable.     

Interaction of dimethyltin(IV) dichloride with 5′‐IMP and 5′‐UMP

The formation constants of the species formed in the systems H⁺ + dimethyltin(IV) + 5′‐IMP and 5′‐UMP, H⁺ + 5′‐IMP and H⁺ + 5′‐UMP have been determined in aqueous solution in the pH range 1.5–9.5 at constant temperature (25 °C) and constant ionic strength (0.1 mol dm⁻³ NaClO₄), using spectrophotometric and potentiometric techniques. ¹H and ³¹P NMR investigations in aqueous solution confirmed the species formation. The precipitated complexes of IMP and UMP by Me₂Sn(IV)²⁺ at low pH values were characterized by elemental analysis and FTIR spectroscopy methods, the bonding sites of the ligands were determined and ruled out purine and pyrimidine moieties (N‐7 and N‐1 in IMP and N‐3 in UMP, respectively) while a bidentated coordination of the phosphate group is concluded in both cases. Finally, the experiments revealed the existence of complexes with trigonal bipyramidal structures that is in agreement with similar systems resulted previously. Copyright © 2008 John Wiley & Sons, Ltd.     

Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine – A Computational Study

It has been shown previously that the reaction of diazomethane with 5‐benzylidene‐3‐phenylrhodanine ( 1 ) in THF at ?20° occurs at the exocyclic C?C bond via cyclopropanation to give 3a and methylation to yield 4 , respectively, whereas the corresponding reaction with phenyldiazomethane in toluene at 0° leads to the cyclopropane derivative 3b exclusively. Surprisingly, under similar conditions, no reaction was observed between 1 and diphenyldiazomethane, but the 2‐diphenylmethylidene derivative 5 was formed in boiling toluene. In the present study, these results have been rationalized by calculations at the DFT B3LYP/6‐31G(d) level using PCM solvent model. In the case of diazomethane, the formation of 3a occurs via initial Michael addition, whereas 4 is formed via [3+2] cycloaddition followed by N₂ elimination and H‐migration. The preferred pathway of the reaction of 1 with phenyldiazomethane is a [3+2] cycloaddition, subsequent N₂ elimination and ring closure of an intermediate zwitterion to give 3b . Finally, the calculations show that the energetically most favorable reaction of 1 with diphenyldiazomethane is the initial formation of diphenylcarbene, which adds to the S‐atom to give a thiocarbonyl ylide, followed by 1,3‐dipolar electrocyclization and S‐elimination.