Synthesis and characterization of trans-di(nitrobenzo)- and di(aminobenzo)-18-crown-6 derivatives with high selectivity

The dibenzo-18-crown-6 derivatives such as di(nitrobenzo)-18-crown-6 and di(aminobenzo)-18-crown-6 were synthesized by nitration reaction and catalytic hydrogenation with high selectivity. The chemical structures were determined by FTIR, ¹H NMR, ¹³C NMR, and UV. Regarding the mixture of Ac₂O and HNO₃ as nitrating agent, the reaction exhibited commendable trans-isomer selectivity. Effects of nitrating agent ratio, reaction temperature and reaction time on yield of trans-di(nitrobenzo)-18-crown-6 were investigated. The yield of trans-di(nitrobenzo)-18-crown-6 was 62.9% for nitrating agent ratio of 1/1, reaction temperature of 50?°C and reaction time of 5?h. Moreover, effect of reaction time on trans-di(aminobenzo)-18-crown-6 was also studied.     

Synthesis of pyrazolo-fused heterocycles by a tandem appel's dehydration/electrocyclization methodology

The hydrazones of benzophenone, benzil, and acetophenone were allowed to react with acetoacetanilide to give azinoamides 18 , and the reaction of 18 with Appel's dehydrathon contiditons (triphenylphosphine/carbon tetra-chloride/triethylatnine) led to the corresponding azinoketimines 19 , which underwent elctrocyclic ring closure under the reaction conditions to give pyrazolo-fused heterocycles. Azinoamide 18a gave a 4,9-dihydropyazolo-[5,1-b]quinazoine 21 , while 18b yielded 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-2-one 26 and 1H-imidazo[1,2-b]-pyrazole 29 . Compound 18c gave a monocyclic N-α-styryl-5-(phenylamino)pyrazole 32 .     

Thermodynamic characteristics of alanine-18-crown-6 ether complexes in binary water-acetone solvents

The formation of 18-crown-6 ether (18C6) complexes with D,L-alanine (Ala) in mixed wateracetone solvents with 0.0, 0.08, 0.17, 0.22, and 0.30 mole fractions of acetone (T = 298.15 K) was investigated by means of calorimetry. Thermodynamic characteristics of the reaction of the molecular [Ala18C6] complex formation (Δ_r G°, Δ_r H°, and TΔ_r S°) were calculated on the basis of calorimetric data. Analysis of solvation contributions of reagents into the enthalpy of the [Ala18C6] formation reaction showed that the changes in the reaction energy when the solvent composition is varied are determined by the changes in the solvate state of 18C6.     

Effect of solvation on the thermodynamics of the formation of molecular complexes of 18-crown-6 ether with glycine in water-dimethylsulfoxide solutions

Complexation of the 18-crown-6 ether (18C6) with glycine (Gly) in mixed H₂O-DMSO solvents with the composition of 0.1, 0.2, and 0.25 mole fraction of DMSO (T = 298.15 K) was studied calorimetrically. Thermodynamic characteristics of the reaction of the formation of the molecular Gly18C6 complex (Δ_r G°, Δ_r H°, TΔ_r S°) were calculated from the calorimetric data. It was established that the change in the stability of the Gly18C6 complex is mainly determined by the predominance of the enthalpy component of the Gibbs energy over the entropy component. It was shown during the analysis of the enthalpy contributions of the reagents to the enthalpy of the reaction of the formation of Gly18C6 that the change in the enthalpy of the reaction upon a change the solvent composition was due to changes in the solvation state of 18C6.     

A new synthetic route to 7H-imidazo[1,2-b][1,2,4]triazoles

The reaction of benzil 1-ureidoethylidene hydrazones 8 with a mixture of triphenylphosphine, carbon tetrachloride, and triethylamine provides a general route to 7H-imidazo[1,2-b][1,2,4]triazoles 18 via the thermal reaction of the expected keto azine carbodiimide intermediates 13, and the structure of 18 was confirmed by X-ray crystallographic analysis.     

Micellar effects of a triazole-based cationic gemini surfactant on the rate of a nucleophilic aromatic substitution reaction

The reaction between 2,4-dinitrochlorobenzene (DNCB) and hydroxide ion was studied spectrophotometrically at 25 °C in micelles of a triazole-based cationic gemini surfactant 18-triazole-18 or micelles of the conventional cationic surfactant CTAB. Both CTAB and 18-triazole-18 accelerated this nucleophilic aromatic substitution reaction. The binding constant of the substrate to the micelle, K _S, for 18-triazole-18 (K _S=335 M⁻¹) was found to be much larger than that for CTAB (85 M⁻¹) by fitting the kinetic results with pseudophase ion-exchange (PIE) model, which suggests that DNCB binds with gemini micelles more easily than it does with CTAB micelles. It was also found that 18-triazole-18 catalytic system was in accordance with PIE model at surfactant concentrations below ca. 0.5 mM, above which the increase of viscosity and the change of micelle size with increased surfactant concentration may remarkably influence the reaction. This was quite different from the reaction catalyzed by micelles of the conventional surfactant CTAB.     

Synthesis of Unique Ceramides and Cerebrosides Occurring in Human Epidermis

The sphingolipids 1a , b and 2a , b which play important roles in epidermal barrier function, were synthesized by N-acylation of C₁₈-sphingosine 3 and 1-O-glucosylated C₁₈-sphingosine 6 , respectively, with ω-acyloxy-substituted fatty acids 4 and 5 (Scheme 1). These fatty acids were obtained from ω-hydroxy-substituted fatty acids 8 and 9 by esterification with linoleic acid ( 7 ). The C₃₄-fatty acid 8 was prepared as follows: C₂₅-Compound 18 was obtained by means of a Wittig reaction of C₁₃-aldehyde 13 with C₁₂-phosphonium salt 15 or of C₁₂-aldehyde 24 with C₁₃-phosphonium salt 21 , respectively, and subseqent hydrogenation and O-deprotection (Scheme 2). Alternatively, 8 was prepared via 30 by copper-catalyzed coupling of C₁₃-alkyl halide 19 with the Grignard reagent derived from C₁₂-alkyl bromide 14 (Scheme 2). Oxidation of 18 to aldehyde 39 and Wittig reaction with C₉-phosphonium salt 41 furnished the desired ω-hydroxy-substituted fatty acid 8 , after O-deprotection (Scheme 3). Similarly, Wittig reaction of C₁₁-phosphonium salt 22 with C₁₂-aldehyde 24 furnished C₂₃-aldehyde 40 , after hydrogenation, O-deprotection, and oxidation; Wittig reaction with compound 41 and subsequent deprotection afforded the desired C₃₂-fatty and 9 (Scheme 3). an alternative strategy furnished compound 8 by a coupling reaction of alkyne 53 with ω-bromo-substitued fatty acid 52 , obtained from compounds 24 and 47 by Wittig reaction, hydrogenation, and introduction of bromide (Scheme 4). Hydrogenation (Lindlar's catalyst) of the resulting C₃₄-alkyne 54 and deprotection furnished 8 .     

Biosynthesis of Dodecano-4-lactone in Ripening Fruits: Crucial Role of an Epoxide-Hydrolase in Enantioselective Generation of Aroma Components of the Nectarine (Prunus persica var. nucipersica) and the Strawberry (Fragaria ananassa)

Early steps in the biosynthesis of dedecano-4-lactone in ripening nectarines (Prunus persica var. nucipersica) and strawberries (Fragaria ananassa) were studied using cis-9,10-([¹⁸O]epoxy)heptadecanoic acid ( 5 ), instead of the natural C₁₈-precursor epoxystearic acid 1 . In nectarines, an epoxide hydrolase catalyzed, in a highly regio- and enantioselective reaction, the attack of H₂O at C(9) of epoxy acid 5 yielding preferentially (9R,10R)-dihydroxyheptadecanoic acid 6a as an early intermediate and, after further metabolization, undecano-4-lactone 7a . In strawberries, the same transformation exhibited only a moderate regio- and enantioselectivity. Besides the previously established function of phytogenic epoxide hydrolases involved in generating oxygenated fatty-acid derivatives, which are used in cutin monomer production and plant defence, a new rǒle for these enzymes now emerges in the enantioselective production of aroma components of ripening fruits. The cis-9,10-([¹⁸O]epoxy)heptadecanoic acid (≥ 98% ¹⁸O; 5 ) was obtained in good overall yield (68%) from isopropyl (9Z)-heptadec-9-enoate using ¹⁸O₂ gas in a free-radical chain reaction in the presence of 2-methylbutanal.     

Synthesis,Characterization, and Antioxidant Evaluation of Some Novel Pyrazolo[3,4‐c][1,2]diazepine and Pyrazolo[3,4‐c]pyrazole Derivatives

5‐Hydrazineyl‐3‐methyl‐1H‐pyrazole ( 1 ) was used as a starting material for the synthesis of novel pyrazolo[3,4‐c][1,2]diazepine derivatives 3 , 4 , and 6a,b by its reaction with acetylacetone, ethyl acetoacetate, and isatylidene derivatives 5a,b , respectively. Also, pyrazolo[3,4‐c][1,2]diazepine derivative 11 was synthesized via multicomponent reaction of 1 , benzaldehyde, and malononitrile. Moreover, compound 1 was used for synthesis novel pyrazolo[3,4‐c]pyrazole derivative 7 by its reaction with isatin. In addition, pyrazolo[3,4‐c]pyrazole derivatives 18a–c were synthesized by treatment of 2‐cyano‐N′‐(3‐methyl‐1H‐pyrazol‐5‐yl)acetohydrazide ( 13 ) with aromatic aldehydes 16a–c . The newly synthesized compounds were valeted by means of analytical and spectral data. All newly synthesized compounds were screened for their antioxidant activities. Compounds 3 , 13 , 18b , and 18c showed higher radical‐scavenging activities.     

Synthese von Sulfolenobilinen und deren Cyclisierung zu Chlorinatozink‐Fulleren‐Dyaden

Synthesis of Sulfolenobilins and Their Cyclization Directed to Chlorinatozinc‐Fullerene Dyads A novel chlorinatozinc‐fullerene dyad 18 was synthesized to model the photosynthetic reaction center. The synthetic key step for the formation of the dyad 18 is an unusual one‐pot reaction of the (sulfolenobilinato)nickel rac‐ 16a , b with concomitant generation of the chlorin macrocycle and linkage to the [5,6]fullerene‐C₆₀‐I_h. This one‐pot reaction is a complex cascade of single reaction steps with a total yield of 32% and an average yield of 83% for the individual steps. The chlorinatozinc‐fullerene dyad is so far one of three examples that contain chlorin moieties, the chromophores in naturally occurring photosynthetic systems.     

Diepoxy[18]annulene(10.0) : (Z,E,Z,E,Z)‐Diepoxy[18]annulen(10.0) – ein hochdynamisches Annulen

Diepoxy[18]annulenes(10.0): ( Z , E , Z , E , Z )‐Diepoxy[18]annulene(10.0) – a Highly Dynamic Annulene The McMurry reaction of (all‐E)‐5,5′‐([2,2′‐bifuran]‐5,5′‐diyl)bis[penta‐2,4‐dienal] ( 13 ) only occurs intramolecularly to give a mixture of the diepoxy[18]annulenes(10.0) 6 and 7 . Tetraepoxy[36]annulene(10.0.10.0) resulting from an intermolecular McMurry reaction is not formed. According to spectroscopic data, 6 is (Z,E,Z,E,Z)‐ and 7 (Z,E,E,Z,E)‐configured. The ¹H‐NMR data confirm that in 6 the (E)‐ethene‐1,2‐diyl bonds (C(11)=C(12) and C(15)=C(16)) rotate around the adjacent σ‐bonds. Beginning at −70°, this rotation freezes, and 6 is becoming a diatropic aromatic ring system. Beside [18]annulene itself, (Z,E,Z,E,Z)‐diepoxy[18]annulene(10.0) 6 is the only hitherto known [18]annulene derivative with dynamic properties.     

Carbon Tunneling in the Automerization of Cyclo[18]carbon

Cyclo[18]carbon (C₁₈), a recently synthesized carbon allotrope, was found to have a polyynic ground-state structure with D_9h symmetry and formally alternating single and triple bonds. Yet, under less influencing experimental conditions this molecule might undergo an automerization reaction between its two degenerate geometries through a cumulenic (non-alternating, adjacent double bonds) D_18h transition state. Herein, we discuss the role of quantum mechanical tunneling (QMT) in this degenerate reaction. Our computations predict that at the experimental temperature (5 K) the reaction in the gas phase is completely driven by an extremely rapid heavy atom tunneling (k=2.1×10⁸ s⁻¹). Even when approaching room temperature, the QMT rate is still an order of magnitude faster than the semi-classical one. We propose an experimental test to support our prediction, by measuring a characteristic tunneling energy splitting within the radio wave region. Additionally, we examine the role of QMT in other hypothetical C_4n+2 carbon clusters.     

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Four putative functionalized α‐chloroakyllithiums RCH₂CHLiCl, where R=CHCH₂ ( 18 a ), CCH ( 18 b ), CH₂OBn ( 18 c ), and CH[O(CH₂)₂O] ( 18 d ), were generated in situ by sulfoxide–lithium exchange from α‐chlorosulfoxides, and investigated for the stereospecific reagent‐controlled homologation (StReCH) of phenethyl and 2‐chloropyrid‐5‐yl ( 17 ) pinacol boronic esters. Deuterium labeling experiments revealed that α‐chloroalkyllithiums are quenched by proton transfer from their α‐chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α‐deuterated α‐chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid‐base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b , the instability of which was attributed to a facile 1,2‐hydride shift. By contrast, 18 d , a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a , 18 b , and 18 d in 16, 0, and 68 % yield, respectively; α‐deuterated isotopomers D ‐ 18 a and D ‐ 18 d gave yields of 33 and 79 % for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (?)‐epibatidine ( 15 ). One‐pot double StReCH of boronate 17 by two exposures to (S)‐D ‐ 18 a (≤66 % ee), followed by work‐up with KOOH, gave the expected stereodiad product in 16 % yield (d.r.～67:33). The comparable reaction using two exposures to (S)‐D ‐ 18 d (≤90 % ee) delivered the expected bisacetal containing stereodiad (R,R)‐DD ‐ 48 in 40 % yield (≥98 % ee, d.r.=85:15). Double StReCH of 17 using (S)‐D ‐ 18 d (≤90 % ee) followed by (R)‐D ‐ 18 d (≤90 % ee) likewise gave (R,S)‐DD ‐ 48 in 49 % yield (≥97 % ee, d.r.=79:21). (R,S)‐DD ‐ 48 was converted to a dideuterated isotopomer of a synthetic intermediate in Corey’s synthesis of 15 .     

Acyl‐Phosphide Anions via an Intermediate with Carbene Character: Reactions of K[PtBu2] and CO

The analogy of the reactivity of group 1 phosphides to that of FLPs is further demonstrated by reactions with CO, affording a new synthetic route to acyl‐phosphide anions. The reaction of [K(18‐crown‐6)][PtBu₂] ( 1 ) with CO affords [(18‐crown‐6)K?THF₂][Z‐tBuP=C(tBu)O] ( 2?THF₂ ) as the major product, and the minor product [K₆(18‐crown‐6)][(tBu₂PCO)₂]₃ ( 3 ). Species 2 reacts with either BPh₃ or additional CO to give [K(18‐crown‐6)][(Ph₃B)tBuPC(tBu)O] ( 4 ) and [K(18‐crown‐6)][(OCtBu)₂P] ( 5 ), respectively. The acyl‐phosphide anion 2 is thought to be formed by a photochemically induced radical process involving a transient species with triplet carbene character, prompting 1,2‐tert‐butyl group migration. A similar process is proposed for the subsequent reaction of 2 with CO to give 5 .     

Metal Complexes of Functionalized Sulfur‐Containing Ligands. Part XIX

The title compounds were prepared starting from the dihydropyrrolones 4 – 6 . Nucleophilic displacement and ring closure yielded the 1H‐pyrrolo[3,2‐c]isothiazol‐5(4H)‐ones 8 and 10 . The fused systems formed salts with strong acids and electrophiles ( 15, 16 ), as well as with bases. Oxidation led either to S(2)‐oxides ( 18a, 20a ) or to the corresponding bicyclic sultams ( 18b, 20b ), depending on the reaction conditions. The sulfinamide 18a was also obtained from the known 1,2‐dithiolopyrrolone S‐oxide 21 by a ring‐opening/ring‐closure reaction sequence. O‐Methylation of 8 furnished the ‘azafulvene' 17 . The oxidative addition of [Pt(η²‐C₂H₄)L₂] ( 24a : L=Ph₃P, 24b : L=1/2 dppf, 24c : L=1/2 (R,R)‐diop) to 18a and 20a led to the cis‐amido‐sulfenato Pt complexes 25 and 26a – c , respectively.     

Pyrimidines. 21. Novel reactions of 5-cyano-1,3-dimethyluracil with carbon nucleophiles. A facile preparation of certain pyrido[2,3-d]pyrimidines

Treatment of 5-cyano-1,3-dimethyluracil ( 8 ) with an activated acetonitrile, such as malononitrile, ethyl cyanoacetate or cyanoacetamide, in base afforded 7-amino-6-cyano-, 7-amino-6-ethoxycarbonyl-, and 7-amino-6-aminocarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18b, 18c and 18d , respectively) in high yields. On the other hand, reaction of 8 with acetonitrile in base gave the Michael adduct, 5-cyano-6-cyanomethyl-5,6-dihydrouracil ( 15 , R = H), and the hydrated product, 1,3-dimethyluracil-5-carboxamide ( 9 ) as the major products, and 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18a ) in only very low yield. Similar reaction with butanone gave 7-ethyl-1,3-dimethyl- and 1,3,6,7-tetramethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 10b and 10c ) in low yields. When 8 was treated with diethylmalonate in base, only a small amount of 6-ethoxycarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione ( 19 ) was obtained together with 1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 20 ) and 18c (also in low yields). Treatment of 8 in ethanolic sodium ethoxide without added carbon nucleophile gave significant amounts (14%) of 20 and a small amount of 18c .     

Synthesizing 4′,4″(5″) Di‐tert‐butyldibenzo 18‐crown‐6 Monitored by Online FTIR

4′,4″(5″) Di‐tert‐butyldibenzo 18‐crown‐6 (DTBB18C6) was successfully synthesized by S_N2 nucleophilic substitution with 4‐tert‐butyl catechol as starting material. Effects of cyclization reagents, solvents, and templates were investigated. Reaction process was monitored by the real‐time online FTIR to study the actual reaction route. The highest DTBB18C6 yield (above 33%) was obtained by using Cs₂CO₃ as the template, 2,2′‐diethylene glycol ditosylate as the cyclization reagent, and THF as the solvent. From the result of FTIR, four different reaction stages of DTBB18C6 synthesis process were proposed.     

A Novel Route for the Synthesis of Deoxy Fluoro Sugars and Nucleosides

The reaction of (diethylamino)sulfur trifluoride (DAST) with methyl 5-O-benzoyl-β-D -xylofuranoside ( 1 ) followed by column chromatography afforded the riboside 2 (62%) and the ribo-epoxide 3 (18%) (Scheme 1). Under similar reaction conditions, the α-D -anomer 4 gave the riboside 5 and the difluoride 6 in 60 and 9% yield, respectively. Treatment of the β-D -xyloside 10 with DAST gave, after chromatographic purification, the riboside 11 as the principal product (48%; Scheme 2). These results suggest that the C(3)−O−SF₂NEt₂ derivatives were initially formed in the case of the xylosides studied. The distinctive feature of the reaction of DAST with the β-D -arabinoside 12 consists in the formation of a 3- or 5-benzylideneoxoniumyl-substituted intermediate on one of the consecutive transformations, which finally give rise to the inversion of the configuration at C(3) affording the xylosides 17 (18%) and 18 (55%); the lyxoside 14 was also isolated from the reaction mixture in a yield of 25% (Scheme 3). In the presence of the non-participating 5-O-trityl group, i.e., from the reaction products of 21 with DAST, the compounds 23 and 24 were isolated in 16 and 52% yield, respectively (Scheme 4). It may be thus reasonable to conclude that, in the case of the β-D -arabinosides 12 and 21 , the principal route of the reaction is the formation of the intermediate C(2)−O−SF₂NEt₂ derivative. Unlike 21 , the α-D -arabinoside 26 was converted to the lyxo-epoxide 25 (53%) and the lyxoside 27 (14%), which implies the intermediate formation of the C(3)−O−SF₂NEt₂ derivative (Scheme 5).     

A new synthetic route to polycarbonate

A detailed study has been carried out on the new synthetic reaction of poly(p-xylylene carbonate) from potassium carbonate and p-xylylene dibromide by using a variety of crown ethers as a catalyst, which was recently found by the present authors. Crown ethers having 18-member ring showed the best catalytic property of the various crown ethers, and the reaction was conducted in various solvents at 50–160°C by using 18-crown-6-ether. Both the polymer yield and the molecular weight of the polymer increased in proportion to the amount of potassium carbonate, and they increased rapidly and reached constant values with increasing the concentration of 18-crown-6-ether. They also depended significantly upon the reaction temperature as well as the solvent used. A maximum yield with the highest molecular weight was obtained from the reaction at 100–120°C in diglyme solvent. The spectroscopic analysis of the polymer indicated that all the end groups of the resulting polymer had the structure of benzyl bromide. From these results, a plausible mechanism was proposed for the reaction. Similar reactions were also conducted by using several aliphatic dibromides, Br? (CH₂)_x? Br, in place of p-xylylene dibromide. The products were strongly dependent of the value of x: polycarbonate was obtained from dibromides with ≧4, and cyclic carbonates from dibromides with ≦3.     

Bis(4-benzhydryl-benzoxazol-2-yl)methane – from a Bulky NacNac Alternative to a Trianion in Alkali Metal Complexes

A novel sterically demanding bis(4-benzhydryl-benzoxazol-2-yl)methane ligand 6 (^4−BzhH2BoxCH₂) was gained in a straightforward six-step synthesis. Starting from this ligand monomeric [M(^4-BzhH2BoxCH)] (M=Na ( 7 ), K ( 8₁ )) and dimeric [{M(^4-BzhH2BoxCH)}₂] (M=K ( 8₂ ), Rb ( 9 ), Cs ( 10 )) alkali metal complexes were synthesised by deprotonation. Abstraction of the potassium ion of 8 by reaction with 18-crown-6 resulted in the solvent separated ion pair [{(THF)₂K@(18-crown-6)}{bis(4-benzhydryl-benzoxazol-2-yl)methanide}] ( 11 ), including the energetically favoured monoanionic (E,E)-(^4-BzhH2BoxCH) ligand. Further reaction of ^4−BzhH2BoxCH₂ with three equivalents KH and two equivalents 18-crown-6 yielded polymeric [{(THF)₂K@(18-crown-6)}{K@(18-crown-6)K(^4-BzhBoxCH)}]_n (n→∞) ( 12 ) containing a trianionic ligand. The neutral ligand and herein reported alkali complexes were characterised by single X-ray analyses identifying the latter as a promising precursor for low-valent main group complexes.