含苯并三唑色酮及1,3,4-噁二唑啉类化合物的合成

研究了一种简便的合成2位含氮杂环色酮类化合物的方法。1H-苯并三唑与ClCH~2COOH反应制得1H-苯并三唑-1-乙酸(1),以此为原料合成了一系列2位含1H-苯并三唑-1-甲基色酮(5)和相关的1,3,4-噁二唑衍生物(8)。     

一些含氮杂环的脱氢松香酸甲酯衍生物的合成

以歧化松香为原料,将其纯化得到脱氢松香酸,用硫酸二甲酯酯化后,通过12位溴代、7位氧化、脱异丙基硝化等步骤,得到了3个重要的中间体.该3个中间体分别经过亲核取代、还原关环反应后,得到了一些脱氢松香酸甲酯含氮杂环衍生物;产物结构经红外光谱、核磁共振谱、质谱和元素分析进行了表征.     

Electrophilic hydrogen-deuterium exchange of some deactivated pyrroles

The rate coefficients and partial rate factors for the hydrogen-deuterium exchange of some 1-substituted pyrroles (1-substituents = -COCH₃, - COC₆H₅, -SO₂CH₃, -SO₂CF₃, -N(CH₃)₃, -NH(CH₃)₂, -SO₂C₆H₅) in deuterated trifluoroacetic acid have been determined. In all cases the rate of exchange is faster at the 2-position. Similarly, the hydrogen-deuterium exchange of some pyrroles with electron withdrawing substituents in the 2-position indicate a relative reactivity of 4→ 5→ 3-position with the selectivity being greatest for the more electron withdrawing groups. A nitro group in the 3-position of pyrrole shows a relative reactivity of 5→2→4-position for the hydrogen-deuterium exchange in deuterated trifluoroacetic acid. A linear correlation is observed for the log of the rate coefficient of the hydrogen-deuterium exchange at the 4-position of some 2-substituted pyrroles and the difference in the calculated energy of formation of the pyrrole and the corresponding 4-deuterated cation.     

The Reactivity of C–H Bonds in the Cyclohexyloxy Moiety of Cyclohexyl Acetate toward the tert-Butylperoxy Radical

The effect of the functional group on the partial rate constants of the reactions of the tert-butylperoxy radical with CH bonds in the cyclohexyloxy moiety of cyclohexyl acetate at 333 K was studied by the Howard–Ingold method. The ester group activates the CH bond at the 1-position and deactivates the CH bonds at the 3-position and, especially, the 2-position. The reactivity of CH bonds at the 4-position is close to the reactivity of CH bonds in cyclohexane.     

Quantitative structure-activity relationships of H1-antihistaminic benzimidazole derivatives

The quantitative structure-activity relationships (QSAR) of 2-(4-substituted-1-piperazinyl)benzimidazole derivatives for antihistaminic activity were examined. Taking into consideration the specific conformations of some derivatives, a significant correlation was obtained using Verloop's STERIMOL parameters B3 and L of the substituent at the 1-position of the benzimidazole nucleus. The results indicated that the derivatives having a substituent with a small breadth and an appropriate length at the 1-position showed potent activity. From the results, a model of the binding site is proposed. The QSAR of side effects (anticholinergic activity and central nervous system depressive effect) were also examined and the results showed that a sterically small substituent at the 1-position was required to decrease side effects.     

A novel class of platelet activating factor (PAF) antagonists. I. Synthesis and structure-activity studies on PAF-sulfonamide isosteres.

New platelet activating factor (PAF) antagonists, 3 were synthesized by replacing the charged phosphate and trimethylammonium moieties with sulfonamide and heterocyclic quaternary ammonium functionalities, respectively (PAF-sulfonamide isosteres). Darmstoff phosphatidic acid analogues of this class (Darmstoff-sulfonamide isosteres), 6 were also synthesized. The activity of these compounds as PAF antagonists was evaluated from their in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma. Among the compounds tested, some of the 2-methoxypropane derivatives with an octadecylcarbamoyloxy or octadecylcarbamoylthio side chain at the 1-position and a propylsulfonamide function bearing a terminal polar substituent such as a quaternary quinolinium or substituted quinolinium group at the 3-position were found to be the most potent (IC50 = 0.3-0.6 microM).     

Facile and regioselective synthesis of novel 2,4-disubstituted-5-fluoropyrimidines as potential kinase inhibitors

2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluoropyrimidine-2-carboxamides and 5-fluoropyrimidine-4-carboxamides) were successfully executed. For the first series, regioselective substitution at the 4-position of the pyrimidine with an amine (HNR¹R²) was achieved, followed by preparation of the amide at the 2-position. The route to the second series involved introduction of the methoxy protecting group at the 4-position, which allowed subsequent amine substitution to occur at the 2-position. The 4-amide substituent was finally introduced by direct conversion of the 4-methoxy into a 4-chloro group followed by transformation into an amide by palladium catalysis.     

High selectivity from configurational match/mismatch in carbon-hydrogen insertion reactions of steroidal diazoacetates catalyzed by chiral dirhodium(II) carboxamidates.

Diazo decomposition of steroidal diazoacetates, where the point of attachment is the 3-position of the steroid A-ring, catalyzed by chiral dirhodium(II) carboxamidates results in products from carbon-hydrogen insertion in high yield and selectivities. Use of S-configured catalysts shows a distinctive preference for insertion into the 3-position to form beta-lactone products. The R-configured catalysts direct insertion preferentially to the equatorial C-H bond at the 2-position. Substituents or functional groups at the 5/6-position prevent C-H insertion from taking place at the 4-position. Even in the best case with the 5/6-positions fully saturated, however, insertion into the 3-position remains competitive with insertion into the 4-position. Corresponding 3-substituted phenyldiazoacetates give only beta-lactone products, and selectivity here is highest with chiral dirhodium(II) prolinate catalysts. A model is presented to explain these results. Overall, this methodology is versatile for functionalization of the steroid A-ring at positions 2 and 3.     

Triethylamin-mediated addition of 2-aminoethanethiol hydrochloride to chalcones: Synthesis of 3-(2-aminoethylthio)-1-(aryl)-3-(thiophen-2-yl) propan-1-ones and 5,7-diaryl-2,3,6, 7-tetrahydro-1,4-thiazepines

The triethylamin-mediated addition of 2-aminoethanethiol hydrochloride to chalcone analogs was investigated. This addition, bearing a 2-thienyl group at the 3-position, gave the only addition adduct at room temperature in 3 h, whereas the chalcones bearing the 2-furyl group at the 1-position gave an addition-cyclization product (1, 4-thiazepine) in the same conditions. The effect of the groups to the reaction was investigated by changing the 1- and 3-position groups. The chalcones bearing the 2-thienyl group at the 1-position and the others afforded the mixture of products in different ratio at rt for 0.5–24 h. Moreover, the addition–cyclization products (1,4-thiazepine) were obtained under reflux conditions in 36 h. The structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, infrared, and elemental analysis.     

Mechanism of the second sulfenylation of indole

Sulfenylation of indole using a sulfenyl chloride occurs initially at the 3-position of the ring, leading to a 3-indolyl sulfide. When an excess of sulfenyl chloride is used, a second sulfide group is introduced at the 2-position, and an indolyl 2,3-bis-sulfide results. We have demonstrated that this second sulfenylation occurs not by direct introduction of the second sulfide at the 2-position but via initial formation of an indolenium 3,3-bis-sulfide intermediate, followed by migration of one of the sulfide groups to the 2-position. This was achieved by the isolation of two examples of 3H-indole 3,3-bis-sulfides and by subsequent demonstration that they rearrange to the indolyl 2,3-bis-sulfides by treatment with sulfenyl halides.     

A facile synthesis of methyl 2-substituted-4-benzoxazolecarboxylates

Methyl 2-substituted-4-benzoxazolecarboxylates were synthesized from methyl 2-amino-3-hydroxybenzoate and the corresponding acid chloride or ortho acetal with pyridinium p-toluenesulfonate as an acid catalyst. Decomposition due to hydration at the 2-position was seen for some compounds during purification.     

Two complementary routes to 7-substituted chlorins. Partial mimics of chlorophyll B

Chlorophyll a and chlorophyll b exhibit distinct spectra yet differ only in the nature of a single substituent (7-methyl versus 7-formyl, respectively). Two complementary approaches have been developed for the synthesis of 7-substituted chlorins. The first approach is a de novo route wherein 2,9-dibromo-5-p-tolyldipyrromethane (Eastern half) and 9-formyl-2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin (Western half) undergo acid-catalyzed condensation followed by metal-mediated oxidative cyclization. The resulting zinc chlorin is sterically uncongested and bears (1) a geminal dimethyl group in the reduced, pyrroline ring, (2) a bromo substituent at the 7-position, and (3) a p-tolyl group at the 10-position. The second approach entails regioselective 7-bromination of a 10,15-diarylchlorin that lacks a substituent at the 5-position. In an extension of this latter approach, a 5,15-diarylchlorin that lacks a substituent at the 10-position undergoes regioselective bromination at the 8-position. The introduction of a TIPS-ethynyl, acetyl, or formyl group at the 7-position was achieved using Pd-catalyzed reactions with the corresponding 7-bromochlorin. In the 10-p-tolyl-substituted zinc chlorins, the series of substituents (7-TIPS-ethynyl, 7-acetyl, 7-formyl) progressively causes (1) a bathochromic shift in the absorption maximum of the B band (405 to 426 nm) and (2) a hypsochromic shift in the position of the Qy band (605 to 598 nm). The trends mirror those for chlorophyll b versus chlorophyll a but are of lesser magnitude. Taken together, the facile access to chlorins that bear auxochromes at the 7-position enables wavelength tunability and provides the foundation for fundamental spectroscopic studies.     

The regiospecific lithiation of aromatic acetals

The dimethylacetal of benzaldehyde and some 3, 3,4 and 3,4,5 oxygenated derivatives thereof are regiospecifically deprotonated at the 2-position by alkyl lithiums. The resulting aryl lithiums provide various 2-substituted benzaldehydes in moderate to excellent yields.     

PHOTOCHEMICAL COUPLING OF 5-BROMOURACIL TO TRYPTOPHAN, TYROSINE AND HISTIDINE, PEPTIDE-LIKE DERIVATIVES IN AQUEOUS FLUID SOLUTION

Direct irradiation of 5-bromouracil (BU) in aqueous fluid solution in the presence of tryptophan (trp), tyrosine (tyr) or histidine (his) derivatives using a XeCl excimer laser at 308 nm yielded photocoupling of BU to the aromatic ring of each amino acid. Irradiation of BU at 308 nm most likely results in excitation of the n-φ* transition, intersystem crossing to the triplet manifold, and coupling via electron transfer from the aromatic amino acid. The coupling observed was regiospecific between the 5-position of uracil (U) and the 2-position of the indole and phenol rings and the 5-position of the imidazole ring of the respective amino acids. Quantum yields of photocoupling to BU ranged from 1 × 10^-3 to 7 × 10^-3 and paralleled known rates of electron transfer and ionization potentials of the aromatic rings. The photocoupling between BU and some of the aromatic amino acid peptide-like derivatives possibly mimics photocrosslinking of BU-DNA to associated proteins, a potentially useful photoreaction for studying nucleic acid-protein interactions. Formation of crosslinks of the type proposed here might be detected by the characteristic fluorescence emission of the uracil amino acid adducts.     

Regiochemically flexible substitutions of di-, tri-, and tetrahalopyridines: the trialkylsilyl trick

[reactions: see text] 2,4-Difluoropyridine, 2,4-dichloropyridine, 2,4,6-trifluoropyridine, 2,4,6-trichloropyridine and 2,3,4,6-tetrafluoropyridine react with standard nucleophiles exclusively at the 4-position under halogen displacement. However, the regioselectivity can be completely reversed if a trialkylsilyl group is introduced in the 5-position of the 2,4-dihalopyridines or in the 3-position of the 2,4,6-trihalopyridines or 2,3,4,6-tetrahalopyridine. Then only the halogen most remote from the bulky silyl unit (at the 2-position in the case of the 2,4-halopyridines, at the 6-position with the other substrates) gets involved in the exchange process. After removal of the silyl protective group the nucleophile is invariably found to occupy the nitrogen-neighboring position.     

Synthesis of 3,20-disubstituted chlorophyll-a derivatives and reactivity of the substituents

Methyl 20-bromo-pyropheophorbide-a possessing a vinyl group at the 3-position and its analogs having 3-ethyl, 3-(1-hydroxyethyl) and 3-acetyl groups were prepared by modifying naturally occurring chlorophyll(Chl)-a. The 20-bromo-chlorins were cross-coupled with vinyl- and 1-ethoxyvinyl-tributyltins in the presence of a Pd(0) catalyst to afford 20-vinyl- and acetyl-chlorins, respectively. The interconversions among the above four C2-functional groups at the 3-position were readily performed in the semi-synthetic Chl derivatives, but no modification of the 20-vinyl and acetyl groups was observed. The difference of the chemical reactivity is ascribable to the steric factor: the 3¹-position was less sterically hindered than the 20¹-position. Single hydrogenation and hydration of 3,20-divinyl-chlorin and reduction of 3,20-diacetylchlorin proceeded exclusively at the 3-position. The redmost (Qy) bands in electronic absorption spectra of the semi-synthetic Chl derivatives in a diluted dichloromethane solution were controlled by the 3,20-substituents. The 3-substituent effect on their Qy maxima was determined by the electronic factor (their electronegativity), while the 20-substituent effect was primarily dependent on the steric factor (their local size).     

Pharmacologically interesting compounds—I: High resolution mass spectra of phenothiazines

The mass spectra of twenty-six commercially available medicinal phenothiazines have been determined at high resolution. In each compound, the side chain attached to the 10-position of the phenothiazine ring contains nitrogen and fission of the C? C bond α to this nitrogen gives in most cases the base peak. Some of the compounds are also substituted at the 2-position and this substituent generally remains intact, though some substituents such as acetyl, propionyl, methoxyl and methylthio can undergo fragmentation. Fragmentations fall into three groups; those which give ions representing a part of the side chain; those which give ions representing the intact phenothiazine ring with part of the side chain attached; those which give ions representing a partially fragmented ring system.     

N-alkenyl indoles as useful intermediates for alkaloid synthesis

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K(3)PO(4) as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C(2)-position of the indole ring. An alternative strategy for selective functionalization at the C(2)-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.     

Sodium periodate oxidation of tetrahydro-β-carboline derivatives

The oxidation of some 3-(methoxy- and ethoxycarbonyl)tetrahydro-β-carboline derivatives with sodium periodate led to the formation of 1, 4-benzodiazonine derivatives or fully aromatic β-carbolines depending on both nature and number of substituents at 1-position.     

Intramolecular photocycloadditions of 6,6′-dimethyl-4,4′-polymethylenedioxy-di-2-pyrones

Photosensitized reactions of 4,4′-polymethylene-di-2-pyrones 2b-e afforded [2+2]-cycloadducts 3-5 , site-selectively. The selectivity depended upon the methylene chain length. Namely, the three carbon chain gave a syn head-to-head adduct 3b at the 3,4-position of the 2-pyrone ring, the four to six carbon chains gave syn head-to-head adducts 4c-e at the 5,6-position and/or anti head-to-head adducts 5d,e at the 5,6-position, respectively. The intramolecular cycloaddition mechanism was also explained from results calculated by means of PM3-CI method.