Synthesis of Dialkyl 1,4-Dihydro-2,6-dimethyl-4-(heteroaryl)-pyridine-3,5-dicarboxylates as Calcium Channel Antagonists

The Hantzsch condensation of the heteroarylcarboxaldehydes 3a-c with alkyl acetoacetates 4a-c and alkyl 3-aminocrotonates 5a-b afforded the respective dialkyl 1,4-dihydro-2,6-dimethyl-4-(heteroaryl)-pyridine-3,5-dicarboxylates 6a-f possessing a C-4 4-quinolinyl, 8-quinolinyl or 1-oxido-4-pyridinyl substituent Calcium channel antagonist structure-activity relationships acquired indicate that i) the position of the quinolyl nitrogen atom was not a determinant of activity, ii) increasing the size of the C-3 and C-S alkyl ester substituents decreases potency and iii) a C-4 1-oxido-4-pyridinyl substituent abolishes activity. The most active, and equipotent C-4 4-quinolinyl 6a and 8-quinolinyl 6b analogs, were approximately 8-fold less potent calcium channel antagonists than the reference drug nifedipine.     

Enhanced diastereoselectivity via confinement: photoisomerization of 2,3-diphenylcyclopropane-1-carboxylic acid derivatives within zeolites

From the perspective of asymmetric induction, the photochemistry of 24 chiral esters and amides of cis-2,3-diphenylcyclopropane-1-carboxylic acid from excited singlet and triplet states has been investigated within zeolites. The chiral auxiliaries placed at a remote location from the isomerization site functioned far better within a zeolite than in solution. Generally, chiral auxiliaries with an aromatic or a carbonyl substituent performed better than the ones containing only alkyl substituents. A model based on cation-binding-dependent flexibility of the chiral auxiliary accounts for the observed variation in de between aryl (and carbonyl) and alkyl chiral auxiliaries within zeolites. Cation-dependent diastereomer switch was also observed in select examples.     

Silicalite as a stationary phase for HPLC

A molecular sieve known as Silicalite was used as the column packing for HPLC. Silicalite contains channels (or cavities) approximately 6 Å in diameter but, unlike most other molecular sieves, Silicalite is hydrophobic. The retention times of methyl ketones and substituted phenols containing n-alkyl groups increase with increasing chain length of the substituent. However, phenols with very bulky substituents appear to be excluded from the Silicalite channels and elute very quickly. Excellent separations were obtained for a number of compounds with only slight differences in chemical structure. These include phenol isomers with a primary- or secondary alkyl group, position isomers of substituted phenols, and aliphatic cis-trans isomers.     

A carbon-13 NMR study of some alkyl-substituted indenes. An experimental study of the baker-nathan order of hyperconjugation in the neutral ground state

Carbon-13 NMR spectra of several alkyl-substituted indenes have been assigned and analysed. For structures having an alkyl substituent in the C-2 position an increased shielding was observed for the remote conjugated positions C-4 and C-6, an alternating trend similar to that found for the 2-cycloaminoindenes. The hyperconjugative behaviour was slightly more pronounced for the methyl group compared with an isopropyl or tert-butyl substituent, a fact which supports a model where C? H σ–π interactions are more efficient than those involving C? C bonds.     

Trifluoroacetylation of pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrazines

A study was carried out on the reaction of pyrrolo[1,2-a]pyrazines containing an alkyl, aryl, or aralkyl substituent at C-1 with trifluoroacetic anhydride. Trifluoroacetylation products may be formed either by reaction in the pyrrole ring or at the aryl or aralkyl groups at C-1. Products of electrophilic substitution at C-6 are formed in the trifluoroacetylation of pyrrolo[1,2-a]pyrazines containing at C-1 a substituent bulkier than a methyl group but lacking substituents at C-6 (the α-position of the pyrrole ring). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1226–1233, August, 2007.     

The mass spectra of some alkyl and aryl oxazoles

The mass spectra of a variety of alkyl and aryl oxazoles have been determined and the spectra analyzed with the aid of deuterium labelling and high resolution mass spectrometry. In contrast to the corresponding benzenoid compounds, the mass spectra of isomeric alkyl oxazoles are distinctive and in this respect are akin to those of the corresponding pyridines. Further analogy to the pyridines is suggested by the unfavorable nature of a carbonium ion adjacent to the 2-position and this effect may be used to locate alkyl substituents attached to the oxazole nucleus. The loss of carbon monoxide from the molecular ions of 2,5-disubstituted oxazoles probably occurs with ring opening and migration of the C-5 substituent (e.g.Br) to the C-4 position.     

Synthesis and structure-activity relationship of a new series of potent angiotensin II receptor antagonists: pyrazolo[1,5-a]pyrimidine derivatives.

We have already reported 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives, which are potent in vitro angiotensin II (AII) antagonists, but have no oral antihypertensive activity. Removal of the carboxylic acid and replacement of the heteroaromatic system afforded potent in vitro antagonists. Removal of the carbonyl oxygen and changing the position of the biphenyltetrazole substituent were critical to the display of oral activity. To improve the in vitro and oral activities, modifications were made of the substituents at the 3- and 5-positions of the pyrazolo[1,5-a]pyrimidine. Structure-activity studies showed the methyl substituent at the 3-position to be essential for potent in vivo activity. We present the design, syntheses, and biological data of a series of pyrazolo[1,5-a]pyrimidine derivatives, which are orally active AII receptor antagonists.     

Combined computational and experimental studies of the mechanism and scope of the retro-Nazarov reaction

Density functional theory calculations (B3LYP/6-31+G) demonstrate that conjugating and electron-donating substituents at carbons three and four of a cyclopentenyl oxyallylic cation should have a rate-accelerating effect on the retro-Nazarov reactions of these species. The retro-Nazarov reaction of these intermediates is predicted to exhibit significant torquoselectivity when carbon three is substituted with a methoxy and a methyl group. Experimental studies show that oxyallylic cations can undergo effective retro-Nazarov reactions when two alkyl and one aryl/vinyl groups are on carbons three and four. An equal number of alkyl substituents or a single aryl substituent is not effective in promoting the reaction. Interestingly, a single alkoxy substituent at carbon three is sufficient for the retro-Nazarov reaction to occur. The methodology developed was used in a total synthesis of the natural product turmerone.     

Photoinduced Aromatization of Unsymmetrically Substituted 1,4‐Dihydropyridines

Irradiation of unsymmetrically substituted 1,4‐dihydropyridines ( 1b ‐ 1j ) while bubbling oxygen or argon through the solution resulted in aromatization to the corresponding pyridine derivatives ( 3b ‐ 3j ). Compound 1a with 2‐nitrophenyl substituent in 4‐position undergoes elimination of water upon irradiation under both oxygen and argon atmospheres and formation of 3a with 2‐nitrosophenyl substituent. On the other hand, irradiation of the compounds 1e , 1k and 1l with 4‐hydroxy‐3‐methoxyphenyl, 5‐methyl‐2‐furyl and 2‐furyl substituent in this position, respectively, resulted in the expulsion of these substituents and formation of a pyridine derivative unsubstituted in position 4, namely compound 2 . Chloroform as a solvent causes the photo‐oxidation of these compounds by an electron transfer mechanism which is supported by the formation of dichloromethane according to GC analysis and presence of acid (HCl) in the solution after irradiation.     

Synthesis and characterization of a series of diverse poly(2‐oxazoline)s

This article describes the synthesis and characterization of a variety of new poly(2‐oxazoline)s. With regard to functional polymers, 2‐oxazolines represent an interesting class of monomers because of the easy variation of the substituent in 2‐position. Starting from the corresponding nitriles, different 2‐oxazolines were obtained containing a diverse set of 2‐substituents, including thioether bonds ( M11 ), trifluoromethyl groups ( M8 , M10 ), and alkyl‐ or aryl groups ( M1 – M7 ). The subsequent polymerization of the majority of these monomers proceeded in a living manner, which was demonstrated by linear first‐order kinetics, a linear increase of molar mass with conversion, and relatively narrow molar mass distributions. In addition, selected thermal and surface properties of the polymers were studied utilizing DSC and contact‐angle measurements to determine the effects of different 2‐substituents on the macroscopic properties. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3829–3838, 2009     

2-(4-Biphenylyl)-1,3,4-oxadiazoles: synthesis and mesogenic studies

A series of 2-(4-biphenylyl)-1,3,4-oxadiazoles bearing alkyl or alkoxy substituents at the 4? position, and a hydrogen, or alkyl substituent (linear, branched, fluorinated or functionalised) at the 5 position were synthesised and characterised (51 compounds). Their mesogenic properties were evaluated using differential scanning calorimetry and polarising optical microscopy. Results show that substitution of the 1,3,4-oxadiazole ring for a terminal benzene ring in a conventional p-terphenyl enriched the mesogenic properties. Most of the new oxadiazole compounds exhibit either monotropic or enantiotropic smectic A mesophases with widths ranging from 3 to 50°C. A few compounds (short tailed) exhibit nematic phases and some compounds with branched or fluorinated alkyl substituents at the 5 position are also mesogenic.     

Lithium salts of [1,12-dialkyl-CB11Me10]- anions

We report the syntheses of several [1-R-CB(11)-Me(11)](-) and [1-R-12-R'-CB(11)-Me(10)](-) anions (R, R' = alkyl) and the solubilities of their lithium salts in cyclohexane. These solutions are of interest as Lewis acid catalysts. The new anions are not directly accessible by methylation with methyl triflate because of intervening triflyloxy substitution on one or more boron vertices. The difficulty has been circumvented in two ways. Either (i) an iodo substituent is first introduced into position 12, permitting a clean decamethylation, and then replaced with a methyl by reaction with trimethylaluminum or (ii) the offending triflyloxy substituents are replaced with methyls by reaction with trimethylaluminum.     

Synthesis of 19-substituted steroids of the 16α,17α-cyclohexanopregnane series and study of their interactions with rat uterine cytosol and blood serum proteins

New 16α,17α-cyclohexanopregnanes (pregna-D′₆-pentaranes) containing alkyl or heteroatomic substituents in position 19, namely, 19-methylidene-, 19-methyl-, 19-methoxyimino-, and 19-(3-methoxycarbonylpropoxyimino)-16α,17α-cyclohexanopregn-4-ene-3,20-diones were synthesized, and their interactions with the progesterone receptor and pentarane-binding proteins of rat uterus cytosol and rat blood serum was studied. The same substituent in position 19 of the steroid molecule can affect in opposite direction its affinity to these proteins. These results suggest differences in the structures of the ligand-binding pockets of the three proteins in the region surrounding the C(10) atom of the steroid nucleus. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2579–2584, November, 2005.     

Study on the influence of methyl groups and their location on properties of triphenylamino-based charge transporting hydrazones

Abstract  

Methyl substituent effects on the HOMO and LUMO energy levels, and the ability to transport charge and form stable molecular glasses of 4-(diphenylamino)benzaldehyde phenylhydrazones were investigated. Thermal properties, HOMO and LUMO energy levels, and hole mobility values are dependent on the number of methyl substituents and their position in the investigated transporting materials. Surprisingly, however, the presence of methyl groups at any position negatively affects the hole drift mobility of the molecularly doped polymers containing those hydrazones.     

Effect of meso-substituents on the osmium tetraoxide reaction and pinacol-pinacolone rearrangement of the corresponding vic-dihydroxyporphyrins

To investigate the effects of electron-donating and electron-withdrawing substituents upon the reaction of porphyrins with osmium tetraoxide, and the pinacol-pinacolone rearrangement of the resulting diols, a series of meso-substituted porphyrins were prepared by total synthesis. Porphyrins with electron-donating substitutents at the meso-positions gave vic-dihydroxychlorins in which the adjacent pyrrole subunit was predominantly oxidized. No such selectivity was observed in a porphyrin containing a methoxycarbonyl as the electron-withdrawing group, whereas a formyl substituent again resulted in oxidation at the pyrrole unit adjacent to the meso-substituent. Under pinacol-pinacolone conditions, vic-dihydroxy chlorins containing 4-methoxyphenyl or 3,5-dimethoxyphenyl groups at the meso-position showed preferential migration of the ethyl group over the methyl group to give 8-ketochlorins, whereas the diol with an n-heptyl substituent under similar reaction conditions gave both 7- and 8-ketochlorins. In contrast, the diol containing a meso-formyl substituent produced the corresponding 7-ketochlorin exclusively. These results indicate that it is not possible to predict the reactivity of meso-substituted porphyrins in the osmium tetraoxide reaction nor the general substituent migratory aptitudes in the pinacol-pinacolone rearrangement based on simple electronic arguments, most likely because many parameters (e.g., meso-beta-pyrrolic steric crowding and long-range electronic effects) ultimately determine the reactivity. The structural assignments of the porphyrin diols and the keto-analogues were confirmed by extensive (1)H NMR studies; some of the dihydroxychlorins and ketochlorins were found to display unusual features in their (1)H NMR spectra.     

Preparation of vinylogous 2-sulfonylindolines by the palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones and their further transformation to indoles and carbazoles.

The palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones provides a convenient route to vinylogous 2-sulfonylindolines 3. The reaction proceeds in DMF/water in the presence of potassium carbonate and catalytic palladium(II) acetate and is compatible with both electron-donating and -withdrawing substituents in the para position of the aniline, and with an alkyl substituent at C-2 of the dienyl sulfone. The indolines underwent oxidation with DDQ to afford the corresponding indoles 4. The latter were then employed as dienes in Diels-Alder reactions with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate, or methyl acrylate. In the case of the latter two dienophiles, the cycloadditions were highly regioselective, affording the corresponding 1,3-products (with respect to the relative positions of the sulfone and ester groups), exclusively. The cycloadducts from acetylenic dienophiles were converted to the corresponding carbazoles by elimination of the sulfone moiety with DBU, and that from methyl acrylate was subjected to reductive desulfonylation and oxidation to the corresponding carbazole with DDQ. The method thus provides access to carbazoles with various substituents at the 3-, 4-, and 6-positions.     

Nanofold‐decorated surfaces from the electrodeposition of di‐alkyl‐cyclopentadithiophenes

This work describes the synthesis and subsequent electrodeposition of 4H‐cyclopenta[2,1‐b:3,4‐b′]dithiophene (cyclopentadithiophene) monomers di‐substituted with alkyl chains. Each monomer was electropolymerized in solution to observe their capacity at creating well‐structured, rough surfaces. The length of the alkyl chain substituent has a significant influence on the overall surface morphology and wetting behavior after electropolymerization. In the case of nonsubstituted cyclopentadithiophene monomers or those with short alkyl (methyl and ethyl) substituents, the polymerization proceeds readily, forming rough surfaces that follow the Wenzel regime of wetting. In these cases, the surfaces were decorated with globular agglomerates and woven mat features. The measured surface roughness decreases with alkyl chain length as steric hindrance caused by the alkyl substituents limits electropolymerization. As the alkyl chain substituent increases to propyl chain length and beyond, the increase in steric hindrance is so significant that the surface morphology formed during electrodeposition is primarily due to π‐stacking interactions between very short oligomers formed in solution. With propyl and butyl substituents, nanofold morphology is observed, leading to surfaces with much higher contact angles with water (~132°) that follow the Cassie‐Baxter regime of wetting. This type of surface morphology has only been demonstrated one other time and with the use of fluorinated constituents. This work exposes a mild, fluorine‐free synthetic route to creating nanofold‐decorated surfaces.     

Thermodynamic characteristics of sorption of heterocyclic compounds m capillary gas chromatography

Dependences of sorption energies of sulfur-, oxygen-, and nitrogen-containing heterocyclic compounds on the nature of heteroatoms, structure of substituents and their position in the ring were studied. The contributions of heteroatoms, functional and alkyl groups to the energy of dispersive interaction of position isomers with nonpolar stationary phases were determined for imidazoles, piperidines, morpholines, thiomorpholines, dioxalanes, oxathiolanes, dithiolanes, thiophenes, and furans. The nonequivalence of contributions of the same substituents to the sorption energy of each of the heterocyclic compounds, depending on the nature of the heteroatom and position of the substituent, was shown. The obtained values of contributions of heteroatoms and substituents can be used for apriori calculation of retention indices of position isomers of five- and six-membered heterocycles containing one or two heteroatoms in the ring.Translated from lzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 2033–2038, August, 1996.     

Conformational analysis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges: destabilization of the cone form by axial alkyl substituents

The stereochemistry of calix[4]arenes substituted by a pair of identical alkyl substituents in a trans fashion at two distal bridges is analyzed. MM3 calculations suggest that increasing the bulk of the alkyl group at the bridges destabilizes those conformations possessing an axial disposition of the substituent. In contrast to the 1,3-dimethyl ether of p-tert-butylcalix[4]arene, which adopts a cone conformation, solution NMR data indicate that the 1,2-alternate conformation is preferred in the dimethyl ether derivatives 5b (alkyl = i-Pr) and 5c (alkyl = t-Bu). In the derivative substituted by the less bulky methyl substituent (5a), both the cone and 1,2-alternate forms coexist in CDCl3. Increasing the polarity of the solvent increases the relative population of the cone form of 5a and 5b. The steric destabilization ensuing from the presence of the axial substituent is so large in the cone conformation of 5c that the 1,2-alternate conformer is the major form even in polar solvents. The cone --> 1,2-alternate interconversion barrier of 5a is 18.2 kcal mol(-1), indicating that the presence of an axial methyl group both destabilizes the cone conformation and decreases its rigidity.     

29Si NMR Investigation of Si‐alkylsubstituted 1,3,5‐Trisilacyclohexanes

²⁹Si NMR spectra of 29 Si‐alkylsubstituted derivatives of 1,3,5‐trisilacyclohexanes have been recorded and analyzed. A systematic preparation of alkyl derivatives with mixed substituents made it possible to evaluate substituent‐induced chemical shift (SCS) values for the ring silicon atoms in α and γ position. It is found that the equatorial α‐effect increases in the order Me < Et < i‐Pr < t‐Bu. For the alkyl groups Me, Et, and i‐Pr the axial α‐effect is similar in magnitude to the α_e‐effect. Axial SCS values for the t‐Bu group are not accessible because chair conformations with an axial t‐Bu group are energetically unfavourable and escape into a twisted boat form. The observed γ‐effects exhibit the γ_gauche‐effect for axial substituents as known from compounds with a pure carbon framework.