The versatile chemistry of thiophene. Some contributions by the Gronowitz' group

Investigations of the author in thiophene chemistry developed during the last four decades are reviewed. Stereochemical studies, metallation and halogen-metal exchange, spectral studies (mainly those of NMR in thiophene and related series), studies of tautomerism in hydroxythiophenes and atropisomerism in bithienyl derivatives, ring opening of 3-thienyllithium derivatives and thiophene-1,1-dioxides, as well as studies of thieno fused heteroaromatic boron compounds are considered in detail.     

Effect of the organic modifier on the retention of retinoids in reversed-phase liquid chromatography

Summary The retention of retinoids in reversed-phase liquid chromatography was studied using aqueous mobile phases of different composition (methanol 94–86% and acetonityrile 92–82%) at five temperatures (40–60 °C). With both organic modifiers the effect of the molecular structure increased as the water content and the polarity of the mobile phase increased. The temperature-dependence increased in the same manner with aqueous acetonitrile mobile phases. The - interactions between the retinoids and acetonitrile diminish when the water content of the mobile phase is increased, as happens also to the hydrophobic interactions with both organic modifiers. The net effect of these changes depends on the composition of the mobile phase. There was excellent correlation of retention with all polarity parameters studied(, P, x_e, x_d, x_n, E _T ^N , _T, , _o and _d), when the calculations were made separately with methanol and acetonitrile. The volume fraction of the organic modifier, , was the only parameter describing the retention well in both organic modifiers simultaneously.     

Validation of the Hygicult E dipslides method in surface hygiene control: a Nordic collaborative study

A collaborative study with Enterobacteriaceae was conducted to validate Hygicult E dipslides by comparison with violet red bile glucose agar (VRBGA) contact plates and swabbing, using stainless steel surfaces artificially contaminated with microbes at various levels. Twelve laboratories participated in the validation procedure. The total number of collaborative samples was 108. The microbial level in each sample was assessed in triplicate by using the 3 above-mentioned methods. No Enterobacteriaceae were used at the low inoculation level. At the middle inoculation level, the percentages detached from the test surfaces were 16.6 with the Hygicult E method, 15.3 with the contact plate method, and 14.6 with swabbing; at the high innoculation level, the percentages were 14.5, 15.8, and 9.8, respectively. The percentage of acceptable results after the removal of outliers was 97.2. Repeatability relative standard deviations ranged from 33.4 to 44.9%; reproducibility relative standard deviations ranged from 45.2 to 77.1%. The Hygicult E dipslide, VRBGA contact plate, and swabbing methods gave similar results at all 3 microbial levels tested: <1.0 colony-forming units (CFU)/cm2 at the low level, 1.2-1.3 CFU/cm2 at the middle level (theoretical yield 8.0 CFU/cm2), and 1.2-2.0 CFU/cm2 at the high level (theoretical yield 12.5 CFU/cm2).     

Synthesis and nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,8-naphthyridines

Through the use of Pd(0)-catalyzed coupling between 2- and 4-formyl-3-thiopheneboronic acid and 4-iodo-3-aminopyridine ( 1 ) and 3-bromo-2-aminopyridine, convenient one-pot procedures for the preparation of thieno[2,3-c]-1,7-naphthyridine ( 2 ), thieno[3,4-c]-1,7-naphthyridine ( 3 ), thieno[2,3-c]-1,8-naphthyridine ( 6 ) and thieno[3,4-c]-1,8-naphthyridine ( 7 ) have been developed. Thieno[3,2-c]-1,7-naphthyridine ( 4 ) and thieno[3,2-c]-1,8-naphthyridine ( 8 ) were obtained through the coupling of 2-tri-n-butylstannyl-3-thiophenaldehyde with 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide and 3-bromo-2-acetamidopyridine ( 1 ). The yield of 8 was further increased when copper(II) oxide was used as the co-reagent. The ¹³C nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,6-naphthyridines are discussed.     

On the bromination of thieno[c]-fused 1,5-naphthyridines and their isomeric N-oxides using dibromoisocyanuric acid in fuming sulfuric acid

Thieno[2,3-c]-1,5-naphthyridine ( 3 ), thieno[2,3-c]1,5-naphthyridine 5-oxide ( 7 ), thieno[3,2-c]-1,5-naphthyridine ( 5 ) and thieno[3,2-c]-1,5-naphthyridine 5-oxide ( 9 ) could conveniently be brominated at room temperature using dibromoisocyanuric acid in fuming sulfuric acid. Bromination occurred in good to moderate yields at the β position in the thiophene ring. Thieno[2,3-c]-1,5-naphthyridine 9-oxide ( 12 ) and thieno[3,2-c]-1,5-naphthyridine 9-oxide ( 13 ) also gave substitution in the thiophene ring at 95°. It was also found that 12 was deoxygenated under these reaction conditions. Direct oxidation of the brominated thieno[c]naphthyridines with m-chloroperbenzoic acid gave the 5-oxides in high yield.     

Analysis of small molecules by ultra thin-layer chromatography-atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry

The feasibility of ultra thin-layer chromatography atmospheric pressure matrix-assisted laser desorption ionization mass spectrometry (UTLC-AP-MALDI-MS) has been studied in the analysis of small molecules. Because of a thinner adsorbent layer, the monolithic UTLC plates provide 10-100 times better sensitivity in MALDI analysis than conventional high performance thin-layer chromatography (HPTLC) plates. The limits of detection down to a low picomole range are demonstrated by UTLC-AP-MALDI-MS. Other advantages of UTLC over HPTLC include faster separations and lower solvent consumption. The performances of AP-MALDI-MS and vacuum MALDI-MS have been compared in the analysis of small drug molecules directly from the UTLC plates. The desorption from the irregular surface of UTLC plates with an external AP-MALDI ion source combined with an ion trap instrument provides clearly less variation in measurements of m/z values when compared with a vacuum MALDI-time-of-flight (TOF) instrument. The performance of the UTLC-AP-MALDI-MS method has been applied successfully to the purity analysis of synthesis products produced by solid-phase parallel synthesis method.     

Ultraviolet B irradiation modulates the immune system of fish (Rutilus rutilus, Cyprinidae). Part III: Lymphocytes

The effects of short-term exposure to ultraviolet B (UVB) radiation on lymphocyte-related parameters were studied under controlled laboratory conditions using roach (Rutilus rutilus), a cyprinid teleost, as the model fish. In vitro lymphoproliferative responses stimulated with a T-cell-specific mitogen, concanavalin A (ConA), or a B-cell-specific activator, lipopolysaccharide (LPS), were decreased in exposed fish. Also nonstimulated proliferation was lower than in unexposed fish. ConA-activated responses returned to normal levels within 7 days after exposure, but LPS-activated responses were reduced throughout the 14 day follow-up. The capability of UVB-exposed fish to produce an antibody response was studied by intraperitoneal immunization with bovine gamma-globulin (BGG). The concentration of anti-BGG antibodies in plasma as well as the number of anti-BGG-specific antibody-secreting cells in the spleen or blood were not decreased in fish exposed either to a single dose of UVB prior to immunization, or to single dose of UVB prior to immunization followed by three additional doses after immunization. Immunoglobulin M (IgM) production, when assayed as plasma IgM level or as the number of IgM-secreting cells in the spleen or blood, was not suppressed after exposure to UVB irradiation. These results indicate that a single dose of UVB or short-term exposure to UVB irradiation has no negative effects on IgM production or reactivity against antigen administered via the intraperitoneal route. However, the suppression of in vitro lymphoproliferative responses suggest that exposure to UVB has the potential to interfere with lymphocyte-related functions in fish.     

An unexpected [2+2]-cycloaddition reaction of 4-methyldithieno-[3,4-b:3′,2′-d]pyridinium iodide with dimethyl acetylenedicarboxylate

An unexpected [2+2]-cycloaddition occured in the reaction of 4-methyldithieno-[3,4-6:3′,2′-d]pyridinium iodide (3)with two equivalents of DMAD, giving 4-(trans-1,2-dicarbomethoxy-2- iodovinyl)-5-methyl-6,7-dicarbomethoxy-4,5-dihydrothieno [23-c]quinoline (4) in 54% yield. 4 is formed via 4-methyl-5-(trans-1,2-dicarbomethoxy-2-iodo-4,5-dihydrothieno [3,4-b:3′,2′-d]pyridine (16), followed by [2+2]-cycloaddition. The primary adduct rearranges via a thiepin to an episulfide which eliminates sulfur to give 4.     

Syntheses of various 5-(bromoaryl)-substituted uracils

The Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium, previously further developed by us, has been used for regioselective preparation of 5-(2′-bromo-5′-furyl)-, 5-(2′-bromo-4′-furyl)-, 5-(2′-bromo-5′-thienyl)-, 5-(2′-bromo-4′-thienyl)-, 5-(4′-bromo-2′-thiazolyl)-, 5-(3′-bromophenyl)-, 5-(6′-bromo-2′-pyridyl)- and 5-(4′-bromo-2′-pyrimidyl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4-di-t-butoxy-5-pyrimidineboronic acid and the nine different aryl dibromides that were tried as coupling partners, only the 2,4- and 2,5-dibromothiazoles did not give satisfactory yields, 15% and 0%, respectively. The other seven aryl dibromides gave the desired 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 58-89% yield. Attempts to synthesise 2,4-di-t-butoxy-5-(2′-bromo-4′-thienyl)pyrimidine from 2-bromo-4-iodothiophene failed. Dealkylation of the 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 2.5 M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields.     

A New method for the synthesis of 4-oxo-4,5-dihydrofuro[3,2-c]quinoline

A new method for the synthesis of 4-oxo-4,5-dihydrofuro[3,2-c]quinoline is the Pd(0)-catalyzed coupling of o-bromonitrobenzene with 3-formyl-2-tributylstannylfuran, followed by reductive ring closure to furo[3,2-c]quinoline N-oxide and rearrangement.