Five-membered Heterocyclic Systems Research Articles

Current density maps, magnetizability, and nuclear magnetic shielding tensors of bis-heteropentalenes. II. Furo-furan isomers.

Magnetic susceptibility and nuclear magnetic shielding at the nuclei of bis-heteropentalenes formed by two furan units ([2,3-b], [3,2-b], [3,4-b], and [3,4-c] isomers) have been computed by several approximated techniques and a large Gaussian basis set to achieve near Hartree-Fock estimates. Ab initio models of the ring currents induced by a magnetic field normal to the molecular plane were obtained for the three isomeric systems of higher symmetry, showing that the pi electrons give rise to intense diamagnetic circulation. The pi currents are responsible for enhanced magnetic anisotropy and strong out-of-plane proton deshielding. The theoretical findings are used to build up a "diatropicity matrix" for two fused five-membered heterocyclic systems.

Synthesis of 1,2-dithiolane analogues of leucine for potential use in peptide chemistry.

[reaction: see text]1,2-Dithiolanes present several points of interest for both peptide and medicinal chemistry, yet no chiral alpha-amino acids containing this five-membered heterocyclic system are available. We report here the first synthesis of N- and C-protected derivative of (S)-2-amino-3-(1,2-dithiolan-4-yl)propionic acid (Adp) and its 1,3-dithiolic form.

Total synthesis of cystothiazoles A and C.

An efficient pathway culminating in the enantiocontrolled preparation of cystothiazoles A and C has been described. The cystothiazoles demonstrate potent antifungal activity and function as novel inhibitors of mitochondrial oxidation at a specific site on the cytochrome bc(1) complex. These studies outline a general and flexible plan that can be readily adapted for the synthesis of a variety of related five-membered heterocyclic systems and for biological investigations of structure-activity relationships. The core [2,4']bisthiazole component 8 was prepared in six steps, and the use of the Horner-Emmons olefination to yield the alpha,beta-unsaturated ester 10 set the stage for an asymmetric Evans aldol process, which established the required C(4)/C(5) stereochemistry. Finally the cystothiazoles A and C were prepared via a stereocontrolled O-alkylation of the precursor beta-keto esters 22a and 22b.

Facile synthesis of cyclopropene analogues of aluminum and an aluminum pinacolate, and the reactivity of LAl[eta(2)-C(2)(SiMe(3))(2)] toward unsaturated molecules (L=HC[(CMe)(NAr)](2), Ar=2,6-i-Pr(2)C(6)H(3)).

Reduction of LAlI(2) (1) (L = HC[(CMe)(NAr)](2), Ar = 2,6-i-Pr(2)C(6)H(3)) with potassium in the presence of alkynes C(2)(SiMe(3))(2), C(2)Ph(2), and C(2)Ph(SiMe(3)) yielded the first neutral cyclopropene analogues of aluminum LAl[eta(2)-C(2)(SiMe(3))(2)] (3), LAl(eta(2)-C(2)Ph(2)) (4), and LAl[eta(2)-C(2)Ph(SiMe(3))] (5), respectively, whereas reduction of 1 in the presence of Ph(2)CO gave an aluminum pinacolate LAl[O(2)(CPh(2))(2)] (6), irrespective of the amount of Ph(2)CO employed. The unsaturated molecules CO(2), Ph(2)CO, and PhCN inserted into one of the Al-C bonds of 3 leading to ring enlargement to give novel aluminum five-membered heterocyclic systems LAl[OC(O)C(2)(SiMe(3))(2)] (7), LAl[OC(Ph)(2)C(2)(SiMe(3))(2)] (8), and LAl[NC(Ph)C(2)(SiMe(3))(2)] (9) in high yields. In contrast, 3 reacted with t-BuCN, 2,6-Trip(2)C(6)H(3)N(3) (Trip = 2,4,6-i-Pr(3)C(6)H(2)), and Ph(3)SiN(3) resulting in the displacement of the alkyne moiety to afford LAl[N(2)(Ct-Bu)(2)] (10) with an unprecedented aluminum-containing imidazole ring, and the first monomeric aluminum imides LAlNC(6)H(3)-2,6-Trip(2) (11) and LAlNSiPh(3) (12). All compounds have been characterized spectroscopically. The variable-temperature (1)H NMR studies of 3 and ESR measurements of 3 and 4 suggest that the Al-C-C three-membered-ring systems can be best described as metallacyclopropenes. The (27)Al NMR resonances of 2 and 3 are reported and compared. Molecular structures of compounds 3, 4, 6.OEt(2), 8.OEt(2), and 9 were determined by single-crystal X-ray structural analysis.

ChemInform Abstract: Nucleophilic Cleavage of 1‐Oxo‐2,8‐disubstituted‐2,5,8‐triaza‐1λ 5‐phosphabicyclo[3.3.0]octanes: A New Route to Eight‐ and Five‐Membered Heterocyclic Systems.

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Nucleophilic cleavage of 1-oxo-2,8-disubstituted-2,5,8-triaza-1λ5-phosphabicyclo[3.3.0]octanes: a new route to eight- and five-membered heterocyclic systems

Five 1-oxo-2,8-disubstituted-2,5,8-triaza-1λ5-phosphabicyclo[3.3.0]octanes 1 have been prepared and the nucleophilic cleavage of one of their P–N bonds has been studied. The acid-catalyzed alcoholysis involves in each case the cleavage of the P–N(5) bond, yielding the eight-membered monocyclic diamides 2. In the base-catalyzed reaction, the N(2),N(8)-dialkyl substituted substrates 1 yielded the same products 2, while for the N(2),N(8)-diaryl derivatives the exclusive cleavage of the P–N(2) (or P–N(8)) bond was observed yielding the isomeric 1,3,2-diazaphospholidine products 3. Products 2 are stable as N(5) ammonium salts or N(5)-acyl derivatives, but as free bases they rearrange spontaneously to products 3 via the intramolecular N(5)→P nucleophilic attack accompanied with the P–N(2) (or P–N(8)) bond cleavage. The effect of the N(2)- and N(8)-substituents in 2 on the rate of the 2→3 rearrangement, as well as on the product distribution for the unsymmetrically disubstituted substrates has been investigated. The mechanism of the formation of products 3 via the rearrangement and via the direct 1→3 nucleophilic cleavage is discussed in terms of the reactivity of the attacking nucleophile, the electrophilicity of the phosphoryl center, and of the basicity of the departing amine in the P–N bond cleavage step.

The Photochemistry of N-Iminopyridinium Ylides in Retrospect. From a Simple Concept to Some Applications

Azomethine-imines are well known to undergo ground-state 1,3-dipolar cycloaddition reactions with olefins or acetylenes, leading thereby to five-membered heterocyclic systems. When excited by UV light, some of these 1,3-dipolar azomethine-imines lead to the isomeric three-membered diaziridines via disrotatory electrocyclisation. The following review article shows that many N-iminopyridinium ylides – which are aromatic analogues of azomethine-imines – also lead to electrocyclisation from their photo-excited electronic (singlet) state to give the expected non-aromatic and boat-shaped 1H-1,2-diazepine isomers. Diazanorcaradienes – i.e. bicyclic diaziridines – are the postulated intermediates for these photoinduced ring-expansion processes.Ylides Y (Scheme 3) being mesoionic compounds have a large dipole moment; as a consequence, they are hydrophilic/lipophobic species, whereas diazepines D are poorly polar and, therefore, lipophilic/hydrophobic molecules. This very pronounced change of polarity triggered off the synthesis of some novel negative photoresists which are based on the photoisomerisation of water-soluble polymeric pyridinium ylides to the corresponding hydrophobic polymeric diazepines.Thermal activation of diazepines D led to ring contraction back to the corresponding ylides Y – obviously via norcaradiene intermediates N – and permitted to establish the kinetic and thermodynamic parameters for this process. Diazepines D are higher-energy (by ca. 85 kJ/mol) isomers of ylides Y. They react smoothly and chemospecifically as dipolarophiles with diazoisopropane to give pyrazoline cycloadducts. From these latter ones, novel small-ring compounds could be prepared, e.g. homodiazepines (cyclopropane derivatives), their tricyclic staircase-like isomers (fused cyclopropane/cyclobutane derivatives) as well as the first example of a cyclopropapyridine (a cyclopropene derivative).

Tetrahydrothiadiazoloisoquinolines: synthesis and inhibition of phenylethanolamine-N-methyltransferase.

A series of 7,8-fused heterocyclic tetrahydroisoquinolines were synthesized and tested as inhibitors of rabbit adrenal phenylethanolamine-N-methyltransferase (PNMT). 6,7,8,9-Tetrahydro[1,2,3]thiadiazolo[5,4-h]isoquinoline 5 (SK&F 86607) was found to be a potent inhibitor of PNMT with an IC50 similar to that of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (1, SK&F 64139). The isomeric tetrahydro[1,2,3]thiadiazolo[4,5-h]- and tetrahydro[1,2,5]thiadiazolo[3,4-h]isoquinolines, 13 and 20, were also potent PNMT inhibitors. However, substitution of Cl at position 5 (17) resulted in loss of potency similar to the loss observed in the 5-chloro analogue of 1. The 1,2,5 isomer 20 showed only a small drop in activity at 10(-6) M. All of the thiadiazoles were more potent than the 7,8-benzo-fused analogue 36. Fusion of other five-membered heterocyclic ring systems at the 7,8-position, e.g. triazole 22 and imidazoles 24 and 26, resulted in a decrease of PNMT inhibition. The alpha-adrenoreceptor affinities of 1 and 5 were also compared.

Sterically crowded five-membered heterocyclic systems. Part 3. Unexpected formation of stable flexible pyrrolidinoxyl biradicals via nitrone aldol dimers: a spectroscopic and mechanistic study

Addition of methylmagnesium iodide to various substituted cyclic nitrones (1) and subsequent aerial oxidation gave new pyrrolidinoxyl radicals (4) and the corresponding crystalline biradical species, to which the structure (5) was assigned unequivocally from spectroscopic (e.s.r., u.v.-visible, mass, and 1H and 13C n.m.r. spectra) and mechanistic considerations. Base-catalysed self-condensation of the nitrones (1), to give the nitrone hydroxylamines (18), is followed by Grignard addition to give the crowded bis-N-hydroxy compounds (3); these are then oxidised to the biradicals (5). The possibility of intramolecular charge transfer interaction between the two aminoxyl groups of the biradicals (5)(in order to explain the observed u.v. absorption at ca. 328 nm), and also the dimerisation of 1-pyrroline 1-oxides (particularly those that are sterically crowded), are discussed briefly.

ChemInform Abstract: Sterically Crowded Five‐membered Heterocyclic Systems. Part 2.

Chemischer InformationsdienstVolume 17, Issue 2 Physical Organic Chemistry ChemInform Abstract: Sterically Crowded Five-membered Heterocyclic Systems. Part 2. M. CYGLER, M. CYGLERSearch for more papers by this authorK. DOBRYNIN, K. DOBRYNINSearch for more papers by this authorM. J. GRABOWSKI, M. J. GRABOWSKISearch for more papers by this authorR. B. NAZARSKI, R. B. NAZARSKISearch for more papers by this authorR. SKOWRONSKI, R. SKOWRONSKISearch for more papers by this author M. CYGLER, M. CYGLERSearch for more papers by this authorK. DOBRYNIN, K. DOBRYNINSearch for more papers by this authorM. J. GRABOWSKI, M. J. GRABOWSKISearch for more papers by this authorR. B. NAZARSKI, R. B. NAZARSKISearch for more papers by this authorR. SKOWRONSKI, R. SKOWRONSKISearch for more papers by this author First published: January 14, 1986 https://doi.org/10.1002/chin.198602059AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume17, Issue2January 14, 1986 RelatedInformation

Sterically crowded five-membered heterocyclic systems. Part 2. Conformation of 2,2,5,5-tetramethylpyrrolidin-3-ol from nuclear magnetic resonance spectroscopy, crystal structure, and molecular mechanics calculations

The conformation of 2,2,5,5-tetramethylpyrrolidin-3-ol (2) was investigated by 1H n.m.r. spectroscopy, X-ray diffraction, and molecular mechanics calculations. In solution there is an equilibrium between the forms of the pyrrolidine ring with axial and equatorial orientations of the hydroxy group. The temperature dependence of the 3J(HH) coupling constants indicates a somewhat lower energy for the axial conformers. The puckering of the CH2CHOH part of the ring was estimated from the extended R value method, optimized for a five-membered ring, to be 32.9° at 263 K. The crystal structure of (2) was solved by direct methods and refined to R = 0.045. Two independent molecules in the asymmetric unit adopt nearly identical conformations with the pyrrolidine ring in the 2T3 twist form with the hydroxy group and the nitrogen proton in an axial orientation. Molecules are connected by O–H ⋯ N hydrogen bonds (O ⋯ N = 2.82 Å) into chains along the z-axis. There are also weak N–H ⋯ O bonds (N ⋯ O = 3.40 Å) between molecules in neighbouring chains. The conformational space of (2) was explored by molecular mechanics calculations. Several local energy minima were characterized. In all of them the ring is flattened around the fully substituted C-2 or C-5 atoms. The energy difference between these conformations is of the order of 5–7 kJ mol–1. The conformation observed in the crystal corresponds very well to the calculated global energy minimum conformation.

Primary steric effects in five-membered heterocyclic systems : Acetylation of alkylthiophenes

The relative importance of primary steric effects in acetylation of benzene and thiophene rings was studied. The smaller steric hindrance found in the heteroaromatic system is explained in terms of molecular geometry. A correlation is suggested between the “steric ratio” and bond angles.

Electrophilic substitutions in five-membered heterocyclic systems. Part VII. The reactivity of selenophen towards electrophiles. A comparison with thiophen

The relative reactivities of selenophen and thiophen in five electrophilic substitutions have been determined by kinetic or competitive procedures. The results have been compared with those available in the literature for furan. In all the reactions examined selenophen exhibits a reactivity intermediate between furan and thiophen.

Electrophilic substitution in five-membered heterocyclic systems—VIII : Relative rates of trifluoroacetylation

The relative rates for the reaction of thiophene (1), selenophene (6·5), furan (1·4 × 10 2) and pyrrole (5·3 × 10 7) with trifluoroacetic anhydride at 75° in 1,2-dichloroethane have been determined using a competitive procedure.

Electrophilic substitution in five-membered heterocyclic systems. Part VI. Kinetics of the bromination of the 2-methoxycarbonyl derivatives of furan, thiophen, and pyrrole in acetic acid solution

The kinetics of bromination of the 2-methoxycarbonyl derivatives of thiophen, furan, and pyrrole in acetic acid in the presence of an excess of bromide ions exhibit the same characteristic features as those of the bromination of benzene derivatives. The relative rates for bromination at the α-position are : 2-methoxycarbonylthiophen 1, 2-methoxycarbonylfuran 1·2 × 102, and 2-methoxycarbonylpyrrole 5·9 × 108.

An investigation by nuclear magnetic resonance spectroscopy of some group V elements in heterocyclic compounds

The orientations of substituents about atoms of group V elements in five-membered heterocyclic systems have been determined from the shapes of the NMR absorption bands of vicinal ring methylene protons.

Catalytic dehydrocyclization of diethyl ether forming a five-membered heterocyclic system

When diethyl ether is placed in contact with certain noble metals of group VIII, dehydrocyclization of the ether occurs, forming tetrahydrofuran and its decomposition products. The observed reaction is analogous to C5-dehydrocyclization of hydrocarbons and cyclization of secondary amines to pyrrolidine.