An efficient novel synthesis of beta-(azuleno[1,2-b]benzothienyl)- and beta-(azuleno[2,1-b]benzothienyl)-alpha,beta-unsaturated ketones by the tropylium ion-mediated intramolecular furan ring-opening reaction and X-ray investigation of methyl ketone derivative

Intramolecular reaction of 2-tropylio-3-(5-substituted 2-furyl)benzothiophenes (3), prepared from the corresponding 2-cycloheptatrienyl-3-(5-substituted 2-furyl)benzothiophenes (2), afforded the beta-(azuleno[1,2-b]benzothienyl)-alpha,beta-unsaturated ketones (4), which are otherwise difficult to obtain, in moderate yields. The reaction involves a ring-opening process of the furan ring by intramolecular attack of the tropylium ion onto the 2-position of the furan ring. Similarly, beta-(azuleno[2,1-b]benzothienyl)-alpha,beta-unsaturated ketones (8) were obtained from the corresponding 3-tropylio-2-(5-substituted 2-furyl)benzothiophenes (7) albeit in lower yields. The molecular and crystal structures of the methyl ketone derivative, 8a, are discussed on the basis of X-ray structure analysis.     

Furan derivatives-IX : A convenient new method of arylation of furan reaction of diazoaminobenzenes with furan and isopentyl nitrite

A convenient new method for the arylation of furan with derivatives of diazoaminobenzene and isoamyl nitrite is described. Using this method the substituted 2-(X-phenyl)furan derivatives, where X is H, 4-CH₃, 4-Cl, 4-Br, 3-Cl, 3,4-diCl, 4-NO₂, 4-COOCH₃, 4-COOH, 4-Cl-3-CF₃ and 2-(3-pyridyl)furan were prepared. The reaction of methyl 4-aminobenzoate with furan and isopentyl nitrite gave (besides 2-(4-carbmethoxyphenyl)furan) 4,4′-dicarbmethoxydiazoaminobenzene, the structure of which was proved by mass spectrometry and by synthesis. This diazoaminobenzene derivative was unstable in the reaction medium and with isopentyl nitrite and furan at 30° gave 2-(4-carbmethoxyphenyl)furan. The mechanism of the reaction is discussed.     

Ab Initio studies on the rotational equilibria of 2-substituted furan and thiophene carbonyl derivatives

Summary The relative stabilities of syn- and anti-isomers of 2-substituted furan and thiophene carbonyl derivatives are investigated by theab initio MO method. The energy differences between the rotamers are 1–3 kcal mol^–1 but the barriers to rotation are ca. 10 kcal mol^–1 so that free rotational mode is predicted to be a rather difficult process. Application of the self-consistent reaction field (SCRF) method to account for the solvent effect indicates that the isomer with a higher dipole moment (syn) is favored in solution. An electron withdrawing 2-substituent favors syn-isomers for furan carbonyls in contrast to thiophene carbonyls for which anti-isomers are favored. These trends are ascribable to a decrease in electrostatic repulsive and attractive interactions, respectively, in the syn forms of furan and thiophene carbonyls. Contribution of non-bonded repulsive interaction in the anti-isomer is important for the relative stability of the syn-isomer of furan carbonyl derivative. Solvent effects due to higher dielectric continuum are small on the absolute values of energy differences but can reverse the order of stability of the two isomers due to a greater stability acquired by an isomer (syn) with higher dipole moment in solution. The major factor determining stability, or instability, of syn-isomer is a repulsive electrostatic interaction between the two oxygen atoms for furan carbonyls and an attractive electrostatic interaction between the sulfur and oxygen atoms for thiophene carbonyls.     

A convenient synthesis of a permethyl-substituted β-cyclodextrin-containing polysiloxane stationary phase using an amide linking group

A novel amide-linked permethyl-substituted β-cyclodextrin-bound polysiloxane stationary phase was prepared in only four steps. First, mono(6-O-toluenesulfonyl)-β-cyclodextrin was treated with sodium azide. Second, the resulting azide derivative was treated with methyl iodide and base followed by reduction with hydrogen to give amine-substituted permethylcyclodextrin 3 . Third, cyclodextrin 3 was treated with p-(allyloxy)benzoyl chloride to form 6^A-(p-allyloxybenzamido)-substituted permethyl-β-cyclodextrin 4 . Lastly, β-cyclodextrin 4 was hydrosilylated onto a polysiloxane backbone containing hydrogen, methyl, and p-tolyl substituents. This new phase separated the enantiomers of certain chiral lactones and alcohols in capillary supercritical fluid chromatography.     

1H- und 13C-NMR-Untersuchungen zur Struktur N-substituierter Tetrazole—Die Strukturen des N-Methoxycarbonyl-, N-Acetyl- und N-(Tri-n-butylstannyl)-tetrazols sowie Substituenteneffekte auf δ13C und 1J(CH)

The ¹H and ¹³C NMR spectra of several isomeric N-substituted tetrazoles have been investigated. ¹³C NMR is shown to be more useful for distinguishing between structural isomers of N-substituted tetrazoles except for those carrying electropositive substituents like SnBu₃. Correlations of δC-5 (inverse) and ¹J(C-5,H) with s?₁ found for 1-substituted tetrazole allowed the identification of the N SnBu₃ derivative as 1-(tri-n-butylstannyl)tetrazole. The phenyl carbon chemical shift difference ΔC′ = δC-3′-δC-2′ is insignificant for structure elucidation and conformational studies of N-substituted 5-phenyltetrazoles; ΔH′ from ¹H NMR spectra seems to be more useful.     

Stereochemistry of alkyl 3-substituted 4-halotetrahydro-2-oxo-3-furancarboxylates: 2—1H and 13C NMR spectra

The ¹H NMR parameters of methyl 3-substituted cis-4-halotetrahydro-2-oxo-3-furancarboxylates are reported, with assignments of the ring protons based on solvent-induced changes in the vicinal trans coupling constants, ³J(H-4, H-5). Preferred conformations, ce with a pseudo-equatorial halogen for the cis isomers and ta with a pseudo-axial halogen for the trans isomers, have been suggested on comparison of the magnitudes of J(trans) and J(gem) in both series. The ³J(¹³CH₃, H-4) values measured for methyl cis-4-bromotetrahydro-3-methyl-3-furancarboxylate, methyl trans-4-bromotetrahydro-3-methyl-3-furancarboxylate and trans-3,4-dibromodihydro-3-methyl-2(3H)-furanone have confirmed the stereochemical assignments.     

Group IVB organometallic compounds of furan: 13C, 29Si and 119Sn n.m.r. Spectra

The ¹³C, ²⁹Si and ¹¹⁹Sn chemical shifts of 2- and 2,5-substituted organometallic (M=C, Si, Ge, Sn, Pb) derivatives of furan were measured. The most important factors, determining the specific features of the studied spectra, are d-orbital availability and atomic radius of the central atom M, as well as the relatively higher (as compared with benzene) energies of the π-electron energy levels of the furan ring.     

2-(2-Furyl)-5,6-dihydro-1(3)H-acenaphtho[4,5-d]imidazole. Synthesis and electrophilic substitution reactions

2-(2-Furyl)-5,6-dihydro-1(3)H-acenaphtho[4,5-d]imidazole was synthesized by the Weidenhagen reaction of acenaphthene-4,5-diamine with furfural. Alkylation of the title compound with methyl iodide in KOH-DMSO gave isomeric 1- and 3-methyl derivative, the latter being the major product. 2-(2-Furyl)-3-methyl-5,6-dihydro-3H-acenaphtho[4,5-d]imidazole was subjected to electrophilic substitution reactions (bromination, nitration, formylation, acylation, and sulfonation. Depending on the conditions, electrophilic attack was directed at the furan ring or acenaphthene fragment or both these.     

Synthesis of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and its N,N′-dimetallated complexes (lithium, sodium and potassium): X-ray crystal structures of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and the polymeric tetrahydrofuran adduct of the dilithiated complex

The synthesis of 2,5-bis{(diethyl-3′-indolyl)methyl}furan by the acid catalysed condensation of 2,5-bis(diethylhydroxymethyl)furan with indole is presented. Dilithium, disodium and dipotassium derivatives are prepared by the reaction of the bis(indole) with n-BuLi, NaH and K, respectively, in the presence of various Lewis bases. The X-ray structures of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and the dilithiated derivative (as a polymeric tetrahydrofuran adduct) are reported.     

Preparation of 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones and 2H-1-benzothiopyran-2-ones from carboxylic esters and methyl salicylates or methyl thiosalicylate

C(α)-Carboxylic acid esters were treated with excess lithium diisopropylamide, condensed with methyl salicylates or methyl thiosalicylate, followed by acid cyclization to either 4-hydroxy-3-substituted, 2H-1-benzopyran-2-ones (coumarins), or 2H-1-benzothiopyran-2-ones (thiocoumarins).     

Reaction of 9-substituted 1-aminoadenine with hydrazine

Reaction of 9-substituted (methyl or benzyl) 1-aminoadenines 1 with hydrazine afforded 9-substituted 6-hydrazinopurines 2 and 1-substituted 5-ammo-4-(4-amino-1,2,4-triazol-3-yl)imidazole ( 4 ). The product ratio of 2 to 4 rose with increasing amounts of methanol used as the solvent. When the same reaction was carried out using 1,9-dimethyladenine instead of 1 , compounds 2 and 4 were also obtained with N⁶,9-dimethyladenine. A possible mechanism for formation of 2 and 4 is discussed.     

Synthetic transformations of higher terpenoids: XVII. Intramolecular cyclization of N-furfuryl amides of the labdane series

16-(Benzylaminomethyl)lambertianic acid methyl ester reacts with 2-methylprop-2-enoyl chloride to give unsaturated amide which readily undergoes intramolecular [4 + 2]-cycloaddition with formation of terpenoid derivatives of 10-oxa-3-azatricyclo[5.2.1.0^1,5]decenone. Acetylation of lambertianic acid methyl ester with acetic anhydride occurs preferentially at the 2-position of the furan ring and is accompanied by migration of the exocyclic double bond. Reductive amination of 16-acetyl-15,16-epoxylabda-8(9),13,14-triene and subsequent reaction of the resulting amine with 2-methylprop-2-enoyl chloride give intramolecular cyclization products in high yield without isolation of intermediate furfurylacryloyl derivative. Reactions of methyl 16-(benzylaminomethyl)-15,16-epoxylabda-8(9),13,14- and -8(17),13,14-trien-18-oates with maleic anhydride lead to the formation of the corresponding 10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid derivatives as mixtures of diastereoisomers.     

Structure of 2(5)-alkyl-4-hydroxy-3,4-diphenylcyclopent-2-en-1-ones,cyclocondensation products of benzil with aliphatic ketones

The reaction of benzil with methyl alkyl ketones gave three isomeric cyclopentenone derivatives, 2-substituted and cis- and trans-5-substituted 4-hydroxy-3,4-diphenylcyclopent-2-en-1-ones. cis- and trans-2,5-Disubstituted 4-hydroxy-3,4-diphenylcyclopent-2-en-1-ones were formed in analogous reaction of benzil with dialkyl ketones. The structure of the products was confirmed by ¹H NMR spectroscopy and molecularmechanics calculations.     

Convenient preparation of N-substituted 2-amino-4H-3,l-benzoxazin-4-ones and 3-substituted 2,4(1H,3H)-quinazolinediones

Room temperature treatment of 2-(3-arylureido)benzoic acids ( 1 ) and methyl 2-(3-alkyl-, or 3-arylureido)- benzoates ( 2 ) with concentrated sulfuric acid leads to N-substituted 2-amino-4H-3,l-benzoxazin-4-ones ( 3 ) in generally very good yields. The isomeric 3-substituted 2,4(1H,3H)-quinazolinediones ( 4 ) are conveniently made in high yield by the action of aqueous-ethanolic sodium hydoxide on 2.     

The preparation of some 1-(2-furyl)-2-arylethylenes

Some 1-(2-furyl)-2-arylethylenes, where the furan nucleus is substituted in position 5 with a methyl or p-chlorophenyl group and where the aryl group is phenyl, p-nitrophenyl, α-naphthyl or β-naphthyl, have been prepared by the Perkin reaction and subsequent decarboxylation of the acid. The compounds 1-12 were prepared lor of photochemistry and photoelectron spectroscopy studies. Their geometrical configurations has been established by ¹H nmr and ir spectra.     

1H and 13C NMR spectra of cyclic trimers,tetramers and pentamers derived from p-substituted phenylacetylenes

The ¹H and ¹³C spectra of p-substituted 1,3,5-triarylbenzenes, 7- and p-substituted 1,3,9-triaryl-9-methyl-fluorenes and 2-, 10- and p-substituted 6,12,13a-triaryl-12-methylbenzo(6,7)cycloheptadieno[1,2,3-jk]fluorenes have been examined. p-Substituents were methoxy, methyl and fluorine groups. The ¹H spectra were recorded at 300 MHz and permitted assignments for the aromatic protons by selective proton decouplings. Partial assignment of the carbon atoms in the ¹³C spectra was also possible.     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Synthese von heterocyclen. V. 1, 3, 4-thiadiazol-2 (3 H)-one

A new and highly versatile method for the synthesis of 1, 3, 4-thiadiazol-2 (3 H)ones 1 is described. Methoxy-1,3,4-thiadiazoles- 5 , which are readily available by condensation of O-methyl thiocarbazate ( 2 ) with acid derivatives 3 , undergo an efficient cleavage to 1 and methyl chloride with hydrochloric acid in an anhydrous medium. Many new 5-substituted thiadiazolones, unavailable by earlier routes, were synthesized. Preparative as well as mechanistic aspects are discussed. With the aid of ¹³C-NMR. spectroscopy, the tautomerism of 1 was studied, and the tautomeric equilibria was shown to be dependent on the nature of the substituent in the 5-position. The thiadiazolones 1 exist predominantly in the oxo form. The percentage of the hydroxy form, however, increases with strongly electron withdrawing substituents in the 5-position. A good correlation with pK^a? and σ-values was observed.     

Synthesis and spectral properties of 2-methylthio-3H-4-(para-substituted-phenyl)-7-[(o-, and p-substituted)-phenylthio]-1,5-benzodiazepines

A series of twelve new 2-methylthio-3H-4-(p-substituted phenyl)-7-[(o-, and p-substituted)phenylthio]-1,5-benzodiazepines, which have potentially useful pharmacological properties, has been synthesized by condensing the 3,3-dimercapto-1-(para-substituted-phenyl)-2-propen-1-one with 3,4-diamino phenyl-R-phenylthio ethers, and subsequently the 1H-1,5-benzodiazepine-2-thiones obtained were treated with sodium hydride and methyl iodide. The structure of all products was corroborated by ir, ¹H-nmr, ¹³C-nmr and ms.     

Potential antipsychotic agents. Part 8. Antidopaminergic properties of a potent series of 5-substituted (−)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybcnzaimides. Synthesis via common lithio intermediates

A series of 5-substituted (?)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with (S)-1-ethylpyrrolidine-2-methylaruine (→ 14–16 , 18–21 ). The acids required were prepared in a regiospecific manner from 5-bromo-2,3-dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8 ), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC1³CCl³ or MeSSMe), and hydrolyzed (→ 9–13 ). Alternatively, (-)-(S)-5-bromo-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-di-methoxybenzamide was treated with KH followed by BuLi and an electrophile (I₂ or Me³SiCl) to give the 5-iodo and 5-(trimethylsilyl) derivatives 17 and 22 , respectively. All 5-substituted amides were highly potent inhibitors of [³H]spiperone binding in rat striatal membranes with IC⁵⁰ values of 0.5 to 5 nM (Table 3). Thus, a relatively large steric bulk can be accomodated in the position para to the 2-MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine-induced behavioural responses in the same dose range as haloperidol and raclopride (Table 4). This new group of benzamides is suitable for investigations of dopamine D-2 receptors in labelled or unlabelled form.