Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

2,4-Disubstituted Pyrrolo[2,3-d]pyrimidine α-D- and β-D-Ribofuranosides Related to 7-Deazaguanosine

Nucleobase-anion glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), MeCN) of the pyrrolo[2,3-d]pyrimidines 4a – d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribo-furanosyl chloride ( 5 ) gave the protected β-D -nucleosides 6a – d stereoselectively (Scheme 1). Contrary, the β-D -halogenose 8 yielded the corresponding α-D -nucleosides ( 9a and 9b ) apart from minor amounts of the β-D -anomers. The deprotected nucleosides 10a and 11a were converted into 4-substituted 2-aminopyrrolo[2,3-d]-pyrimidine β-D -ribofuranosides 1 . 10c , 12 , 14 , and 16 and into their α-D -anomers, respectively (Scheme 2). From the reaction of 4b with 5 , the glycosylation product 7 was isolated, containing two nucleobase moieties.     

β-Cleavage of Bis(homoallylic) Potassium Alkoxides. Preparation of 3-Hydroxypropyl and 4-Hydroxybutyl Propenyl Ketones from γ- and δ-Lactones. Synthesis of (±)-Rose oxide

Starting from γ- and δ-lactones 1 – 3 , a two-step preparation of 3-hydroxypropyl and 4- hydroxybutyl propenyl ketones 10 – 18 is described, involving as the key step the β-cleavage of the bis(homoallylic) potassium alkoxides 4a – 9a . The novel methodology is illustrated by a short synthesis of (±)-rose oxide( 20 ).     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Synthese und IR.-spektroskopische Identifizierung epimerer 3-Äthinyl-5 α-cholestan-3-ole

Synthesis and IR. Spectroscopic Identification of Epimeric 3-Ethinyl-5α-cholestan-3-ols The syntheses of the 3β-ethinyl-5α-cholestan-3α-ols 2a, 2b, 2c and of the corresponding epimeric 3α-ethinyl-5 α-cholestan-3 β-ols 3a, 3b, 3c are described. Bands at 1000 cm^?1 for the α-alcohols and at 1030 cm^?1 for the β-alcohols are found to be useful for the IR. spectroscopic identification of epimeric 3-ethinyl-5α-cholestan-3-ols.     

Neue β-Lactam-Antibiotika. Zur Funktionalisierung von 3-Hydroxy-3-cephem-4-carbonsäureestern durch die Wittig-Reaktion. Modifikationen von Antibiotika. 16. Mitteilung [1]

New β-lactam antibiotics. Functionalisation of 3-hydroxy-3-cephem-4-carboxylic esters through the Wittig reaction The 3-hydroxy-ceph-3-em-esters 1a, b reacted smoothly with stabilized phosphor-ylids to give a series of derivatives which were converted into the microbiologically active acids 14a, c, 15c and 20 by known procedures. The synthesis of the amides 23, 24, 26 and of the ester 28 from the 3-carboxymethyl-derivative 19 is also reported.     

Über die Umsetzung von 1-Phenylpyrazol mit Äthylmagnesiumbromid. 8. Mitteilung über Grignard-Reaktionen [1]

In contrast to butyllithium, ethylmagnesium-bromide reacts with 1-phenyl-pyrazole exclusively by deprotonation, at the ortho position of the phenyl-ring. With nitriles the intermediate 2-(1-pyrazolyl)-phenylmagnesiumbromide gave good to excellent yields of 1-(2-aroyl or 2-hetaroyl-phenyl)-pyrazoles (Table 1, compounds 5a – 5i ); with ketones the corresponding methanol derivatives (Table 2, compounds 6a – 6c ) were found, whilst CO₂ yielded the corresponding 1-(2-carboxyphenyl)-pyrazole ( 3 ). Surprisingly enough, 1-(o-bromo-phenyl)-pyrazole and magnesium did not yield a single product, but a mixture of 3 compounds, which on reaction with 4-benzoylpyridine gave the three alcohols 19 , 20 and 21 .     

Ein neuer Reaktionsweg zu 1, 3-Dicarbonylderivaten. Modelluntersuchungen am A/B-Teil von 3-Oxo-5α-steroiden

A New Route to 1, 3-Dicarbonyl Derivatives, Model Investigations on the A/B-Part of-3-Oxo-5α-steroids Starting from 1 the 1, 3-dicarbonyl compounds 4a – d were synthetized via the enynes 2a – e and the relatively unstable epoxides 3a – d . The latter were reacted with 95% formic acid to gave 4a – d ; small amounts of the furane derivatives 5a – c were identified as by-products in this last step. In the presence of catalytic amounts of HgSO₄ the epoxides 3a – c yielded with 95% formic acid the furanes 5a – c , but no detectable amounts of 4a – c .     

d5-Reactions of Doubly Deprotonated γ,δ-Unsaturated Carbonyl Derivatives with Electrophiles. A Novel Approach to the Synthesis of Tetrahydrofuran and Tetrahydropyran Derivatives

The dienone-dianion derivatives 1 react with all types of electrophiles tested (alkyl halide, silyl chloride, ester, ketone, aldehyde, epoxide) to give β, γ-unsaturated carbonyl compounds of type A (see Formulae 2 – 6 , 13 , 14 and Tables 1–5). The α- and β-hydroxyalkylation products obtained from 1a – 1d can be converted to tetra-hydrofuran and tetrahydropyran derivatives 7 and 16 , respectively (Tables 1 and 2), those from the sulfur analogues 1e and 1f to ketene thioacetals 9 and to dienone derivatives 10 and 12. The t-butyl and α-hydroxy-ketones are cleaved to give nitriles, amides, carboxylic acids and esters (Formulae 16 - 25 ). The reagents 1 allow to synthesize products with distant functional groups in one step (cf. 1,8-diketones 14 and Formulae 26 – 30 ); they correspond to the d⁵-synthons 31 – 33 ; in Table 6, they are compared with other d⁵-reagents.     

Synthesis,Characterization, and Anti‐inflammatory Activity of Novel Isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates

A series of novel isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates ( 17a – i) were synthesized by a three‐component reaction of 4‐amino‐3‐methyl‐5‐styrylisoxazole 14 , β‐keto ester 15 , and 3‐phenacylideneoxindole 16 , in the presence of CAN catalyst in ethanol. The structures of the synthesized compounds have been established on the basis of spectral and analytical data. The title compounds 17a – i were evaluated for their anti‐inflammatory activity. Compounds 17b and 17c exhibited potent anti‐inflammatory activity as that of standard drug.     

Reaktionen von 5H-1,2λ5-Azaphospholen mit Arylazocarbonitrilen sowie Acetylendicarbonsäure-estern

Reactions of 5H,2λ⁵-Azaphospholes with Arylazocarbonitriles and Dialkyl Acetylenedicarboxylates Azaphospholes 1a – c react with activated arylazocarbonitriles to 1,5,2λ⁵-diazaphosphorines 2a – c and 3a – c . The reaction of 1a – c with diethyl or dimethyl acetylenedicarboxyiates yields 7H-1,4λ⁵-azaphosphepines 4a – c . The structures of 2b , 3a , and 4a are established by an X-ray diffraction analysis.     

A Novel Synthesis of 4‐Pyridazineacetic Acids via Ring Expansion of N‐Cyanomethylated 3‐Pyrazoline‐4‐acetic Acids

A novel synthetic route to 4‐pyridazineacetic acids 10 – 12 has been achieved by the ring‐expansion reaction of N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 – 9 . 1H‐Pyrazole‐4‐acetic acids 1 – 3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C‐cyanomethylated 1H‐pyrazole‐4‐acetic acids 4 – 6 as major products together with N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 9 as major products. Thermal treatment of 7 – 9 with sodium hydride in N,N‐dimethylformamide caused ring expansion to yield the corresponding 4‐pyridazineacetic acids 10 – 12 .     

Reactions of α,β‐Unsaturated Thioamides with Diazo Compounds

Several reactions of the α,β‐unsaturated thioamide 8 with diazo compounds 1a – 1d were investigated. The reactions with CH₂N₂ ( 1a ), diazocyclohexane ( 1b ), and phenyldiazomethane ( 1c ) proceeded via a 1,3‐dipolar cycloaddition of the diazo dipole at the C?C bond to give the corresponding 4,5‐dihydro‐1H‐pyrazole‐3‐carbothioamides 12a – 12c , i.e., the regioisomer which arose from the bond formation between the N‐terminus of the diazo compound and the C(α)‐atom of 8 . In the reaction of 1a with 8 , the initially formed cycloadduct, the 4,5‐dihydro‐3H‐pyrazole‐3‐carbothioamide 11a , was obtained after a short reaction time. In the case of 1c , two tautomers 12c and 12c ′ were formed, which, by derivatization with 2‐chlorobenzoyl chloride 14 , led to the crystalline products 15 and 15 ′. Their structures were established by X‐ray crystallography. From the reaction of 8 and ethyl diazoacetate ( 1d ), the opposite regioisomer 13 was formed. The monosubstituted thioamide 16 reacted with 1a to give the unstable 4,5‐dihydro‐1H‐pyrazole‐3‐carbothioamide 17 .     

Dual Functionalization of White Phosphorus: Formation,Characterization, and Reactivity of Rare‐Earth‐Metal Cyclo‐P3 Complexes

The [3+1] fragmentation reaction of rare‐earth metallacyclopentadienes 1 a – c with 0.5 equivalents of P₄ affords a series of rare‐earth metal cyclo‐P₃ complexes 2 a – c and a phospholyl anion 3. 2 a – c demonstrate an unusual η³ coordination mode with one P−P bond featuring partial π‐bonding character. 2 a – c are the first cyclo‐P₃ complexes of rare‐earth metals, and also the first organo‐substituted polyphosphides in the category of Group 3 and f‐block elements. Rare‐earth metallacyclopentadienes play a dual role in the combination of aromatization and Diels–Alder reaction. Compounds 2 a – c can coordinate to one or two [W(CO)₅] units, yielding 4 a – c or 5 c , respectively. Furthermore, oxidation of 2 a with p ‐benzoquinone produces its corresponding phospholyllithium and regenerated P₄.     

Dual Functionalization of White Phosphorus: Formation,Characterization, and Reactivity of Rare‐Earth‐Metal Cyclo‐P3 Complexes

The [3+1] fragmentation reaction of rare‐earth metallacyclopentadienes 1 a – c with 0.5 equivalents of P₄ affords a series of rare‐earth metal cyclo‐P₃ complexes 2 a – c and a phospholyl anion 3. 2 a – c demonstrate an unusual η³ coordination mode with one P−P bond featuring partial π‐bonding character. 2 a – c are the first cyclo‐P₃ complexes of rare‐earth metals, and also the first organo‐substituted polyphosphides in the category of Group 3 and f‐block elements. Rare‐earth metallacyclopentadienes play a dual role in the combination of aromatization and Diels–Alder reaction. Compounds 2 a – c can coordinate to one or two [W(CO)₅] units, yielding 4 a – c or 5 c , respectively. Furthermore, oxidation of 2 a with p ‐benzoquinone produces its corresponding phospholyllithium and regenerated P₄.     

β-SrNH und β-SrND – Synthese und Kristallstrukturbestimmung mittels Röntgen- und Neutronenbeugung an Pulvern

β-SrNH and β-SrND – Synthesis and Crystal Structure Determination by X-Ray and Neutron Powder Diffraction By reaction of strontium with NH₃ in a flow tube at 750 °C a novel modification of strontium imide, β-SrNH, was obtained as a dark yellow powder. According to X-ray powder diffractometry und crystal structure determination by direct methods β-SrNH and β-SrND adopt a highly distorted variant of the NaCl type of structure (Pnma, a = 757.70(1), b = 392.260(4), c = 569.652(9) pm, Z = 4, wR_p = 0.098, R_p = 0.075, R_F = 0.044). Temperature dependent neutron powder diffraction of β-SrND revealed the position of the D atoms which in contrast to α-SrND are crystallographically ordered. At higher temperatures β-SrNH transforms to α-SrNH.     

Photochemische Reaktionen. 52. Mitteilung [1]. Zur Photochemie von α,β-ungesättigten cyclischen Ketonen: Spezifische Reaktionen der n,π*- und π,π*-Triplettzustände von O-Acetyl-testosteron und 10-Methyl-Δ1,9-octalon-(2)

The photochemistry of the conjugated cyclohexenones O-acetyl testosterone ( 1 ) and 10-methyl-Δ^1,9-octalone-(2) ( 24 ) has been investigated in detail. The choice of reaction paths of both ketones depends strongly on the solvent used. In t-butanol, a photostationary equilibrium 1 ? 3 is reached which is depleted solely by the parallel rearrangement 1 → 5 (Chart 1; for earlier results on these reactions see [2a] [6] [7]). In benzene, double bond shift 1 → 16 (Chart 3) occurs instead, which is due to hydrogen abstraction from a ground-state ketone by the oxygen of an excited ketone as the primary photochemical process. In toluene, the major reaction is solvent incorporation ( 1 → 17 , Chart 4) through hydrogen addition to the β-carbon of the enone, accompanied by double bond shift and formation of saturated dihydroketone as the minor reactions. Contrary in part to an earlier report [19], the photochemical transformation of the bicyclic enoné 24 exhibit a similar solvent dependence. The corresponding products 25 – 29 are summarized in Chart 5 and Table 1. Sensitization and quenching experiments established the triplet nature of the above reactions of 1 and 24 . Based on STERN -VOLMER analyses of the quenching data (cf. Figures 2, 4–8, and Table 3), rearrangement, double bond reduction and toluene addition are attributed to one triplet state of the enones which is assigned tentatively as ³(π, π*) state, and the double bond shift is attributed to another triplet assigned as ³(n, π*) state (cf. Figure 9). The stereospecific rearrangement of the 1α-deuterated ketone 2 to the 4β-deuterio isomer 4 shows the reaction to proceed with retention at C-1 and inversion at C-10. The 4-substituted testosterone derivatives 33 – 36 (Chart 8) were found to be much less reactive in general than 1 . In particular, 4-methyl ketone 33 remains essentially unchanged on irradiation in t-butanol, benzene and toluene.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

Synthesis of 2‐Azulenyl‐1,1,4,4‐tetracyano‐3‐ferrocenyl‐1,3‐butadienes by [2+2] Cycloaddition of (Ferrocenylethynyl)azulenes with Tetracyanoethylene

1‐, 2‐, and 6‐(Ferrocenylethynyl)azulene derivatives 10 – 16 have been prepared by palladium‐catalyzed alkynylation of ethynylferrocene with the corresponding haloazulenes under Sonogashira–Hagihara conditions. Compounds 10 – 16 reacted with tetracyanoethylene (TCNE) in a [2+2] cycloaddition–cycloreversion reaction to afford the corresponding 2‐azulenyl‐1,1,4,4,‐tetracyano‐3‐ferrocenyl‐1,3‐butadiene chromophores 17 – 23 in excellent yields. The redox behavior of the novel azulene chromophores 17 – 23 was examined by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed their multistep electrochemical reduction properties. Moreover, a significant color change was observed by visible spectroscopy under electrochemical reduction conditions.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.