Solid-phase synthesis of an isoxazolinopyrrole library

A four-step solid-phase synthesis of isoxazolinopyrroles 8 that employs an acid-labile 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL resin 1 is reported. Resin-bound vinyl sulfone 5 is obtained by DIC coupling with acid 4, which was in turn synthesized in solution phase by a regioselective nitrile oxide 1,3-dipolar cycloaddition. The resin-bound pyrrole 7 was synthesized on solid phase by pyrrole annulation with various isocyano derivatives and potassium t-butoxide in which the sulfone alpha-anion generated by Michael addition gives the desired pyrrole through internal condensation followed by a sigmatropic [1,5]-hydrogen shift. The resulting isoxazolinopyrroles 8 were released from resin 7 by 10% TFA in moderate to excellent overall yields from 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL resin 1.     

Synthetic methods for γ-lactam and pyrrole derivatives exploiting a three-component coupling strategy

4-Aryloxymethyl-3-pyrrolines and their isomeric pyrrolidines--assembled via a one-pot, three-component coupling of propargylic amines, vinyl sulfones, and phenols--may be elaborated further to provide an easy access to 2,4-disubstituted pyrrole-3-carboxylates and 3,4-disubstituted pyrrolidin-2-ones. The latter were prepared by means of an unprecedented rearrangement process involving hydrogenolysis of 2-aryl pyrrolidine-3-carboxylates, whereas the pyrrole carboxylates arose from aromatization of the corresponding pyrrolines.     

Regioselective synthesis of 5-unsubstituted benzyl pyrrole-2-carboxylates from benzyl isocyanoacetate

A general synthesis of 5-unsubstituted benzyl pyrrole-2-carboxylates was developed based on the reaction of β-nitroacetates with benzyl isocyanoacetate. The advantage of this route over other pyrrole syntheses was the regiochemical control of the substitution pattern on the pyrrole ring.     

Lipid-lowering effects of ethyl 2-phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in rodents

A series of substituted 2-phenacyl-3-phenyl-1H-pyrrole-4-carboxylates were prepared from substituted acetophenones in 6 steps. The final condensations between a chloroenal and an aminoketone were carried out under neutral conditions in parallel to yield the series listed below. Selected pyrrole derivatives proved to be potent hypolipidemic agents lowering serum triglyceride concentrations in CF-1 male mice after 14 days of I.P. administration. One agent orally lowered serum cholesterol in Sprague-Dawley male rats at 2mg/kg/day after 14 days. The agents demonstrated a lowering of mouse serum LDL- cholesterol levels and selected compounds showed an elevation of serum HDL-cholesterol levels. The cholesterol concentrations in the liver were raised while the cholesterol and triglyceride contents of the aorta were significantly lowered by the selected trisubstituted pyrrole.     

过渡金属催化合成吡咯-2-甲酸酯的研究进展

吡咯-2-甲酸酯广泛存在于生物活性分子中,在医药领域具有十分重要的应用,因此吡咯-2-甲酸酯类化合物的合成研究受到了广泛关注.过渡金属催化的环加成反应在合成吡咯骨架方面应用广泛,具有区域选择性专一的优点.且过渡金属配体导向的C-N键构筑方法具有原子步骤经济性较高、效率高、反应条件温和以及选择性高等优点.按照过渡金属催化剂分类,对吡咯-2-甲酸酯的[3+2]、[4+1]与[2+2+1]等成环反应的合成方法进行综述,介绍了过渡金属催化吡咯-2-甲酸酯化合物的机理及其应用,并对吡咯-2-甲酸酯的合成进行了展望.     

An unusual dehalogenation in the Suzuki coupling of 4-bromopyrrole-2-carboxylates

An unusual dehalogenation of 4-bromopyrrole-2-carboxylates under Suzuki coupling conditions has been observed. This dehalogenation can be suppressed by protection of the pyrrole nitrogen. Using a BOC protecting group, not only is dehalogenation suppressed, but the protecting group is also removed under the reaction conditions.     

Vinyl sulfones in solid-phase synthesis: preparation of 4,5,6,7-tetrahydroisoindole derivatives

The preparation of functionalized 4,5,6,7-tetrahydroisoindole via a traceless solid-phase sulfone linker strategy is described. Thermolytic extrusion of SO(2) from polymer-bound 3-(phenylsulfonyl)-3-sulfolene (7) generated polymer-bound 2-(phenylsulfonyl)-1,3-butadiene (9) in situ which underwent Diels--Alder cycloaddition with various dienophiles to furnish vinyl sulfone resins 10-14. To complete a traceless linker cleavage strategy, (p-tolysulfonyl)methyl isocyanide or ethyl isocyanoacetate was employed to react with the vinyl sulfone moiety to liberate functionalized 4,5,6,7-tetrahydroisoindole products from the resin. Using this chemistry, nine tetrahydroisoindole derivatives (6, 15-22) were prepared in 32-41% overall yields from polystyrene/divinylbenzene sulfinate 1.     

Reactions of zinc enolates derived from 1-aryl-2-bromo-2-phenylethanone and 2-bromoindan-1-one with alkyl 2-oxochromene-and 6-bromo-2-oxochromene-3-carboxylates

Zinc enolates derived from 1-aryl-2-bromo-2-phenylethanone react with alkyl 2-oxochromene-3-carboxylates and methyl 6-bromo-2-oxochromene-3-carboxylate to give, respectively, alkyl 4-(2-aryl-2-oxo-1-phenylethyl)-2-oxochroman-3-carboxylates and methyl 6-bromo-4-(2-aryl-2-oxo-1-phenylethyl)-2-oxochroman-3-carboxylate as a single stereoisomer. Zinc enolates derived from 2-bromoindan-1-one react with alkyl 2-oxochromene-3-carboxylates to give alkyl 2-oxo-4-(1-oxoindan-2-yl)chroman-3-carboxylates as a single stereoisomer.     

Synthesis and characterization of new sulfone‐derivatized phenylenevinylene‐based conjugated copolymers with evolving energy levels and gaps

A new series of stable, processable, and chain end functionalizable sulfone‐derivatized phenylenevinylene‐based conjugated polymers (SFPVs) containing different donor type comonomers have been synthesized and characterized. The polymer main chains are consisted of a sulfone‐phenylene electron accepting unit coupled with an electron donating unit which is derived from one of the dialdehyde comonomers based on benzene, thiophene, and pyrrole (with or without alkoxy side chains). The optical energy gaps (E_g) of the new polymers (in solvent) are in a range of 1.9–2.3 eV, with the lowest energy gap obtained from the polymer containing pyrrole as the donor unit. By using a combination of strong donor unit (such as pyrrole) and a relatively weak but stable acceptor unit (sulfone‐substituted benzene), E_g of the conjugated polymers can be tailored to below 2 eV, while the vinylene bonds on the polymer main chain are still chemically stable to survive strong basic conditions as compared with the S,S‐dioxo‐thiophene‐based PTV polymers developed earlier for potential supra‐molecular block copolymer systems. The lowest energy gap P(Pyrrole‐SFPV) exhibited 10 times better photoelectric power conversion efficiency than P(TV‐SFPV). © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis of 2,5 -Bis(4-methyl-2-thienyl)thiophene and 2,5-Bis(4-methyl-2-thienyl)pyrrole

Syntheses of 2,5-bis(4-methyl-2-thienyl)thiophene 3 and 2,5-bis(4-methyl-2-thienyl)pyrrole 4 are described. The key step involves Stetter reaction between 4-methyl-2-thiophenecarboxaldehyde and divinyl sulfone. Cyclizaton of the resulting 1,4-bis-(4-methyl-2-thienyl)-1,4-butanedione 2 with Lawesson's reagent gives 2,5-bis(4-methyl-2-thienyl)thiophene 3, whereas condensation with ammonium acetate provides the 2,5-bis(4-methyl-2-thienyl)pyrrole 4.     

Reactions of 2,3-dioxopyrrolo[2,1-<Emphasis Type="Italic">a</Emphasis>]isoquinolinecarboxylic acid esters and amides with nitrogen-centered nucleophiles

Reactions of ethyl 2,3-dioxopyrrolo[2,1-a]isoquinoline-1-carboxylates with active nitrogen-centered nucleophiles (phenylhydrazine, hydroxylamine, and benzylamine) involve opening of the pyrrole ring with formation of 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)-N′¹,N′⁴-diphenyl-3-(2-phenylhydrazono) succinohydrazide, 5-(6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)-2,3,4,5-tetrahydro-1H-1,2-oxazine-3,4,6-trione, and ethyl 4-benzylamino-2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)-3,4-dioxobutanoate, respectively. Cyclic amides derived from 5,5-dimethyl-2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-1-carboxylic acid react with benzylamine in a similar way. Reactions of the title compounds with weaker nucleophiles, such as semicarbazide and thiosemicarbazide, are not accompanied by opening of the pyrrole ring, and the products are the corresponding semicarbazones and thiosemicarbazones at the C²=O carbonyl group.     

Convenient synthesis of bis(indolyl)alkanes and bis(pyrrolyl)alkanes by Cu(OTf)2-catalyzed addition of indole and pyrrole to acetylenic sulfone

Sulfonyl-containing bis(indolyl)alkanes and bis(pyrrolyl)alkanes were synthesized conveniently by Cu(OTf)₂-catalyzed double Michael addition of indole and pyrrole to acetylenic sulfone.     

Reaction of alkyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylates with zinc enolates prepared from zinc and 1-arul-2-bromo-2-phenylethanones, 2 bromoindanone, and 2-bromo-6-methyltetralone

Alkyl 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylates react with zinc enolates prepared from 1-aryl-2-bromo-2-phenylethanones, 2-bromo indanone, 2-bromo-6-methyltetralone and zinc with formation of ethyl 4-(2-aryl-2-oxo-1-phenyl-ethyl)-5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylates, alkyl 5,5-dimethyl-2-oxo-4-(1-oxoindan-2-yl)tetrahydrofuran-3-carboxylates, and ethyl 5,5-dimethyl-4-(6-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-oxotetrahydrofuran-3-carboxylates respectively, mainly as single diastereomers.     

Synthesis of alkyl hexahydropyrazino-[1,2-<Emphasis Type="Italic">c</Emphasis>]pyrimidine-9-carboxylates

Cyclocondensation of 3-alkoxycarbonylmethylidenepiperazin-2-ones with α-chlorobenzyl isocyanates gave alkyl 8-aryl-1,6-dioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates. The use of 1-aryl-2,2,2-trifluoroethyl isocyanates in an analogous cyclization gave 6-aryl-1,8-dioxo-6-trifluoromethyl-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-carboxylates.     

The simplest synthesis of 5,5-disubstituted and spiranic methyl 4-amino-2,2-dioxo-2,5-dihydro-1,2λ6-oxathiole-3-carboxylates

We report the short and the simplest strategy for the synthesis of methyl 4-amino-2,2-dioxo-2,5-dihydro-1,2λ⁶-oxathiole-3-carboxylates bearing aliphatic substituents at the 5th position. A number of cyanohydrins were forced to react with methyl 2-(chlorosulfonyl)acetate to give the interim methyl 2-[(cyanomethoxy)sulfonyl]acetates that upon Et₃N-mediated conditions underwent the CSIC [Carbanion mediated Sulfonate (Sulfonamido) Intramolecular Cyclization] reaction yielding the 5,5-disubstituted and spiranic methyl 4-amino-2,2-dioxo-2,5-dihydro-1,2λ⁶-oxathiole-3-carboxylates.     

Regiochemical switching in Diels-Alder cycloadditions by change in oxidation state of removable diene sulfur substituents. Synthesis of carbazoles by sequential heteroannulation and Diels-Alder cycloaddition

The palladium-catalyzed heteroannulation of N-carbobenzyloxy-o-iodoanilines with 1-phenylthio-1,3-butadiene afforded indolines 7, which were oxidized with DDQ to produce vinylogous 2-(phenylthio)indoles 8. The latter compounds underwent highly regioselective Diels-Alder cycloadditions with methyl propiolate in the presence of MeAlCl(2) or AlCl(3), with simultaneous elimination of benzenethiol, to afford methyl N-(carbobenzyloxy)carbazole-3-carboxylates 9 and, in some cases, the N-deprotected derivatives 11. This is the opposite regiochemistry of that observed previously with the corresponding sulfone analogues of 8. Thus, the regiochemistry of the cycloaddition can be effectively controlled by appropriate choice of oxidation state of the diene sulfur substituent.     

Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2"S)-diastereomer

The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2"R, 5"R, 7"R) after initial synthesis of the unnatural (2"S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2"R, 5"S, 7"S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2"S, 5"R, 7"R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2"S, 5"S, 7"S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.     

Synthesis,spectral analysis,and <Emphasis Type="Italic">in vitro</Emphasis> microbiological evaluation of ethyl 7,9-diaryl-1, 4-diazaspiro[4.5]dec-9-ene-6- carboxylates as a new class of antibacterial and antifungal agents

A series of novel ethyl 7,9-diaryl-1,4-diazaspiro[4.5]dec-9-ene-6-carboxylates was synthesized by the reaction of ethyl 4,6-diaryl-2-oxocyclohex-3-ene-1-carboxylates with ethylenediamine in the presence of p-toluenesulfonic acid without a solvent under focused microwave irradiation. The title compounds were screened for their antimicrobial activities against a spectrum of clinically isolated microorganisms.     

Reactions of 1-Aryl-2,2-dibromobutan-1-ones with Zinc and Alkyl 6-Bromo-2-oxo-2-H-chromen-3-carboxylate

Zinc enolates formed from 1-aryl-2,2-dibromobutan-1-ones and zinc react with alkyl 6-bromo-2-oxo-2-H-chromen-3-carboxylates affording alkyl 1-aroyl-6-bromo-2-oxo-1-ethyl-1,7b-dihydrocyclopropa[c]-chromen-1a(2H)-carboxylates as a single isomer.     

Reaction products of methyl tricyclo[4.1.0.02,7]heptane-1-carboxylate and tricyclo[4.1.0.02,7]hept-1-yl phenyl sulfone with dinitrogen tetraoxide

The reaction of methyl tricyclo[4.1.0.0^2,7]hepatne-1-carboxylate with dinitrogen tetraoxide in diethyl ether at ?10 to 0°C, followed by treatment of the reaction mixture with methanol, gave approximately equal amounts of methyl exo,syn-6,7-dinitro-and exo-6-hydroxy-syn-7-nitrobicyclo[3.1.1]heptane-endo-6-carboxylates. Tricyclo[4.1.0.0^2,7]hept-1-yl phenyl sulfone reacted with dinitrogen tetraoxide under analogous conditions to produce a mixture of diastereoisomeric exo,syn-and endo,syn-6,7-dinitro-6-phenylsulfonylbicyclo-[3.1.1]heptanes and 6,6-dimethoxy-endo-7-nitrobicyclo[3.1.1]heptane at a ratio of 4.5:2:1. Probable factors responsible for the different stereoselectivities in the addition of N₂O₄ at the central C¹-C⁷ bond of the initial tricycloheptane compounds were discussed. The structural parameters of the dinitro ester and related dinitro sulfone were compared on the basis of the X-ray diffraction data.