1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

Facile synthesis and characterization of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one and pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine incorporating 1,3-diarylpyrazole moiety

4-(3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-6-phenyl-2-thioxo-1,2-di hydro-pyridine-3-carbonitrile (1) reacted with ethyl chloroacetate (2) in ethanolic sodium acetate solution to yield the corresponding ethyl (3-cyanopyridin-2-ylsulphanyl)acetate derivative 3. Intramolecular cyclization of compound 3 was achieved by its heating in DMF containing potassium carbonate to afford the corresponding ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate derivative 4 which reacted with hydrazine hydrate in refluxing pyridine to yield the starting material 3-aminothieno[2,3-b]pyridine-2-carbohydrazide derivative 7. Compound 7 reacted with different reagents such as triethylorthoformate, formic acid, acetic acid and acetic anhydride to afford the target molecules pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 8–10, 12 and 13 in good to excellent yields. On the other hand, pyridine-2(1H)-thione derivative 1 reacted with hydrazine hydrate in refluxing pyridine to give the other starting material 3-amino-1H-pyrazolo[3,4-b]pyridine derivative 20 which reacted with acetylacetone under reflux to afford the target molecule pyrido[2′,3′:3,4]pyrazolo[1,5-a]-pyrimidine derivative 21 in a good yield. The structures of target molecules were elucidated using elemental analyses and spectral data.     

2-Ethanethioamide in Heterocyclic Synthesis: Synthesis and Characterization of Several New Pyridine and Fused Azolo- and Azinopyridine Derivatives

Pyridine-2(1H)-thione derivatives 3a,b were synthesized from the reaction of 1-(phenyl-sulfanyl)acetone (1) and cinnnamonitrile derivatives 2a,b. Compounds 3a,b reacted with different halogenated reagents 7a–f to give 2-S-alkylpyridine derivatives 8a–l, which could be, in turn, cyclized into the corresponding thieno[2,3-b]pyridine derivatives 9a–l. Compounds 9d,j reacted with acetic anhydride, formic acid, carbon disulfide, phenyl isothiocyanate, and nitrous acid to yield the corresponding pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine 12a,b, 15a,b, 17a,b, 20a,b, and pyrido[3′,2′:4,5]thieno[2,3-d][1,2,3]triazinone derivatives 22a,b, respectively.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Synthesis of some new spiroindoline derivatives incorporated with pyrazoloheterocycles

Indole-2,3-dione ( 1 ) was treated with malonic acid ( 2 ) in a mixture of ethanol/pyridine to afford 1-[3-(2-oxoindolinylidene)]acetic acid ( 3 ). Compound 3 reacted with thionyl chloride to give the corresponding acid chloride ( 4 ). The acid chloride 4 reacted with arenes in the presence of AlCl₃ to yield 3-(2-oxoindolinylidene)acetophenones 5a–c . Compounds 5a–c reacted with 3-methylpyrazolin-5-one derivatives 6a , b to give 3-aracyl-3-[4′-(3′-methylpyrazolin-5-onyl)]-indoline-2-one derivatives 7a–f . Compounds 7a–f were treated with phosphorus pentoxide in phosphoric acid, with ammonium acetate or methanolic methylamine and with phosphorus pentasulfide to give spiro[indoline-3,4′-(pyrazolo[4,5-b]pyran)]-2-ones 8a–f , spiro[indoline-3,4′-(pyrazolo[4,5-b]-dihydropyridine)]-2-ones 9a–f , 10a–f and spiro[indoline-3,4′-(pyrazolo[4,5-b]thiopyran)]-2-ones 10a–f , respectively. All of the synthesized spiroheterocycle derivatives were identified by conventional spectroscopic methods (IR, ¹H NMR) and elemental analyses. © John Wiley & Sons, Inc.     

The Synthesis of Some Pyrazolyl- and Thiazolylthienopyridines

2-acetyl-3-amino-4,6-dimethylthieno[2,3-b]pyridine 1 reacted with dimethoxy-tetrahydrofuran in acetic acid and ethyl cyanoacetate in the presence of ammonium acetate or with NaNO₂ in the presence of an AcOH/HCl mixture to produce 2–4. Compound 2 reacted with aromatic aldehydes, semicarbazide hydrochloride, thiosemicarbazide, and phenyl hydrazine or with hydrazine hydrate to give compounds 5a–c and 11a–d, respectively.

Chalcone 5 reacted with hydrazines, hydroxylamine hydrochloride, or thiourea to produce compounds 6–9. Thiosemicarbazone 11b reacted with α -haloester to produce the corresponding thiazolidinone derivatives 12a, b ; also it reacted with ω -bromoacetophenone to give thiazoline derivatives 13a, b .     

Synthesis,reactions, and antioxidant activity of 3-(pyrrol-1-yl)-4,6-dimethyl selenolo[2,3-b]pyridine derivatives

Ethyl 4,6-dimethyl-3-(pyrrol-1-yl) selenolo[2,3-b]pyridine-2-carboxylate (2) was synthesized by the reaction of previously prepared ethyl 3-amino-4,6-dimethyl selenolo[2,3-b]pyridine-2-carboxylate (1) with 2,5-dimethoxytetrahydrofuran in acetic acid. The pyrrolyl ester (2) was converted into the corresponding carbohydrazide 3 which reacted with acetyl acetone, aromatic aldehydes, carbon disulfide in pyridine, and sodium nitrite to afford the corresponding dimethyl pyrazolyl 4, arylidene carbohydrazides 5a–d, oxadiazolyl thiole 6, and caboazide compound 8, respectively. The carboazide 8 reacted with different alcohols and amines to give the corresponding carbamates 9a–c and the aryl urea derivatives 10a–d. Heating of carboazide 8 in dry xylene afforded the pyridoselenolo-pyrrolopyrazinone 11. The latter compound was used as a versatile starting precursor for synthesis of other pyridoselenolo-pyrrolopyrazine compounds. The newly synthesized compounds and their derivatives were characterized by elemental analysis and spectroscopy (IR, ¹H-NMR, and mass spectra). Some of the newly synthesized pyrrolyl selenolopyridine compounds showed remarkable antioxidant activity compared to ascorbic acid.     

Reactivity of 4-bromomethylquinoline derivatives towards glycine and thioglycolic acid. A new ring system

Condensation of 4-bromomethylquinoline derivatives1 a-1 c with glycine and thioglycolic acid gave the corresponding quinolylmethylglycine and quinolylmethylthioacetic acid derivatives2 a-2 c and2 d-2 f, respectively. Cyclization of2 a-2 f was affected either by polyphosphoric acid or concentrated sulphuric acid to give3 a-3 f. Chlorination of2 a-2 f and3 a-3 f were also accomplished.

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Die Reaktivität von 4-Brommethylchinolin-Derivaten gegenüber Glycin und Thioglycolsäure. Ein neues Ringsystem

Zusammenfassung Die Reaktion von 4-Brommethylchinolin-Derivaten1 a-c mit Glycin und Thioglycolsäure gab die entsprechenden Kondensationsprodukte2 a-c und2d-f.2 a-f konnten mit Polyphosphorsäure bzw. mit konzentrierter Schwefelsäure zu Benzo[c]-2,6-naphthyridinen3 a-f zyklisiert werden.2 a-f und3 a-f waren einer Chlorierung (POCl₃) zugängig.

     

Efficient synthesis and characterization of novel bis-heterocyclic derivatives and benzo-fused macrocycles containing oxazolone or imidazolone subunits

Bis(3-(arylthiomethyl)benzaldehydes), linked to aliphatic spacers via ethers, were prepared and used as key synthons for the bis(2-phenyloxazol-5(4H)-ones) via their reaction with benzoylglycine in acetic anhydride in the presence of fused sodium acetate at 100°C for 6 hours. Bis(oxazol-5(4H)-ones) were reacted with the appropriate aromatic or heterocyclic amines in glacial acetic acid in the presence of fused sodium acetate at 100°C for 24 hours to afford a novel series of bis(2-phenylimidazol-4-ones) and their related hybrids with benzo[d]thiazole and pyrimidine-2,4(1H,3H)-dione. Moreover, bis(oxazol-5(4H)-ones) reacted with (4-aminobenzoyl)glycine to afford bis[(4-(5-oxo-1H-imidazol-1-yl)benzoyl)glycine] derivatives followed by their reaction with anisaldehyde in acetic anhydride containing fused sodium acetate at 100°C for 12 hours to afford bis(5-oxo-1H-imidazol-1-yloxazol-5(4H)-one) hybrids. Furthermore, bis(3-(arylthiomethyl)benzaldehydes) were reacted with 2,2′-(terephthaloylbis(azanediyl))diacetic acid in acetic anhydride containing fused sodium acetate at 100°C for 12 hours to give benzo-fused macrocycles containing oxazolone subunits which reacted with appropriate aromatic amines in DMF and glacial acetic acid containing fused sodium acetate at 100°C for 24 hours to give benzo-fused macrocycles containing imidazolone subunits.     

Pyridine-2(1H)-thione in Heterocyclic Synthesis: Synthesis of Some New Nicotinic Acid Ester,Thieno[2, 3-b]pyridine,Pyrido[3′, 2′: 4, 5]thieno [3, 2-d]pyrimidine,and Thiazolylpyrazolo[3, 4-b]pyridine Derivatives

Nicotinic acid esters 3a–c were prepared by the reaction of pyridine-2(1H)-thione derivative 1 with α-halo-reagents 2a–c. Compounds 3a–c underwent cyclization to the corresponding thieno[2, 3-b]pyridines 4a–c via boiling in ethanol/piperidine solution. Compounds 4a–c condensed with dimethylformamide-dimethylacetal (DMF-DMA) to afford 3-{[(N,N-dimethylamino)methylene]amino}thieno[2, 3-b]- pyridine derivatives 6a–c. Moreover, compounds 4a–c and 6a–c reacted with different reagents and afforded the pyrido[3′,2′:4, 5]thieno[3, 2-d]pyrimidine derivatives 10a–d, 11a–c, 12a,b, 14a,b, 17, and 19. In addition, pyrazolo[3, 4-b]pyridine derivative 20 (formed via the reaction of 1 with hydrazine hydrate) reacted with ethylisothiocyanate yielded the thiourea derivative 21. Compound 21 reacted with α-halocarbonyl compounds to give the 3-[(3H-thiazol-2-ylidene)amino]-1H-pyrazolo[3, 4-b]pyridine derivatives 23a–c, 25, and 27a,b.     

Influence of Chelating Groups on the Luminescence Properties of Europium(III) and Terbium(III) chelates in the 2,2′-bipyridine series

Eight different 2,2′-bipyridine derivatives, i.e. 2, 5, 8, 10, 12, 13, 15 , and 19 (Schemes 1 and 2), were prepared to study the influence of the chelating groups on the luminescence properties of their Eu^III and Tb^III chelates. According to our luminescence results, 2,2′-(methylenenitrilo)bis(acetic acid) as well as (methylenenitrilo)bis-(methylphosphonic acid) in 6- and 6′-position of 2,2′-bipyridine is a suitable group when developing luminescent markers for bioaffinity assays based on time-resolved luminescence measurement.     

Preparation and Oxidative-Chlorination Splitting of Nitro Derivatives OF 1,4-Dithiino[2,3-C:5,6-C′]Diquinoline as a Source of 4-Substituted 5- and 8-Nitro-3-Quinolinesulfonic Acid Derivatives

Abstract

Treatment of 1,4-dithiino[2,3-c:5,6-c′]diquinoline (a thioquinanthrene) (1a) with an excess of nitrating mixture (0 °C, 14 days) led to a mixture of mono- and dinitrothioquinanthrene 7-oxides 2b–e and 2f–h. This mixture was: (i) reduced to a mixture of mono- and dinitrothioquinanthrenes 1b– e, or (ii) oxidatively chlorinated with a gaseous chlorine/80% acetic acid/hydrochloric acid system to a mixture of 4-chloro-3-chlorosulfonylquinoline 3a and its 5- and 8-nitroderivatives 3b and 3d. Sulfochlorides 3a– d were independently synthesized from 3,4′-diquinolinyl sulfides 4 and converted to the respective 4-dimethylamino-3-quinoline-N,N-dimethylsulfonamides 9a–d.     

Chromium trioxide oxidation products from 4-spiro-1-phenylisochromans

Chromium trioxide oxidation of 1-phenylisochroman-4-spiro-1′-cyclopentane (Ia) in acetic acid led to the expected 1-(2-benzoylphenyl)cyclopentanecarboxylic acid (IIa), while its 6,7-dimethoxy analogue Ib and 6,7-dimethoxy-1-phenylisochroman-4-spiro-4′-(1′-methyl)piperidine (Ic) under the same conditions gave a mixture of their related 1-hydroxy derivatives VIIIb and VIIIc and of the p-benzoquinones, 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)cyclopentane (IXb) and 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)-1-methylpiperidine (IXc). Cyclization of Ila with hydrazine or monomethylhydrazine led to the 5-spiro-substituted 1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones IIIa or XIa.     

Reaction of 2-carboxy-1-methylindole-3-acetic acid anhydride with amines and with S-methylisothiosemicarbazide

2-Carboxy-1-alkylindole-3-acetic acid anhydrides (I) condensed with S-methylisothiosemicarbazide in DMF to form 5,11-dihydro-6-methyl-2-methylthioindolo[3′,2′:4,5]pyrido[1,2-b]-s-triazol-5-one (II). Compound II underwent ring opening on refluxing with sodium hydroxide solution to give IV. The anhydride I reacted with primary amines in benzene to give 2-carboxy-1-alkylindole-3-acetanilide derivatives (VI) which yielded l-methylindole-3-acetic acid by decarboxylation followed by hydrolysis. Compound II oxidised to the diketo compound X which could be prepared by the hydrolysis of the azomethine derivative IX with acetic acid-hydrochloric acid mixture. Compound II reacted with benzyl chloride to yield the dibenzyl derivative XII, condensed with p-chlorobenzaldehyde to form the 11-p-chlorobenzylidene derivative XI and coupled with arenediazonium salt to give the 11-arylhydrazone derivatives XIII.     

Über die Darstellung von substituierten 3,4-Dihydro-2(1H)-pyrimidin-iminen und 2-Aminopyrimidinen aus Guanidin und α,β-ungesättigten Ketonen

Guanidine reacts with the 2-alken-1-ones4 a-f and5 to give the unstable dihydropyrimidinimines (or-amines respectively)8 a-f (I, II or III respectively) and the hexahydroquinazolinimine (-amine)9 (I, II or III);8 a-f lose H₂, partly in the course of the reaction, partly during recrystallization to yield the 2-pyrimidinamines10 a-c, e, f, and the 4-methyl-5,6,7,8-tetrahydro-2-quinazolinamine11. With picric acid the unstable compounds8 d, f and9, resp. are converted into the stable 2-amino-3,4-dihydro-1H-2-pyrimidinylium picrates12 d and into the 2-amino-4-methyl-3,5,6,7,8,8 a-hexahydro-1H-2-quinazolinium picrate (13 resp.14, 15)¹⁸, whereas8 e reacts with HCl to give the chloride12 e. The structures of12 d-f follow from their NMR-spectra, and of10 a-c, e, f and11 by alternative syntheses by known methods^12–17 (e.g. from -diketones and guanidine). The reaction of8 d-f and9 to10 d-f and11 respectively is compared with previously described dehydrogenation and disproportionation reactions, especially of 3,4-dihydro-2(1H)-pyrimidinones (6 d ⁴,23 ²⁰) and-thiones (30 ¹) of similar structure and formulated as a base-catalysed elimination of H₂.

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HerrnA. Fuchsgruber danken wir für die Aufnahme und Hilfe bei der Interpretation der NMR-Spektren.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

KF-Al2O3 Induced the Condensation of 2-Nitrofluorene and Para-Substituted Acetophenones with Aromatic Aldehydes

In the presence of KF-Al₂O₃ as a solid base, 2-nitrofluorene 1 condensed with aromatic aldehydes 2a-f in methanol to give 2-nitrodibenzo-fulvenes 3a-f in high yield. The para-substituted acetophenones 4a-f reacted with cinnamic aldehyde to give 1, 5-diaryl-2, 4-pentadien-1-ones 6a-f in moderate yield.     

Facile Syntheses of Some Thieno[2,3-d] Pyrimidine Derivatives

In one-pot synthesis 2-arylidene-5,6,7,8-tetrahydrothiazolo[3,2-a] cyclopenteno-thieno[2,3-d] pyrimidine-3,5-diones (3) were prepared via the reaction of a ternary mixture of 2-thioxo-1,3,4,5,6,7-hexahydr cyclopentinothieno [2,3-d]-4-one (2), chloroacetic acid and a proper aldehyde. Compound 2 reacted with 3-chloropent-2, 4-dione in ethanolic potassium hydroxide yielding the S-acetyl acetone derivative 5f . The latter compound reacted with hydrazine hydrate and phenyl hydrazine yielded the 2-pyrazolthio derivative 10a, b. Compound 5f also underwent cyclization on heating with acetic acid—pyridine solution to give 11. The 2-methylthio derivative 5a, when treated with hydrogen peroxide gave the corresponding oxidized product 9.     

Synthesis and Antiinflammatoryand Anticancer Activity Evaluation of Some Condensed Pyrimidines

Summary.  Upon condensation with 4-isothiocyanato-4-methyl-2-pentanone, 2,3-diaminonaphthalene and N-aminoethyladenosine gave in good yields substituted pyrimidonaphthoimidazole and imidazopyrimidine thione. Refluxing pyrimidobenzthiazole with methanol H₂SO₄ at pH∼1 resulted in S-methyl pyrimidobenzthiazole in moderate yield. Pyrimidobenzimidazole derivatives could be reacted to S-alkylated and N-acylated derivatives by refluxing with ethyl bromoacetate in the presence of anhydrous potassium carbonate in THF and by heating in an acetic acid/acetic anhydride mixture. Heating of pyrimidobenzimidazole with 75% aqueous H₂SO₄ on a water bath ended up in a rearranged product. All compounds gave correct ¹H NMR, IR, and HR mass spectra. Results of antiinflammatory, analgesic, and anticancer activity screening of the new compounds are described. Received October 29, 1999. Accepted (revised) January 13, 2000     

SYNTHESIS AND REACTIONS OF SOME NEW THIENO[2,3-b]-PYRIDINES AND THE ANTIMICROBIAL EFFECTS

Abstract

3,5-Dicyano-6-mercapto-4-phenylpyridin-2(1H)-one (1) was reacted with ethyl chloroacetate to give compound (II) which on reaction with hydrazine hydrate gave the corresponding hydrazide derivative (III). Acylation of (III) with acetic acid, phenylisocyanate, or phenylisothiocyanate gave different monoacyl derivatives (IV-VI). Condensation of III with aromatic aldehydes and acetylacetone gave compounds VII_a-c, VIII respectively. Compound I was reacted with chloroanilides, bromoacetone and phenacyl bromide to yield the IX-XI; these and compound II gave thieno[2,3-b]-pyridines (XU-XV) on treatment with sodium ethoxide solution. Reaction of XII with acetic anhydride gave the diacetyl derivative XVI. Hydrolysis of compound XII with sodium hydroxide gave the corresponding acid (XVII) which on treatment with acetic anhydride gave the oxazine derivative (XVIII). Reaction of oxazine compound XVIII with ammonium acetate and hydrazine hydrate gave pyrido[3′,2′:4,5] thieno[3,2-d]pyrimidin-4.7-dione derivative (XIX) and (XX) respectively. The N-amino derivative (XX) was reacted with 4-nitrobenzaldehyde to give the corresponding azomethine (XXI).

Significant in vitro gram-positive and gram negative antibacterial activities as well as anti-fungal effect were observed for some members of the series.     

Efficient Synthesis of Ferrocenylquinolines via the Friedländer Reaction

Acylferrocenes 2a–c reacted with ortho-aminoarylaldehydes 1a–e via the Friedländer condensation reaction to afford the corresponding ferrocenylquinolines 3a–o in moderate yields in the presence of sodium ethoxide (30 mmol%) under mild reaction conditions. Under the same reaction conditions, 1,1′-diacetylferrocene 2d and 1,1′-dipropionylferrocene 2e reacted with ortho-aminoaldehydes 1a–e to afford the corresponding 1,1′-bis(substituted quinolin-2-yl)ferrocene derivatives 3p–t. The structures of compounds 3a–t were determined and characterized by infrared, ¹H NMR, mass spectrometry, and elemental analysis. The crystal structures of 3e and 3q were determined by x-ray crystallography.