An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

The conversion of 2-cyano cyanothioformanilides into 3-aminoindole-2-carbonitriles using triphenylphosphine

2-Cyano cyanothioformanilide 3a reacts with triphenylphosphine in the presence of water to give 2-(cyanomethyleneamino)benzonitrile 4a, 2-(cyanomethylamino)benzonitrile 5, 3-aminoindole-2-carbonitrile 2a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 6a. In the presence of p-toluenesulfonic acid in MeOH the reaction between 2-cyano cyanothioformanilide 3a and triphenylphosphine (2 equiv) gives 3-aminoindole-2-carbonitrile 2a in 90% yield. Under the same conditions 2-(cyanomethyleneamino)benzonitrile 4a gives anthranilonitrile 8a, 3-aminoindole-2-carbonitrile 2a and N-(2-cyanophenyl)formamide 9. In addition, substituted 2-cyano cyanothioformanilides 3b-f react with triphenylphosphine and p-toluenesulfonic acid in MeOH to give 3-aminoindole-2-carbonitriles 2b-f in 63-75% yields. Under analogous conditions 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 2g gives only 4,5-dimethoxyanthranilonitrile 8g and 4,6,7-trimethoxyquinazoline-2-carbonitrile 14g, but in refluxing dry PhMe in the absence of p-toluenesulfonic acid 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 3g, (2-cyano-5,6-dimethoxyindol-3-yl)iminotriphenylphosphorane 6g and 2-(cyanomethyleneamino)-4,5-dimethoxybenzonitrile 4g are obtained. The structure of 2-(cyanomethyleneamino)-4,5-dimethoxybenzonitrile 4g is supported unambiguously via independent synthesis and comparison to the isomeric 6,7-dimethoxyquinazoline-2-carbonitrile 15. All new compounds are fully characterised and a tentative mechanism for the transformation of 2-cyano cyanothioformanilides to indoles is proposed.     

Stereochemical studies—XIII: Cyclic aminoalcohols and related compounds—VI synthesis of the four 2-amino-4-t-butylcyclopentanol isomers

From diethyl 3-t-butyladipate (5), via cis- and trans-4-t-butylcyclopentene-1,2-oxide (31, 32) as key compounds, the syntheses of cis-2-amino-cis-4-t-butylcyclopentanol (1), cis-2-amino-trans-4-t-butylcyclopentanol (2), trans-2-amino-cis-4-t-butylcyclopentanol (3) and trans-2-amino-trans-4-t-butylcyclopentanol (4) have been achieved. 1, 3 and 4 were also synthesized from the corresponding 2-hydroxy-4-t-butylcarboxylic acids by Curtius degradation of the hydrazides (11, 18, 19). The steric course of process leading to the above compounds is discussed.     

Manganese(III) acetate based oxidative cyclizations of 3-oxopropanenitriles with conjugated alkenes and synthesis of 4,5-dihydrofuran-3-carbonitriles containing heterocycles

4,5-Dihydrofuran-3-carbonitriles 3a-i were obtained through oxidative cyclizations of 3-oxo-3-phenylpropanenitrile 1a, 3-oxo-3-thien-2-ylpropanenitrile 1b, 3-(2-furyl)-3-oxopropanenitirle 1c, 3-(1-benzofuran-2-yl)-3-oxopropanenitrile 1d, and 4,4-dimethyl-3-oxopropanenitrile 1e mediated manganese(III) acetate with 1,1-diphenyl-1-butene 2a and 1,2-diphenyl-1-pentene 2b. The treatments of these 3-oxopropanenitriles with 2-thienyl substituted alkenes such as 2-[(E)-2-phenylvinyl]thiophene 2c, 2-[(E)-1-methyl-2-phenylvinyl]thiophene 2d, and 2-(1-phenylvinyl)thiophene 2e formed 5-(2-thienyl)-4,5-dihydrofuran-3-carbonitriles 3j-r in good yields (45-93%). As a result, 2-thienyl substituted alkenes formed products in higher yields than phenyl substituted derivatives.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Syntheses of rac/meso-{PhP(3-t-Bu-C5H3)2}-Zr{RN(CH2)3NR}, structural analyses of rac-{PhP(3-t-Bu-C5H3)2}Zr{RN(CH2)3NR} (where R is SiMe3 or Ph), and meso to rac isomerization

Syntheses of rac/meso-{PhP(3-t-Bu-C₅H₃)₂}Zr{Me₃SiN(CH₂)₃NSiMe₃} (rac-3/meso-3) and rac/meso-{PhP(3-t-Bu-C₅H₃)₂}Zr{PhN(CH₂)₃NPh} (rac-4/meso-4) were achieved by metallation of K₂[PhP(3-t-Bu-C₅H₃)₂] · 1.3 THF (2) with Zr{RN(CH₂)₃NR}Cl₂(THF)₂ (where R = SiMe₃ or Ph, respectively) using ethereal solvent. These isomeric pairs were characterized by ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopy; rac-3 and rac-4 were also examined via single crystal X-ray crystallography. The structures of rac-3 and rac-4 are notable in the tendency of the cyclopentadienyl rings towards η³ coordination. While isolated samples of rac-3/meso-3 and rac-4/meso-4 slowly isomerize in tetrahydrofuran-d₈ to equilibrium ratios, the isomerization rate for 3 is more than 15-fold greater than that for 4. In addition, equilibrium ratios are rapidly reached when isolated samples of rac-3/meso-3 and rac-4/meso-4 are exposed to tetrabutylammonium chloride in tetrahydrofuran-d₈ solvent. We propose that a nucleophile (either chloride or the phosphine interannular linker) brings about dissociation of one cyclopentadienyl ring, thus promoting the rac/meso isomerization mechanism.     

Synthesis of a new class of azathia crown macrocycles containing two 1,2,4-triazole or two 1,3,4-thiadiazole rings as subunits

A series of new 1,2/1,3-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-4-yl)phenoxy]alkane derivatives 3a-d and bis[o-(N-methylidenamino-2-thiol-1,3,4-thiadiazole-5-yl)phenoxy]alkanes 6a-c were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiols 2a-b or 2-amino-5-mercapto-1,3,4-thiadiazole with bis-aldehydes 1a-c. Further reaction of compounds 3a-d and 6a-c with dibromoalkanes afforded the new macrocycles 5a-f and 8a-d. The cyclization does not require high dilution techniques and provides the expected azathia macrocycles in good yields, ranging from 55% to 68%.     

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile-nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile (3, 27%) and 4-isocyano-2-(1-TIPS-1H-pyrrol-3-yl)but-2-enenitrile (7, 20%), in addition to our previously reported pyrido[3,4-b]thienopyrrole (2, 29%) and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (6, 71%) products. Minor amounts of 2-(thien-3-yl)-1H-pyrrole-3-carbonitrile (4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.     

Facile access to stereodefined dienoates and cyclopropylenoates containing a trifluoromethyl group

Ethyl (2E,4E)-3-trifluoromethyl-2,4-dienoates 1a-e and ethyl (E)-3-trans-alkylcyclopropyl-4,4,4-trifluoro-2-butenoates 2a-e were prepared from the trans-alkenylboronic acids 3a-e and the trans-cyclopropylboronic acids 4a-e with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate (5) by the Suzuki cross-coupling reaction in high yields (88-95%). The configurations of both 3a-e or 4a-e and 5 were retained in the reaction.     

Synthesis and thermal behavior of cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene

The cothermolysis of benzoyl(tert-butyl)bis(trimethylsilyl)silane with 2,3-dimethylbutadiene in a sealed tube at 140 °C for 24 h afforded cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (2 and 3) in a ratio of approximately 1:1 in 66% combined yield. When cis-silacyclohex-4-ene 2 was heated in a sealed tube at 250 °C for 24 h, dyotropic ring contraction took place to give 1-[(tert-butyl)(trimethylsiloxy)(trimethylsilyl)silyl]-3,4-dimethyl-1-phenylcyclopent-3-ene (4), but not trans-2-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (6). The thermolysis of trans-silacyclohex-4-ene 3 under the same conditions, however, afforded two products, 1-silyl-1-phenylcyclopent-3-ene 4 and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-2-(trimethylsilyl)-1-silacyclohex-4-ene (5). The theoretical calculations were carried out to characterize the transition states and other local minima, and to evaluate the activation energies for the dyotropic rearrangement of 2 to 4 and 6, and 3 to 4 and 5. The energy barriers between 2 and 4, between 3 and 4, and between 3 and 5 were evaluated to be 188, 191, 192 kJ mol⁻¹, respectively. The energy barrier between 2 and 6, however, was calculated to be 201 kJ mol⁻¹ or higher. These results are consistent with the experimental finding that the thermal isomerization of 2 affords only 4, but 3 produces both 4 and 5.     

Synthesis of indenes by ytterbium-catalyzed carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes with acetals

Ytterbium-catalyzed tandem carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes 1 with acetals 2 afforded the corresponding indene derivatives 3 in good to high yields. For example, in the presence of 10 mol % of Yb(OTf)₃ the reaction of 1-phenylbenzylidenecyclopropane 1a with the dimethyl acetals of benzaldehyde 2a, p-tolualdehyde 2b, and p-anisaldehyde 2c gave 1,3-diphenyl-2-(2-methoxyethyl)indene 3a, 2-(2-methoxyethyl)-3-phenyl-1-(p-tolyl)indene 3b, and 1-(p-anisyl)-2-(2-methoxyethyl)-3-phenylindene 3c in 82%, 80%, and 80% yields, respectively.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

New reaction of ethenetetracarbonitrile with N-arylisoindolines

N-Arylisoindolines 1a-i react with ethenetetracarbonitrile 2 in aerated benzene by formation of [3-(2-aryl-3-dicyanomethylene-2,3-dihydro-1H-isoindol-1-ylidene)-2-aryl-2,3-dihydro-1H-isoindol-1-ylidene]propanedinitriles 8a-i (20-36%), N-aryl-3-dicyanomethylene-isoindol-2-ones 9a-i (15-21%) and N-arylphthalimides 10a-i (4-9%) as well as 1,1,2,2-tetracyanoethane 11 (35-55%). The structure of 8d has been unambiguously confirmed by a single crystal X-ray structure analysis. A rationale for the formation of products 8-11 is presented.     

Photobehaviour of 2- and 3-heteroaryl substituted o-divinylbenzenes; formation of fused 2,3- and 3,2-heteroareno-benzobicyclo[3.2.1]octadienes and 3-heteroaryl benzobicyclo[2.1.1]hexenes

New β-3-thienyl (8) and β-3-furyl derivatives of o-divinylbenzene (9) have been synthesised and their photochemical behaviour compared with 2-thienyl (7) and 2-furyl derivatives (2). Whereas the β-(2-heteroaryl) substituted o-divinylbenzenes (7 or 2) give only bicyclo[3.2.1]octadiene structure (14 or 1) by 1,6-ring closure of the biradical intermediate, β-(3-heteroaryl) substituted o-divinylbenzenes (8 or 9) give bicyclo[3.2.1]octadiene structure (23 or 24) and bicyclo[2.1.1]hexene structure (25 or 26) by 1,6- and 1,4-ring closure, respectively. This photochemical approach provides a simple method to 2,3- and 3,2-fused thiophene and furan polycyclic compounds.     

Synthesis of pyrrolo[3,2-b]benzofurans and pyrrolo[3,2-b]naphthofurans via addition of a silyloxypyrrole to activated quinones

The uncatalyzed reaction of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 with 1,4-quinones bearing an electron withdrawing group at C-2 has been studied. Use of 1,4-quinones 4, 5 bearing an ester group at C-2 provided an efficient synthesis of the respective pyrrolidinobenzofuran adduct 9 or pyrrolidinonaphthofuran adduct 10 whereas use of 1,4-quinones 6, 7 and 8 bearing an acetyl group at C-2 afforded silyloxypyrroles 11, 12 and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of Eu(fod)₃ to the reaction of 2-acetyl-1,4-naphthoquinone 7 and 3-acetyl-5-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 provided a method for obtaining the pyrrolidinonaphthofuran adducts 14 and 15 together with silyloxypyrroles 12 and 13. Oxidative rearrangement of pyrrolidinonaphthofuran adduct 15 to pyrrolidino pyranonaphthoquinone 16 using ceric ammonium nitrate in acetonitrile provided a novel approach for the synthesis of an aza-analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

Cyclopalladation of enantiopure oxazolines having the prochiral CMe2 moiety at position 2 of the heterocycle

(R)-4-Ethyl-2-(1,1-dimethylpropyl)-2-oxazoline (1) and (S)-4-tert-butyl-2-(1,1-dimethylbutyl)-2-oxazoline (2) were synthesized in two steps from the corresponding enantiopure amino alcohols and acid chlorides in a total yield of 95% and 72%, respectively. (S)-2-(1-Adamantyl-1-methylethyl)-4-isobutyl-2-oxazoline (3) was obtained from adamantyl bromide and l-leucinol in five steps in a total yield of 82%. Reactions of oxazolines 1–3 with Pd(OAc)₂ in AcOH or CH₂Cl₂ followed by treatment with LiCl afforded the corresponding μ-Cl dimeric cyclopalladated complexes 15, 17, and 20 in good yield. Compounds 15, 17, and 20 reacted with PPh₃ to furnish the corresponding mononuclear complexes 16, 19, and 21. The ³¹P NMR spectra of trans(N,P) adducts 16, 19, and 21 contained signals of two diastereomers in a ratio of ca. 1.3:1.     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Synthesis, structures and rac/meso isomerization behaviour of bisplanar chiral bis(phosphino-η-indenyl)iron(II) complexes

Syntheses of the phosphinoindenes 1-(diphenylphosphino)-3-methylindene (1b), 3-(diphenylphosphino)-2-methylindene (1c), 1-(diphenylphosphino)-2,3-dimethylindene (1d), 4,7-dimethyl-3-(diphenylphosphino)indene (1e), 1-(diphenylphosphino)-3,4,7-trimethylindene (1f) and 3-(diisopropylphosphino)indene (1i) were carried out by treatment of the appropriate indenide with the appropriate chlorophosphine. The silylphosphinoindene 3-(diphenylphosphino)-1-(trimethylsilyl)indene (1h) was prepared by treatment of the indenide of 3-(diphenylphosphino)indene (1a) with trimethylsilylchloride. These indenes, in addition to 1a, were then used, after deprotonation with BuLi, to prepare the corresponding indenyl ferrocenes, 2a-2e, 2h and 2i, by treatment with ferrous chloride in a 2:1 ratio. These compounds were characterized by ¹H, ¹³C, and ³¹P NMR spectroscopy, as well as by mass spectrometry, except for the highly-sensitive diisopropylphosphine 2i that could only be characterized by ³¹P NMR spectroscopy. All of these ferrocene complexes are bisplanar chiral systems that can potentially form rac and meso isomers. In all cases both isomers were observed but for 2b and 2h only one could be isolated. The rac isomers of complexes 2a, 2b, 2d, and 2e, as well as the meso isomer of 2e, were studied by X-ray crystallography. Only complexes 2a and 2i were observed to undergo rac/meso isomerization processes at ambient temperature in THF solvent. We were unable to prepare the sterically congested hexamethylferrocene 2f. Generally, it was found that increasing substitution on the indenyl ring increases the reactivity and sensitivity of the ferrocene.