A convenient synthesis of di- and trisubstituted 2-aminoimidazoles from 1-amidino-3-trityl-thioureas

Convenient synthesis of 2-amino-1,5-disubstituted and 2-amino-1,4,5-trisubstituted imidazoles has been reported using readily available starting materials and simple reagents under mild conditions. Guanylation of 1-amidino-3-trityl-thioureas 1 and 7 using mercury(II) chloride (Caution) as a thiophile resulted in corresponding guanidines 2 and 8 which on reaction with α-bromo ketones yielded 2-tritylaminoimidazoles. Deprotection of 2-tritylaminoimidazoles using trifluoroacetic acid at room temperature furnished desired 2-aminoimidazoles 4 and 10 in good to moderate yields.     

Organometallic reagent-mediated one-pot synthesis of 3,5,6-trisubstituted naphthostyrils

A one-pot synthesis of 3,5,6-trisubstituted naphthostyrils is described. Addition of organometallic reagents to β-iodovinyl ketone 1 followed by elimination gave the Z-form β-alkyl vinyl ketone 15. Intramolecular cyclization of 15 under the reaction conditions afforded 3,5,6-trisubstituted naphthostyrils 4.     

Preparation of 5-amino-6-oxo-1,6-dihydro[1,2,4]triazine-3-carboxylic acid derivatives and synthesis of compound libraries thereof

Treatment of [1,3,5]triazine-2,4,6-tricarboxylic acid triethyl ester (4) with arylhydrazines provided 5-amino-6-oxo-1,6-dihydro[1,2,4]triazine-3-carboxylic acid ethyl esters 5a-g in moderate to good yields. Hydrolysis under basic conditions gave the corresponding free carboxylic acids 6a-d. Despite the relatively high number of heteroatoms present the amido as-triazine compounds 6a-d showed good solubility in phosphate buffer as determined by a lyophilization solubility assay. Building block 5a served as starting point for the syntheses of two discrete exocyclic 5-amido and 3-amido compound libraries 7 and 8, respectively.     

Stereospecific synthesis of 2,2,3-trisubstituted tetrahydroquinolines: application to the total syntheses of benzastatin E and natural virantmycin

An efficient methodology for the synthesis of 2,2,3-trisubstituted tetrahydroquinolines has been developed, which involves the triphenylphosphine-CCl₄-mediated stereospecific rearrangement of α,α-disubstituted indoline-2-methanols 15 to 2,2,3-trisubstituted tetrahydroquinolines 26. The rearrangement precursors 15 are readily prepared by the diastereoselective Grignard addition to 2-acylindolines 13. The total syntheses of (+)-benzastatin E (1) and natural virantmycin (2a) were accomplished utilizing this methodology. This rearrangement reaction might afford some chemical precedent for the biogenetic pathway of the benzastatin family.     

Selective reactivity of diamino Fischer-type carbene complexes towards 2,6-disubstituted and 2,4,6-trisubstituted pyrylium salts and 2,4,6-trichloro-1,3,5-triazine

The synthesis of new amino Fischer-type carbene complexes 2a-d with amino-containing side chain is presented. The reaction of these complexes with 2,4,6-triarylpyrylium salts gave the corresponding pyridinium salt 4a, 4c-e as expected from the initial attack of the free amino group onto the pyrylium α-carbon. When using the 2,6-diphenylpyrylium salt, a γ-addition of the amino group occurred, leading - after an hydrogen migration and a ring opening step - to the new organometallic unsaturated aminoketone 5. Finally, the reactivity of the diaminocarbene 2b with 2,4,6-trichloro-1,3,5-triazine has been investigated. The new triazine 6 bearing a ferrocenylaminocarbene group was isolated.     

Synthesis and properties of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)-triones

The synthesis and properties of a novel type of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)-triones (13a-c) and (14a-c) are studied. The synthetic procedure is based on addition of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid and subsequent oxidation by o-chloranil. Structural characteristics of 13a-c and 14a-c were clarified on inspection of the ¹³C NMR spectral data and X-ray crystal analysis. Based on the investigation of the UV-vis spectra of 13a-c and 14a-c and their protonated cations, conformational change of the heteroazulene-moiety and the barbituric acid-moiety is suggested. In the CV measurements of 13a-c and 14a-c, two reversible reduction waves are observed, indicating the stabilizing ability of heteroazulenes toward the corresponding radical and anion species. Furthermore, 13a-c and 14a-c exhibit one irreversible oxidation wave and the corresponding reduction wave appearing in a far negative region, which suggested a conformational change in the radical cation during the redox process. The conformational change is rationalized on the basis of the MO calculations.     

Synthesis of novel 1,4,5-trisubstituted 3-trifluoromethylpyrazoles via microwave-assisted Stille coupling reactions

1,5-Disubstituted 3-trifluoromethylpyrazoles were reacted with N-bromosuccinimide in DMF at room temperature or 70-80 °C for 1-2 h to afford the corresponding 4-bromo-substituted pyrazoles 2 in 95-99% yields. The microwave-assisted Stille coupling reactions of 2 with arylstannanes having a substituent on the benzene ring and allylstannane in refluxing CH₃CN in the presence of Pd(PPh₃)₄ provided the corresponding 1,4,5-trisubstituted 3-trifluoromethylpyrazoles 3 in 75-98% yields.     

An expedient route to indoles via a cycloaddition/cyclization sequence from (Z)-1-methoxybut-1-en-3-yne and 2H-pyran-2-ones

The cycloaddition of (Z)-1-methoxybut-1-en-3-yne (2) with 5,6-disubstituted 3-acylamino-2H-pyran-2-ones 1 under microwave-irradiation conditions, with classical heating or at high-pressures (13-15 kbar) affords the benzene derivatives 3 with a strategically positioned 2-methoxyethenyl moiety. In some cases, at high-pressures after long reaction times, 2,2-dimethoxyethyl products 4 were obtained. Adducts 3 and 4 can be cyclized under mild conditions into 1,5,6-trisubstituted indole derivatives 5.     

Anti-AIDS agents 68. The first total synthesis of a unique potent anti-HIV chalcone from genus Desmos

The first total synthesis of a unique highly functionalized and potent anti-HIV chalcone 1, isolated from genus Desmos, was achieved from commercially available 2,4,6-trihydroxytoluene (3) or 2,4,6-trihydroxybenzaldehyde (2) in five (from 3) or six steps (from 2).     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Stereospecific route to enantiopure all cis-2,3,6-trisubstituted piperidines. Facile synthesis of (−)-deoxocassine and (+)-azimic acid

Reduction of the enantiopure β-amino esters 10 provides the γ-amnio alcohol 11, which is condensed with 2,4-pentadione to afford 12. Stepwise cyclization of 12 produced the cyclic enamine 13, which is hydrogenated to deliver all cis-2,3,6-trisubstituted piperidine 14. Using this reaction sequence and subsequent Baeyer-Villiger oxidation as the key step (−)-deoxocassine and (+)-azimic acid are synthesized.     

The case of a Cd2Cu2 complex containing an apparently C3-symmetric ligand: Erroneous ligand-structure assignment by X-ray diffraction data analysis

A simplified synthesis of a previously reported Cd₂Cu₂ complex 4 was developed in order to have a more readily available source of 1,3,5-tris(trifluoromethyl)-cyclohexane-cis,cis-1,3,5-triol 1, a unique tridentate ligand, only tentatively identified elsewhere. Attempts to liberate the ligand from 4 resulted in the sole formation of 2,4,6-tris(trifluoromethyl)-tetrahydropyran-cis,cis-2,4,6-triol (2); no traces of 1 were detected. A newly conducted X-ray analysis of complex 4 led to diffraction data that could be explained either by the previously reported structure for 4 or by the statistically disordered structure 5, containing ligand 2 rather than 1. Whereas refinement of both models led to equivalent merit factors, mass spectral data and elemental analysis of the crystals revealed unequivocally the sole presence of the tetrahydropyran derivative within the complex and proved thus the erroneous structure assignment 4 previously published for compound 5.     

Synthetic studies of 3-(3-fluorooxindol-3-yl)-l-alanine

Oxidative fluorination of several protected tryptophans 8b-g with Selectfluor™ proceeded smoothly in aqueous media to give a diastereomeric mixture of the corresponding 3-fluorooxindoles 9b-g. Attempted deprotection of the 3-fluorooxindoles 9b-g under various conditions did not afford 3-(3-fluorooxindol-3-yl)-l-alanine (6). Reaction of the suitably protected tryptophan derivative 16 with Selectfluor™ produced the fluorinated product 17. Simultaneous cleavage of all protective groups of 17 under acidic conditions successfully gave the target compound 6 in excellent yield.     

Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

An asymmetric synthesis of the 3-substituted Δ^3,4-unsaturated prolines 7a-e and 3-substituted 4-methylene prolines 14a-c starting from the corresponding γ,δ-unsaturated α-amino acids 4a-e and 11a-c, respectively, is described. Amino acid derivatives 4a-e and 11a-d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes 2a-e and 10a-d, respectively, with the N-tert-butylsulfonyl imino ester 3. Activation of sulfoximines 4a-e and 11a-c through methylation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a-e and 12a-c, respectively, to the corresponding allyl aminosulfoxonium salt 6a-e and 13a-c, respectively, and a subsequent intramolecular nucleophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in medium to high yields.     

Synthesis of a proposed 1,3,4-trisubstituted isoquinoline

The isoquinoline ring system is a reoccurring structural motif in alkaloids¹ and pharmaceuticals.² Consequently, the synthesis and functionalization of isoquinolines have attracted considerable attention from the synthetic community.³ We previously reported a facile synthesis of 1,3,4-trisubstituted isoquinolines from commercially available 1,3-dichloroisoquinoline 1 (Scheme 1).⁴ A key step in the process is the direct lithiation of 1 at C4. The resulting lithium species 2 was trapped with a variety of electrophiles to produce 4-substituted-1,3-dichloroisoquinoline 3, which was further elaborated to give1,3,4-trisubstituted isoquinoline 4 by exploiting the different reactivity of C1-Cl and C3-Cl bonds under Pd-catalysis.     

Synthesis and biological evaluation of new 3-trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives as antidiabetic and antimicrobial agents

Fluorinated pyrazoles, and benzenesulfonylurea and thiourea derivatives as well as their cyclic sulfonylthioureas 2-18 were prepared as hypoglycemic and antibacterial agents. The chemistry involves the condensation of 4-hydrazino benzenesulfonamide hydrochloride with 1-trifluoromethyl diketones 1 to give pyrazole derivatives 2 which upon bromination gave the bromopyrazole 3. Reaction of 2 or 3 with isocyanates and isothiocyanates gave the corresponding ureas 4 and 5 and thioureas 6 and 7. Cyclization of thiourea derivatives with ethyl bromoacetate, ethyl β-bromopropionate, 1,3-dichloroacetone and α-bromoacetophenone yielded the corresponding 4-oxothiazolidines 8 and 9, 4-oxo-5,6-dihydrothiazine 10, 5-oxo-4,5-dihydrothiazines 11 and 12 and thiazolines 13 and 14. Preliminary biological screening of the prepared compounds revealed significant antidiabetic and antibacterial activities.     

Synthesis of heterocyclic methylenebisphosphonates by 1,3-dipolar cycloaddition of ethyl diazoacetate to 1,2-benzoxaphosphorin-3-phosphonates

Reaction of salicylaldehydes with tetraethyl ester of methylenebisphosphonic acid, under Knoevenagel reaction conditions, gives the corresponding 1,2-benzoxaphosphorin-3-phosphonates 5 in good yields. The [3+2] regio- and stereoselective cycloaddition of 5a and 5b with ethyl diazoacetate gives two P-4 epimers of the corresponding pyrazoline bisphosphonate tetraethyl esters 9 and 10. Analogously, ethyl diazoacetate reacts with 1 and 2 to give the expected pyrazolines 6-8. The structures of the new compounds are revealed and confirmed by analytical, spectroscopic data and X-ray crystallographic analysis.     

Substituted lithiumtrimethylsiloxysilanides LiSiRR′(OSiMe3) - Investigations of their synthesis, stability and reactivity

The reactions of the trimethylsiloxychlorosilanes (Me₃SiO)RR′SiCl (1a-h: R′ = Ph, 1a: R = H, 1b: R = Me, 1c: R = Et, 1d: R = ⁱPr, 1e: R = ^tBu, 1f: R = Ph, 1g: R = 2,4,6-Me₃C₆H₂ (Mes), 1h: R = 2,4,6-(Me₂CH)₃C₆H₂ (Tip); 1i: R = R′ = Mes) with lithium metal in tetrahydrofuran (THF) at −78 °C and in a mixture of THF/diethyl ether/n-pentane in a volume ratio 4:1:1 at −110 °C lead to mixtures of numerous compounds. Dependent on the substituents silyllithium derivatives (Me₃SiO)RR′SiLi (2b-i), Me₃SiO(RR′Si)₂Li (3a-g), Me₃SiRR′SiLi (4a-h), (LiO)RR′SiLi (12e, 12g-i), trisiloxanes (Me₃SiO)₂SiRR′ (5a-i) and trimethylsiloxydisilanes (6f^∗, 6h^∗, 6i^∗) are formed. All silyllithium compounds were trapped with Me₃SiCl or HMe₂SiCl resulting in the following products: (Me₃SiO)RR′SiSiMe₂R″ (6b-i: R″ = Me, 7c-i: R″ = H), Me₃SiO(RR′Si)₂SiMe₂R″ (8a-g: R″ = Me, 9a-g: R″ = H), Me₃SiRR′SiSiMe₂R″ (10a-h: R″ = Me, 11a-h: R″ = H) and (HMe₂SiO)RR′SiSiMe₂H (13e, 13g-i). The stability of trimethylsiloxysilyllithiums 2 depends on the substituents and on the temperature. (Me₃SiO)Mes₂SiLi (2i) is the most stable compound due to the high steric shielding of the silicon centre. The trimethylsiloxysilyllithiums 2a-g undergo partially self-condensation to afford the corresponding trimethylsiloxydisilanyllithiums Me₃SiO(RR′Si)₂Li (3a-g). (Me₃)Si-O bond cleavage was observed for 2e and 2g-i. The relatively stable trimethylsiloxysilyllithiums 2f, 2g and 2i react with n-butyllithium under nucleophilic butylation to give the n-butyl-substituted silyllithiums ⁿBuRR′SiLi (15g, 15f, 15i), which were trapped with Me₃SiCl. By reaction of 2g and 2i with 2,3-dimethylbuta-1,3-diene the corresponding 1,1-diarylsilacyclopentenes 17g and 17i are obtained.X-ray studies of 17g revealed a folded silacyclopentene ring with the silicon atom located 0.5 Å above the mean plane formed by the four carbon ring atoms.     

Unique sodium dithionite initiated coupling of CF3CHClBr with 1,3,5-trimethoxybenzene: Synthesis and structure of trifluoromethyl-bis(2,4,6-trimethoxyphenyl)methane

Sodium dithionite initiated reaction of 1-bromo-1-chloro-2,2,2-trifluoroethane with 1,3,5-trimethoxy-benzene (1) in an acetonitrile-water mixture gives trifluoromethyl-bis(2,4,6-trimethoxyphenyl)methane (2) as the only isolable product in over 32% yield. The structure of compound 2 was evidenced by spectral methods and X-ray crystal analysis.     

Synthesis, electrochemical behavior and magnetic properties of polyradicals of the TTM series

Condensation reactions between (4-amino-2,6-dichlorophenyl)bis(2,4,6-trichlorophenyl)methyl radical and a new hexafunctionalized radical of the TTM series, tris(3,5-dichloroformil-2,4,6-trichlorophenyl)methyl radical or its corresponding diamagnetic precursor 6 yield macromolecular heptaradical 3 and hexaradical 4, respectively, with high magnetic purity. Both solid polyradicals show stability in nitrogen at temperatures up to 300 °C and in solution their electronic absorptivities do not decrease appreciably for weeks. EPR studies of both polyradicals in solution suggest that unpaired electrons are exchange coupled, and at low temperatures they show weak dipolar spin-spin couplings. Their electrochemical behavior was analyzed by cyclic voltammetry and differential pulse voltammetry. Heptaradical 3 is reduced in seven-electron two-stage processes, and oxidized in seven-electron one-stage process.