Electron-transfer-catalyzed rearrangement of unsymmetrically substituted diiron dithiolate complexes related to the active site of the [FeFe]-hydrogenases

Novel asymmetrically substituted azadithiolate compounds [Fe2(CO)4(kappa2-dppe){micro-SCH2N(R)CH2S}] (R=iPr, 1a; CH2CH2OCH3, 1b; CH2C6H5, 1c) have been synthesized by treatment of [Fe2(CO)6(micro-adt)] [adt=SCH2N(R)CH2S, with R=iPr, CH2CH2OCH3, CH2C6H5] with dppe (dppe=Ph2PCH2CH2PPh2) in refluxing toluene in the presence of Me3NO. 1a-c have been characterized by single-crystal X-ray diffraction analyses. The electrochemical investigation of 1a-c and of [Fe2(CO)4(kappa2-dppe)(micro-pdt)] (1d) [pdt=S(CH2)3S] in MeCN- and THF-[NBu4][PF6] has demonstrated that the electrochemical reduction of 1a-d gives rise to an Electron-transfer-catalyzed (ETC) isomerization to the symmetrical isomers 2a-d where the dppe ligand bridges the iron centers. Compounds 2a-d were characterized by IR and NMR spectroscopy, elemental analysis, and X-ray crystallography for 2a.     

Deoxysugars via microbial reduction of 5-acyl-isoxazolines: application to the synthesis of 3-deoxy-D-fructose and derivatives

5-Acylisoxazolines 3a-d were obtained by 1,3-dipolar cycloaddition from acetoxymethyl vinyl ketone and nitro precursors. Compounds 3a-d were biotransformed by Aspergillus niger into a 1:1 mixture of stereomers of 5-dihydroxyethyl isoxazolines (+)-4a-d (anti) and (-)-5a-d (syn). Both stereomers were obtained in good yields and with high optical purities. Carbonyl reduction by Aspergillus niger produces alcohols of R-configuration thus giving an access to D-sugar analogues: Compound (+)-4d was converted to 3-deoxy-D-erythro-hexulose and several protected derivatives. Total synthesis of 3-deoxy-D-fructose-6-phosphate was also achieved in two steps and 64% overall yield from (+)-4d.     

Bis(phosphine imide)s: easily tunable organic electron donors

[graph: see text] The electrochemical, structural, and spectroscopic properties of bis(phosphine imide)s have been investigated. p-Phenylenebis(phosphine imide)s Ar3PNC6H4NPAr3 (1a-d) have two reversible single-electron oxidations. The first oxidation potentials can be varied from -0.05 to 0.15 V (versus SCE) by modification of the substituents on phosphorus (Ar). Electron-donating substituents lower the oxidation potential, while electron-withdrawing substituents increase the oxidation potential. The difference between the first and second oxidation potential (deltaE, 0.41-0.50) and the electronic coupling (Hab, 1.1 eV) are similar for 1a-d. Computational (DFT) and UV-visible-NIR spectroscopic investigations of 1a-d suggest that the first oxidation leads to a delocalized radical cation 1a*+ while the second oxidation leads to a quinonoidal dicationic state 1a2+. The aromatic linker between phosphine imides has also been modified. Upon oxidation, N,N'-4,4'-biphenylene(bis(triphenyl)phosphine imide) (3) forms radical cationic and a dicationic species similar to 1a-d. While deltaE (0.18 V) and Hab (0.63 eV) are smaller, suggesting weaker electronic communication between the two P=N units in the radical cationic state, the presence of NIR absorptions with vibrational fine structure (768, 861, and 983 nm) supports the formation of delocalized radical cation for 3*+.     

Photolysis of acetyl esters of 2,2′-dinitrodiphenyl-carbinols in protic and aprotic solvents

Irradiation ofacetyl esters of 2,2′-dinitrodiphenyl-carbinols (1a-d) in aprotic medium like 2-propanol yielded dibenzol [c,f]-[1,2]diazepin-11-one-5-oxides (5a-d) as the major product. Dibenzoi[c,f]-[1,2]diazepin-11-one (2a-d), 2,2′-dinitrobenzophenones (3a-d), 2-amino-2′-nitrobenzophenones (4a-d), and N-hydroxyacridones (6a-d) were also formed in varying amounts. Irradiation of 1a-d in an aprotic medium like benzene yielded the above products along with benzisoxazoles (7a-d) also. When triethylamine was used as the solvent the major product obtained was N-hydroxyacridones (6a-d). Plausible mechanisms for the formation of the products are discussed     

Molecular design of a new class of spin-labeled ribonucleosides with N-tert-butylaminoxyl radicals

We designed a new type of spin-labeled nucleosides with an N-tert-butylaminoxyl radical which is introduced to the nucleobase directly. Purine and pyrimidine ribonucleosides containing the aminoxyl radical such as 1a-d, 2, 3, and 4 were synthesized to investigate the stability and behavior of the N-tert-butylaminoxyl radical on a nucleobase. Lithiation of tri-O-silylated 6-chloropurine ribonucleoside (5) followed by reaction with 2-methyl-2-nitrosopropane (MNP) gave the key compound 6a, which was further converted to 6b-d. Oxidation of the obtained 6a-d and their triols (7a-d) with Ag(2)O led to formation of the corresponding stable spin-labeled nucleosides (8a-d and 1a-d), which were confirmed by EPR spectroscopy. Similarly, the precursors of spin-labeled pyrimidines (13, 20, and 23) were synthesized by site-selective lithiation of tri-O-protected pyrimidine derivatives (9, 18, and 21) followed by the reaction with MNP and deprotection. An EPR study showed that the aminoxyl radicals (2, 3, and 4) were stable and that their hyperfine structures were dependent on the position of the radical. Electron densities of pyrimidine also affected hyperfine structures.     

Synthesis of 6-arylazo-substituted 5-hydroxy-2-hydroxymethyl-4-pyridones and related compounds

5-Hydroxy-2-hydroxymethyl-4-pyridone ( 1 ) and 5-hydroxy-2-hydroxymethyl-1-methyl-4-pyridone ( 2 ) reacted with arenediazonium salts to give 6-arylazo-substituted compounds 3a-d and 4a-d , respectively. Compounds 3a-d were methylated with diazomethane to afford 6-arylazo-2-hydroxymethyl-4,5-dimethoxypyridines 5a-d .     

Synthesis and properties of a fluorene-capped isotruxene: a new unsymmetrical star-shaped pi-system

An unsymmetrical star-shaped pi-system (1) with an isotruxene core and three fluorene arms has been synthesized, and its photophysical, electrochemical, and thermochemical properties have been investigated and compared with the corresponding symmetrical truxene derivatives 2a-d (Kanibolotsky, A. L.; Berridge, R.; Skabara, P. J.; Perepichka, I. F.; Bradley, D. D. C.; Koeberg, M. J. Am. Chem. Soc. 2004, 126, 13695-13702). Stronger electronic couplings between the arms in 1 vs 2a-d lead to lower optical band gap, larger splitting in oxidation potentials, and superior thermostability. [structure: see text]     

Diels-Alder reactions of 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone. An expedient methodology for the synthesis of bicyclo[2.2.2]oct-5-en-2-ones and bicyclo[2.2.2]octa-5,7-dien-2-ones

The synthesis of 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienone (13), bicyclo[2.2.2]octenones 1a-j and 15a-j, and bicyclo[2.2.2]octadienones 2a-f, 6a-d, and 11a-f is described. The 2,4-cyclohexadienones 4 and 13 were used for the first time as nondimerizing and easily accessible alternatives to 2,6,6-trimethyl-2,4-cyclohexadienone 12 in Diels-Alder reactions with acetylene derivatives 5a-d to prepare the adducts 6a-d and 11a-e in excellent yields. Compounds 11a-d were initially prepared by the alcoholysis of 6a-d to afford bicyclo[2.2.2]octene-2,5-diones 7a-dfollowed by treatment of 7a-d with N-phenyltriflimide in the presence of LHMDS at -78 degrees C. Diels-Alder reaction of 13 with an acetylene equivalent, phenyl vinyl sulfoxide, was also studied. A detailed study of the Diels-Alder reactions of various olefinic dienophiles 14a-j with 13 has been carried out to furnish cycloadducts 15a-j in high yields. Reductive removal of triflyloxy group of vinyl triflates 11a-f and 15a-j was performed in the presence of [Pd(PPh(3))(2)Cl(2)-Bu(3)N-HCO(2)H] to obtain the desired bicyclo[2.2.2]octadienones 2a-f and bicyclo[2.2.2]octenones 1a-j, respectively, in good overall yields.     

Synthesis and Reactions of Some New Heterocyclic Compounds Containing Cycloalka[e]thieno[2,3‐b]pyridine Moiety

Hydrolysis of ethyl 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxylates ( 3a-d) gave the corresponding o-aminocarboxylic acids 4a-d . Heating the latter compounds ( 4a-d) with acetic anhydride furnished the oxazinone derivatives 5a-d which, in turn, underwent recyclization reaction to give the corresponding pyrimidinones 6a-d upon treatment with ammonium acetate in acetic acid. Reaction of 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides ( 3f,h ) with triethyl orthoformate gave pyrimidinone derivatives 7a,b . Reaction of 3-amino-4-phenyl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides 3e,h with aromatic aldehydes furnished tetrahydropyridothienopyrimidinones 8a-d . Chlorination of 7a,b and 6a-d by using phosphorous oxychloride produced 4-chlorocycloalka[5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives 9a-f which were used as key intermediates in the synthesis of several new cycloalkapyrido-thienopyrimidines 10a-f ˜ 14a-f . Moreover, some cycloalkapyridothienotriazinones 15a,b-17a,b were synthesized.     

Intramolecular Diels-Alder reactions of brominated masked o-benzoquinones. A detour method to synthesize highly functionalized oxatricyclic [m.3.1.0] ring systems from 2-methoxyphenols

Intramolecular Diels-Alder (IMDA) reactions of masked o-benzoquinones (MOBs) 5a-d to 7a-d and 17a-d to 19a-d generated in situ from 2-methoxyphenols 2-4 and 14-16, respectively, in the presence of alkenols 1a-d, resulting in highly functionalized oxatricyclic [m.3.1.0] ring systems are described. The MOBs 5a-d to 7a-d underwent the IMDA reactions to furnish the adducts 8a-d, 10a-d, and 12a-d (direct method) in poor yields with the concomitant formation of considerable amounts of unexpected byproducts 9a-d, 11a-d, and 13a-d, respectively. To avoid the formation of byproducts and to improve the yields of the desired cycloadducts, a detour method comprising sequential bromination of 2-methoxyphenols 2-4, tandem oxidative acetalization-Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 14-16 in the presence of alkenols 1a-d produced the corresponding MOBs 17a-d to 19a-d, which underwent cycloaddition to afford the cycloadducts 20a-d to 22a-d, respectively, as sole products in good to high yields in a highly regio- and stereoselective manner. Treatment of the bromoadducts 20a-d to 22a-d with tributylammonium formate-palladium reagent produced the corresponding debrominated products 8a-d, 10a-d, and 12a-d in high to excellent yields. In general, the latter oxatricycles were obtained in higher overall yields via the detour method than those via the direct method.     

Solid phase synthesis and application of trisubstituted thioureas

Resin-bound amines 1a-e condense with isothiocyanates to give thiourea resins 2a-i. Resins 2a-g subsequently react with iodomethane followed by cleavage affording S-methyl isothioureas 4a-g, and resins 2a-b,h-i react with acyl chlorides to afford N-acylated thioureas 6a-d. N-Acylthioureas 8a-f (R(2) = H) were prepared directly from resin-bound amines 1a-d with acyl isothiocyanates. N-Acylthioureas 8a-d,f(R(2) = H) were used for the preparation of S-methyl-N-acylisothioureas 10a-e. Alkylation was performed using methyl iodide. Resin-bound S-methyl-N-acylisothioureas 10a,b,d are converted by an action of hydrazines into 3-amino-1,2,4-triazoles 13a-d. Condensation of resins 8a-e (R(2) = H) with 2-bromoacetophenones in the presence of TEA affords thiazoles 15 a-e. All transformations proceeded in high yields and gave products of good purities.     

Synthese von 4-halogensubstituierten Analogen von Trimethoprim

The Synthesis of 4-Halogen-substituted Analogs of Trimethoprim The four 2,4-diamino-5-(4-halo-3,5-dimethoxybenzyl)pyrimidines 20a-d have been synthesized along known routes, i.e. form the corresponding aldehydes 17a-d via the aminomethylidene-derivatives 18a-d and 19a-d , respectively (Scheme 4). All four aldehydes were prepared from a common intermediate, methyl 4-amino-3,5-dimethoxybenzoate ( 3 ), which was obtained from dimethyl 2,6-dimethoxyterephthalate ( 2 ) and hydroxylamine in a regioselective Lossen-type rearrangement mediated by polyphosphoric acid (Scheme 1). Under identical rearrangement conditions 2,6-diethoxyterephthalate ( 12 ) led, in addition to the amine 14 , to the benzoxazolone 15 (Scheme 2). Scope and mechanism of this reaction are discussed. - The antimicrobial activity of the diamino-pyrimidines 20a-d , expressed as the inhibition of E. coli-dihydrofolate reductase, has been measured and compared with that of trimethoprim ( 1 ), an established antimicrobial agent.     

Peri- and enantioselectivity of thermal, scandium-, and [pybox/scandium]-catalyzed Diels-Alder and hetero-Diels-Alder reactions of methyl (E)-2-oxo-4-aryl-butenoates with cyclopentadiene

The cycloaddition between methyl (E)-2-oxo-4-aryl-3-butenoates (2 a-d) and cyclopentadiene, in addition to the expected normal Diels-Alder (DA) adducts endo-3 a-d and exo-4 a-d, gives the less expected endo-5 a-d products of the [4+2] hetero-Diels-Alder (HDA) reaction in which the alpha-ketoester behaves as a heterodiene. If a comparison is made between the thermal and the scandium(III) triflate-catalyzed conditions, the periselectivity changes and whereas under thermal conditions the main products are those from the DA reaction (3 a-d), in the presence of Sc(OTf)3 (OTf=triflate), the HDA products 5 a-d become largely predominant. The reactions are enantioselectively catalyzed by the scandium(III) triflate complex of (4'S,5'S)-2,6-bis[4'-(triisopropylsilyl)oxymethyl-5'-phenyl-1',3'-oxazolin-2'-yl]pyridine (1) and both the DA and the HDA products are obtained with excellent enantiomeric excess, up to >99% ee. The X-ray crystallographic structure determination of 5 c assigns it the 4R,4aS,7aR absolute configuration. The thermal retro-Claisen rearrangement of 3 c into (4R,4aS,7aR)-5 c allows the correlation of their absolute configuration, and 3 c has therefore the 2R,3R configuration. By analogy the same absolute configuration can be assigned to 3 a,b,d and 5 a,b,d, and the stereospecific thermal Claisen rearrangement of the optically active 5 a,b,d into 3 a,b,d completes the correlation between their absolute configuration. The [3,3]-sigmatropic rearrangements can be easily carried out under catalytic conditions with scandium(III) triflate, which promotes the equilibration between 3 a-d and 5 a-d, with a different degree of enantioselectivity characterizing the process starting from 3 a-d or 5 a-d. The unambiguous attributions of the configuration to the products allows us to propose a rationale of the stereochemical outcome of the catalyzed cycloaddition and to investigate the reaction mechanism of the competing DA and HDA reactions and shifts in products distribution by acid catalysis.     

A New Synthesis of 4, 4-Diaryl/Diheteroaryl-3-butenyl Derivatives of Nipecotic Acids as GABA Transporter Inhibitors

A new method for the synthesis of 4, 4-diaryl/diheteroaryl-3-butenyl derivatives of nipecotic acid as GABA transporter inhibitors is described. The key intermediates 4-tosyl-1, 1-diaryl/diheteroaryl-1-butene 10a-d were synthesized by Wittig reaction, and followed by alkylation with （R）-3-piperidinecarboxylate. The resulting N-cycloalkylated amino acid esters 11a-d were saponified and then acidified to get the target compounds 1a-d. The preliminary bioassays showed that la-d exhibited excellent inhibition of [3H]-GABA uptake in vitro of culture cells.     

A convergent synthesis of Hexahomotriazacalix

A new, convergent synthesis of hexahomotriazacalix[3]arenes 1a-e is described. The key transformation in this synthesis involves the coupling of the triamines 4a-d with 2, 6-bis(chloromethyl)-4-methylphenol 5 and results in the formation of the hexahomotriazacalix[3]arenes 1a-d in 90-95% yield. The triamines 4a-d were constructed by the one-pot reaction of monochloroaldehyde 3 and a primary amine followed by reduction to yield the triamines 4a-d in 50-55% yield. Deallylation of macrocycle 1d was accomplished by palladium catalysis to obtain the N-unsubstituted macrocycle 1e, which has the potential to be a precursor to a variety of N-substituted hexahomotriazacalix[3]arenes.     

Preparation and antimicrobial studies of acyclic sulfamates.

A series of acyclic sulfamates have been prepared and tested for antimicrobial activity. Thus, the oxysulfonyl isocyanates, ROSO2NCO (1a, R = 4-methoxyphenyl; 1b, R = phenyl; 1c, R = 4-chlorophenyl and 1d, R = 2,2,2-trifluoroethyl) have been prepared in 76-91% yield from chlorosulfonyl isocyanate. Treatment of 1a-d with glycidol gave the glycidyl carbamates 2a d. Internal cyclisation afforded the corresponding 4-hydroxymethyl-2-oxazolidinones 3a-d, which in turn were hydrolysed to give the free amino alcohols 4a-d. The yields were in the range 39-85%. A preliminary agar diffusion test of 2a-d, 3a-d, 4a-d indicated 2a-d and 3c to be possible antimicrobial agents. A more thorough analysis of these compounds revealed a minimum inhibition concentration (MIC) of 128 and 64 mg l-1 for glycidyl p-methoxyphenoxysulfonylcarbamate (2a) and glycidyl phenoxysulfonylcarbamate (2b) respectively, against Branhamella catarrhalis.     

Chiral ligands derived from Abrine 8. An experimental and theoretical study of free ligand conformational preferences and the addition of diethylzinc to benzaldehyde

Three structurally similar series of 1,2,3,4-tetrahydro-beta-carboline ligands, 4a-d, 6a-d and 7a-d, and two series of chiral oxazolidines, 8a-d and 9a-g, were synthesized and used as chiral catalysts in the addition of diethylzinc to benzaldehyde. The enantioselectivities of the resulting 1-phenyl-1-propanol were obtained in each case, and these ee values were, in most cases, related to the conformational populations of the free ligand as expressed by the calculated differences in the energies of the ligand conformations formed by inversion at nitrogen. This suggested the possible existence of a linear free energy relationship. The effect on enantioselectivity of the carbon chain length of the R group located (1) on the C-3 substituent of 4a-d, 6a-d, and 7a-d or (2) at C-5 in 8a-d and 9a-g was studied in detail. On the basis of the correlations observed and the ligands' structural characterization, a structure was proposed for the transition state during ethyl group transfer when using ligands 8a-d. Furthermore, the change in enantioselectivity was successfully predicted when diastereomeric ligands 11 and 12 were compared in this chiral addition.     

Synthesis of new visnagen and khellin furochromone pyrimidine derivatives and their anti-inflammatory and analgesic activity

6-[(4-Methoxy/4,9-dimethoxy)-7-methylfurochromen-5-ylideneamino]-2-thioxo-2,3-dihydropyrimidin-4-ones 1a,b were prepared by reaction of 6-amino-2-thiouracil with visnagen or khellin, respectively. Reaction of 1a,b with methyl iodide afforded furochromenylideneaminomethylsulfanylpyrimidin-4-ones 2a,b. Compounds 2a,b were reacted with secondary aliphatic amines to give the corresponding furochromen-ylideneamino-2-substituted pyrimidin-4-ones 3a-d. Reaction of 3a-d with phosphorus oxychloride yielded 6-chlorofurochromenylidenepyrimidinamines 4a-d, which were reacted with secondary amines to afford furochromenylideneamino-2,6-disubstituted pyrimidin-4-ones 5a-d. In addition, reaction of 5a-d with 3-chloropentane-2,4-dione gave 3-chloro-furochromenylpyrimidopyrimidines 6a-d. The latter were reacted with piperazine and morpholine to give 1-(furochromenyl)-pyrimidopyrimidine-3,6,8-triylpiperazines or -3,6,8-triylmorpholines 7a-d. The chemical structures of the newly synthesized compound ware characterized by IR, 1H-NMR, 13C-NMR and mass spectral analysis. These compounds were also screened for their analgesic and anti-inflammatory activities. Some of them, particularly 3-7, exhibited promising activities.     

Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives

A novel strategy for the synthesis of (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (1a-d) via (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), starting from alendronate has been developed with reasonable 51-77% overall yields. Intermediate products, (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), were prepared in water with reasonable to high yields (52-94%).     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.