The first entry to 5,6-dihydroxy-3-mercaptoindole, 5-hydroxy-3-mercaptoindole and their 2-carbomethoxy derivatives by a mild thiocyanation/reduction methodology

The hitherto unknown 5,6-dihydroxy-3-mercaptoindole (4a) and its 2-carbomethoxy derivative (4b), as well as the analogous 5-hydroxy 3-mercaptoindoles, have been conveniently obtained as O,S-acetyl derivatives 3a-d by thiocyanation of the corresponding acetoxyindoles 1a-d with the NH₄SCN/oxone system followed by SmI₂ reduction and acetylation.     

Intramolecular Heck reaction strategy for the synthesis of functionalised tetrahydroanthracenes: a facile formal total synthesis of the linear abietane diterpene, umbrosone

Rapid annulation employing an intramolecular Heck reaction yielded the functionalised 1,1,10-trimethyl-6-methoxy-1,2,3,4-tetrahydroanthracene 4a, a key intermediate for the linear diterpenoid quinone umbrosone (1), and the related compounds 4b-d. A similar strategy was also successfully adopted for the synthesis of the 9-methyl tetrahydroanthracene ester 5 and the tetrahydrodibenzo[a,d]cycloheptene ester 6.     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

Design,synthesis and screening of some novel benzoxazole based 1,3,4-oxadiazoles as potential antimicrobial agents

A series of novel 2-(5-substituted-[1,3,4]oxadiazol-2-yl)-benzoxazoles (7a–h) were synthesized in good yields in two different directions by involving benzoxazole-2-carboxylic acid (1) as raw material and benzoxazole-2-carbonyl chloride (2), benzoxazole-2-carboxylic acid methyl ester (3), benzoxazole-2-carboxylic acid hydrazide (4), benzoxazole-2-carboxylic acid N′-acetyl hydrazide (5a–d) and benzoxazole-2-carboxylic acid-ethylidene-hydrazides (6a–d) as reactive intermediates. The chemical structures of all the synthesized compounds were elucidated by their IR, ¹H NMR and ¹³C NMR and mass spectral data. Further, the target compounds were screened for their antimicrobial activity against various Gram-positive and Gram-negative bacteria.     

Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

Novel generation and cycloaddition reactivity of N-phenylsulfonylbenzonitrilimine via thermal decomposition of N-(phenylsulfonyl)benzohydrazonoyl chloride

Thermal decomposition of N(phenylsulfonyl)-benzohydrazonoyl chloride (1) in refluxing toluene generated N-phenylsulfonylbenzonitrilimine (2) which gave 1,3-dipolar cycloadducts with ethyl (4a) and methyl acrylate (4b), acrylonitrile (4c), styrene (4d), norbornene (4e), and norbornadiene (4f). The reactions with 4a–d, 2 afforded regiospecifically 5-R substituted pyrazolines 5a–d in lower yields. The raction of 2 with 4e gave only exo adduct 5e, while the reaction with 4f gave both exo- (5f_x) and endo adducts (5f_n) as well as their retro-Diels-Alder product 6.     

Unconventional nucleotide analogues—XVIII: Ring expansion of uridine halocarbene adducts. Synthesis of diazepine nucleosides

The diastereomeric adducts of dichlorocarbene and dibromocarbene with (protected) uridine react with alcohols to give diazepine nucleosides (4a–c). The endo-chloro-exo-fluorocarbene adducts (1d and 2d) also react analogously to yield diazepine nucleoside 4d. On the other hand, the corresponding exo-chloro-endo-fluoro isomers (1e and 2e) are totally inert under the same reaction conditions. The adducts 1b and 2b yield, besides the ring-expanded product (4b), uridine-5-aldehyde (6a) in varying amounts which depend upon the conformation of the diastereomer. These results are explained on the basis of a possible role of the ring-oxygen of the ribose moiety.     

Amidoalkylation of mercaptans with glyoxylic acid derivatives

The synthesis of α-alkyl mercaptohippuric acid (3a–d), N-benzyloxycarbonyl-α-methylthioglycine (3e) and their methyl esters (5a–d) by the amido-alkylation of mercaptans with α-hydroxyhippuric acid (2a), α-hydroxy-N-benzyloxycarbonylglycine (2b) and their methoxymethyl ester derivatives 4a and 4b is described. Oxidation with m-chloroperbenzoic acid afforded the corresponding sulfoxides and sulfones and treatment with N-bromosuccinimide in methanol or chlorine in carbon tetrachloride solution exchanged the sulfur containing side chain for a methoxy or a chloro group respectively. (4a, 8).     

Phosphorus-nitrogen compounds part 22. Syntheses, structural investigations, biological activities and DNA interactions of new mono and bis (4-fluorobenzyl) spirocyclophosphazenes

The reactions of hexachlorocyclotriphosphazene, N₃P₃Cl₆, with mono (1 and 2) and bis(4-fluorobenzyl) diamines (3-5), FPhCH₂NH(CH₂)_nNHR (RH or FPhCH₂-), produce mono (1a and 2a) and bis(4-fluorobenzyl) monospirocyclophosphazenes (3a-5a). The tetraaminomonospirocyclophosphazenes (1b-2d) are obtained from the reactions of the partly substituted phosphazenes (1a and 2a) with excess pyrrolidine, morpholine and 1,4-dioxa-8-azaspiro[4,5]decane (DASD), respectively. The tetrachlorobis(4-fluorobenzyl) monospirocyclophosphazenes (4a and 5a) with excess pyrrolidine, morpholine and DASD afford the fully substituted bis(4-fluorobenzyl) monospirocyclophosphazenes (4b, 4d-5d) in boiling THF. In addition, monochlorobis(4-fluorobenzyl) monospirocyclophosphazenes (4e and 4f) have also been isolated from the reactions with excess morpholine and DASD in boiling THF. The structural investigations of the compounds have been verified by elemental analyses, MS, FTIR, ¹H, ¹³C, ¹⁹F (for 1d and 2d), ³¹P NMR, HSQC and HMBC techniques. The crystal structures of 3a, 4a, 5a and 2b have been determined by X-ray crystallography. The compounds 2a-5a, 1b-2d, 4b, 4d-5d, 4e and 4f have been screened for antibacterial effects on bacteria and for antifungal activity against yeast strains. The compounds 1b and 4b showed antimicrobial activity against three species of bacteria, Bacillus subtilis, Bacillus cereus and Staphylococcus aureus, and two fungi, Candida albicans and Candida tropicalis. Minimum inhibitory concentrations (MIC) were determined for 1b and 4b. The MIC values were found to be 5000 μM for each bacteria. The most effective compound, 4b has exhibited activity with a MIC of 312 μM for C. albicans and 625 μM for C. tropicalis. DNA-binding and the nature of the interaction with pBR322 plasmid DNA are studied. All of the compounds induce changes on the DNA mobility and intensity. Prevention of HindIII digestion with the compounds indicates that the compounds bind with AT nucleotides in DNA.     

Synthesis, characterization, and derivatization of some novel types of fluorinated mono- and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities

A series of thirty eight novel imidazolidineiminothiones (6a-g, 10a-h, 13a,b, 15a-d, and 16a), 5-thioxoimidazolidine-2,4-diones (7a-d, 11a-e, 14a,b, and 16b), and bis-imidazolidineiminothiones (17-20) with various fluorinated aromatic substituents at N-(1) and N-(3) were prepared in 75-85% yields. The imidazolidineiminothiones were synthesized from fluorinated N-arylcyanothioformanilides and substituted aromatic isocyanates, and by the reactions of fluorinated aromatic isocyanates with fluorinated and non-fluorinated aromatic N-arylcyanothioformanilides. Subsequent hydrolysis of selected products produced the corresponding 5-thioxoimidazolidine-2,4-diones. Preliminary screening of several compounds against Ehrlich ascites carcinoma (EAC) cells indicated that 6f and 16a were the most active (90% and 80% inhibition, respectively). Further evaluation for cytotoxicity against other tumor cell lines gave IC₅₀ values ranging from 0.67 to 3.83 μg/mL, where compounds 15a and 16a were markedly active against all cell lines. This highlights the synergistic effect of the suitably positioned fluorinated substituents on N-(1) and N-(3) of the imidazolidineiminothiones. Compounds 6a,e-g, 10a-c, 13b, 15a-d, and 17-20 were tested against microbial organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Sarcina lutea), and fungal strains (Candida albicans, Aspergillus niger, and Aspergillus flavus). Whereas compound 6a exhibited the highest antibacterial activity against Gram positive and Gram negative bacteria, 13b displayed the strongest antifungal activity against all fungal strains, reaching as high as 30 mm. Finally, 15a,b,d were subjected to in vitro testing of antiviral activity against hepatitis A virus (HAV), human herpes simplex virus 1 (HSV1), and Coxsackie B4 (COxB4) viral strain, where 15b was the most effective, reducing virus plaque count of HSV1 and COxB4 by 50% and 60%, respectively.     

Photochemistry—xiii: The photokomerization of pyridazine 1 ,2-dioxides: formation of 3a,6a-dihydroisoxazolo[5,4-d]isoxazole

Products, generated from a photolysis of 1,2-dioxides (1) of unsubstituted (a), 3-Me-(b), 4-Me-(c), 3,6-diMe (d), 3-Ph-(e), 3-Me-6-Ph-(f) and 3,6-diPh-(g) pyridazines, have been investigated.Dioxides (1a–g) afforded 3a,6a-dihydroisoxazolo[5,4-d]isoxazoles (2a-g). Dioxides (1e and 1g) afforded 3-phenylisoxazole(7) besides 2. The structure of 2a was examined by X-ray crystallography.The compound 2d was also obtained by oxidation of the hexa-3-ene-2,5-dione dioxime. A mechanism generating those products has been speculated.     

Total synthesis of monocyclic β-lactam antibiotics,nocardicin A and D

The total synthesis of monocyclic β-lactam antibiotics, nocardicins A (1a) and D (1d), is described. 3-Aminonocardicinic acid (3-ANA, 2) was synthesized from p-hydroxyphenylglycine via an acid chloride-imine cyloaddition reaction. The side chain amino acid 13 was prepared via a key step of condensation of p-hydroxyacetophenone and α-phthalimidobutyrolactone. Acylation of 3-ANA with 13 gave nocardicin D, from which nocardicin A was obtained by oximation.     

Efficient, recoverable, copper-catalyzed aerobic oxidation of alcohols under FBS and thermomorphic mode

A series of fluorinated bipyridine derivatives, (4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy) {R_f = n-C₈F₁₇ (1a), n-C₉F₁₉ (1b), n-C₁₀F₂₁ (1c), n-C₁₁F₂₃ (1d)} have been successfully synthesized using 4,4′-bis(bromomethylene)-2,2′-bpy and fluorinated alkoxides. Bpy 1a-d have been characterized by multi-nuclei (¹H, ¹⁹F, and ¹³C) NMR, GC/MS and FTIR. The Cu complexes 2a-d could be generated in situ by stirring ligands 1a-d with CuBr·Me₂S at room temperature, respectively. The 3-component systems 3c-d, CuBr·Me₂S/Bpy (1c-d)/2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), were successfully used to the aerobic oxidation of alcohols under the fluorous biphasic system (FBS). The resulting products from FBS could be easily recovered by two phase separation with high yields up to 8 runs (>90%). In order to avoid using the expensive fluorous solvents, systems 3a-d, CuBr·Me₂S/Bpy (1a-d)/TEMPO, were also successfully shown to catalyze the aerobic alcohol oxidation under the thermomorphic condition (in C₆H₅Cl), and the yields of oxidation of 4-nitrobenzyl alcohol were close to 100% even after 8 runs. In particular, 3a was most effective under the thermomorphic mode in the chemoselectivity of aerobic oxidation of aliphatic primary alcohols to aldehydes without any overoxidized acids.     

An efficient synthesis of enantiomerically pure 2-[(2R)-arylmorpholin-2-yl]ethanols,key intermediates of tachykinin receptor antagonist

We report herein an efficient and practical synthetic method for the preparation of enantiomerically pure 2-[(2R)-arylmorpholin-2-yl]ethanols 1a–d, key intermediates of tachykinin receptor antagonist. Sharpless catalytic asymmetric dihydroxylation of 4a–d was employed to introduce the required absolute stereochemistry, and cyclization of 7a–d was accomplished by the Mitsunobu reaction.     

Autoxidation of terpenic aldehydes—I

The autoxidation reaction of diterpenic 4-axial-aldehyde torulosal (1b) has been studied. Naturally occurring 4-hydroxy-nor-diterpenes have been proved to be artefacts arising in the autoxidation of the corresponding 4-aldehyde. Hydroperoxides (1d) and (2d), the main autoxidation products of 1b, have also been postulated as intermediates in the formation of 4-hydroxy-nor-diterpenes (1a and 2a).     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Synthesis and characterization of a series of chiral NHC–Pd complexes derived from l-phenylalanine

The synthesis of a series of chiral Pd(L)PyBr₂ (3a–3e) and Pd(L)PyCl₂ (4d and 4e) complexes from l-phenylalanine is presented (L = (S)-3-allyl-4-benzyl-1-(2,6-diisopropylphenyl)-imidazolin-2-ylidene (a), (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(naphthalen-2-ylmethyl)imidazolin-2-ylidene (b), (S)-4-benzyl-3-(biphenyl-4-ylmethyl)-1-(2,6-diisopropylphenyl)imidazolin-2-ylidene (c), (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(naphthalen-1-ylmethyl)imidazolin-2-ylidene (d) or (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(2,4,6-trimethylbenzyl)imidazolin-2-ylidene (e). The complexes were characterized by physicochemical and spectroscopic methods, and the X-ray crystal structures of 3a–3c and 4d are reported. In each case, there is a slightly distorted square-planar geometry around palladium, which is surrounded by imidazolylidene, two trans halide ligands and a pyridine ligand. There are π–π stacking interactions in the crystal structures of these complexes. Complex 3a showed good catalytic activity in the Cu-free Sonogashira coupling reaction under aerobic conditions.     

Microwave-assisted synthesis of sydnonyl-substituted imidazoles

3-Aryl-4-formylsydnones 1a-d react with symmetrical 1,2-dicarbonyl compounds, such as benzil (2a), 4,4′-dimethoxybenzil (2b), 4,4′-difluorobenzil (2c), and di-2-thienylethanedione (2d), in glacial acetic acid, using ammonium acetate as the ammonia source, to yield 4,5-diaryl-2-sydnonyl-substituted imidazoles 3a-6d under conventional heating. In a similar treatment, 4,5-diaryl-2-sydnonyl-1-substituted imidazoles 8a-10a can be prepared by the one-pot condensation of 3-(4-ethoxyphenyl)-4-formylsydnone (1d), benzil derivatives, ammonium acetate, and primary amines. However, such reactions, which take 1-3 days at high temperature under classical conditions, are completed successfully within a few minutes under microwave irradiation.     

Synthesis, characterization, and applications in Heck and Suzuki coupling reactions of amphiphilic cyclopalladated ferrocenylimines

A series of novel amphiphilic ferrocenylimines and their cyclopalladated complexes of general formula [Fe(η⁵-C₅H₅)(η⁵-C₅H₄CR₁NR₂)] (R₁=H, R₂=C₁₂H₂₅-n4a, R₁=H, R₂=C₁₆H₃₃-n4b, R₁=CH₃, R₂=C₁₂H₂₅-n4c, R₁=CH₃, R₂=C₁₆H₃₃-n4d), [PdCl{[(η⁵-C₅H₅)]Fe[(η⁵-C₅H₃)CR₁NR₂]}]₂ (5a-d), [PdCl{[(η⁵-C₅H₅)]Fe[(η⁵-C₅H₃)-CR₁NR₂]}(PPh₃)] (6a-d), were prepared and characterized by ¹H NMR, ¹³C NMR, ³¹P NMR, IR, HRMS, and elemental analysis. The crystal structures of 5c,d were determined by X-ray crystallography. These amphiphilic cyclopalladated complexes are thermally stable and insensitive to oxygen and moisture. The redox properties of 4a-d, 5a-d, 6a-d were also investigated using cyclic voltammetric technique. Compounds 5a-d, 6a-d displayed good activity in the Heck reaction of a variety of aryl halides with ethyl acrylate or styrene and the Suzuki-Miyaura cross-coupling reaction of aryl bromides with phenylboronic acid in bulk solution. They are also suitable for formation of Langmuir-Blodgett (LB) films.     

Electrochemical study of catechol and some 3-substituted catechols in the presence of 4-hydroxy coumarin: application to the electro-organic synthesis of new coumestan derivatives

Electrochemical oxidation of catechol (1d), 3-methylcatechol (1a), 3-methoxycatechol (1b) and 2,3-dihydroxybenzoic acid (1c) in the presence of 4-hydroxycoumarin as nucleophile in aqueous solution has been studied using cyclic voltammetry and controlled-potential coulometry. The results indicate that (1a–1d) participating in a 1,4 (Michael) addition reaction convert to coumestan derivatives (5a–5d). The electrochemical synthesis of 5a–5d has been successfully performed in an undivided cell in good yield and purity.