Photochemistry of benzene and quinoxaline fused Δ-1,2,3-triazolines and their trapping products

The benzene and quinoxaline fused Δ²-1,2,3-triazolines 1a and 1b were synthesized in good yields using Knoevenagel condensation and intramolecular 1,3-dipolar cycloaddition as two of the key reactions. Photolysis (254 nm) of Δ²-1,2,3-triazoline 1a or 1b in acetonitrile led to the homolytic cleavage of nitrogen that generated diethyl diazomalonate 7, highly reactive intermediates aziridines 8a,b, and isoindoles B. The latter two species subsequently underwent rearrangement to give the nitrogen extrusion products 9a,b, and polymers. Furthermore, the reactive intermediates were trapped by dienophiles to give the corresponding cycloadducts. Subsequent rearrangement of the N-bridged cycloadducts gave N-substituted pyrrolo[3,4-b]quinoxalines 12b and 15b in 6% and 9% yields, respectively. Irradiation of 1a in the presence of fumaronitrile led to the isolation of cycloadduct 16a with retention of stereochemistry. Thermal reaction of 1b gave more nitrogen extruded product 9b (58-63% yield) than that by photolysis (5-23% yield), which implied that zwitterionic intermediate might be involved in the former.     

Synthesis of l-azaisotryptophan and its analogs: a general access to new 2-substituted azaindoles

l-(N-Cbz)-7-azaisotryptophan, l-(N-Cbz)-1a, a new isostere of tryptophan, was synthesized by reacting Li₂-(N-Boc)-2-amino-3-picoline, Li₂-(N-Boc)-2a, with appropriately protected l-aspartic acid followed by simple functional group manipulation. This synthetic success led us to access a set of analogs of azaisotryptophan (4a–c; 6a–c) as well as a new class of chiral amines (7a–c; 8a–c) for future application in asymmetric synthesis and design of homochiral ligands. Further, we have generalized the method substantiating a variety of new azaindol-2-yl derivatives (10aa–10lc) with functionalized substituents. In a preliminary luminescence characterization, l-(N-Cbz)-1a has exhibited about 30 nm bathochromic shifted fluorescence emission compared to tryptophan and (N-Cbz)-tryptophan.     

N-Nosyl as a stereoselectivity-improving and easily removable group in the O-glycosylation of d-allal and d-galactal-derived allyl aziridines. Stereospecific synthesis of 4-amino-2,3-unsaturated-O-glycosides

The glycosylation of alcohols, phenol, and partially protected monosaccharides with the diastereoisomeric d-allal and d-galactal-derived N-nosyl aziridines 2α and 2β leads to the corresponding 4-N-(nosylamino)-2,3-unsaturated-α-O- (6α) and β-O-glycosides and disaccharides (6β), respectively, in a stereospecific substrate-dependent O-glycosylation process. The N-(nosylamino) group of 6α and 6β can easily be deprotected to give the corresponding 4-amino-2,3-unsaturated-O-glycosides 7α and 7β, with an increased value to our glycosylation protocol.     

A convenient synthesis of 1′-H-spiro-(indoline-3,4′-piperidine) and its derivatives

A simple synthetic route has been developed to prepare 1′-H-spiro(indoline-3,4′-piperidine) (1d). Dialkylation of 2-fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′-N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds (1a, 1b and 1d) can be utilized as templates to synthesize compounds for GPCR targets.     

An expedient, regioselective synthesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]indoles

1-Benzenesulfonyl-5-aminoindole 5, prepared from 5-nitroindole 3, was condensed with alkyl isothiocyanates and separately with carbon disulfide and alkyl bromides/iodides to furnish efficiently the corresponding N-alkyl-thioureidoindoles 6a-c and the alkyl N-(indol-5′-yl)dithiocarbamates 9a-e, respectively. Their cyclisation using N-bromosuccinimide (NBS) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in the cold, followed by indolic N-deprotection, furnished regioselectively the 2-alkylamino- and the 2-alkylthiothiazolo[5,4-e]indoles 8a-c and 11a-e, respectively, in good overall yields.     

Synthesis of N,N′-bis and N,N,N′,N′-tetra-[(3,5-di-substituted-1-pyrazolyl)methyl]para-phenylenediamines: new candidate ligands for metal complex wires

A series of tridentate ligands N,N-bis-[(di-substituted-1-pyrazolyl)methyl]arylamines 2-3a,b and benzylamine 4a,b, tetradentate N,N′-bis-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 7a,b and hexadentate N,N,N′,N′-tetra-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 8a,b has been prepared in good yield by condensation of arylamines, benzylamine or para-phenylenediamine with N-hydroxymethyl disubstituted pyrazoles 1a,b. The synthesis and characterisation of these various polydentate ligands are described.     

Synthesis of imidazo[5,1-b]thiazoles or spiro-β-lactams by reaction of imines with mesoionic compounds or ketenes generated from N-acyl-thiazolidine-2-carboxylic acids

New mesoionic compounds (2H, 3H-thiazolo[3,2-c]oxazol-7-ones) (β) or ketenes ((3-acyl-1,3-thiazolidin-2-ylidene)methanone) (β′) were generated from N-acetyl and N-benzoyl-thiazolidine-2-carboxylic acids (7a,b) using different methods, and their reactivity towards N-(phenylmethylene)benzenesulfonamide (2) and N-(phenylmethylene)aniline (3) was tested. When (7a,b) were treated with (2) and acetic anhydride in refluxing toluene solution, only imidazo[5,1-b]thiazoles (8a,b) were obtained from the mesoionic compound intermediates (β). When the ketene intermediates (β′) were generated from (7a,b) by means of Mukaiyama's reagent, only spiro-β-lactams (9a,b) were isolated.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

Synthesis of acyclic nucleoside analogues based on 1,2,4-triazolo[1,5-a]pyrimidin-7-ones by one-step Vorbrüggen glycosylation

New acyclovir analogues were obtained by reaction of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 4a–i with (2-acetoxyethoxy)methyl acetate 5 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst (Vorbrüggen procedure). Coupling between compounds 4a–f and 5 led to a mixture of N3- and N4-isomers 6 and 7, respectively. On the contrary, the reaction of compounds 4g–i with 5 proceeded selectively with formation of N3-isomers only. It was found that the ratio of 6a–f and 7a–f depends on the presence or the absence of N,O-bis(trimethylsilyl)acetamide (BSA). Glycosylated products 6a–f and 7a–f underwent reversible isomerization under TMSOTf treatment. The ratio of glycosylated products of the coupling reaction between 4 and 5 was thermodynamically controlled. A similar reaction occurred if ZnCl₂ was chosen as a catalyst, although lower yields of the acyclic analogues of nucleosides were observed. The glycosylation of other purines (adenine and guanine) can be achieved via the non-BSA modification of the Vorbrüggen procedure.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Molecular recognition of biotin, barbital and tolbutamide with new synthetic receptors

We have measured, by means of NMR titrations, the binding constants for the complexes between hosts N,N′-bis(6-methylpyridin-2-yl)-1,3-benzenedicarboxamide (7) and 4-chloro-N,N′-bis(6-methylpyridin-2-yl)-2,6-pyridinedicarboxamide (8, hydrated) with biotin methyl ester (1), N,N′-dimethylurea (2), 2-imidazolidone (3), N,N′-trimethylenurea (4), barbital (5) and tolbutamide (6) as guests. Molecular Mechanics calculations (Monte Carlo Conformational Search, AMBER and OPLS force fields, MacroModel v.8.1) on the complexes formed between the foregoing guests and hosts 7 and 8, comparatively with 4-oxo-N,N′-bis(6-methylpyridin-2-yl)-1,4-dihydro-2,6-pyridinedicarboxamide (9a) have been carried out in order to determine the correlation between experimental and theoretical results and to understand the behaviour of the designed new hosts. Finally we have performed single point DFT [B3LYP/6-31G(d,p)] calculations on the optimised Molecular Mechanics geometries for the complexes between hosts 7-9 and water.     

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.     

Preparation and structures of 6- and 7-coordinate salen-type zirconium complexes and their catalytic properties for oligomerization of ethylene

A series of salen-type zirconium complexes of the general formula LZrCl₂ (L = N,N′-ethylenebis(salicylideneiminate), 3a; N,N′-ethylenebis(3,5-di-tert-butylsalicylideneiminate), 3b; N,N′-ethylenebis(5-methoxysalicylideneiminate), 3c; N,N′-ethylenebis(5-chlorosalicylideneiminate), 3d; N,N′-ethylenebis(5-nitrosalicylideneiminate), 3e; N,N′-o-phenylenebis(salicylideneiminate), 4a; N,N′-o-phenylenebis(3,5-di-tert-butylsalicylideneiminate), 4b; N,N′-o-phenylenebis(5-methoxysalicylideneiminate), 4c; N,N′-o-phenylenebis(5-chloro-salicylideneiminate), 4d) were prepared. The crystal structures of 6- and 7-coordinate zirconium complexes 4b and [4b · OCMe₂] were determined by X-ray crystallography, which reveals that a salen-type zirconium complex possesses a labile coordination site on the Zr center with a relatively stable framework and that the coordination and the dissociation of O-donor molecules occur readily at this site. The catalytic properties of 3(a-e) and 4(a-d) were studied for ethylene oligomerization in combination with Et₂AlCl as co-catalyst. Complex 3c featuring a methoxy-substituted salen ligand displayed higher activity than its analogous precursors having chloro and nitro groups as substituents. The catalytic reactions by 3(a-e) and 4(a-d) gave C₄-C₁₀ olefins and low-carbon linear α-olefins in good selectivity.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.     

Stereocontrolled conversion of some optically active (4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Optically active (4S,5R)-dihydroisoxazoles 5a-c (90-91% ee) have been prepared by reaction of the epoxyketones 4a-c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b.     

Studies on the Suzuki reaction on methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroaryl-pyrrolidin-2-carboxylate derivatives: synthesis of N-aryl modified monocyclic γ-lactam derivatives in search for newer antibacterial agents

A large number of novel N-aryl modified monocyclic γ-lactam derivatives have been prepared via Pd(0) catalyzed heteroarylation in the N-aryl part of (±) cis and (±) trans γ-lactam carboxylate derivatives 3(a–f) and 6(a–f), respectively, with furan-2-boronic acid and thiophen-2-boronic acid. (±) cis Methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroarylpyrrolidin-2-carboxylate derivatives 3(a–f), were prepared in good yields from 1(a–f) via hydrolysis, stereoselective decarboxylation, followed by esterification. Corresponding trans isomers 6(a–f) were prepared by the standard method already reported by us.     

Synthesis of novel multidentate carbohydrate-triazole ligands

Cu(I)-catalyzed 1,3-dipolar cycloaddition (click reaction) of 1 mol equiv of N,N′-di-prop-2-ynyl-phthalamide (1a), N,N′-di-prop-2-ynyl-isophthalamide (1b), and pyridine-2,6-dicarboxylic acid bis-prop-2-ynylamide (1c), respectively with 2 mol equiv of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide (2a), 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (2b), and 2-azidoethyl 2,3,4,6-tetra-O-acetyl-α-d-mannopyranoside (2c), respectively, afforded the corresponding bis-cycloadducts 3-5, containing two 1,2,3-triazole moieties each, in 38-76% yield. Reaction of 1 mol equiv of 2c with 1 mol equiv of 1c under otherwise identical conditions gave the mono-cycloadduct 6, containing one 1,2,3-triazole and one 2-propynylamide moiety, in 77% yield. Reaction of 6 with 2a afforded 7, containing two different sugar moieties, in 67% yield.     

Diels-Alder cycloaddition of 2-azadienes to methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate in the synthesis of methyl 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates

A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by Diels-Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to isomerization of the cycloadducts 7 and 8 or by isomerization of the CN bond of the diene during the reaction. The isomer 10 is formed from diene 2e, and a single diastereoisomer structure 4a-i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been hydrolyzed leading to functionalised aziridines 12, 13 and 15.     

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.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).