A convenient synthesis of substituted 2,2′:6′,2″-terpyridines

The 2,2′:6′,2″-terpyridines 7a-c were prepared in good yield by reacting α-acetoxy-α-chloro-β-keto-esters 3a-c with bis-amidrazone 4 and 2,5-norbornadiene 6 in ethanol at reflux. Compounds 3a and 3b gave the 2,2′:6′,2″-terpyridines 9a and 9b, respectively, in moderate yield when treated with compound 4 and enamine 8.     

Synthesis of 2,2′-bipyridyl derivatives using aza Diels-Alder methodology

Amidrazone 1 and the tricarbonyl derivatives 2a-c gave the triazines 3a-c, respectively, which reacted with 2,5-norbornadiene 4 in boiling ethanol yielding the corresponding novel 2,2′-bipyridines 5a-c in good yield. Triazine 6 gave the 2,2′-bipyridyl derivative 7 (65%) with compound 4 in 1,2-dichlorobenzene at 140°C.     

Thermal and microwave assisted reactions of 2,5-disubstituted thienosultines with [60]fullerene: non-Kekulé biradicals and self-sensitized oxygenation of the cycloadduct

Refluxing an o-dichlorobenzene solution of 2,5-disubstituted thienosultines 10a-f with [60]fullerene for 2-24 h gave both 1:1 and 2:1 cycloadducts in 37-79% isolated yields. The reaction was highly accelerated by microwave irradiation giving comparable yields of cycloadducts. Sultines 10a-f underwent cheletropic extrusion of SO₂ to form the corresponding non-Kekulé biradical intermediates 11a-f, which were subsequently trapped by [60]fullerene to form corresponding cycloadducts. The activation energy barriers (ΔG_c^≠) determined for the boat-to-boat inversion of these 4′,5′,6′,7′-tetrahydrobenzo[c]thieno-[5′,6′:1,2][60]fullerene adducts 12a-f were found to be in the range of 13.5-14.8 kcal/mol. Unexpectedly, one of the monoadduct 12a was found to be labile when kept in air under ambient light. Two new products 15 (a sulfine-enone) and 16 (an endione) were isolated from the decomposed 12a and were found to derive from self-sensitized singlet oxygen reaction on the 2,5-dimethylthieno moiety of 12a.     

Synthesis of pyridine and 2,2′-bipyridine derivatives from the aza Diels-Alder reaction of substituted 1,2,4-triazines

Amidrazone 1a and the tricarbonyl derivatives 2b-d reacted in boiling ethanol in the presence of 2,5-norbornadiene 5 giving the pyridine derivatives 6b-d respectively (59-72%) and in the presence of 2,3-dihydrofuran 7 yielding the lactones 10b-d (39-44%). The 2,2′-bipyridine derivatives 6e-g were similarly obtained in good yield (81-87%) from the reaction of amidrazone 1b and tricarbonyl derivatives 2b-d in the presence of 2,5-norbornadiene 5.     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

Synthesis of planar-chiral bridged bipyridines and terpyridines by metal-mediated coupling reactions of pyridinophanes

We have accomplished efficient synthesis of planar-chiral bridged 2,2′-bipyridine (S)-6, C₂-symmetric bipyridinophane (S,S)-7, bridged 2,2′:6′,2″-terpyridines (S)-11, and C₂-symmetric terpyridine (S,S)-12 by metal-mediated biaryl cross-coupling or homo-coupling reactions of the corresponding 6-halo[10](2,5)pyridinophanes. Stille-type and Negishi cross-coupling reactions are particularly useful for the syntheses of 6, 11, and 12. On the other hand, nickel-mediated homo-coupling reaction worked best for achieving the synthesis of structurally unique bipyridinophane 7.     

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 and ring opening reactions of 2-glyco-1,4-dimethyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes

The high-pressure asymmetric Diels-Alder reactions of d-galacto- (1a) and d-manno-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-nitrohept-1-enitol (1b) with 2,5-dimethylfuran (2) afforded mixtures of cycloadducts, from which the (2S,3R)-3-exo-nitro (3a and 3b), (2R,3S)-3-exo-nitro (4a and 4b), and (2R,3S)-1′,2′,3′,4′,5′-penta-O-acetyl-1′-C-(1,4-dimethyl-3-endo-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl)-d-galacto-pentitol (5b) were isolated pure. Deacetylation of these compounds led to new chiral mono-, bi-, and tricyclic ethers, being their asymmetric centers arising from the chiral inductor used in the cycloaddition reaction. A ring opening mechanism through a 1-nitro-1,3-cyclohexadiene intermediate has been proposed.     

Synthesis and crystal structure of 2′-deoxy-2′-fluoro-4′-thioribonucleosides: substrates for the synthesis of novel modified RNAs

We report herein the synthesis of appropriately protected 2′-deoxy-2′-fluoro-4′-thiouridine (5), -thiocytidine (7), and -thioadenosine (35) derivatives, substrates for the synthesis of novel modified RNAs. The synthesis of 5 and 7 was achieved via the reaction of 2,2′-O-anhydro-4′-thiouridine (3) with HF/pyridine in a manner similar to that of its 4′-O-congener whereas the synthesis of 35 from 4′-thioadenosine derivatives was unsuccessful. Accordingly, 35 was synthesized via the glycosylation of the fluorinated 4-thiosugar 25 with 6-chloropurine. The X-ray crystal structural analysis revealed that 2′-deoxy-2′-fluoro-4′-thiocytidine (8) adopted predominately the same C3′-endo conformation as 2′-deoxy-2′-fluorocytidine.     

A novel approach to conformationally strained 2,2′-bipyridine thiacrown ethers and their chiral sulfoxides by sequential homo-coupling/DA-rDA reaction of 5,5′-bi-1,2,4-triazine-containing thiamacrocycles

The synthesis of conformationally strained 2,2′-bipyridine thiamacrocycles 5, 6, 9, 10 and their chiral sulfoxides 11-14 is elaborated using, (1) homo-coupling of 1,2,4-triazine sulfide 3 with potassium cyanide and (2) Diels-Alder/retro Diels-Alder (DA-rDA) with 2,5-norbornadiene or 1-pyrrolidino-1-cyclopentene as the key steps. The crystal structure determinations of 4-6 and the theoretical calculations at DFT/B3LYP/6-311G^∗∗ level were conducted thus establishing conformational preferences of the target thiamacrocycles     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-tetrahydropyrano[2,3-b]indole derivatives

The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole 20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, respectively, was performed starting from the racemic spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared as key intermediates for the synthesis of enantiopure compounds (−)-19 and (−)-20. Since the amino acid 14 is the common intermediate for the chemoselective preparation of derivatives 19 and 20, experimental and computational studies were performed in order to selectively obtain these compounds and to provide a mechanistic rationalization for their formation.     

A practical and expeditious method for the preparation of the potential anticancer agent 5,6,11,12,17,18,23,24-octahydrocyclododeca[1,2-b:4,5-b′:7,8-b″:10,11-b?]tetraindole (CTet)

A new synthetic method to obtain the potential anticancer agent 5,6,11,12,17,18,23,24-octahydrocyclododeca[1,2-b:4,5-b′:7,8-b′′:10,11-b′′′]tetraindole (CTet), starting from 1H-indole-3-carboxaldehyde and sulfamide, is described. Although a mixture of CTet and cyclic indole trimer (CTr) is formed, higher CTet/CTr ratio (4:6) and CTet yield (15%) make our protocol more favorable than those reported in the literature. A discussion on the possible reaction mechanism is reported.     

(N-7-Azaindolyl)oligothiophenes: synthesis, characterization, and photophysical properties

The synthesis of a new series of mono- and oligothiophenes capped by 7-azaindoles such as 2-(N-azaindolyl)thiophene (1), 2-(N-azaindolyl)-5′-(bromo)oligothiophenes (2a-4a), and 2,5′-bis(N-azaindolyl)oligothiophenes (2b-4b) has been investigated. The reaction of 7-azaindole with 2-bromothiophene under the modified Ullmann condensation conditions led to the formation of 1. Simple extension of the same method to the reaction of 2,5′-dibromooligothiophenes in the presence of 4-5 M excess of 7-azaindole led to the formation of 2a-4a and 2b-4b in moderate overall yields (40-55%). All compounds were fully characterized by analytical and various spectroscopic techniques. The structures of 2b, 3b, and 4b were determined by X-ray diffraction analyses. All three compounds show several intermolecular C(π)?H interactions leading to the formation of herringbone packing in the solid-state structure. The UV absorption spectra of 1-4 consist of three characteristic electronic transitions corresponding to n→π^∗ and π→π^∗ transitions arising out of the π-conjugation of the entire molecule as well as local aromatic units. The emission spectra of the same compounds show intense fluorescence bands at the wavelengths between 422 and 495 nm. The length of the thiophene chain and the presence of bromine atom influence the band position of both absorption and emission spectra. While the extension in π-conjugation causes the reduction in the band gap, the bromine atom shifts the electronic transition energy to the blue region. The cyclic voltammetric measurements were performed with 1-4, which show that the compounds exhibit a typical pseudo-reversible redox wave with E_ox in the range 0.6-1.2 V.     

Emission of 2-phenylethanol from its β-d-glucopyranoside and the biogenesis of these compounds from [H8] l-phenylalanine in rose flowers

The hydrolysis of 2-phenylethyl β-d-glucopyranoside (3) was found to be partially inhibited by feeding with 2-phenyl-N-glucosyl-acetamidiumbromide (8), a β-glucosidase inhibitor, resulting in a decrease in the diurnal emission of 2-phenylethanol (2) from Rosa damascena Mill. flowers. Detection of [1,1,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2′,3′,4′,5′,6′-²H₇]-2 from R. ‘Hoh-Jun’ flowers fed with [1,1,2,2′,3′,4′,5′,6′-²H₈]-3 suggested that β-glucosidase, alcohol dehydrogenase, and reductase might be involved in scent emission. Comprehensive GC-SIM analyses revealed that [1,2,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2,2′,3′,4′,5′,6′-²H₈]-3 must be biosynthesized from [1,2,2,2′,3′,4′,5′6′-²H₈] l-phenylalanine ([²H₈]-1) with a retention of the deuterium atom at α-position of [²H₈]-1.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

The highly regiospecific synthesis and crystal structure determination of 1,1′-2,5′ substituted ring-locked ferrocenes

1,1′-Ferrocene biscarboxaldehyde (1) has been prepared and the aldehyde groups were subsequently protected with acetal groups to produce 1,1′-bisacetalferrocene (2). A ring-locked ferrocene was synthesised by further derivatisation of the cyclopentadiene rings at the 2,2′ positions with phosphine substituents to produce 2,2′-bis-(acetal)-1,1′-diphenylphosphinoferrocene (3), which was subsequently coordinated to either a nickel chloride (5) or nickel bromide (6) metal centre. The ring-locked ferrocene complexes produced 2,5′-bis-(acetal)-1,1′-diphenylphosphinoferrocene substitution patterns. The acetal protecting groups of 2,2′-bis-(acetal)-1,1′-diphenylphosphinoferrocene were removed to produce 1,1′-bis-carboxaldehyde-2,2′-diphenylphosphinoferrocene (4). The Cp rings of 1,1′-bisacetalferrocene were also further derivatised at the 2,2′ positions with a silane to produce the ring-locked 1,1′-siloxane-2,5′-bisacetalferrocenophane (7). The acetal protecting groups were removed from this to produce 1,1′-siloxane-2,5′-ferrocenophanecarboxaldehyde (8). For both the phosphine and siloxane electrophiles, the substitution on the Cp rings gives chiral products (obtained as racemic mixtures). Due to the highly regioselective nature of the reaction and diastereoselectivity in the products only C₂-symmetric compounds were observed without the presence of meso diastereoisomers. Subsequent ring-locking forced the Cp rings to rotate, leading to 1,1′-ring-locked ferrocenes with 2,5′-arrangement of the acetal groups (i.e. on opposite faces of the ferrocene unit).     

Amberlyst 15 catalyzed synthesis of indole-pyrazole based tri(hetero)arylmethanes

An expedient synthesis of 1,3-diaryl-4-(3,3′-diindolyl)methylpyrazoles 3a-m has been developed using Amberlyst 15 catalyzed condensation of 1,3-diaryl-4-formyl pyrazoles 2 with indoles 1. This reaction was further extended to the synthesis of 4,4′-bis(3,3′-diindolyl)methylphenoxy-alkanes 5a-b by coupling of 4,4′-di(formylphenoxy)alkane 4 with indole 1.     

A new protecting group ‘3,5-O-sulfinyl’ for xylo-nucleosides. A simple and efficient synthesis of 3-amino-3-deoxyadenosine (a puromycin intermediate), 2,2-anhydro-pyrimidine nucleosides and 2,3-anhydro-adenosine

We developed a new protecting group, the cyclic sulfite for the protection of the 3^′,5^′-dihydroxy group of nucleosides. Seven cyclic sulfites, 4a-c, 5a-b, and 6a-b were prepared in high yields from the corresponding xylo-uridines 1 and 2, and xylo-adenosines 3 with thionyl chloride, respectively. Synthesis of the puromycin intermediate 8 was carried out by deprotection of the sulfite moiety through an intramolecular cyclization of the 2^′-α-carbamate 7.     

Investigation of hydrazine addition to functionalized furans: synthesis of new functionalized 4,4′-bipyrazole derivatives

The addition of hydrazine to functionalized furans 2a-d leads to a variety of 4,4′-bipyrazoles 4a-c depending on the structure of the starting materials. In one example, compound 2c was first converted to an intermediate, furo[3,4-d]pyridazine 3c which was then transformed into 4,4′-bipyrazole 4c on reacting with hydrazine.