The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.     

Design and synthesis of boron containing 2,4-disubstituted-phthalazin-1(2H)-one and 3,7-disubstituted-2H-benzo[b][1,4] oxazine derivatives as potential HGF-mimetic agents

We synthesized boron containing 2-(4-methoxybenzyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioaborolan-2-yl)phenyl) phthalazin-1(2H)-one 3 and 7-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-benzo[b][1,4] oxazine 8. The reaction of compound 2 with B₂pin₂ using potassium acetate as the base and Pd(PPh₃)₂Cl₂ as the catalyst, produced the corresponding boron-containing derivative 3 as a white solid in 65% yield. Alternatively, we have synthesized compound 8 as a yellow solid in 59% yield using the Miyaura borylation reaction. The potassium trifluoro(4-(-methyl-2H-benzo[b][1,4]oxazine-3-yl)phenylborate 9 was then obtained after treatment of 8 with aqueous solution of KF₂H in methanol as white solid product in 60% yield. The biological activities of the synthetic compounds are currently being evaluated.     

Synthesis and structures of the silyl bridged bis(indenyl) diruthenium complexes and a novel indenyl nonanuclear ruthenium cluster Ru9(μ6-C)(CO)14(μ3-η:η:η-C9H7)2

Thermal treatment of C₉H₇SiMe₂C₉H₇ and C₉H₇Me₂SiOSiMe₂C₉H₇ with Ru₃(CO)₁₂ in refluxing xylene gave the corresponding diruthenium complexes (E)[(η⁵-C₉H₆)Ru(CO)]₂(μ-CO)₂ [E = Me₂Si (1), Me₂SiOSiMe₂ (2)]. A desilylation product [(η⁵-C₉H₇)Ru(CO)]₂(μ-CO)₂ (3) was also obtained in the latter case. Similar treatment of C₉H₇Me₂SiSiMe₂C₉H₇ with Ru₃(CO)₁₂ gave a novel indenyl nonanuclear ruthenium cluster Ru₉(μ₆-C)(CO)₁₄(μ₃-η⁵:η²:η²-C₉H₇)₂ (5) with carbon-centered tricapped trigonal prism geometry, in addition to the diruthenium complex (Me₂SiSiMe₂)[(η⁵-C₉H₆)Ru(CO)]₂(μ-CO)₂ (4) and the desilylation product 3. Complex 4 can undergo a thermal rearrangement to form the product [(Me₂Si)(η⁵-C₉H₆)Ru(CO)₂]₂ (6). The molecular structures of 1, 2, 4, 5, and 6 were determined by X-ray diffraction.     

Boron coordination compounds derived from 2-phenyl-benzimidazole and 2-phenyl-benzotriazole bidentate ligands

The syntheses and structural analyses of a series of boron heterocycles derived from 2-(1H-benzimidazol-2-yl)-phenylamine (1), 2-(1H-benzimidazol-2-yl)-phenol (2), 2-(1H-benzimidazol-2-yl)-benzenedisulfide (3), 2-[3-(1,1,1,3,-tetramethyl-butyl)-phenyl]-2H-benzotriazole (4), 2-[3,5-bis-(1-methyl-1-phenylethyl)-phenyl]-2H-benzotriazole (5) and (C₆H₅)₂BOH or BF₃·OEt₂ are reported. The new boron compounds: diphenyl-[2-(1H-benzimidazol-2-yl-κN)-phenylamide-κN]-boron (6), diphenyl-[2-(1H-benzimidazol-2-yl-κN)-phenolate-κO]-boron (7), diphenyl-[2-(1H-benzimidazol-2-yl-κN)-benzenethiolate-κS]-boron (8), diphenyl-[2-(2H-benzotriazol-2-yl-κN)-4-(1,1,3,3-tetramethyl-butyl)-phenolate-κO]-boron (9), diphenyl-[2-(2H-benzotriazol-2-yl-κN)-4,6-(1-methyl-1-phenylethyl)-phenolate-κO]-boron (10), difluoro-[2-(1H-benzimidazol-2-yl-κN)-phenolate-κO]-boron (11), difluoro-[2-(2H-benzotriazol-2-yl-κN)-4-(1,1,3,3-tetramethylbutyl)-phenolate-κO]-boron (12) and difluoro-[2-(2H-benzotriazol-2-yl-κN)-4,6-(1-methyl-1-phenylethyl)-phenolate-κO]-boron (13) have four fused rings, with boron included in a six-membered ring and bound to N, O or S atoms and strongly coordinated by a nitrogen atom from the imidazole or triazole rings. Their structures are zwitterionic, with a negative charge on the boron and a delocalized positive charge on the ligand. Compounds 6-12 were studied by NMR, IR, mass spectrometry, and 6-10 and 12 by X-ray diffraction analyses.     

Osmium assisted C-H activation and CN cleavage of N-(2′-hydroxyphenyl) benzaldimines. Synthesis, structure and electrochemical properties of some organoosmium complexes

Reaction of N-(2′-hydroxyphenyl)-4-R-benzaldimines (L-R, R = OCH₃, CH₃, H, Cl and NO₂) with [Os(PPh₃)₃Br₂] in refluxing 2-methoxyethanol in the presence of triethylamine affords two families of organoosmium complexes (1-R and 2-R). In both 1-R and 2-R complexes a benzaldimine ligand is coordinated to the metal center as tridentate C,N,O-donor. In the 1-R complexes, a bidentate N,O-donor imionsemiquinonate ligand, derived from the hydrolysis of another benzaldimine, and a PPh₃ ligand are also coordinated to osmium. In the 2-R complexes, a carbonyl, derived from decarbonylation of 4-R-benzaldehyde (derived from the same hydrolysis stated above), and two PPh₃ ligands take up the remaining coordination sites on osmium. Structures of the 1-Cl and 2-OCH₃ complexes have been determined by X-ray crystallography. All the 1-R and 2-R complexes are diamagnetic, and show characteristic ¹H NMR signals and intense MLCT transitions in the visible region. Cyclic voltammetry on the 1-R complexes shows a reversible Os(III)-Os(IV) oxidation within 0.47-0.67 V (vs SCE), followed by an irreversible oxidation of the imionsemiquinonate ligand within 1.10-1.36 V. An irreversible Os(III)-Os(II) reduction is also displayed by the 1-R complexes within −1.02 to −1.14 V. Cyclic voltammetry on the 2-R complexes shows a reversible Os(II)-Os(III) oxidation within 0.29-0.51 V, followed by a quasi-reversible oxidation within 1.04-1.29 V, and an irreversible reduction of the coordinated benzaldimine ligand within −1.16 to −1.31 V.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

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 and photochemistry of pH-sensitive GFP chromophore analogs

GFP chromophore analogs (7a-e, 8, and 10a,b) containing 2-thienyl-, 5-methyl-2-furyl-, 2-pyrryl, and 6-methyl-2-pyridyl-groups were synthesized and their fluorescence spectra recorded in the pH range 1-7. NMR studies showed that protonation of 8 (2-thienyl system) inhibited photoisomerization (Z-E) about the exocyclic double bond but that protonation of 7c (E + Z) (2-pyrryl system) gave only 7cE. Fluorescence studies revealed enhancement of fluorescence intensity of 7c and 7b,e (furyl system) below pH 2.5 and gave a similar result for 10a (pyridyl system) below pH 6. Quantum yields at pH 1 were low, probably due to excited state proton transfer (ESPT).     

Comparative reactivity studies of dppf-containing CpRu and (C6Me6)Ru complexes towards different donor ligands (dppf=1,1-bis(diphenylphosphino)ferrocene)

[CpRu(dppf)Cl] (Cp=η⁵-C₅H₅) (1) and [(HMB)Ru(dppf)Cl]PF₆ ((HMB)=η⁶-C₆Me₆) (3) react with different donor ligands to give rise to N-, P- and S-bonded complexes. The stoichiometric reactions of 1 and 3 with NaNCS give the mononuclear complexes [CpRu(dppf)(NCS)] (2) and [(HMB)Ru(dppf)(NCS)]PF₆ (4), respectively, in yields above 80%, while 3 also gives a dppf-bridged diruthenium complex [(HMB)Ru(NCS)₂]₂(μ-dppf) (5) in 67% yield from reaction with four molar equivalents of NaNCS. Compound 5 is also obtained in 70% yield from the reaction of 4 with excess NaNCS. With CH₃CN in the presence of salts, both 1 and 3 give their analogous solvento derivatives [CpRu(dppf)(CH₃CN)]BPh₄ (6) and [(HMB)Ru(dppf)(CH₃CN)] (PF₆)₂ (7). With phosphines, the reaction of 1 gives chloro-displaced complexes [(CpRu(dppf)L]PF₆ (L =PMe₃ (8), PMe₂Ph(9)), whereas the reaction of 3 with PMe₂Ph leads to substitution of dppf, giving [(HMB)Ru(PMe₂Ph)₂Cl] PF₆ (10). The reaction of 1 with NaS₂CNEt₂ gives a dinuclear dppf-bridged complex [{CpRu(S₂CNEt₂)}₂(μ-dppf)] (11), whereas that of 3 results in loss of the HMB ligand giving a mononuclear complex [Ru(dppf)(S₂CNEt₂)₂] (12). With elemental sulfur S₈, 1 is oxidized to give a dinuclear CpRu^III dppf-chelated complex [{CpRu(dppf)}₂(μ-S₂)](BPh₄)Cl (13), whereas 3 undergoes oxidation at the ligand, giving a dppf-displaced complex [(HMB)Ru(CH₃CN)₂Cl]PF₆ (14) and free dppfS₂. The structures of 1, 2, 5-9, 11, 13 and 14 were established by X-ray single crystal diffraction analyses. Of these, 5 and 11 both contain a dppf-bridge between Ru^II centers, while 13 is a dinuclear CpRu^III disulfide-bridged complex; all the others are mononuclear. All complexes obtained were also spectroscopically characterized.     

Syntheses and NMR study of [(2-dimethylaminomethyl)phenyl]vinylsilane derivatives and [(2-dimethylaminomethyl)phenyl]ethylsilane derivatives

Various vinylsilanes, SiX(CHCH₂)(CH₃)[2-(CH₃)₂NCH₂C₆H₄], and ethylsilanes, SiX(CH₂CH₃)(CH₃)[2-(CH₃)₂NCH₂C₆H₄] [X=Cl (1); OMe (2); H (3); F (4); OSiMe₃ (5); NMe₂ (6); Me (7)], were synthesized in order to investigate the electronic effect of vinyl group on silicon atom having an intramolecular coordination arm. The magnitude of Δδ (ethyl→vinyl for ²⁹Si-NMR) of chlorosilane, 1, was the biggest one among 1-7. The differences of ²⁹Si chemical shifts between vinylsilanes and ethylsilanes increased in the following order: X=Me, NMe₂<H<OSiMe₃<OMe<F<Cl.     

Phosphorus-supported multidentate coumarin-containing fluorescence sensors for Cu

Phosphorus hydrazides PhP(O)[N(Me)NH₂]₂, (S)P[N(Me)NH₂]₃, and N₃P₃[N(Me)NH₂]₆ were condensed with 7-diethylaminocoumarin-3-aldehyde (RCHO) to afford the corresponding hydrazones PhP(O)[N(Me)NCHR]₂ (1), (S)P[N(Me)NCHR]₃ (2), and N₃P₃[N(Me)NCHR]₆ (3). The structural characterization of 1-3 was carried out by their HRMS, ¹H and ³¹P{¹H} NMR spectra. The molecular structure of 2 was established by a single-crystal X-ray analysis. Interaction of 1 and 2 with various transition metal ions revealed substantial fluorescence enhancement upon interaction with Cu²⁺ enabling a selective detection mechanism for this metal ion. However, such a fluorescence enhancement was not observed in the case of 3. A 1:1 complex [2·Zn][ClO₄]₂·4CH₂Cl₂ was isolated in the reaction of 2 with Zn(ClO₄)₂·6H₂O. The molecular structure of this complex revealed that the Zn^II is encapsulated by the ligand utilizing a 3N, 3O coordination set.     

Coupling and fast decarboxylation of aryloxyl radicals of 4-hydroxycinnamic acids with formation of stable p-quinomethanes

The reaction at room temperature of 3,5-di-tert-butyl- and 3,5-di-methoxy-4-hydroxycinnamic acids 1 and 2 with the dpph radical in acetone or other non-hydroxylic polar solvents yields interesting dimeric p-quinomethanes 10-16 characterized by a broad and strong absorption in the visible region. Although the yields appear to be low to moderate (10-40%), this simple synthesis affords quinones not otherwise obtainable, which contain an unsaturated γ-lactone ring (14-16). The structures have been elucidated by interpretation of ESI-MS, FT-IR and NMR spectral data. In particular, FT-IR spectra in a KBr matrix demonstrate the quinone nature of these compounds because of the presence of strong absorption bands at 1604-1640 cm⁻¹ and allows excluding the presence of carboxylic acid groups in the molecules. Kinetic evidence and molecular structures suggest that the formation of these p-quinomethanes is best explained through an 8-8 C-C coupling of the aryloxyl radicals derived from 1 and 2 and a subsequent fast mono- or di-decarboxylation of the initial dimer by an S_E1-type mechanism. Further oxidation of the phenolic intermediates by dpph yields the final quinones.     

Enantioselective total synthesis of pyrroloquinolone as a potent PDE5 inhibitor

A concise enantioselective strategy for the synthesis of key PDE5 inhibitor 2 was developed in 5 and 6 steps using asymmetric hydrogenation and one-pot chiral auxiliary approaches, respectively. The synthesis features the use of imine 6 obtained through Bischler-Napieralsky reaction from amide 5. Absolute R configuration was introduced in (+)-7 by asymmetric transfer-hydrogenation reaction with Ru(II) catalyst followed by establishing the tricyclic pyrroloquinalone core using the Winterfeldt oxidation. Another alternative synthetic approach for the introduction of chirality in the molecule employed imine 6 and chloroformates of different chiral auxiliaries, which achieved N-acyliminium ion intermediates that were reduced in situ using PdCl₂/Et₃SiH protocol. These synthetic routes were applied in the total synthesis of promising male erectile dysfunction (MED) PDE5 inhibitor 1.     

Synthesis and chemistry of tricyclic cyclopropene-tricyclo[3.2.2.0]nona-2(4),6-diene

The 1,2-bridged tricyclic cyclopropene, tricyclo[3.2.2.0^2,4]nona-2(4),6-diene (1), has been synthesized by the elimination of 2-bromo-4-chlorotricyclo[3.2.2.0^2,4]-non-6-ene (5). Cyclopropene 1 will undergo different isomerizations in ether solution and in neat conditions. Compound 1 rearranged to an anti-Bredt compound 4 via diradical mechanism in ether and tricyclic compound 6 via vinyl carbene mechanism in neat conditions. Compound 1 can be trapped with DPIBF at different temperatures yielding different results: the exo-endo adduct 2 (exo-addition from the view of the cyclopropene and endo-addition from the view of bicyclo[2.2.2]octene) is a sole product at 0°C by slowly addition of methyllithium, and the exo-endo adduct 2, endo-endo adduct 9, anti-Bredt adduct 3, and styrene 8 are isolated at ether refluxing temperature. Styrene 8 is proposed to be formed from endo-endo adduct 9 by diradical mechanism. The chemistry of exo-endo adduct 2 and endo-endo adduct 9 is as well studied. The exo-endo adduct 2 undergoes hydration in trifluoroacetic acid to generate 1,3-cis-diol 11 followed by eliminations of water and formaldehyde to give naphthalene 12. The endo-endo adduct 9 reacts with water in tetrahydrofuran-containing silica gel to yield 1,4-cis-diol 10. Both 9 and 10 react with trifluoroacetic acid to form trans-3-hydroxy trifluoroacetate 13. Compound 13 will undergo hydrolysis and isomerization to generate 1,3-cis-diol 11 in trifluoroacetic acid.     

Synthesis of 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles and 4-aryl-3-cyano-5,5-dimethyl Δ-pyrazolines by cycloaddition of 2-diazopropane with iminoethers and propenenitriles

A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane 3 to iminoethers 1a-c, carried out at 0 °C, afforded in two steps the corresponding 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a-c. Under the same conditions, 3-arylpropenenitriles 2a-d led to 3-cyano-5,5-dimethyl Δ¹-pyrazolines 6a-d. Products 4-6 were obtained in good yields (69-85%).     

Dimethylthallium(III) complexes with picolinic acid and its hydroxyl derivatives

The reaction of dimethylthallium(III) hydroxide with picolinic acid (Hpic), 3-hydroxypicolinic acid (H₂3hpic) and 6-hydroxypicolinic acid (H₂6hpic) in an aqueous/methanol mixture afforded the complexes [TlMe₂(pic)] (1), [TlMe₂(H3hpic)] (2) and [TlMe₂(H6hpic)] (3), respectively. Complex 3′, [NaTlMe₂(6hpic)₂]_n, was obtained as a minor product from a methanolic solution of 3. Compounds 1–3 were characterized by IR and Raman spectroscopy and, in the cases of 1, 2 and 3′, by single-crystal X-ray diffraction. Complex 3′ is the first example of an H6hpic⁻ heterobimetallic compound to be isolated. The ¹H and ¹³C NMR spectra of 1 and 2 are also discussed.     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.     

Synthesis of polyfunctionalized furans from 3-acetyl-1-aryl-2-pentene-1,4-diones

The BF₃-catalyzed cyclization of 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-e in the presence of water in boiling tetrahydrofuran gave bis(3-acetyl-5-aryl-2-furyl)methanes 2a-e in 26-79% yields along with a small amount of 3-acetyl-5-aryl-2-methylfurans 3a-e. The exact structure of 2a was determined by X-ray crystallography. The use of a half volume of the solvent for the reaction of 1a resulted in the formation of 2,4-bis(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-phenylfuran (4) together with 2a and 3a. A similar reaction of 1a was carried out in the presence of 3-acetyl-5-(4-methylphenyl)-2-methylfuran (3d) to afford 4-(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-(4-methylphenyl)-2-methylfuran (5) in 49% yield. The BF₃-catalyzed reaction of 1a with 2,4-pentanedione in dry tetrahydrofuran at 23°C gave 3-(3-acetyl-5-phenyl-2-furfuryl)-4-hydroxy-3-penten-2-one (6a) and 3-(3-acetyl-2-methyl-4-phenyl-5-furyl)-4-hydroxy-3-penten-2-one (7a) in 66 and 24% yields, respectively. The product distribution depended on the reaction temperature. A similar reaction of 1b-e also yielded the corresponding trisubstituted furans 6b-e and tetrasubstituted furans 7b-e in good yields. These results suggested the presence of the furfuryl carbocation intermediate A during the reaction. The one-pot synthesis of 6a and 7a was also achieved by a similar reaction using phenylglyoxal. The deoxygenation of 1a with triphenylphosphine gave 3a in 88% yield, while 1a was treated with concentrated hydrochloric acid to yield 3-acetyl-2-chloromethyl-5-phenylfuran (8) which was quantitatively transformed in ethanol into 3-acetyl-2-ethoxymethyl-5-phenylfuran (9) and in water into 3-acetyl-5-phenylfurfuryl alcohol (10), respectively. In addition, the Diels-Alder reaction of cyclopantadiene with 1a gave the corresponding [4+2] cycloaddition products 11 and 12.     

Synthesis of substituted (S)-2-aminotetralins via ring-opening of aziridines prepared from l-aspartic acid β-tert-butyl ester

This paper describes the total synthesis of the hydrochloride salts of (2S)-2-amino-7-methoxytetralin (21-HCl) and (2S)-2-amino-6-fluoro-7-methoxytetralin (ST1214), from a common enantiomerically pure aziridine 4b, which was available from l-aspartic acid β-tert-butyl ester. The synthesis of 21-HCl and ST1214 proceeded in nine steps and 5 and 6% overall yields, respectively. Key steps are the regioselective ring-opening of 4b with ArMgBr/CuBr·SMe₂ and the intramolecular Friedel-Crafts cyclisation providing α-tetralone. Substituted naphthalenes were formed as side products in the latter reaction.