A highly stereoselective preparation of CF3-substituted 1-aryl-1,2-diphenylethenes: application to the synthesis of panomifene

β-CF₃-α,β-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be crystallized in a mixture of CH₂Cl₂ and hexane. The addition-elimination reaction of (E)-4a with phenyllithium having substituents on the benzene ring provided 5a-j in 51-82% yields stereospecifically. Similarly, the treatment of (E)-4a with p-chloroethoxyphenyllithium in the presence of 12-crown-4 (20 mol %) at −10 °C, followed by slowly warming to room temperature, resulted in the formation of the corresponding panomifene precursor 6 in 82% yield.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Synthesis of N,N-di(arylmethylidene)arylmethanediamines by flash vacuum pyrolysis of arylmethylazides

Flash vacuum pyrolysis of arylmethylazides 7a-d gave 2,4-diazapentadienes 5a-d in high yield (76-92%). The thermal cyclization of 5a-d gave cis-imidazolines 1a-d, further heating or Swern oxidation of 1a-d gave dehydrogenated products, imidazoles 2a-d.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines

A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a-j and aryl/heteroaryl tethered pyrimidin-4-yl acetonitriles 6a-e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 3 using 2-aminopyrazine 4a and arylamidinium salts 4b, separately.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Synthesis of trifluoromethyl-promoted functional pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones

Ethyl 5-amino-3-trifluoromethyl-1H-pyrazole-4-carboxylate (1) was efficiently synthesized via the condensation of ethyl cyanoacetate and trifluoroacetic anhydride, followed by chloridization and the condensation with aqueous hydrazine. Its unique reactivity was exploited for the synthesis of trifluoromethylated pyrazolo[1,5-a]pyrimidine (5) and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones (8a-j). Among them, 5 was firstly found to be a novel fluorescent molecule that might be exploited as an attractive fluorophore for possessing many binding sites, and its fluorescence intensity was obviously stronger than its methyl analogue. 8 were found to be a new chemical class of potential monocotyledonous Echinochloa crus-galli L. Beauv inhibitors, and were more active than their methyl analogues.     

Simple preparation of phenylpropenoid β-d-glucopyranoside congeners by Mizoroki-Heck type reaction using organoboron reagents

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and arylboronic acid congeners gave the corresponding cinnamyl 2,3,4,6-tetra-O-acetyl- β-d-glucopyranosides (4a-m) in good yield. Among them, coupling products 4a-m were converted to not only the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-e) but also the unnaturally ones (1f-m).     

Synthesis of 2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones by the domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates

2-Alkoxyiminoimidazolidines 2-3 react with acetylene dicarboxylates and ethyl phenylpropiolate to give 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones C, which subsequently undergo a sterically induced multihetero-retro-ene fragmentation to give imidazo[1,2-a]pyrimidin-5(1H)-ones 4-7 together with formaldehyde or benzaldehyde. On the other hand, a similar reaction of 2-3 with ethyl propiolate gives corresponding 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones 8-10. The unsubstituted imidazo[1,2-a]pyrimidin-5(1H)-one 11 can be prepared by retro-ene reaction of 9 upon prolonged heating in refluxing ethanol. A direct synthetic approach to 1-formyl-7-phenyl-imidazo[1,2-a]pyrimidine-5(1H)-one 14 is reported using DMF/sulfonyl chloride as a new Vilsmeier-type N-formylating reagent.     

Synthesis and combinatorial approach of the reactivity of 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones

This paper describes a general procedure for the synthesis of new substituted thiaisatoic anhydrides or 6- or 7-aryl-1H-thiéno[3,2-d][1,3]oxazine-2,4-diones 3a-j and 4a-f. They were synthesized in large scale under microwave heating conditions with high yields. The reactivity vs nucleophilic reagents of these compounds was studied and permitted to develop a simple combinatorial procedure to synthesize a library of new thiophene ureidoacids 7a-j and 8a-j.     

Convenient synthesis of antisepsis agent TAK-242 by novel optical resolution through diastereomeric N-acylated sulfonamide derivative

A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By condensation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39% yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from rac-1.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

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 novel fluorescent 3-aryl- and 3-methyl-7-aryl-[1,2,3]triazolo[1,5-a]pyridines by Suzuki cross-coupling reactions

Two series of compounds, 3-aryl- (series A, compounds 2a-j) and 3-methyl-7-aryl-[1,2,3]triazolo[1,5-a]pyridines (series B, compounds 3a-j) have been synthesized by Suzuki cross-coupling reactions, with a triazolopyridine halide and an aryl or heteroaryl boronic acid in moderate to good yields. All compounds obtained are fluorescents, the quantum yields, particularly those of compounds 3f-j, are very high.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

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.     

PhP-PPh group bound to 1,8-positions of naphthalene: Preparation of cis isomer and synthesis of binuclear complex

A thermodynamically less stable cis isomer of 1,2-diphosphacycle was prepared from the corresponding trans isomer. Diphosphine, in which a PhP-PPh bond bridges the 1,8-positions of naphthalene, 1,2-diphenyl-1,2-dihydronaphtho[1,8-cd][1,2]diphosphole (1), was first prepared according to a previously reported method, and the trans isomer of 1 was irradiated in tetrahydrofuran with UV-vis light to reach equilibrium with cis-1 in a trans:cis ratio of 1:2. When a similar photochemical conversion was carried out using a saturated hexane solution of trans-1, cis-1 was precipitated in a good yield of 94%. The configuration of cis-1 was confirmed by X-ray analysis. Both cis- and trans-1 diphosphine ligands were used for the preparation of binuclear gold complexes. The crystal structure of (μ-cis-1)-[AuCl]₂ demonstrated that the two lone pairs of cis-1 are suitably directed for arrangement of the two gold centers in close proximity to each other. The two independent (μ-cis-1)-[AuCl]₂ molecules in the crystal were found to form a dimer through the multiple intermolecular interaction among the gold centers.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Studies on isocyanides: synthesis of tetrazolyl-isoindolinones via tandem Ugi four-component condensation/intramolecular amidation

The Ugi four-component condensation between methyl o-formylbenzoates 1, anilines 2a-c, isocyanides 3, and trimethylsilyl azide (4) afforded the expected Ugi adducts 5a-d, which were cyclized to the title compounds 6a-d upon treatment with sodium ethoxide in ethanol. Starting from aralkyl- or alkylamines 2d-g the Ugi adducts underwent a spontaneous cyclization to tetrazolyl-isoindolinones 6e-j.     

Design, synthesis and conformational analysis of turn inducer cyclopropane scaffolds: microwave assisted amidation of unactivated esters on catalytic solid support to obtain γ-turn mimic scaffolds

Novel constrained 1-aroyl-cyclopropane-2,3-cis-dicarboxylic acid bis-[(2-hydroxy-ethyl)-amides] (17a-e) with varied torsional angles have been synthesized in high yield from unactivated esters of 1-aroyl-2,3-cis-diethoxycarbonylcyclopropanes (15a-e) on a catalytic solid support with reduced reaction times by using the monomode-microwave irradiation; 15a-e were obtained by diastereoselective ethoxycarbonylmethylene transfer from a sulfur ylide to ethyl β-aroylacrylates (10a-e). Torsional angles and interatomic distance measurements on the energy minimized structures of the obtained molecules (17a-e, DFT, B3LYP/6-31G^∗ level) have established these molecules as valuable γ-turn mimic scaffolds.