Solid-state photocycloaddition of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones with benzophenone

Photocycloaddition reactions of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones (4a-c) with benzophenone (2a) by mixing in the solid state (solid solution) afforded the corresponding oxetane derivatives (5a-c; 1:2 adducts) with high site- and regioselectivity across the C5-C6 and C5′-C6′ double bonds in 4 via the triplet excited state of benzophenone. The oxetane formation proceeded more effectively in the solid state than in solution. The reaction mechanism was inferred by MO methods to be initiated by electrostatic interaction between the C6 position of 4a-c and the carbonyl oxygen of 2a in their ground states. The solid-state interaction may be enhanced by the electron density at the carbonyl oxygen of the triplet 2a. The transition state (TS) analysis of the [2+2] cycloaddition reactions also suggested some triplet complexes and high regioselectivity. The hydrogen-bonding interaction between 2a and 4a-c and the triplet reaction mechanism were also explained by the IR analyses and the quenching experiments, respectively.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

1,1,3,3,3-Pentafluoro-2-pentafluorophenyl-1,2-epoxypropane and trimethylphosphite: unusual 1,4-dioxan-2,5-dione ring formation

1,1,3,3,3-Pentafluoro-2-pentafluorophenyl-1,2-epoxypropane 1 reacted with trimethylphosphite giving two diastereomers, (Z)- and (E)-3,6-bis(trifluoromethyl)-3,6-bis(pentafluorophenyl)-1,4-dioxan-2,5-dione 2a, b in a 1:1 ratio, cyclodimerisation product of the intermediately generated α-lactone 4. Compounds 2a, b were hydrolysed to furnish 3,3,3-trifluoro-2-hydroxy-2-(2,3,4,5,6-pentafluorophenyl)propionic acid 5.     

Formation of bis- and tris[2]catenanes via the cross-catenation of Pd(II)- and Pt(II)-linked coordination rings

We have demonstrated the self-assembly of linear oligo[2]catenanes via selective cross-catenation. A Pd(II)-linked double looped molecule 1 was transformed into the cyclic trimer c-(1)₃ through the catenation. When 1 was treated with a kinetically inert Pt(II)-linked single looped molecule 2a in aqueous media (1:1.2 DMSO/H₂O) at room temperature, linear oligo[2]catenanes of 2a-(1)_n-2a (n=1 and 2) were selectively obtained, because the kinetically inert Pt(II)-linked ring 2a is allowed to thread on only kinetically labile Pd(II)-linked ring of 1. The distribution of the oligomers depends on the monomer ratio of 1 to 2a. When the ratio of 1 to 2a was 1:2, bis[2]catenane 3a (2a-1-2a) was quantitatively assembled. When the ratio of 1 to 2a was 1:1, not only 3a but also tris[2]catenane 4 (2a-1-1-2a) was assembled. The ratio of 3a to 4 was carefully determined to be 1:1 by NMR. The lengths of 3a and 4 in an extended conformation were estimated by MD/MM2 simulation to be 3.6 and 5.4 nm, respectively.     

Large-scale synthesis of 1,1,3,3,6-pentamethyl-1,3-disilaindan-5-ol via a CoBr2/Zn-catalyzed [2+2+2] cycloaddition reaction

1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-ol (2) is a key intermediate in the synthesis of new sila-substituted gonadotropin releasing hormone receptor antagonists, such as 1. In order to produce sufficient quantities of 1 for pharmacological and toxicological evaluation, an efficient synthesis of 2 has been developed. (1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-yl)methanal (11) was synthesized in a one-pot procedure. CoBr₂/Zn-catalyzed [2+2+2] cycloaddition of diyne 3 with the commercially available monoalkyne 15 was achieved through a slow addition of 3 and CoBr₂ to a mixture of 15 and zinc powder in refluxing acetonitrile, giving rise to 5-(diethoxymethyl)-1,1,3,3,6-pentamethyl-1,3-disilaindane (14). In-situ aqueous acidification yielded 11. Conversion to 2 was then achieved via a Baeyer-Villiger oxidation followed by hydrolysis under basic condition. This novel methodology is useful, not only for the rapid, large-scale synthesis of 2, but also for the synthesis and development of new sila-substituted drugs derived from 11.     

De-novo approach for a unique spiro skeleton-1,7-dioxa-2,6-dioxospiro[4.4]nonanes

2-Oxoglutaric acid (1) underwent facile indium mediated allylation with allyl bromide (2), and ethyl 4-bromocrotonate (3), cinnamyl bromide (4) and subsequent in situ dehydration to provide respective 5-oxotetrahydrofuran-2-carboxylic acids 5-7 (90-95%). The reaction of 1 with 3 and 4 proceeded with high regio and stereo selectivity to provide only γ-addition products with syn stereochemistry as ascertained from their cyclic products. Compounds 5-7 underwent diastereoselective iodocyclization to provide respective 1,7-dioxa-2,6-dioxospiro[4.4]nonanes 8-13. The relative stereochemistries have been ascertained by single crystal X-ray structures, NOE experiments and coupling constants in ¹H NMR spectra.     

Control of molecular weight distribution in polycondensation polymers 2. Poly(ether ketone) synthesis

Synthesis of aromatic poly(ether ketone) (3) with a narrow molecular weight distribution (M_w/M_n) was investigated via polycondensation. M_ns of 3 could be controlled varying the feed ratio of monomer (1) and initiator (2) maintaining relatively narrow M_w/M_ns (<1.3). The kinetics of polycondensation obeyed a first-order relationship between polycondensation time and -(1/[2]₀) ln([1]/[1]₀), and the rate of polycondensation was estimated as 2.57 mol⁻¹ L h⁻¹. MALDI-TOF mass analysis of 3 indicated that polycondensation should proceed via chain growth manner to give 3 having an initiator unit in each chain end.     

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 difluoroethyl perfluorosulfonate monomer and its application

The novel difluoroethyl perfluorosulfonate monomer 20 and its application have been developed. The difluoroethyl perfluorosulfonate monomer 20, which was prepared by the reaction of the vinyl sulfonic acid 19 with vinylidene fluoride, was copolymerized with tetrafluoroethylene (TFE) to give the difluoroethyl perfluorosulfonate copolymer 21. The copolymer 21 was easily converted to the perfluorosulfonic acid ionomer 2 in one step by heating and/or alcoholysis. This property of 21 enables the efficient preparation of the polymer solution of 2.     

Synthesis and characterization of fluorinated ionomer p-perfluoro-[1-(2-sulfonic)ethoxy]ethylated polyacrylonitrile-styrene

Fluorinated ionomer p-perfluoro[1-(2-sulfonic)ethoxy]ethylated polyacrylonitrile-styrene (SFAS) (5) was synthesized via electron transfer reaction between polyacrylonitrile-styrene (AS) (1) and perfluoro-di[2-(2-fluorosulfonyl)ethoxy]propionyl peroxide (FAP) (2) and followed by alkali hydrolysis and acidification of p-perfluoro[1-(2-fluorosulfonyl)ethoxy]ethylated polyacrylonitrile-styrene (3). The microstructure of ionomer 5 was well characterized by FTIR and ¹⁹F NMR. Its desulfonation occurred above 197 °C was found by TGA, the degree of substitution (DS) and ion exchange capacity (IEC) determined by titration were well controlled through changing the molar ratio of 2:1. The proton exchange membranes made of ionomer 5 have water uptake from 13.4 to 135.3% and conductivity up to 10⁻² S cm⁻¹ at 25 °C.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

Syntheses and structures of iron carbonyl complexes derived from N-(5-methyl-2-thienylmethylidene)-2-thiolethylamine and N-(6-methyl-2-pyridylmethylidene)-2-thiolethylamine

The reaction of N-(5-methyl-2-thienylmethylidene)-2-thiolethylamine (1) with Fe₂(CO)₉ in refluxing acetonitrile yielded di-(μ₃-thia)nonacarbonyltriiron (2), μ-[N-(5-methyl-2-thienylmethyl)-η¹:η¹(N);η¹:η¹(S)-2-thiolatoethylamido]hexacarbonyldiiron (3), and N-(5-methyl-2-thienylmethylidene)amine (4). If the reaction was carried out at 45 °C, di-μ-[N-(5-methyl-2-thienylmethylidene)-η¹(N);η¹(S)-2-thiolethylamino]-μ-carbonyl-tetracarbonyldiiron (5) and trace amount of 4 were obtained. Stirring 5 in refluxing acetonitrile led to the thermal decomposition of 5, and ligand 1 was recovered quantitatively. However, in the presence of excess amount of Fe₂(CO)₉ in refluxing acetonitrile, complex 5 was converted into 2-4. On the other hand, the reaction of N-(6-methyl-2-pyridylmethylidene)-2-thiolethylamine (6) with Fe₂(CO)₉ in refluxing acetonitrile produced 2, μ-[N-(6-methyl-2-pyridylmethyl)-η¹ (N_py);η¹:η¹(N); η¹:η¹(S)-2-thiolatoethylamido]pentacarbonyldiiron (7), and μ-[N-(6-methyl-2-pyridylmethylidene)-η²(C,N);η¹:η¹(S)-2- thiolethylamino]hexacarbonyldiiron (8). Reactions of both complex 7 and 8 with NOBF₄ gave μ-[(6-methyl-2-pyridylmethyl)-η¹(N_py);η¹:η¹(N);η¹:η¹(S)-2-thiolatoethylamido](acetonitrile)tricarbonylnitrosyldiiron (9). These reaction products were well characterized spectrally. The molecular structures of complexes 3, 7-9 have been determined by means of X-ray diffraction. Intramolecular 1,5-hydrogen shift from the thiol to the methine carbon was observed in complexes 3, 7, and 9.     

Electrochemical fluorination of several esters derived from oxolane-2-yl-carboxylic acid, oxolane-2-yl-methanol and oxane-2-yl-methanol

Electrochemical fluorination (ECF) of the ester derivatives of oxolane-2-yl-carboxylic acid (1), oxolane-2-yl-methanol (2) and oxane-2-yl-methanol (3) were investigated. Perfluoro(oxolane-2-yl-carbonylfluoride) (4) was obtained from derivatives of 1 and 2, and perfluoro(oxane-2-yl-carbonylfluoride) (5) was obtained from derivatives of 3 as the desired compounds, respectively. From the ECF of acetates of 2 and 3, perfluorospiroethers having a dioxolane ring were also obtained as the cyclization product in low yield together with the desired perfluoroacid fluoride (4 and 5). The structure of these perfluorospiroethers was confirmed by analyzing the chlorinated products, which were obtained by the reaction with AlCl₃.     

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane with enol ethers of cyclic ketones

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane (1) with methyl and trimethylsilyl ethers of cyclopentanone and cyclohexanone enols (2a-d) in a MeCN/H₂O system were investigated. 2-(2,2,2-Trifluoroethylidene)cyclopentanone (4a) and 2-(2,2,2-trifluoroethylidene)-cyclohexanone (4b), respectively, were obtained as the main products and isolated in reasonable yields. The reaction with a 1:1 mixture of 5- and 3-methyl substituted 1-methoxycyclohexenes, 2e and 2f, revealed strong influence of steric hindrance on the reaction rate; a mixture of 2-(2,2,2-trifluoroethylidene)-5-methylcyclohexanone (6) and 2-(2,2,2-trifluoroethylidene)-3-methylcyclohexanone (7) in a 9:1 ratio was formed. Ketones 4a and 4b were reduced to the corresponding alcohols 8 and 9 and the reaction of 4b with hydrazine gave an indazole derivative 10.     

Sodium dithionite initiated fluoroalkylation of trimethoxybenzenes, mesitylene and pyrroles with BrCF2CF2Br

Sodium dithionite initiated reaction of 1,2-dibromotetrafluoroethane with 1,3,5-trimethoxybenzene (1a) in an acetonitrile-water mixture proceeded efficiently at ambient temperature to give 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) almost quantitatively. Similar reaction with 1,2,3-trimethoxybenzene (1b) gave only reasonable yield of regioisomers of (2-bromotetrafluoroethyl)-trimethoxybenzenes 3 and 4 and small amount of a substitution product of the central trimethoxy group, 1-(2-bromotetrafluoroethyl)-2,6-dimethoxybenzene (5). The reaction with mesitylene (6) gave complex mixtures from which, depending on the temperature and a mesitylene/BrCF₂CF₂Br ratio, the expected (2-bromotetrafluoroethyl)mesitylene (8) or a dimeric product, 4,4′-bis(2-bromo-1,1,2,2-tetrafluoroethyl)-1,3,5,1′,3′,5′-hexamethylbicyclohexyl-2,5,2′,5′-tetraene (7), were isolated in a yield of 18 and 13%, respectively. The reactions of BrCF₂CF₂Br with pyrrole (9) and 1-methylpyrrole (11) gave the respective alkylated compounds, 2-(2-bromotetrafluoroethyl)pyrrole (10) and 2-(2-bromotetrafluoroethyl)-1-methylpyrrole (12) in over 70% yields; the former was found to be fairly unstable. The reactivity of the terminal bromine atom in 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) was also investigated.     

One-pot synthesis of macrocyclic compounds possessing two cyclobutane rings by sequential inter- and intramolecular [2+2] photocycloaddition reactions

Sensitized photocycloaddition reactions of 6,6′-dimethyl-4,4′-[1,3-bis(methylenoxy)phenylene]-di-2-pyrone (1) with electron-poor α,ω-diolefins such as ethylene diacrylate (2a) and polyoxyethylene dimethacrylates (2b-d) afforded site- and stereoselective macrocyclic dioxatetralactones (3a-d) and (4b) having 18- to 25-membered rings across the C5-C6 and C5′-C6′ double bonds, or C5-C6 and C3′-C4′ double bonds in 1, respectively. Similar photoreactions of 1 with electron-rich α,ω-diolefins such as poly(ethylene glycol)divinyl ether (2e and 2f) afforded crown ether-type macrocyclic compounds (5e and 5f) having 18- and 21-membered rings across the C3-C4 and C3′-C4′ double bonds in 1, respectively. The stereochemical features of 3b, 5e-xx, and 5e-nn were determined by the X-ray crystal analysis. The reaction mechanism was inferred by MO methods.     

Use of epoxidation and epoxide opening reactions for the synthesis of highly functionalized 1-oxaspiro[4.5]decan-2-ones and related compounds

Epoxidation of ethyl 3-(6-hydroxycyclohex-1-en-1-yl)propanoate (11) provided the syn epoxide 12. By invoking chelation controlled epoxide opening the triol derivatives 13 and 14 or the spiro lactone 25 could be obtained. Elimination of HBr from the bromides 26 and 27 produced the spiro cyclohexenones 28 and 29. Epoxidation of the double bond occurred in a diastereoselective manner to give epoxides 30 and 31, respectively. Treatment of the epoxide 31 with LiBr/AcOH gave the bromo hydrin 38. In a ‘merry go round’ fashion 38 was further functionalized on the cyclohexane ring by elimination, epoxidation, and epoxide opening resulting in the bromo hydrin 43. Other cyclohexane derivatives that were produced during these studies include the cyclohexenone 19 and the cyclohexanediol 23. In addition, enolate azidation of the spiro lactone 29 proceeded in a diastereoselective manner providing the α-azido lactone 32.     

Electrochemical synthesis of 1,3,4-thiadiazol-2-ylthio-substituted catechols in aqueous medium

Anodic oxidation of catechols 1a-e in the presence of 5-methyl-2-mercapto-1,3,4-thiadiazole 2 has been studied in acetate buffer solution by cyclic voltammetry and controlled-potential electrolysis techniques. The effects of various electrolytic conditions (amount of passed charge, anodic materials, pH of the electrolytic solution, applied potential, and concentration of substrates) on the yield have also been investigated. The results showed that the position of the initial substituent of the starting catechol derivatives dominated the formation of monothiadiazol-2-ylthio-substituted or/and dithiadiazol-2-ylthio-substituted products. For 4-substituted catechols 1a-b, monothiadiazol-2-ylthio-substituted products (3a-b) were exclusively produced in high to excellent yields. However, in the cases of catechol itself (1c) and 3-substituted catechols (1d-e), both monothiadiazol-2-yl-substituted (3c-e and 5d-e) and dithiadiazol-2-ylthio-substituted products (4c-e) were isolated. In addition, the nature of the initial substituent of the starting 3-substituted catechols (1d and 1e) affected the relative ratio of the two monothiadiazol-2-ylthio-substituted isomers (3d-e vs 5d-e).     

[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.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.