Reductive opening of 1H,3H-benzo[de]isochromene: synthesis of 1,8-difunctionalised naphthalenes

The lithiation of 1H,3H-benzo[de]isochromene (6) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5% molar) in THF at −50 °C gives dianionic intermediate 7, which by reaction with different electrophiles {H₂O, D₂O, ^tBuCHO, PhCHO, Me₂CO, (CH₃CH₂)₂CO, [CH₃(CH₂)₄]₂CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone} at the same temperature followed by hydrolysis leads to functionalised alcohols 8. If after addition of a carbonyl compound as the first electrophile [^tBuCHO, (CH₂)₅CO, (−)-menthone], the resulting dialcoholate 9 is allowed to react at 0 °C, a second lithiation takes place to give intermediate 10 which by reaction with a second electrophile [H₂O, ^tBuCHO, (CH₂)₅CO, CO₂], yields, after hydrolysis, 1,8-difunctionalised naphthalenes 11. Cyclization under acidic conditions of diols 8e-i gives oxygen-containing eight-membered heterocycles, which are homologous to the starting material 6.     

Regiochemistry in the reductive opening of phthalan derivatives

The lithiation of phthalan derivatives 4, 9 and 12 with an excess of lithium in the presence of a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB) in THF at −78 °C gives dianionic intermediates 5, 10 and 13, respectively, which by reaction with different electrophiles [H₂O, t-BuCHO, Me₂CO, (EtO)₂CO] at the same temperature, followed by hydrolysis, leads to regioselective functionalised naphthalenes 7, and biphenyls 11 and 14. The reductive opening takes place with high or total regioselectivity and can be explained considering the electron density in the dianion or in the radical anion, which are formed previous to the carbon-oxygen bond excision. The lithiation of the dihydrofurophthalan derivative 18 with the same reaction mixture but at higher temperature (0 °C) leads to intermediates 19 and 20, resulting from a single and a double reductive cleavage, respectively, which after addition of H₂O and benzaldehyde as electrophiles gives a mixture of compounds 21 and 22.     

Reductive ring opening of dihydrodibenzothiepine and dihydrodinaphtho-oxepine and -thiepine

The 4,4′di-tert-butylbiphenyl (DTBB)-catalysed lithiation of dihydrodibenzothiepine (1) at −78 °C for 30 min followed by reaction with a carbonyl compound [^tBuCHO, Ph(CH₂)₂CHO, PhCHO, (n-C₅H₁₁)₂CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone] at the same temperature leads, after hydrolysis with 3 M hydrochloric acid, to sulphanyl alcohols 2. If after addition of a carbonyl compound as the first electrophile [Me₂CO, (CH₂)₅CO, (−)-menthone], the resulting dianion of type II is allowed to react at room temperature for 30 min, a second lithiation takes place to give an intermediate of type III, which by reaction with a second electrophile [Me₂CO, Et₂CO, (CH₂)₅CO, ClCO₂Et], yields, after hydrolysis, difunctionalised byphenyls 4. The cyclisation of the sulphanyl alcohol 2c under acidic conditions yields the eight-membered sulphur containing heterocycle 3. The lithiation of dihydrodinaphthoheteroepines 7 and 10 with 2.2 equiv of lithium naphthalenide in THF at −78 °C followed by reaction with different electrophiles [H₂O, D₂O, ^tBuCHO, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO] at the same temperature leads, after hydrolysis, to unsymmetrically 2,2′-disubstituted binaphthyls 9 and 12, respectively. When the lithiation is performed with an excess of lithium in the presence of a catalytic amount of DTBB (10% molar), a double reductive cleavage takes place to give the dianionic intermediate VII, which by reaction with different electrophiles [H₂O, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO], followed by hydrolysis with water, yields symmetrically 2,2′-disubstituted binaphthyls 8 and 11. In the case of starting from (R)- or (S)-dihydrodinaphthoheteroepines 7 and 10, these methodologies allow us to prepare enantiomerically pure compounds 8, 11 and 12.     

Regioselective reductive opening of substituted phthalans: synthetic applications

The reductive opening of substituted phthalans 6, 11, 12, 20, 21 and 28 with lithium and a catalytic amount of DTBB leads to the formation of corresponding functionalised organolithium intermediates 8, 15, 16, 23, 25 and 29+30 in a regioselective manner. The further reaction of these dianions with different electrophiles, mainly carbonyl compounds, gives the expected functionalised benzylic alcohols 9, 17, 18, 24, 26 and 31+32. The observed stereochemistry can be easily explained taking into account the values of the electron densities deduced by semiempirical PM3 calculations.     

Reductive ring opening of cis- and trans-2,3-diphenyloxirane: a common intermediate

The reaction of both cis- and trans-2,3-diphenyloxirane (7 and 4, respectively) with an excess of lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 2.5 mol%) in the presence of different carbonyl compounds as electrophiles (Barbier conditions) in THF at temperatures ranging between −80 and −50 °C gives the same organolithium intermediate 5 and consequently, the same 1,3-diols 6. In the case of cis-epoxide an inversion of the configuration at the benzylic carbanionic center can explain the obtained results. Only for the dicyclopropyl ketone derivative (6h) some amount (14%) of the corresponding epimer (6′h) resulting from a process with retention of the configuration of the intermediate is obtained. In representative cases, the structure of the final products (6) was unequivocally determined by X-ray diffraction analysis.     

Ti-catalyzed reactions of 4,4′-bis(trimethylsilyl)bicyclohexyl-2,2′-diene with various electrophiles

Reductive disilylation (Li + Me₃SiCl − THF) of 1,3-cyclohexadiene led to 4,4′-bis(trimethylsilyl)bicyclohexyl-2,2′-diene (1). In the presence of TiCl₄ in dichloromethane, 1 reacted with some acyl chlorides, anhydrides, and aldehydes to give tricyclo[7.4.0.0^3,8]trideca-4,12-diene-2-yl derivatives.     

Arene-catalysed lithiation of phenyl- and 1,1-diphenylcyclopropane: synthetic applications

The reaction of phenylcyclopropane (1) with an excess of lithium and a catalytic amount of DTBB (2.5% molar) in THF at room temperature, followed by treatment with an electrophile [Me₃SiCl, PhMe₂SiCl, t-BuCHO, PhCHO, Me₂CO, Et₂CO, (CH₂)₅CO, adamantan-2-one, i-Pr₂CO, di(cyclopropyl)ketone] and final hydrolysis with water leads to allylic products 10 or 11 depending on the structure of the electrophile: whereas for chlorosilanes or crowded ketones γ-products 11 are isolated, for aldehydes and non-congested ketones α-products 10 are formed. The application of the same protocol to 1,1-diphenylcyclopropane (7) leads to a mixture of products 13-15 resulting from the introduction of one or two electrophilic fragments to the open-chain mono- or dilithiated intermediate: also in this case the regiochemistry of the reaction is governed by steric reasons.     

2,2′-Dilithiobiphenyl by direct lithiation of biphenylene

The reaction of biphenylene (1) with an excess of lithium powder (1:14 molar ratio) and a catalytic amount of DTBB (10 mol %) in THF at room temperature leads to the formation of the dilithiated species I by reductive opening of the four-membered ring. Further reaction of this intermediate with different electrophiles [Electrophile = H₂O, D₂O, Me₃SiCl, t-BuCHO, Et₂CO, n-Pr₂CO, (CH₂)₅CO, Ph₂CO and adamantanone] at 0 °C yields the corresponding products 2, after hydrolysis with water. Cyclisation of some representative examples of compounds 2 with H₃PO₄ gives the corresponding dibenzoxepines 3.     

Arene-promoted lithiation of 1,n-dihaloalkanes (n=2-6): a comparative study

The reaction of 1,n-dichloroalkanes 3a (n=2-6) with an excess of lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB; 2.5 mol %) in the presence of different carbonyl compounds [Bu^tCHO, PhCHO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone], in THF at −78 °C leads, after hydrolysis with water, to the expected 1,(n+2)-diols 4, yields being <25% for n=2, 3 and in the range of 45-79% for n=4-6. When the same protocol is applied to 1,n-bromochloroalkanes 3b and 1,n-dibromoalkanes 3c (n=2-6), diols 4 are obtained in general with lower yields.     

Stereoselective synthesis of 3-substituted tetrahydroisoquinolines from phthalan and chiral N-sulfinylimines

The reaction of the dianionic intermediate [resulting from the reductive opening of phthalan (1) with lithium] with chiral N-tert-butylsulfinyl aldimines 3 in the presence of ZnMe₂ gives, after hydrolysis, N-tert-butylsulfinyl amino alcohols 4 with high diastereoselectivity. Successive treatment of compounds 4 with hydrogen chloride in methanol, thionyl chloride in chloroform and sodium hydroxide yields 3-substituted tetrahydroisoquinolines 6.     

Reductive dearomatization of biphenyl: sequential one-pot regioselective introduction of two different electrophiles

The reaction of biphenyl (1) with an excess of lithium in THF at room temperature leads to a solution of the corresponding dianion (I), which by successive reactions with an alkyl fluoride [E₁ = n-C₈H₁₇F, c-C₅H₉CH₂F, CH₂CH(CH₂)₄F] at 0 °C and another electrophile [E₂ = n-C₄H₉Br, Et₂CO, Me₂C(O)CH₂, i-Pr₃SiCl] at −78 °C yields the corresponding 1,4-disubstituted 1,4-dihydrobiphenyls 3 in a regioselective manner, as mixtures of cis- and trans-isomers. The diastereomers of 3 are separated by column chromatography.     

Uracil ring opening in the reaction of 5-formyl-2′-deoxyuridine with primary alkyl amines

Treatment of 5-formyl-2′-deoxyuridine (f⁵dU) with stoichiometric amounts of strongly nucleophilic, non-hindered primary alkyl amines led to fast and quantitative formation of the corresponding Schiff bases. In the presence of excess amines, novel nucleosides with ring opened pyrimidine bases were formed as a result of the Michael addition of a second amine to the pre-formed imines. In the reaction of f⁵dU with aromatic amines, the formation of Schiff base derivatives was slower and even under prolonged treatment with an excess of amine the uracil ring remained intact.     

Chiral syntheses of 6′-β-fluoroaristeromycin, 6′-β-fluoro-5′-noraristeromycin and aristeromycin

Carbocyclic nucleosides substituted at the C-6′ position are receiving increasing attention. Chiral synthetic accessibility to the biologically promising 6′-β-fluoroaristeromycin is lacking. Its preparation and that of the 5′-nor analogue are described. Along the way, a new method to aristeromycin arose as an outgrowth of a requisite structure proof.     

Environmentally benign and highly regioselective ring opening of epoxides accelerated by ultrasound irradiation

Regioselective ring opening of aliphatic and aromatic epoxides with nitrogen heterocycles such as indoles and imidazoles was accelerated using an ultrasonic technique as a green approach. An optimized procedure with the catalyst of choice, MCM-41, represents a real alternative to the conventional reaction protocols owing to the catalyst recyclability, simplicity, green conditions and time-saving aspects.     

Comparison of HPLC enantioseparation of substituted binaphthyls on CD‐, polysaccharide‐ and synthetic polymer‐based chiral stationary phases

Retention and enantioseparation behavior of ten 2,2′‐disubstituted or 2,3,2′‐trisubstituted 1,1′‐binaphthyls and 8,3′‐disubstituted 1,2′‐binaphthyls, which are used as catalysts in asymmetric synthesis, was investigated on eight chiral stationary phases (CSPs) based on β‐CD, polysaccharides (tris(3,5‐dimethylphenylcarbamate) cellulose or amylose CSPs) and new synthetic polymers (trans‐1,2‐diamino‐cyclohexane, trans‐1,2‐diphenylethylenediamine and trans‐9,10‐dihydro‐9,10‐ethanoanthracene‐(11S,12S)‐11,12‐dicarboxylic acid CSPs). Normal‐, reversed‐phase and polar‐organic separation modes were employed. The effect of the mobile phase composition was examined. The enantiomeric separation of binaphthyl derivatives, which possess quite similar structures, was possible in different enantioselective environments. The substituents and their positions on the binaphthyl skeleton affect their properties and, as a consequence, the separation system suitable for their enantioseparation. In general, the presence of ionizable groups on the binaphthyl skeleton, substitution with non‐identical groups and a chiral axis in the 1,2′ position had the greatest impact on the enantiomeric discrimination. The 8,3′‐disubstituted 1,2′‐binaphthyl derivatives were the most easily separated compounds in several separation systems. From all the chiral stationary phases tested, cellulose‐based columns were shown to be the most convenient for enantioseparation of the studied analytes. However, the polymeric CSPs with their complementary behavior provided good enantioselective environments for some derivatives that could be hardly separated in any other chromatographic system.     

Zirconyl nitrate mediated regioselective ring opening of epoxides and aziridines: an easy synthesis of β-nitrato-alcohols and -sulfonamides

Epoxides and aziridines are cleaved efficiently and regioselectively in the presence of zirconyl nitrate at room temperature to afford the corresponding β-nitrato-alcohols and -sulfonamides, respectively, in high yields.     

Synthesis,characterization, and mechanism studies on novel rare‐earth calixarene complexes initiating ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate

Rare‐earth (Nd, Y) p‐tert‐butylcalix[n]arene (n = 4, 6, and 8) complexes without coligands were synthesized from rare‐earth isopropoxides in toluene. The products were characterized as the following structures: [C4(OH)O₃ · CH₃C₆H₅]Nd ( 4 ), [C6(OH)₂O₄ · CH₃C₆H₅]₃Ln₄ [Ln = Nd ( 5 ), Y ( 6 )], and [C8(OH)₂O₆ · CH₃C₆H₅]Nd₂ ( 7 ). 2,2‐Dimethyl trimethylene carbonate (DTC) can be polymerized with complexes 4 – 7 alone as the initiator. PolyDTC (weight‐average molecular weight: 5700, polydispersity index: 1.11, measured by gel permeation chromatography) initiated by complex 5 was obtained with a conversion of 69.1% within 6 h in toluene at 80 °C. The thermal behavior of polyDTC has been compared with the published data. The DTC ring is opened via acyl‐oxygen bond cleavage with end‐group examination. NMR analyses of the polymerization reaction mixture indicated that the polymerization proceeds via a coordination‐insertion mechanism. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1390–1399, 2003     

Facile acid-catalyzed condensation of 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone with phenols, methoxyaromatic systems and enols

Various phenols, methoxy aromatic compounds, 3- and 4-hydroxycoumarins and enols smoothly condense with 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone 1 in an acid medium producing 2-aryl/alkyl-2,2′-biindan-1,1′,3,3′-tetrones in high yields. The adducts of resorcinol, 1,3,5-trihydroxybenzene and α- and β-naphthols of 1 preferably remain in the intramolecular hemi-ketal form, confirmed by X-ray diffraction studies. On the other hand para and meta substituted phenols condense with 1 in an acid medium to produce 6 or 7 substituted 2′,4-spiro(1′,3′-indanedion)-indeno[3,2-b]chromenes in good yields.     

Less toxic acetylacetonates as initiators of trimethylene carbonate and 2,2‐dimethyltrimethylene carbonate ring opening polymerization

This article presents the results of TMC and DMC polymerization with the use of acetylacetonates of low‐toxic metals: iron, zinc, and zirconium. Zinc (II) acetylacetonate proves to be a very good initiator of homopolymerization. The reaction carried out with the use of this initiator at 110 °C is very rapid and of high yield. Using both zinc and iron (III) acetylacetonates, as well as the zirconium (IV) one, in high temperatures it is possible to obtain PTMC possessing high molecular mass, thus ensuring optimization of the relation between the duration of the polymerization and its yield. A strong influence of thermal degradation on the course of the reaction has been observed, particularly at 160 °C, with the use of Fe(acac)₃ as the initiator. DMC polymerization proceeds much more slowly when initiated by iron and zinc acetylacetonates. A high conversion of the monomer is obtained in this case as well. The relation between the molecular mass of the obtained PDMC and the conversion of the monomer is directly proportional; however, those masses, determined on the basis of polystyrene standards, are much lower than those estimated theoretically. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1913–1922, 2005     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.